Korro Bio, Inc. (KRRO) Business

Item 1. Business.

Overview

We are a biopharmaceutical company with a mission to discover, develop and commercialize a new class of genetic medicines based on editing RNA, enabling the treatment of both rare and highly prevalent diseases. We are generating a portfolio of differentiated programs that are designed to harness the body’s natural RNA editing process to effect a precise yet transient change to a single nucleoside (adenosine to an inosine edit). By editing RNA instead of DNA, we are expanding the reach of genetic medicines by delivering additional precision and tunability, which has the potential for increased specificity and improved long-term tolerability. We use an oligonucleotide-based approach and expect to bring our medicines to patients by leveraging our proprietary platform with precedented delivery modalities, including N-acetylgalactosamine, or GalNAc, -conjugated delivery for subcutaneous administration, manufacturing know-how, and established regulatory pathways of approved oligonucleotide medicines. However, the scientific evidence to support the feasibility of developing lead candidates using our RNA editing technology is both preliminary and limited. Moreover, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and limited clinical data has been generated to date.

The versatility of RNA editing combined with our OPERA platform broadens the therapeutic target space significantly. The advent of large-scale genome sequencing has progressively revealed causal genetic variation underlying several human diseases, both rare and highly prevalent. Genetic mutations, including single nucleotide variants, or SNVs, implicated in disease have been found to be diverse in nature and can affect the function of genes and their associated downstream biochemical pathways. Data correlating DNA to RNA to disease phenotype have demonstrated that SNVs lead to a loss-of-function or a gain-of-function of the gene. In addition, the majority of SNVs implicated in complex diseases are due to modulation of gene function. By editing RNA to mimic a SNV, we believe we will be able to address unmet patient need by transiently modifying gene expression and the resultant protein function.

As our understanding of genetic drivers of disease has increased, significant advances have been made in technologies designed to introduce specific yet permanent changes at the DNA level to treat diseases. While these DNA editing approaches offer great promise for the treatment of certain rare diseases, they present significant risks from potential permanent adverse “off-target” edits. Additionally, the complex nature of DNA editing drug products presents multiple challenges including lack of efficient delivery to target cells and scalable manufacturing, impeding their application to treat complex highly prevalent diseases of larger patient populations. These potential limitations have spurred exploration of alternative approaches to genetic medicine development, such as RNA editing.

Mammals and other lower species like cephalopods have an endogenous process of modifying single nucleosides on RNA, referred to as RNA editing. RNA editing is a natural physiological process, similar to RNA interference, or RNAi, that occurs in cells, including a mechanism mediated by an enzyme called Adenosine Deaminase Acting on RNA, or ADAR. Our RNA editing approach involves co-opting this endogenous editing system via proprietary engineered oligonucleotides to introduce precise edits to RNA. We iteratively optimize the editing efficiency of our oligonucleotides using a combination of ADAR biology, chemistry and machine learning expertise. Using this approach, we can edit the transcriptome with high efficiency and specificity. The application of such an approach can provide the ability to alter a nucleoside and affect biology in meaningful ways.

As opposed to gene silencing with small interfering RNA, or siRNA, or antisense oligonucleotide, or ASO, gapmers, where oligonucleotides are used to silence and knock-down genes and proteins, we intend to either repair or activate biological pathways by editing RNA. Our pipeline has multiple programs, all of which are focused on modifying proteins to provide clinical benefit. These modification approaches can unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases with potentially large addressable patient populations traditionally out-of-scope for other genetic medicine approaches and current traditional drug modalities. Each of our programs demonstrates the versatility of the oligonucleotide-based RNA editing approach to bring additional precision and tunability to address a broad range of rare and highly prevalent diseases.

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Enabling synthetic rescue through engineering de novo versions of existing proteins: A SNV observed in human genetic association studies has the potential to inform how to transiently modify a small amount of native protein. We can generate this de novo protein with preferred properties using our RNA editing oligonucleotides. In most cases, 10 – 50% of modified version of the native protein is sufficient to provide significant benefit, rather than needing 100% modification. This synthetic rescue approach is designed to restore cellular function without repairing the primary disease-causing genetic mutation. Our lead program, KRRO-121, exemplifies this approach by engineering a de novo version of glutamine synthetase, or GS, that is designed to stabilize the protein and enhance ammonia clearance, overcoming the challenges with a dysfunctional urea cycle.

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Repairing pathogenic variants: A SNV that is a pathogenic G-to-A mutation, leading to an aberrant amino acid on a protein, can be repaired using our RNA editing approach. Such an approach is relevant when the patient population has a heterogenous spectrum of disease manifestations from mild-to-severe, and the willingness and utility of a transient repair of the protein is preferable to a DNA modification. Our next-generation GalNAc conjugated lead candidate targeting patients with AATD exemplifies this approach.

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Activating protein pathways: A single SNV observed in human genetic association studies has the potential to inform how to transiently activate a protein pathway. We can generate this protein transiently using our RNA editing approach with an oligonucleotide, thereby engineering a de novo protein with preferred properties. Our longevity and liver health program targeting AMP-activated protein kinase gamma 1 protein, or AMPKγ1, exemplifies this approach.

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Other target classes: There are multiple other target classes that can be addressed such as preventing protein aggregation, selectively modulating ion channels and activating kinases that have been traditionally hard to leverage for developing medicines.

Figure 1: RNA editing, just a single A-to-I nucleoside change, can have profound impact on biological pathways. The applications span a multitude of avenues to impact biology. We are focused on activating and repairing pathways rather than competing with RNA interference technologies.

Our Pipeline

The pipeline chart below demonstrates the breadth of indications, with an initial focus on four wholly-owned programs:

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KRRO-121, our hyperammonemia program, targeting the increased clearance of ammonia in multiple indications;

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Our AATD (GalNAc-conjugated delivery) program targeting the repair of the alpha-1 antitrypsin, or AAT, protein;

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Our longevity and liver health program targeting the activation of AMPKγ1 pathway (GalNAc-conjugated delivery); and

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Our ALS program targeting the creation of a de novo variant of TDP-43 (with intrathecal delivery).

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We may also have up to two programs partnered with Novo Nordisk, which entered a 12-month pause in November 2025. All of our programs are still in the research or preclinical stage of development and the risk of failure of all of our programs is high.

1De novo protein variant to prevent toxic gain-of-function, or GoF, with TDP43 aggregation, and continue downstream signaling by overcoming toxic loss-of-function, or LOF.

KRRO-121 – Hyperammonemia Program

We continue to make meaningful advancements across our programs, including KRRO-121 as a potential first-in-class treatment for hyperammonemia that has the potential to address substantial unmet need in patients with poor ammonia control, including those with urea cycle disorders, or UCD, and hepatic encephalopathy, or HE. KRRO-121 is an RNA-editing oligonucleotide conjugated with GalNAc in preclinical development for the potential treatment of UCDs of any mutational background in adults and adolescents. Utilizing our proprietary platform, we designed KRRO-121 to edit the GS mRNA to generate a stabilized, de novo variant of GS with enhanced ammonia clearance capacity. This synthetic rescue approach creates a compensating protein rather than repairing the underlying urea cycle defect. By editing GS mRNA to create a de novo protein with a single amino acid change that prevents glutamine-induced proteasomal degradation of GS, we aim to maintain consistent ammonia clearance capacity irrespective of the specific enzyme deficiency in patients with UCD and to reduce ammonia levels in patients with HE.

Hyperammonemia, or elevated ammonia in the blood, can lead to neurological impairment that can be potentially permanent, frequent hospitalization, highly restricted diet, elevated infection risk, and additional non-neurological complications. Hyperammonemia can be caused by cirrhosis or urea cycle dysfunction, and clinical studies have shown benefit of lowering ammonia in multiple indications. We believe our approach for treating hyperammonemia has multiple potential advantages:

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Provides a pan-UCD approach addressing multiple UCD subtypes irrespective of their enzyme deficiencies in the urea cycle.

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Direct ammonia control through stabilization of GS protein in the liver.

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Convenient subcutaneous delivery using precedented GalNAc-conjugated technology.

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Potential for reduction in hyperammonemic crises for UCD patients and reduction in HE events for HE patients.

We have generated compelling preclinical data demonstrating proof of concept across multiple RNA editing oligonucleotides targeting GS, including KRRO-121.

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KRRO-121 stabilized GS in ornithine transcarbamylase, or OTC, -deficient and argininosuccinate synthase 1, or ASS1, -deficient iPSC-derived hepatocytes, maintaining GS protein levels during ammonia challenge.

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In both OTC-deficient and CPS-1-deficient mice challenged with ammonia, treatment with a mouse-optimized oligonucleotide reduced ammonia, supporting potential to increase protein intake and dietary liberalization.

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In a humanized liver mouse model (PXB), KRRO-121 reduced basal ammonia levels and enhanced ammonia clearance following challenge, with production of stabilized de novo GS variant.

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In non-human primates, or NHPs, KRRO-121 displayed 90% delivery to liver, confirmed liver localization with pericentral GS, and no observed changes in liver or kidney function, coagulation, complement, platelets, or cytokines.

Additionally, KRRO-121 represents a significant market opportunity in UCD and HE. There are an estimated 4,200 severe late-onset UCD patients in the United States, or U.S., and 5,100 in the European Union, or EU, and United Kingdom, or UK. UCD patients frequently have ammonia levels greater than 1.5 times the upper limit of normal, leading to increased hyperammonemia risk. Ammonia control is highly challenging in UCD patients today, often requiring nitrogen scavengers plus a strict diet that can lead to malnutrition. In addition to UCD, KRRO-121 has an opportunity to potentially address significant unmet need in HE. There are approximately 2.2 million patients with cirrhosis in the United States, of which approximately 140,000 have severe or recurring HE. Up to 80,000 addressable patients in the United States with severe or recurring HE, high ammonia levels (≥1.5x upper limit of normal), and sufficient liver function may benefit from ammonia-lowering treatment, with an additional 150,000 patients in the European Union and United Kingdom. High ammonia significantly increases hospitalization risk, with greater than 2-fold increase in HE-related hospitalization for addressable HE patients versus all severe or recurring HE patients, and over $10 billion in inpatient charges for HE in the United States each year.

Based on the preclinical data, we believe KRRO-121 has potential to be a best-in-class treatment for ammonia control. We anticipate a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. The compelling product profile for controlling ammonia is expected to drive strong patient engagement and recruitment. While we believe we can demonstrate many of the key advantages of our development candidate KRRO-121, we are early in our development efforts and not yet certain of the results we may achieve in humans. Such uncertainties include, but are not limited to, the level of ammonia control needed in a target tissue type to achieve a clinical benefit, and associated safety of the de novo protein variants we create in humans.

Our AATD Program

We are also developing a next-generation GalNAc-conjugated RNA editing oligonucleotide for the treatment of AATD that has the potential to be disease-modifying and provide a differentiated therapeutic option. Following extensive evaluation of our initial AATD program, KRRO-110, we have strategically pivoted from a lipid nanoparticle, or LNP, based delivery approach to GalNAc-conjugated delivery and made significant improvements on the potency of the next-generation oligonucleotide, to advance a potential best-in-class therapy for AATD patients. We anticipate nominating a development candidate for this program in the second quarter of 2026.

AATD is an inherited genetic disorder that can cause severe progressive lung and liver disease due to a lack of normal AAT protein, with varying intensity based on patient genotype and environmental factors. Patients often develop chronic obstructive pulmonary disorder, or COPD, in the lungs and cirrhosis of the liver, which can result in liver failure or death. There are an estimated 5.5 million individuals with deficiency allele combinations worldwide. The only U.S. Food and Drug Administration, or FDA, -approved treatment for patients with lung manifestations of AATD is augmentation therapy, which utilizes AAT protein purified from pooled human plasma administered weekly by intravenous infusion. Despite being minimally effective and not fully addressing the needs of many AATD patients, augmentation therapy currently represents approximately $1.4 billion in annual sales worldwide, highlighting the significant unmet medical need and commercial opportunity for a superior therapeutic approach.

Our next-generation GalNAc-conjugated AATD program utilizes a proprietary RNA editing oligonucleotide specifically designed to leverage endogenous ADAR to make a single base edit in SERPINA1 RNA, correcting the pathogenic G to A SNV that results in the E342K amino acid substitution. This approach is designed to restore the production of normal AAT protein in liver hepatocytes through convenient subcutaneous administration. Our goal is to bring individuals with the Z allele to a phenotype where over 90% of RNA has been modified to produce normal AAT protein, resulting in levels of AAT consistent with individuals in the upper half of the PiMZ genotype and the fully healthy PiMM genotype. We believe the GalNAc-conjugated delivery approach has the potential to offer multiple advantages over our previous LNP-based intravenous approach, including improved potency of the next-generation construct, improved delivery to liver cells using GalNAc conjugation, convenient subcutaneous administration that significantly improves patient experience, and potentially enhanced durability of effect.

Our preclinical studies have demonstrated compelling proof of concept for the GalNAc-conjugated approach to AATD treatment. A GalNAc-conjugated RNA editing lead candidate achieved greater than 90% editing of the SERPINA1 transcript in vivo in a human transgenic mouse model that expresses the human SERPINA1 gene with the Z-mutation. These results demonstrate both the high efficiency and consistency of our next-generation RNA editing oligonucleotide with the GalNAc-conjugated approach in a well-characterized AATD mouse model. Our potential development candidates have also demonstrated

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high specificity with minimal off-target effects, supporting the potential for a favorable safety profile in clinical development. The editing efficiency achieved with our GalNAc-conjugated approach represents a significant advancement over our earlier studies and positions our program to potentially deliver transformative outcomes for AATD patients. We anticipate nominating a development candidate among our lead candidates for this program in the second quarter of 2026.

Our OPERA Platform

We have assembled a suite of technologies and capabilities to build our RNA editing platform, Oligonucleotide Promoted Editing of RNA, or OPERA.

OPERA integrates a deep understanding of ADAR biology with expertise in oligonucleotide chemistry, machine learning optimization of oligonucleotides and fit-for-purpose, derisked delivery, all of which are expected to enable rapid iteration of our development candidates across therapeutic targets. OPERA relies on the following key components that enable us to generate the proprietary RNA editing oligonucleotides that form the basis of our differentiated development candidates:

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Expertise in ADAR biology, supported by extensive preclinical research using in vitro assays and proprietary mouse models as well as the fundamental work of our scientific advisors and founders to elucidate key insights and know-how of ADAR biology. This enables an understanding of ADAR activity translation among different species and disease states, allowing us to develop novel lead candidates.

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Expertise in oligonucleotide chemistry, enabled by the ability to identify and incorporate chemical modifications to generate a fully modified synthetic oligonucleotide. This increases our ability to generate potent oligonucleotides with drug-like properties, thereby increasing the editing and translational efficiency of our lead candidates.

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Machine learning optimization of oligonucleotides and target identification, driven by data science and computational capabilities for rapid and efficient design and iteration resulting in optimal lead candidates for each disease or disease target being pursued.

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Leveraging known and derisked delivery modalities, made possible by tissue-specific and validated delivery technologies that may potentially derisk our lead candidates and enhance biodistribution, specificity, durability and editing efficiency of lead candidates.

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Such lead candidates are single stranded oligonucleotides designed to have high target efficiency and specificity by leveraging the pillars of OPERA. The versatility of RNA editing combined with our OPERA platform broadens the therapeutic target space significantly.

Our Strategy

Our mission is to discover, develop and commercialize a new class of RNA editing therapies capable of improving the lives of patients with rare and highly prevalent diseases. We do this by applying our proprietary RNA editing platform, OPERA, which combines our unique expertise in ADAR biology and oligonucleotide chemistry with machine learning-driven optimization and leveraging existing delivery. Our RNA editing oligonucleotides are designed to harness the body’s natural RNA editing processes to make a precise single A-to-I edit on RNA. However, this has primarily been observed in preclinical studies and in a limited number of human subjects in our now terminated REWRITE clinical program investigating KRRO-110, an LNP-encapsulated oligonucleotide as a treatment for AATD.

Our lead program, KRRO-121 for hyperammonemia, utilizes GalNAc-conjugated delivery with a regulatory filing anticipated in the second half of 2026. Our goal is to develop a portfolio of RNA editing oligonucleotides, to help alleviate major unmet medical needs, with best-in-class properties by executing on the following key pillars of our strategy:

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Develop a pipeline of programs focused on modifying proteins to activate biological pathways using RNA editing. We are leveraging significant advances in the understanding of the relationship between DNA, RNA and disease phenotypes to develop novel therapeutic approaches across a range of validated biological targets. Our novel class of RNA editing therapeutics combines the precision of genomic therapies with the properties associated with traditional approved drugs, such as titratability and ability to re-dose. Using our approach, in preclinical studies, we have demonstrated the ability to modify protein function or engineer proteins to potentially endow them with desirable properties to treat disease. This approach can unlock validated target classes that have historically been deemed undruggable, enabling us to pursue a broad range of diseases, including those with high prevalence.

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Advance KRRO-121 as a potentially first-in-class treatment for hyperammonemia, our first example of synthetic rescue. Our lead program, KRRO-121, has the potential to provide a differentiated therapeutic option for patients with UCD and HE by enhancing ammonia clearance. KRRO-121 can potentially achieve this through the stabilization of GS, specifically in the liver. Our preclinical data has demonstrated proof of concept across multiple in vitro and in vivo models, including a humanized liver mouse model. KRRO-121 utilizes GalNAc-conjugated delivery for convenient subcutaneous administration. We anticipate a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. However, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies.

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Develop a best-in-class GalNAc-conjugated therapy for patients with AATD. We are advancing a GalNAc-conjugated RNA editing oligonucleotide for AATD that utilizes subcutaneous delivery to repair the protein malfunction caused in the AATD patients, by editing the SERPINA1 RNA in the liver. Our RNA editing lead candidates for AATD have generated compelling preclinical data demonstrating greater than 90% editing of the SERPINA1 transcript achieved using GalNAc delivery in vivo, thus restoring the production of normal AAT protein. We expect to nominate a development candidate for our AATD program in the second quarter of 2026. Depending on the evidence of efficacy and tolerability, we intend to pursue expedited regulatory pathways globally.

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Continue to optimize and enhance our OPERA platform. We believe we have built a leading RNA editing company through a combination of our OPERA platform, intellectual property strategy and human capital. Our computationally driven approach enables rapid design and optimization of potential lead candidates. We intend to continue to incorporate new data into these machine learning models to improve their ability to predict editing efficiency and to more expeditiously optimize and nominate new development candidates, although there is no guarantee that this will result in an accelerated development or approval timeline, if at all.

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Maximize the potential of our OPERA platform through collaborations and strategic partnerships. We believe the versatility of our OPERA platform has the potential to create transformative genetic medicines for both rare and highly prevalent diseases. To fully realize this potential, we have established and plan to continue to actively seek out innovative collaborations, licenses, and strategic alliances with clinical leaders, academic medical centers of excellence, patient advocacy groups, and pioneering companies, including, for example, our collaboration with Novo Nordisk for up to two partnered programs for cardiometabolic diseases, which entered a 12-month pause in November 2025. Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially

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in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.

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Invest in human capital and encourage innovation to maintain a leading position and advance the frontiers of genetic medicines. We are a mission-driven organization, and we thrive through a strong culture that embodies our core values. We are actively working to rewrite the future of medicine and remain on the cutting edge of science and research by working better together and being dynamically different in employing a diverse team with varied expertise, enabled by kindness, integrity and respect. We have attracted a talented team of industry experts and experienced scientists as part of a high-performing and nimble organization. Our research and development organization is comprised of individuals with relevant expertise in drug development.

Positioned for Value Creation in 2026 and Beyond

We are well positioned to create significant value in 2026 and beyond with multiple anticipated milestones, with multiple anticipated development candidates:

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Regulatory filing for KRRO-121 for hyperammonemia anticipated in the second half of 2026.

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Development candidate nomination for our next-generation GalNAc-conjugated AATD program expected in the second quarter of 2026.

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Continued advancement of our longevity and liver health and ALS programs, with cash runway into the second half of 2028 supporting achievement of these milestones

We believe RNA editing has potential beyond the treatment of rare genetic diseases, and our goal is to apply our OPERA platform to help patients with highly prevalent diseases, including HE.

Expanding the Frontiers of Genetic Medicines: RNA Editing

The advent of large-scale genome sequencing has progressively revealed causal genetic variation underlying several human diseases, both rare and highly prevalent. Genetic mutations, including SNVs, implicated in disease have been found to be diverse in nature and can affect the function of genes and their associated downstream biochemical pathways. Natural genetic variations, revealed by population-level genomic studies, have also been shown to protect against or to increase the risk of disease. Beyond these developments, groundbreaking advances in gene therapy, cell therapy and RNA therapeutics have resulted in several approvals that have transformed the treatment of certain genetic diseases and cancers as well as the prevention of infectious diseases, such as COVID-19. In addition, various DNA editing approaches have been developed that introduce specific genetic changes to DNA to treat diseases. First generation CRISPR-Cas9 DNA editing has demonstrated the potential to knockout pathogenic mutations at the single gene level with several programs in clinical development and the first ex vivo DNA editing therapeutic for a rare hematological condition on file at the FDA. Next generation DNA editing approaches have entered the clinic and hold the promise to edit DNA at the single nucleotide level.

Despite these advances, significant risks exist with DNA editing approaches. A key concern is the introduction of unwanted DNA modifications (“off-target” edits), which could have permanent adverse effects such as chromosomal integration and non-specific insertions, deletions and substitutions. Additionally, due to the complexity of a multicomponent DNA editing product, delivery to target cells can be challenging and even more so if there is a need to edit multiple genetic loci. Furthermore, manufacturing is highly complex and expanding to commercial scale remains challenging, specifically for a highly prevalent indication. Given these challenges, DNA editing approaches will likely remain a focus for certain rare diseases, while its ability to treat diseases of high prevalence continues to be limited.

ADAR-mediated RNA editing

RNA editing involves altering a sequence of RNA, which intrinsically has the potential to address some of the limitations of DNA editing. RNA editing mediated by adenosine deaminase acting on RNA, or “ADAR-mediated” RNA editing, has emerged as a differentiated approach that can generate oligonucleotide having features that combine the precision of genomic therapies with the properties commonly associated with current approved drugs such as titratability and ability to re-dose. Importantly, these drug-like characteristics enable ADAR-mediated RNA editing candidates to be potentially safer and target diseases with high prevalence that would be difficult for DNA editing approaches to address.

ADARs are a family of enzymes present inside a cell, that bind RNA. ADARs bind double-stranded RNA structures, and convert a single base of adenosine (A) on RNA, into an inosine (I) that is typically translated as a guanosine (G), using an

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enzymatic process. ADAR mediated editing is found at high levels in cephalopods both on the coding and non-coding regions of the RNA. In humans, there are fewer recoding events, and most of the endogenous editing events occur in non-coding regions.

Humans have two known active endogenous ADAR enzymes, ADAR1 and ADAR2. ADAR1 is constitutively expressed and is present in most tissues within the body, whereas ADAR2 is more highly expressed in tissues such as the brain. The ADARs are essential enzymes for normal physiologic function. ADAR-driven RNA editing has been found to be critical for the function of a number of proteins, such as the glutamate ionotropic receptor, which has been found to be almost always RNA-edited in humans. Given ADARs’ natural function to catalyze A-to-I edits, this endogenous editing system can be leveraged to make programmed edits to RNA. This ability to introduce programmed highly targeted edits into RNA has the potential to expand the reach of genetic medicines with an ability to modify proteins to achieve a desired function.

Oligonucleotide-based ADAR-mediated RNA Editing

There are multiple therapeutic approaches to utilize ADAR-mediated RNA editing, including synthetic oligonucleotides, engineered ADARs, and Cas-based editing approaches. Our therapeutic approach delivers oligonucleotides to target tissues and cells to introduce precise edits to RNA through recruitment of endogenous ADAR.

Normally, ADARs are recruited to target RNA editing sites through recognition of specific double-stranded RNA structures such as naturally occurring hairpins or loops in endogenous transcripts. Importantly, one can mimic these double-stranded RNA structures by introducing complementary synthetic oligonucleotides into cells. An oligonucleotide can be engineered to mimic the double-stranded RNA structure such that endogenous ADAR is recruited. Using this targeted approach, a site directed specific A-to-I edit can be introduced.

Figure 2: Mechanism of RNA editing using our proprietary platform

Key Advantages of Oligonucleotide-Based ADAR-Mediated RNA Editing as a Therapeutic Modality

Over the last two decades, there has been significant research around and development of oligonucleotide-based therapeutics, including modalities such as siRNA and ASOs, that has led to the approval of multiple drugs. Specifically, developments in oligonucleotide chemistry, delivery technologies, tolerability, and manufacturing, combined with better defined regulatory pathways, have led to the approval of oligonucleotide-based therapeutics specific for multiple different tissue types. We believe that oligonucleotide-based ADAR-mediated RNA editing is a groundbreaking technology that is ideally suited to expand the application of genetic medicines for indications that DNA editing is unable to address. We differentiate our approach from DNA-editing by leveraging the know-how from approved oligonucleotide therapies in development of our lead candidates.

While we believe we can demonstrate many of the key advantages of RNA editing, including specificity, delivery, tolerability, manufacturing, and regulatory, we are very early in our development efforts and not yet certain of the results we may achieve. Such uncertainties include but are not limited to the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans.

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Specificity: Oligonucleotide-based ADAR-mediated RNA editing enables highly precise edits at the target single nucleotide level on the RNA with low risk of off-target or bystander edits, addressing a key safety concern associated with other DNA editing approaches that carry the risk of permanent insertions and deletions as well as chromosomal

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integration. Using synthetic oligonucleotides, appropriate chemical modifications can be introduced to increase the overall specificity and targeting efficiency for the site directed RNA editing. The OPERA oligonucleotides are designed to be highly site selective with minimal to no bystander effects or halo effects. To assess global off-target editing, we use a bulk RNA-seq approach to detect base frequency changes at potential off target sites between control and treated samples. We sequence target amplicons via next-generation sequencing and assess potential A to G editing at all sites across the transcript. In preclinical in vivo studies, we have shown that off-target RNA editing using our technology is negligible and transient.

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Delivery: Oligonucleotide-based ADAR-mediated RNA leverages well-established, clinically precedented delivery approaches used in other approved products, such as ligand-based approaches. One example of a well-established and clinically validated ligand-based delivery approach is GalNAc delivery of oligonucleotides, which provides highly specific and effective delivery to hepatocytes with improved durability and enables convenient subcutaneous administration. Multiple FDA-approved products utilize GalNAc-conjugated delivery, including GIVLAARI and OXLUMO.

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Tolerability: ADAR-mediated RNA editing has a low risk of immunogenicity and can potentially lower off-target editing events resulting in an improved tolerability profile compared to DNA editing approaches. The lower risk of immunogenicity enables the ability to re-dose patients if required, a significant limitation of editing approaches that utilize viral vectors and bacterial Cas systems that carry a higher risk of immunogenicity. The transient and reversible nature of ADAR-based editing confers an ability to modify or cease dosing as needed.

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Manufacturing: Reliance on endogenous ADAR enzymes and the simple drug constructs of oligonucleotide-based therapies has significant advantages over the complexities associated with the manufacturing and delivery of multi-component exogenous complexes used in DNA editing. Manufacturing processes for oligonucleotide-based therapies are well established, cost efficient and scalable to effectively address highly prevalent indications.

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Regulatory: Precedence of marketed oligonucleotide drugs with similar size and types of chemical modifications that therapeutic RNA editing lead candidates exhibit. Guidance for the development of oligonucleotide therapeutics by global agencies, including the FDA, provides for an established pathway for the approval of this class of therapeutics. However, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and limited clinical data has been generated to date.

Our OPERA – Oligonucleotide Promoted Editing of RNA – Platform

We believe we are the leading RNA editing company and have assembled a suite of technologies and capabilities called OPERA, Oligonucleotide Promoted Editing of RNA, to generate differentiated RNA editing lead candidates. A key challenge in developing a therapeutic approach for site-directed RNA editing is to design and optimize oligonucleotides that can drive high-efficiency. This efficiency is facilitated both by the ability to repurpose and optimize oligonucleotide constructs based on existing methods as well as utilizing computational methods to innovate on chemistry and design of the constructs. Our oligonucleotides capable of forming Watson-Crick base pairing with the target RNA and efficiently inducing the deamination reaction by endogenously recruiting ADAR enzymes.

We have assembled a suite of technologies and capabilities to build our RNA editing platform, Oligonucleotide Promoted Editing of RNA, or OPERA.

OPERA relies on the following key components that enable us to generate our differentiated RNA editing oligonucleotides:

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Expertise in ADAR biology: Our insights and know-how of ADAR biology allow us to design oligonucleotides that efficiently recruit ADARs and promote deamination while maintaining selectivity and stability. RNA editing is dependent on endogenous ADAR expression levels and requires expertise in the physiological role of ADAR, its cell and tissue distribution, the factors that lead to efficient recruitment of ADAR to targeted sites and any consequences that may arise from co-opting ADAR from its normal function.

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We have found no evidence that our RNA editing oligonucleotides interfere with endogenous RNA editing occurring naturally in a cell. ADAR naturally edits thousands of targets for a variety of reasons. We have looked at natural editing sites and chose AJUBA, COG and COPA as they have shown to be edited by ADAR to different degrees. In this experiment outlined in Figure 3, ZZ HLC cell lines were transfected with RNA editing oligonucleotides targeting two different genes. The assays were evaluated for % editing for Target A and Target B sites as well as natural editing sites in COG, COPA and AJUBA. As shown below, natural editing sites remained unaffected compared to the

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control group, demonstrating that our RNA editing oligonucleotides are not likely to have any effect on the degree of editing of native RNA molecules.

Figure 3. Our RNA editing oligonucleotides show no evidence of interference with endogenous ADAR editing as demonstrated at the above endogenous sites

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Expertise in oligonucleotide chemistry: We have a differentiated ability to create oligonucleotide designs capable of efficiently recruiting endogenous ADAR with chemical modifications that direct high specificity editing. Our oligonucleotides increase the potency and durability of ADAR activation, thereby increasing the editing efficiency and translational efficacy of our RNA editing oligonucleotides. We have identified critical structural, sequence, and chemistry requirements for our RNA editing oligonucleotides that drive efficient recruitment of ADARs and subsequent A-to-I editing. Examples of differentiation include oligonucleotide length for efficient ADAR recruitment, use of precedented and proprietary chemistries within the oligonucleotide, as well as backbone chemistries that provide improved metabolic stability. Additionally, we combine this with 2’ modification chemistries that, together, create oligonucleotides with improved editing efficiency and durability. As RNA editing is an emerging technology, there is a lack of guiding principles to design site-selective RNA editing oligonucleotides. To address this knowledge gap, we developed a robust in-house process using our high-throughput cell-based assay and machine learning capabilities to design and synthesize up to approximately 1,200 oligonucleotides per month and generate up to 6,000 assay data points for any given target.

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Machine learning optimization of oligonucleotides and target identification: We have built data science capabilities and a dedicated team to extract lessons from existing and newly generated experimental data to expeditiously and efficiently design and optimize RNA editing oligonucleotides. Our proprietary machine learning models have been trained to accurately predict oligonucleotide structure and observed levels of editing. We have been able to demonstrate that these models are able to make accurate editing predictions even for previously unseen chemical modifications demonstrating their generalizability across targets. We have demonstrated the utility of our machine learning models through an increase in overall editing efficiency of new RNA editing oligonucleotides. In some cases, we have been able to go from design-to-data in as little as five weeks. However, there is no guarantee that this will result in an accelerated development or approval timeline, if at all.

Figure 4. We have shown our ability to rapidly iterate RNA editing oligonucleotides to maximize editing efficiency

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Structural modeling is another tool that complements our ability to increase the efficiency of our RNA editing oligonucleotides. Detailed structural modeling includes shape, size and orientation requirements that can lead to successful deamination at the editing site. These aspects have an important impact on our ability to optimize RNA editing oligonucleotides. As an example, a modification predicted by structural analyses led to a conformational change that was shown to improve editing efficiency in the coding region of the Target A in vivo.

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Leveraging known delivery modalities: Our RNA editing oligonucleotides utilize short synthetic oligonucleotides, which we believe can be efficiently delivered using technologies such as GalNAc, which is well established and clinically validated and has been developed for precedented modalities such as siRNAs and ASOs. GalNAc has optimal characteristics suited for a given therapeutic application, and we believe has the potential to derisk our lead candidates. Using RNA editing oligonucleotides, we achieved greater than 50% editing in vivo utilizing a ligand-based GalNAc conjugate delivery approach. Ligand-based approaches (e.g., GalNAc for liver hepatocytes) can also be used for effective delivery and to improve durability with OPERA’s RNA editing oligonucleotides, which we have also evaluated in preclinical in vivo models. In contrast to treatments targeting liver hepatocytes where there is a need for a delivery system, our RNA editing oligonucleotides have been delivered intrathecally to the central nervous system without a need for any delivery system in preclinical mouse models. Thus, our choice of delivery system is a fit-for-purpose model that is dependent on the oligonucleotide design as well the suitability for the indication and tissue localization of the target.

Our Pipeline Demonstrates the Versatility of the OPERA Platform

We are advancing a broad pipeline of four programs that are wholly owned and demonstrate the versatility of our OPERA platform. We also have the opportunity to advance up to two programs under our collaboration with Novo Nordisk, which entered a 12-month pause in November 2025. Our most advanced program, KRRO-121 for hyperammonemia, is advancing toward a regulatory filing anticipated in the second half of 2026. Our AATD program is progressing with a next-generation GalNAc-conjugated candidate, with development candidate nomination expected in the second quarter of 2026. All of our programs are in the research or preclinical stage of development. The risk of failure of all of our programs is high.

1De novo protein variant to prevent toxic GoF with TDP43 aggregation and continue downstream signaling by overcoming toxic LOF

Approximately 85% of the human proteome has historically been considered undruggable through traditional therapeutic modalities as many proteins lack defined small molecule binding sites or are inaccessible by biologics. The versatility of RNA editing, combined with our OPERA platform, addresses a meaningful portion of the undruggable human proteome and broadens the target space. Our target identification and selection for programs is based on strong genetic evidence implicating each target in its disease pathology.

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Figure 5: Applications of RNA editing are broad and can be applied in multiple ways to generate a de novo protein with enhanced and augmented properties by just modifying a single amino acid through RNA editing.

Our initial focus is to make edits to the coding region of a transcriptome. Making changes post-transcriptionally, after the mRNA has been created and prior to the protein being translated, provides an exquisite, selective approach for modifying proteins. In preclinical studies, we have demonstrated that single RNA changes can stabilize proteins, disrupt protein-protein interactions, prevent protein aggregation, selectively modulate an ion channel and selectively activate a kinase. These modification approaches have the potential to unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases, including those with high prevalence and large market opportunities.

Stabilize Protein: We are using OPERA to engineer protein stability and enable synthetic rescue. Enabling synthetic rescue provides a novel modality to target intracellular proteins. Our lead program, KRRO-121, exemplifies this synthetic rescue approach by engineering a de novo GS protein with a single amino acid change that is designed to prevent glutamine-induced proteasomal degradation, thereby maintaining ammonia clearance capacity. This approach creates a protein that is engineered to retain full enzymatic activity while resisting the natural degradation pathway, highlighting the broad capabilities of what our OPERA RNA editing platform can accomplish in driving biological change. By focusing specifically on hepatocytes, and delivering our RNA editing oligonucleotides via a GalNAc conjugate, we have the ability to provide control over the cell types on which the GS is stabilized, thereby enhancing the safety profile of the candidate.

Figure 6. KRRO-121 introduces a single amino acid change in GS to enhance ammonia clearance

Repairing pathogenic variants: Our OPERA platform enables the development of RNA editing therapies that can repair SNVs on RNA to express normal proteins through the introduction of precise genetic changes without creating permanent changes to the genome. These normal proteins can be uniquely expressed at desired levels and duration to address both rare and

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highly prevalent diseases caused by a pathogenic SNV. This approach is especially relevant when the same underlying genetic SNV manifests in a broad disease phenotype from mild to severe forms of the disease.

Our program for AATD addresses a single genetic SNV in the SERPINA1 gene that causes the development of AAT deficiency, which has a high unmet medical need and for which there are no disease modifying treatment options. The disease manifests with a heterogenous population having both liver and lung pathologies. By specifically editing a single nucleotide, the normal synthesis of AAT is restored, resulting in secretion of normal AAT to levels that are predicted to protect the lung from further decline in function. The correction of a subset of AAT produced also prevents aggregation of AAT protein in the liver, thereby potentially alleviating damage to the liver.

Figure 7: A glutamic acid was converted to a lysine with a single RNA edit, leading to the correction of the AAT protein in patients with AATD with a at least a single Z-allele

Other Target Classes: In addition to engineering protein stability and repairing proteins, we are also advancing lead candidates to selectively activate intracellular kinases in the liver and in the central nervous system to prevent protein aggregation within neuronal cells.

Rather than treating late-stage disease, we are focused on extending organ health-span, or longevity. The three fundamental reasons as to why organs age are: metabolic dysfunction, oxidative stress, and inflammation accumulation. AMPK, when activated, inhibits anabolic pathways like lipogenesis and protein synthesis, activates catabolic pathways including fatty acid oxidation and autophagy, and regulates glucose homeostasis by enhancing insulin sensitivity. The γ1 subunit—AMPKγ1—represents the optimal liver therapeutic target because of its hepatocyte enrichment. Our longevity and liver health program targeting AMPKγ1 in the liver exemplifies our kinase activation approach, where a single RNA edit is designed to activate a master metabolic regulator with the goal of restoring metabolic status and improving liver function.

In addition to our longevity and liver health program, we have been focused on creating a de novo version of a normal protein that, under certain disease states, can prevent the aggregation of the native version, while preserving the native protein’s intrinsic function. This is a therapeutic approach that has the potential to provide a differentiated therapeutic option over knocking down or silencing the protein through alternate mechanisms. Intracellular protein aggregation is a cause of multiple diseases across the body. Specifically in neurodegenerative diseases, accumulation of specific proteins within neurons are pathogenic including Alzheimer’s disease, Parkinson’s disease, and ALS. In pathological conditions, such as ALS, TAR DNA-binding protein 43, or TDP-43, is depleted from the nucleus and accumulates as protein aggregates in the cytoplasm in hyperphosphorylated, ubiquitinated, and cleaved forms. These aggregates are observed in more than 90% of ALS patients. A single RNA edit to TDP-43 transcript is predicted to lead to the synthesis of a de novo protein that does not aggregate and preserves its normal function. Given TDP-43 is essential for neuronal health, knocking down the protein could be detrimental.

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Figure 8. Our lead candidates can reduce pathogenic aggregation of undesirable proteins

We believe that the elegance and versatility of our RNA editing approach will enable a robust pipeline of potentially disease modifying development candidates to treat diseases previously unattainable by genetic medicine approaches. While the above examples demonstrate the breadth of applications enabled by OPERA, we believe our RNA editing approach will bring the first genetic medicine to address the complex genetic underpinnings of highly prevalent diseases.

Our Hyperammonemia Program: KRRO-121 – Stabilizing Glutamine Synthetase to Clear Ammonia

Our development candidate, KRRO-121, is a potential first-in-class treatment for hyperammonemia that could address substantial unmet need in patients with poor ammonia control, including those with UCD and HE. KRRO-121 is an RNA-editing oligonucleotide conjugated with GalNAc to deliver the construct specifically to the liver. Utilizing our proprietary OPERA platform, KRRO-121 is designed to generate a stabilized, de novo variant of GS with enhanced ammonia clearance capacity.

There are an estimated 4,200 severe late-onset UCD patients in United States, and 5,100 in the European Union and United Kingdom, and there are approximately 80,000 addressable patients in the United States with severe or recurring HE, high ammonia levels (≥1.5x upper limit of normal), and sufficient liver function may benefit from ammonia-lowering treatment, with approximately an additional 150,000 patients in the European Union and United Kingdom.

In addition to the inherent benefits of ADAR-based RNA editing described earlier, we believe our approach for potentially treating hyperammonemia has additional potential advantages:

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Provides a pan-UCD approach addressing multiple UCD subtypes irrespective of their enzyme deficiencies in the urea cycle.

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Stabilization of GS protein specifically in the liver.

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Convenient subcutaneous delivery with the potential for once in 2-week delivery using precedented GalNAc-conjugated technology.

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Potential for additional benefits including a reduction in hyperammonemic crises and diet liberalization for UCD patients, and a reduction in HE events for HE patients.

We have generated compelling preclinical data demonstrating proof of concept for stabilizing GS using mouse surrogate compounds as well as for KRRO-121 in human systems. KRRO-121 maintains GS protein levels during ammonia challenge in OTC-deficient and ASS1-deficient iPSC-derived hepatocytes. In OTC-deficient mice challenged with ammonia, treatment with a mouse-optimized oligonucleotide reduced ammonia, supporting the potential to both maintain ammonia levels as well as the potential to increase protein intake and dietary liberalization in patients with UCD. In CPS-1 deficient mice, ammonia was reduced post-ammonia challenge, with nonsignificant increase in plasma glutamine levels. In a humanized liver mouse model (PXB), KRRO-121 reduced basal ammonia levels and enhanced ammonia clearance following challenge, with production of stabilized de novo GS variant. In NHPs, KRRO-121 displayed 90% delivery to liver, confirmed liver localization with pericentral GS, and no observed changes in liver or kidney function, coagulation, complement, platelets, or cytokines.

Based on the preclinical data, we believe KRRO-121 has potential to be a first-in-class treatment for ammonia control. We anticipate submitting a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. The compelling product profile for controlling ammonia is expected to drive strong patient engagement and recruitment. While we

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believe we can demonstrate many of the key advantages of RNA editing, we are very early in our development efforts and not yet certain of the results we may achieve. Such uncertainties include, but are not limited to, the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans.

Hyperammonemia Overview

Ammonia is a toxic byproduct of protein metabolism. The body clears ammonia through two complementary pathways: the urea cycle, which is expressed primarily in the liver and converts ammonia to urea for excretion, and the GS pathway, which is expressed in many tissues including the liver, brain and muscle, and converts ammonia and glutamate into glutamine.

Hyperammonemia, characterized by elevated levels of toxic ammonia in the blood, is a life-threatening condition resulting from the body’s diminished clearance capacity. When this clearance is compromised, ammonia accumulates systemically, driving pathology across multiple disease states. High ammonia levels are directly linked to severe clinical outcomes. The pathology of hyperammonemia manifests through:

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Neurological Impairment: Elevated ammonia is neurotoxic, leading to cognitive decline, encephalopathy, and potentially permanent brain damage.

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Systemic Complications: Beyond the brain, hyperammonemia is associated with elevated infection risks and other non-neurological complications.

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Severe Lifestyle Restrictions: Patients currently face highly restricted diets to limit protein intake, which can paradoxically lead to malnutrition and metabolic instability.

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High Healthcare Utilization: Uncontrolled ammonia drives frequent, costly hospitalizations.

Glutamine Synthetase and its function

GS is an enzyme primarily responsible for clearing toxic ammonia from the body. It catalyzes the condensation of glutamate and ammonia to form glutamine. This reaction is a critical, complementary pathway to the urea cycle for detoxifying ammonia. While the urea cycle is expressed primarily in the liver, GS is expressed in many tissues, including the liver, brain, and muscle. GS plays a “scavenging” role, in addition to the urea cycle, to prevent the ammonia from staying in systemic circulation. The stability and activity of GS are tightly regulated by the levels of its product, glutamine. When glutamine levels rise, it drives the degradation of GS protein through known mechanisms. This degradation mechanism involves the acetylation of key N-terminal lysine residues on the GS protein, which tags it for proteasomal degradation. This creates a feedback loop where high glutamine leads to reduced GS levels, diminishing the body’s ammonia clearance capacity. Conversely, when glutamine is low, GS remains stable (without lysine acetylation) to maximize ammonia clearance.

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Figure 9. Depicts the glutamine-mediated feedback regulation of GS protein stability, illustrating how elevated glutamine levels trigger degradation of GS, thereby modulating the body’s ammonia clearance capacity.

Urea Cycle Disorders

UCDs are a group of severe, inherited metabolic diseases caused by mutations in the genes that encode one or more of the eight enzymes and transporters necessary to convert ammonia into urea. The inability of the body to properly metabolize ammonia leads to the accumulation of toxic systemic levels in circulation, ultimately resulting in severe health outcomes, such as neurologic disability, seizure and death. UCDs occur across all age groups, from infants to adults, and mild symptoms may go unnoticed until a stressor, such as illness, surgery, protein consumption or environmental stress, overwhelms compensatory functions, resulting in hyperammonemic crisis. The incidence of UCDs in the United States is estimated to be approximately one in 35,000 births. The most common UCD, accounting for approximately 60% of UCD diagnoses, is OTC deficiency. The next two most common genetic subtypes are caused by mutations in the genes coding for the enzymes argininosuccinate lyase, or ASL, and ASS1, affecting approximately 16% and 14% of UCD patients, respectively.

There are approximately 6,500 UCD patients in the United States, of which approximately 4,600 are post-neonatal onset and approximately 4,200 are severe late-onset patients who we believe could benefit from pharmacological therapy. We estimate an additional approximately 5,100 addressable patients exist in the European Union and United Kingdom. There are no FDA-approved, disease-modifying therapies to treat the most prevalent UCDs. The standard of care is supportive in nature and intended to reduce the frequency of, but not eliminate, hyperammonemic crises. Current protocols for patients involve strict adherence to a low-protein diet along with the prophylactic use of nitrogen scavenger agents, which carry an onerous pill regimen and significantly diminish the quality of life for patients. Despite these measures, 20% to 25% of patients experience breakthrough hyperammonemic crises. Liver transplantation is the only definitive treatment option.

Current standard of care for all UCD subtypes are drugs that fall in the class of nitrogen scavengers. These include Sodium phenylbutyrate (NaPBA, Buphenyl®) and Glycerol phenylbutyrate (GPB, Ravicti®), both of which are prodrugs of phenylacetic acid, which is converted to phenylacetyl glutamine and excreted in urine. Both the approved products are an oral suspension taken three times a day. The current approved products have the potential to control ammonia levels in UCD patients; however, it is challenging for multiple reasons including compliance in school age kids and adolescents, severe dietary restrictions where the diets sometimes do not resemble food, and both drugs having a narrow therapeutic index despite the need to take it multiple times a day.

Hepatic Encephalopathy

HE is a brain dysfunction caused by liver insufficiency and/or portal systemic shunting. Because the damaged liver in cirrhosis cannot function normally, neurotoxins such as ammonia are inadequately removed from systemic circulation and travel to the brain, where they affect neurotransmission. This can cause episodes of HE, which may present as alterations in consciousness, cognition, and behavior that range from minimal to severe. Overt HE occurs in 30% to 40% of patients with

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cirrhosis at some point during the clinical course of their disease. As the burden of chronic liver disease and cirrhosis is increasing, the frequency of HE is also increasing.

There are approximately 2.2 million patients with cirrhosis in the United States, of whom approximately 140,000 experience severe or recurring HE. We estimate that up to approximately 80,000 of these patients who have high ammonia levels and sufficient liver function could potentially benefit from an ammonia-lowering treatment such as KRRO-121. We estimate an additional approximately 150,000 addressable patients in the European Union and United Kingdom. Current standard of care includes rifaximin and lactulose, which reduce ammonia production by gut bacteria but do not directly address ammonia clearance capacity. The unmet need, like UCD patients, is very high. The current standard of care does not reduce ammonia to levels that is needed, drugs approved for UCD are not used in HE patients as they are not approved and/or the compliance in HE patients is challenging given all of the other drugs needed. HE is also not prioritized for a liver transplant. In addition, the healthcare utilization of these patients is one of the highest for patients with liver disease, making the unmet need high both from a medical and pharmacoeconomic standpoint.

Alternative Treatments in Development for UCD and HE

The treatment landscape for UCD remains an area of active investigation, with multiple modalities in clinical development. Gene therapy and gene editing approaches attempt to deliver a functional copy of the deficient urea cycle gene, most notably OTC. Given the inherent risks associated with DNA-based approaches, both these approaches would likely be most applicable for only the most severe patients, and clinical development is presently limited to only those with OTC deficiency. An mRNA-based approach to deliver functional mRNA to hepatocytes via LNPs has also been tested in patients. However, the requirement for repeated intravenous dosing and the potential for immune responses to the delivery vehicle may limit long-term feasibility and restrict patient independence.

Our approach has distinct potential advantages over these alternative treatments in development, including:

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Pan-UCD applicability with potential to address all subtypes regardless of genotype.

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Improved ammonia control complementary to the existing standard of care.

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Transient, redosable, and titratable approach with convenient subcutaneous administration.

For hepatic encephalopathy, the pipeline remains limited and has faced multiple recent setbacks. Approaches targeting ammonia removal have shown signs of efficacy in early-stage trials, but none appear to be in active clinical development. Microbiome-based approaches have also been tested, but to date, none have successfully progressed through late-stage clinical development for the treatment of HE, and there is limited evidence supporting ammonia-lowering effects of these approaches.

Our Differentiated Approach: Engineering a Stable GS Variant Through Synthetic Rescue

KRRO-121

KRRO-121 exemplifies our synthetic rescue approach, in which a targeted mRNA edit is introduced to compensate for the functional deficiency caused by a primary disease-causing mutation. Rather than attempting to repair the underlying genetic defect in the urea cycle, KRRO-121 is designed to leverage endogenous ADAR to make a single nucleoside edit to GS mRNA, corresponding to a single amino acid change, thereby creating a de novo GS variant that is designed to bypass the degradation vulnerability and restore ammonia clearance capacity. Under normal physiological conditions, GS is subject to glutamine-induced feedback degradation: when glutamine levels rise, key N-terminal lysine residues on GS are acetylated, leading to ubiquitination and proteasomal degradation of the enzyme. This degradation reduces the cell’s capacity to clear ammonia precisely when ammonia clearance is most needed. The modification introduced by KRRO-121 replaces a lysine residue with an arginine, which is resistant to acetylation and therefore resistant to glutamine-induced degradation. The resultant de novo GS protein is intended to retain full enzymatic activity but resist proteasome-mediated degradation, potentially providing sustained ammonia detoxification capacity regardless of the specific UCD enzyme deficiency. This synthetic rescue strategy is engineered to enable KRRO-121 to address hyperammonemia through a pathway independent of the urea cycle, rather than attempting to repair the specific enzyme deficiency. This approach is supported by human genetic evidence. Published genetic studies have identified

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patients with start-loss variants in GS that result in loss of N-terminal lysine residues, leading to stabilized GS protein and stable enzymatic activity.

Figure 10. Depicts KRRO-121's lysine residue replacement to create a stabilized de novo GS variant that resists glutamine degradation, intended to maintain ammonia clearance.

We believe our approach has multiple potential advantages:

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Pan-UCD approach through synthetic rescue: By enhancing ammonia clearance through a pathway independent of the urea cycle, KRRO-121 has the potential to benefit patients with UCD regardless of the specific enzyme deficiency, including OTC, ASL, ASS1 and other subtypes.

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Dual indication potential: The ammonia-lowering mechanism of KRRO-121 may address both UCD and HE, two distinct conditions with a shared pathology of hyperammonemia.

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Convenient subcutaneous delivery: KRRO-121 utilizes GalNAc-conjugated delivery, a well-established and clinically validated approach that enables convenient subcutaneous administration with targeted delivery to liver hepatocytes.

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Potential for dietary liberalization: By providing enhanced ammonia clearance capacity, KRRO-121 may enable relaxation of the strict dietary protein restrictions that significantly diminish quality of life for UCD patients.

Summary of our preclinical studies and data generated leading to KRRO-121 selection

We have generated compelling preclinical data establishing proof of concept for KRRO-121 across multiple model systems:

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In vitro studies in primary human hepatocytes demonstrated dose-dependent RNA editing.

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In vitro studies in human induced pluripotent stem cell-derived hepatocytes bearing either the OTC-D175V or the ASS1D309 mutation demonstrated the ability to maintain stable levels of GS under conditions of ammonia overload in two subtypes of UCD.

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Figure 11. OTC D175V human iPSC-derived hepatocytes differentiated for 14 days, then treated with oligonucleotide.

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In vivo activity was demonstrated in OTC mice (OTCspf/ash), with 50% improved ammonia clearance.

Figure 12. Ammonia Reduction in OTC-Deficient Mice

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In vivo activity in a humanized mouse model (PXB) demonstrated approximately 20% editing at the mRNA level, leading to improved ammonia clearance during hyperammonemia challenge, resulting in approximately 20% of the stabilized protein post ammonia challenge without any significant degradation in the total protein. KRRO-121 significantly reduced ammonia levels in both basal state and following ammonia challenge, while maintaining steady glutamine levels post-challenge.

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Favorable tolerability profiles were observed in exploratory toxicology studies conducted in mice and NHPs. In NHPs, KRRO-121 displayed 90% delivery to liver, confirmed liver localization with pericentral GS, and no observed changes in liver or kidney function, coagulation, complement, platelets, or cytokines.

While we believe we can demonstrate many of the key advantages of RNA editing, we are early in our development efforts and not yet certain of the results we may achieve. Such uncertainties include, but are not limited to, the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans.

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KRRO-121 Next Steps

We anticipate a regulatory filing for KRRO-121 to enable commencement of a first-in-human clinical trial in the second half of 2026. Good laboratory practice, or GLP, -compliant toxicology studies in mouse and monkey are planned to support the proposed first-in-human study. KRRO-121 is being developed for the treatment of UCDs in adults and adolescents, with potential expansion into HE. However, KRRO-121 is in preclinical development and there is no guarantee that it will be successful.

Our AATD Program: RNA Editing to Repair Pathogenic Missense Variant

We are developing a next-generation GalNAc-conjugated RNA editing oligonucleotide for the potential treatment of AATD that has the potential to be disease-modifying and provide a differentiated therapeutic option. AATD is an inherited genetic disorder that can cause severe progressive lung and liver disease due to a lack of normal AAT, with varying intensity based on patient genotype and environmental factors. Patients often develop chronic obstructive pulmonary disorder, or COPD, in the lungs and cirrhosis of the liver, which can result in liver failure or death.

There are an estimated 5.5 million individuals with deficiency allele combinations worldwide. There is a single approved modality, a once-a-week infusion of pooled human plasma derived AAT, that does not adequately address the lung or liver manifestations of AATD. Within the United States alone, the opportunity to improve the existing standard of care and expand the treated population represents a large market opportunity.

Our AATD lead candidates are proprietary RNA editing oligonucleotides conjugated with GalNAc and administered subcutaneously with delivery to liver hepatocytes, where they co-opt endogenous ADAR to edit a nucleoside in the SERPINA1 transcript and restore production of normal AAT. The GalNAc conjugate approach enables convenient subcutaneous administration with targeted, liver-specific delivery to hepatocytes. GalNAc-conjugated delivery is a well-established and clinically validated approach that has been used in multiple FDA-approved products, including GIVLAARI and OXLUMO, providing a precedented delivery technology with an established safety and efficacy profile. By repairing the protein, we aim to bring individuals with the Z mutation to a phenotype where over 90% of RNA has been corrected to produce normal AAT, preserving lung and liver function and preventing further damage.

In addition to the inherent benefits of ADAR-based RNA editing described earlier, we believe our approach has additional potential advantages, including convenient subcutaneous delivery:

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Provides a disease modifying therapy for both lung and liver manifestations by transiently editing over 90% of RNA transcripts in hepatocytes to restore normal AAT protein

•
Provides a treatment option that can be tailored to address the broad spectrum of severity within the AATD population

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Potential to enable physiologic regulation of AAT using endogenous ADAR, thereby increasing normal AAT production during inflammation

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Convenient subcutaneous dosing using precedented GalNAc-conjugated delivery with liver-targeted specificity

We have generated compelling preclinical data demonstrating proof of concept across multiple RNA editing oligonucleotides targeting the SERPINA1 gene. We have achieved greater than 90% editing of the SERPINA1 transcript using GalNAc delivery in vivo, with results demonstrated in both NSG-PiZ and C57BL/6-PiZ mouse models. We first pursued a development candidate, KRRO-110, for the treatment of AATD, which used an LNP delivery modality. However, following initial results from our REWRITE trial announced in November 2025, we pivoted to a GalNAC delivery modality. See “—Termination of REWRITE Clinical Program” below.

AATD Overview

AAT function

AAT is a protease inhibitor belonging to the Serpin family. It is produced in the liver and circulates in its native state in human blood at approximately 1.5 g/L, one of the highest concentrations observed for protease inhibitors. The main role of AAT is to protect tissue from proteases released by neutrophils, such as neutrophil elastase. Neutrophil elastase is an enzyme that fights infections in the lungs but can also attack normal lung tissue. If not sufficiently inhibited by AAT, neutrophil elastase destroys elastin in the lung, leading to degradation of lung function. Factors that increase lung inflammation, such as smoking or

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infections, increase the elastase burden in the lung, leading to severe and potentially life-threatening lung damage in AATD patients.

Genotypes of AATD

AATD is an inherited, autosomal recessive genetic disorder that is most frequently caused by a single nucleotide variant, or SNV, mutation in the SERPINA1 gene. The most common of these SNVs is the “Z” mutation, corresponding to a mutation of glutamate 342 to lysine, or E342K. A healthy individual typically exhibits an “MM” genotype, or PiMM, while an individual with a single Z allele would exhibit a heterozygous, or PiMZ genotype, and an individual with two Z alleles would exhibit a homozygous, or PiZZ, genotype.

Figure 13. PiMM genotype (normal liver and lung)

Impact of Z mutations on liver and lung function

The presence of a single Z allele can lead to insufficient production of normal AAT, as well as the production of dysfunctional AAT, causing manifestations of disease in both the lungs and liver. The severity of disease manifestation can vary according to each patient’s genotype, as well as environmental factors, such as exposure to inflammatory respiratory agents or other complications.

PiZZ individuals experience greater manifestations of disease as a result of their very low levels of normal AAT (10% - 15% of normal levels), which are insufficient to prevent lung damage after an influx of neutrophils. They are also at high risk of developing emphysema or COPD, which can present in individuals as early as in their thirties and forties. PiZZ individuals with additional environmental risk factors such as smoking or infection frequently develop COPD as early adults and develop very severe symptoms.

In addition to lung disease, PiZZ individuals can also manifest with liver disease as a result of dysfunctional AAT aggregating in the liver. In adults, this can cause liver inflammation and cirrhosis, ultimately leading to liver failure or cancer. In addition, as many as 10% of newborns with the PiZZ genotype develop cholestatic hepatitis. A quarter of impacted neonates suffer acute liver failure and require an emergency transplant.

Figure 14. PiZZ genotype that results in fibrotic liver and decreased lung function

Data from the UK Biobank, or UKBB, as well as published literature, have allowed researchers to determine the threshold levels of circulating AAT that are directly linked to the PiMZ and PiZZ genotypes. In Figure 15 below, the range of AAT levels associated with normal individuals (PiMM) is compared with the range of AAT levels observed in mutated PiMZ and PiZZ patients.

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Figure 15. Median Levels of AAT and link to outcomes in liver and lung

In Figure 16 below, the Odds Ratios, or OR, associated with developing COPD and cirrhosis of the liver are compared across the two genotypes, with key findings summarized below:

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COPD: PiMZ individuals have minimal increased risk of developing COPD relative to healthy PiMM individuals, while PiZZ individuals are at very high risk with an OR of 8.8

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Cirrhosis of the liver: PiMZ individuals have mildly elevated risk of developing cirrhosis of the liver with an OR of 1.5, while PiZZ individuals have significantly elevated risk with an OR of 7.8

Figure 16. Risk of developing COPD and cirrhosis for different genotypes associated with AATD. Adapted from “The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes.” By Nakanishi T, Forgetta V, Handa T, et al. Eur Respir J 2020; 56:2001441

Based on these findings, we believe that achieving normal AAT protein levels between the ranges of the PiMZ and PiMM genotypes has the potential to alleviate the increased risk of COPD and cirrhosis of the liver, and to meaningfully improve clinical outcomes for PiZZ patients. We further believe that by achieving greater than 90% editing efficiency across cells, we can reach these target levels and modify disease progression.

Prevalence of AATD and limitations of currently approved therapy

AATD is one of the three most common, potentially lethal, rare diseases affecting those of European descent. Worldwide, there are an estimated 5.5 million individuals with deficiency allele combinations. Studies suggest that clinical unawareness of AATD results in a significant number of patients that go undiagnosed or misdiagnosed. There are currently an estimated 100,000 patients in the United States with a PiZZ genotype, and 125,000 patients across the United Kingdom, Germany, France, Spain and Italy. Studies of PiMZ prevalence suggest as many as one in 49 individuals in the United States and one in 58 individuals across Europe.

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The only FDA-approved treatment for patients with lung manifestations of AATD (co-indicated with COPD) is augmentation therapy, which utilizes AAT protein purified from pooled human plasma. The purified AAT is administered weekly by intravenous infusion with the goal of maintaining a serum level of AAT above the 11 µM threshold. Even when the serum level can be maintained at or above this threshold, augmentation therapy has not clearly demonstrated its ability to adequately address lung damage nor liver inflammation caused by AAT aggregation. Augmentation therapy is approved in only a few countries due to its limited efficacy. Lung and/or liver transplantation are the only other available treatment options, outside of standard management of the disease manifestations of AATD.

Despite being minimally effective and not fully addressing the needs of many AATD patients, augmentation therapy currently represents approximately $1.4 billion in annual sales worldwide.

Alternative Treatments in Development for AATD

There are a number of therapies in development to treat AATD. Certain DNA editing approaches attempt to add a normal copy of SERPINA1 gene or permanently correct the mutation within the SERPINA1 gene. DNA editing as a treatment would likely be evaluated on a risk-benefit trade-off relative to the severity of the manifestation of AATD, limiting the applicability of DNA editing approaches to the broader AATD patient population.

Additional approaches outside of DNA editing are also in development. There are approaches which attempt to use siRNA to knock-out the production of dysfunctional AAT protein, which only alleviates the liver manifestation of AATD, while potentially worsening the lung manifestation. Replacing plasma derived protein for augmentation therapy with a fusion protein is another approach in development. This fusion protein aims to introduce AAT on an antibody scaffold to improve upon the existing dosing paradigm and activity levels achieved in augmentation therapy. Fusion proteins do not resolve the liver manifestation and are unable to physiologically regulate AAT levels.

We believe many of these approaches have inherent limitations including the following:

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Inability to adequately address the spectrum of clinical pathologies associated with AATD

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Inability to achieve adequate expression of normal AAT to bring patients back to PiMM genotype

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Considerable safety and tolerability concerns

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Potential issues around manufacturability and scalability for the AATD population

Our Approach to Overcome the Limitations: Transiently Correcting the SERPINA1 Variant on RNA

We are developing a GalNAc-conjugated RNA editing oligonucleotide to treat patients with AATD. Our lead candidates are designed to leverage endogenous ADAR to make a single base edit in SERPINA1 mRNA, correcting the amino acid codon created by the pathogenic E342K SNV which stems from a single G-to-A mutation. Specifically, our oligonucleotide edits the adenosine (A) to an inosine (I), thereby correcting the faulty amino acid and leading to the production of normal AAT protein.

Our goal is to bring individuals with the Z mutation to a phenotype where over 90% of RNA has been corrected to produce normal AAT protein. This would result in levels of AAT consistent with individuals in the upper half of the PiMZ genotype and the fully healthy PiMM genotype. Through our GalNAc-conjugated approach in human transgenic mouse models, we have shown our ability to drive the required change in RNA sequence with high efficiency, leading to secretion of AAT at target levels.

We believe our approach has multiple potential advantages, in addition to those conferred by the RNA editing modality:

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Provides a tailored disease modifying treatment option to address the heterogeneity of the AATD population: We leverage a transient base editing approach leading to restoration of normal AAT. The transient nature of our approach allows us to address a broader AATD patient population, inclusive of PiMZ and PiZZ genotypes. As transient editing is not permanent in nature, we have the ability to adjust dosing and even cease dosing as needed, providing a meaningful benefit in potential safety profile.

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Provides a disease modifying therapy for both lung and liver manifestations: By transiently editing over 90% of RNA transcripts in hepatocytes, we believe we can restore levels of normal AAT protein consistent with a PiMZ to PiMM phenotype. These levels of normal AAT have the potential to prevent further lung damage and reduce the risk of dysfunctional AAT aggregating in the liver.

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Potential to enable physiologic regulation of AAT using endogenous ADAR: Augmentation therapy and other treatments targeting static thresholds for AAT expression do not address the underlying mechanism of AAT

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regulation, which is endogenously regulated by inflammation and can sometimes lead to as much as 90uM of AAT in humans. During an inflammatory response, there is a simultaneous increase in ADAR levels. Our ADAR-based therapy has the potential to restore natural physiologic regulation by increasing the prevalence of editing during periods of greater AAT production.

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Liver-targeted delivery using precedented GalNAc-conjugated technology: GalNAc conjugates provide highly specific delivery to hepatocytes with proven clinical track record. This delivery approach enables convenient subcutaneous administration, improving patient experience compared to intravenous infusion.

Next-Generation GalNAc-Conjugated AATD Program

We are developing a next-generation GalNAc-conjugated RNA editing oligonucleotide for AATD with development candidate nomination anticipated in the second quarter of 2026. Our preclinical studies have demonstrated compelling proof of concept for the GalNAc-conjugated approach.

We have generated highly compelling preclinical data that forms the basis for our proof of mechanism. We have affirmed that multiple disease modifying early generation lead candidates have demonstrated proof-of-concept in in vivo studies leading to the anticipated selection of our next-generation GalNAc-conjugated development candidate for AATD. To assess and differentiate our GalNAc-conjugated lead candidates in mouse models used widely in the AATD field, we used the NSG-PiZ and C57BL/6-PiZ transgenic mouse models. These mice express the human SERPINA1 gene with the Z-mutation. Subcutaneous administration of GalNAc-conjugated RNA editing oligonucleotides resulted in 90% editing of SERPINA1 transcript in the NSG-PiZ mouse model following dosing at 10 mg/kg every other day for a total of three doses, with results observed one week (seven days) post first dose. This demonstrates the high efficiency and consistency of the GalNAc-conjugated approach across two independent AATD mouse models.

Figure 17. AATD GalNAC RNA editing in C57BL/6-PiZ and NSG-PiZ mouse models

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Termination of REWRITE Clinical Program

In November 2025, we announced that our first-generation AATD program, KRRO-110, our proprietary RNA editing oligonucleotide with an LNP delivery system, did not reach projected levels of functional protein following a single administration. We pivoted to GalNAc delivery for AATD and have terminated our REWRITE clinical program investigating KRRO-110 as a treatment for AATD.

AATD GalNAc Program Next Steps

We expect to nominate a development candidate for our AATD GalNAc program in the second quarter of 2026. We are continuing to design and screen additional oligonucleotides to optimize editing efficiency and drug-like properties for GalNAc-conjugated subcutaneous delivery. However, this program is in preclinical development and there is no guarantee that it will be successful.

Our Longevity and Liver Health Program: AMPKγ1 Activation

The longevity space has attracted approximately $8 billion in biotech investment. We've seen combinations of GLP-1 agonists, SGLT2 inhibitors, and PCSK9 inhibitors contributing to meaningful increases in lifespan. Rising U.S. health spending on chronic conditions underscores both the challenge and the opportunity. Top aging experts are pointing to four FDA-approved drugs that hold promise for extending life including GLP-1 agonists. Rather than treating late-stage disease, we are focused on extending organ healthspan and going after three fundamental reasons as to why organs age: metabolic dysfunction, oxidative stress, and inflammation accumulation.

When activated, AMPK inhibits anabolic pathways like lipogenesis and protein synthesis, activates catabolic pathways including fatty acid oxidation and autophagy, and regulates glucose homeostasis by enhancing insulin sensitivity. The γ1 subunit—AMPKγ1—represents the optimal liver therapeutic target because of its hepatocyte enrichment. AMPK activation provides direct metabolic reprogramming—increasing fatty acid oxidation, decreasing lipogenesis, boosting mitochondrial biogenesis, and increasing glucose uptake in an insulin-independent manner, all with minimal central appetite effects. It is hepatocyte-restricted rather than systemically exposed. GLP-1 agonism, by contrast, works primarily through appetite suppression—central satiety signaling, delayed gastric emptying, increased insulin secretion, and decreased glucagon release. These are complementary mechanisms.

We are developing proprietary oligonucleotides designed to activate AMPKγ1, with the goal of restoring metabolic status and improving liver function. We enable the activation by creating a single amino acid change on the native AMPK protein, specifically in the liver, such that it stays in a hyper-phosphorylated state, creating an allosteric modulator. This program utilizes GalNAc-conjugated delivery for subcutaneous administration targeting the liver, thus avoiding activating AMPK in the rest of the body. Prior programs have not moved forward due to the systemic exposure, and the lack of specificity of the AMPK isoform.

We are in early preclinical development for this program. We have demonstrated oligonucleotide-mediated editing in mouse hepatocytes with 60% at 100 nM and 40% at 10 nM editing resulting in two-fold increases in phospho-ACC to total ACC

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ratio in vivo in wild type mice, demonstrating in vivo functional downstream signaling. We are promoting allosteric activation of the γ1 subunit to enable sustained activation, what we believe is needed for durable therapeutic benefit.

Figure 18. Hepatic AMPKγ1 activation improved liver function in obese mice

Our GalNAc-conjugated oligonucleotides enable liver-specific targeting. In diet-induced obesity mice, we dosed once daily for five days at 10 mg/kg. We achieved 23.9% editing in liver with ALT dropping from 230 to 122 U/L (back toward the lean mouse range of 60) and AST improving from 208 to 108 (approaching the lean mouse level of 100). Liver function was improved and metabolic signaling restored without affecting food intake. The body weight curves were essentially identical, and food consumption was unchanged, highlighting a direct metabolic reprogramming, not appetite suppression. Our GalNAc-conjugated oligonucleotide is fundamentally different from GLP-1s, which we believe potentially makes it an ideal combination partner.

Next Steps

We are continuing to design and screen additional oligonucleotides to identify proprietary oligonucleotides for further evaluation. Furthermore, we are identifying and characterizing metabolic dysfunction-associated steatohepatitis, or MASH, and liver fibrosis models and patient cell lines, to test the efficacy of de novo AMPK γ1 protein in disease models. We anticipate progressing this program towards achieving a development candidate.

Our Amyotrophic Lateral Sclerosis Program: Disrupting Protein Aggregation

We are developing proprietary oligonucleotides targeting the mRNA for TAR DNA binding protein 43, or TDP-43, a protein associated with the etiology of ALS.

Amyotrophic Lateral Sclerosis

ALS is an adult-onset, progressive, and fatal neurodegenerative disorder that causes muscle weakness, paralysis, and ultimately death. The majority of ALS patients die from respiratory failure within three to five years after symptom appearance, with a small percentage of patients surviving beyond 10 years. Despite being classified as a rare disease by the FDA and the European Medicines Agency, or EMA, ALS is considered one of the more common neurodegenerative diseases worldwide. Prevalence estimates vary, but it is widely accepted that there are approximately 30,000 ALS patients in the United States. There is currently no cure for ALS, and currently approved therapies either only provide symptomatic relief or slow the overall progression of the disease.

Our Differentiated Approach and Results

Our approach is to selectively modulate TDP-43, an RNA/DNA-binding protein, which carries out a variety of important functions in healthy neurons, including initiation of transcription, pre-mRNA splicing and miRNA processing. Hyper-phosphorylated and ubiquitinated TDP-43 deposits form inclusion bodies in the brain and spinal cord of patients with ALS and frontotemporal dementia, or FTD. The majority of ALS and FTD cases are sporadic, and more than 90% and 45% of ALS and FTD patients, respectively, have TDP-43 aggregations in neurons. Less than 10% of ALS cases are familial, and mutations in TARDBP, the gene encoding TDP-43, are responsible for approximately 4% of familial ALS. Given the importance of the role of TDP-43 in maintaining healthy neurons, the generation of a protein variant with the desired non-aggregating property could potentially have therapeutic benefit for the majority of ALS and FTD patients. We believe that by leveraging the ability of RNA

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editing to affect a single base edit in TARDBP, we can lead to the synthesis of a TDP-43 protein variant that does not aggregate, thereby restoring normal function.

Figure 19. Continued splicing of factors downstream of TDP-43

We have created a series of TDP-43 variants that contain single amino acid changes designed to alter post-translational modification by phosphorylation, ubiquitination, acetylation or cleavage with the intent of reducing the ability to aggregate while maintaining function in RNA metabolism. We believe that modulating TDP-43 through the introduction of specific amino acid changes into TDP-43 mRNA sequence is preferable to other approaches that try to address protein aggregates after they form, to non-specifically prevent stress granule formation, or to target a single TDP-43 downstream target. In preclinical studies, our TDP-43 variant demonstrated reduced mis-splicing of critical genes (maintaining STMN2 and POLDIP3 expression) and decreased cytosolic mis-localization of TDP-43 protein in iPSC-derived motor neurons under cell stress conditions. These results support the potential of our approach to reduce pathogenic aggregation of TDP-43 while preserving its normal cellular functions.

Figure 20. Re-localization of the TDP43 protein inside the nucleus

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Next Steps

We are continuing to design and screen additional oligonucleotides to identify proprietary oligonucleotides for further evaluation. Furthermore, we are identifying and characterizing ALS cell lines including genetic-induced models and patient cell lines, to test the efficacy of TDP-43 protein variants in disease models.

Pioneering RNA Editing to Deliver the Future of Medicine

Each of our programs demonstrate the versatility of the ADAR-mediated RNA editing approach. Importantly, we are able to not only address classes of diseases caused by deleterious effects of misfolded or misdirected proteins, but we can also potentially utilize genetics to identify highly prevalent diseases where therapeutic benefit can be generated through alteration of protein function or expression. We will continue to selectively identify and pursue additional targets and indications based on a range of technical, clinical, and commercial factors to build a robust and differentiated pipeline. However, RNA editing is a novel technology that is not yet clinically validated for human therapeutic use. The approaches we take to discover and develop novel therapeutics are unproven and may never lead to marketable products. While limited clinical data for RNA editing therapies has been generated to date, we are not aware of any clinical trials for safety or efficacy having been completed by any third party using RNA editing and nor are we aware of any RNA editing therapeutic product that has been approved in the United States or Europe. It will be many years before we commercialize an approved product, if ever.

Collaborations

We believe the versatility of our OPERA platform has the potential to create transformative genetic medicines for both rare and highly prevalent diseases. To fully realize this potential, we have established and plan to continue to actively seek out innovative collaborations, licenses, and strategic alliances with clinical leaders, academic medical centers of excellence, patient advocacy groups, and pioneering companies. Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.

Novo Nordisk

In September 2024, we entered into a research collaboration and license agreement with Novo Nordisk, pursuant to which we granted Novo Nordisk an exclusive worldwide license under certain intellectual property rights to research, develop, manufacture, commercialize or otherwise exploit certain licensed compounds and licensed products for an initial target in the cardiometabolic field and for a second target (to be nominated by Novo Nordisk within a specified time period as set forth in the agreement). Under the agreement, we are responsible for certain research and development activities with respect to licensed compounds and licensed products directed against the initial target and the second target (if nominated by Novo Nordisk), and we are eligible to receive cost reimbursement from Novo Nordisk for our performance of such research and development activities under the agreement with respect to such target(s). Novo Nordisk may undertake subsequent worldwide development, manufacturing, marketing and commercialization of the licensed products directed against the initial target and the second target (if applicable). In November 2025, the collaboration entered a 12-month pause. For additional information relating to the financial terms of such agreement, see Note 12 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

Manufacturing and Supply Arrangements

We currently have no commercial manufacturing capabilities. For our initial wave of clinical programs, we intend to use qualified third-party CMOs with relevant manufacturing experience in genetic medicines. We plan to partner with suppliers and CMOs to produce or process critical raw materials, bulk compounds, formulated compounds, viral vectors or engineered cells for investigational new drug, or IND, -supporting activities and early-stage clinical trials. At the appropriate time in the product development process, we will determine whether to establish in-house good manufacturing practice capabilities for some core technologies or continue to rely on third parties to manufacture commercial quantities for any products that we may successfully develop.

We also in-license technology for our fit-for-purpose delivery systems, including LNP delivery systems. For example, in March 2023, we entered into a collaboration and license agreement with Genevant, a well established leader in the LNP space, to provide access to clinically validated LNP technology to optimize delivery of our now terminated REWRITE clinical program investigating KRRO-110 as a treatment for AATD. For additional information relating to the financial terms of such agreement, see Note 12 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

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Competition

The pharmaceutical and biotechnology industries, including the gene therapy and gene editing fields, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property. While we believe that our differentiated technology, scientific expertise, and intellectual property position provide us with competitive advantages, we face potential competition from a variety of companies in these fields. There are several companies using synthetic oligonucleotide or base editing technology, including AIRNA, Beam Therapeutics, Prime Medicine, ProQR, Tessera Therapeutics, Verve Therapeutics, Wave Life Sciences, and YolTech Therapeutics. Several additional companies utilize other editing technologies, including Edigene and Shape Therapeutics. In addition, we face competition from companies utilizing gene therapy, oligonucleotides, and DNA editing technologies such as base and prime editing.

Any development candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our development candidates. This may include other types of therapies, such as small molecule, antibody, and/or protein therapies.

In addition, many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials and approved products than we do today. Mergers and acquisitions in the pharmaceutical, biotechnology and gene therapy industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. We also compete with these companies in recruiting, hiring and retaining qualified scientific and management talent, establishing clinical trial sites and patient registration for clinical trials, obtaining manufacturing slots at contract manufacturing organizations, and in acquiring technologies complementary to, or necessary for, our programs. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, particularly if they represent cures, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all of our programs are likely to be their efficacy, safety, convenience, and availability of reimbursement.

Intellectual Property

Overview

We strive to protect the proprietary technology that we believe is important to our business, including seeking and maintaining patent protection in the United States and internationally for our current and future lead candidates and development candidates. We also rely on trademarks, copyrights, trade secrets, confidentiality procedures, employee disclosure, invention assignment agreements, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.

We seek to obtain domestic and international patent protection, and endeavor to promptly file patent applications for new commercially valuable inventions. We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

We plan to continue to expand our intellectual property estate by filing patent applications directed to platform technologies and pipeline programs, including composition of matter, pharmaceutical compositions, methods of treatment, and methods of manufacture. Our success will depend on our ability to obtain and maintain patent and other proprietary protection for commercially important technologies, inventions and know-how related to our business, defend and enforce any patents that we may obtain, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

The patent positions of companies like us are generally uncertain and involve complex legal, scientific and factual questions. In addition, the coverage claimed in a patent may be challenged in courts after issuance. Moreover, many jurisdictions permit third parties to challenge issued patents in administrative proceedings, which may result in further narrowing or even cancellation of patent claims. We cannot guarantee that our pending patent applications, or any patent applications that we may in the future file or license from third parties, will result in the issuance of patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or at all, whether the claims of any patent applications, should they issue, will cover our lead candidates and development candidates, or whether the claims of any issued patents will provide sufficient protection from competitors or otherwise provide any competitive advantage. We cannot predict

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the scope of claims that may be allowed or enforced in our patents. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Consequently, we may not obtain or maintain adequate patent protection for any of our lead candidates and development candidates.

Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months or potentially even longer, and because publication of discoveries in the scientific or patent literature often lags behind actual discoveries and patent application filings, we cannot be certain of the priority of inventions covered by pending patent applications. Accordingly, we may not have been the first to invent the subject matter disclosed in some of our patent applications or the first to file patent applications covering such subject matter, and we may have to participate in derivation proceedings declared by the U.S. Patent and Trademark Office, or USPTO, to determine priority of invention. Further, periodic maintenance fees, renewal fees, annuity fees and various other government fees on patents and/or applications will be due to be paid to the USPTO and various government patent agencies outside of the United States over the lifetime of our patents and patent applications. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Patent Portfolio

We strive to protect our proprietary RNA editing platform, OPERA, and related technologies, and our lead candidates and development candidates, including seeking and maintaining patent protection intended to cover various target-specific editing strategies, the composition of matter of our lead candidate and development candidates, their methods of use, related delivery technologies, and other inventions. The intellectual property that is available to us is critical to our business, and we strive to protect it, including by obtaining, maintaining, defending, and enforcing patent protection in the United States and internationally. As of December 31, 2025, our patent portfolio in total consisted of 42 patent families, with six U.S. patents and five patents in foreign jurisdictions (e.g., Australia, Japan and Taiwan), including pending U.S. provisional patent applications, pending Patent Cooperation Treaty, or PCT, applications, and various pending non-provisional applications world-wide (e.g., United States, Australia, Canada, China, Europe, South Korea, and Japan).

Our patent portfolio relates to our RNA editing platform OPERA, as well as numerous disease programs listed below. Patents and pending applications in the portfolio are directed to various oligonucleotide formats, nucleotide compositions, oligonucleotide chemistries, modifications, specific linkage chemistries, oligonucleotides having a specific structures, methods of deaminating an adenosine using such oligonucleotides, methods of oligonucleotide delivery, and methods of treating disease by administering such oligonucleotides.

We have three patent families with pending applications directed to specific oligonucleotide structures useful in ADAR editing oligonucleotides. Each of these three families have pending applications in Australia, Canada, China, Europe, Japan, South Korea and the United States. Absent any term extensions available via patent term extension or patent term adjustment, patents in these families will expire in 2040. These patent families include three granted U.S. patents: U.S. Patent No. 11,479,575 directed to specific oligonucleotide structures and expires in 2040; U.S. Patent No. 11,453,878 directed to methods of deamination of an adenosine in an mRNA using oligonucleotide with specific structures and also expires in 2040; and U.S. Patent No. 12,031,131 directed to specific oligonucleotide structures and expires in 2040.

In addition to the patent families described above, we also have other patent families directed to additional target-specific editing strategies, oligonucleotide compositions and their methods of use, related delivery technologies, and other inventions related to early-stage research and development efforts not reflected in our pipeline. Patents issued from or issuing from applications in these families will expire between 2041 and 2046, absent any available additional term for patent term extension or patent term adjustment.

In addition to platform and non-target specific patent families, we also have patent families pending that are directed to specific target programs.

Our patent portfolio that relates to our hyperammonia program includes two patent families directed to specific target sites and oligonucleotides that edit the target. The first patent family consists of PCT patent and issued patents in this family would expire in 2045, absent any available additional term for patent term extension or patent term adjustment. The second patent family is directed to oligonucleotides that direct editing of the target. This second patent family consists of two provisional patent applications, and if re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in 2046.

Our patent portfolio that relates to our AATD program includes one patent family with a pending U.S. provisional patent application. This patent family has been filed as a provisional patent application and if refiled as PCT or non-provisional applications, and issued, patents in this family would expire in 2046, absent any available additional term for patent term extension or patent term adjustment.

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Our patent portfolio that relates to our longevity and liver health program includes two patent families. The first patent family is directed to specific target sites. This first patent family consists of one PCT patent application, and issued patents in this family would expire in 2046, absent any available additional term for patent term extension or patent term adjustment. The second patent family is directed to oligonucleotides that direct editing of AMPKγ1. This second patent family consists of one provisional patent application, and if re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in 2046.

Our patent portfolio that relates to our ALS program includes two patent families directed to specific target sites and oligonucleotides that direct edit TDP-43. The first patent family consists of one PCT issued patents in this family would expire in 2045, absent any available additional term for patent term extension or patent term adjustment. The second patent family is directed to oligonucleotides that direct editing of TDP-43. This second patent family consists of one provisional patent application, and if re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in 2046.

Patent Term

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, including the United States, the base term is 20 years from the filing date of the earliest-filed non-provisional patent application from which the patent claims priority. The term of a U.S. patent can be lengthened by patent term adjustment, which compensates the owner of the patent for administrative delays at the USPTO. In some cases, the term of a U.S. patent is shortened by terminal disclaimer that reduces its term to that of an earlier-expiring patent. The term of a U.S. patent may be eligible for patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act, to account for at least some of the time the drug is under development and regulatory review after the patent is granted. With regard to a drug for which FDA approval is the first permitted marketing of the active ingredient, the Hatch-Waxman Act allows for extension of the term of one U.S. patent that complies with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other regulatory requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale.

We may become subject to administrative or judicial sanctions or other legal consequences. These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending FDA applications, issuance of clinical holds for ongoing studies, suspension or revocation of approved at least one claim covering the composition of matter of such an FDA-approved drug, an FDA-approved method of treatment using the drug and/or a method of manufacturing the FDA-approved drug. The extended patent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug, and a patent cannot be extended more than once or for more than a single product. During the period of extension, if granted, the scope of exclusivity is limited to the approved product for approved uses. Some foreign jurisdictions, including Europe and Japan, have analogous patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

In the future, if and when our development candidates receive FDA approval, we expect to apply, if appropriate, for patent term extension on patents directed to those development candidates, their methods of use and/or methods of manufacture. However, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Reservation of Rights by the U.S. Government

Our in-licensed patent rights may be subject to a reservation of rights by one or more third parties, including the U.S. government. Pursuant to the Bayh-Dole Act of 1980, the U.S. government has certain rights in inventions developed with government funding. These U.S. government rights include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. When new technologies are developed with government funding, in order to secure ownership of patent rights related to the technologies, the recipient of such funding is required to comply with certain government regulations, including timely disclosing the inventions claimed in such patent rights to the U.S. government and timely electing title to such inventions. A failure to meet these obligations may lead to a loss of rights or the unenforceability of relevant patents or patent applications. In addition, the U.S. government has the right, under certain limited circumstances, to require the licensor to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (1) adequate steps have not been taken to commercialize the invention; (2) government action is necessary to meet public health or safety needs; or (3) government action is necessary to meet requirements for public use under federal regulations (also referred to

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as “march-in rights”). While the U.S. government has not successfully exercised its march-in rights to date, recent developments in regulatory pharmaceutical product pricing schemes indicate that these march-in rights could be exercised to affect pricing.

If the U.S. government exercised its march-in rights in our future intellectual property rights that are generated through the use of U.S. government funding or grants, we could be forced to license or sublicense intellectual property that we license on terms unfavorable to us, and there can be no assurance that we would receive compensation from the U.S. government for the exercise of such rights. If the U.S. government decides to exercise these march-in rights, it is not required to engage us as its contractor in connection with doing so. The U.S. government’s rights may also permit it to disclose the funded inventions and technology, which may include our confidential information, to third parties and to exercise march-in rights to use or allow third parties to use the technology that was developed using U.S. government funding. Intellectual property generated under a government funded program is also subject to certain reporting requirements, compliance with which may require us to expend substantial resources. In addition, the U.S. government requires that any products embodying any of these inventions or produced through the use of any of these inventions be manufactured substantially in the United States. This preference for U.S. industry may be waived by the federal agency that provided the funding if the owner or assignee of the intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be likely to manufacture substantially in the United States or that under the circumstances domestic manufacture is not commercially feasible. This preference for U.S. industry may limit our ability to contract with non-U.S. product manufacturers for products covered by such intellectual property. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Trade Secrets

In addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position. We typically rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection. We protect trade secrets and know-how by establishing confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and collaborators. These agreements provide that all confidential information developed or made known during the course of an individual or entities’ relationship with us must be kept confidential during and after the relationship. These agreements also provide that all inventions resulting from work performed for us or relating to our business and conceived or completed during the period of employment or assignment, as applicable, shall be our exclusive property. In addition, we take other appropriate precautions, such as physical and technological security measures, to guard against misappropriation of our proprietary information by third parties.

Although we take steps to protect our proprietary information and trade secrets, including through contractual means with our employees and consultants, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Governmental Regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, clinical trial, testing, manufacture, quality control, import, export, safety, efficacy, labeling, packaging, storage, distribution, recordkeeping, approval, distribution, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs. We, along with our vendors, contract research organizations, or CROs, clinical investigators and CMOs will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our development candidates. The process of obtaining regulatory approvals of drugs and ensuring subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

Overview of U.S. Drugs Development Process

In the United States, the FDA regulates drug products under the Federal Food, Drug and Cosmetic Act, or FD&C Act, and its implementing regulations. Drugs are also subject to other federal, state and local statutes and regulations. If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other legal requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or

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judicial sanctions or other legal consequences. These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending applications, warning or untitled letters, product withdrawals or recalls, product seizures, relabeling or repackaging, total or partial suspensions of manufacturing or distribution, injunctions, fines, civil penalties or criminal prosecution.

Our development candidates must be approved for therapeutic indications by the FDA before they may be marketed in the United States. For drug development candidates regulated under the FD&C Act, FDA must approve a New Drug Application, or an NDA. The process generally involves the following:

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completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with GLP requirements and applicable requirements for the humane use of laboratory animals or other applicable regulations;

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completion of the manufacture, under current good manufacturing practice, or cGMP, conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

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submission to the FDA of an IND which must become effective before clinical trials may begin;

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payment of user fees for FDA review of the NDA;

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approval by an institutional review board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated;

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performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

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preparation and submission to the FDA of an NDA;

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a determination by the FDA within 60 days of its receipt of an NDA to file the application for review;

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satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug product’s identity, strength, quality and purity;

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satisfactory completion of potential FDA audit of the preclinical study clinical trial sites that generated the data in support of the NDA; and

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FDA review and approval of the NDA, including, where applicable, consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States.

Preclinical Studies and Clinical Trials for Drugs

Before testing any drug in humans, the development candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluations of product chemistry, formulation and stability, as well as in vitro and animal studies to assess safety and in some cases to establish the rationale for therapeutic use. The conduct of preclinical studies is subject to federal and state regulation and requirements, including GLP requirements for safety/toxicology studies. The results of the preclinical studies, together with manufacturing information and analytical data, must be submitted to the FDA as part of an IND.

An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before clinical trials may begin. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials. The IND also includes the results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. Some long-term preclinical testing may continue after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions about the conduct of the clinical trial, including concerns that human research subjects will be exposed to unreasonable health risks, and imposes a full or partial clinical hold. FDA must notify the sponsor of the grounds for the hold and any identified deficiencies must be resolved before the clinical trial can begin. Submission of an IND may result in the FDA not allowing clinical trials to commence or not allowing clinical trials to commence on the terms originally specified in the IND. A clinical hold can also be imposed once a trial has already begun, thereby halting the trial until the deficiencies articulated by FDA are corrected.

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The clinical stage of development involves the administration of the development candidate to healthy volunteers or patients under the supervision of qualified investigators, who generally are physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirements that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters and criteria to be used in monitoring safety and evaluating effectiveness. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable compared to the anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. The FDA, the IRB, or the sponsor may suspend or discontinue a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trials to public registries. Information about clinical trials, including results for clinical trials other than Phase 1 investigations, must be submitted within specific timeframes for publication on www.ClinicalTrials.gov, a clinical trials database maintained by the National Institutes of Health.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether or not a clinical trial may move forward at designated check points based on access that only the group maintains to available data from the trial and may recommend halting the clinical trial if it determines that the participants or patients are being exposed to an unacceptable health risk or other grounds, such as no demonstration of efficacy. Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.

A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, FDA will nevertheless accept the results of the study in support of an NDA if the study was well-designed and well-conducted in accordance with GCP requirements, including that the clinical trial was performed by a qualified investigator(s); the data are applicable to the U.S. population and U.S. medical practice; and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials to evaluate therapeutic indications to support NDAs for marketing approval are typically conducted in three sequential phases, which may overlap.

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Phase 1 – Phase 1 clinical trials involve initial introduction of the investigational product in a limited population of healthy human volunteers or patients with the target disease or condition. These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, excretion the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness.

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Phase 2 – Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the drug’s potential efficacy, to determine the optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

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Phase 3 – Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and physician labeling. Generally, two adequate and well-controlled Phase 3 trials are required by the FDA for approval of an NDA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials or post-marketing studies, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of NDA approval.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA. Written IND safety reports must be submitted to the FDA and the investigators fifteen days after the trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human volunteers and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information. During the development of a new drug product, sponsors have the opportunity to meet with the FDA at certain points, including prior to submission of an IND, at the end of Phase 2 and

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before submission of an NDA. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date and for the FDA to provide advice on the next phase of development.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the development candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the development candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the development candidate does not undergo unacceptable deterioration over its shelf life.

U.S. Review and Approval Process for Drugs

Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. An NDA is a request for approval to market a new drug for one or more specified indications and must contain proof of the drug’s safety and efficacy for the requested indications. The marketing application is required to include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings. Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational drug, to the satisfaction of the FDA. FDA must approve an NDA before a drug may be marketed in the United States.

The FDA reviews all submitted NDAs to ensure they are sufficiently complete to permit substantive review before it accepts them for filing and may request additional information rather than accepting the NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt, and such decision could include a refusal to file by the FDA. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the NDA. The FDA reviews an NDA to determine, among other things, whether the product is safe and effective for the indications sought and whether the facility in which it is manufactured, processed, packaged or held meets standards, including cGMP requirements, designed to assure and preserve the product’s continued identity, strength, quality and purity. Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of a new molecular entity NDA and respond to the applicant, and six months from the filing date of a new molecular entity NDA for priority review. The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

Further, under PDUFA, as amended, each NDA must be accompanied by a substantial user fee. The FDA adjusts the PDUFA user fees on an annual basis. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA also may require submission of a risk evaluation and mitigation strategy, or REMS, if it believes that a REMS is necessary to ensure that the benefits of the drug outweigh its risks. A REMS can include use of risk evaluation and mitigation strategies like medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, special monitoring or other risk-minimization tools.

The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, which reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCP and other requirements and the integrity of the clinical data submitted to the FDA.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a Complete Response Letter. A Complete Response Letter indicates that the review cycle of the application is complete and

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the application is not ready for approval. A Complete Response Letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response Letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling. In issuing the Complete Response Letter, the FDA may require additional clinical or preclinical testing or recommend other actions, such as requests for additional information or clarification, that the applicant might take in order for the FDA to reconsider the application. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

Even if the FDA approves a product, depending on the specific risk(s) to be addressed it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan drug designation to a drug intended to treat a rare disease or condition, which is a disease or condition with either a patient population of fewer than 200,000 individuals in the United States, or a patient population of 200,000 or more individuals in the United States when there is no reasonable expectation that the cost of developing and making the product available in the United States for the disease or condition will be recovered from sales of the product. Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process, though companies developing orphan products are eligible for certain incentives, including tax credits for qualified clinical testing and user-fee waivers.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to a seven-year period of marketing exclusivity during which the FDA may not approve any other applications to market the same therapeutic agent for the same approved use or indication, except in limited circumstances, such as a subsequent product’s showing of clinical superiority over the product with orphan exclusivity or where the original applicant cannot produce sufficient quantities of product. Competitors, however, may receive approval of different therapeutic agents for the indication for which the orphan product has exclusivity or obtain approval for the same therapeutic agent for a different indication than that for which the orphan product has exclusivity. Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same approved use or indication before we do, unless we are able to demonstrate that our product is clinically superior. If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity. Further, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

The FDA may further reevaluate its regulations and policies under the Orphan Drug Act. It is unclear as to how, if at all, the FDA may change the orphan drug regulations and policies in the future.

Expedited Development and Review Programs for Drugs

The FDA maintains several programs intended to facilitate and expedite development and review of new drugs to address unmet medical needs in the treatment of serious or life-threatening diseases or conditions. These programs include Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval, and the purpose of these programs is to either expedite the development or review of important new drugs to get them to patients more quickly than standard FDA review timelines typically permit.

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A new drug is eligible for Fast Track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for such disease or condition. Fast track designation applies to the combination of the development candidate and the specific indication for which it is being studied. Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed. Rolling review means that the FDA may review portions of the marketing application before the sponsor submits the complete application.

In addition, a new drug may be eligible for Breakthrough Therapy designation if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug, alone or in combination with one or more other drugs, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Breakthrough Therapy designation provides all the features of Fast Track designation in addition to intensive guidance on an efficient product development program beginning as early as Phase 1, and FDA organizational commitment to expedited development, including involvement of senior managers and experienced review staff in a cross-disciplinary review, where appropriate.

Any product submitted to the FDA for approval, including a product with Fast Track or Breakthrough Therapy designation, may also be eligible for additional FDA programs intended to expedite the review and approval process, including Priority Review designation and Accelerated Approval. A product is eligible for Priority Review, once an NDA is submitted, if the product that is the subject of the marketing application has the potential to provide a significant improvement in safety or effectiveness in the treatment, diagnosis or prevention of a serious disease or condition. Under priority review, the FDA’s goal date to take action on the marketing application is six months compared to ten months for a standard review.

Products are eligible for Accelerated Approval if they can be shown to have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or an effect on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, which is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Accelerated Approval is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, adequate and well-controlled additional post-approval confirmatory studies to verify and describe the product’s clinical benefit, and under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the FDA may require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Further, under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a product or an indication approved under Accelerated Approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product. In addition, for products being considered for Accelerated Approval, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination or publication within 120 days of marketing approval be submitted to the agency for review during the pre-approval review period. After the 120-day period has passed, all advertising and promotional materials must be submitted at least 30 days prior to the intended time of initial dissemination or publication.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened. Furthermore, Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval, though they may expedite the development or review process.

U.S. Post-Approval Requirements for Drugs

Drugs manufactured or distributed pursuant to FDA approvals are subject to continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, reporting of adverse experiences with the product, complying with promotion and advertising requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label use”) and limitations on industry-sponsored scientific and educational activities.

Although physicians may prescribe approved products for off-label uses, manufacturers may not market or promote such uses. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, including not only by company employees but also by agents of the company or those speaking on the company’s behalf, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including investigation by federal and state authorities. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Promotional materials for approved drugs must be submitted to the FDA in conjunction with their first use or first publication. Further, if there are any modifications to the drug,

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including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials.

The FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the FDA may require post-market testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization. In addition, manufacturers and their subcontractors involved in the manufacture and distribution of approved drugs and those supplying products, ingredients and components of them, are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMPs, which impose certain procedural and documentation requirements on sponsors and their CMOs. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that a sponsor may use. Additionally, manufacturers and other parties involved in the drug supply chain for prescription drugs must also comply with product tracking and tracing requirements and for notifying FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States. Accordingly, manufacturers must continue to expend time money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. Failure to comply with statutory and regulatory requirements may subject a manufacturer to possible legal or regulatory action, such as warning letters, suspension of manufacturing, product seizures, injunctions, civil penalties or criminal prosecution. There is also a continuing, annual program user fee for any marketed product.

The FDA may withdraw approval of a product if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, requirements for post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS. Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product;

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fines, warning letters or holds on post-approval clinical trials;

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refusal of the FDA to approve applications or supplements to approved applications, or suspension or revocation of product approvals;

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product seizure or detention, or refusal to permit the import or export of products;

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injunctions or the imposition of civil or criminal penalties;

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consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; and

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mandated modification of promotional materials and labeling and issuance of corrective information.

U.S. Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration and specifics of FDA approval of our future development candidates, some of our United States patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit restoration of the patent term of up to five years as compensation for patent term lost during the FDA regulatory review process. Patent term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date and only those claims covering such approved drug product, a method for using it or a method for manufacturing it may be extended. The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term

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extension or restoration. In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond a patent’s current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

Marketing exclusivity provisions under the FD&C Act also can delay the submission or the approval of certain drug product applications. The FD&C Act provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an Abbreviated New Drug Application, or ANDA, or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement. The FD&C Act also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Privacy and Cybersecurity

Our operations entail the collection, use, disclosure, transfer, and processing of sensitive and personal information. These operations subject us to privacy and data security laws and regulations in the United States, Europe and internationally. Our operations extend to commercial partnerships and third-party processors, each of which may be governed by their distinct privacy regulations and data security laws. These laws are constantly evolving and subject to varying interpretations, requiring us to periodically update our policies and measures to maintain compliance.

With respect to Europe, we are subject to the European data protection laws where we collect and use personal information relating to Europe in certain circumstances, including to conduct and enroll subjects in clinical trials in the United Kingdom, or the UK, European Union, or the EU, or the European Economic Area, or the EEA. This includes the EU General Data Protection Regulation, or EU GDPR, the UK General Data Protection Regulation, or UK GDPR, as well as applicable data protection laws in effect in the Member States of the EEA and in the UK (including the UK Data Protection Act 2018) that govern the processing of personal information (known as “personal data” under the GDPR) in connection with the offering goods or services to individuals in the EEA and UK; monitoring the behavior of individuals in the EEA and UK; or the activities of an establishment in the EEA and UK. The UK’s data protection regime is independent from but aligned to the EU’s data protection regime. In this Annual Report on Form 10-K, “GDPR” refers to both the EU GDPR and the UK GDPR, unless specified otherwise. The GDPR is wide-ranging in scope and imposes numerous obligations on companies that process personal information, including (i) stringent requirements on the processing of health and other sensitive data, (ii) providing information to individuals regarding data processing activities; (iii) ensuring a legal basis or condition applies to the processing of personal data and, where applicable, obtaining consent from individuals to whom the data processing relates; (iv) responding to data subject requests; (v) imposing requirements to notify the competent national data protection authorities and data subjects of personal data breaches; (vi) implementing safeguards in connection with the security and confidentiality of the personal data; (vii) accountability requirements; and (viii) taking certain measures when engaging third-party processors. The GDPR’s definition of personal data includes coded data, and it requires changes to informed consent practices and detailed notices for clinical trial subjects and investigators. The GDPR also imposes strict rules on the transfer of personal data to countries outside of the EEA and the UK that do not ensure an adequate level of protection, including the United States in certain circumstances, unless derogation exists or a valid GDPR transfer mechanism (for example, the European Commission approved Standard Contractual Clauses, or the SCCs, and the UK International Data Transfer Agreement or Addendum, or the UK IDTA, have been put in place. Where relying on the SCCs or the UK IDTA for data transfers, transfer impact assessments are required to assess whether the recipient is subject to local laws which allow public authority access to personal data. Failure to implement valid mechanisms for personal data transfers from Europe may result in increased exposure to regulatory actions, substantial fines and injunctions against processing personal data from Europe. Inability to export personal data may also: (i) restrict our activities outside Europe; (ii) limit the ability to collaborate with partners as well as other service providers, contractors and other companies outside of Europe; and/or (iii) require us to increase our processing capabilities within Europe at significant expense or otherwise cause us to change the geographical location or segregation of our relevant systems and operations – any or all of which could adversely affect our operations or financial results.

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The GDPR provides that EU member states or the UK may make their own further laws and regulations limiting the processing of personal data, including genetic, biometric, or health data. In addition, following the UK’s exit from the EU, or Brexit, there is increasing scope for divergence in application, interpretation and enforcement of the data protection laws between these territories. For example, the UK has recently introduced a new Data (Use and Access) Bill. This development could reshape the UK’s data protection landscape, distancing it from the EU’s data protection regime and threaten the UK adequacy decision from the EU Commission allowing the free flow of personal data from the UK to the EEA, which may lead to additional compliance costs and could increase our overall risk. This lack of clarity on future UK laws and regulations and their interaction with those of the EU could add legal risk, uncertainty, complexity, and cost; and any resulting divergence in laws could increase our risk profile and necessitate further compliance measures.

Failure to comply with the GDPR can result in significant practical, legal, and financial repercussions, including the destruction of improperly gathered or used personal data, substantial fines of up to €20 million (£17.5 million for the UK) or 4% of the company’s global annual turnover, mandatory audits, orders to cease or modify data use, and a private right of action enabling data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

In the United States, privacy and security of personal information are regulated by various federal and state laws, such as health information privacy laws, comprehensive state privacy laws, security breach notification laws, and consumer protection laws. At the state level, numerous states now have comprehensive privacy laws in effect, adding complexity, variation in requirements, restrictions and potential legal risk requiring additional investment of resources in compliance programs. These laws impose certain obligations on covered businesses, including obligations to provide specific disclosures in privacy notices and affording individuals certain rights concerning their personal data. While existing state comprehensive privacy laws exempt some data processed in the context of clinical trials, these developments may further complicate compliance efforts, and increase legal risk and compliance costs for us and the third parties upon whom we rely.

Federal and state legislators and regulators in the United States are also imposing new and heightened protections for health and other sensitive information that could impact our business. For example, the Federal Trade Commission, or the FTC, has imposed stringent requirements on the collection and disclosure of sensitive categories of personal information, including health information, and has expanded the application of its Health Breach Notification Rule. Through executive and legislative action, the federal government has also taken steps to restrict data transactions involving certain sensitive data categories – including health data, genetic data, and biospecimens – with persons affiliated with China, Russia, and other countries of concern. Additionally, a small number of states have passed or are considering laws governing the privacy of consumer health data. Washington’s My Health My Data Act, which went into effect in March 2024, requires regulated entities to obtain consent to collect health information, grants consumers certain rights, including to request deletion, and provides for robust enforcement mechanisms, including enforcement by the state attorney-general and by litigants through a private right of action for consumer claims. These current and future data privacy laws and regulations may require us to modify our data collection or processing practices and policies, incur substantial costs and expenses in an effort to comply and increase our potential exposure to regulatory enforcement, reputational damage, and/or litigation.

Further, regulators and legislators in the United States are increasingly scrutinizing and restricting certain personal data transfers and transactions involving foreign countries. For example, the Department of Justice’s January 8, 2025, rule on “Preventing Access to U.S. Sensitive Personal Data and Government-Related Data by Countries of Concern or Covered Persons,” prohibits data brokerage transactions involving certain sensitive personal data categories, including health data, genetic data, and biospecimens, to countries of concern, including China. The regulations also restrict certain investment agreements, employment agreements and vendor agreements involving such data and countries of concern, absent specified cybersecurity controls. Actual or alleged violations of these regulations may be punishable by criminal and/or civil sanctions, and may result in exclusion from participation in federal and state programs.

There is a further risk that we may not be able to adequately protect our information systems from cyberattacks. Such security breaches, incidents and compromises could result in the disclosure of confidential, protected, or personal information, damage our reputation, and expose us to significant financial and legal exposure, including potential civil fines and penalties, litigation, and regulatory investigations or enforcement actions under laws such as HIPAA and the GDPR. Further, all 50 states in the United States have laws including obligations to provide notification of unauthorized acquisition of personal information to affected individuals, state officers and others. Some laws may also impose physical and electronic security requirements regarding the safeguarding of personal information. In order to comply with privacy and information security laws, we have confidentiality and information security standards and procedures in place for our business activities.

Compliance with these multifaceted privacy and data security laws can be time-consuming, and failure to comply with any of these regulations could lead to significant fines and penalties (potentially including criminal prosecution), adversely affecting our reputation, business, financial condition, and operational results. Changes in statutes, regulations, or interpretations of existing

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regulations could impose additional requirements on our operations, such as modifications to data processing arrangements, changes to privacy policies, recall or discontinuation of certain data processing methods, or additional recordkeeping requirements. These changes could adversely affect the operation of our business.

In addition to the risks outlined above, the legal or regulatory actions may also divert our management from their primary operations. Prohibitions, restrictions, or allegations of violations of these laws could materially and adversely affect our business. Hence, ensuring consistent compliance with privacy and data security laws and regulations remains a critical operational imperative for us.

Other Regulatory Matters

Manufacturing, labeling, packaging, distribution, sales, promotion and other activities of development candidates following product approval, where applicable, or commercialization are also potentially subject to federal and state consumer protection and unfair competition laws, among other requirements to which we may be subject. Additionally, the activities associated with the commercialization of development candidates are subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

The distribution of pharmaceutical drugs is subject to additional requirements and regulations, including extensive recordkeeping, licensing, storage and security requirements intended to prevent the unauthorized sale of such pharmaceutical products.

The failure to comply with any of these laws or regulatory requirements may subject firms to legal or regulatory action. Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines or other penalties, injunctions, exclusion from federal healthcare programs, requests for recall, seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, relabeling or repackaging, or refusal to allow a firm to enter into supply contracts, including government contracts. Any claim or action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. Prohibitions or restrictions on marketing, sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

Changes in statutes, regulations, or the interpretation of existing regulations could impact our business in the future by requiring, for example: (i) changes to our manufacturing arrangements; (ii) additions or modifications to product labeling or packaging; (iii) the recall or discontinuation of our products; or (iv) additional recordkeeping requirements. If any such changes were to be imposed, they could adversely affect the operation of our business.

Regulation Outside of the United States

In addition to regulations in the United States, we are subject to a variety of regulations in other jurisdictions governing clinical studies, commercial sales, and distribution of our products. Most countries outside of the United States require that clinical trial applications be submitted to and approved by the local regulatory authority for each clinical study. Whether or not we obtain FDA approval for a product, we must obtain approval of a product by the comparable regulatory authorities of countries outside the United States before we can commence marketing of the product in those countries. The approval process and requirements vary from country to country, so the number and type of nonclinical, clinical, and manufacturing studies needed may differ, and the time may be longer or shorter than that required for FDA approval.

Regulatory Framework in the EU and United Kingdom

In the EU an application must be submitted to the national competent authority and an independent ethics committee in each country in which we intend to conduct clinical trials, much like the FDA and IRB, respectively. Under the new CTR (EU) No 536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022, a single application is now made through the Clinical Trials Information System, or CTIS, for clinical trial authorization in up to 30 EU/EEA countries at the same time and with a single set of documentation.

The assessment of applications for clinical trials is divided into two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation). Part I is assessed by a coordinated review by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted, or Member States concerned of a draft report prepared by a Reference Member State. Part II is assessed separately by each

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Member State concerned. The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the Member State concerned, however overall related timelines are defined by the CTR. The new CTR also provides for simplified reporting procedures for clinical trial sponsors.

To obtain regulatory approval of our medicinal products under the EU’s regulatory system, we are required to submit a marketing authorization application, or MAA, to be assessed in the centralized procedure. The centralized procedure allows applicants to obtain a marketing authorization, or MA, that is valid throughout the EU, and the additional Member States of the European Economic Area (Iceland, Liechtenstein and Norway), or EEA. It is compulsory for medicinal products manufactured using biotechnological processes, orphan medicinal products, advanced therapy medicinal products (gene-therapy, somatic cell-EU and which is intended for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, auto-immune and other immune dysfunctions, viral diseases or diabetes). The centralized procedure is optional for any other products containing new active substances not authorized in the EU or for products which constitute a significant therapeutic, scientific, or technical innovation or for which a centralized authorization is in the interests of patients at EU level. When a company wishes to place on the market a medicinal product that is eligible for the centralized procedure, it sends an application directly to the European Medicines Agency, or EMA, to be assessed by the Committee for Medicinal Products for Human Use, or CHMP. The CHMP is responsible for conducting the assessment of whether a medicine meets the required quality, safety, and efficacy requirements, and whether the product has a positive risk/benefit profile. Once the CHMP has completed its assessment, the CHMP will give a favorable or unfavorable opinion as to whether to grant the authorization. The time limit for the evaluation procedure is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP). The EMA then has fifteen days to forward its opinion to the European Commission, which will make a binding decision on the grant of an MA within 67 days of the receipt of the CHMP opinion.

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States. Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as an orphan medicinal product if it is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition that affects no more than five in 10,000 persons in the EU when the application is made. In addition, orphan designation can be granted if the product is intended for a life threatening, seriously debilitating, or serious and chronic condition in the EU and when, without incentives, it is unlikely that sales of the product in the EU would be sufficient to justify the necessary investment in its development. Orphan designation is only available if there is no other satisfactory method approved in the EU of diagnosing, preventing, or treating the applicable orphan condition, or if such a method exists, the proposed orphan medicinal product will be of significant benefit to patients affected by such condition, as defined in Regulation (EC) 847/2000.

Orphan designation provides opportunities for fee reductions, protocol assistance, and access to the centralized procedure. In addition, if a product which has an orphan designation subsequently receives a centralized MA for the indication for which it has such designation, the product is entitled to orphan market exclusivity, which means the EMA may not approve any other application to market a similar medicinal product for the same indication for a period of ten years. A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication. The exclusivity period may be reduced to six years if, at the end of the fifth year, it is shown that the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity. Additionally, an MA may be granted to a similar medicinal product for the same indication at any time if:

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the second applicant can establish that its product, although similar to the authorized product, is safer, more effective or otherwise clinically superior;

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the MA holder of the authorized product consents to a second orphan medicinal product application; or

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the MA holder of the authorized product cannot supply enough orphan medicinal product.

A pediatric investigation plan, or PIP, in the European Union is aimed at ensuring that the necessary data are obtained to support the authorization of a medicine for children, through studies in children. All applications for MAs for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver. This requirement also applies when an MA holder wants to add a new indication, pharmaceutical form, or route of administration for a medicine that is already authorized and covered by intellectual property rights. Several rewards and incentives for the development of pediatric medicines for children are available in the EU. Medicines authorized across the EU with the results of studies from a PIP included in the product information are eligible for an extension of their supplementary protection certificate, or SPC, by six months (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to two years before the SPC expires). This is the case even when the studies’ results are negative. For orphan medicinal products, the incentive is an additional two years of market exclusivity. Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines.

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In March 2016, the EMA launched an initiative, the Priority Medicines scheme, or the PRIME scheme, to facilitate development of development candidates in indications, often rare, for which few or no therapies currently exist. The PRIME scheme is intended to encourage development of products in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies on the basis of compelling non-clinical data and tolerability data from initial clinical trials. Many benefits accrue to sponsors of development candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted. Importantly, once a candidate medicine has been selected for the PRIME scheme, a dedicated contact and rapporteur from the CHMP or from the Committee for Advanced Therapies, or CAT, are appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s committee level. An initial meeting with the CHMP/CAT rapporteur initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies. PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designation or eligibility will result in expedited review or approval. The aforementioned EU rules are generally applicable in the EEA. The United Kingdom left the EU on January 31, 2020.

The United Kingdom have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021. The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide for wholesale mutual recognition of United Kingdom and EU pharmaceutical regulations. At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended). Except in respect of the new EU Clinical Trials Regulation, the regulatory regime in Great Britain therefore largely aligns with current EU medicines regulations, however it is possible that these regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of United Kingdom and EU pharmaceutical legislation. However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new framework which will be put in place by the Medicines and Healthcare products Regulatory Agency, or MHRA, the United Kingdom’s medicines regulator, from January 1, 2024, the MHRA will take into account decisions on the approval of MAs from the EMA (and certain other regulators) when considering an application for a Great Britain MA.

On February 27, 2023, the United Kingdom government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”. This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the United Kingdom. In particular, the MHRA will be responsible for approving all medicinal products destined for the United Kingdom market (i.e., Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland. A single United Kingdom-wide MA will be granted by the MHRA for all medicinal products to be sold in the United Kingdom, enabling products to be sold in a single pack and under a single authorization throughout the United Kingdom. On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply after January 1, 2025.

There is now no pre-MA orphan designation in Great Britain. Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MAA. The criteria are essentially the same, but have been tailored for the Great Britain market, i.e., the prevalence of the condition in Great Britain (rather than the EU) must not be more than five in 10,000. Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in Great Britain or the EU, wherever is earliest.

Regulatory Framework in Australia

We conducted the REWRITE Phase 1/2a trial in Australia and may, in the future, conduct additional clinical trials in Australia. The Therapeutic Goods Administration, or TGA, and the National Health and Medical Research Council set the legislative, regulatory and good clinical practice requirements for conducting clinical research in Australia, and compliance with these laws and codes is mandatory. Australia has also adopted international codes, such as those promulgated by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, or ICH. The ICH guidelines, as annotated by teh TGA, must be complied with across all fields of clinical research, including those related to pharmaceutical quality, nonclinical and clinical data requirements and trial designs. The basic requirements for preclinical data to support a first-in-human trial under ICH guidelines are applicable in Australia, and will form part of the Common Technical Document for the registration of medicines. Requirements related to adverse event reporting in Australia are similar to those required in other major jurisdictions.

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The Therapeutic Goods Act 1989 and related regulations establish and maintain the national system of controls relating to the efficacy, quality, safety and timely availability of drugs and medical devices in Australia. The TGA is the Australian regulatory authority for therapeutic goods. The TGA describes its remit as being to safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods. The TGA administers two pathways for clinical trials, the Clinical Trials Notification, or CTN, and Clinical Trials Approval, or CTA, schemes. These provide an avenue through which 'unapproved' therapeutic goods may be lawfully supplied for use solely for experimental purposes in humans. The choice of which route to use (CTN or CTA) lies firstly with the Australian clinical trial sponsor and then with the Human Research Ethics Committee, or HREC, that approves the protocol. The CTA pathway, requiring prior regulatory approval, is generally designed for high-risk or novel treatments where there is no or limited knowledge of safety.

Clinical trials of medicines and biologicals typically proceed through 'phases' of development, which generally follow: Phase 1 (human pharmacology), Phase 2 (therapeutic exploratory), and Phase 3 (therapeutic confirmatory). Phase 4 may be conducted for post-marketing surveillance or resolution of treatment uncertainties. Clinical development pathways are becoming less rigid with respect to phase and seamless adaptive trial designs and other cross-phase studies exist.The use of therapeutic goods in any clinical trial must be in accordance with the Guideline for Good Clinical Practice, the National Statement on Ethical Conduct in Human Research and the protocol approved by the HREC responsible for monitoring the conduct of the trial. The trial sponsor must also comply with the requirements of any other Commonwealth and/or state and territory legislation in relation to clinical trials and the supply of therapeutic goods.

Approval for inclusion in the Australian Register of Therapeutic Goods, or ARTG, is required before a pharmaceutical product that is not otherwise the subject of a relevant exemption or exclusion may be marketed (or imported, exported, manufactured or supplied) in Australia. In order to obtain registration of the product on the ARTG, it is required that:

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adequate and well-controlled clinical trials demonstrate the quality, safety and efficacy of the therapeutic product;

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evidence is compiled which demonstrates that the manufacture of the therapeutic product complies with the principles of cGMP;

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manufacturing and clinical data is derived to submit to the relevant independent advisory committee to the TGA, which makes recommendations as to whether or not to grant approval to include the therapeutic product in the ARTG; for example, the Advisory Committee on Medicines; and

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an ultimate decision is made by the Secretary of the Department of Health and Aged Care, via the TGA, whether to include the therapeutic product in the ARTG.

Therapeutic goods need to be entered on the ARTG before they can be supplied in Australia, unless a relevant exemption or exclusion applies. However, aside from use during an approved clinical trial, there are a limited ways that patients may gain access to such products or indications that have not been approved for use in Australia, for example:

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the Special Access Scheme allows a health practitioner to access an unapproved therapeutic good for an individual patient on a case-by-case basis;

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medical professionals can apply to the TGA to become an Authorised Prescriber of a specific unapproved good to specific patients with a particular medical condition. In some instances, doctors also need to have their application approved by a human research ethics committee or endorsed by a specialist college.

Pharmaceutical Coverage and Reimbursement

Patients in the United States and markets in other countries generally rely on third-party payors to cover and reimburse all or part of the costs associated with their treatment, including the cost of drugs. Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance for any product that we may commercialize. Our ability to successfully commercialize our development candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.

Additionally, the process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which products they will pay for and establish reimbursement levels. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs (for example, formularies, prior authorization, step therapy, quantity limits, and site-of-care restrictions,

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among other). Third-party payors may limit coverage for a product for narrower patient subpopulations or might not include all of the approved products for a particular indication. Net prices for products may also be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of products from countries where they may be sold at lower prices than in the United States. Increasingly, third-party payors are requiring that pharmaceutical companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained. Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment.

There is also significant uncertainty related to the insurance coverage and reimbursement of newly approved products and coverage may be more limited than the purposes for which the medicine is approved by the FDA or comparable foreign regulatory authorities. In the United States, the principal decisions about reimbursement for new medicines are typically made by CMS. CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.

We currently expect that any drugs we develop may need to be administered under the supervision of a physician on an outpatient basis. Under currently applicable U.S. law, certain drugs that are not usually self-administered (such as most injectable drugs) may be eligible for coverage under the Medicare Part B program if:

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they are incident to a physician’s services;

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they are reasonable and necessary for the diagnosis or treatment of the illness or injury for which they are administered according to accepted standards of medical practice; and

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they have been approved by the FDA and meet other requirements of the statute.

Pharmaceutical companies whose products are reimbursed under Medicare Part B must calculate and report certain price reporting metrics to the government, such as average sales price, and best price. Penalties may apply in some cases when such metrics are not submitted accurately and timely. Further, these prices for development candidates may be reduced by mandatory discounts or rebates required by government healthcare programs.

Outside the United States, ensuring coverage and adequate payment for a product also involves challenges. Pricing of prescription pharmaceuticals is subject to government control in many countries. In some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, the European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular development candidate to currently available therapies. A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our development candidates. Historically, products launched in the European Union do not follow U.S. price structures and generally prices tend to be significantly lower.

Other Healthcare Laws

Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business that may constrain the financial arrangements and relationships through which we research, as well as sell, market and distribute any products for which we obtain marketing authorization. Such laws include, without limitation, (i) fraud and abuse laws, such as the federal Anti-Kickback Statute and federal and state false claims and related laws (including the False Claims Act and Civil Monetary Penalties Law); (ii) healthcare fraud and false statement statutes; (iii) privacy and security requirements for health information under HIPAA, as amended by HITECH, and analogous state and foreign data protection laws; (iv) transparency and reporting requirements, including the federal Physician Payments Sunshine Act and state equivalents; (v) federal and state drug price reporting and disclosure laws; and (vi) anti-corruption laws, including the Foreign Corrupt Practices Act and similar foreign requirements. Many state and foreign laws are broader than their federal counterparts, may apply regardless of payor, and may impose additional or different obligations. If our operations are found to be in violation of any of such laws or any other governmental

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regulations that apply, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and responsible individuals may be subject to imprisonment.

Healthcare Reform Measures

Payors, whether domestic or foreign, or governmental or private, are developing increasingly sophisticated methods of controlling healthcare costs and those methods are not always specifically adapted for new technologies such as gene therapy and therapies addressing rare diseases such as those we are developing. In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact our ability to sell our products profitably. In particular, in 2010, the ACA was enacted, which, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program; extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations; subjected manufacturers to new annual fees and taxes for certain branded prescription drugs; created a Medicare Part D coverage gap discount program, in which manufacturers were required to agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D (later replaced under the Inflation Reduction Act with the Manufacturer Discount Program); and provided incentives to programs that increase the federal government’s comparative effectiveness research.

Since its enactment, there have been numerous judicial, administrative, and executive, challenges to certain aspects of the ACA. In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted. For example, the American Rescue Plan Act of 2021 eliminated the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024. Further, the Budget Control Act of 2011 and subsequent legislation, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of 2% per fiscal year, which remain in effect through fiscal year 2032.

The U.S. American Taxpayer Relief Act of 2012 also further reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

The Inflation Reduction Act of 2022, or IRA, includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket cap for Medicare Part D beneficiaries to $2,000 starting in 2025; impose new manufacturer financial liability on certain drugs under Medicare Part D; allow the U.S. government to negotiate Medicare Part B and Part D price caps for certain high-cost drugs without generic competition; require companies to pay rebates to Medicare for certain drug prices that increase faster than inflation; and delay until January 1, 2032 the rebate rule that would limit the fees that pharmacy benefit managers can charge. Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one or more orphan designations and for which the only approved indication or indications are for a rare disease or condition. Further, judicial challenges to the IRA may have an impact on the implementation of the IRA’s provisions; and the overall effects of the IRA on our business and the healthcare industry in general is not yet known.

Recently, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products. Such scrutiny has resulted in several recent U.S. Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare, and reform government program reimbursement methodologies for pharmaceutical products. The costs of drugs have also been the subject of considerable discussion in the United States. To date, there have been several recent U.S. congressional inquiries, as well as proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products. The current U.S. administration has issued executive orders and supported proposed regulatory initiatives in 2025 that could have a significant impact on the prices that we, or any collaborators, may receive for any approved development candidates.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain drug access and marketing cost disclosure and transparency measures, and designed to encourage importation from other countries and bulk purchasing. Legally mandated price controls on payment amounts by

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third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. This could reduce the ultimate demand for our drugs or put pressure on our drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any development candidates for which we may obtain regulatory approval or the frequency with which any such development candidate is prescribed or used.

Other U.S. Environmental, Health and Safety Laws and Regulations

We may be subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may also produce hazardous waste products. Even if we contract with third parties for the disposal of these materials and waste products, we cannot completely eliminate the risk of contamination or injury resulting from these materials. In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.

We maintain workers’ compensation insurance to cover costs and expenses we may incur due to injuries to our employees as well as insurance for environmental liability, but this insurance may not provide adequate coverage against potential liabilities. However, we do not maintain insurance for toxic tort claims that may be asserted against us.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. Current or future environmental laws and regulations may impair our research, development or production efforts. In addition, failure to comply with these laws and regulations may result in substantial fines, penalties or other sanctions.

Employees and Human Capital Resources

As of December 31, 2025, we had 58 full-time employees, including 44 who hold Ph.D. degrees or other advanced degrees; 39 employees are engaged in research and development and 19 employees are engaged in management or general and administrative activities. None of our employees are subject to a collective bargaining agreement or represented by a trade or labor union. We consider our relationship with our employees to be good. We also employ consultants from time to time.

Our human capital objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees. The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards and cash-based performance bonus awards.

Corporate Information

We were incorporated as a Delaware corporation, on November 13, 2014 under the name “Frequency Therapeutics, Inc.”. On November 3, 2023, we completed a business combination and changed our name to Korro Bio, Inc. Our principal executive office is located at 60 First Street, 2nd Floor, Suite 250, Cambridge, MA 02141, and our telephone number is 617-468-1999. Our website address is https://www.korrobio.com/. The information contained on, or that can be accessed through, our website is not incorporated by reference into this Annual Report on Form 10-K or in any other report or document we have filed or may file with the Securities and Exchange Commission, or SEC, and any reference to our website address is intended to be an inactive textual reference only. We will make available on our website, free of charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC. The SEC maintains an Internet site, http://www.sec.gov, containing reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC.