Janux Therapeutics, Inc. (JANX) Business

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Item 1. Business.

Unless the context otherwise requires, the terms “Janux Therapeutics,” “Janux,” “we,” “us,” “our” and similar references in this Annual Report on Form 10-K refer to Janux Therapeutics, Inc.

Overview‌

We are an innovative clinical-stage biopharmaceutical company developing a broad pipeline of novel immunotherapies by applying our proprietary technologies to our Tumor Activated T Cell Engager (TRACTr), Tumor Activated Immunomodulator (TRACIr), and Adaptive Immune Response Modulator (ARM) platforms. The TRACTr platform produces T cell engagers (TCEs) with a tumor antigen-binding domain and a CD3 T cell binding domain, while the TRACIr platform produces bispecifics with a tumor antigen-binding domain and a costimulatory CD28 binding domain. The goal of our TRACTr and TRACIr platforms is to provide cancer patients with safe and effective therapeutics that direct and guide their immune system to eradicate tumors while minimizing safety concerns. Our initial focus is on developing a novel class of TRACTr therapeutics designed to target clinically validated TCE drug targets, while overcoming the liabilities associated with prior generations of TCEs. While TCE therapeutics have displayed potent anti-tumor activity in hematological cancers, developing TCEs to treat solid tumors has faced challenges due to the limitations of prior TCE technologies, namely (i) on-target healthy tissue immune activation that contributes to cytokine release syndrome (CRS) and healthy tissue toxicity and (ii) poor pharmacokinetics (PK) leading to short half-life.

Our first clinical candidate, JANX007, is a prostate-specific membrane antigen (PSMA) TRACTr being investigated in a Phase 1 clinical trial in adult subjects with metastatic castration-resistant prostate cancer (mCRPC). In December 2024, we announced updated interim clinical data for JANX007 demonstrating meaningful and prolonged prostate-specific antigen (PSA) reductions, evidence of anti-tumor activity, a favorable safety profile with CRS and treatment-related adverse events (TRAEs) primarily limited to cycle 1 and lower grades, and pharmacokinetics consistent with the TRACTr mechanism of action. In May 2025, we provided updated results from the patients reported in December 2024 that demonstrated consistent durability and safety profile supporting the initiation of Phase 1b expansion studies. In December 2025, we announced updated interim clinical data demonstrating durability across both once-weekly (QW) and every-two-week (Q2W) Phase 1a expansion cohorts. JANX007 continued to demonstrate a manageable safety profile, with CRS primarily limited to cycle 1 and grades 1 and 2, and preliminary Phase 1b data in taxane-naïve patients demonstrated rapid and deep PSA reductions with primarily grade 1 CRS. Based on the safety, pharmacokinetic and preliminary efficacy data observed to date, we initiated the first of our planned Phase 1b expansion cohorts designed to further characterize JANX007 and inform potential registrational development strategies. These cohorts are designed to evaluate JANX007 in clinically relevant patient populations, including taxane-naïve mCRPC, combination with an androgen receptor pathway inhibitor (darolutamide), and patients whose disease has progressed following prior PARP inhibitor therapy. In May 2025, we announced initiation of the Phase 1b expansion study in taxane-naïve mCRPC. These studies are designed to help refine dosing, patient selection and combination strategies and provide insights to support the design of future late-stage clinical development.

Our second clinical candidate, JANX008, is an epidermal growth factor receptor (EGFR) TRACTr being investigated in a Phase 1 clinical trial for the treatment of multiple solid tumors. The first patient in this trial was dosed in April 2023, and in February 2024 we announced early clinical data demonstrating anti-tumor activity across multiple tumor types, with low-grade CRS and predominantly low-grade treatment-related adverse events. In December 2025, we announced the initiation of Phase 1a expansion cohorts in selected solid tumor indications based on the efficacy and safety data observed in the completed dose-escalation portion of the study. Building on the results from dose escalation, the ongoing expansion cohorts are evaluating JANX008 in tumor types where early signals of activity and tolerability were observed. These studies are designed to refine patient selection, optimize dosing and inform the prioritization of indications for future clinical development.

Our ARM platform builds upon our expertise to redesign bispecific T cell engagers to address the limitations of conventional approaches in autoimmune diseases and oncology. The platform is designed to enable controlled T cell activation and expansion followed by contraction, with the goal of achieving deep and durable target cell depletion while improving safety and convenience. Based on nonclinical data, our lead CD19-ARM program has demonstrated rapid, deep and durable B-cell depletion in peripheral blood and lymphoid tissues with prolonged memory B-cell reset and a large safety window in non-human primates. We have initiated a Phase 1 clinical study of our CD19-ARM program (JANX011), which is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JANX011 in healthy volunteers. JANX011 is being developed for autoimmune diseases, and the initiation of this study represents an important step in the advancement of our ARM platform from preclinical development into the clinic.

We are also generating a number of additional TRACTr, TRACIr and ARM programs for potential future development, including a PSMA x CD28 TRACIr designed to enhance T cell activation and durability of JANX007 in patients with mCRPC.

The promise of TCE technologies and their current limitations in solid tumors

TCEs are an emerging class of immunotherapies that bridge a tumor cell and a T cell to activate and redirect T cells to attack and eliminate tumors. TCEs have demonstrated promising anti-tumor activity in early clinical trials and in multiple animal models that rivals that of chimeric antigen receptor T cell (CAR T cell) therapies, with the distinct advantage that they are not cell therapies and have the potential to be offered as readily available, off-the-shelf therapies, which would avoid the lengthy, complicated, and expensive manufacturing process required for approved autologous CAR T cell therapies.

Three properties of existing TCEs have limited their potential to treat solid tumors:

•
Cytokine release syndrome (CRS). CRS arises from the systemic activation of T cells and can result in life-threatening elevations in inflammatory cytokines such as interleukin-6 (IL-6). Severe and acute CRS leading to dose-limiting toxicities and deaths has been observed upon the dosing of TCEs developed using other platforms to treat cancer patients in prior clinical studies. This toxicity severely restricts the maximum blood levels of TCEs that can be safely dosed.

•
On-target, healthy tissue toxicity. On-target, healthy tissue toxicity, arising from expression of the tumor target in healthy tissue and scarcity of highly tumor-selective antigens, is another limitation hindering the development of TCEs to treat solid tumor cancers. TCEs developed using other platforms not designed for tumor-specific activation have resulted in clinical holds and dose-limiting toxicities resulting from target expression in healthy tissues.

•
Short half-lives. TCEs quickly reach sub-therapeutic levels after being administered as they are quickly eliminated from the body due to their short exposure half-lives. For this reason, TCEs such as blinatumomab (BLINCYTO) are typically administered by a low-dose, continuous infusion pump over a period of weeks to overcome the challenge of a short half-life and maintain therapeutic levels of the drug in the body. This continuous infusion dosing regimen represents a significant burden for patients.

Our TRACTr and TRACIr platforms‌

We believe our proprietary TRACTr and TRACIr platforms offer the potential to expand the breadth of patients that can be treated with TCEs and non-TCE based immunomodulators while reducing the risk of life-threatening toxicities. Each of our proprietary TRACTrs and TRACIrs are comprised of an antigen-binding domain, a T cell-binding domain, domain-optimized peptide masks, an albumin-binding domain, and cleavable peptide linkers. The mask is a peptide designed to bind to the tumor or T cell-binding domain. It inhibits the binding domain’s interaction with its target, thereby inhibiting the activation of T cells. The antigen and T cell-binding domains in our TRACTr and TRACIr product candidates may be covalently attached to peptide masks that block binding and activity until they are removed. We use proprietary peptide linker sequences composed of tumor protease recognition sites to attach these masks to the antigen-binding domains in a way designed to make the masks highly sensitive to removal by tumor proteases but highly stable in the absence of these proteases. In addition, we attach an albumin-binding domain to one mask, which is designed to extend the half-life of our TRACTr and TRACIr product candidates until they become activated inside a tumor.

While our TRACTr and TRACIr platforms are novel and unproven and our product candidates remain in the early clinical, preclinical or discovery stage, our technology is designed to offer the following features for the discovery and development of novel therapies for the treatment of solid tumors:

•
Potential to reduce CRS and on-target, healthy tissue toxicity risk. By engineering our TRACTrs and TRACIrs with novel peptide masks that are designed (i) to be selectively activated in the tumor microenvironment and (ii) for any activated TCEs or non-TCE based immunomodulators to be rapidly cleared from healthy tissue upon escaping from the tumor, our product candidates have the potential to overcome the toxicity challenges of TCEs, non-TCE based immunomodulators and systemic immunotherapies in general.

•
Potential for extended half-life of our TRACTrs and TRACIrs. We designed our TRACTrs and TRACIrs with an albumin-binding domain to be stable in the bloodstream and to have an extended serum half-life before activation. Our TRACTrs and TRACIrs have demonstrated long half-lives in NHPs. This contrasts to first-generation TCEs and non-TCE based immunomodulators that are rapidly cleared and require high frequency or continuous dosing.

•
Potential for activity at low levels of target expression. Our TRACTrs and TRACIrs are designed to be active at low levels of tumor target expression where other treatment modalities lose efficacy. In preclinical studies, our TRACTrs and TRACIrs did not require high levels of tumor target expression to activate T cells to kill cancer cells.

•
Modularity. Our TRACTr and TRACIr platforms’ modular characteristics enable us to leverage the learnings from the development of our product candidates to progress the discovery process of new TRACTr and TRACIr candidates against a wide variety of targets.

•
Manufacturability. The development, manufacturing and control processes of our TRACTr and TRACIr molecules closely resemble those used for monoclonal antibodies (mAbs) with the expectation for a relatively lower cost of goods.

A schematic of our proprietary TRACTrs and TRACIrs in development and their modular components is depicted below.

The promise of TCE technologies and their current limitations in autoimmune disease

TCEs redirect T cells to eliminate autoreactive B cells and plasma cells, addressing the root cause of disease instead of broadly suppressing immunity. For this reason, TCEs represent a transformative approach to autoimmune disease treatment by enabling an immune reset rather than mere symptom suppression. Unlike CAR T-cell therapy, which is logistically complex, TCEs offer an off-the-shelf, scalable solution with subcutaneous administration, making them more accessible and patient-friendly. Academic investigators and industry sponsors have published data demonstrating the potential for a TCE to achieve sustained improvements in disease manifestations, including durable remission from symptoms in some cases, in multiple autoimmune disease indications.

Despite their promise, TCEs face notable challenges that could limit widespread adoption. CRS, though less severe than in oncology, remains a safety concern, as observed in RA patients treated with blinatumomab and teclistamab. Infections have also occurred, highlighting immunosuppression risks. Mechanistically, incomplete depletion of pathogenic B cells in lymphoid tissues and sites of inflammation can lead to suboptimal efficacy, especially in refractory disease. Furthermore, the need for step-up dosing and close monitoring complicates treatment logistics compared to conventional biologics.

Our ARM platform

Our ARM platform builds upon our expertise to redesign bispecific TCEs and is designed to address key limitations of conventional TCEs. By enabling rapid, deep, and durable depletion of B cells in blood and lymphoid tissues the ARM platform can achieve prolonged memory B‑cell reset, with the goal of achieving immune re‑tolerance rather than transient disease control in autoimmune disease. Based on non‑clinical evaluations, ARM demonstrates a large safety window and reduced CRS relative to contemporary TCEs that often require step‑up dosing and inpatient monitoring due to CRS and healthy‑tissue toxicities. The ARM platform is engineered to sustain T‑cell function, expand memory T cell compartments and limit exhaustion, providing the potential for improved durability of response and a lower risk of infection versus conventional TCE approaches. In addition, ARM’s off‑the‑shelf, subcutaneous, and re‑dosable format is intended to support community‑based outpatient administration and flexible retreatment.

Our lead programs

Our lead TRACTr clinical candidates are designed to target PSMA and EGFR. Each of these tumor targets is clinically validated and implicated in solid tumors with high prevalence. We are also developing a PSMA x CD28 TRACIr designed to enhance T cell activation and durability of JANX007. Our lead ARM program is designed to target CD19 because non-malignant B cells express the CD19 target and play a role in numerous autoimmune diseases which can affect multiple organ systems. We are also generating a number of unnamed TRACTr, TRACIr and ARM programs for potential future development, some of which are at development candidate stage or later. Our wholly-owned pipeline is summarized below. In addition to our wholly-owned pipeline programs, we have strategic research collaborations with Merck Sharp & Dohme Corp. (Merck) and Bristol Myers Squibb to develop product candidates directed against cancer targets.

Our Clinical TRACTr Programs

We are building a broad portfolio of TRACTr programs led by our PSMA and EGFR targeted TRACTrs.

Our PSMA-TRACTr (JANX007)

Our lead clinical candidate is JANX007, our PSMA-TRACTr designed to target PSMA, a protein expressed in prostate cancer tumors and the vasculature of other tumors. Excluding nonmelanoma skin cancer, prostate cancer is the second most common cancer in the United States. PSMA is highly expressed in prostate cancer which has led to the development of PSMA-targeted biologics, including TCEs. A third-party clinical trial with a continuously infused PSMA-TCE demonstrated clinical benefit, suggesting the potential of a PSMA-TCE approach. Given the challenges of continuous infusion, other companies are developing TCEs that enable less frequent dosing. However, clinical trial results have shown dose-limiting CRS toxicities as single agents, highlighting the limitations of traditional TCEs. Our PSMA-TRACTr is designed to generate potent anti-tumor activity in mCRPC patients by enabling the delivery of higher concentrations of active drugs to tumors than traditional TCEs. Our PSMA-TRACTr product candidate is designed to deliver therapeutic benefits to patients while minimizing severe adverse events (SAEs), including the prevention of dose-limiting CRS. In December 2024, we announced updated interim clinical data for JANX007 demonstrating meaningful and prolonged PSA reductions, evidence of anti-tumor activity, a favorable safety profile with CRS and treatment-related adverse events (TRAEs) primarily limited to cycle 1 and lower grades, and PK consistent with the TRACTr mechanism of action. In May 2025, we provided updated results from the patients reported in December 2024 that demonstrated consistent durability and safety profile supporting the initiation of Phase 1b expansion studies. In December 2025, we announced updated interim clinical data demonstrating durability across both the QW and Q2W Phase 1a expansion cohorts. JANX007 continued to demonstrate a manageable safety profile, with CRS primarily limited to cycle 1 and grades 1 and 2, and preliminary Phase 1b data in taxane-naïve patients demonstrated rapid and deep PSA reductions with primarily grade 1 CRS.

Based on the safety, pharmacokinetic and preliminary efficacy data observed to date, we initiated the first of our planned Phase 1b expansion cohorts designed to further characterize JANX007 and inform potential registrational development strategies. These cohorts are designed to evaluate JANX007 in clinically relevant patient populations, including taxane-naïve mCRPC, combination with an androgen receptor pathway inhibitor (darolutamide), and patients whose disease has progressed following prior PARP inhibitor therapy. In May 2025, we announced initiation of the Phase 1b expansion study in taxane-naïve mCRPC. These studies are

designed to help refine dosing, patient selection and combination strategies and provide insights to support the design of future late-stage clinical development.

Our EGFR-TRACTr (JANX008)

Our second clinical candidate, JANX008, is an EGFR-TRACTr designed to target EGFR, a well-validated target that is overexpressed in many cancer types.

JANX008 is designed to deliver anti-tumor activity while minimizing on-target, off-tumor healthy tissue toxicities and dose-limiting CRS. JANX008 is being studied in a Phase 1 clinical trial for the treatment of multiple solid cancers. The first patient was dosed in April 2023. Early clinical data reported in February 2024 displayed anti-tumor activity across multiple tumor types with low-grade CRS and predominantly low-grade TRAEs. In December 2025, we announced the initiation of Phase 1a expansion cohorts in selected solid tumor indications based on efficacy and safety data observed to date in the completed dose-escalation portion of the study.

Our Collaboration with Merck Sharp & Dohme Corp.

In December 2020, we entered into a research collaboration and exclusive license agreement with Merck to develop TRACTr product candidates distinct from those in our internally developed pipeline. Merck had the right to select up to two collaboration targets related to next-generation TCE immunotherapies for cancer treatment, both of which have been selected. Merck received an exclusive worldwide license for each selected target and intellectual property from the collaboration. In return, we are eligible to receive up to $500.5 million per target in upfront and milestone payments, plus royalties on sales of the products derived from the collaboration. Merck is providing research funding under the collaboration. In August 2025, we announced the first patient dosed in the lead collaboration program.

Our Collaboration with Bristol Myers Squibb

In January 2026, we entered into an exclusive license and collaboration agreement with Bristol Myers Squibb to develop and commercialize an undisclosed, novel tumor-activated therapeutic targeting a validated solid tumor antigen expressed across several human cancer types. Under the terms of the agreement, we will complete preclinical development until IND submission, and Bristol Myers Squibb will hold the IND and be responsible for subsequent development and global commercialization, with our continued involvement through completion of the first Phase 1 clinical study. We received an upfront payment from BMS of $15 million and, upon achievement of certain development, regulatory and sales milestones, we may receive up to $785 million in milestone payments, including $35 million related to a near term milestone. In addition, we are eligible to receive tiered royalty payments based on global product annual net sales, if approved and commercialized.

Our Strategy

Our goal is to harness the strength of our TRACTr, TRACIr and ARM platforms technology to transform the lives of patients. To achieve this goal, critical elements of our strategy include the following:

•
Advance our lead TRACTr programs through clinical development. In December 2025, we announced updated interim clinical data which displayed durability observed in both the QW and Q2W Phase 1a expansions. JANX007 demonstrated a manageable safety profile with CRS primarily limited to cycle 1 and grades 1 and 2. Preliminary Phase 1b data in taxane-naïve patients demonstrated rapid and deep PSA reductions with primarily grade 1 CRS. In December 2025, we announced the initiation of Phase 1a expansion studies for JANX008 in multiple solid tumor indications. The tumor types were selected based on efficacy and safety data observed to date in the now concluded Phase 1a escalation study. These ongoing studies are intended to further characterize JANX007 and JANX008 and inform future late-stage clinical development.

•
Broaden our portfolio of TRACTr product candidates. Our TRACTr platform technology’s modular characteristics enable us to leverage the learnings from the development of our product candidates to progress the discovery process of new TRACTr candidates against a wide variety of targets. We are actively pursuing the development of additional TRACTr programs against several clinically validated targets. Once an antibody is identified, we have demonstrated the ability to develop a masked tumor-binding domain in less than six months to begin evaluating TRACTr development candidates.

•
Expand our internal pipeline into logical classes of therapeutics beyond TCEs. Our tumor-activated masking and bispecific molecule design enable more molecular phenotypes than classic CD3 targeted TCEs. For example, our proprietary technology allows the masking and tumor activation of different T cell therapy modalities, including costimulation via CD28 engagement and our TRACIr platform. Our CD28-based TRACIr platform is designed to enhance T-cell activation and durability of responses and may be used in combination with our CD3-based TRACTr programs. We are also applying our proprietary technology to create molecules designed to attract, redirect, or mobilize different types of immune cells to tumor sites that exclude or lack resident immune cells.

•
Utilize our expertise in TCEs to redesign novel bispecifics and expand pipeline beyond cancer. Our ARM platform builds upon our expertise to redesign bispecific TCEs and is designed to address key limitations of conventional TCEs in autoimmune disease and oncology. We have initiated a Phase 1 clinical study of our CD19-ARM program and plan to continue advancing additional ARM candidates.

•
Selectively evaluate opportunities to maximize the potential of our programs in partnership with leading biopharmaceutical companies. We have established strategic collaborations, including with Merck and Bristol Myers Squibb, and we intend to continue to selectively pursue partnerships that complement our internal development efforts and help maximize the global potential of our platforms.

TCEs as novel therapeutics to overcome the limitations of current immunotherapies in solid tumors

Background

Immunotherapy has ushered in a new era of cancer treatment with unprecedented responses in many tumor types. Unleashing the power of the immune system on cancer cells has been one of the most promising new advancements in a field long dominated by suboptimal approaches such as chemotherapy. One class of immunotherapy, checkpoint inhibitors, has generated clinically meaningful efficacy results and represents the standard of care (SOC) in selected tumor types. However, despite this clinical benefit for a subset of patients, only a fraction of all cancer patients in the United States respond to checkpoint inhibitors. Tumors have evolved to evade and dampen tumor immune surveillance. Consequently, new classes of immunotherapy designed to overcome the various immune-evasion mechanisms that tumors employ have emerged.

TCEs are immunotherapies that bridge tumor-fighting T cells and tumors in a way that overcomes this challenge. TCEs are bivalent biologics; that is, they can bind to two different cell surface targets. By selecting one target on a tumor cell and another on a T cell, the TCE bridges these two cell types to trigger tumor cell killing by the T cell. TCEs can be mass-produced and made available as off-the-shelf therapies. Furthermore, TCEs, as biologics, have pharmacologic properties that allow control of the amount of active drug in the body at any one time. The doses that are delivered can be titrated, and the pharmacokinetics generally follow those of other biologics.

Other approaches to immunotherapy, like cell therapies, such as CAR T cell therapy, are also emerging. We believe the unique characteristics of TCEs render them an attractive immunotherapy alternative to these approaches. While cell therapies have displayed efficacy in treating cancer, these treatments have also led to morbidity and mortality resulting from toxicity. Cell therapies also typically require complex and costly manufacturing strategies, making them unsuitable for several aggressive tumors and advanced disease patients. They are primarily confined to treatment for hematological malignancies, and CAR T cell therapies have not to date been successfully developed for any solid tumor.

While we believe that TCEs hold promise in treating solid tumors, three properties of TCEs derived from other platforms have limited their potential:

•
Cytokine release syndrome (CRS). CRS arises from the systemic activation of T cells and can result in life-threatening elevations in inflammatory cytokines such as IL-6. Severe and acute CRS leading to dose-limiting toxicities and deaths has been observed upon the dosing of TCEs developed using other platforms to treat cancer patients in prior clinical studies. This toxicity severely restricts the maximum blood levels of TCEs that can be safely dosed.

•
On-target, healthy tissue toxicity. On-target, healthy tissue toxicity, arising from the expression of the tumor target in healthy tissue and scarcity of highly tumor-selective antigens, is another limitation hindering the development of TCEs to treat solid tumor cancers. TCEs developed using other platforms not designed for tumor-specific activation have resulted in clinical holds and dose-limiting toxicities resulting from target expression in healthy tissues.

•
Short half-lives. TCEs quickly reach sub-therapeutic levels after being administered as they are quickly eliminated from the body due to their short exposure half-lives. For this reason, TCEs such as blinatumomab (BLINCYTO) are typically administered by a low-dose, continuous infusion pump over a period of weeks to overcome the challenge of a short half-life and to maintain therapeutic levels of the drug in the body. This continuous infusion dosing regimen represents a significant burden for patients.

Next generation approaches to overcome the challenges of conventional TCEs

First-generation immuno-oncology drugs have an increased risk of systemic toxicity due to the active drug circulating throughout the body. Second generation immuno oncology drugs, such as protease-activated antibodies, have attempted to limit systemic toxicities by being administered in an inactive form and only activated upon exposure to tumor proteases within the tumor microenvironment. However, once these activated drugs leave the tumor, they circulate throughout the body and accumulate over time, leading to on-target, healthy tissue toxicity in‌ target-expressing tissues. Several product candidates have been developed that take advantage of tumor-associated proteases to activate potent drugs in tumors. These include prodrugs such as leucine-doxorubicin and masked antibodies such as Probodies developed by CytomX. In initial clinical trials, CytomX has demonstrated clinical benefit in patients and a mechanistic proof-of-concept for this masked antibody approach. However, an unwanted consequence of CytomX’s

approach is that the relatively long half-lives of its drugs in active form led to their accumulation in healthy tissue throughout treatment.

We are developing our TRACTr and TRACIr platforms to address the limitations of previous generations of immuno-oncology drugs and to restrict activity to tumors. Our TRACTrs and TRACIrs are designed to be activated by tumor-specific proteases but, upon activation, be converted to a form that has a short half-life to eliminate them from the body rapidly should they re-enter the circulatory system. A representation of the pharmacokinetic design of first and second-generation TCEs and our TRACTrs / TRACIrs is shown in the figure below.

Figure 1. Our TRACTr and TRACIr platforms are designed to limit the activity of our therapies to tumor sites, reducing the risk of on-target, healthy tissue toxicity

Our TRACTr and TRACIr Platforms‌

Our TRACTr and TRACIr platforms are designed to offer the following features for the discovery and development of novel therapies for the treatment of solid tumors:

•
Potential to reduce CRS and on-target, healthy tissue toxicity risk. By engineering our TRACTrs and TRACIrs with novel peptide masks that are designed to be selectively activated in the tumor microenvironment and designed for any activated TCEs or non-TCE based immunomodulators to be rapidly cleared from healthy tissue upon escaping from the tumor, our product candidates have the potential to overcome the toxicity challenges of TCEs, non-TCE based immunomodulators and systemic immunotherapies in general.

•
Potential for the extended half-life of our TRACTrs and TRACIrs. We designed our TRACTrs and TRACIrs with an albumin-binding domain to be stable in the bloodstream and to have an extended serum half-life before activation. Our TRACTrs and TRACIrs have demonstrated long half-lives in NHPs. This contrasts with first-generation TCEs or non-TCE based immunomodulators that are rapidly cleared and require high frequency or continuous dosing.

•
Manufacturability. The development, manufacturing and control processes of our TRACTr and TRACIr molecules closely resemble those used for monoclonal antibodies with the expectation for a relatively lower cost of goods.

TRACTr and TRACIr design and structure

Our TRACTr and TRACIr product candidates are biologics comprised of multiple domains that have been designed to serve specific functions but engineered to function as a single unit. At their core, our TRACTr and TRACIr product candidates are TCEs and non-TCE based immunomodulators, respectively, that couple a tumor antigen binding domain to a T cell-specific antigen binding domain. Masks cover both binding sites and block activity while our TRACTr or TRACIr product candidate are in circulation and exposed to healthy tissues. We use proprietary peptide linker sequences composed of tumor protease recognition sites to attach these masks to the antigen-binding domains in a way that is designed to make the masks highly sensitive to release by tumor proteases. This release exposes both the tumor-binding domain and the T cell antigen binding domains to generate a fully activated TCE or non-TCE based immunomodulator. This is designed to enable our TRACTr or TRACIr product candidates to bridge the T cells and tumor cells into close proximity and to enable T cell-mediated killing of tumor cells.

Our TRACTr and TRACIr product candidates also have a proprietary albumin-binding domain designed to increase their half-life in serum. This proprietary domain is designed to bind albumin and, by doing so, prevent the rapid degradation and elimination of TRACTr or TRACIr product candidates. In contrast, blinatumomab (BLINCYTO), a TCE that lacks an albumin-binding domain, has a very short half-life in serum and is administered through continuous infusion for 28 days per treatment cycle, with hospitalization recommended for up to the first nine days.

Our TRACTrs and TRACIrs are designed to limit binding to their targets in healthy cells. When our TRACTr or TRACIr product candidates are in the non-activated state, they are designed not to activate T cells before reaching the tumor. Upon exposure to tumor proteases, the linkers are designed to be cleaved, and the masks and albumin-binding domains are designed to be released to generate a fully active TCE or non-TCE based immunomodulator. This is designed to enable tumor-specific T cell activation and tumor cell killing while priming the activated TCE or non-TCE based immunomodulator for rapid elimination should it leave the tumor and re-enter circulation. We believe that our technology’s design to restrict T cell activation specifically to tumor sites provides the opportunity to generate TCEs and non-TCE based immunomodulators with broader therapeutic windows. We summarize our TRACTr and TRACIr structure, activation mechanism in tumor tissue, and rapid elimination from healthy tissue once activated below.

Our TRACTr and TRACIr development process

We have developed robust processes to select specific sequences for each of these components in a TRACTr or TRACIr both for their individual properties and for their ability to contribute to the desired properties of our fully assembled product candidates.

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Antigen-binding domains. Our initial product candidates are based on antigen binding domains, which have been incorporated into other products associated with clinical activity. As we expand our pipeline, we are developing proprietary antigen binding domains against novel targets.

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Geometry connecting the antigen binding domains. The orientation of a tumor-specific and a T cell-specific antigen binding domain is central to creating a TCE or non-TCE based immunomodulator with optimal T cell activation. We have found that the orientation between the two antigen-binding domains profoundly affected activity in preclinical studies. For

example, we constructed two PSMA TCEs with similar binding domains but of different geometry, where their potency in T cell-directed, PSMA-specific tumor cell killing differed by over 900-fold, as shown in the figure below.

Figure 2. The orientation of the two antigen binding domains in a PSMA-TCE led to an over 900-fold difference in potency in preclinical studies (top), and the configurations of these two TCEs, VH and VL (bottom)

•
Mask Discovery. Each mask sequence is designed to be optimized for a specific antigen-binding domain through an iterative process of phage display and quantitative binding assays designed to select for those masks that can prevent binding to the target antigen. We use a directed evolution-based process using proprietary phage libraries. We go through multiple cycles of selection and amplification of potential inhibitory peptides capable of blocking the antigen-binding domain from binding to its target to optimize masked TCE or non-TCE based immunomodulator stability in serum and limit cleavage to the tumor microenvironment thereby reducing toxicity. We depict our mask discovery process in the figure below.

Figure 3. Using directed evolution and phage display technology, we identify potential mask sequences that are designed to completely block antigen recognition by our antigen binding domains

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Single versus dual masks. Our technology allows us to develop product candidates with either one or both antigen-binding domains masked depending on the tumor target’s profile. For tumor targets with minimal healthy tissue expression or toxicity concerns, we develop single mask TRACTrs or TRACIrs designed to block the T cell-binding domain to prevent non-tumor-specific activation of T cells that contributes to CRS. For targets with high/broad healthy tissue expression or toxicity concerns, we develop dual mask TRACTrs or TRACIrs designed to mask both domains to minimize the risk of healthy tissue toxicity and CRS. We depict the single and dual mask TRACTr and TRACIr structures in the figure below.

Figure 4. We design both single and dual masked TRACTr and TRACIr product candidates based on the healthy tissue expression levels of the tumor-targeted antigen and the risk of healthy tissue toxicity

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Cleavage linker. We optimized the selection of cleavage linkers by a process involving identifying the predominant proteases in solid tumors and mining databases for potential substrates of these proteases. We then screened peptide sequences for their sensitivity to cleavage by these proteases. We specifically identified potential cleavage linker sequences that were rapidly cleaved by a tumor-specific protease to improve anti-tumor TRACTr or TRACIr activities potentially, yet remain stable in human, NHP, and mouse serum to limit non-tumor activation. We have identified several

proprietary cleavable linkers that we utilize to optimize efficacy and stability in our TRACTrs and TRACIrs, as shown in the schematic below.

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Albumin-binding domain. We developed our proprietary albumin-binding domain derived from a llama antibody optimized for its ability to bind to albumin from both humans and NHPs, the primary preclinical species in which we conduct our in vivo experiments due to the similarity in target sequences and immune function with humans. As shown in the figure below, our albumin-binding domain has a nearly identical binding affinity to albumin from these two species.

Figure 5. Our proprietary albumin-binding domain had potent binding to both NHP and human albumin

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Development viability. Once we have identified the critical components for any product candidate, we assemble them and modify the assembled construct using standard techniques to make it more human-like. We then assess its feasibility for development. We are primarily concerned with the following attributes of a potential product candidate:

o
Manufacturability using standard mammalian cell expression systems;

o
Drug-like properties such as solubility, thermal stability, and stability in human serum; and

o
Optimal performance with efficient linker cleavage, mask removal, antigen-binding, albumin-binding, and functional activity.

Our extensive library of masks and linkers combined with our protein engineering expertise allows us to generate product candidates that meet the high standards that we have set for therapeutic candidates that we believe have the potential to have clinical activity across a broad spectrum of indications.

Initial proof of technology study

To demonstrate proof of concept for TRACTrs, we tested a TRACTr and a first-generation TCE that targeted EGFR using identical antigen-binding domains. We assessed the risk of developing CRS by dosing both agents in non-human primates (NHPs), a

species that was chosen because of the similarity in antigen binding affinities in these NHPs compared to humans, and demonstrating that an EGFR bi-specific T cell engager (EGFR-BiTE, or EGFR-TCE) triggered significant CRS and healthy tissue toxicity up to and including death.

Our EGFR-TRACTr included an albumin-binding domain intended to increase its half-life in serum to extend the interval between dosing while simultaneously utilizing the protease-mediated cleavage of the linker to remove the domain once our TRACTr was activated. In NHPs, our EGFR-TRACTr was found to have a half-life of over 100 hours compared to approximately one hour for the corresponding EGFR-TCE, as demonstrated below. Furthermore, we believe the rapid elimination of the unmasked TCE minimizes the risk of TCE-induced CRS due to short circulation time in serum.

Figure 6. Our EGFR-TRACTr was shown to have an extended half-life in NHPs compared to a corresponding TCE while the unmasked form was rapidly eliminated

In this same study, a dose of 3µg/kg and 10µg/kg of the EGFR-TCE resulted in the release of high levels of the inflammatory cytokine IL-6. In comparison, 600µg/kg of our EGFR-TRACTr reduced those levels to less than 500pg/ml, shown below, even though the plasma levels were substantially higher with the TRACTr than the TCE. Published studies have shown median IL-6 levels of 122pg/ml in patients with Grade 0-3 CRS and 8,300pg/ml in Grade 4-5 CRS patients. A similar reduction in the other inflammatory cytokines measured was observed with our TRACTr compared to the EGFR-TCE.

Figure 7. Our EGFR-TRACTr did not lead to CRS in NHPs even at high doses. Inflammatory cytokines evaluated in this study included IL-6, tumor necrosis factor alpha (TNFa), interferon gamma (IFNg), and interleukin-2 (IL-2). TNFa, IFNg, and IL-2 were all below the quantification limit (BQL)

The lack of induction of inflammatory cytokines in NHPs associated with CRS in humans is consistent with the potential for the peptide masks to prevent antigen binding and thereby T cell activation. In these studies, the EGFR-TRACTr maximum tolerated dose (MTD) was higher than 600µg/kg due to a lack of CRS, lack of safety observations, and lack of healthy tissue toxicity. In contrast, a published study using a constant infusion of an EGFR-TCE observed an MTD of 30pM plasma levels and 300pM lethal dose plasma levels, where significant liver and kidney toxicities were reported. In similar models, our TRACTr dosed at 600µg/kg had no signs of toxicity and a Cmax of 360nM, further suggesting the potential for improvement in safety via masking.

In a separate study in a mouse model of human CRC using human HCT116 tumor cells and human immune cells, our EGFR-TRACTr displayed potent anti-tumor activity. As shown in the figure below, our EGFR-TRACTr dosed for 10 days at 1.5mg/kg led to significant tumor shrinkage, which was roughly equivalent to that observed with 0.5mg/kg of the EGFR-TCE.

With the observation of reduced CRS risk for our EGFR-TRACTr relative to the EGFR-TCE (at a substantially lower dose than the TRACTr) in our NHP study, and the observation of comparable anti-tumor activity of our EGFR-TRACTr and the EGFR-TCE (at one third of the dose of the our TRACTr) in our mouse model of human CRC, we believe our EGFR-TRACTr may offer reduced CRS risk relative to the EGFR-TCE when dosed at levels expected to result in anti-tumor activity in humans.

Figure 8. Our EGFR-TRACTr led to significant tumor shrinkage in an HCT116 mouse tumor model

Our Lead Programs

Our lead TRACTr clinical candidates are designed to target PSMA and EGFR. These tumor targets are clinically validated and implicated in solid tumors with high prevalence.

Our PSMA-TRACTr (JANX007) for the treatment of mCRPC

We are developing our PSMA-TRACTr product candidate for the treatment of mCRPC. In a preclinical study, PSMA-TRACTr showed a 500-fold reduced ability to induce T cell-mediated killing of prostate cancer cells when masked compared to when unmasked. In addition, we found that our PSMA-TRACTr was well-tolerated in NHPs, substantially reduced cytokine release relative to the unmasked TCE, and had a prolonged half-life.

Prostate cancer overview

Excluding nonmelanoma skin cancer, prostate cancer is the most common type of cancer in men and the second most common type of cancer in the United States. Approximately 3.5 million men live with prostate cancer in the United States. Approximately 13 percent of men will be diagnosed with prostate cancer at some point during their lifetime. In 2026, an estimated 333,830 new prostate cancer diagnoses in the United States are expected, representing approximately 15 percent of all new cancer diagnoses. An estimated eight percent of prostate cancer patients develop metastatic disease, which is associated with a five-year survival rate of approximately 38 percent. There will be an estimated 36,320 deaths in the United States due to prostate cancer in 2026.

Treatment options for prostate cancer

Patients diagnosed with the localized, low-risk disease may be followed by active surveillance or treated with definitive therapy by prostatectomy or radiation therapy. Patients with recurrent disease are typically treated with androgen deprivation therapy (ADT), and, for higher-risk disease, ADT in combination with chemotherapy and/or novel hormonal therapies. Androgens, including testosterone and dihydrotestosterone, activate androgen receptor-dependent gene transcription that drives the growth of prostate cancer cells. ADT blocks testicular production of testosterone, otherwise known as a chemical castration, and is administered for patients who present with regional or advanced disease at diagnosis or who develop advanced disease at recurrence. Most ADT-treated patients progress and develop castration-resistant prostate cancer.‌

Treatment options for mCRPC

Castration-resistant prostate cancer (CRPC) is a disease that progresses despite castrate levels of testosterone achieved through orchiectomy or medical castration. The cancer might still respond to other forms of hormone therapy, though such therapy may not be effective.

Novel hormonal therapies, including abiraterone, enzalutamide, apalutamide and darolutamide, are commonly used in combination with ADT across multiple stages of advanced prostate cancer. The prostate cancer vaccine sipuleucel-T may be used in selected patients with minimally symptomatic disease.

Chemotherapy with the drug docetaxel is a standard treatment option and has demonstrated survival benefit, with cabazitaxel available following progression.

Depending on which treatments a patient has had, other options at some point might include: a different type of hormone therapy, such as abiraterone or enzalutamide (if not already used); or for cancers that are PSMA positive, radiopharmaceutical therapy targeting PSMA, including lutetium Lu 177 vipivotide tetraxetan, an approved treatment option for patients with PSMA-positive disease that represents an important advancement in the treatment landscape. For patients whose tumors harbor homologous recombination repair gene alterations such as BRCA1 or BRCA2, PARP inhibitors, including olaparib, rucaparib, talazoparib and niraparib, may be used, including in combination with hormonal therapies. Checkpoint inhibitor immunotherapy may be used for the subset of patients whose tumors exhibit MSI-H, dMMR or high tumor mutational burden.

PSMA is a validated prostate cancer antigen

PSMA is a prostate-specific transmembrane protein expressed at a 100-fold to a 1,000-fold higher level in prostate adenocarcinoma than in the benign prostate. Of importance, PSMA expression is (i) increased when patients are on ADT and (ii) highest in high-grade and mCRPC. Higher PSMA expression has been associated with more aggressive prostate cancer biology and an increased risk of disease recurrence following definitive local therapy, including radical prostatectomy. PSMA’s restricted expression and strong tumor enrichment have driven the development of multiple therapeutic modalities, including imaging agents, radioligand therapies, and a growing number of bispecific T‑cell engagers (TCEs).

Clinical results published in the journal Immunotherapy in 2020 from a Phase 1 trial of pasotuxizumab, a PSMA-targeted TCE, highlight the potential of targeting mCRPC with a PSMA-targeted TCE and the limitations of current approaches. Patients in this trial were initially treated with daily subcutaneous injections, but anti-drug antibodies (ADAs) developed in all treated patients, likely due to the high doses administered. These high doses of the drug, which have a short half-life, were required to achieve sufficient drug exposure to the tumor. The trial was then amended so that clinicians could dose patients using continuous intravenous infusion. PSA levels are a validated measure of disease severity in prostate cancer patients. A dose-dependent reduction in serum PSA levels was observed in the intravenous group, achieving a median best PSA change from baseline of approximately 55 percent in the high dose group. The percentage of patients with PSA reduction of greater than 50 percent in the top three groups was 33 percent. Two patients had long-term PSA responses. One patient had long-term stable disease with 337 days to tumor progression. One patient had near-complete regression of lymph node lesions and bone metastases, with 500 days to disease progression. One of the patients who had initially presented with extensive metastatic disease had a reduction in PSA of greater than 96 percent. Within 43 days of treatment, the extent of the PSMA-expressing tumor was significantly reduced. By day 85, there was little evidence of tumor remaining. While no on-target healthy tissue toxicity was reported, treatment-emergent increases in alanine‌ aminotransferase and aspartate aminotransferase did occur, and over half of patients in this trial developed Grade 3 or Grade 4 drug-related SAEs. Three patients dosed with continuous infusion developed CRS; two were Grade 2 and one was Grade 3.

However, subsequent findings presented at major oncology meetings have indicated that pasotuxizumab’s development was ultimately discontinued due to early ADA formation and the impracticality of continuous infusion dosing. Additionally, multiple next‑generation PSMA T cell engagers have reported CRS, immunogenicity, pharmacokinetic limitations and dosing challenges.

Our TRACTr platform is designed to address these limitations. By incorporating tumor‑activated CD3 masking and improved pharmacokinetic properties, TRACTr is designed to deliver the antitumor activity demonstrated in early PSMA‑TCE studies while aiming to reduce systemic T‑cell activation and mitigate CRS risk.

Our solution: JANX007

We designed JANX007 as a single-masked TRACTr in which the PSMA-binding domain is unmasked. The T cell-specific binding domain (CD3e) is masked to prevent CRS. We illustrate the JANX007 structure in the figure below.

We observed that our PSMA-TRACTr product candidate demonstrated an approximately 500-fold shift in activating T cell killing of PSMA expressing tumor cells in an in vitro assay in its masked form compared with the unmasked form, as shown in the figure below. This difference may reduce toxicities associated with PSMA expression outside of tumors.

Figure 9. Our masked PSMA-TRACTr was 500-fold less potent in activating T cell killing of PSMA expressing tumors than when the mask was removed in an in vitro assay

In non-human primates (NHPs), our PSMA-TRACTr demonstrated a half-life of approximately 119 hours. By comparison, pasotuxizumab has been reported to have a half-life of approximately one to three hours in humans and required continuous intravenous infusion for 5 weeks to maintain sufficient drug exposure, representing a potential burden for patients. The figure below illustrates our PSMA-TRACTr and the PSMA-TCE half-lives in NHPs. For reference, the projected human efficacious dose (pHED) of 100pM for pasotuxizumab, based on the clinical trial protocol for its Phase 1, study is also shown.

Figure 10. Our PSMA-TRACTr had a half-life of 119 hours in NHPs

In this same study, dosing our PSMA-TRACTr at 87µg/kg resulted in minimal levels of inflammatory cytokine production relative to an unmasked PSMA-TCE at 10µg/kg, which led to a greater than 130-fold expression of IL-6, as shown in the figure below. These data suggest our PSMA-TRACTr will have the potential to reduce CRS risk relative to an unmasked PSMA-TCE. In a separate study, our PSMA-TRACTr dosed at 1,000µg/kg once-weekly for three weeks in NHPs, and no dose-limiting toxicities were identified.

Figure 11. Dosing of our PSMA-TRACTr in NHPs had minimal effects on inflammatory cytokine levels, several of which were below the limit of quantification (LOQ). In contrast, dosing of a PSMA-TCE led to substantial levels of IL-6 as well as elevation of other inflammatory cytokines commonly observed in CRS.

Clinical development

In October 2022, the first patient was dosed with JANX007 in a first-in-human Phase 1 clinical trial in patients with prostate cancer. This open-label, multicenter study to assess the safety, tolerability, PK, PD, and the preliminary efficacy of JANX007 administered as a single agent in adult subjects with mCRPC (NCT05519449).

In December 2025, updated interim clinical data demonstrated durability across both QW and Q2W Phase 1a expansion cohorts. As of the October 15, 2025 data cutoff, a total of 109 patients had been treated across the Phase 1a dose escalation and Phase 1b expansion trials of JANX007. The patients enrolled in the Phase 1a trial were heavily pre-treated with a median of four prior lines of therapy. The patients enrolled in the Phase 1b expansion trial were taxane-naïve mCRPC. Patients from the Phase 1 trials

demonstrated high PSA response rates and deep PSA declines. Anti-tumor activity was observed with confirmed and unconfirmed partial responses in 30% (8/27) of RECIST-evaluable patients. Encouraging durability was observed in both the QW and Q2W expansions with radiographic progression-free survival (rPFS) ranging from 7.9 to 8.9 months and the rPFS of the Q2W expansion group comparing favorably to the QW expansion group. Preliminary Phase 1b data in taxane-naïve patients demonstrated rapid and deep PSA reductions with primarily grade 1 CRS. Additionally, tumor burden analysis suggested potential for improved rPFS in JANX007 treated earlier line patients. JANX007 demonstrated a manageable safety profile with CRS primarily limited to cycle 1 and grades 1 and 2. Additionally, a CRS mitigation strategy was identified that maintains the grade 1 and 2 CRS profile. Based on the safety and preliminary efficacy observed to date, we have initiated the first of our planned Phase 1b expansion cohorts to further characterize JANX007 and guide future development. These cohorts include taxane-naïve mCRPC, combination with an androgen receptor pathway inhibitor (darolutamide), and patients whose disease has progressed following prior PARP inhibitor therapy. In May 2025, we announced initiation of the Phase 1b expansion study in taxane-naïve mCRPC. We believe these studies will help refine patient selection, dosing and combination strategies to support potential late-stage development.

rPFS data

Updated interim rPFS analyses from the expanded patient set as of October 15, 2025 were consistent with the rPFS data previously reported in May 2025. The Q2W expansion cohort demonstrated rPFS that compared favorably to the QW cohort, and informed our Phase 1b development strategy.

Figure 12. Updated rPFS consistent with May 2025 update and Q2W compared favorably

Phase 1b data

As of the October 15, 2025 data cutoff, Phase 1b data in taxane-naïve patients demonstrated rapid and deep PSA reductions with primarily grade 1 CRS.

Figure 13. P1b taxane-naïve Patients receiving 6mg QW dose regimen

Our EGFR-TRACTr (JANX008)

JANX008 is being studied in a Phase 1 clinical trial for the treatment of multiple EGFR-overexpressing solid tumors.

Our solution: JANX008

We designed JANX008 as a dual-masked TRACTr in which both the EGFR and T cell-binding domains are designed to be masked. We illustrate the JANX008 structure below.

Figure 14. Structure of JANX008

We found that our EGFR-TRACTr product candidate exhibited an 8,500-fold shift in activating T cell killing of EGFR expressing HCT116 tumor cells in an in vitro assay when it was masked than when the mask was removed, as shown below. We believe this differential in activity can significantly reduce healthy tissue toxicities caused by EGFR expression outside of tumors.

Since these cells harbor KRAS mutations and are resistant to anti-EGFR antibodies, the observed EGFR-TCE activity suggests that EGFR inhibitor-resistant (including KRAS mutants sensitive to our EGFR-TRACTr) CRC will be sensitive to our EGFR-TRACTr. Our observation is consistent with published studies demonstrating EGFR-TCE activity in cell lines resistant to EGFR mAbs and harbored KRAS mutations. The results of our study are depicted in the figure below.

Figure 15. Our masked EGFR-TRACTr was over 8,500-fold less potent at T cell-mediated killing of EGFR-expressing tumor cells than an equivalent unmasked TCE in an in vitro assay

In NHPs, our EGFR-TRACTr demonstrated a half-life of approximately 94 hours. This compares to the half-life of the unmasked EGFR-TCE of approximately one hour. In the figure below, we illustrate our EGFR-TRACTr and the EGFR-TCE half-lives in a study in NHPs.

Figure 16. Our EGFR-TRACTr had a half-life of approximately 94 hours in NHPs

In this same study, dosing our EGFR-TRACTr at 100µg/kg resulted in minimal levels of inflammatory cytokine release, relative to an unmasked EGFR-TCE at 10µg/kg, which led to a greater than 20-fold expression of IL-6. We believe these data suggest that our EGFR-TRACTr has the potential to reduce CRS risk relative to an unmasked EGFR-TCE. Furthermore, in a separate study of our EGFR-TRACTr dosed at 600µg/kg once-weekly for three weeks in NHPs, no dose-limiting toxicities were identified.

Figure 17. Dosing of our EGFR-TRACTr in NHPs had minimal effects on inflammatory cytokine levels. In contrast, dosing of an EGFR-TCE led to substantial levels of IL-6 as well as elevation of other inflammatory cytokines commonly observed in CRS

Clinical development

The first patient was dosed with JANX008 in April 2023 and in February 2024 we announced positive early data for JANX008 that displayed anti-tumor activity in multiple tumor types with low-grade CRS and predominantly low-grade TRAEs. In December 2025, we announced the initiation of Phase 1a expansion studies in multiple solid tumor indications. The tumor types were selected based on efficacy and safety data observed to date in the now concluded Phase 1a escalation study. Building on the results from dose escalation, the ongoing expansion cohorts are evaluating JANX008 in tumor types where early signals of activity and tolerability were observed. These studies are designed to refine patient selection, optimize dosing and inform the prioritization of indications for future clinical development.

Our ARM platform

Our ARM platform applies our tumor-activated masking technology to bispecific T cell engagers to address key limitations of conventional approaches. The platform is designed to enable rapid, deep and durable B-cell depletion in blood and lymphoid tissues with prolonged memory B-cell reset. Based on nonclinical evaluations, ARM has shown a large safety window and reduced CRS relative to contemporary TCEs. The ARM platform is engineered to sustain T‑cell function, expand memory T cell compartments and limit exhaustion, providing the potential for improved durability of response and a lower risk of infection versus conventional TCE approaches. In addition, ARM’s off‑the‑shelf, subcutaneous, and re‑dosable format is intended to support community‑based outpatient administration and flexible retreatment.

Figure 18. Janux ARMs are designed to improve efficacy and safety of TCEs in oncology and I&I

Our CD19-ARM

Our lead ARM program is designed to target CD19 because non-malignant B cells express the CD19 target and play a role in numerous autoimmune diseases which can affect multiple organ systems. The CD19-ARM is designed to deliver deep and durable B-cell depletion with the goal of resetting the immune system and achieving extended drug-free remission for patients. The CD19-ARM leverages a bispecific antibody format to target CD19-expressing B cells, aiming to overcome the limitations of conventional TCEs by providing rapid, tissue-penetrant B-cell depletion and a favorable safety profile. Non-clinical and preclinical data support the potential for prolonged memory B-cell reset, predominantly naïve B-cell repopulation, and reduction of autoantibodies, positioning CD19-ARM as a differentiated, off-the-shelf therapy for autoimmune indications.

CD19-ARM achieved rapid and deep B-cell depletion in both peripheral blood and lymphoid tissues of non-human primates, with a single dose resulting in sustained depletion of memory B-cell populations. The observed kinetics demonstrate that B-cell counts drop sharply within days of dosing and remain low for several weeks, supporting an extended dosing interval for autoimmune patients. Importantly, the repopulation phase is characterized by a predominance of naïve B cells, which provides the potential for durable clinical responses with the ability to re-treat with a single dose to address disease flares.

Figure 19. CD19-ARM displayed in periphery and tissues with a prolonged memory cell reset

CD19-ARM demonstrated a ≥100-fold safety margin in non-human primate studies relative to contemporary TCEs with respect to CRS. Data reflects that competitor bispecifics are limited by CRS dosing constraints, often requiring euthanasia at higher doses, whereas CD19-ARM enables efficacy without triggering significant cytokine release. Peak IL-6 levels following CD19-ARM administration are substantially lower than those observed with other agents, supporting the potential for outpatient treatment and flexible dosing. This safety advantage is attributed to the ARM platform’s design, which minimizes cytokine-driven toxicities and healthy tissue adverse events, thereby enabling higher dosing and deeper B-cell depletion.

Figure 20. CD19-ARM displayed potentially differentiated safety and CRS profile

Ex vivo data demonstrated that CD19-ARM consistently achieved potent and complete B-cell depletion across multiple autoimmune patient samples, including those with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and myasthenia gravis (MG). The platform shows low EC50 values and high percentages of B-cell killing in disease-relevant peripheral blood mononuclear cells (PBMCs), indicating robust activity regardless of disease context. These results support the broad applicability of CD19-ARM in diverse autoimmune indications and reinforce its potential to deliver deep and durable responses where conventional therapies may be limited.

Figure 21. CD19-ARM demonstrates activity in multiple autoimmune patient samples

Clinical development

We have initiated a Phase 1 clinical study of our CD19-ARM program (JANX011), which is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JANX011 in healthy volunteers. JANX011 is being developed for autoimmune diseases, and the initiation of this study represents an important step in the advancement of our ARM platform from preclinical development into the clinic.

Manufacturing

Certain features of our TRACTr, TRACIr and ARM molecules allow for their development, manufacturing and control processes to closely resemble those used for standard monoclonal antibodies. First, our platform molecules are readily expressed at high levels recombinantly in common Chinese hamster ovary cells. Second, our platform molecules bind protein A via the anti-albumin-binding domain. Protein A affinity chromatography is the standard technique for capturing recombinant monoclonal antibodies and is a very robust purification procedure due to its specificity. After the protein A affinity chromatography step,

TRACTrs, TRACIrs and ARMs are further purified and polished using standard ion exchange, hydrophobic-interaction and/or multi-modal chromatography, virus filtration, and ultrafiltration/diafiltration formulation steps. Our dosing strategy gives us the advantage of manufacturing at relatively modest scale and formulating our drug products at tolerable protein concentrations in typical formulation matrices. Through developability and manufacturability assessments, we continue to verify that our platform constructs have advantageous properties that include high solubility, minimal aggregation, and good stability. We believe all these attributes allow our products to be manufactured at a substantially lower cost-per-dose than monoclonal antibodies.

We do not own or operate and currently have no plans to establish current good manufacturing practice (cGMP) manufacturing facilities and laboratories. We currently rely on third-party manufacturers and suppliers for the raw materials and starting components used to make our TRACTrs, TRACIrs and ARMs, and we expect to continue to do so to meet our development, clinical and commercial needs. Our third-party manufacturers are qualified to manufacture our product candidates under cGMP requirements and other applicable laws, guidance and regulations. We believe there are multiple sources for all the materials and components required for the manufacture of our product candidates.

All our TRACTrs, TRACIrs and ARMs are and will continue to be manufactured from a vial of a master cell bank or working cell bank of that biologic therapeutic’s production cell line. We have or intend to have one master cell bank for each of our platforms that was or will be produced and tested in accordance with cGMP and applicable regulations. Each master cell bank is or will be stored in two independent locations, and we intend to produce working cell banks for each product candidate later in the course of product development. It is possible that we could lose our cell banks from our storage locations and have our manufacturing severely impacted by the need to replace the cell banks. However, we believe we have an adequate backup should any particular cell bank be lost in a catastrophic event.

We currently and plan to continue to obtain bulk drug substance (BDS) for our TRACTrs, TRACIrs and ARMs from a third-party contract manufacturer. While any reduction or halt in the supply of BDS from this contract manufacturer could limit our ability to develop our product candidates until a replacement contract manufacturer is found and qualified, we believe that we will have sufficient BDS and future manufacturing campaign capacity to support current and future clinical trial programs. We have developed our supply chain for each of our product candidates and intend to continue to put in place agreements under which our third-party contract manufacturers will generally provide us with necessary quantities of BDS and drug product on a project-by-project basis, based on our development and commercial supply needs.

Competition

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on proprietary products. We face potential competition from many different sources, including large pharmaceutical and biotechnology companies, academic institutions, government agencies, and other public and private research organizations that conduct research, seek patent protection, and establish collaborative arrangements for the research, development, manufacturing, and commercialization of cancer immunotherapies. Any product candidates that we successfully develop and commercialize will compete with new immunotherapies that may become available in the future.

We compete in the segments of pharmaceutical, biotechnology, and other related markets that develop immuno-oncology and autoimmune disease treatments. Many other companies have commercialized and/or are developing immuno-oncology or autoimmune treatments including large pharmaceutical and biotechnology companies, such as AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Gilead, GSK, Johnson & Johnson, Merck & Co., Lilly, Novartis, Pfizer, Regeneron, Sanofi, Takeda and Roche/Genentech.

We face significant competition from pharmaceutical and biotechnology companies that target specific tumor-associated antigens using immune cells or other cytotoxic modalities. These generally include immune cell redirecting therapeutics (e.g., TCEs, T cell immunomodulators), adoptive cellular therapies (e.g., CAR T cell therapies), antibody-drug conjugates, targeted radiopharmaceuticals, targeted immunotoxin, and targeted cancer vaccines.

With respect to our lead PSMA-TRACTr, we are aware of multiple PSMA-targeting therapeutics in development, which include, but are not limited to: T cell engagers from AbbVie, Amgen, Crescendo Biologics, GSK, Johnson & Johnson, Lava Therapeutics, Chugai/Roche, Regeneron, Takeda, Vir Biotechnology and Xilio Therapeutics; T cell immunomodulators from Astellas, Regeneron, Johnson & Johnson, Roche and Xencor; antibody-drug conjugates from AbbVie, AstraZeneca, Daichii/Merck, Novartis and Johnson & Johnson; CAR T cell therapies from Gilead; and radiopharmaceuticals from AstraZeneca, BMS, Johnson & Johnson, Novartis, Lantheus/Lilly, Telix and Bayer. In addition, cellular therapies, including PSMA-targeted CAR-T approaches, are being evaluated in clinical development.

With respect to our EGFR-TRACTr, we face competition from several targeted therapies approved by the U.S. Food and Drug Administration (FDA) to treat NSCLC, SCCHN, RCC and CRC, including, but not limited to, Genmab/Janssen’s amivantamab, Roche’s bevacizumab, Amgen’s panitumumab, Eli Lilly/Merck KGaA’s cetuximab, Bayer’s regorafenib, and Eli Lilly’s ramucirumab. We also face competition from other anti-EGFR immunotherapies that are in clinical development. We believe that the most advanced candidates are those being developed by AstraZeneca, Bristol Myers Squibb, Dragonfly, KangaBio, Lava Therapeutics/Pfizer, Merus, Regeneron, Chugai/Roche and Vir Biotechnology. Additional approaches include antibody-drug conjugates targeting EGFR that are in clinical development.

With respect to our CD28 TRACIr platform, we are aware of other CD28-based multispecifics that are in clinical development for solid tumors. We believe the most advanced candidates are ‌Regeneron’s nezastomig, REGN5668 and REGN7075, Sanofi’s SAR443216, Janssen/Xencor’s XmAb808 and Johnson & Johnson’s JNJ-9401. Additional competition may come from other companies developing costimulatory multispecifics, including, but not limited to AbbVie, AstraZeneca, Genmab/BioNTech, Inhibrx, Incyte/Merus, Johnson & Johnson, Chugai/Roche and Xencor.

We are currently developing a pipeline of TRACTr and other protease-activated therapeutics that face increasing competition from other biologic prodrug developers, which include, but are not limited to, Adagene, Astellas, BioAtla, Chugai Pharmaceutical Co./Roche Holding AG, CytomX Therapeutics, Merck & Co., Regeneron, Vir Biotechnology and Xilio Therapeutics.

With respect to our CD19-ARM, we expect to face competition across three broad therapeutic approaches in autoimmunity: (i) B‑cell depletion and B‑cell–targeting modalities (including anti‑CD19/anti‑CD20 biologics, emerging CD19/CD20 bispecific T‑cell engagers and immunomodulators, and CD19‑directed CAR‑T cell therapies) from companies such as AbbVie/Genmab, Amgen, Antengene, BMS, Cabaletta, Candid Therapeutics, Cullinan Therapeutics, Fate Therapeutics, Gilead, Kyverna Therapeutics, Lilly, Novartis, Regeneron, Roche/Genentech, TG Therapeutics, Xencor and Zenas BioPharma, (ii) therapies that lower pathogenic autoantibodies or otherwise modulate humoral immunity (e.g., FcRn antagonists) from companies such as Argenx, Biogen, Dianthus Therapeutics, Immunovant, Johnson & Johnson, Sanofi and UCB and (iii) agents directed at B‑cell survival/aplasia pathways (e.g., BAFF/BAFF‑R inhibitors) from companies such as GSK, Novartis, Otsuka, RemeGen, Vera Therapeutics, Vor Biopharma and Vertex. Additional approaches include CD20 monoclonal antibodies, anti-CD19 monoclonal antibodies and cellular therapies being developed for autoimmune diseases.

Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved drugs than we do. Mergers and acquisitions in the pharmaceutical, biotechnology, and diagnostic 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. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites, and enrolling subjects for any future clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

We could see a reduction or elimination of our commercial opportunity if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we or our collaborators may develop. Our competitors also may obtain FDA or foreign regulatory approval for their products more rapidly than we may obtain approval for our product candidates, which could result in our competitors establishing a strong market position before we or our collaborators are able to enter the market. The key competitive factors affecting the success of all of our programs are likely to be efficacy, safety, and convenience. If we are not successful in developing, commercializing, and achieving higher levels of reimbursement than our competitors, we will not be able to compete against them and our business would be materially harmed.

Research Collaboration and Exclusive License Agreement with Merck Sharp & Dohme Corp.

On December 15, 2020, we and Merck Sharp & Dohme Corp. (Merck), entered into a research collaboration and exclusive license agreement (the Merck Agreement). The Merck Agreement provides that we and Merck will use commercially reasonable efforts to engage in certain research and development activities related to our TRACTr platform technology that are to be funded by Merck up to specified annual limits. Pursuant to the agreement, Merck had the right to designate up to two TRACTr product candidates in each case to be developed against a target (a Collaboration Target). We granted Merck an exclusive, worldwide, royalty-bearing, sublicensable license to certain of our patent rights and know-how with respect to the Collaboration Targets, in each case once designated by Merck, to research, develop, make, have made, use, import, offer to sell, and sell compounds and any licensed products related thereto. Merck selected one of the Collaboration Targets upon execution of the Merck Agreement and selected the second Collaboration Target in May 2022. In August 2025, we announced the first patient was dosed in the lead collaboration program. Following the research term, Merck will have the sole right to research, develop, manufacture, and commercialize the licensed compounds and products directed against the Collaboration Targets.

In consideration of the rights granted to Merck under the Merck Agreement, Merck paid us a one-time upfront payment of $8.0 million in respect of the first Collaboration Target and paid us an additional one-time payment of $8.0 million upon the selection of the second Collaboration Target. In addition, Merck is required to make milestone payments to us upon the successful completion of certain regulatory and development milestones, in an aggregate amount not to exceed $142.5 million for each of the two Collaboration Targets ($285.0 million collectively for both Collaboration Targets). Merck is also required to make milestone payments to us upon the successful completion of certain sales milestones, in an aggregate amount not to exceed $350.0 million for each licensed product under either of the Collaboration Targets.

Merck is also required to make tiered royalty payments on a product-by-product and country-by-country basis, ranging from low single-digit to low teens percentage royalty rates, on specified portions of annual net sales for licensed products under either of the Collaboration Targets that are commercialized. Such royalties are subject to reduction, on a product-by-product and country-by-country basis, for licensed products not covered by patent claims, or that require Merck to obtain a license to third-party intellectual

property in order to commercialize the‌ licensed product, or that are subject to compulsory licensing. Merck’s royalty obligation with respect to a given licensed product in a given country begins upon, and ends no less than 10 years following, the first sale of such product in such country.

The Merck Agreement will terminate at the end of the calendar year in which the expiration of all royalty obligations occurs for all licensed products under the agreement. Merck has the unilateral right to terminate the agreement in its entirety or on a Collaboration Target by Collaboration Target basis at any time and for any reason upon prior written notice to us. Both parties have the right to terminate the agreement for an uncured material breach, certain illegal or unethical activities, and insolvency of the other party. Upon expiration of the agreement but not early termination thereof, and provided all payments due under the agreement have been made, Merck’s exclusive licenses under the agreement will become fully paid-up and perpetual.

License Agreement with WuXi Biologics (Hong Kong) Limited

In April 2021, we entered into a cell line license agreement (Cell Line License Agreement) with WuXi Biologics (Hong Kong) Limited (WuXi Biologics), pursuant to which we received a non-exclusive, worldwide, sublicensable license under certain of WuXi Biologics’ patent rights, know-how and biological materials (WuXi Biologics Licensed Technology), to use the WuXi Biologics Licensed Technology to make, use, sell, offer for sale and import certain therapeutic products produced through the use of the cell line licensed by WuXi Biologics under the Cell Line License Agreement (WuXi Biologics Licensed Product). Specifically, the WuXi Biologics Licensed Technology is used to manufacture a component of our PSMA-TRACTr and EGFR-TRACTr product candidates.

In consideration for the license, we agreed to pay WuXi Biologics a non-refundable, one-time license fee of $0.2 million upon Wuxi Biologics’ achievement of a certain technical milestone, which was achieved in May 2021. Additionally, if we do not engage WuXi Biologics or its affiliates to manufacture the WuXi Biologics Licensed Products for our commercial supplies, we are required to make royalty payments to WuXi Biologics in an amount equal to a low single-digit percentage of specified portions of net sales of WuXi Biologics Licensed Products manufactured by a third-party manufacturer. We have the right (but not the obligation) to buy out our remaining royalty obligations with respect to each WuXi Biologics Licensed Product by paying WuXi Biologics a one-time payment in an amount ranging from low single digit million dollars to a maximum of $15.0 million depending on the development and commercialization stage of the WuXi Biologics Licensed Product (the Buyout Option), and upon such payment, our license with respect to such WuXi Biologics Licensed Product will become fully paid-up, irrevocable, and perpetual. The royalty obligations will remain in effect during the term of the Cell Line License Agreement so long as we have not exercised the Buyout Option.

The Cell Line License Agreement will continue indefinitely unless terminated (i) by us upon three months’ prior written notice and our payment of all amounts due to WuXi Biologics through the effective date of termination, (ii) by either party for the other party’s material breach that remains uncured for 30 days after written notice, or (iii) by WuXi Biologics if we fail to make a payment and such failure continues for 30 days after receiving notice of such failure.

Exclusive License and Collaboration Agreement with Bristol-Meyers Squibb Company

In January 2026, we entered into an exclusive license and collaboration agreement (BMS Agreement) with Bristol-Myers Squibb Company (BMS) to develop and commercialize an undisclosed, novel tumor-activated therapeutic targeting a validated solid tumor antigen expressed across several human cancer types (BMS Collaboration Target).

Under the BMS Agreement, we granted BMS an exclusive, sublicensable, royalty-bearing license, under the relevant patents and know-how owned or in-licensed by us, to develop, manufacture, commercialize and otherwise exploit a tumor-activated therapeutic targeting the BMS Collaboration Target (Licensed Compounds, and products containing Licensed Compounds, Licensed Products) worldwide for all uses. We agreed, during the term of the BMS Agreement, not to (i) engage in any discovery, research, development, manufacturing or commercialization activities related to any T-cell engager directed to the BMS Collaboration Target, other than the conduct of activities under the BMS Agreement, or (ii) enable any third party to do so, subject to customary exceptions.

Under the BMS Agreement, we are responsible for conducting, at our own expense and pursuant to an agreed joint development plan, pre-clinical development until IND submission for one Licensed Compound. Thereafter, BMS will have the sole right, at its own expense, to develop, manufacture and commercialize Licensed Products, except that we will manufacture and supply Licensed Products to BMS for early clinical development for a limited time period. BMS is obligated to use commercially reasonable efforts to develop and seek regulatory approval of and commercialize at least one Licensed Product in the U.S.

As consideration for the rights granted to BMS under the BMS Agreement, we will receive an upfront payment of $15.0 million and, upon achievement of certain development, regulatory and sales milestones, up to $785.0 million in milestone payments, including $35.0 million related to a near term milestone. In addition, BMS is obligated to make tiered royalty payments to us based on annual net sales of Licensed Products, with the applicable royalty rates ranging from high-single digit to low-double digit percentages, subject to certain customary reductions. Such royalty obligation is on a Licensed Product-by-Licensed Product and country-by-country basis, beginning on the first commercial sale of a Licensed Product in a country and expiring on the latest of (i) 10 years from such first commercial sale in such country, (ii) the expiration of the last to expire valid claim of the relevant patents in such country or (iii) expiration of regulatory exclusivity for such Licensed Product in such country.

The BMS Agreement will remain in effect until it expires on a Licensed Product-by-Licensed Product and country-by-country basis with the expiration of the applicable royalty term. Each party may terminate the BMS Agreement for the uncured material breach or bankruptcy of the other party. BMS may also terminate the BMS Agreement for safety reasons and for convenience, and we may terminate the BMS Agreement for BMS’ cessation of development and commercial activities for Licensed Products. Upon termination of the BMS Agreement, all rights and licenses granted to BMS for the Licensed Compounds and Licensed Products will terminate.

Intellectual Property

We strive to protect and enhance the proprietary technology, inventions, and improvements that are commercially important to our business, including seeking, maintaining and defending patent rights, whether developed internally or licensed from third parties. We own the patents and patent applications relating to our TRACTr, TRACIr and ARM platform technologies. Our intellectual property policy includes seeking to protect our proprietary position by, among other methods, striving to obtain issued patents by filing and prosecuting patent applications in the United States and in jurisdictions outside of the United States, directed to our proprietary technology, inventions, improvements, and product candidates that are important to the development and implementation of our business. We also rely on trade secrets and know-how relating to our proprietary technology and product candidates, continued innovation, and in-licensing opportunities to develop, strengthen and maintain our proprietary position in the field of immunotherapy. We also plan to rely on data exclusivity, market exclusivity, and patent term extensions when available. Our commercial success will depend in part on our ability to obtain and maintain patent and other proprietary protection for our technology, inventions, and improvements; to preserve the confidentiality of our trade secrets and know-how; to obtain and maintain licenses to use intellectual property owned by third parties; to defend and enforce our proprietary rights, including any patents that we may own in the future; and to operate without infringing on the valid and enforceable patents and other proprietary rights of third parties.

As of February 10, 2026, we own 42 pending U.S. provisional and non-provisional patent applications, 4 U.S. patents, 9 pending patent applications filed under the Patent Cooperation Treaty (PCT), 115 foreign patent applications and 7 foreign patents. Specifically, we have 1 U.S. non-provisional patent application and 6 foreign patent applications directed to compositions of our TRACTr and TRACIr platform technologies that are applicable across our product candidates for our PSMA-TRACTr (JANX007) and EGFR-TRACTr (JANX008) programs. We also have 1 U.S. patent, 2 U.S. non-provisional patent applications, 19 foreign patent applications, and 6 foreign patents that cover compositions and applications of various components and aspects of our TRACTr and TRACIr platform technologies and have general applicability across product candidates. We have 3 U.S. non-provisional patent applications and 15 foreign patent applications that cover compositions and applications of components of our TRACTr platform technology that has general applicability to TRACTr product candidates or backup sequences for future development. We further have 1 U.S. patent, 8 U.S. provisional and non-provisional patent applications, 26 foreign patent applications and 1 foreign patent specific to JANX007, and 4 U.S. non-provisional patent applications, 2 U.S. patents, 1 PCT patent application, and 18 foreign patent applications specific to JANX008, and 2 PCT patent applications and 2 foreign patent applications specific to PSMA x CD28 TRACIr. We have 11 U.S. provisional and non-provisional patent applications, 3 PCT patent applications, and 27 foreign patent applications that are directed to unnamed TRACTr and TRACIr programs for potential future development and 1 PCT patent application and 2 foreign patent applications that cover components and aspects of TRACIr platform technology. In addition, we have 13 U.S. provisional and non-provisional patent applications and 2 PCT patent applications relating to compositions of our other proprietary antibodies, compounds, technology, inventions, improvements, and other aspects of our technology. Any patents and patents that issue from these pending patent applications are expected to expire between 2038 and 2046 absent any patent term adjustments or extensions. Related to the strategic research collaboration with Merck we also co-own with Merck Sharpe & Dohme LLC 1 U.S. non-provisional patent application, 1 PCT patent application, and 5 foreign patent applications which are expected to expire in 2045 absent any patent term adjustments or extensions. We also possess substantial know-how and trade secrets relating to the development and commercialization of our product candidates, including related manufacturing processes and technology.

With respect to our product candidates and processes, we intend to develop and commercialize in the normal course of business, and we intend to pursue patent protection directed to, when possible, compositions, methods of use, methods of making, dosing, and formulations. We may also pursue patent protection with respect to manufacturing, therapeutic development processes and technologies, and therapeutic delivery technologies.

Issued patents can provide protection for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance, and the legal term of patents in the countries in which they are obtained. In general, patents issued for applications filed in the United States can provide exclusionary rights for 20 years from the earliest effective filing date excluding U.S. provisional applications. In addition, in certain instances, the term of an issued U.S. patent that is directed to or claims an FDA approved product can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period, which is called patent term extension. The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval. The term of patents outside of the United States varies in accordance with the laws of the foreign jurisdiction, but typically is also 20 years from the earliest effective filing date excluding U.S. provisional applications. However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its claims, the availability of regulatory-related extensions, the availability of legal remedies in a particular country, and the validity and enforceability of the patent.

The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions. No consistent policy regarding the scope of claims allowable in patents in the field of immunotherapy has emerged in the United States. The relevant patent laws and their interpretation outside of the United States is also uncertain. Changes in either the patent laws or their interpretation in the United States and other countries may diminish our ability to protect our technology or product candidates and enforce the patent rights that we may license, and could affect the value of such intellectual property. In particular, our ability to stop third parties from making, using, selling, offering to sell, or importing products that infringe our intellectual property will depend in part on our success in obtaining and enforcing patent claims that cover our technology, inventions, and improvements. With respect to company-owned intellectual property, we cannot guarantee that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may file in the future, nor can we be sure that any patents that may be granted to us in the future will be commercially useful in protecting our products, the methods of use or manufacture of those products. Moreover, even the issued patents that we license do not guarantee us the right to practice our technology in relation to the commercialization of our products. Patent and other intellectual property rights in the pharmaceutical and biotechnology space are evolving and involve many risks and uncertainties. For example, third parties may have blocking patents that could be used to prevent us from commercializing our product candidates and practicing our proprietary technology, and the issued patents that we may in-license and those that may issue in the future may be challenged, invalidated, or circumvented, which could limit our ability to stop competitors from marketing related products or could limit the term of patent protection that otherwise may exist for our product candidates. In addition, the scope of the rights granted under any issued patents may not provide us with protection or competitive advantages against competitors with similar technology. Furthermore, our competitors may independently develop similar technologies that are outside the scope of the rights granted under any issued patents that we own or that we may exclusively in-license. For these reasons, we may face competition with respect to our product candidates. Moreover, because of the extensive time required for development, testing and regulatory review of a potential product, it is possible that, before any particular product candidate can be commercialized, any patent protection for such product may expire or remain in force for only a short period following commercialization, thereby reducing the commercial advantage the patent provides. A comprehensive discussion on risks relating to intellectual property is provided under the section of this Annual Report titled “Risk Factors—Risks Related to Our Intellectual Property.”

Government Regulation

Government authorities in the United States at the federal, state and local level and in other countries and jurisdictions, including the European Union (EU), extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products, such as our investigational medicines and any future investigational medicines. Generally, before a new drug or biologic can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

Regulatory Approval in the United States

In the United States, pharmaceutical products are subject to extensive regulation by the FDA. The Federal Food, Drug, and Cosmetic Act (FDCA) and the Public Health Service Act (PHSA), and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of biologic products. Failure to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to approve pending biologics license applications (BLAs), warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution.

A biologic must be approved by the FDA pursuant to a BLA before it may be legally marketed in the United States. The process generally involves the following:

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completion of extensive preclinical laboratory and animal studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice (GLP) requirements;

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submission to the FDA of an investigational new drug application (IND), which must become effective before human clinical trials may begin;

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

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

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submission to the FDA of a BLA;

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payment of any user fees for FDA review of the BLA;

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a determination by the FDA within 60 days of its receipt of a BLA to accept the filing for review;

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

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satisfactory completion of any potential FDA audits of the clinical trial sites that generated the data in support of the BLA to assure compliance with GCPs and integrity of the clinical data;

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FDA review and approval of the BLA, including consideration of the views of any FDA advisory committee; and

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compliance with any post-approval requirements, including REMS, where applicable, and post- approval studies required by the FDA as a condition of approval.

Preclinical Studies

Before testing any biological product candidates in humans, the product candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluation of product candidates and formulations, as well as in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical studies, among other things, 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 human clinical trials may begin. Some long-term preclinical testing may continue after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

Clinical Trials

The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control. Clinical trials must be conducted: (i) in compliance with federal regulations; (ii) in compliance with GCPs, an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators and monitors; as well as (iii) under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated in the trial. Each protocol involving testing on U.S. patients and subsequent protocol amendments 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 in relation to 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. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. Information about certain clinical trials, including clinical trial results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website. Information related to the product, patient population, phase of investigation, clinical trial sites and investigators and other aspects of the clinical trial is then made public as part of the registration.

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, the sponsor may submit data from the clinical trial to the FDA in support of a BLA. The FDA will accept a well-designed and well-conducted foreign clinical trial not conducted under an IND if the clinical trial was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials are generally conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, which may overlap or be combined:

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Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpose of these clinical trials is to assess the metabolism, pharmacokinetics, pharmacologic action, side effect tolerability, safety of the product candidate, and, if possible, early evidence of effectiveness.

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Phase 2 clinical trials generally involve studies in disease-affected patients to evaluate proof of concept and/or determine the dosing regimen(s) for subsequent investigations. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified, and a preliminary evaluation of efficacy is conducted.

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Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an

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adequate basis for product labeling. In most cases, the FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the efficacy of the biologic.

A single Phase 3 or Phase 2 trial with other confirmatory evidence may be sufficient in rare instances to provide substantial evidence of effectiveness (generally subject to the requirement of additional post-approval studies).

The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including non-compliance with regulatory requirements or a finding that the patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biologic has been associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether a trial may move forward at designated checkpoints based on access to certain data from the trial.

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

FDA Review Process

Following completion of the clinical trials, the results of preclinical studies and clinical trials are submitted to the FDA as part of a BLA, along with proposed labeling, chemistry and manufacturing information to ensure product quality and other relevant data. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety, purity, and potency of the investigational product to the satisfaction of the FDA. FDA approval of a BLA must be obtained before a biologic or drug may be marketed in the United States. The cost of preparing and submitting a BLA is substantial. Under the PDUFA, each BLA 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 BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication. The applicant under an approved BLA is also subject to an annual program fee.

The FDA reviews all submitted BLAs before it accepts them for filing and may request additional information. The FDA must make a decision on accepting a BLA 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 review of the BLA. Under the goals and policies agreed to by the FDA under PDUFA, the FDA has 10 months, from the filing date, in which to complete its initial review of an original BLA and respond to the applicant, and six months from the filing date of an original BLA designated for priority review. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs, and the review process can be extended by FDA requests for additional information or clarification.

Before approving a BLA, the FDA will generally conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

The FDA also may audit data from clinical trials to ensure compliance with GCP requirements and the integrity of the data supporting safety and efficacy. Additionally, the FDA may refer applications for novel products or products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions, if any. The FDA is not bound by recommendations of an advisory committee, but it generally follows such recommendations when making decisions on approval. The FDA likely will reanalyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process.

After the FDA evaluates a BLA, it will issue either an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the biologic with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter generally outlines the deficiencies in the BLA and may require additional clinical data, additional pivotal clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing in order for FDA to reconsider the application. If a Complete Response Letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application or request an opportunity for a hearing. Even if such data and information are submitted, the FDA may decide that the BLA does not satisfy the criteria for approval.

As a condition of BLA approval, the FDA may require a Risk Evaluation and Mitigation Strategy (REMS) to help ensure that the benefits of the biologic outweigh the potential risks to patients. A REMS can include medication guides, communication plans for healthcare professionals and elements to assure a product’s safe use (ETASU). An ETASU can include, but is not limited to, special

training or certification for prescribing or dispensing the product, dispensing the product only under certain circumstances, special monitoring and the use of patient-specific registries. The requirement for a REMS can materially affect the potential market and profitability of the product. Moreover, the FDA may require substantial post-approval testing and surveillance to monitor the product’s safety or efficacy.

Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan designation to a biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States but for which there is no reasonable expectation that the cost of developing and making the product for this type of disease or condition will be recovered from sales of the product in the United States.

Orphan drug designation must be requested before submitting a BLA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation on its own does not convey any advantage in or shorten the duration of the regulatory review and approval process.

Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the BLA application user fee. In addition, 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 orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same product for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care, or in instances of drug supply issues. Competitors, however, may receive approval of either a different product for the same indication or the same product for a different indication. In the latter case, because healthcare professionals are free to prescribe products for off-label uses based on their independent medical judgement, the competitor’s product could be used for the orphan indication despite another product’s orphan exclusivity.

An orphan-designated product may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation. In addition, exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates.

For example, the fast track program is intended to expedite or facilitate the process for reviewing new products that meet certain criteria. Specifically, product candidates are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to both the product and the specific indication for which it is being studied. The sponsor of a new biologic candidate can request the FDA to designate the candidate for a specific indication for fast track status concurrent with, or after, the submission of the IND for the candidate. The FDA must determine if the biologic candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request. For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s BLA before the application is complete. This “rolling review” is available if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA. Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite development and review, such as breakthrough therapy, priority review and accelerated approval.

Breakthrough therapy designation may be granted for products that are intended, alone or in combination with one or more other products, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Under the breakthrough therapy program, the sponsor of a new biologic candidate may request that the FDA designate the candidate for a specific indication as a breakthrough therapy concurrent with, or after, the submission of the IND for the biologic candidate. The FDA must determine if the biological product qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request. The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical studies in an efficient manner.

Priority review may be granted for products that are intended to treat a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies. The FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review, and for original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).

Accelerated approval may be granted for products that are intended to treat a serious or life-threatening disease or condition on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that 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. In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions or survives. The accelerated approval pathway is most often used in settings in which the course of a disease is long, and an extended period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large studies to demonstrate a clinical or survival benefit. As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

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 standards for approval, but may expedite the development or approval process.

Pediatric Information

Under the Pediatric Research Equity Act (PREA), BLAs or supplements to BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective. The FDA may grant full or partial waivers, or deferrals, for submission of data.

The Best Pharmaceuticals for Children Act (the BPCA) provides a six-month extension of any exclusivity—patent or non-patent—for a biologic if certain conditions are met. Conditions for exclusivity include the FDA’s determination that information relating to the use of a new biologic in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe. Applications under the BPCA are treated as priority applications, with all of the benefits that designation confers.

Post-Approval Requirements

Once a BLA is approved, a product will be subject to certain post-approval requirements. For instance, the FDA closely regulates the post-approval marketing and promotion of biologics, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities and promotional activities involving the Internet. Biologics may be marketed only for the approved indications and in a manner consistent with the provisions of the approved labeling. Although physicians may prescribe products for off-label uses as the FDA and other regulatory authorities do not regulate a physician’s choice of drug treatment made in the physician’s independent medical judgment, they do restrict promotional communications from companies or their sales force with respect to off-label uses of products for which marketing clearance has not been issued. Companies may only share truthful and not misleading information that is otherwise consistent with a product’s FDA approved labeling.

Adverse event reporting and submission of periodic safety summary reports is required following FDA approval of a BLA. The FDA also may require post-marketing testing, known as Phase 4 testing, REMS, and surveillance to monitor the effects of an approved product, or the FDA may place conditions on an approval that could restrict the distribution or use of the product. In addition, quality control, biological product manufacture, packaging and labeling procedures must continue to conform to cGMPs after approval. Biologic manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies. Registration with the FDA subjects entities to periodic unannounced inspections by the FDA, during which the agency inspects a biologic product’s manufacturing facilities to assess compliance with cGMPs. Accordingly, manufacturers must continue to expend time, money and effort in the areas of production and quality-control to maintain compliance with cGMPs. Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with required regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered.

Once an approval is granted, the FDA may withdraw the approval 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, imposition of post-market studies or clinical studies to assess new safety risks or imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:

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

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fines, warning or other enforcement-related letters or holds on post-approval clinical studies;

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refusal of the FDA to approve pending BLAs or supplements to approved BLAs, 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; or

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injunctions or the imposition of civil or criminal penalties.

Biosimilars and Exclusivity

The Biologics Price Competition and Innovation Act of 2009 (the BPCIA) created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference biological product. Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or trials. Interchangeability requires that a biological product be biosimilar to the reference product and that the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times to an individual, that the product and the reference product may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological product without such alternation or switch. A reference biological product is granted 12 years of exclusivity from the time of first licensure of the product and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product. “First licensure” typically means the initial date the particular product at issue was licensed in the United States. Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest or other related entity) for a change (not including a modification to the structure of the

biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity or potency.

Regulatory Approval in the European Union

The European Medicines Agency (EMA) is an agency of the European Union. It coordinates the evaluation and monitoring of centrally authorized medicinal products. Through its Committees, particularly the Committee on Human Medicinal Products (CHMP) it conducted scientific evaluation of applications for EU marketing authorizations, as well as the development of technical guidance and the provision of scientific advice to sponsors.

There are similarities between the process regarding approval of medicinal products in the European Union and that in the United States.

Clinical Trials in the EU

In the EU, clinical trials are governed by the new Clinical Trials Regulation (EU) No 536/2014 (CTR), which entered into application that came into force on January 31, 2022 repealing and replacing the former Clinical Trials Directive 2001/20 (CTD). The CTR is intended to harmonize and streamline clinical trial authorizations, simplify adverse event reporting procedures, improve the supervision of clinical trials and increase transparency. Specifically, the Regulation, which is directly applicable in all EU Member States, introduces a streamlined application procedure via a single entry point, the Clinical Trials Information System (“CTIS”); a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors. A harmonized procedure for the assessment of applications for clinical trials has been introduced and is divided into two parts. Part I assessment is led by the competent authorities of a reference Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU Member States. This assessment is then submitted to the competent authorities of concerned Member States in which the trial is to be conducted for their review. Part II is assessed separately by the competent authorities and Ethics Committees in each concerned EU Member State. Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory. The CTR foresaw a three-year transition period that ended on January 31, 2025. Since this date, all new or ongoing trials are subject to the provisions of the CTR.

In all cases, clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. Medicines used in clinical trials, including ATMPs, must be manufactured in accordance with the guidelines on cGMP and in a GMP licensed facility, which can be subject to GMP inspections.

Manufacturing and import into the EU of investigational medicinal products is subject to the holding of appropriate authorizations and must be carried out in accordance with cGMP.

Review and Approval

Authorization to market a product in the European Union member states proceeds under one of four procedures: a centralized authorization procedure, a mutual recognition procedure, a decentralized procedure or a national procedure. Since our products by their virtue of being antibody-based biologics fall under the centralized procedure, only this procedure will be described here.

Certain drugs, including medicinal products developed by means of biotechnological processes, must be approved via the centralized authorization procedure for marketing authorization. A successful application under the centralized authorization procedure results in a marketing authorization from the European Commission, which is automatically valid in all European Union member states. The other European Economic Area (EEA) countries (namely Norway, Iceland and Liechtenstein) are also obligated to recognize the European Commission decision. The EMA and the European Commission administer the centralized authorization procedure.

Under the centralized authorization procedure, the Committee for Medicinal Products for Human Use (the CHMP), serves as the scientific committee that renders opinions about the safety, efficacy and quality of human products on behalf of the EMA. The CHMP is composed of experts nominated by each member state’s national drug authority, with one of them appointed to act as Rapporteur for the co-ordination of the evaluation with the assistance of a further member of the CHMP acting as a Co-Rapporteur. The CHMP is required to issue an opinion within 210 days of receipt of a valid application, though the clock is stopped if it is necessary to ask the applicant for clarification or further supporting data. The process is complex and involves extensive consultation with the regulatory authorities of member states and a number of experts. Once the procedure is completed, a European Public Assessment Report is produced. If the CHMP concludes that the quality, safety and efficacy of the medicinal product is sufficiently proven, it adopts a positive opinion. The CHMP’s opinion is sent to the European Commission, which uses the opinion as the basis for its decision whether or not to grant a marketing authorization.

After a medicinal product has been authorized by the European Commission and launched in the EEA, it is a condition of maintaining the marketing authorization that all aspects relating to its quality, safety and efficacy must be kept under review by the MAH. Sanctions may be imposed for failure to adhere to the conditions of the marketing authorization. In extreme cases, the authorization may be revoked, resulting in withdrawal of the product from sale.

Conditional Approval and Accelerated Assessment

As per Article 14-a of Regulation (EC) 726/2004, a medicine that is demonstrated to fulfill an unmet medical need may, if its immediate availability is in the interest of public health, be the subject of a conditional marketing authorization on the basis of less complete clinical data than are normally required, subject to specific obligations being imposed on the authorization holder. Fulfilment of these specific obligations is reviewed annually by the EMA. A conditional authorization is valid for 12 months, and may be renewed.

When an application is submitted for a marketing authorization in respect of a medicinal product for human use which is of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure pursuant to Article 14.9 of Regulation (EC) 726/2004. Under the accelerated assessment procedure, the CHMP is required to issue an opinion within 150 days of receipt of a valid application, subject to clock stops. We believe that some of the disease indications in which our product candidates are currently being or may be developed in the future qualify for this provision, and we will take advantage of this provision as appropriate.

Period of Authorization and Renewals

A marketing authorization is initially valid for five years and may then be renewed on the basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state. Once renewed, the marketing authorization shall be valid for an unlimited period, unless the European Commission or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal period. Any authorization which is not followed by the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization shall cease to be valid (the “sunset clause”).

The EU provides opportunities for data and market exclusivity related to certain types of marketing authorizations. Upon grant of related marketing authorization, innovative medicinal products generally benefit from eight years of data exclusivity and 10 years of market exclusivity. Data exclusivity, if granted, prevents regulatory authorities in the EEA from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar marketing authorization application can be submitted, and the innovator’s data may be referenced. The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EEA until 10 years have elapsed from the initial marketing authorization of the reference product in the EEA. The overall ten year period may, occasionally, be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical/biological entity, and products may not qualify for data exclusivity.

Pediatric Development

In the EU, Regulation (EC) No 1901/2006 provides that all MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan (PIP) agreed with the EMA’s Pediatric Committee (PDCO). The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the medicinal product for which MA is being sought. The PDCO can grant a deferral of the obligation to implement some or all of the measures provided in the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults. Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data are not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Once the MA is obtained in all EU Member States and study results are included in the product information, even when negative, the product is eligible for a six-month extension to the Supplementary Protection Certificate (SPC), if any is in effect at the time of authorization or, in the case of orphan medicinal products, a two-year extension of orphan market exclusivity.

Orphan Medicinal Product Designation

In the EU, Regulation (EC) No. 141/2000, as implemented by Regulation (EC) No. 847/2000 provides that a medicinal product can be designated as an orphan medicinal product by the European Commission if its sponsor can establish that (1) the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating conditions; (2) either (a) such conditions affect no more than five in ten thousand persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in developing the medicinal product; and (3) there exists no satisfactory authorized method of diagnosis, prevention or treatment of the condition that has been authorized in the EU or, even if such method exists, the product will be of significant benefit to those affected by that condition.

Regulation (EC) No 847/2000 sets out further provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product. An application for the designation of a medicinal product as an orphan medicinal product must be submitted at any stage of development of the medicinal product but before filing of an MAA. An MA for an orphan medicinal product may only include indications designated as orphan. For non-orphan indications treated with the same active pharmaceutical ingredient, a separate marketing authorization has to be sought.

Orphan medicinal product designation entitles an applicant to incentives such fee reductions or fee waivers, protocol assistance, and access to the centralized MA procedure. Upon grant of an MA, orphan medicinal products are entitled to a ten-year period of market exclusivity for the approved therapeutic indication, which means that the EMA cannot accept another MAA, or grant an MA, or accept an application to extend an MA for a similar product and the European Commission cannot grant an MA for the same indication for a period of ten years. The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed PIP. No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications. Orphan medicinal product designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The period of market exclusivity may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria on the basis of which it received orphan medicinal product designation, including where it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold. Additionally, an MA may be granted to a similar medicinal product with the same orphan indication during the 10 year period if: (i) if the applicant consents to a second original orphan medicinal product application, (ii) if the manufacturer of the original orphan medicinal product is unable to supply sufficient quantities; or (iii) if the second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior to the original orphan medicinal product. A company may voluntarily remove a product from the register of orphan products.

Post-authorization Requirements

Where an MA is granted in relation to a medicinal product in the EU, the holder of the MA is required to comply with a range of regulatory requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products.

Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the individual EU Member States. The holder of an MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (“PSURs”).

All new MAAs must include a risk management plan (“RMP”), describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product. The regulatory authorities may also impose specific obligations as a condition of the MA. Such risk-minimization measures or post-authorization obligations may

include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

In the EU, the advertising and promotion of medicinal products are subject to both EU and EU Member States’ laws governing promotion of medicinal products, interactions with physicians and other health care professionals, misleading and comparative advertising and unfair commercial practices. General requirements for advertising and promotion of medicinal products, such as directed-to-consumer advertising of prescription medicinal products are established in EU law. However, details are governed by regulations in individual EU Member States and can differ from one country to another. For example, applicable laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”), which may require approval by the competent national authorities in connection with an MA. The SmPC is the document that provides information to physicians and other health care professionals concerning the safe and effective use of the product. Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EU.

Data Privacy and Security

In the ordinary course of our business, we process personal or other sensitive, proprietary, and confidential information. Accordingly, we are or may become subject to numerous data privacy and security obligations, including federal, state, local, and foreign laws, regulations, guidance, and industry standards related to data privacy and security. Such obligations may include, without limitation, the Federal Trade Commission Act, the Telephone Consumer Protection Act of 1991, the Children’s Online Privacy Protection Act of 1998, the Controlling the Assault of Non-Solicited Pornography And Marketing Act of 2003, the California Consumer Privacy Act of 2018 (CCPA), the Canadian Personal Information Protection and Electronic Documents Act, Canada’s Anti-Spam Legislation, the European Union’s General Data Protection Regulation 2016/679 (EU GDPR), the EU GDPR as it forms part of United Kingdom (UK) law by virtue of section 3 of the European Union (Withdrawal) Act 2018 (UK GDPR) (EU GDPR and UK GDPR collectively as GDPR), the ePrivacy Directive, and the Payment Card Industry Data Security Standard (PCI DSS). Several states within the United States have enacted or proposed data privacy and security laws. Additionally, we are, or may become, subject to various U.S. federal and state consumer protection laws which require us to publish statements that accurately and fairly describe how we handle personal information and choices individuals may have about the way we handle their personal information.

The CCPA and GDPR are examples of the increasingly stringent and evolving regulatory frameworks related to personal information processing that may increase our compliance obligations and exposure for any noncompliance. For example, the CCPA imposes obligations on covered businesses to provide specific disclosures related to a business’s collection, use, and disclosure of personal information and to respond to certain requests from California residents related to their personal information (for example, requests to know of the business’s personal information processing activities, to delete the individual’s personal data, and to opt out of certain personal information disclosures). Also, the CCPA provides for civil penalties and a private right of action for data breaches which may include an award of statutory damages.

Foreign data privacy and security laws (including but not limited to the GDPR) impose significant and complex compliance obligations on entities that are subject to those laws. As one example, the EU GDPR applies to any company established in the EEA and to companies established outside the EEA that process personal information in connection with the offering of goods or services to data subjects in the EEA or the monitoring of the behavior of data subjects in the EEA. These obligations may include limiting personal information processing to only what is necessary for specified, explicit, and legitimate purposes; requiring a legal basis for personal information processing; requiring the appointment of a data protection officer in certain circumstances; increasing transparency obligations to data subjects; requiring data protection impact assessments in certain circumstances; limiting the collection and retention of personal information; increasing rights for data subjects; formalizing a heightened and codified standard of data subject consents; requiring the implementation and maintenance of technical and organizational safeguards for personal information; mandating notice of certain personal information breaches to the relevant supervisory authority(ies) and affected individuals; and mandating the appointment of representatives in the UK and/or the EU in certain circumstances.

See the section titled “Risks Related to Government Regulation” for additional information about the laws and regulations to which we may become subject and about the risks to our business associated with such laws and regulations.

Marketing

Similarly to the Anti-Kickback Statute prohibition in the United States, as described below, the provision of benefits or advantages to physicians and other health care professionals to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the EU. Interactions between pharmaceutical companies and health care professionals are governed by strict laws, such as national anti-bribery laws of European countries, national sunshine rules, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment

Payments made to physicians and other health care professionals in certain European Union Member States must be publicly disclosed. Moreover, agreements with physicians and other health care professionals often may require prior notification and approval by the physician’s or health care professional’s employer, their competent professional organization and/or the regulatory authorities of the individual European Union member states. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

International Regulation

In addition to regulations in the United States and the European Union, a variety of foreign regulations govern clinical trials, commercial sales and distribution of product candidates. The approval process varies from country to country and the time to approval may be longer or shorter than that required for FDA or European Commission approval.

Other Healthcare Laws and Regulations and Legislative Reform

Healthcare Laws and Regulations

Healthcare providers, including physicians, and third-party payors will play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval. Our operations, including any arrangements with healthcare providers, physicians, third-party payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws that may affect the business or financial arrangements and relationships through which we would research, as well as market, sell and distribute any products for which we obtain marketing approval. Our current and future operations are subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to the Centers for Medicare and Medicaid Services (CMS), U.S. Department of Health and Human Services, (HHS) (including the Office of Inspector General, Office for Civil Rights and the Health Resources and Service Administration), the U.S. Department of Justice (DOJ) and individual U.S. Attorney offices within the DOJ, and state and local governments. The healthcare laws that may affect our ability to operate include, but are not limited to:

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The federal Anti-Kickback Statute, which prohibits any person or entity from, among other things, knowingly and willfully soliciting, receiving, offering or paying any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of an item or service reimbursable, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs. The term “remuneration” has been broadly interpreted to include anything of value. A person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it to have committed a violation. The federal Anti-Kickback Statute has also been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary managers on the other hand. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, but the exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.

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Federal civil and criminal false claims laws, such as the False Claims Act (FCA), which can be enforced by private citizens on behalf of the government through civil whistleblower or qui tam actions, and the federal civil monetary penalty laws prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, false, fictitious or fraudulent claims for payment of federal funds, and knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to avoid, decrease or conceal an obligation to pay money to the federal government. For example, pharmaceutical companies have been prosecuted under the FCA in connection with their alleged off-label promotion of drugs, purportedly concealing price concessions in the pricing information submitted to the government for government price reporting purposes, and allegedly providing free product to customers with the expectation that the customers would bill federal healthcare programs for the product. In addition, a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA. As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S. government. In addition, manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

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The U.S. federal Health Insurance Portability and accountability Act of 1996 (HIPAA), among other things, imposes criminal liability for executing or attempting to execute a scheme to defraud any healthcare benefit program, including private third-party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and creates federal criminal laws that prohibit knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement or representation, or making or using any false writing or document knowing the same to contain any materially false, fictitious or fraudulent statement or entry in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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In addition, HIPAA, as amended by Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH), imposes certain requirements on covered entities, which include certain healthcare providers, health plans and healthcare clearinghouses, and their business associates and covered subcontractors that receive or obtain protected health information in connection with providing a service on behalf of a covered entity relating to the privacy, security and transmission of individually identifiable health information.

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The federal transparency requirements under the Physician Payments Sunshine Act, created under the Patient Protection and Affordable Care Act (the Affordable Care Act), which requires, among other things, certain manufacturers of drugs, devices, biologics and medical supplies reimbursed under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to payments and other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physicians assistants or nurse practitioners), and teaching hospitals, as well as ownership and investment interests held by the physicians described above and their immediate family members.

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Analogous state and foreign anti-kickback and false claims laws that may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers, or that apply regardless of payor; state and foreign laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the government; state and local laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures; and state and foreign laws that require the reporting of information related to drug pricing; and state and local laws requiring certain regulatory licenses to manufacture or distribute products commercially and/or the registration of pharmaceutical sales representatives.

Any action brought against us for violation of these laws or regulations, 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. If our operations are found to be in violation of any of these laws and regulations, we may be subject to any applicable penalty associated with the violation, including, among others, significant administrative, civil and criminal penalties, damages, fines, disgorgement, reputational harm, imprisonment, integrity oversight and reporting obligations, and exclusion from participation in federal healthcare programs such as Medicare and Medicaid or comparable foreign programs.

Legislative Reform

We operate in a highly regulated industry, and new laws, regulations and judicial decisions, or new interpretations of existing laws, regulations and decisions, related to healthcare availability, the method of delivery and payment for healthcare products and services could negatively affect our business, financial condition and prospects. There is significant interest in promoting healthcare reforms, and it is likely that federal and state legislatures within the United States and the governments of other countries will continue to consider changes to existing healthcare legislation.

For example, the United States and state governments continue to propose and pass legislation designed to reduce the cost of healthcare. In 2010, the U.S. Congress enacted the Affordable Care Act, which included changes to the coverage and reimbursement of drug products under government healthcare programs and access to health insurance.

There have been executive, judicial and congressional challenges and amendments to certain aspects of the Affordable Care Act. For example, on July 4, 2025, the One Big Beautiful Bill Act (the OBBBA) was signed into law, which narrowed access to Affordable Care Act marketplace exchange enrollment and declined to extend the Affordable Care Act enhanced advanced premium tax credits that expired at the end of 2025, which, among other provisions in the law, are anticipated to reduce the number of Americans with health insurance. The OBBBA also is expected to reduce Medicaid spending and enrollment by implementing work requirements for some beneficiaries, capping state-directed payments, reducing federal funding, and limiting provider taxes used to fund the program. Congress is considering proposed legislation intended to further reduce healthcare costs with alternatives to replace the expired Affordable Care Act subsidies.

In addition, there have been and continue to be a number of initiatives at the federal and state level in the United States that seek to reduce healthcare costs. These changes include aggregate reductions to Medicare payments to providers of 2% per fiscal year, which began in 2013 and will remain in effect until 2032 unless additional Congressional action is taken.

The current administration is pursuing policies to reduce regulations and expenditures across government agencies including at HHS, the FDA, CMS and related agencies. These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business. For example, the current administration has announced agreements with several pharmaceutical companies that require the drug manufacturers to offer, through a direct to consumer platform (TrumpRx), U.S. patients and Medicaid programs prescription drug Most-Favored Nation pricing equal to or lower than those paid in other developed nations, with additional mandates for direct-to-patient discounts and repatriation of foreign revenues. Other recent actions, for example, include (1) directing agencies to reduce agency workforce and cut programs; (2) directing HHS and other agencies to lower prescription drug costs through a variety of initiatives; (3) imposing tariffs on imported pharmaceutical products; and (4) as part of the Make America Healthy Again (MAHA) Commission’s Strategy Report released in September 2025, working across government agencies to increase enforcement on direct-to-consumer pharmaceutical advertising. Additionally, the current administration recently called on Congress to enact "The Great Healthcare Plan," to codify and expand Most-Favored Nation pricing, lower government subsidies to private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase, and enact restrictions on pharmacy benefit manager (PBM) payment methodologies, among other things. These actions and policies may significantly reduce U.S. drug prices, potentially impacting manufacturers’ global pricing strategies and profitability, while increasing their operational costs and compliance risks. In June 2024, the U.S. Supreme Court’s Loper Bright decision greatly reduced judicial deference to regulatory agencies, which could increase

successful legal challenges to federal regulations affecting our operations. Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program.

On January 12, 2025, Regulation No 2021/2282 on Health Technology Assessment (HTA Regulation), entered into application through a phased implementation. The HTA Regulation initially applies to new active substances for oncology and ATMPs. It will be expanded to orphan medicinal products in January 2028, and to all centrally authorized medicinal products as of 2030. Select high-risk medical devices also came into scope in 2026. The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including new medicinal products, and establishes a framework for EU level joint clinical assessments, joint scientific consultations and the early identification of emerging health technologies. The HTA Regulation permits EU Member States to use common health technology assessment (HTA) tools, methodologies and procedures across the EU and requires them to rely on EU level joint clinical assessment reports for the clinical components of their national HTA evaluations. Individual EU Member States continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technologies and making decisions on pricing and reimbursement.

In addition, on December 11, 2025, the European Commission, the Parliament and the European Council reached a political agreement on a comprehensive overhaul of EU pharmaceutical legislation (Pharma Package). The reform has been under negotiation since the European Commission submitted its proposal in April 2023. This package, comprised of a new directive and regulation to replace existing legislation, aims to modernize the EU framework. The political agreement is still subject to formal approval by the European Parliament and Council. If approved in the form proposed, the Pharma Package will, among other changes, reduce the baseline market protection period by one year, with limited opportunities for extensions; reshape the incentives regime for orphan medicinal products; and expand the Bolar exemption, a patent-related regulatory safe harbor, to permit generic and biosimilar manufacturers to conduct preparatory activities for regulatory submissions, including pricing and reimbursement, and participate in procurement tenders while patent protection remains in force.

Environmental, Health and Safety Laws and Regulations

We and our third-party contractors are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the use, generation, manufacture, distribution, storage, handling, treatment, remediation and disposal of hazardous materials and wastes. Hazardous chemicals, including flammable and biological materials, are involved in certain aspects of our business, and we cannot eliminate the risk of injury or contamination from the use, generation, manufacture, distribution, storage, handling, treatment or disposal of hazardous materials and wastes. In the event of contamination or injury, or failure to comply with environmental, health and safety laws and regulations, we could be held liable for any resulting damages, fines and penalties associated with such liability could exceed our assets and resources. Environmental, health and safety laws and regulations are becoming increasingly more stringent. We may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations.

Pharmaceutical Coverage, Pricing and Reimbursement

The availability and extent of coverage and adequate reimbursement by governmental and private third-party payors are essential for most patients to be able to afford expensive medical treatments. In both domestic and foreign markets, sales of our product candidates, if approved, will depend substantially on the extent to which the costs of our product candidates will be covered by third-party payors, such as government health programs, commercial insurance and managed healthcare organizations. These third-party payors decide which products will be covered and establish reimbursement levels for those products.

Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:

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a covered benefit under its health plan;

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safe, effective and medically necessary;

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appropriate for the specific patient;

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cost-effective; and

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neither experimental nor investigational.

Obtaining coverage approval and reimbursement for a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide supporting scientific, clinical and cost-effectiveness data for the use of our products to the payor. We may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement at a satisfactory level. If coverage and adequate reimbursement of our future products, if any, are unavailable or limited in scope or amount, such as may result where alternative or generic treatments are available, we may be unable to achieve or sustain profitability. Adverse coverage and reimbursement limitations may hinder our ability to recoup our investment in our product candidates, even if such product candidates obtain regulatory approval. For products administered under the supervision of a physician, obtaining coverage and adequate reimbursement may be particularly difficult because of the higher prices often associated with such products. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future. Additionally,

separate reimbursement for the product itself or the treatment or procedure in which the product is used may not be available, which may impact physician utilization.

There is significant uncertainty related to the insurance coverage and reimbursement of newly approved products. There is no uniform policy for coverage and reimbursement in the United States and, as a result, coverage and reimbursement can differ significantly from payor to payor. In the United States, private payors often, but not always, follow Medicare coverage and reimbursement policies with respect to newly approved products. It is difficult to predict what third-party payors will decide with respect to coverage and reimbursement for fundamentally novel products such as ours, as there is no body of established practices and precedents for these new products. Further, one payor’s determination to provide coverage and adequate reimbursement for a product does not assure that other payors will also provide coverage and adequate reimbursement for that product. We may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our product candidates. There can be no assurance that our product candidates will be considered medically necessary or cost-effective. In addition to third-party payors, professional organizations and patient advocacy groups such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology can influence decisions about reimbursement for new medicines by determining standards for care. Therefore, it is possible that any of our product candidates, even if approved, may not be covered by third-party payors or the reimbursement limit may be so restrictive that we cannot commercialize the product candidates profitably.

Further, the U.S. government, state legislatures and foreign governments have shown increased interest in implementing cost containment programs to limit government-paid health care costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. For example, HHS imposes rebates on many Medicare Part B and Medicare Part D products to penalize price increases that outpace inflation on an annual basis. HHS has also been empowered to negotiate the price of certain single-source biologics that have been on the market for at least eleven years covered under Medicare as part of the Medicare Drug Price Negotiation Program. Each year up to twenty products will be selected by HHS for the Medicare Drug Price Negotiation Program. Products subject to the Medicare Drug Price Negotiation Program are expected to experience a significant reduction in reimbursement from the Medicare program on a per unit basis.

Reimbursement in the European Union may be more restrictive than reimbursement provided by payors in the United States. For example, a number of cancer products have been approved for reimbursement in the United States but not in certain European countries. In Europe, pricing and reimbursement schemes vary widely from country to country. For example, some countries provide that products may be marketed only after an agreement on reimbursement price has been reached. Such pricing negotiations with governmental authorities can take considerable time after receipt of marketing approval for a product. Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Other countries require the completion of additional health technology assessments that compare the cost- effectiveness of a particular product candidate to currently available therapies. In addition, the European Union provides options for its member states to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. European Union member states may approve a specific price for a product, may adopt a system of direct or indirect controls on the profitability of the company placing the product on the market or monitor and control prescription volumes and issue guidance to physicians to limit prescriptions. . In addition, EU Member States often require the completion of additional HTAs that compare the cost-effectiveness of a particular product candidate to currently available therapies. The HTA process is the procedure according to which the assessment of the public health impact, therapeutic impact and the economic and societal impact of use of a given medicinal product in the national healthcare systems of the individual country is conducted. The outcome of an HTA regarding specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU Member States. At the EU level, on January 12, 2025, the HTA Regulation entered into application through a phased implementation. The HTA Regulation initially applies to new active substances for oncology and ATMPs. It will be expanded to orphan medicinal products in January 2028, and to all centrally authorized medicinal products as of 2030. Select high-risk medical devices also came into scope in 2026. The HTA Regulation is intended to boost cooperation among Member States in assessing health technologies, including new medicinal products. The HTA Regulation establishes a framework for EU level joint clinical assessments, joint scientific consultations and the early identification of emerging health technologies. The HTA Regulation permits EU Member States to use common tools, methodologies, and procedures and requires them to rely on EU level joint clinical assessment reports for the clinical components of their national HTA evaluations. Individual EU Member States will continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technologies and making decisions on pricing and reimbursement.

Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices. Furthermore, many countries in the European Union have increased the amount of discounts required on pharmaceutical products, and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the European Union. The downward pressure on healthcare costs in general, and prescription products in particular, has become increasingly intense. As a result, there are increasingly higher barriers to entry for new products. There can be no assurance that any country that has reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products, if approved in those countries. Accordingly, the reimbursement for any products in the European Union may be reduced compared with the United States and may be insufficient to generate commercially reasonable revenues and profits.

Furthermore, the containment of healthcare costs has become a priority of foreign and domestic governments as well as private third-party payors. The prices of drugs have been a focus in this effort. Governments and private third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications, which could affect our ability to sell our product candidates profitably. We also expect to experience pricing pressures due to the trend towards managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. These and other cost-control initiatives could cause us to decrease the price we might establish for products, which could result in lower-than-anticipated product revenues. In addition, the publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries. If pricing is set at unsatisfactory levels or if coverage and adequate reimbursement of our products is unavailable or limited in scope or amount, our revenues and the potential profitability of our product candidates in those countries would be negatively affected.

Janux Therapeutics, Inc. (JANX) Business

Overview‌

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Our TRACTr and TRACIr platforms‌

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Our ARM platform

Our lead programs

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Our Clinical TRACTr Programs

Our PSMA-TRACTr (JANX007)

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Our EGFR-TRACTr (JANX008)

Our Collaboration with Bristol Myers Squibb

Our Strategy

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Background

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Our TRACTr and TRACIr Platforms‌

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Table of Contents

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Our Lead Programs

Prostate cancer overview

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Table of Contents

Our solution: JANX007

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Clinical development

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rPFS data

Phase 1b data

Our EGFR-TRACTr (JANX008)

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Our solution: JANX008

Figure 14. Structure of JANX008

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Clinical development

Our ARM platform

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Our CD19-ARM

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Clinical development

Manufacturing

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Competition

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License Agreement with WuXi Biologics (Hong Kong) Limited

Exclusive License and Collaboration Agreement with Bristol-Meyers Squibb Company

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Intellectual Property

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Government Regulation

Regulatory Approval in the United States

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Preclinical Studies

Clinical Trials

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A single Phase 3 or Phase 2 trial with other confirmatory evidence may be sufficient in rare instances to provide substantial evidence of effectiveness (generally subject to the requirement of additional post-approval studies).

FDA Review Process

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Orphan Drug Designation

Expedited Development and Review Programs

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Pediatric Information

Post-Approval Requirements

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Biosimilars and Exclusivity

Regulatory Approval in the European Union

Clinical Trials in the EU

Manufacturing and import into the EU of investigational medicinal products is subject to the holding of appropriate authorizations and must be carried out in accordance with cGMP.

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Review and Approval

Conditional Approval and Accelerated Assessment

Period of Authorization and Renewals

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cost-effective; and