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Item 1. Business

2026-02-25 compared with 2025-02-25 · 146 added, 189 removed, 525 unchanged (39% of the section changed)

Company Overview

We are a clinical-stage biopharmaceutical company focused on creating best-in-class therapies.

Using our robust and highly efficient drug discovery capability, we have created a significant portfolio of investigational products which are in clinical development, with our most advanced molecule, an anti-TIGIT antibody, now in multiple Phase 3 registrational studies targeting lung and gastrointestinal ("GI") cancers.

Our deep portfolio of novel small molecules and enabling antibodies allows us to create highly differentiated therapies, which we are developing to treat multiple large indications.

We expect our clinical-stage portfolio to continue to expand and to include molecules targeting immuno-oncology, cancer cell-intrinsic and immunological pathways.

Our vision is to create, develop and commercialize highly differentiated therapies that have a meaningful impact on patients.

The below summarizes our current clinical-stage portfolio:

cabozantinib;

chemotherapy;

domvanalimab;

etrumadenant;

gemcitabine/nab-paclitaxel;

immuno-oncology;

pembrolizumab;

quemliclustat;

renal cell carcinoma;

zanzalintinib;

*+/- biologic, e.g.

bevacizumab or biosimilar, will be included for all patients in whom it is not contraindicated.

Our Clinical Product Portfolio

We currently have seven clinical programs focused on unique targets including HIF-2α, TIGIT, PD-1, adenosine A2a and A2b receptors, CD73, CD39, and AXL.

In 2020, we entered into an Option, License and Collaboration Agreement (as amended, the "Gilead Collaboration Agreement") with Gilead to strategically advance our portfolio through a collaborative relationship.

The Gilead Collaboration Agreement provides Gilead with an exclusive license to our anti-PD-1 program (including zimberelimab) and time-limited exclusive option rights to our clinical programs, which they have exercised for our anti-TIGIT program (including domvanalimab), adenosine receptor antagonist program (including etrumadenant) and CD73 program (including quemliclustat).

Our HIF-2α program (including casdatifan) is no longer subject to Gilead’s option under the Gilead Collaboration Agreement and Gilead has no further rights to the program.

The Gilead Collaboration Agreement and our strategic partnership with Gilead is discussed in more detail below under “License and Collaborations—Gilead Collaboration”.

HIF-2α Program

Casdatifan is our oral, small-molecule inhibitor of HIF-2α and is our first investigational product against a cancer cell-intrinsic target to enter clinical development.

We are a late clinical-stage biopharmaceutical company focused on developing differentiated molecules for patients with cancer and inflammatory and autoimmune diseases.

Our most advanced molecules are in Phase 3 registrational studies for various cancer indications and we expect our next wave of clinical-stage molecules to come from our inflammation and autoimmune disease programs.

Our vision is to leverage our internal small-molecule discovery capabilities to create, develop and commercialize highly differentiated therapies that can have a meaningful impact on patients.

The chart below summarizes our current clinical and late pre-clinical stage portfolio:

* Taiho holds exclusive licenses in Japan and certain other Asian countries, excluding China, for casdatifan (the “Taiho Territory”).

† Gilead and Arcus co-develop globally and share co-promotion rights in the U.S.

for domvanalimab and quemliclustat.

Gilead holds commercialization rights outside of the U.S.

subject to Taiho’s rights for the Taiho Territory.

‡ Gilead has certain option rights as further described under “Licenses and Collaborations”.

Oncology Programs

Casdatifan (HIF-2α Inhibitor)

Casdatifan is our oral, small-molecule inhibitor of HIF-2α, a target that has been commercially validated by the approval of Merck & Co., Inc's ("Merck") HIF-2α inhibitor belzutifan.

HIF-2α is a protein that is involved in sensing oxygen availability in multiple organs.

In certain tumors, HIF-2⍺ activity is highly dysregulated as a result of genetic abnormalities.

In certain tumors, particularly clear cell renal cell carcinoma ("ccRCC"), HIF-2⍺ activity is highly dysregulated as a result of genetic abnormalities.

This creates a situation of pseudohypoxia and the abnormal increase in HIF-2⍺-mediated expression of a wide array of proteins involved in cancer cell proliferation, survival, treatment resistance and angiogenesis.

Our focus for casdatifan is to maximize the opportunity in clear cell renal cell carcinoma ("ccRCC") across a variety of settings using a multi-pronged clinical development plan.

The initial registrational pathways that we plan to pursue will focus on combination approaches that build on top of standard of care therapies, while also exploring opportunities for casdatifan to become a foundational standard of care.

Our development program for casdatifan currently includes the following:

• PEAK-1 is a planned Phase 3 clinical trial to evaluate casdatifan and cabozantinib in ccRCC patients that have received prior immunotherapy, which we expect to initiate in the second quarter of 2025.

• A planned Phase 1b clinical trial that is part of AstraZeneca’s eVOLVE portfolio, where we expect to evaluate casdatifan and volrustomig (AstraZeneca’s anti-PD-1 / anti-CTLA-4 bispecific antibody) in patients with advanced ccRCC who have not received prior immunotherapy (IO-naive setting).

Ipilimumab, an anti-CTLA-4 antibody, plus nivolumab, an anti-PD-1 antibody, is approved as a standard of care therapy in first-line ccRCC.

We expect the Phase 1b portion to be initiated by the middle of 2025.

• ARC-20 is a Phase 1 clinical trial evaluating casdatifan in multiple cohorts, including cohorts evaluating:

(1) casdatifan monotherapy (50 mg, 100 mg and 150 mg) in late-line ccRCC;

(2) casdatifan and cabozantinib in second-line ccRCC;

(3) casdatifan plus zimberelimab in first-line ccRCC;

(4) casdatifan monotherapy in first-line ccRCC patients with IMDC score of “favorable risk”;

and (5) casdatifan monotherapy in ccRCC patients that have received prior immuno-oncology therapy.

We recently shared interim data from three cohorts of our ARC-20 study, each evaluating casdatifan monotherapy in ccRCC patients at different doses.

At the time of data cut-off (January 3, 2025), the analysis showed that most patients in each cohort (81-87%) experienced disease control with either a partial response or stable disease and were still on treatment.

Key highlights from the analysis include an observed 33% response rate in the cohort administering 100mg of casdatifan once daily and the cohort administering 50mg of casdatifan twice a day showing a median progression-free survival ("mPFS") of 9.7 months (the mPFS for the other cohorts had not been reached at the time of the data cut-off).

Anti-TIGIT Program

We designed casdatifan to have superior pharmacokinetic and pharmacodynamic properties relative to belzutifan, with the goal of achieving greater efficacy in ccRCC patients.

The ability for casdatifan to achieve greater efficacy has now been demonstrated in a clinical study in patients.

Specifically, in our Phase 1/1b ARC-20 study, which evaluated casdatifan monotherapy in approximately 120 late-line ccRCC patients, casdatifan achieved improvement on every efficacy measure including rate of primary progressive disease, overall response rate ("ORR") and progression-free survival ("PFS"), relative to data reported for belzutifan in a similar patient population.

Our goal for casdatifan is to leverage the potential best-in-class efficacy profile and maximize the opportunity for casdatifan by developing this molecule across multiple settings and with optimal combination partners.

ARC-20 is designed to generate safety and proof-of-concept clinical data to support and inform our registrational studies for casdatifan.

To date, we have completed enrollment of eight cohorts, including four monotherapy cohorts in late-line ccRCC, a cohort evaluating casdatifan plus cabozantinib in ccRCC patients previously treated with immunotherapy and three cohorts evaluating casdatifan in early line settings of ccRCC.

The initial registrational studies for casdatifan will focus on combination approaches that build on top of standard of care therapies, while also exploring opportunities for casdatifan to become a foundational standard of care.

Our first Phase 3 clinical trial, PEAK-1, is evaluating casdatifan and cabozantinib in ccRCC patients that have received prior immunotherapy, which we believe has a potential global peak sales opportunity of greater than $2 billion.

This study has a primary endpoint of PFS and is currently enrolling.

Our second Phase 3 clinical trial is expected to evaluate casdatifan in a Tyrosine Kinase Inhibitor ("TKI")-free regimen for the treatment of first-line ccRCC, which we believe represents a potential global peak sales opportunity of greater than $3 billion.

This strategy capitalizes on the strong desire by clinicians and patients to avoid TKIs and their associated toxicities in the first-line setting.

This Phase 3 study, which we are targeting initiation of by the end of 2026, will be informed by emerging data from the following ongoing cohorts and studies:

• A cohort in ARC-20 evaluating casdatifan plus zimberelimab, our anti-PD-1 antibody, in first-line ccRCC.

Casdatifan plus anti-PD-1 is likely to serve as the backbone of our front line TKI-free strategy.

This cohort has completed enrollment.

• We are enrolling a cohort in ARC-20 to evaluate casdatifan in combination with ipilimumab and zimberelimab in first-line ccRCC.

Ipilimumab, an anti-CTLA-4 antibody, plus nivolumab, an anti-PD-1 antibody, are approved as a standard of care therapy in first-line ccRCC.

• eVOLVE-RCC02 is a Phase 1b/3 clinical trial operationalized by AstraZeneca plc ("AstraZeneca") evaluating casdatifan and volrustomig (AstraZeneca’s anti-PD-1 / anti-CTLA-4 bispecific antibody) in first-line ccRCC.

A decision was made to temporarily pause recruitment, after observing certain immune-mediated AEs.

We and AstraZeneca are evaluating emerging data which will inform next steps for the study.

Quemliclustat (CD73 Inhibitor)

Under conditions of cellular damage or cell death, such as in response to certain chemotherapies, large amounts of adenosine triphosphate ("ATP") are released into the extracellular environment, where it is converted into adenosine monophosphate by the enzyme CD39 and then into adenosine by the enzyme CD73.

The generation of large amounts of extracellular adenosine results in an immunosuppressive response that counteracts some of the potentially beneficial effects of chemotherapy.

Quemliclustat is a small-molecule inhibitor that targets the CD73 enzyme that plays a critical role in the last step in the conversion of extracellular ATP into adenosine.

Further, we believe targeting CD73 could be a highly effective approach to inhibiting adenosine-mediated immune suppression by suppressing adenosine generation.

We believe quemliclustat was the first small-molecule CD73 inhibitor to enter clinical development.

We believe that a small-molecule approach to CD73 inhibition could offer several advantages over antibody approaches, including more complete inhibition of CD73 enzymatic activity, deeper tumor penetration, and potential for both intravenous and oral delivery.

We are evaluating quemliclustat in the following study:

• PRISM-1 is a Phase 3 study in metastatic pancreatic cancer evaluating quemliclustat with gemcitabine and nab-paclitaxel (the standard-of-care chemotherapies used for advanced pancreatic cancer) against gemcitabine and nab-paclitaxel.

This study completed enrollment in September 2025, less than 12 months after study initiation, and we expect results from this study in the first half of 2027.

Domvanalimab (Anti-TIGIT Antibody)

TIGIT is believed to play an important role in suppressing the immune response to cancer.

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TIGIT is an inhibitory receptor highly expressed on T cells displaying an exhausted phenotype, tumor-infiltrating Treg, and NK cells.

During the past couple of years, expression of TIGIT, along with PD-1, on precursor exhausted T cells ("Tpex"), a key population that mediates some of the therapeutic effects of anti-PD-1 agents, has become well documented.

The ligands for TIGIT, including CD155, are broadly expressed on multiple cell types in the tumor microenvironment, including cancer cells.

CD155 binding to TIGIT results in inhibition of immune cells.

As T cells are important in the immune response, domvanalimab was engineered to lack Fc-receptor binding in order to minimize the risk of depleting such cells, which we believe may provide domvanalimab with an advantage over Fc-enabled anti-TIGIT antibodies.

We are pursuing a broad Phase 2 and Phase 3 development program for domvanalimab in combination with our anti-PD-1 antibody, zimberelimab, in multiple settings, including lung, GI and head and neck cancers.

As described below, each of our Phase 3 studies are evaluating domvanalimab with a PD-(L)1 antibody versus the relevant global standard of care.

We estimate that the total addressable market for the ongoing and planned Phase 3 trials of domvanalimab is over $10 billion annually, based on the size of the drug treatable U.S.

patient populations.

We have the following ongoing Phase 3 studies for domvanalimab:

• STAR-221 is a Phase 3 study evaluating domvanalimab in combination with zimberelimab and chemotherapy versus nivolumab and chemotherapy in first-line unresectable or metastatic GI cancers.

As T cells are important in the immune response, domvanalimab was engineered to lack Fc-receptor binding in order to minimize the risk of depleting such cells.

In December 2025, we announced that our Phase 3 STAR-221 clinical trial, which evaluated domvanalimab in combination with zimberelimab and chemotherapy in first-line metastatic GI cancers, is being discontinued due to futility.

Based on this result, we are also discontinuing our Phase 2 EDGE-Gastric study.

The following Phase 3 studies for domvanalimab are still ongoing:

• STAR-121 is a Phase 3 study evaluating domvanalimab in combination with zimberelimab and chemotherapy versus pembrolizumab and chemotherapy in first-line non-small cell lung cancer ("NSCLC").

A futility analysis is expected to be conducted for this study in the first quarter of 2026.

• PACIFIC-8 is a Phase 3 study evaluating domvanalimab in combination with durvalumab following chemoradiation in Stage 3 NSCLC, a setting in which durvalumab is already approved.

In addition, we are evaluating domvanalimab in the following Phase 2 studies:

• EDGE-Gastric is a Phase 2 study evaluating the combination of domvanalimab and zimberelimab with and without FOLFOX in GI cancers.

• EDGE-Lung is a Phase 2 study evaluating the combination of domvanalimab and zimberelimab with and without quemliclustat and chemotherapy in first- and second-line NSCLC.

• VELOCITY-Lung is a Phase 2 study evaluating domvanalimab with and without zimberelimab and sacituzumab govitecan-hziy ("Trodelvy ® ") in first- and second-line NSCLC.

Anti-PD-1 Program

We are currently evaluating zimberelimab with various intra-portfolio combination partners in many of our ongoing clinical studies.

Zimberelimab has been approved in China for classical Hodgkin’s Lymphoma, based on data generated independently by Guangzhou Gloria Biosciences, Co.

("Gloria Biosciences"), which owns the commercial rights to zimberelimab in China.

To date, zimberelimab has been evaluated by us and Gloria Biosciences, either alone or in combination with other agents, in over 2,500 patients.

Adenosine Pathway Programs

The generation of large amounts of extracellular adenosine results in an immunosuppressive response that counteracts some of the potentially beneficial effects of chemotherapy.

Two receptors important in mediating the effect of adenosine are A2a, which is expressed on T and NK cells, and A2b, which is co-expressed with A2a on myeloid cells.

We currently have three clinical programs targeting the adenosine pathway.

Quemliclustat is a small molecule inhibitor that targets the CD73 enzyme in the ATP-adenosine pathway.

The CD73 enzyme plays a critical role in the last step in the conversion of extracellular ATP into adenosine.

We believe targeting CD73 could be a highly effective approach to inhibiting adenosine-mediated immune suppression by suppressing adenosine generation.

We believe quemliclustat was the first small-molecule CD73 inhibitor to enter clinical development.

While there are several anti-CD73 antibodies in development, we believe that a small-molecule approach to CD73 inhibition could offer several advantages, including more complete inhibition of CD73 enzymatic activity, deeper tumor penetration, and potential for both intravenous and oral delivery.

In addition to the EDGE-Lung study described above, we are evaluating quemliclustat in the following studies:

• ARC-8 is a Phase 1b study in metastatic pancreatic cancer evaluating quemliclustat with gemcitabine and nab-paclitaxel (the standard-of-care chemotherapies used for advanced pancreatic cancer) with or without zimberelimab.

Adenosine Receptor Antagonist Program

Etrumadenant is an orally bioavailable small molecule.

Unlike most other clinical-stage adenosine receptor antagonists, which only target one of the two receptors, etrumadenant is a highly potent and reversible antagonist of the adenosine A2a and A2b receptors.

We believe that activation of the adenosine A2a receptors on T cells, NK cells and myeloid cells mediates a significant portion of the immunosuppressive effects of adenosine.

Further, because binding of adenosine to A2b receptors on myeloid cells also contributes significantly to intra-tumoral immune suppression, we believe that activating these A2b receptors will further mitigate adenosine’s immunosuppressive effects.

Consequently, etrumadenant could prove to have more robust anti-tumor effects and activity in a broader range of tumor types than other adenosine A2a or A2b antagonists in clinical development.

Our studies evaluating etrumadenant are designed to support the potential of etrumadenant in multiple indications that represent substantial market opportunities with significant unmet need.

We are evaluating etrumadenant in our ARC-9 study.

ARC-9 is a Phase 2 study evaluating etrumadenant with zimberelimab and FOLFOX, and with and without bevacizumab vs.

FOLFOX with and without bevacizumab or regorafenib in second- and third-line metastatic colorectal cancer.

CD39 is a key enzyme in the adenosine pathway and facilitates the removal of ATP from the tumor microenvironment and its conversion into adenosine.

AB598 is our anti-CD39 antibody.

By targeting the CD39 enzyme, we hope to increase ATP in the tumor environment which could, in turn, lead to an enhanced adaptive (T cell) immune response against tumors.

We are evaluating AB598 in our ARC-25 study.

ARC-25 is a Phase 1/1b study evaluating AB598 with and without zimberelimab and chemotherapy in gastric cancers.

The AXL receptor tyrosine kinase ("AXL") is a transmembrane protein overexpressed in a variety of cancers and certain immune cells.

AXL signaling has been implicated in creating an immunosuppressive tumor microenvironment, promoting resistance to chemotherapy and immunotherapy drugs, and is associated with poor prognosis in a variety of cancers.

AB801 is our AXL inhibitor and is being evaluated in our ARC-27 study.

ARC-27 is a Phase 1b study evaluating AB801 with and without chemotherapy in NSCLC.

Our Early-Stage Drug Discovery Programs

We have active early-stage discovery efforts focused on the creation of additional development candidates aimed at regulating various aspects of the anti-tumor immune response as well as other cancer-intrinsic pathways, which we believe play an important role in many human cancers.

Casdatifan, quemliclustat, etrumadenant, AB801 and AB598 are all products of our internal discovery program.

We are currently pursuing several new small molecules aimed at modulating key biological pathways in various types of cancer that are responsible for the abnormal growth and resistance to current therapies.

We also have several active early-stage discovery efforts focused on the discovery of molecules that regulate excessive immune activity in the context of various types of inflammation and auto-immune diseases.

Zimberelimab (Anti-PD-1 Antibody)

Zimberelimab has been evaluated in clinical trials, either alone or in combination with other agents, in over 2600 patients across several studies conducted by us.

The clinical results to date have shown that zimberelimab has an efficacy and safety profile consistent with anti-PD-1 mechanism of action.

We are currently evaluating zimberelimab in combination with casdatifan for the treatment of first-line ccRCC in our Phase 1/1b ARC-20 study.

We are also initiating two additional cohorts in this study to evaluate casdatifan in combination with zimberelimab and ipilimumab in first-line ccRCC utilizing two different dosing regimens.

Inflammation Programs

We have active discovery efforts focused on the creation of development candidates aimed at regulating excessive immune activity in the context of various types of inflammation and autoimmune diseases.

These discovery efforts leverage the small molecule-focused infrastructure and capabilities that led to our pipeline of oncology development candidates, including casdatifan.

Our goal is to develop best-in-class, oral, small-molecule drugs to displace injectable biologics for the treatment of the most common inflammatory and autoimmune diseases.

Our inflammation portfolio is currently comprised of five research and preclinical programs directed to MRGPRX2, TNF, CCR6, CD89 and CD40 ligand, and we expect to advance our first development candidate from these programs into the clinic in 2026.

MRGPRX2 Antagonist Program

Our most advanced inflammation program has identified an orally active, highly potent and selective, small-molecule inhibitor of MRGRX2 that we believe has the potential to be best-in-class.

In recent years, the MRGPRX2 receptor has been identified as a major regulator of mast cell function, playing an important role in the interplay between inflammation and pain sensation in certain dermal atopic conditions, such as chronic urticaria and atopic dermatitis.

Due to its potency, our development candidate is expected to achieve similar biological activity as the most advanced MRGPRX2 inhibitor in clinical development, but at much lower plasma levels, thereby avoiding the toxicities that have been observed with competitor molecules at higher drug exposures.

Initially, we plan to develop our MRGPRX2 inhibitor in chronic spontaneous urticaria ("CSU"), an inflammatory disease characterized by hives and pruritus.

We believe that inhibiting MRGPRX2 may offer several advantages over other approaches for the treatment of CSU, including the ability to treat patients whose disease is not primarily driven by immunoglobulin E ("IgE"), oral administration, greater specificity for mast cells, and fewer side effects such as neutropenia and hair depigmentation.

We also believe that MRGPRX2 inhibition has the potential to treat other inflammatory disorders, such as atopic dermatitis, in which mast cells play key pathological roles.

Both CSU and atopic dermatitis represent multi-billion dollar sales opportunities.

We expect to initiate our first study for our MRGPRX2 inhibitor in 2026 in healthy volunteers to identify the optimal dosing for our molecule.

Following these studies in healthy volunteers, we expect to initiate a proof-of-concept study in subjects with chronic inducible urticaria.

TNF Inhibitor Program

Our TNF program is focused on the design of orally active, small molecules that selectively block the activity of TNF on its pro-inflammation receptor, known as TNFR1, while sparing the ability of TNF to signal via its other receptor ("TNFR2"), which is generally understood to be important for orchestrating anti-inflammatory processes and tissue repair.

The value proposition for this approach is the ability to replace the injectable anti-TNF molecules, which have been considered the standard of care for many inflammatory and autoimmune diseases for many years, with a pill and a more selective agent that may not suffer from the undesirable consequences of TNFR2 blockade.

We believe there is currently only one other small-molecule TNF inhibitor in clinical development, demonstrating the difficulty of developing highly potent and selective small molecules against this target.

We expect to identify our lead development candidate for this program in early 2026 and to file an IND for this molecule in late 2026 or early 2027.

Commercialization Plans

Subject to timely exercise of Gilead's and Taiho Pharmaceutical Co., Ltd.'s ("Taiho") respective option rights discussed below, the Gilead Collaboration Agreement provides us with a potential commercialization partner for the U.S.

and the rest of the world, excluding Japan and certain other Asian countries, and the Option and License Agreement that we entered into with Taiho (the "Taiho Agreement") provides us with a potential commercialization partner for Japan and certain other Asian countries.

For those investigational products being developed in a program that Gilead does not exercise its option to (such as casdatifan), we expect to have the infrastructure or additional third-party collaborations in place to commercialize such projects with an experienced sales, marketing and distribution organization.

In the U.S., we have an option to co-promote with Gilead, which we have elected for domvanalimab and zimberelimab.

As we approach commercialization, we intend to begin building the necessary infrastructure and sales, marketing and commercial capabilities to co-promote our products, if approved, for the U.S.

We currently own all of the commercial rights to casdatifan, with the exception of rights in Japan and certain other Asian countries (excluding China) which were optioned from us by Taiho Pharmaceutical Co., Ltd ("Taiho").

If we receive positive data from a registrational Phase 3 study for casdatifan, we expect to build the necessary infrastructure and sales, marketing and commercial capabilities to commercialize this program in the U.S.

Outside the U.S., we could commercialize casdatifan on our own in certain regions, or with potential partners.

With respect to quemliclustat, domvanalimab and zimberelimab and subject to timely exercise of Gilead's and Taiho's respective option rights to other molecules in our pipeline, as discussed below, Gilead has certain commercialization rights under the Gilead Collaboration Agreement, and Taiho has commercial rights in Japan and certain other Asian countries based on the Option and License Agreement that we entered into with Taiho (as amended, the "Taiho Agreement").

In the U.S., we have an option to co-promote with Gilead, which we have elected for domvanalimab and zimberelimab, and expect to elect for quemliclustat.

Licenses and Collaborations

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Clinical Programs

Under the Gilead Collaboration Agreement, Gilead obtained an exclusive license to develop and commercialize our anti-PD-1 program (including zimberelimab) in certain markets and time-limited exclusive options to develop and commercialize (i) any of our clinical programs existing at the time of entering into the Gilead Collaboration Agreement and (ii) any programs that enter clinical development during the 10-year collaboration term.

Under the Gilead Collaboration Agreement, Gilead has exclusive licenses to develop and commercialize our anti-TIGIT program (including domvanalimab), anti-PD-1 program (including zimberelimab) and CD73 program (including quemliclustat) in certain markets.

Gilead also has time-limited exclusive options to develop and commercialize (i) any of our clinical programs existing at the time of entering into the Gilead Collaboration Agreement and (ii) any programs that enter clinical development during the 10-year collaboration term.

Gilead's continued option rights are contingent upon Gilead making $100 million continuation payments on each anniversary of the agreement in 2026 and 2028.

Gilead's options expire, on a program-by-program basis, after a prescribed period, following the achievement of a clinical development milestone in such program and our delivery to Gilead of the requisite data package.

To date, Gilead has exercised its option to our anti-TIGIT program (including domvanalimab), adenosine receptor antagonist program (including etrumadenant) and CD73 program (including quemliclustat).

Gilead's option rights to our HIF-2α program (including casdatifan) have expired.

Gilead may exercise its option to additional programs at any time prior to the expiration of the option and upon payment of an option fee of $150 million per program.

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Preclinical Programs

Under the Gilead Collaboration Agreement, Gilead has also received options to two oncology research programs (the "Oncology Research Programs") and up to four jointly selected research programs that target inflammatory diseases (the "Inflammation Research Programs").

Under the Gilead Collaboration Agreement, Gilead has also received options to two oncology research programs (the "Oncology Research Programs") and two jointly selected research programs that target inflammatory diseases (the "Inflammation Research Programs").

We will lead discovery and early development activities for all Oncology Research Programs and Inflammation Research Programs.

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If the option is exercised by Gilead at this later clinical stage for an option payment of $150 million, the collaboration terms for optioned programs will be applicable to the joint development program including that, with respect to commercialization outside of the U.S., Gilead would pay us tiered royalties as a percentage of revenues ranging from the high-teens to the low twenties.

With respect to the Inflammation Research Programs, we have received an aggregate of $35 million for the two Inflammation Research Programs that have been jointly selected and will receive an upfront payment of $17.5 million for any additional Inflammation Research Program selected prior to May 12, 2025.

For Inflammation Research Programs, Gilead will have an option to license each program at two separate, prespecified time points.

For the first two Inflammation Research Programs, Gilead has the right, on a program-by-program basis, to either (i) exercise its option upon our completion of certain IND-enabling activities for an option payment of $45 million or (ii) extend its option and exercise it following the achievement of a clinical development milestone for an option payment of $150 million.

If Gilead exercises its option at the earlier time point for the first two programs, we would be eligible to receive up to $375 million in regulatory and commercial milestone payments as well as tiered royalties for each optioned program.

For any other Inflammation Research Program option exercised by Gilead, the parties would have rights to co-develop and share global development costs and to co-commercialize and share profits in the U.S.

With respect to the Inflammation Research Programs, Gilead will have an option to license each program at two separate prespecified time points, either (i) exercise its option upon our completion of certain IND-enabling activities for an option payment of $45 million or (ii) extend its option and exercise it following the achievement of a clinical development milestone for an option payment of $150 million.

If Gilead exercises its option at the earlier time point, we would be eligible to receive up to $375 million in regulatory and commercial milestone payments as well as tiered royalties for each optioned program.

For any other Inflammation Research Program option exercised by Gilead, the parties would have rights to co-develop and share global development costs and to co-promote and share profits in the U.S.

for that program.

Common Stock Purchase Agreement and Investor Rights Agreement

In connection with our entry into the Gilead Collaboration Agreement, we and Gilead entered into a Common Stock Purchase Agreement (as amended, the "Stock Purchase Agreement") and Investor Rights Agreement (as amended, the "Investor Rights Agreement").

In connection with our entry into the Gilead Collaboration Agreement, we and Gilead entered into a Common Stock Purchase Agreement (as amended, the "Stock Purchase Agreement"), which expired in July 2025, and Investor Rights Agreement (as amended, the "Investor Rights Agreement").

We refer to the Gilead Collaboration Agreement, Stock Purchase Agreement and Investor Rights Agreement as the "Gilead Agreements".

Under the Stock Purchase Agreement, Gilead has the right, at its option, to purchase additional shares from us, up to a maximum ownership of 35% of our then-outstanding voting common stock, from time to time until July 2025, at a purchase price per share equal to the greater of a 20% premium to market (based on a trailing five-day average closing price) at the time Gilead exercises such option, and the $33.54 initial purchase price per share.

The Investor Rights Agreement provides Gilead with registration rights, pro rata participation rights in certain future financings and the right to designate three individuals, which they have exercised, to be appointed to our board of directors.

The Investor Rights Agreement provides Gilead with the right to designate three individuals, which they have exercised, to be appointed to our board of directors.

Taiho License

In 2017, we entered into the Taiho Agreement pursuant to which Taiho obtained an exclusive option to in-license development and commercialization rights to programs during a five-year term for which IND-enabling studies had begun.

In 2017, we entered into the Taiho Agreement pursuant to which Taiho obtained an exclusive option to in-license development and commercialization rights to programs for which IND-enabling studies had begun during a five-year term.

These rights are geographically limited to Japan and certain other Asian countries (excluding China) (the "Taiho Territory").

To date, Taiho has exercised its option to (i) etrumadenant (the adenosine receptor antagonist program);

(ii) zimberelimab (the anti PD-1 program);

(iii) domvanalimab and AB308 (the anti-TIGIT program);

and (iv) quemliclustat (the CD73 program).

While the five-year term expired in September 2022, Taiho retains option rights to our HIF-2α program (including casdatifan) and CD39 program (including AB598).

Taiho’s options to these programs expire, on a program-by-program basis, after a prescribed period following the achievement of a clinical development milestone in such program and our delivery to Taiho of the requisite data package.

For each Taiho optioned program, Taiho is obligated to pay to us (i) an option exercise payment for each program that is between $3 million to $15 million, (ii) clinical, regulatory and commercialization milestones of up to $275 million and (iii) royalties on net sales in Taiho’s territories ranging from high single digits to mid-teens.

To date, Taiho has exercised its option to our HIF-2α inhibitor program (including casdatifan), anti-TIGIT program (including domvanalimab), anti-PD-1 program (including zimberelimab), CD73 program (including quemliclustat) and adenosine receptor antagonist program (including etrumadenant).

The five-year term expired in September 2022 and Taiho retains option rights to our CD39 program (including AB598).

Taiho’s option to this program expires after a prescribed period following the achievement of a clinical development milestone in such program and our delivery to Taiho of the requisite data package.

For each Taiho optioned program, Taiho is obligated to pay to us (i) an option exercise payment for each program that is between $3 million to $15 million, (ii) clinical, regulatory and commercialization milestones of up to $275 million except for casdatifan (the HIF-2α program) for which we may receive up to $317 million, and (iii) royalties on net sales in Taiho’s territories ranging from high single digits to mid-teens.

Royalties will be payable on a licensed product-by-licensed product and country-by-country basis during the period of time commencing on the first commercial sale of a licensed product in a country and ending upon the later of:

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and (b) expiration of the last-to-expire valid claim of our patents covering the manufacture, use or sale or exploitation of such licensed product in such country.

Taiho is also responsible for the development and commercialization of licensed products in the Taiho Territory.

Taiho is also responsible for the development and commercialization of licensed products in the Taiho Territory except for casdatifan wher e we are responsible for global development and Taiho is responsible for commercialization in the Taiho Territory.

WuXi Biologics License - anti-PD-1

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Our sublicensees, however, may manufacture, at any time, certain portions of their requirements for such product subject to certain conditions.

We made certain covenants not to commercialize any anti-PD-1 antibody licensed or obtained by us after the date of the license agreement with WuXi Biologics other than anti-PD-1 antibodies licensed from WuXi Biologics, subject to certain exceptions as set forth in the WuXi Agreement.

This agreement terminates, on a licensed product-by-licensed product and country-by-country basis, on expiration of the royalty term for such licensed product for the applicable country.

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Under the agreement, we may be required to make additional clinical, regulatory and commercialization milestone payments of up to $88 million.

The Abmuno Agreement terminates on the latest of (i) the expiry of the last-to-expire Abmuno licensed patent that covers a product that contains an anti-TIGIT antibody, (ii) the date on which there is no longer an Abmuno licensed patent application that is still pending and has been pending for a certain period of time that covers a product that contains an anti-TIGIT antibody and (iii) 10 years from the date of first commercial sale.

Our overarching vision is to create a broad portfolio of best-in-class therapies and develop combinations that bring transformative clinical benefits over current treatment options.

Our clinical development approach aims to generate meaningful data in the most efficient manner possible in order to rapidly advance our investigational products through clinical trials.

Some of the key elements of our strategy include:

• Building a differentiated portfolio by focusing on intra-portfolio combinations.

We are building a diverse portfolio of small-molecule investigational products, such as casdatifan, that target different immune mechanisms, as well as cell-intrinsic pathways important for cancer growth and metastasis.

In addition to small molecules, we are also developing antibody investigational products that target what we believe are some of the most important immune checkpoint receptors, including PD-1 and TIGIT, that we expect to be critical components of our intra-portfolio combinations.

By combining these antibody candidates with our internally discovered small-molecule investigational products, we believe we can create highly differentiated combination products.

• Designing our clinical trials to advance our compounds as quickly and efficiently as possible .

Our goal is to identify the best combinations and settings and to rapidly generate randomized proof-of-concept data for our investigational products early in their development.

We leverage platform trial designs, such as our ARC-20 and EDGE-Lung studies, which allow us to evaluate multiple dosages, combinations and settings for a single tumor type in one clinical trial and compare those combinations against combinations that include the standard-of-care.

• Pursuing combinations and indications based on strong biological rationales .

In selecting indications to pursue, we are focusing on those that are most dependent on the pathways targeted by our agents.

We are also focusing on patient populations and settings where we believe there is still considerable unmet need.

As an example, several oncology indications, such as pancreatic cancer and colorectal cancer, have a high percentage of cases that are driven by certain oncogenic mutations (e.g., KRAS mutations) which are associated with poor responses to current available therapies and poor overall survival, and are associated with high expression levels of CD73.

• Maximizing the value of our portfolio through strategic collaborations and research and development arrangements.

We seek to establish collaborative relationships that will provide us with access to capital, opportunities and/or expertise.

For example, as of December 31, 2024, our collaboration with Gilead has provided us with nearly $1.7 billion in funding, through both non-dilutive payments and equity investments.

For each program that Gilead exercises its option to, we have received, or will receive, a substantial option payment and, subject to certain exceptions, Gilead will share 50% of the global costs for our activities within our joint development plan for that program, while preserving for us the option to co-promote our investigational products in the U.S., should they be approved.

See “—Licenses and Collaborations—Gilead Collaboration” above for more information about Gilead’s cost sharing obligations.

Similarly, the Taiho Agreement provides us with a development and, if approved, commercialization partner for the Taiho Territory.

We intend to continue to establish strategic collaborations so that we can bring our investigational products to the broadest patient population possible.

This agreement terminates on the latest of (i) the expiry of the last-to-expire Abmuno licensed patent that covers a product that contains an anti-TIGIT antibody, (ii) the date on which there is no longer an Abmuno licensed patent application that is still pending and has been pending for a certain period of time that covers a product that contains an anti-TIGIT antibody and (iii) 10 years from the date of first commercial sale.

Manufacturing and Supply

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We rely, and expect to continue to rely, on third parties for the manufacture of our investigational products for preclinical and clinical testing.

If any of our optioned investigational products obtain marketing approval, we expect to continue to use third-party manufacturers along with Gilead’s internal manufacturing infrastructure, as appropriate, to deliver commercial supply.

If any of our investigational products obtain marketing approval, we expect to continue to use third-party manufacturers and may also use Gilead’s internal manufacturing infrastructure for their optioned products, as appropriate, to deliver commercial supply.

We also rely, and expect to continue to rely, on third parties to package, label, store and distribute our investigational products, as well as for our commercial products if marketing approval is obtained.

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Any investigational products that we successfully develop and commercialize will compete with new immunotherapies that may become available in the future.

We will compete in the segments of the pharmaceutical, biotechnology and other related markets that develop immuno-oncology treatments.

There are many other companies that have commercialized and/or are developing immuno-oncology treatments for cancer including large pharmaceutical and biotechnology companies, such as AstraZeneca plc ("AstraZeneca"), BeiGene, Ltd.

("BeiGene"), The Bristol-Myer Squibb Company ("Bristol-Myers Squibb"), GlaxoSmithKline plc ("GSK"), Merck & Co., Inc.

("Merck"), Novartis Inc.

We compete in the segments of the pharmaceutical, biotechnology and other related markets that develop treatments for cancer and inflammatory and autoimmune diseases.

There are many other companies that have commercialized and/or are developing oncology treatments for cancer including large pharmaceutical and biotechnology companies such as AstraZeneca, BeiGene, Ltd.

("BeiGene"), The Bristol-Myer Squibb Company ("Bristol-Myers Squibb"), GlaxoSmithKline plc ("GSK"), Merck, Novartis Inc.

("Novartis"), Pfizer Inc.

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("Sanofi"), and Roche Holdings AG through its subsidiary Genentech ("Roche/Genentech").

For our anti-TIGIT antibody, domvanalimab, we are aware of several pharmaceutical companies developing antibodies against this target, including AstraZeneca, BeiGene, iTeos Therapeutics, Inc.

("iTeos") in partnership with GSK, Merck and Roche/Genentech.

There are also many other companies that have commercialized and/or are developing treatments for inflammatory and autoimmune diseases, including large pharmaceutical and biotechnology companies such as Novartis, Roche/Genentech, Celldex Therapeutics, Inc., Abbvie Inc.

("Abbvie"), Amgen Inc., Sanofi and Regeneron.

For our HIF-2α inhibitor, casdatifan, Merck received approval for belzutifan in Von Hippel-Lindau disease in 2021, advanced renal cell carcinoma in 2023 and has a number of clinical studies assessing its activity in cancer settings.

Other pharmaceutical companies, including Novartis and NiKang Therapeutics, Inc., have small-molecule HIF-2α inhibitors in development.

Arrowhead Pharmaceuticals Inc.

has an RNA-based anti-HIF-2α agent in Phase 2 development.

For our anti-TIGIT antibody, domvanalimab, AstraZeneca has initiated more than nine registrational studies for rilvegostomig, its investigational anti-TIGIT/anti-PD-1 bispecific antibody.

To our knowledge, there are no approved anti-TIGIT antibodies, and the most advanced agents are in Phase 3 development.

For our dual adenosine receptor antagonist, etrumadenant, we are aware that Merck (through Merck KGaA) has initiated clinical development of dual adenosine receptor antagonists.

We are aware of clinical-stage selective adenosine A2a receptor antagonists being developed by other companies, including AstraZeneca, iTeos, and Portage Biotech Inc.

Clinical-stage selective adenosine A2b receptor antagonists are also being developed by companies such as Palobiofarma S.L.

To our knowledge, there are no adenosine receptor antagonists approved for the treatment of cancer, and the most advanced is in Phase 2 development.

For our small molecule CD73 inhibitor, quemliclustat, we are aware of several pharmaceutical companies developing antibodies against this target, including AstraZeneca, Bristol-Myers Squibb, I-MAB Biopharma (Shanghai) Co., Ltd., Incyte Corporation, Innate Pharma S.A., Innovent Biologics, Inc.

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For our anti-PD-1 antibody, zimberelimab, multiple large pharmaceutical companies have already received regulatory approvals for their anti-PD-1/PD-L1 antibodies, including AstraZeneca, BeiGene/Novartis, Bristol-Myers Squibb, Merck, Pfizer in partnership with Merck KGaA, Regeneron in partnership with Sanofi Genzyme and Roche/Genentech, and there are also many other anti-PD-1 and anti-PD-L1 antibodies in clinical development.

Other pharmaceutical companies, including Novartis and NiKang Therapeutics, Inc., have small-molecule HIF-2α inhibitors in development.

Arrowhead Pharmaceuticals Inc.

has an RNA-based anti-HIF-2α agent in Phase 2 development.

Many of the companies which we may compete with 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.

For our inflammation and immunology portfolio, we will be competing against large pharmaceutical and biotechnology companies with established products, such as Dupixent®, which is marketed by Sanofi and Regeneron, Xolair®, which is marketed by Genentech and Novartis, and Humira®, which is marketed by Abbvie.

Many of the companies against which we may compete have significantly greater financial resources and expertise in R&D, 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.

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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 U.S.

Food and Drug Administration (the "FDA") or foreign regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we or our collaborators are able to enter the market.

Our competitors also may obtain FDA or foreign regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we or our collaborators are able to enter the market.

The key competitive factors affecting the success of all of our investigational products, if approved, are likely to be their efficacy, safety, convenience, price, the effectiveness of companion diagnostics (if required), the level of biosimilar or generic competition and the availability of reimbursement from government and other third-party payors.

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subjects and subsequent protocol amendments must be submitted to the FDA as part of the IND.

While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected AEs, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

The FDA may order the temporary or permanent discontinuation of a clinical trial at any time, or impose other sanctions if it believes that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial subjects.

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Expedited Development and Review Programs

The FDA has various programs, including Fast Track, priority review, accelerated approval and Breakthrough Therapy, which are intended to expedite or simplify the process for reviewing investigational products designed to address serious or life threatening conditions, or provide for the approval of a such investigational products on the basis of an effect on a surrogate or intermediate endpoint.

The FDA has various programs, including Fast Track, Breakthrough Therapy, priority review, accelerated approval, and Commissioner's National Priority Voucher ("CNPV"), which are intended to expedite or simplify the process for reviewing investigational products designed to address serious or life threatening conditions, or provide for the approval of a such investigational products on the basis of an effect on a surrogate or intermediate endpoint.

Even if an investigational product qualifies for one or more of these programs, the FDA may later decide that the investigational product no longer meets the conditions for qualification or that the time period for FDA review or approval will not be shortened.

For example, Fast Track is a process designed to facilitate the development and expedite the review of investigational products designed to treat serious or life-threatening diseases or conditions, demonstrate the potential to address unmet medical needs for the disease or condition.

The sponsor of a Fast Track product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA or BLA is submitted, the application may be eligible for priority review.

With regard to a Fast Track product candidate, the FDA may consider for review sections of the NDA or BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA or BLA, the FDA agrees to accept sections of the NDA or BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA or BLA.

The sponsor of a Fast Track investigational product has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA or BLA is submitted, the application may be eligible for priority review.

With regard to a Fast Track investigational product, the FDA may consider for review sections of the NDA or BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA or BLA, the FDA agrees to accept sections of the NDA or BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA or BLA.

In addition, the FDA also provides Breakthrough Therapy designation.

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In addition, for products being considered for Accelerated Approval, the FDA requires pre-approval of promotional materials within certain timeframes, which could adversely impact the timing of the commercial launch of the product.

The newly implemented CNPV approach could further shorten the review time to 1-2 months with CMC and labeling information submitted 60 days prior to the full NDA or BLA submission.

However, the non-traditional review process may face legal challenges.

Orphan Drug Designation

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The FDA may revoke orphan drug designation, and if it does, it will publicize the drug is no longer designated as an orphan drug.

If an investigational product with orphan drug designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the investigational product is generally entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same investigational product for the same disease or condition, except in very limited circumstances, for seven years.

Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition.

Orphan drug exclusivity, however, could also block the approval of an investigational product for seven years if a competitor obtains approval of the same investigational product, as defined by the FDA, or if such investigational product is determined to be contained within the competitor’s investigational product for the same condition or disease.

If an investigational product with orphan drug designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the investigational product is generally entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same investigational product for the same approved indication or use within the designated disease or condition, except in very limited circumstances, for seven years.

Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same indication or use within the relevant disease or condition, or the same drug for a different disease or condition.

Orphan drug exclusivity, however, could also block the approval of an investigational product for the approved orphan indication or use for seven years if a competitor obtains approval of the same investigational product, as defined by the FDA, or if such investigational product is determined to be contained within the competitor’s investigational product for the same condition or disease.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the disease or condition for which it received orphan designation.

In addition, orphan drug exclusive marketing rights in the U.S.

may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if a second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if a second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity within the relevant indication or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs relating to the approved indication or use of patients with the rare disease or condition.

Patent Term Restoration

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Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the biological investigational product and the reference product in terms of safety, purity, and potency.

Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of Health and Human Services waives a required element.

Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of the U.S.

Department of Health and Human Services ("HHS") waives a required element.

A biosimilar investigational product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

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Healthcare Laws and Compliance Requirements

In the U.S, our activities 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 & Medicaid Services (the "CMS") other divisions of the U.S.

Department of Health and Human Services ("HHS"), such as the Office of Inspector General, the U.S.

Department of Justice (the "DOJ") and individual U.S.

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(iii) expanded the availability of lower pricing under the 340B drug pricing program by adding new entities to the program;

(iv) increased the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program, to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively and capped the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price ("AMP");

(iv) increased the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program, to 23.1% and 13% of the Average Manufacturer Price ("AMP") for most branded and generic drugs, respectively and capped the total rebate amount for innovator drugs at 100% of the AMP;

(v) expanded the eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals, thereby potentially increasing manufacturers’ Medicaid rebate liability;

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For example, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 ("IRA"), into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and by creating a new manufacturer discount program.

The IRA also eliminates the "donut hole" under the Medicare Part D program which began in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and by creating a new manufacturer discount program.

Further legislation or regulation could be passed that could harm our business, financial condition and results of operations.

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For example, in August 2011, the Budget Control Act of 2011, was signed into law which, among other things, included aggregate reductions to Medicare payments to providers that went into effect beginning on April 1, 2013 and, due to subsequent legislation, will stay in effect until 2032 unless additional Congressional action is taken.

Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap, which was previously set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap, which was previously set at 100% of a drug’s AMP, for single source and innovator multiple source drugs, beginning January 1, 2024.

Additionally, there has been increasing legislative and enforcement interest in the U.S.

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Congressional inquiries and proposed federal legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

In August 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law.

In August 2022, the IRA was signed into law.

Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;

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and replaces the Part D coverage gap discount program with a new discounting program (which began in 2025).

CMS has published the negotiated prices for the initial ten drugs, which will first be effective in 2026, and has published the list of the subsequent 15 drugs that will be subject to negotiation.

The IRA permits the Secretary of the Department of Health and Human Services, or HHS, to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

CMS has published the negotiated prices for the initial ten drugs, which will first be effective in 2026, and the subsequent 15 drugs, which will first be effective in 2027.

The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

HHS has and will continue to issue and update guidance as these programs are implemented, although the Medicare drug price negotiation program is currently subject to legal challenges.

For that and other reasons, it is currently unclear how the IRA will be effectuated, or the impact of the IRA on our business.

The One Big Beautiful Bill Act (the "OBBBA") also included significant reforms to Medicaid, including an estimated $1 trillion in reduced federal Medicaid spending from 2025 through 2034, the imposition of work requirements for certain adult enrollees, more frequent eligibility redeterminations, and increased cost-sharing for beneficiaries.

These changes are expected to reduce overall Medicaid enrollment and access to care.

Although the effect on our business is currently unknown, any decrease in the number of insured patients or reimbursement levels for our products could adversely affect our revenue and commercial prospects.

In addition, the Trump administration is pursuing a two-fold strategy to reduce drug costs in the U.S.

While it is unclear whether and how the Trump proposals will be implemented, the Trump policies are likely to have a negative impact on the pharmaceutical industry and on our ability to receive adequate revenues for investigational products, if approved.

On the one hand, President Trump has threatened to impose significant tariffs on pharmaceutical manufacturers that do not adopt pricing policies such as most favored nation pricing, which would tie the price for drugs in the U.S.

to the lowest price in a group of other countries.

In response, multiple manufacturers have reportedly entered into confidential pricing agreements with the federal government.

On the other hand, the Trump administration is pursuing traditional regulatory pathways to impose drug pricing policies, although final regulations have not yet been published.

Even regulatory proposals or executive actions that are ultimately deemed unlawful could negatively impact the U.S.

pharmaceutical sector and our business.

In addition, pharmaceutical pricing and marketing has long been the subject of considerable discussion in Congress and among policymakers.

On December 7, 2023, the former Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

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The competent authority of the RMS prepares a draft assessment report, a draft summary of the drug characteristics ("SPC") and a draft of the labeling and package leaflet, which are sent to the other member states (the "Member States Concerned") for their approval.

If the Member States Concerned raise no objections, based on a potential serious risk to public health, to the assessment, SPC, labeling, or packaging proposed by the RMS, the drug is subsequently granted a national marketing authorization in all the member states ( i.e.

, in the RMS and the Member States Concerned).

We will be subject to additional regulations with respect to any activities we conduct in the EU and the UK.

For example, the EU General Data Protection Regulation (the "EU GDPR") and the United Kingdom’s General Data Protection Regulation (the "UK GDPR" and, together with the EU GDPR, the "GDPR") applies to health-related and other personal data of individuals in the EU and UK, respectively.

The GPDR imposes more stringent operational requirements on processors and controllers of personal data, including, for example, expanded disclosures about how personal data is collected, used and shared, limitations on retention of personal data, more stringent requirements pertaining to genetic, biometric and health data, mandatory data breach notification requirements, and higher standards for controllers to demonstrate valid consent for certain data processing activities.

For example, the EU General Data Protection Regulation (the "EU GDPR") and the United Kingdom's (the "UK") General Data Protection Regulation (the "UK GDPR" and, together with the EU GDPR, the "GDPR") applies to health-related and other personal data of individuals in the EU and UK, respectively.

The GDPR further provides that EU member states may implement their own additional laws and regulations in relation to the processing of genetic, biometric or health data, which could result in differences in the GDPR’s implementation among member states.

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We do the right things for the right reasons.

We take pride in hard work and approach our mission—to create, develop and commercialize highly differentiated combination therapies that have the potential to cure—with a great sense of urgency.

We take pride in hard work and approach our mission—to create, develop and commercialize highly differentiated therapies that have a meaningful impact on patients—with a great sense of urgency.

We recognize that our employees are a critical component to our success and we strive to attract the best talent from a range of sources, including an internship program through which we have developed strong relationships with multiple universities to foster talent and attract skilled graduates.

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As of December 31, 2025, we had 601 full-time employees, approximately 49% of whom hold Ph.D., M.D., R.N., or similar degrees and certifications.

Of our employees, approximately 81% were engaged in research and development activities.

Of our employees, approximately 81% were engaged in R&D activities.

None of our employees are represented by labor unions or covered by collective bargaining agreements.

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As of December 31, 2025, 58% of our employees and 48% of our leadership identify as being from diverse racial and ethnic groups.

On our board of directors, four of our eleven directors self-identify as female, and two self-identify as being from a diverse racial or ethnic group.

We recognize that attracting skilled talent is only one part of the equation.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business