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Rusfertide

Rusfertide is a first-in-class investigational injectable mimetic of the natural hormone hepcidin in development for the treatment of the rare blood disorder polycythemia vera (“PV”). We discovered rusfertide, advanced it into Phase 3 development, and in early 2024 entered into a co-development and co-commercialization arrangement with Takeda Pharmaceuticals, Inc. (“Takeda”) under a license and collaboration agreement entered into in January 2024. We

remained primarily responsible for clinical development activities through rusfertide’s NDA filing for the treatment of erythrocytosis in patients with PV, which we and Takeda submitted in December 2025. Rusfertide has also received Orphan Drug status, Fast Track designation and, in August 2025, Breakthrough Therapy designation (“BTD”). BTD is a process designed to expedite the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. BTD also provides eligibility for priority NDA review, and Orphan Drug status qualifies sponsors for various incentives, including the potential for extended market exclusivity. Takeda has disclosed that it expects to launch rusfertide in the second half of 2026, subject to regulatory approval.

IL-17 Program

PN-881. We are developing PN-881, a potential best-in-class oral peptide IL-17 antagonist, for the treatment of immune-mediated skin diseases. PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), and may offer potential treatment options for plaque psoriasis, psoriatic arthritis (“PsA”), hidradenitis suppurativa (“HS”), and spondyloarthritis.

In October 2025, the first human subject was dosed in our Phase 1 trial of PN-881 (ClinicalTrials.gov identifier NCT07153146) evaluating its safety, tolerability, pharmacokinetics and pharmacodynamics in healthy adults. Results of the PN-881 Phase 1 study are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial. We expect to complete the Phase 1 study in mid-2026 and initiate a Phase 2 study of PN-881 in psoriasis by the end of 2026.

Obesity Program

PN-477. In June 2025, we nominated PN-477, a potential best-in-class novel triple GLP-1, GIP and GCG receptor agonist peptide with oral (“PN-477o”) and subcutaneous (“PN-477sc”) routes of administration, as a development candidate for the treatment of obesity. We designed PN-477 to offer an optimal combination of total body weight loss, improved gastrointestinal tolerability and fat to lean mass ratio, with the dosing convenience of a once-daily oral agent and the added optionality of a once-weekly subcutaneous administration. IND-enabling studies of PN-477 are underway and the initiation of Phase 1 clinical studies in PN-477sc and PN-477o are anticipated by mid-2026 and in the second half of 2026, respectively.

PN-458. In December 2025, we nominated development candidate PN-458, a potential best-in-class novel dual GLP-1 and GIP receptor agonist peptide, as a development candidate for the treatment of obesity, with optionality for both an oral (“PN-458o”) and subcutaneous (“PN-458sc”) formulation. IND-enabling studies for PN-458o and PN-458sc are ongoing.

Oral Hepcidin Program

PN-8047. In December 2025, we nominated development candidate PN-8047, an orally administered hepcidin functional mimetic small molecule, which we believe may be complementary to the injectable rusfertide for offering the best treatment options for PV. IND-enabling studies for PN-8047 are ongoing.

Other Programs

We also have a number of pre-clinical stage drug discovery programs addressing biologically and commercially validated targets, including an oral IL-4R alpha antagonist for the treatment of atopic dermatitis and moderate-to-severe asthma, and amylinR-based oral and subcutaneous mono- and poly-agonists for the treatment of obesity.

Significant Cash Resources

We ended fiscal 2025 with cash, cash equivalents and marketable securities of approximately $646.0 million, as compared to cash, cash equivalents and marketable securities of approximately $559.2 million as of December 31, 2024. In 2026 and beyond, we are eligible to receive significant milestone, royalty and other payments from our collaborations with JNJ and Takeda, as described below. The receipt of future royalties and commercial milestones is contingent upon the relevant products receiving FDA approval and achieving a successful commercial launch.

Collaboration Agreements

JNJ License and Collaboration Agreement

We and JNJ are parties to a license and collaboration agreement related to the development and commercialization of Icotyde. We entered into the agreement in July 2017, and amended it in May 2019, July 2021 and November 2024 (as amended, the “JNJ License and Collaboration Agreement”). Pursuant to the JNJ License and Collaboration Agreement, we were primarily responsible for the discovery, IND-enabling studies and the initial Phase 1 study for Icotyde, and JNJ is primarily responsible for conducting all further development.

We have earned a total of $337.5 million in milestone payments from JNJ under the agreement, including a $165.0 million milestone payment earned in the fourth quarter of 2024. We are eligible to receive up to $630.0 million in future development and sales milestone payments, including the following potential milestones:

We will also receive upward tiering royalties on net worldwide Icotyde product sales at percentages ranging from 6% to 10%. Our weighted average royalty rate on the first $4.0 billion in annual net sales is 7.25%, and the rate on net sales over $4.0 billion is 10%. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for additional information.

Takeda Collaboration Agreement

In January 2024, we entered into a worldwide license and collaboration agreement for rusfertide with Takeda (the “Takeda Collaboration Agreement”) related to rusfertide (and specified second-generation injectable hepcidin mimetic compounds developed and commercialized under the agreement that are not currently in development). In December 2025, Takeda submitted an NDA to the FDA for rusfertide in PV. We were primarily responsible for the clinical development of rusfertide through NDA filing and remain primarily responsible for the conduct of ongoing rusfertide long-term extension studies. Under the terms of the agreement, we received an upfront payment of $300.0 million in April 2024 and a $25.0 million milestone payment in September 2025 upon completion of the Phase 3 VERIFY clinical trial (NCT05210790) report.

Under the Takeda Collaboration Agreement, we and Takeda share equally in profits and losses (50% to us and 50% to Takeda) associated with rusfertide in the United States. We also will receive tiered royalties ranging from 10% to 17% on ex-U.S. net sales of rusfertide. However, we have the right under the Takeda Collaboration Agreement to opt-out of the U.S. profit and loss sharing arrangement. We currently expect to exercise that right in the second quarter of 2026, within the 90-day opt-out window beginning 120 days after the NDA filing date as prescribed in the agreement.

If we exercise our opt-out right, Takeda will have an exclusive worldwide license to develop and commercialize rusfertide, and we will receive royalties of 14% to 29% on annual worldwide net sales, with a weighted average royalty rate of 21% at $1.5 billion in net sales and a rate of 29% for net sales over $1.5 billion. In addition, under the agreement, we are eligible to receive up to an aggregate of $975.0 million in development, regulatory and sales milestones, including the $25.0 million milestone payment already received in September 2025, and up to $400.0 million in payments for exercising the opt-out right. Upcoming potential development milestones and potential sales milestones under the agreement if we exercise our opt-out right include the following:

If we do not exercise our opt-out right, we will be eligible to receive up to an aggregate of $305.0 million in development, regulatory and sales milestones and will continue sharing equally in profits and losses associated with rusfertide in the United States. In addition, we will receive tiered royalties ranging from 10% to 17% on ex-U.S. net sales of rusfertide.

See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for further details related to the agreement, including our opt-out rights.

OUR INFLAMMATORY AND IMMUNOLOGY (“I&I”) PROGRAM

Our I&I program focuses on immune-mediated inflammatory diseases driven by the IL-23 and IL-17 pathways. The program includes Icotyde, an IL-23R peptide antagonist licensed to JNJ, and PN-881, a wholly owned oral IL-17 antagonist. Both candidates leverage our proprietary peptide platform to develop targeted, orally delivered therapies for multiple chronic inflammatory diseases.

Disease Background and Market Opportunity

The IL-23 and IL-17 signaling pathways are central drivers of multiple immune-mediated inflammatory diseases, including psoriasis, PsA, HS, axial spondyloarthritis (“axSpA”), and inflammatory bowel disease (“IBD”). These chronic conditions are associated with significant morbidity, impaired quality of life, and long-term healthcare utilization.

Psoriasis

Psoriasis is a chronic inflammatory skin disease affecting approximately 130 million people worldwide and over 8 million people in the United States, or 2% to 3% of the adult population. Comorbidities include cardiovascular disease and obesity, and up to 30% of patients develop arthritic complications. Plaque psoriasis is the most common form, with severity classified by affected body surface area: moderate (3% to 10%) and severe (>10%). Global sales for psoriasis therapies were $25.4 billion in 2024 and are expected to exceed $39.0 billion by 2030.

Targeting the IL-23/IL-17 axis has led to more effective systemic therapies. Key IL-23 inhibitors include Stelara® (p40 antagonist; psoriasis, PsA, UC, CD), Tremfya®, Skyrizi® (p19-specific; psoriasis, PsA, UC, CD), Omvoh® (mirikizumab; UC, CD), and Ilumya® (tildrakizumab; psoriasis). IL-17 inhibitors include Cosentyx®, Taltz®, Bimzelx® (blocks IL-17A and IL-17F), and Siliq® (IL-17 receptor A). The anti-IL-17 class is ineffective in IBD.

Only 25% of biologic-eligible moderate-to-severe psoriasis patients are treated with biologics, in part due to the parenteral route. This treatment gap highlights the impact of chronic injectable administration, patient preference, and access considerations, and underscores the need for effective oral therapies that can expand treatment adoption without compromising efficacy. Oral therapies, such as Otezla® (2014, PDE4 inhibitor) and Sotyktu® (2022, TYK2 inhibitor), offer alternatives, with second-generation TYK2 inhibitors in late-stage development. Despite the clinical success of injectable biologics targeting the IL-23 and IL-17 pathways, their parenteral administration and long-term treatment burden continue to limit utilization, supporting demand for oral therapies that can deliver comparable efficacy with improved convenience.

Psoriatic Arthritis

PsA is an inflammatory disease of the peripheral and axial joints that complicates psoriasis in up to 30% of patients. Among the over 8 million patients in the United States with psoriasis in 2024, it is estimated that approximately 1.7 million patients have PsA. Many patients with active PsA may have mild psoriasis and many patients with severe psoriasis may have only mild PsA symptoms. PsA is associated with several chronic conditions and may present even before skin symptoms in 10% to 15% of patients. Cardiovascular comorbidities have a higher prevalence in PsA than psoriasis and can impact both lifespan and quality of life.

Global market sales of PsA therapies were approximately $7.1 billion in 2024 and are expected to reach more than $10.0 billion in 2034. Treatment options typically overlap with psoriasis therapies; exceptions to this include JAK inhibitors (Xeljanz® and Rinvoq®), which are approved for PsA but not psoriasis. As a result, therapies that are effective across both skin and joint manifestations and that offer improved convenience may provide meaningful clinical and patient-reported benefits in PsA.

Hidradenitis Suppurativa

HS affects approximately 2.9 million patients in the United States and 6.3 million patients globally. It is a chronic, painful inflammatory skin disease that significantly impacts quality of life and productivity. Global HS therapy sales were approximately $1.5 billion in 2024, with global sales projected to reach $6.5 billion ($5.4 billion in the United States) by 2034. Targeted therapies include Humira®, Cosentyx®, and Bimzelx®. While recent biologic approvals have improved outcomes for some patients, HS remains an area of high unmet need, particularly for therapies that combine high efficacy with the convenience of oral administration for long-term disease management.

Axial Spondyloarthritis

axSpA affects approximately 2.0 million U.S. patients and 3.8 million patients globally. It is a systemic arthritis affecting the spine and sacroiliac joints, with progression from non-radiographic (nr-axSpA) to radiographic disease (AS). Global axSpA therapy sales were $4.7 billion in 2024, with global sales projected to reach $7.2 billion ($5.9 billion in the United States) by 2034. Treatments include TNFα inhibitors, IL-17 inhibitors, and JAK inhibitors. Despite the availability of multiple biologic and targeted therapies, many patients experience incomplete symptom control or treatment fatigue, highlighting the need for additional therapeutic options that reduce long-term burden.

Inflammatory Bowel Disease

IBD, comprising ulcerative colitis (“UC”) and Crohn’s disease (“CD”) is diagnosed in over 0.7% of Americans, resulting in a population of approximately 2.4 million patients in the United States. UC primarily involves colon inflammation and bleeding, while CD affects any gastrointestinal tract segment and may cause strictures and fistulae. Management is lifelong and impacts quality of life and productivity.

Global 2023 sales for UC therapies were $7.8 billion, with global sales projected to reach $18.8 billion by 2030. Global 2023 sales for CD therapies were $15.2 billion, with global sales projected to reach $18.7 billion by 2030. Treatment options for UC and CD include TNF-α inhibitors, α4β7 integrin antagonists (Entyvio®), IL-23 inhibitors (Stelara®, Tremfya®, Skyrizi®, Omvoh®), JAK inhibitors, and S1P1 modulators. Despite this expanding therapeutic landscape, remission rates remain limited and loss of response over time is common, underscoring the need for more effective and better-tolerated oral therapies, including those suitable for combination use.

Current Therapeutic Landscape and Unmet Medical Needs

Treatment paradigms across IL-23- and IL-17-mediated diseases are dominated by injectable biologic therapies, including antibodies targeting IL-23, IL-17, TNF-α, and related pathways. These biologics have demonstrated efficacy and are widely used in moderate-to-severe disease across multiple indications.

Despite these advances, unmet medical needs remain. A substantial proportion of biologic-eligible patients remain untreated, in part due to the burden of chronic injections, tolerability considerations, and access limitations. Safety considerations associated with systemic immunosuppression further constrain long-term treatment options. Orally delivered, targeted therapies may reduce burden, improve adherence, and expand patient access.

Our Development Candidates

Icotyde: An Oral IL-23 Receptor Antagonist

Icotyde, an orally delivered IL-23R specific antagonist for the potential treatment of psoriasis, PsA and IBD indications, was discovered through our proprietary technology platform. IL-23, a member of the IL-12 family of pro-inflammatory cytokines, is a protein that regulates inflammatory and immune function and plays a key role in the development of IBD.

We have a worldwide license and collaboration agreement with JNJ to research, develop and co-detail IL-23R antagonist compounds for all indications, including IBD. Pursuant to the JNJ License and Collaboration Agreement, we were responsible for the discovery, IND-enabling studies, and the initial Phase 1 study for Icotyde, and JNJ is responsible for conducting all further development. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.

JNJ is an experienced innovator in therapeutics targeting the IL-23 pathway. Stelara®, a monoclonal antibody targeting IL-12 and IL-23 through their common p40 subunit, is approved in psoriasis, PsA, CD and UC. Stelara® generated $10.4 billion in global sales in 2024 and $6.1 billion in global sales in 2025. It is notable that Stelara® lost patent exclusivity in 2023, with expected biosimilar competition. Tremfya®, a specific IL-23 monoclonal antibody, is approved in psoriasis, PsA, UC and CD. Tremfya® generated $3.7 billion in sales in 2024 and $5.2 billion in 2025. At JNJ’s Enterprise Business Review in December 2023, JNJ highlighted Icotyde as a potential first- and best-in-class drug with potential across multiple indications, including plaque psoriasis, PsA and inflammatory bowel disease, with potential peak year sales projected at greater than $5.0 billion.

PN-881: An Oral IL-17 Receptor Antagonist

PN-881, a wholly owned oral peptide antagonist of the IL-17 pathway, was selected in the fourth quarter of 2024 as a potential best-in-class oral therapy for the treatment of immune-mediated skin diseases.

PN-881 was evaluated in extensive preclinical studies, including for oral stability, potency, tissue distribution, and pharmacokinetics measurements, and was evaluated in immunologic pharmacodynamics and preclinical efficacy models. In multiple preclinical studies with oral dosing, PN-881 showed effective blockade in vivo of IL-17 in serum and skin and achieved pre-clinical proof-of-concept in a skin inflammation rodent disease model.

We initiated a Phase 1 PN-881 first-in-human study in the fourth quarter of 2025. Results of the Phase 1 single ascending dose (“SAD”) and multiple ascending dose (“MAD”) study are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial. Rapid expansion into other IL-17 mediated diseases, including PsA, HS and axSpA, is expected to be based on results observed in the psoriasis studies.

We believe an IL-17 antagonist peptide like PN-881, with best-in-class potential as an oral targeted therapy, may offer an attractive therapeutic option for patients with broad opportunity for multiple indications in addition to psoriasis.

OUR HEMATOLOGY PROGRAM

Our hematology and blood disorders program focuses on disorders of iron homeostasis and red blood cell production. The program includes rusfertide, an injectable hepcidin mimetic in development for the treatment of PV, partnered with Takeda, and PN-8047, a wholly-owned oral hepcidin functional mimetic.

Disease Background and Market Opportunity

PV is a rare myeloproliferative neoplasm commonly associated with a Janus Kinase (“JAK”) 2 mutation. It is characterized by overproduction of red blood cells (“RBCs”), which increases the risk of cardiovascular and thrombotic events such as heart attack and stroke, and carries a risk of progression to myelofibrosis or leukemia. According to National Comprehensive Cancer Network (“NCCN”) guidelines, risk classification is based on age and history of thrombosis. Regardless of risk, NCCN guidelines emphasize maintaining hematocrit below 45% to reduce thrombotic risk.

There are approximately 155,000 patients diagnosed with PV in the United States, of whom approximately 78,000 are treated, with a similar number of diagnosed patients in Europe. Patients are typically diagnosed between ages 50 and 70, with median survival of approximately 14 years.

Current Therapeutic Landscape and Unmet Medical Needs

Early-stage PV is often managed with low-dose aspirin and therapeutic phlebotomy, with hydroxyurea used alone or in combination. Later-stage patients may receive interferons, such as Besremi® or Pegasys®, or the JAK inhibitor ruxolitinib (Jakafi®). These cytoreductive therapies impact multiple cell lines and can be associated with challenging side-effect profiles.

Despite available treatments, significant unmet medical needs persist:

●Inadequate Hematocrit Control: Approximately 78% of treated PV patients do not maintain hematocrit below 45%, highlighting persistent thrombotic risk.

●Treatment Burden and Tolerability: Approximately 55% of treated patients require frequent phlebotomy and high-dose hydroxyurea, creating considerable treatment burden. Approximately 16% of patients experience thrombotic events despite treatment.

●Safety Concerns: Retrospective data presented at the 2023 American Society of Hematology Annual Meeting indicate that PV patients treated with hydroxyurea had nearly double the incidence of cancers compared to phlebotomy-only patients. The mechanisms behind this increased risk are not fully understood.

●Iron Deficiency: Chronic phlebotomy and high RBC turnover exacerbate iron deficiency, underscoring the need for therapies that maintain hematocrit without broad cytoreduction.

Our Development Candidates

Rusfertide: An Injectable Hepcidin Mimetic

Rusfertide was discovered through our proprietary technology platform. Acting as a hepcidin mimetic, it redistributes iron away from the bone marrow, limiting excess RBC production while maintaining iron availability for other physiological functions.

Data from the Phase 2 REVIVE trial (NCT04057040) and pivotal Phase 3 VERIFY trial suggest that rusfertide provides persistent hematocrit control, reduces the need for phlebotomy, and does not induce iron deficiency. Patients with prior thromboembolic adverse events (“TEAEs”), who are at highest risk, generally did not experience recurrent TEAEs while on rusfertide.

In January 2024, we entered into a worldwide license and collaboration agreement for the development and commercialization of rusfertide with Takeda. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.

PN-8047: An Oral Hepciden Functional Mimetic

Our development candidate PN-8047 is an orally administered hepcidin functional mimetic small molecule designed to complement injectable rusfertide and provide additional treatment options for PV. PN-8047 has completed extensive preclinical evaluation, including studies of potency, metabolic stability in liver microsomes, oral permeability, pharmacokinetics, and pharmacodynamics.

PN-8047 has potency similar to rusfertide and greater potency than native hepcidin. In preclinical in vivo studies, PN-8047 demonstrated oral bioavailability and a half-life in rodents, cynomolgus monkeys, and dogs sufficient for once-daily dosing. PN-8047 also produced sustained serum iron reduction in pharmacokinetic/pharmacodynamic models and demonstrated efficacy in an erythropoietin-induced mouse model of erythropoiesis, including reductions in hemoglobin and hematocrit observed after repeated dosing in cynomolgus monkeys. IND-enabling studies for PN-8047 are ongoing.

Strategic Rationale

We are advancing rusfertide and PN-8047 to address persistent gaps in the PV treatment landscape through non-cytoreductive modulation of iron homeostasis:

●Targeted Mechanism: Unlike cytoreductive therapies, both candidates specifically regulate RBC production via iron redistribution, potentially offering improved tolerability.

●Consistent Hematocrit Control: Rusfertide has demonstrated durable hematocrit control while reducing phlebotomy needs and avoiding iron deficiency.

●Oral Delivery Option: PN-8047 provides the convenience of oral administration, potentially improving adherence and patient satisfaction, especially given the chronic nature of PV.

●Broad Patient Applicability: Both candidates may benefit a wide spectrum of patients, either as monotherapy or in combination with cytoreductive therapies, enabling personalized treatment approaches.

The PV market represents a rare disease opportunity with significant unmet need. Treated patients are often on polytherapy and will cycle through various treatments, including phlebotomy, hydroxyurea, ruxolitinib and/or ropeginterferon. Approximately 78% of treated patients do not maintain hematocrit below 45% despite current treatments, and unmet need exists at each step of the treatment landscape. Despite standard-of-care treatments, there is a substantial patient population that remains under treated or untreated. Rusfertide provides consistent hematocrit control and can potentially reduce treatment burden to achieve a peak revenue potential of $1.0 to $2.0 billion. By leveraging non-cytoreductive hepcidin pathway modulation through both injectable and oral delivery, our program seeks to address persistent limitations of current cytoreductive therapies and provide improved hematocrit control for PV patients.

OUR OBESITY AND METABOLIC DISEASE PROGRAM

Our obesity and metabolic disease program represents a strategic expansion into one of the largest and fastest-growing therapeutic markets globally. We are developing a portfolio of differentiated oral and subcutaneous therapies designed to address significant unmet needs in chronic weight management. Our wholly-owned development candidates, PN-477 and PN-458, leverage our proprietary technology platform to target key hormonal and metabolic pathways while addressing persistent barriers to long-term treatment adherence, including gastrointestinal tolerability, the burden of chronic injections, and the potential to support improved body-composition outcomes during weight loss.

Disease Background and Market Opportunity

Obesity is a chronic, relapsing metabolic disease characterized by excessive adiposity that impairs health, quality of life, and overall survival. It is clinically defined as a body mass index of 30 kg/m² or greater, with severe obesity

defined as a BMI of 40 kg/m² or greater. Globally, over one billion adults are estimated to live with obesity. In the United States, nearly 40% of adults meet criteria for obesity and nearly 9% meet criteria for severe obesity.

Obesity is associated with numerous chronic diseases and comorbidities, including Type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular disease, chronic kidney disease, and obstructive sleep apnea. The disease contributes substantially to healthcare utilization and economic burden, including increased direct medical costs and indirect costs associated with lost productivity and disability.

The global market for anti-obesity medications is experiencing unprecedented growth driven by rising disease prevalence, increasing clinical adoption of pharmacologic interventions, and expanded treatment paradigms. The global market for anti-obesity medications is expected to reach more than $120 billion by 2034. In the United States, only an estimated 5% of the approximately 131 million Americans with obesity or who are drug-eligible, overweight individuals currently receive pharmacologic treatment, indicating substantial room for market expansion.

Despite this growth trajectory, discontinuation rates remain high due to tolerability issues, the burden of chronic injections, access limitations, and patient preferences for oral therapies. In 2025, Wegovy® and Zepbound® collectively generated tens of billions of dollars in global revenue, underscoring both the commercial potential of the category and the demand for differentiated next-generation therapies.

Current Therapeutic Landscape and Unmet Medical Needs

The obesity therapeutic landscape has evolved rapidly over the past several years, expanding beyond traditional lifestyle interventions and bariatric surgery to include pharmacologic therapies with demonstrated effects on body weight and metabolic parameters. Injectable incretin-based therapies, particularly GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists, have validated the obesity indication and established proof of concept for hormone-modulating approaches. The current market leaders include Novo Nordisk’s Wegovy® (semaglutide), and Eli Lilly’s Zepbound® (tirzepatide), which serve as standards of care for chronic weight management. In January 2026, oral Wegovy® (semaglutide) launched in the United States, demonstrating industry recognition of patient demand for oral treatment options. Multiple oral candidates from various manufacturers are under regulatory review or in clinical development. Additionally, several next-generation multi-receptor agonist therapies and combination approaches targeting GLP-1, GIP, glucagon, amylin, or other pathways are in mid-to-late stages of clinical development, including Eli Lilly's retatrutide, an injectable triple agonist targeting GLP-1, GIP, and glucagon receptors.

Despite the transformative impact of current GLP-1 and dual agonist therapies, significant unmet medical needs persist:

●Route of Administration and Treatment Burden: High rates of discontinuation are reported with chronic injectable therapies, driven in part by injection burden, needle aversion, and tolerability issues. While oral formulations are beginning to enter the market, options remain limited, particularly for multi-receptor agonist approaches.

●Adherence and Durability: Long-term medication adherence remains suboptimal for many patients across obesity pharmacotherapies. Sustained metabolic benefits beyond active treatment are limited, and weight regain following treatment discontinuation is common, underscoring the chronic nature of obesity and the need for therapies that support sustained adherence.

●Quality of Weight Loss: Rapid weight reduction achieved with current therapies can result in significant loss of lean muscle mass alongside fat mass. This loss of lean muscle mass can negatively affect metabolic health, physical function, and overall treatment outcomes. Therapies that preferentially reduce adipose tissue while preserving or enhancing lean muscle mass represent an important area of innovation.

●Population Penetration and Access: Despite strong clinical evidence and regulatory approvals, a relatively small proportion of adults living with obesity receive pharmacologic therapy. Barriers include

cost, insurance coverage limitations, supply constraints, route of administration preferences, and tolerability concerns.

Our Development Candidates

PN-477: Triple Agonist (GLP-1R/GIPR/GCGR)

PN-477 is a proprietary peptide designed as a triple agonist of the glucagon-like peptide-1 receptor (“GLP-1R”), glucose-dependent insulinotropic peptide receptor (“GIPR”), and glucagon receptor (“GCGR”). This multi-receptor approach is intended to provide comprehensive metabolic benefits by simultaneously addressing appetite regulation, glucose homeostasis, and energy expenditure. The glucagon receptor component is designed to support energy expenditure and may help support relative preservation of lean mass during weight loss, which we believe represents a potential differentiator from single- and dual-pathway approaches.

We have engineered PN-477 with a balanced profile of receptor potencies designed to combine the potential for robust weight-loss potential with favorable gastrointestinal tolerability. PN-477 exhibits nanomolar potency for GLP-1R, GIPR and GCGR. In preclinical studies using diet-induced obesity mouse models, PN-477 demonstrated dose-proportional body-weight loss of up to approximately 50%, showing comparable or differentiated activity relative to publicly disclosed preclinical data for Eli Lilly’s retatrutide, a triple agonist currently in Phase 3 development. We observed preferential fat-mass reduction relative to lean-mass loss in these preclinical studies, which we believe is consistent with glucagon receptor engagement supporting preservation of muscle mass.

PN-477 has demonstrated oral bioavailability in preclinical studies across multiple species, including mice, rats, dogs, and cynomolgus monkeys, with pharmacokinetic profiles supporting the potential for once-daily oral dosing (PN-477o) and once-weekly subcutaneous dosing (PN-477sc). The compound exhibits stability in simulated gastric and intestinal fluids, metabolic stability, and thermostability suitable for commercial development. Both PN-477o and PN-477sc are being developed in parallel to provide treatment flexibility and address differing patient and physician preferences.

PN-458: Dual Agonist (GLP-1R/GIPR)

PN-458 is a dual agonist of the GLP-1 and GIP receptors, representing a high-potency approach to the validated dual-agonist mechanism established by tirzepatide (Zepbound®), a leading anti-obesity medication that demonstrated approximately 20% body-weight loss in clinical trials.

PN-458 demontrates nanomolar potency for both GLP-1R and GIPR and exhibits higher in vitro potency than tirzepatide for both target receptors. The enhanced GIPR potency may have implications for gastrointestinal tolerability, as preclinical studies suggest that balanced GIP receptor engagement can mitigate GLP-1-mediated nausea and vomiting.

PN-458 has demonstrated favorable preclinical proof of concept in diet-induced obesity mouse models, showing activity comparable to tirzepatide. The compound has demonstrated oral bioavailability in preclinical studies across multiple species with pharmacokinetic profiles supporting the potential for once-daily oral dosing (PN-458o) and once-weekly subcutaneous dosing (PN-458sc). As with PN-477, both formulations are being developed in parallel to maximize treatment optionality.

Strategic Rationale

We are advancing PN-477 and PN-458 as part of a strategic expansion into obesity and metabolic disease to address these gaps in the obesity treatment landscape through differentiated mechanisms of action and flexible dosing options. Our obesity and metabolic disease program is designed to create a diversified portfolio that addresses different patient populations and treatment paradigms:

●Optimizing Weight Loss Quality: PN-477’s triple-agonist design, incorporating glucagon receptor engagement, is intended to support energy expenditure and fat oxidation while addressing appetite

regulation and glycemic control. The objective is to preferentially reduce adipose tissue relative to lean mass, which may translate to improved metabolic health outcomes and physical function compared to therapies that do not incorporate glucagon pathway activation.

●Oral Delivery Optionality: Both candidates are being developed with oral formulations designed to align with patient preferences and reduce barriers associated with chronic injections. Given the chronic nature of obesity and the need for long-term therapy, oral options have the potential to improve adherence and expand the addressable patient population. Offering both oral and subcutaneous formulations of the same active compound provides flexibility for physicians and patients to tailor treatment across different phases of care.

●Induction and Maintenance Strategies: Parallel oral and subcutaneous development supports potential treatment strategies that utilize subcutaneous administration during initial weight-loss phases, followed by transition to oral maintenance therapy for sustained weight management. This approach could address both the acute objective of achieving clinically meaningful weight loss and the chronic requirement of maintaining that weight loss over time.

●Portfolio Breadth: PN-458 offers a high-potency dual agonist approach for standard weight management needs, leveraging the proven efficacy of the GLP-1/GIP mechanism while providing oral and subcutaneous options that differentiate it from currently available therapies. PN-477 provides a broader multi-receptor option with the potential for advantages for patients with more complex metabolic needs or those requiring enhanced preservation of lean muscle mass. This portfolio breadth positions us to address both initial weight loss induction and long-term weight maintenance across a range of obesity severities and patient phenotypes.

The obesity and metabolic disease market is among the most rapidly expanding in contemporary therapeutics, driven by epidemiology, unmet medical need, and the emergence of hormone-modulating drugs with demonstrated clinical benefit. By leveraging oral delivery and multi-receptor mechanisms, our program seeks to address persistent limitations of current therapies and deliver differentiated solutions across this large and growing market.

OUR PROPRIETARY TECHNOLOGY PLATFORM

Our proprietary technology platform is purposefully built to exploit the advantages of constrained peptides, which are much smaller than antibody-based drugs and may be delivered orally but are big enough to bind and block the difficult targets that antibodies bind and modulate. The platform has been successfully applied to a diverse set of biological targets that has led to several pre-clinical and clinical stage peptide-based new chemical entities, including our clinical stage product candidates, for a variety of clinical indications. Our platform is comprised of a series of tools and methods, including a combination of molecular design, phage display, stability assays, medicinal chemistry, surrogate biomarkers, formulations, in vitro biochemical, cell and tissue-based assays, and in vivo pharmacology and pharmacokinetic approaches. We apply this platform to the discovery and development of constrained peptides as new drug candidates.

For rusfertide, hit discovery and optimization relied exclusively on medicinal and computational chemistry, with no phage display, to develop potent and selective injectable candidates with enhanced stability and exposure in blood. For injectable products, stability in blood is determined using in vitro assay techniques to identify chemical and biological sites of degradation, which are then optimized while still maintaining potency and selectivity. For Icotyde, phage display is tightly coupled to medicinal chemistry, structural biology and oral stability techniques to develop potent, selective and orally delivered molecules.

Discovery and Pre-clinical Activities

We believe we have built a versatile, well-validated and unique discovery platform. For example, this technology platform has been used to develop product candidates for diverse target classes including G-protein-coupled receptors, ion channels, transporters, cytokines and their receptors for a variety of therapeutic areas. In the future we may tackle

other I&I, blood and metabolic disorders and expand our technology platform to provide potential opportunities to pursue a wider variety of diseases that may include oral, topical and systemic approaches. Our integrated medicinal chemistry and computational capabilities also enable us to pursue small molecule discovery and development for biological targets where high oral bioavailability is required for effective therapies. An example of this approach is the discovery of PN-8047, an oral hepcidin functional mimetic.

We also intend to progress our platform to achieve systemic bioavailability and activity with oral peptides, macrocycles and peptidomimetics, thereby enabling us to address systemic diseases. Examples of this approach are the discovery and development of Icotyde, our IL-23R antagonist in collaboration with JNJ, and PN-881, our wholly-owned Phase 1 IL-17 oral peptide antagonist, as described above.

Competition

The biotechnology and pharmaceutical industries are intensely competitive and subject to rapid and significant technological change. While we believe that our product candidates, technology, knowledge and experience provide us with certain competitive advantages, we face competition from established and emerging pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions, among others.

Icotyde

In psoriasis and PsA, competition will come from companies with approved injectable agents in the IL-17 and IL-12/23 pathway, including Cosentyx® (Novartis), Taltz® (Eli Lilly), Siliq® (Bausch Health), Tremfya® (Johnson & Johnson), and Skyrizi® (AbbVie). Bimekizumab (Bimzelx ®, UCB), an anti- IL-17A and F antibody, was approved for psoriasis in 2023 and for PsA in 2024. Otezla® (Amgen) was the first oral agent approved in both psoriasis and PsA. The oral JAK inhibitors Xeljanz® (Pfizer) and Rinvoq® (AbbVie) are approved in PsA. Several oral TYK2 inhibitors are advancing in development. Bristol Myers Squibb’s Sotyktu® was approved for psoriasis in 2022. Second-generation allosteric TYK2 inhibitors include zasocitinib (TAK-279, Takeda) and envudeucitinib (ESK-001, Alumis), which both reported positive Phase 3 results in late 2025 and early 2026, and are moving toward regulatory submissions for psoriasis and PsA.

In IBD, competition includes approved injectable anti-integrin agents, such as Entyvio® (Takeda), and anti-IL-12/23 agents, including Stelara® (Johnson & Johnson), Skyrizi® (AbbVie), Tremfya® (Johnson & Johnson), and Omvoh® (Eli Lilly), all of which are now approved for both UC and CD. Oral agents approved or in development include JAK inhibitors Xeljanz® (approved in UC) and Rinvoq® (approved in UC and CD), with Pfizer's ritlecitinib in Phase 2 for both indications. S1P receptor modulators Zeposia® and Velsipity® are approved for UC, with Velsipity currently undergoing Phase 3 evaluation for CD. A new class of oral α4β7 integrin inhibitors is emerging, with Eli Lilly's MORF-057 in Phase 2b for UC, alongside candidates GS-1427 (Gilead) and NSHO-101 (Ensho Therapeutics) in mid-stage clinical development.

PN-881

In competitive areas, we believe there continues to be a strong need for a differentiated oral approach. Injectable monoclonal antibodies targeting the IL-17 pathway are well established across multiple inflammatory indications. Cosentyx® and Taltz®, monoclonal antibodies targeting IL-17A, are approved in psoriasis, PsA, and spondyloarthritis, and Cosentyx is also approved in HS. Siliq®, a monoclonal antibody targeting the IL-17 receptor, is approved in psoriasis only and carries a boxed warning for suicidal ideation and behavior. Bimzelx® (bimekizumab), a monoclonal antibody targeting IL-17A, IL-17F, and the IL-17A/F heterodimer, is approved in multiple indications, including psoriasis, PsA, HS, and axSpA. Sonelokimab (MoonLake), an investigational injectable nanobody with activity against IL-17A, IL-17F, and the IL-17A/F heterodimer, has reported clinical data in late-stage trials and continues in clinical development.

In the oral space, we are aware of small-molecule and peptide inhibitors in clinical development. DC-853 (LY4100511), an oral IL-17 small molecule being evaluated by Eli Lilly, has advanced into Phase 2 clinical

investigation. ASC50 (Ascletis Pharma) has reported positive Phase 1 results. Emerging oral macrocyclic peptides, including PeptiDream’s dual IL-17A/IL-17F candidate, are also entering early clinical development and may add to competition in this space.

Rusfertide & PN-8047

In the treatment of PV, competition includes therapies with differing mechanisms of action. Ruxolitinib, marketed as Jakafi® (Incyte), was approved in 2014 for adults with PV who are intolerant of or have an inadequate response to hydroxyurea. Besremi® (ropeginterferon alfa-2b-nicotinamide, PharmaEssentia/AOP), indicated for adults with PV, was approved in November 2021 and carries a black box warning.

We compete with companies developing targeted therapies for PV, including monoclonal antibodies, RNA-based therapies, and small molecules. Several programs are in late-stage development, including bomedemstat (Merck/Imago) and givinostat (Italfarmaco), which represent potential oral alternatives for PV management.

We also face competition from therapies that aim to modulate iron levels or hepcidin activity to control RBC production. These include divesiran (Silence Therapeutics), a siRNA targeting TMPRSS6 in Phase 2, and DISC-3405 (Disc Medicine), a monoclonal antibody targeting TMPRSS6 in Phase 2. Additional RNA-based programs include sapablursen (Ionis Pharmaceuticals) and investigational therapies from Alnylam Pharmaceuticals. CSL Vifor is developing vamifeport, an oral ferroportin inhibitor.

PN-477 & PN-458

In obesity and weight management, competition consists of approved injectable incretin-based therapies and a rapidly expanding pipeline of oral small molecules, multi-receptor agonists, and alternative metabolic pathways, including amylin- and glucagon-based approaches. Competition is led by glucagon-like peptide-1 (“GLP-1”) and glucose-dependent insulinotropic polypeptide (“GIP”) receptor agonists. Approved injectable therapies include Wegovy® (semaglutide, Novo Nordisk) and Zepbound® (tirzepatide, Eli Lilly). In December 2025, the FDA approved oral Wegovy® (Novo Nordisk) for chronic weight management.

The competitive landscape is expanding to include multi-receptor agonists, including triple agonists targeting GLP-1, GIP, and glucagon, as well as dual-acting combination approaches. Retatrutide (Eli Lilly) is a triple-receptor agonist that has reported positive Phase 3 clinical results. CagriSema, a once-weekly injectable fixed-dose combination of semaglutide and the amylin analog cagrilintide (Novo Nordisk), has been submitted for regulatory approval. MariTide (maridebart cafraglutide, Amgen) is a bispecific peptide-antibody conjugate that activates the GLP-1 receptor while antagonizing the GIP receptor and is being evaluated in a Phase 3 clinical program. VK2735 (Viking Therapeutics) is a dual GLP-1/GIP receptor agonist in Phase 3 development for subcutaneous administration, with an oral formulation in mid-stage clinical development.

Several companies are developing non-peptide oral incretin therapies and other next-generation oral candidates. Orforglipron (Eli Lilly) is an oral, non-peptide GLP-1 receptor agonist under regulatory review. Aleniglipron (Structure Therapeutics) is an oral GLP-1 receptor agonist that has completed Phase 2 clinical development. Pfizer, which completed its acquisition of Metsera in 2025, is developing next-generation oral and peptide-based incretin therapies for obesity and related cardiometabolic conditions.

In addition to incretin-based approaches, modalities targeting the amylin pathway are being developed as standalone and combination therapies. Amycretin (Novo Nordisk) is a single-molecule agonist of both GLP-1 and amylin receptors in late-stage clinical development, including oral and subcutaneous formulations. Petrelintide (Zealand Pharma, in collaboration with Roche) is a long-acting amylin analog in mid-stage clinical development.

Other emerging approaches include dual GLP-1/glucagon receptor agonists, such as survodutide (Boehringer Ingelheim) and pemvidutide (Altimmune). Additional early-stage programs are exploring alternative gut hormone pathways, novel peptide delivery technologies, and centrally mediated mechanisms of appetite and metabolism. While many of these programs remain in early development, they may further intensify competition in the obesity treatment landscape.

Material Agreements

Takeda Collaboration Agreement

In January 2024, we entered into the Takeda Collaboration Agreement. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.

JNJ License and Collaboration Agreement

In July 2017, we entered into the JNJ License and Collaboration Agreement. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.

Research Collaboration and License Agreement with Zealand Pharma A/S

In June 2012, we entered into a Research Collaboration and License Agreement (the “Zealand Agreement”) with Zealand Pharma A/S (“Zealand”) to identify, optimize and develop novel disulfide-rich peptides to discover a hepcidin mimetic. We amended this agreement in February 2014, at which point we assumed responsibility for the development program. See Part II, Item 7. “Management’s Discussion and Analysis – Contractual Obligations and Other Commitments” and Note 7 and Note 9 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.

Intellectual Property

We strive to protect and enhance the proprietary technology, inventions, and improvements that are commercially important to the development of our business, including seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties. We also rely on trade secrets relating to our proprietary technology platform and on know-how, and continuing technological innovation to develop, strengthen, and maintain our proprietary position in the field of peptide-based therapeutics that may be important for the development of our business. We will also take advantage of regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available.

Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business; defend and enforce our patents; preserve the confidentiality of our trade secrets; and operate without infringing the valid enforceable patents and proprietary rights of third parties. Our ability to stop third parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities. We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same. For more information, please see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.”

We own or co-own over 30 issued U.S. patents, over 80 granted ex-U.S. patents, and numerous U.S. and ex-U.S. patent applications related to our clinical assets. We possess substantial know-how and trade secrets relating to the discovery, development and commercialization of peptide-based therapeutic products. Our proprietary intellectual property, including patent and non-patent intellectual property, is generally directed to, for example, peptide-based therapeutic compounds and compositions, methods of using these peptide-based therapeutic compounds and compositions to treat or prevent disease, methods of manufacturing peptide-based therapeutic compounds and compositions, and other proprietary technologies and processes related to our lead product development candidates. Specific patents and patent applications are directed to compositions of α4β7 integrin peptides, IL-23R antagonist peptides, IL-17 antagonist peptides, hepcidin mimetics peptides and small molecules, and glucagon superfamily receptor agonists, as well as methods of synthesizing and using these compounds to treat disorders. Applications are currently pending in the United States and other major jurisdictions, including Australia, Canada, China, Japan, and Europe. We

expect our patents and patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire from October 2033 to September 2045 (excluding possible patent term extensions).

Our objective is to continue to expand our portfolio of patents and patent applications in order to protect our clinical assets and related peptide-based drug technologies.

We also license patents and patent applications directed to processes and methods related to our technology platform. These patents have issued in the United States and other major jurisdictions, including Australia and Europe. Some licensed patents are expired. Material aspects of our technology platform are protected by trade secrets and confidentiality agreements.

In addition to the above, we have established expertise and development capabilities focused in the areas of pre-clinical research and development, manufacturing and manufacturing process scale-up, quality control, quality assurance, regulatory affairs and clinical trial design and implementation. We believe that our focus and expertise will help us develop products based on our proprietary intellectual property.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the date of filing the non-provisional application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office in granting a patent or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.

The term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration of a U.S. patent as compensation for the patent term lost during the FDA regulatory review process. The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent. The length of the patent term extension is related to the length of time the drug is under regulatory review. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended. Moreover, a patent can only be extended once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug. When possible, we expect to apply for patent term extensions for patents covering our product candidates and their methods of use.

Trade Secrets

We rely on trade secrets to protect certain aspects of our technology, particularly in relation to our technology platform. However, trade secrets can be difficult to protect. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems. While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions. For more information, see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.”

Manufacturing

We contract with third parties for the manufacturing of our product candidates for pre-clinical studies and clinical trials and eventually for commercial supplies and intend to continue to do so in the future. We do not own or operate any manufacturing facilities, and we have no plans to build any owned clinical or commercial scale manufacturing capabilities. We believe that the use of contract manufacturing organizations (“CMOs”) eliminates the need for us to directly invest in manufacturing facilities, equipment and additional staff. We have established a global supply chain for raw material, active pharmaceutical ingredients (“API”), drug product manufacturing and distribution. We work with contract manufacturers in the United States, Europe and Asia. Although we rely on contract manufacturers, our

personnel and consultants have extensive manufacturing and quality control experience overseeing CMOs. We regularly consider second source or back-up manufacturers for both API and drug product manufacturing. To date, our third-party manufacturers have met the manufacturing requirements for our product candidates. We expect third-party manufacturers to be capable of providing supplies needed for our product candidates to meet anticipated full-scale commercial demands, and we have selected CMOs that can manufacture our product candidates for our ongoing and planned clinical trials as well as commercial supplies. We currently engage CMOs on a “fee for services” basis for our current development and clinical supplies.

JNJ is responsible for the manufacturing of Icotyde pursuant to the JNJ License and Collaboration Agreement. Takeda is responsible for the manufacturing of rusfertide pursuant to the Takeda Collaboration Agreement.

Government Regulation

The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those we are developing. These agencies and other federal, state and local entities regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of our product candidates.

U.S. Government Regulation

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act and its implementing regulations. The process of obtaining regulatory approvals and compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

The process required by the FDA before a drug may be marketed in the United States generally involves the following:

●completion of pre-clinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practices (“GLP”) regulations;

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

●approval by an independent institutional review board (“IRB”) at each clinical site before each trial may be initiated;

●performance of adequate and well-controlled human clinical trials in accordance with good clinical practice (“GCP”) requirements to establish the safety and efficacy of the proposed drug product for each indication;

●submission to the FDA of an NDA (or Biologics License Application (“BLA”) for a biologic product);

●satisfactory completion of an FDA advisory committee review, if applicable;

●satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMP”)

requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

●satisfactory completion of an FDA inspection of one or more clinical trial sites to assure compliance with GCP requirements and the clinical protocol; and

●FDA review and approval of the NDA.

Pre-clinical Studies

Pre-clinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy. These pre-clinical studies must comply with GLP. In April 2025, the FDA published a roadmap to reduce animal testing in preclinical safety studies, including those required in INDs, with scientifically validated new approach methodologies. An IND sponsor must submit the results of the pre-clinical tests, together with manufacturing information, analytical data and any available clinical data or literature to the FDA as part of an IND. Some pre-clinical testing may continue even after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on a clinical hold. In such 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

Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements. GCP requirements mandate that all research subjects provide their informed consent in writing before their participation in any clinical trial. Clinical trials are conducted under protocols detailing the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND (or equivalent international submission). In addition, an IRB or ethics committee must review and approve the plan for any clinical trial at all institutions participating in the clinical trial before it commences at that site. Information about certain clinical trials must be submitted within specific time frames to the National Institutes of Health for public dissemination on www.clinicaltrials.gov.

Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:

●Phase 1: The drug is initially introduced into healthy human subjects or patients with the target disease or condition and is tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness.

●Phase 2: The drug is administered to a limited patient population to identify possible adverse effects and safety risks, and to preliminarily evaluate the efficacy of the investigational drug product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

●Phase 3: The drug is administered to an expanded patient population to establish the overall risk-benefit profile of the product, and to provide adequate labeling information (labeling) for the safe and efficacious administration for the labeling of the product.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk. Similarly, an IRB or ethics committee 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 has been associated with unexpected serious harm to patients.

Marketing Approval

Following successful completion of the required clinical testing and the results of the pre-clinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other information, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. In most cases, the submission of an NDA is subject to an application user fee. Under the Prescription Drug User Fee Act (“PDUFA”) guidelines, the FDA has a target of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to the FDA.

In addition, under the Pediatric Research Equity Act of 2003, certain NDAs or supplements to an NDA must contain data that is adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

The FDA also may require submission of a risk evaluation and mitigation strategy (“REMS”) plan to ensure that the benefits of the drug outweigh its risks. REMS plans typically include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the requested information. The resubmitted application is also subject to review before the FDA accepts it for filing. After the submission is accepted for filing, the FDA begins a substantive review. The FDA reviews an NDA to determine whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

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

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

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a complete response letter. A complete response letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA and may require additional clinical or pre-clinical testing for the FDA to reconsider the application. Even after submission of this additional information, the FDA may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

Even if the FDA approves a product, it may limit the approved indications for use of the product. It may also require that contraindications, warnings or precautions be included in the product labeling or require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval. In addition, the

FDA may mandate testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS. This can materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs. After approval, some types of alterations, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Fast Track Designation

The FDA has various programs, such as fast track designation. These programs are intended to expedite or simplify the process for the development and FDA review of drugs for the treatment of serious or life-threatening diseases or conditions and demonstrate the potential to address unmet medical needs. The purpose of these programs is to provide important new drugs to patients faster. The sponsor of a new drug may request fast track designation concurrent with, or after, the filing of the IND. To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that a product is intended to treat a serious or life threatening disease or condition and demonstrates the potential to address an unmet medical need. A product will fill an unmet medical need if it will provide a therapy where none exists or provide a therapy that may be potentially superior to existing therapy based on efficacy or safety. Fast track designation provides additional opportunities for interaction with the FDA’s review team and may allow for rolling review of NDA components before the completed application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA. However, the FDA’s time goal for reviewing an application does not begin until the last section of the NDA is submitted. The FDA may decide to rescind the fast track designation if it determines that the qualifying criteria no longer apply.

Orphan Designation

The FDA may grant orphan designation to drugs or biologics intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the United States. The FDA may also grant the designation if the disease affects more than 200,000 individuals in the United States, and there is no reasonable expectation that the cost of developing and marketing the product for this type of disease or condition will be recovered from sales in the United States. Orphan designation must be requested before submitting an NDA or BLA. After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Drugs or biologics with orphan designation are not subject to a PDUFA fee upon the submission of an NDA. Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

In the United States, orphan designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers. In addition, if a product receives the first FDA approval for the indication for which it has orphan designation, the product is entitled to orphan exclusivity, which means the FDA may not approve any other application to market the same product for the same indication for a period of seven years, except in limited circumstances. Such circumstances include a showing of clinical superiority over the product with orphan exclusivity or where the manufacturer with orphan exclusivity is unable to assure sufficient quantities of the approved orphan designated product. Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity. Orphan product exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same product as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease. If a drug or biological product designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan product exclusivity.

There is some uncertainty with respect to the FDA’s interpretation of the scope of orphan drug exclusivity. Historically, exclusivity was specific to the orphan indication for which the drug or biologic was approved. As a result, the scope of exclusivity was interpreted as preventing approval of a competing product. However, in 2021, the federal

court in Catalyst Pharmaceuticals, Inc. v. Becerra, suggested that orphan drug exclusivity covers the full scope of the orphan-designated “disease or condition” regardless of whether a drug obtained approval for a narrower use.

Breakthrough Therapy Designation

A sponsor can request designation of a drug candidate as a “breakthrough therapy.” A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Drugs designated as breakthrough therapies are also eligible for accelerated approval and priority review. The FDA must take certain actions, such as holding timely meetings and providing advice, intended to expedite the development and review of an application for approval of a breakthrough therapy. The FDA may decide to rescind the breakthrough designation if it determines that the qualifying criteria no longer apply.

Post-Approval Requirements

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA. These regulations include requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to FDA review and approval. There also are continuing, annual program user fee requirements for any marketed products.

The FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies. They are subject to periodic unannounced inspections by the FDA and state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented. FDA regulations require investigation and correction of any deviations from cGMP requirements and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

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 side effects of unanticipated severity or frequency, problems with manufacturing processes, or failure to comply with regulatory requirements may result in mandatory revisions to the approved labeling to add new safety information, imposition of post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS program. Other potential consequences include:

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

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

●refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product approvals;

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

●injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved prescribing information. The FDA and other agencies enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

Coverage and Reimbursement

Sales of our product candidates, if approved, will depend, in part, on the extent to which the cost of such products will be covered and adequately reimbursed by third-party payors, such as government healthcare programs, commercial insurance and managed health care organizations. These third-party payors are increasingly limiting coverage and reducing reimbursements for medical products and services by challenging the prices and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. If these third-party payors do not consider our products to be cost-effective compared to other therapies, they may not cover our products after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow us to sell our products on a profitable basis.

There is no uniform policy requirement for coverage and reimbursement for drug products among third-party payors in the United States. Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor. Coverage determination can be a time-consuming and costly process that may require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained or applied consistently. Even if reimbursement is provided, market acceptance of our products may be adversely affected if the amount of payment for our products proves to be unprofitable for health care providers or less profitable than alternative treatments, or due to administrative burdens.

In addition, the U.S. government, state legislatures and foreign governments have continued implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results. Decreases in third-party reimbursement for our product candidates or a decision by a third-party payor to not cover our product candidates could reduce physician usage of our products candidates, once approved, and have a material adverse effect on our sales.

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, collectively referred to as the ACA, enacted in March 2010, has had and is expected to continue to have a significant impact on the health care industry. The ACA imposes a significant annual fee on certain companies that manufacture or import branded prescription drug products. The ACA also increased the Medicaid rebate rate and expanded the rebate program to include Medicaid managed care organizations. It also contains substantial new provisions intended to broaden access to health insurance, reduce the growth of health care spending, enhance remedies against health care fraud and abuse, add new transparency requirements for the health care industry, impose new taxes and fees on pharmaceutical manufacturers, and impose additional health policy reforms, any or all of which may affect our business.

There have been executive, judicial and Congressional challenges to certain aspects of the ACA. For example, there have been several Executive Orders and other directives designed to delay the implementation of certain ACA requirements or otherwise circumvent some of the health insurance mandates. Concurrently, Congress considered legislation to repeal or repeal and replace all or part of the ACA. While Congress has not passed comprehensive repeal legislation, several bills affecting the implementation of certain taxes under the ACA have been enacted. The Tax Cuts and Jobs Act of 2017, or the Tax Act, included a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on some individuals who do not maintain qualifying health coverage for all or part of a year. Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and the medical device tax, and also eliminated the health insurance tax. The Bipartisan Budget Act of 2018 amends the ACA to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole,” and increase from 50% to 70% the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in the Medicare Part D program. The Inflation

Reduction Act (“IRA”), enacted August 16, 2022, aims to control prescription drug prices in the upcoming years. The IRA will allow the Centers for Medicare & Medicaid Services (“CMS”) to cap out-of-pocket costs in 2025 and to negotiate prescription drug prices in 2026 for the first time. Additionally, the IRA provides a new “inflation rebate” covering Medicare patients beginning in 2023 to prevent rapid and arbitrary price increases in prescription drugs. These and any other legislation or healthcare reform measures may impact the ACA and our business. There may also be further challenges to the ACA, and new laws may also result in additional reductions in Medicare and other health care funding.

Further, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products. This scrutiny has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products. At the federal level, the current administration implemented drug pricing reform through federal budget proposals, executive orders and policy initiatives. In May 2025, the current administration renewed the idea of international reference pricing through an executive order entitled “Delivering Most-Favored-Nation Prescription Drug Pricing to American Patients,” which, among other things, directs the U.S. Department of Health and Human Services (the “HHS”) and other agencies to communicate most-favored-nation price targets to pharmaceutical manufacturers to bring prices for U.S. patients in line with comparably developed nations and to facilitate direct-to-consumer purchasing programs. The HHS subsequently issued guidance indicating the most-favored-nation (“MFN”) target price will be the lowest price paid in an Organisation for Economic Co-operation and Development country with a gross domestic product (“GDP”) per capita of at least 60% of the U.S. GDP per capital. In addition, in December 2025, CMS proposed new drug payment models to lower drug prices for Medicare beneficiaries; under the models, CMS would explore potential adjustments to Medicare drug inflation rebate calculations by comparison to international drug pricing information. It is currently unclear whether and to what extent these measures will be implemented and what impact any such implementation would have on our business.

Federal and state legislatures have become increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare therapies.

It is uncertain whether and how future legislation, whether domestic or foreign, could affect prospects for our product candidates or what actions payors for health care treatment and services may take in response to such health care reform proposals or legislation. Adoption of price controls and other cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures reforms may prevent or limit our ability to generate revenue, attain profitability or commercialize our product candidates.

Other Health Care Laws and Compliance Requirements

We will also be subject to health care regulation and enforcement by the federal and state government and foreign governments in which we will conduct our business once our products are approved. The laws that may affect our ability to operate include the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic health care transactions and protects the security and privacy of protected health information; the criminal health care fraud statutes under HIPAA also prohibit persons and entities from knowingly and willfully executing a scheme to defraud any health care benefit program, including private payors, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for health care benefits, items or services; the Anti-Kickback Statute, which prohibits persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal health care programs such as the Medicare and Medicaid programs; federal false claims laws and civil monetary penalties laws that prohibit any person or entity from knowingly

presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid; and the Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the CMS information related to payments and other transfers of value made to various healthcare professionals including physicians, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, certified nurse-midwives and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members. Beginning on January 1, 2023, California Assembly Bill 1278 requires California physicians and surgeons to notify patients of the Open Payments database established under the federal Physician Payments Sunshine Act.

The majority of states also have statutes or regulations similar to the federal anti-kickback and false claims laws, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor. We may be subject to state laws governing the privacy and security of health information in certain circumstances, such as California’s Confidentiality of Medical Information Act and Washington’s My Health My Data Act, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts. In addition, we may be subject to reporting requirements under state transparency laws, as well as state laws that require pharmaceutical companies to comply with the industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government that otherwise restricts certain payments that may be made to health care providers and entities. In addition, certain states and local jurisdictions require the registration of pharmaceutical sales representatives.

Even when HIPAA and state health information privacy laws do not apply, according to the FTC and state Attorneys General, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure may constitute unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act and state consumer protection laws.

Because of the breadth of these laws and the narrowness of available statutory and regulatory exceptions, it is possible that some of our business activities could be subject to challenge under one or more of such laws. If we are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including significant administrative, civil and criminal penalties, damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, exclusion of products from reimbursement under U.S. federal or state health care programs, and the curtailment or restructuring of our operations.

Government Regulation Outside of the United States

In addition to regulations in the United States, we will be subject to a variety of regulations in other jurisdictions governing clinical studies and any commercial sales and distribution of our products.

Drug and Biologic Development Process in the European Union (“EU”)

All clinical trials included in applications for marketing authorization for human medicines in the EU must be carried out in accordance with EU regulations. This means that such clinical trials must comply with EU clinical trial legislation, as well as ethical principles equivalent to those set out in the EU and in Iceland, Norway and Liechtenstein (together, the European Economic Area, or “EEA”), including adhering to international good clinical practice and the Declaration of Helsinki. The conduct of clinical trials in the EU is governed by the EU Clinical Trials Regulation (EU) No. 536/2014 (“CTR”) which entered into force on January 31, 2022.

Under the CTR, a sponsor may submit a single application for approval of a clinical trial through a centralized EU clinical trials portal. One national regulatory authority (the reporting EU Member State proposed by the applicant) will take the lead in validating and evaluating the application and consult and coordinate with the other concerned Member States. If an application is rejected, it may be amended and resubmitted through the EU clinical trials portal. If an approval is issued, the sponsor may start the clinical trial in all concerned Member States. However, a concerned EU

Member State may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such Member State. The CTR also aims to streamline and simplify the rules on safety reporting and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical trial results to the EU Database (“CTIS”). Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive need to comply with the CTR and have to be transitioned to CTIS.

National laws, regulations, and the applicable GCP and Good Laboratory Practice standards must also be respected during the conduct of the trials, including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (“ICH”) guidelines on GCP and the ethical principles that have their origin in the Declaration of Helsinki.

Drug Marketing Authorization

In the EEA, after completion of all required clinical testing, pharmaceutical products may only be placed on the market after obtaining a Marketing Authorization (“MA”). To obtain an MA of a drug under EU regulatory systems, an applicant can submit a Marketing Authorization Application (“MAA”) through, amongst others, a centralized or decentralized procedure.

The centralized procedure provides for the grant of a single MA that is issued by the European Commission (“EC”) following the scientific assessment of the application by the EMA that is valid for all EU Member States as well as in the three additional EEA Member States. The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineered medicines), and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other dysfunctions, and viral diseases). For medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that constitute significant therapeutic, scientific or technical innovations or for which the grant of an MA through the centralized procedure would be in the interest of public health at EU level, an applicant may voluntarily submit an application for an MA through the centralized procedure.

Under the centralized procedure, the Committee for Medicinal Products for Human Use (“CHMP”), established at the EMA, is responsible for conducting the initial assessment of a drug. The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA. Under the centralized procedure, the timeframe for the evaluation of an MAA by the CHMP is, in principle, 210 days from receipt of a valid MAA. However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically takes a year or more, unless the application is eligible for an accelerated assessment. Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. Upon request, the CHMP can reduce the time frame to 150 days if the applicant provides sufficient justification for an accelerated assessment. The CHMP will provide a positive opinion regarding the application only if it meets certain quality, safety and efficacy requirements. This opinion is then transmitted to the EC, which has the ultimate authority for granting an MA within 67 days after receipt of the CHMP opinion.

Medicines that fall outside the mandatory scope of the centralized procedure have three routes to authorization: (i) they can be authorized under the centralized procedure if they concern a significant therapeutic, scientific or technical innovation, or if their authorization would be in the interest of public health; (ii) they can be authorized under a decentralized procedure where an applicant applies for simultaneous authorization in more than one EU Member State; or (iii) they can be authorized in an EU Member State in accordance with that state’s national procedures and then be authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization (mutual recognition procedure).

The decentralized procedure permits companies to file identical MA applications for a medicinal product to the competent authorities in various EU Member States simultaneously if such medicinal product has not received marketing approval in any EU Member State before. This procedure is available for pharmaceutical products not falling within the mandatory scope of the centralized procedure. The competent authority of a single EU Member State, known as the reference EU Member State, is appointed to review the application and provide an assessment report. Under this procedure, an applicant submits an application based on identical dossiers and related materials, including a draft summary of product characteristics, and draft labeling and package leaflet, to the reference EU Member State and concerned EU Member States. The reference EU Member State prepares a draft assessment report and drafts of the related materials within 120 days after receipt of a valid application. Subsequently, each concerned EU Member State must decide whether to approve the assessment report and related materials. If an EU Member State cannot approve the assessment report and related materials on the grounds of potential serious risk to public health, the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the EC, whose decision is binding for all EU Member States.

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. RMPs are continually modified and updated throughout the lifetime of the medicine as new information becomes available. An updated RMP must be submitted: (i) at the request of EMA or a national competent authority, or (ii) whenever the risk-management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit-risk profile or as a result of an important pharmacovigilance or risk-minimization milestone being reached. The regulatory authorities may also impose specific obligations as a condition of the MA. Since October 20, 2023, all RMPs for centrally authorized products are published by the EMA, subject only to limited redactions.

MAs have an initial duration of five years. After these five years, the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit balance. Once renewed, the MA is valid for an unlimited period unless the EC or the national competent authority decides on justified grounds relating to pharmacovigilance to proceed with only one additional five-year renewal. Applications for renewal must be made to the EMA at least nine months before the five-year period expires.

European Data Protection Laws

The processing of personal data, including health-related personal data in the European Economic Area (“EEA”) is mainly governed by the provisions of the European General Data Protection Regulation (EU) 2016/679 (“GDPR”) and related data protection laws in individual EEA countries. In the United Kingdom, the processing of personal data is mainly governed by the GDPR as incorporated into UK law pursuant to the European Union (Withdrawal) Act 2018 (the “UK GDPR”). The GDPR and UK GDPR impose strict requirements on the processing of personal data, including the legal basis for the processing, the information that has to be provided to individuals before their data is processed, personal data breaches which may have to be notified to national data protection authorities and data subjects, the measures to be taken when engaging processors, and the technical and organization measures to ensure the security and confidentiality of the personal data. EEA countries may also have additional requirements for the processing of health, genetic, and biometric data through their national legislation. The GDPR also imposes restrictions on the transfer of personal data to countries outside of the EEA that do not provide an adequate level of data protection. To enable such transfers, appropriate safeguards, such as standard contractual clauses (“SCCs”) must be in place. When relying on the appropriate safeguards, data exporters, with the assistance of the data importers, are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the safeguards in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence. Where no supplementary measure is suitable, the data exporter should avoid, suspend or terminate the transfer. Alternatively, such transfers can be based on an adequacy decision by the EU commission. Regarding transfers to the United States, the EU commission issued an adequacy decision for transfers to companies that are certified under the new EU-US Data Privacy Framework, which entered into force on June 10, 2023. Under the adequacy decision, personal data can flow from the EEA to U.S. companies participating in the framework.

Failure to comply with the requirements of the GDPR or UK GFPR and the related national data protection laws of the EEA countries may result in significant monetary fines for noncompliance of up to €20 million or £17.5 million (as applicable), or 4% of the total worldwide annual turnover (for higher-tier infringements). This is enforced by the UK Information Commissioner’s Office (“ICO”) and is entirely separate from fines under EU GDPR. In addition, violations of national laws can trigger additional, administrative penalties, investigations, corrective orders, temporary or definitive bans, and in some jurisdictions, a number of criminal offenses for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed.

Sustainability, Corporate Responsibility and Human Capital Disclosures

Governance and Leadership

Our Board of Directors (“Board”) plays a pivotal role in overseeing our strategic direction, risk management related to sustainability and corporate responsibility matters and our overall governance framework. Our Board composition reflects a wide range of backgrounds, skills and experiences. Our executive leadership team is responsible for driving our performance and guiding our long-term growth initiatives. We believe in fostering a culture of integrity, ethical decision making, and responsible corporate citizenship.

Business Ethics

We are committed to creating an environment where we are able to excel in our business while maintaining high standards of business conduct and ethics. Our Code of Business Conduct and Ethics (“Code of Conduct”) reflects the business practices and principles of behavior that supports this commitment, including our policies on bribery, corruption, conflicts of interest, insider trading, and our whistleblower program. We expect all of our directors, officers, and employees to read, understand, and comply with the Code of Conduct and its application to the performance of his or her business responsibilities.

Environmental Commitment

We are committed to protecting the environment and attempt to mitigate any negative impact of our operations, promoting reuse and recycling and conserving resources, where feasible. We have safety protocols in place for handling biohazardous waste in our operations, including in our clinical trials, and we use third-party vendors for biohazardous waste and chemical disposal.

Social Responsibility

We are committed to providing patients with access to our investigational therapies, to the extent appropriate at the development stage. We are currently focused on our clinical programs and getting our therapies through the approval process and approved as rapidly as possible provided they are shown to be safe and effective. We provide access to our investigational therapies through our clinical trials, including in some cases long-term extensions of those trials that provide access to our therapies for up to several years. We also support educational efforts related to therapeutic areas in focus for our company, and life sciences education more broadly. In addition to financial support of continuing education, we are active sponsors, mentors, and hosts for students seeking to broaden their understanding of life sciences in the interest of advancing human health.

Human Capital

We recognize that our success is driven by the knowledge, skills and dedication of our employees. Our human capital is fundamental to our ability to innovate and develop life-changing drug therapies. We invest in our employees by seeking to foster a supportive and inclusive workplace. We offer competitive compensation and benefits and provide opportunities for professional growth and development.

As of December 31, 2025, our total global workforce consisted of 132 full-time equivalent employees, 103 of whom were in research and development. The remaining 29 employees worked in finance, legal, business development,

human resources, information technology (“IT”) and administrative support. 123 of our full-time equivalent employees are located in the United States and 9 are located in Australia. None of our employees are represented by a labor union or covered by a collective bargaining agreement. We consider our relationship with our employees to be good.

Attracting, developing and retaining talented employees to support the growth of our business is an integral part of our human capital strategy and critical to our long-term success. We have robust recruitment and retention processes in place that are designed to attract and retain individuals who possess the necessary expertise, innovative drive and commitment to contribute to our mission. We offer competitive compensation packages, including performance-based incentives, equity awards, and robust benefits, including 401(k) plan matching contributions and an employee stock purchase plan for U.S. employees. The principal purpose of our equity incentive and annual bonus programs is to attract, retain and motivate personnel through the granting of stock-based compensation awards and cash-based performance bonus awards. As a biopharmaceutical company, we recognize the importance of access to high quality healthcare and as such we currently cover 100% of our U.S. employees’ monthly healthcare premiums.

We have a performance development review process in which managers provide regular feedback to assist with the development of our employees, including the use of individual plans to assist with career development. We also invest in the growth and development of our employees through various training and development programs that help build and strengthen our employees’ leadership and professional skills. This reflects the quality and readiness of our people to take on new roles, as well as our intentional focus on growing and developing careers and promoting from within.

Safeguarding the health and safety of our employees is a top priority. We are committed to providing a safe working environment for all of our employees. Our cross-functional safety committee meets regularly to discuss policies and protocols, strategic planning, business continuity and other matters. We invest in initiatives aimed at promoting employee mental and physical well-being, including providing meals and access to fitness facility onsite. To support our employees personally and professionally, we have Employee Assistance Programs to address employee challenges and needs. We also allow for flexible working arrangements for certain of our employees. We value feedback from our employees and use it to improve our workplace policies and practices.

Corporate and Other Information

Our website address is www.protagonist-inc.com. References to our website address do not constitute incorporation by reference of the information contained on the website, and the information contained on the website is not part of this document.

We make available, free of charge on our corporate website, copies of our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, Proxy Statements, and all amendments to these reports, as soon as reasonably practicable after such material is electronically filed with or furnished to the SEC pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (“Exchange Act”).