A.History and development of the Company We are a late-stage biopharmaceutical company focused on the development and commercialization of innovative therapies for rare diseases with significant unmet need, initially focused on angioedema and other bradykinin-mediated diseases. Our first molecule, deucrictibant (previously referred to as PHA-022121 or PHA121), is a novel, oral, small-molecule bradykinin B2 receptor antagonist under development for the prevention or treatment of attacks due to bradykinin-mediated angioedema (AE-BK), including hereditary angioedema (HAE) and acquired angioedema due to C1-inhibitor deficiency (AAE-C1INH). Deucrictibant has the potential to address unmet medical needs by bringing improvements beyond the therapeutic profile of existing medicines and providing patients with quality of life and convenience that is superior to current standard-of-care. We believe deucrictibant has the potential to provide injectable-like efficacy™ with a well-tolerated profile and the convenience of an oral therapy for both the prophylactic and on-demand treatment of HAE attacks. HAE is a rare and potentially life-threatening genetic condition with symptoms that include episodes of debilitating and often painful swelling in the hands, feet, face (lips and tongue), gastrointestinal tract, urogenital region, or airways. Attacks are unpredictable in frequency, location, timing, and severity, and can be caused by multiple types of triggers. According to scientific publications, patients experience a median of 14 attacks per year, and half of patients experience a potentially life-threatening airway attack at least once in their lifetime. Airway attacks are particularly dangerous and can lead to asphyxiation. If left untreated, attacks can last multiple days and are commonly painful, leading to multiple sick days and even hospitalization. According to HAE International, as of October 2014, HAE affected from 1:30,000 to 1:80,000 individuals globally, or at least 7,000 patients in the U.S. and at least 15,000 patients in the EU. AAE-C1INH is a rare disorder with an estimated prevalence of approximately 1:500,000 patients. The disease manifests with episodes of unpredictable swelling that occur as a result of inadequate control of the kallikrein/kinin system, due to C1-inhibitor deficiency, resulting in excessive bradykinin formation. These episodes of swelling can be debilitating, painful, and even lethal, similar to HAE. However, AAE-C1INH results from underlying conditions such as lymphoproliferative disorders, plasma cell dyscrasias, or autoimmune disorders, and occurs either as a result of consumption of C1-inhibitor (C1INH) owing to activation of the classical complement pathway or as a result of neutralization by autoantibodies. There are no approved medicines available to treat or prevent AAE-C1INH. Bradykinin-mediated vascular leakage and angioedema formation via activation of its bradykinin B2 receptor is involved in various types of angioedema (hereditary or acquired) with different underlying pathogenetic mechanisms. Bradykinin B2 receptor inhibition is a clinically validated mechanism for the treatment of HAE, as demonstrated by icatibant, which is a peptide bradykinin B2 receptor antagonist approved in Europe in 2008 and in the United States in 2011 (as FIRAZYR). Deucrictibant is designed to block the interaction of bradykinin with the bradykinin B2 receptor, rather than blocking an upstream signal in one of the bradykinin production cascades as other treatments; therefore, deucrictibant may prevent bradykinin aberrant signaling regardless the underlying pathway that produces bradykinin and may address a broader range of angioedema attacks than other available treatments. Our legal and commercial name is Pharvaris N.V. In connection with our initial public offering in the first quarter of 2021, we converted the legal form of our company under Dutch law from a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) to a public company with limited liability (naamloze vennootschap) and changed our name from Pharvaris B.V. to Pharvaris N.V. Pharvaris B.V. was incorporated on September 30, 2015, and is based in Leiden, the Netherlands. Our principal executive offices are located in Emmy Noetherweg 2, 2333 BK Leiden, the Netherlands, telephone: +31 (0)71 2036 410. Our agent for service of process in the United States is Chris Deon, who is registered at PO Box 121, Buckingham, PA 19407-4550, USA. Our principal expenditures since inception have been our research and development expenses, as more fully described elsewhere in this Annual Report. To date, we have relied solely on the issuance of equity securities to finance our operations and internal growth. For more information, please see “ITEM 5. OPERATING AND FINANCIAL REVIEW AND PROSPECTS—B. Liquidity and Capital Resources.” The SEC maintains an Internet website that contains reports and other information about issuers, like us, that file electronically with the SEC. The address of that website is www.sec.gov. Our website can be found at www.pharvaris.com. The information on our website is not incorporated by reference into this Annual Report, and you should not consider information contained on our website to be a part of this Annual Report. B.Business Overview Overview Deucrictibant may address unmet medical needs of people living with AE-BK by both preventing attacks from occurring, using an extended-release (XR) tablet formulation of deucrictibant (previously referred to as PHVS719), as well as treat the manifestations of attacks, using an immediate-release (IR) capsule formulation of deucrictibant (previously referred to as PHVS416). The XR tablet formulation is designed to maintain therapeutic levels for over 24 hours and to achieve a steady-state plasma concentration within 72 hours, supporting a once-daily dosing regimen. The IR capsule formulation is designed to rapidly reach therapeutic exposure in order to mitigate HAE attacks symptoms quickly and completely with a single oral dose. 45 Table of Contents In our Phase 1 clinical trials to-date, we have observed rapid exposure and predictable linear pharmacokinetics (PK) with and without food. In addition, we observed deucrictibant to be a potent antagonist of the bradykinin B2 receptor, in vitro and in vivo with healthy volunteers. We conducted a proof-of-concept clinical trial testing the effects of bradykinin in healthy volunteers in our bradykinin-challenge trial, where we evaluated the effect of deucrictibant on cardiovascular parameters affected by bradykinin such as blood pressure, heart rate and cardiac output in healthy volunteers, and evaluated the pharmacodynamic (PD) and PK of deucrictibant to generate a PK/PD correlation model for deucrictibant. The bradykinin challenge was validated as a surrogate assessment for dose selection in the original development program for icatibant, as reviewed by the FDA and the EMA. From the bradykinin challenge model, we were able to predict the efficacious dose range and the duration of effect of a single oral dose of deucrictibant; the topline data from our Phase 2 RAPIDe-1 trial treating HAE attacks were consistent with the predictions of the bradykinin challenge in both onset of symptom relief and duration of effect (use of rescue medication). In our Phase 2 placebo-controlled trial evaluating the efficacy and tolerability of deucrictibant IR capsules for the on-demand treatment of attacks in patients with HAE type 1 and 2 (RAPIDe-1), a statistically significant and clinical meaningful reduction of the patient-reported symptoms of HAE was observed for the attacks treated with all doses of deucrictibant (10, 20, 30 mg) compared to placebo-treated attacks. The study’s primary endpoint—symptom relief at four hours after treatment with study drug—as well as all key secondary efficacy endpoints were met. Consistently with its pharmacokinetic profile, deucrictibant IR demonstrated rapid onset of action, symptom relief, and resolution of the manifestations of HAE attacks as well as sustained clinical effects, with consistent findings across outcome measures. In addition, deucrictibant IR substantially reduced the use of rescue medication compared to placebo. Deucrictibant was well tolerated at all dose levels. We commenced RAPIDe-1 in February 2021 and reported positive topline Phase 2 data in December 2022. Following the readout of RAPIDe-2, we initiated RAPIDe-3, a global, pivotal Phase 3, placebo-controlled study to evaluate deucrictibant IR capsule (20 mg) for the on-demand treatment of attacks in people 12 years and older with HAE, in March 2024 and reported topline data in December 2025. Deucrictibant demonstrated a clinically differentiated profile by meeting the primary and all key secondary efficacy endpoints with statistical significance; compared to placebo, deucrictibant reduced the time to onset of symptom relief (1.28 hours), time to End of Progression™ (17.47 minutes), time to complete symptom resolution (11.95 hours), as well as all other key secondary endpoints. Deucrictibant-treated attacks resulted in less second dose or rescue medication than placebo-treated attacks. In RAPIDe-3, deucrictibant was well tolerated with no treatment-related serious adverse events and no participants discontinuing treatment due to treatment-emergent adverse events. Pharvaris plans to submit a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) in the first half of 2026 for the on-demand treatment of acute attacks of HAE. In our Phase 2 placebo-controlled trial evaluating the efficacy and the safety and tolerability of deucrictibant for long-term prophylaxis against angioedema attacks in HAE type 1 and 2 (CHAPTER-1), a statistically significant and clinical meaningful reduction in mean monthly attack rate was observed compared to placebo-treated attacks. The study’s primary endpoint was met as 40 mg per day orally administered deucrictibant significantly reduced the mean monthly HAE attack rate by 84.5% compared to placebo. In the analysis of the secondary endpoints, deucrictibant demonstrated clinically meaningful improvement in the severity of attacks and a decrease in the number of attacks treated with on-demand medication. Participants on deucrictibant treatment experienced a meaningful improvement in their quality of life. Throughout 12 weeks of treatment in CHAPTER-1, both doses of deucrictibant were well-tolerated. There were no serious adverse events, no severe treatment-emergent adverse events, and no adverse events leading to treatment discontinuation. We commenced CHAPTER-1 in November 2021 using twice-daily dosing of deucrictibant IR capsules as a proof-of-concept for once-daily deucrictibant XR tablets, and announced positive topline data in December 2023. We believe these positive Phase 2 data support further development of deucrictibant as a potential oral prophylactic therapy for HAE attacks. In December 2024, we initiated CHAPTER-3, a global, pivotal, randomized, double-blind, placebo-controlled Phase 3 study of orally administered deucrictibant extended-release tablet for the prophylaxis against angioedema attacks in adults and adolescents (12 years and older) with HAE. The study aims to enroll approximately 81 participants with HAE and randomize them in a 2:1 ratio to receive deucrictibant XR tablet (40 mg/day), which is currently the intended commercial dosage, or placebo, once daily for 24 weeks. The primary endpoint of the study is to evaluate the efficacy of deucrictibant compared to placebo for prophylaxis against angioedema attacks as measured by the time-normalized number of investigator-confirmed HAE attacks during the 24-week treatment period. Other objectives of the study include evaluating additional clinically relevant outcomes, deucrictibant’s safety and tolerability, pharmacokinetics and its impact on health-related quality of life measures in the prophylactic setting. In addition, we are also running open-label extension studies in both on-demand (RAPIDe-2) and prophylactic (CHAPTER-4) settings to collect long-term safety and efficacy data in HAE patients. In October 2025, we initiated CREAATE, a global, pivotal Phase 3 study to assess the efficacy and safety of deucrictibant for the prophylactic and on-demand treatment of AAE-C1INH attacks. In part 1 of CREAATE, participants receive either deucrictibant XR tablet (40 mg) or placebo once daily for 12 weeks to evaluate deucrictibant XR as a prophylactic treatment of AAE-C1INH attacks. In part 2, participants treat two attacks in a cross-over fashion, one attack with deucrictibant IR capsule (20 mg) and one with placebo, to evaluate deucrictibant IR as an on-demand treatment of AAE-C1INH attacks. Part 3 of CREAATE is the open-label extension portion of the study assessing the long-term safety and efficacy of deucrictibant immediate-release capsule (20 mg) for on-demand treatment. Global sales of treatments for HAE in 2024 were estimated at approximately $2.7 billion based on publicly available information and, according to public research reports, are forecast to grow at an approximately 5% compound annual growth rate to $4.7 billion through 2036. 46 Table of Contents The mechanism of action of the most widely used on-demand HAE treatment is inhibition of the bradykinin B2 receptor; other mechanisms include replacement of C1INH or inhibition of plasma kallikrein. Most on-demand therapies are administered by injection, the burden of which causes people to delay or forego treatment of their attacks. An oral on-demand treatment could decrease the burden of therapy by improving convenience through easier administration, portability, and discretion. With the encouraging RAPIDe-3 results, combined with the trusted bradykinin B2 receptor antagonist mechanism seen in both icatibant and deucrictibant, we believe deucrictibant could become standard of care for on-demand treatment. In the prophylactic space, there are several approved injectables, all of which have similar efficacy and tolerability, but continue to compete around less-frequent injections. An oral prophylactic that could offer injectable-like efficacy™, placebo-like tolerability, and the convenience of an oral, could potentially become a market leader in HAE. We believe HAE patients need alternatives that better meet their objectives for ease of treatment, disease control, and improved quality of life. We anticipate that there will be strong interest in safe and effective, orally delivered, small-molecule treatments that can match or improve upon the efficacy profile of existing therapies. Differentiation of deucrictibant Deucrictibant is a novel, highly potent and selective, orally bioavailable small molecule bradykinin B2 receptor antagonist. Deucrictibant has been observed to be a potent inhibitor in vitro as assessed using human recombinant bradykinin B2 receptors (150 pM); ex vivo as studied against endogenous bradykinin B2 receptors in a human umbilical vein model (350 pM); and in vivo in the human bradykinin-challenge model (170 pM). Potency as used in this Annual Report refers to the amount of drug required to produce a pharmacological effect of given intensity and is not a measure of therapeutic efficacy. Deucrictibant demonstrated over 4000-fold selectivity for the bradykinin B2 receptor when compared to approximately 170 other molecular targets, including the bradykinin-B1-receptor. We designed deucrictibant as a new chemotype with properties compatible with oral delivery. We believe that deucrictibant, as the molecule underlying both the IR capsule formulation and the XR tablet formulation, has the potential to be highly differentiated for both the on-demand and prophylactic settings with the key benefits below: In addition to the differentiation of our individual products, having on-demand and prophylactic products with the same active ingredient enables patients to maintain a trusted active medicine when they change their dosing regimen and delivery mechanism moving from on-demand to prophylactic treatment (or back). This may be particularly valued by children or adolescents who typically begin therapy with on-demand only and gradually move to prophylaxis as attack frequency increases (commonly after puberty). To our knowledge, we are the only company that will offer this option to patients. Deucrictibant IR capsule. We believe that deucrictibant IR capsules, an on-demand, rapid exposure softgel capsule, has the potential to be highly differentiated for patients suffering from acute HAE attacks with the following benefits: Efficacy Faster onset of symptom relief Median time to onset of symptom resolution as measured by patient global impression of change (PGI-C) “a little better” of 1.28 hours versus over 12 hours for placebo Median time to End of Progression™ of 17.47 minutes versus 228.67 minutes for placebo Shorter substantial symptom relief Median time to substantial symptom relief by PGI-C “better” of 2.85 hours versus over 12 hours for placebo Median time to substantial symptom relief by patient global impression of severity (PGI-S) ≥1-level improvement of 2.41 hours versus over 12 hours for placebo Faster complete symptom resolution Median time to complete symptom resolution as measured by PGI-S “none” of 11.95 hours versus over 24 hours for placebo Safety/tolerability Placebo-like safety/tolerability profile No drug-related adverse events observedORWell tolerated throughout therapeutic ranges as demonstrated by multiple clinical trials to-date Convenience Oral capsule Easy to carry and swallow formulation with no injection required facilitates early treatment of acute AE-BK attacks Single dose resolution 83% of all attacks completely resolved with a single dose MoA & product features B2R antagonist Clinically validated mechanism that works directly on the inducer of AE attacks and therefore addresses a potentially wider patient population than agents acting upstream in the KKS pathway Treatment flexibility Two formulations, each optimized for either treatment or prevention of angioedema attacks Potency More potent inhibitor than icatibant - Lowest dosage of any oral AE-BK on-demand treatment Half-life Longer half-life than icatibant Absorption Exposure exceeds the anticipated threshold therapeutic plasma level (EC85) in 30 minutes, with or without food 47 Table of Contents Deucrictibant XR tablet. We believe that deucrictibant XR tablets, a prophylactic extended-release tablet designed to be as a daily oral therapy, has the potential to be highly differentiated for HAE patients with the following benefits: Efficacy Protection from attacks Monthly attack reduction and need for rescue medication at par with injectables Safety/tolerability Placebo-like safety/tolerability profile Well tolerated throughout therapeutic ranges as demonstrated by multiple clinical trials to-date Convenience Oral tablet Potential for once-a-day dosing Treatment flexibility Two formulations, each optimized for either treatment or prevention of angioedema attacks MoA & product features B2R antagonist Clinically validated mechanism that works directly on the inducer of AE attacks and therefore addresses a potentially wider patient population than agents acting upstream in the KKS pathway Potency More potent inhibitor than icatibant - Lowest dosage of any oral AE-BK prophylactic treatment Half-life Longer half-life than icatibant Pharmacokinetics Exposure exceeds the anticipated threshold therapeutic plasma level (EC85) from day one of treatment and reaches and maintains steady-state concentration within 72 hours. providing rapid attack protectionAppropriate pharmacokinetic profile with or without food Lifecycle Management of Deucrictibant In June 2025, we shared initial exploratory data around the potential expansion of the treatable population for deucrictibant. Using a biomarker assay of cold-activated plasma samples of people with HAE-1/2, as well as AAE-C1INH and HAE with normal C1INH (HAE-nC1INH), and angioedema of unknown cause (AE-UNK). The data from this biomarker study demonstrate our ability to identify people living with bradykinin-mediated angioedema, potentially expanding the treatable population of deucrictibant. Expansion of the Portfolio Our goal is to expand our portfolio with additional programs addressing other bradykinin-mediated diseases, building on our strategic strength and expertise in the bradykinin B2 receptor pathway. Our approach is to identify additional disease areas and indications with strong scientific rationale, high unmet medical need, a defined target population and significant differentiation potential. In collaboration and discussion with key opinion leaders, we are considering exploratory proof-of-concept studies to validate the potential of bradykinin B2 receptor antagonism in new indications that could include cardiovascular, allergy and immunology and others. 48 Table of Contents Our Strengths Our company is built upon the following strengths: •Broad strength and expertise in the bradykinin B2 receptor pathway. Members of the management team include the leadership team that developed FIRAZYR through European approval, and a key member from the TAKHZYRO development team. In addition, an inventor of icatibant is an advisor to the CEO; •Deucrictibant is an orally available product candidate with a clinically validated mechanism of action that addresses serious unmet medical need in AE-BK; •Positive RAPIDe-3 pivotal Phase 3 data clearly differentiate deucrictibant in the on-demand space by achieving statistical significance in the primary endpoint and all 11 secondary efficacy endpoints; faster time to onset of treatment response, shorter median time to substantial relief, earlier complete symptom resolution, and decreased use of second dose or rescue medication position deucrictibant IR to potentially become standard of care for on-demand treatment; RAPIDe-3 data will be the basis of our future marketing authorization applications; •Derisked prophylactic program is supported by (1) positive CHAPTER-1 Phase 2 proof-of-concept data demonstrating injectable-like efficacy™, placebo-like tolerability, oral convenience, and improved quality of life; (2) optimized PK profile using XR formulation; and (3) demonstrated clinical excellence of Phase 2 to Phase 3 replicability seen in RAPIDe-1 and RAPIDe-3; •We wholly own intellectual property – including issued, allowed and pending patent applications – covering deucrictibant and additional molecules, formulations and use. Our scientific experience allows us to leverage deep insight and experience in the bradykinin B2 receptor pathway to expand our portfolio into other bradykinin-mediated angioedema and bradykinin-mediated diseases beyond angioedema; and •Our deep market expertise across the different functional areas of the company through the hiring of research, clinical development, medical and commercial staff with a long history in HAE. Our Strategy Our strategy is to develop and commercialize therapies that are superior to currently available treatment options and improve patient quality of life and convenience. Our initial approach for AE-BK is based upon extensive patient, physician, and payer research to identify the key needs in the market. According to our analysis, oral therapy remains the highest unmet need for both on-demand and prophylactic use in AE-BK. A therapy for AE-BK, whether for on-demand or prophylaxis, needs to offer strong efficacy, compelling tolerability and safety, and convenient administration. Our intention with the IR capsule formulation and the XR tablet formulation is to develop products for the on-demand and prophylactic setting that can meet all of these needs. We are not aware of any other therapies on the market or in development that are able to provide such a comprehensive value proposition across the spectrum for HAE. The key elements of our strategy include: •Seek approval and access for deucrictibant for on-demand treatment of HAE utilizing a rapid-onset formulation, known as deucrictibant immediate-release (IR) capsules. We intend to file for approval and commercialize deucrictibant IR capsules as a fast-acting, orally available, potent inhibitor and selective on-demand treatment for HAE attacks. We recently announced positive, pivotal topline data from RAPIDe-3, a global, pivotal Phase 3 clinical study of deucrictibant IR capsules for the on-demand treatment of HAE attacks in adults and adolescents. •Advance the development of deucrictibant for prophylactic treatment of HAE utilizing an extended-release formulation, known as deucrictibant extended-release (XR) tablets. We intend to advance deucrictibant XR tablets through clinical development as an extended-release prophylactic treatment of HAE. We plan to leverage our clinical data and experience from the development of deucrictibant in the on-demand setting to expedite our efforts in the prophylactic setting. We are currently enrolling approximately 81 participants in CHAPTER-3, a global, pivotal Phase 3 clinical study of deucrictibant XR tablets for the prophylactic treatment of HAE attacks in adults and adolescents. •Expand the range of bradykinin-mediated angioedema indications to which deucrictibant can be applied. In addition to Type 1 or Type 2 HAE, bradykinin is also an important mediator for other types of non-histaminergic angioedema, such as: hereditary angioedema with normal C1INH (HAE-nC1) and acquired angioedema (AAE) due to C1INH deficiency (AAE-C1INH). We included participants with HAE-nC1 in both RAPIDe-3 and CHAPTER-3 studies, enabling us to explore the efficacy and tolerability of deucrictibant in this population. Additionally, we initiated CREAATE, a clinical study to evaluate the efficacy and safety of deucrictibant for the prevention and treatment of AAE-C1INH. •Expand upon our expertise in the bradykinin B2 receptor pathway. We intend to leverage the strategic strengths, insight, and deep experience of our team in the bradykinin B2 receptor pathway to identify additional disease areas and indications with strong scientific rationale, high unmet medical need, a defined target population and significant differentiation potential. As such, we will seek to develop follow-on product candidates that serve additional bradykinin-mediated diseases beyond angioedema, such as cardiovascular, allergy and immunology, neurological disease or others. •Commercialize our product candidates. We intend to retain economic and commercial ownership of our current product candidates. If approved, we expect to independently commercialize both deucrictibant XR and deucrictibant IR in the United States. In other geographies, we are evaluating both independent commercialization and corporate partnerships. In 2026, we 49 Table of Contents intend to file for approval of deucrictibant IR, and establish a focused commercialization and sales infrastructure suitable for AE-BK in the United States. Bradykinin-Mediated Angioedema Disease Overview Bradykinin-mediated angioedema (AE-BK) is a rare and potentially life-threatening condition. AE-BK includes HAE and AAE-C1INH. HAE is an autosomal dominant disease, meaning that a defect in only one copy of the gene leads to symptoms and that it occurs at similar rates in both males and females. It is mainly caused by one or more mutations (inherited or spontaneous) in the SERPING1 gene, which codes for the C1-inhibitor protein (C1INH). Deficiency or malfunction of C1INH leads to uncontrolled synthesis and activity of plasma kallikrein and unconstrained bradykinin production. Excessive bradykinin production is the key mediator of symptoms in patients with AE-BK and manifests as edema attacks, most commonly in the limbs, face (lips and tongue), intestinal tract, urogenital region, and airways. HAE patients with a deficiency in C1INH activity are classified as Type 1 or Type 2. Type 1 is the most common form and results in low levels of circulating C1INH, and Type 2 results in production of a low function protein. An additional form of HAE, called normal C1INH HAE (HAE-nC1INH), can occur in patients with normal levels of C1INH for a variety of reasons including mutations in genes for Factor XIIa, plasminogen, angiopoietin-1, kininogen-1 and others. Moreover, angioedema attacks may occur in people with underlying disease, referred to as AAE-nC1INH. Excessive bradykinin generation and increased risks for edema attacks in AE-BK may occur during conditions associated with inflammation, infections, ischemia, and allergic reactions. Attacks often lead to discomfort, pain and nausea but can become life-threatening in the case of airway obstruction, with a 30% risk of asphyxiation if the attack remains untreated. Although rare, at least half of AE-BK patients have experienced a life-threatening airway swelling attack and airway attacks remain a major cause of mortality in AE_BK patients. The number and severity of attacks vary highly between patients, and the most severely affected patients can experience attacks every few days. Attacks can occur spontaneously although they often are associated with anxiety, stress, minor trauma, surgery, or illnesses. Commonly, patients are alerted to an impending attack by prodromal symptoms which include rash, fatigue, and muscle aches. The severity of attacks is unpredictable and not related to their underlying frequency. Swelling typically develops over 24 hours and resolves within five days without treatment. Symptoms typically first present in young children and may take 5-10 years (until early adolescence or young adulthood) to be diagnosed. HAE-C1INH affects 1:50,000 individuals globally, HAE-nC1INH affects 1:250,000 individuals globally, and AAE-C1INH affects 1:500,000 individuals globally. As a result of the lifelong nature of HAE, the severe attack burden occurring later and/or at distinct periods in the life of AAE-C1INH patients and the challenges related to the use of many of the injected therapies, patient surveys consistently indicate a desire for an oral therapy. We believe that an effective and tolerable oral agent has the potential to transform treatment for this disease and become standard of care for both prophylaxis and on-demand therapy. Current Treatments and Their Limitations There are currently two treatment approaches to the management of HAE: prevention of attacks (prophylaxis) and on-demand (acute) treatment of attacks. •On-Demand Treatment: Currently approved on-demand therapies for HAE include C1INH replacement products such as human plasma-derived C1INH concentrates (BERINERT, CINRYZE, and CETOR) or recombinant human C1INH (RUCONEST); the plasma kallikrein inhibitor ecallantide (KALBITOR); the bradykinin B2 receptor antagonist icatibant (FIRAZYR, and available as a generic product—which is currently the most widely used therapy); and the oral kallikrein inhibitor sebetralstat (EKTERLY). •Prophylactic Treatment: Currently approved prophylactic therapies for HAE include C1INH replacement products, such as intravenously delivered CINRYZE and subcutaneously delivered HAEGARDA/ BERINERT 2000/3000 (both of which require twice-weekly injections); the bi-weekly injectable monoclonal antibody plasma kallikrein inhibitor lanadelumab-flyo (TAKHZYRO)—current market leader; the oral small-molecule plasma kallikrein inhibitor berotralstat (ORLADEYO); the once-monthly injectable monoclonal antibody Factor XII inhibitor garadacimab-gxii (ANDEMBRY); and the once-monthly injectable plasma kallikrein inhibitor donidalorsen (DAWNZERA). •Acquired Angioedema: There are currently no approved therapies for the treatment of AAE-C1INH. Building on the trusted mechanism of bradykinin B2 receptor antagonism, established through 10+ years of icatibant real-world clinical practice, and unmet need from the AE-BK community, we believe that deucrictibant could become standard of care across both prophylaxis and on-demand treatment of AE-BK attacks. Deucrictibant Overview Since the 1990s, many companies have tried but failed to discover oral bradykinin B2 receptor antagonists, as the bradykinin B2 receptor has proved to be a difficult target for the development of orally available antagonists. Bradykinin is the principal mediator of the signs and symptoms that represent AE-BK attacks, acting as a potent and selective agonist of the bradykinin B2 receptor. 50 Table of Contents In AE-BK, contact activation triggers increased activity of plasma kallikrein, resulting in excessive breakdown of high-molecular-weight kininogen (HMWK) and increased production of cleaved HMWK (cHMWK) and bradykinin. Excessive bradykinin generation, as in HAE, promotes vascular permeability by activating the bradykinin B2 receptor in vascular endothelium cells, leading to plasma extravasation and subcutaneous or submucosal tissue swelling typical of an angioedema attack. As the figure below illustrates, treatment with deucrictibant, a novel, orally-bioavailable, highly potent and selective bradykinin B2 receptor antagonist is intended to block activation of the bradykinin B2 receptor by bradykinin, and, therefore, prevent or halt the angioedema process. Deucrictibant has the therapeutic potential for both prevention and on-demand treatment of attacks in people with AE-BK. Deucrictibant is an orally bioavailable competitive antagonist of the bradykinin B2 receptor with high affinity and high antagonist potency. Deucrictibant has been observed to be a potent inhibitor in vitro as assessed using human recombinant bradykinin B2 receptors (150 pM); ex vivo as studied against endogenous bradykinin B2 receptors in a human umbilical vein model (350 pM); and in vivo in the human bradykinin-challenge model (170 pM). Nonclinical Safety The conducted nonclinical package for deucrictibant includes secondary pharmacodynamics, safety pharmacology, genotoxicity, reproductive and developmental studies and general toxicity studies up to six months in rats and up to nine months in non-human primates. Deucrictibant did not demonstrate any in vitro or in vivo genotoxicity nor in vitro phototoxic potential. No findings considered relevant to humans were observed in GLP (Good Laboratory Practices)-compliant general toxicity studies in rats up to 3-months duration and in cynomolgus monkeys up to 9-months duration at doses up to the maximum tolerated dose in each species. Deucrictibant has not demonstrated any adverse effects on embryo-fetal survival and development in the humanized bradykinin B2 receptor transgenic rat or in the rabbit. Furthermore, male and female fertility studies showed no adverse effects of deucrictibant on gonadal function, mating behavior, and reproductive performance. Findings were observed in the repeat-dose rat data package that were considered not to be related to bradykinin B2 receptor antagonism. Based on review of these nonclinical findings, in 2022, the FDA put a clinical hold on trials of deucrictibant in the U.S. Pharvaris aligned with the FDA to conduct and complete a 26-week rodent toxicology study to address the clinical holds. Following review of data from a preplanned interim analysis of the study, the FDA lifted the clinical hold on the IND application for deucrictibant for the on-demand treatment of HAE in June 2023. In January 2024, the FDA lifted the clinical hold on the IND application for deucrictibant for the prophylactic treatment of HAE attacks following review of the full data set from the completed 26-week rodent toxicology study. Clinical Trial Program 51 Table of Contents Study Number Short Description Design Status Phase 1 C001 Single ascending dose (SAD)and bradykinin challenge/SAD-proofof mechanism (POM) Randomized, double-blind, placebo-controlled, single ascending dose to assess safety and proof-of-concept through BK-challenge Completed C002 SAD extension Randomized, double-blind, placebo-controlled, single ascending dose to assess safety Completed C003 Absorption, metabolism, and excretion (mass balance) Open-label, single dose 14 C-deucrictibant to characterize the absorption, metabolism, and excretion Completed C004 Drug-drug interaction (DDI)— CYP3A4 inhibitor (itraconazole)interaction Open-label, single-sequence, crossover DDI study Completed C005 DDI—CYP interaction (cocktail) Open-label, single-sequence, crossover DDI study Completed C006 Multiple ascending dose (MAD) Randomized, double-blind, placebo-controlled, multiple ascending doses to assess safety and different doses Completed C009 Japanese PK bridging Double-blind, randomized, single oral dose, two-period crossover comparing pharmacokinetics between Japanese and Caucasian volunteers Completed C010 Exploratory XR PK bridging Open-label, randomized five-period crossover single-dose to assess bioavailability of two different extended-release formulations with and without food Completed C012 Hepatic impairment Open-label, single dose to assess the effect of hepatic impairment on pharmacokinetics Completed C013 Renal impairment Open-label, single dose to assess the effect of renal impairment on pharmacokinetics Completed C014 DDI Rabeprazole Open-label, drug interaction study to investigate the effect of multiple doses of the gastric acid-reducing agent rabeprazole on the single dose pharmacokinetics of extended-release tablet. Ongoing C015 Confirmatory XR PK Open-label, multiple doses to assess PK and safety of extended-release formulation Completed C016 DDI CYP3A4 Open-label, single-sequence, drug-drug interaction study to evaluate the effect of multiple oral doses of the moderate CYP3A4 inhibitor verapamil on the single dose PK deucrictibant Completed C017 DDI digoxin and rosuvastatin Open-label, drug interaction study to investigate the effect of the extended-release tablet administered once daily on the pharmacokinetics of the P-gp substrate digoxin and the BCRP substrate rosuvastatin, administered as a drug cocktail Ongoing C018 XR Food Effect Open-label, randomized, two-period, two-waycross-over study to assess the influence of a high-calorie, high-fat meal on the bioavailability of extended-release formulation Ongoing C019 XR multi-ethnicity study Open-label, multiple dose study to compare PK of extended-release formulation between healthy Japanese, Chinese, and Caucasian volunteers Ongoing C020 Biovailability study Open label, randomized, two-period, cross-over single-dose study under fasting condition Ongoing C021 XR4 Food Effect Open-Label, randomized, two-period, cross-over single-dose study in healthy subjects to assess the influence of a high-calorie, high-fat meal on the bioavailability of a 40 mg extended-release (XR) formulation Ongoing Phase 2/3 C201RAPIDe-1 deucrictibant IR capsule on-demand Phase 2, randomized, double blind, placebo-controlled,dose ranging study to assess safety and efficacy Completed C303RAPIDe-2 deucrictibant IR capsule on-demand open-label extension Phase 2/3, Extension Study to evaluate the safety of long-term on-demand treatment with deucrictibant for acute HAE attacks Ongoing C301CHAPTER-1 proof-of-concept deucrictibant prophylaxis and open-label extension A two-part Phase 2, randomized, double blind, placebo-controlled dose ranging study to Part 1: assess safety and efficacy of prophylactic treatment with deucrictibant and Part 2: evaluate long-term safety and efficacy for prophylactic treatment with deucrictibant Completed 52 Table of Contents C306RAPIDe-3 deucrictibant IR capsule on demand A Phase 3, Randomized, Double-blind, Placebo-controlled, Cross-over Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Attacks in Adolescents and Adults with Hereditary Angioedema Completed C305 CHAPTER-3 deucrictibant XR tablet prophylaxis A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Orally Administered Deucrictibant Extended-Release Tablet for Prophylaxis to Prevent Angioedema Attacks in Adolescents and Adults with Hereditary Angioedema Ongoing C307 CHAPTER-4 deucrictibant XR tablet prophylaxis open-label extension A Phase 3, Long-term, Open-label Study of Orally Administered Deucrictibant Extended-release Tablet for Prophylaxis to Prevent Angioedema Attacks in Adolescents and Adults with Hereditary Angioedema Ongoing RAPIDe-1 Phase 2 On-Demand (C201) In December 2022, we announced positive top-line data from RAPIDe-1, a Phase 2, double-blind, placebo-controlled, randomized, crossover, dose-ranging study of deucrictibant IR capsule for the on-demand treatment of HAE type 1 and type 2 (HAE-1/2) attacks. The study, initiated in February 2021, enrolled 74 patients across 13 countries who were randomized into one of three single dose levels of deucrictibant and placebo. The study compared symptom relief during HAE attacks and the safety of each dose of deucrictibant with placebo. In Part I of the study, participants in a non-attack state received the assigned single dose of deucrictibant IR capsule at the study center to assess its pharmacokinetics and safety. In Part II, participants self-administered blinded study drug at home to treat three physician-confirmed HAE attacks with deucrictibant or placebo. The primary endpoint of the study is the change of a three-symptom composite (skin pain, skin swelling, abdominal pain) visual analogue scale (VAS-3) score from pre-treatment to four hours post-treatment, as captured electronically using numerically assisted input. The top-line data from 147 attacks collected by 62 participants show that all three dose levels of deucrictibant significantly reduce attack symptoms. 53 Table of Contents *VAS assessed every 30 minutes up to 4 hours post-treatment, then at 5, 6, 8, 24, 48 hours Composite and individual VAS-3, mean symptom complex severity, or MSCS, and treatment outcome score, or TOS, were assessed up to 48-hours post-dose. All key secondary endpoints in the study were met, demonstrating that deucrictibant significantly shortens the time to onset of symptom relief by a ≥30% reduction in VAS-3 score from the pre-treatment score, decreases time to a ≥50% reduction in VAS-3 score from the pre-treatment score, reduces time to almost complete or complete symptom relief by VAS-3, reduces the MSCS score from pre-treatment to four hours post-treatment, and improves the TOS at four hours post-treatment. All other secondary endpoints were met. Participants on deucrictibant also used substantially less rescue medication compared to placebo. Deucrictibant was generally well tolerated with no treatment-related serious adverse events and no adverse events leading to treatment discontinuation. In the non-attack phase, two treatment-related adverse events were experienced by two patients; in the attack treatment phase, three treatment-related adverse events were reported for one attack treated with deucrictibant 30 mg (2.8%) and one treatment-related adverse event was reported for one attack treated with placebo (1.9%). 54 Table of Contents RAPIDe-2 Phase 2/3 On-Demand Long-Term Extension (C201) Following treatment of participation in RAPIDe-1, participants were eligible to either join the Phase 2 randomized clinical trial of deucrictibant for the prevention of HAE attacks (CHAPTER-1) or roll over to the long-term extension on-demand study (RAPIDe-2). In Part A of RAPIDe-2, participants remained blinded to their dose of deucrictibant (10 mg, 20 mg, 30 mg) but were able to treat every attack with active study drug. In the extension study, participants were able to treat upper airway attacks, including laryngeal attacks. The primary endpoint of the study is to evaluate the long-term safety of deucrictibant as an on-demand agent; secondary endpoints of efficacy were measured using patient global impression of change (PGI-C) and patient global impress of severity (PGI-S) patient reported outcome (PRO) scales. RAPIDe-2 includes 465 attacks from 19 participants, 14 of the attacks were upper airway attacks. Deucrictibant was well tolerated across all doses, with no treatment-related treatment-emergent adverse events (TEAEs), with no TEAEs leading to treatment discontinuation, study withdrawal, or death. Secondary endpoints from the RAPIDe-2 study included time to onset of symptom relief as measured by a PGI-C rating of at least “a little better” for two consecutive timepoints (1.1 hours), time to substantial symptom relief as measured by a PGI-C rating of at least “better” for two consecutive timepoints (2.5 hours), time to reduction in attack severity as measured by at least one level reduction in PGI-S from pre-treatment for two consecutive endpoints (2.8 hours), and time to complete attack resolution as measured by a PGI-S rating of “none” (10.6 hours). In the upper airway attacks treated, there were similar times to relief and resolution of attacks as seen in the full data set. The majority of the attacks were treated with a single dose of deucrictibant and without rescue medication within 24 hours. The final results from Part A of the RAPIDe-2 extension were consistent with the Phase 2 RAPIDe-1 study and provide evidence on the long-term safety and efficacy of deucrictibant IR capsule for treatment of repeat HAE attacks. The RAPIDe-2 study is still ongoing. RAPIDe-3 Phase 3 Pivotal On-Demand (C306) The RAPIDe-3 global Phase 3, placebo-controlled study evaluated orally administered deucrictibant immediate-release (IR) capsule (20 mg) for the on-demand treatment of attacks in people 12 years and older with HAE. The study enrolled a total of 134 participants from 24 countries on six continents. The patient population studied included adolescents and adults; participants on and not on long-term prophylaxis (LTP); people with HAE type 1, HAE type 2, and HAE with normal C1 inhibitor; and attacks studied included those of varying severities and across all body locations. The primary endpoint and all 11 secondary efficacy endpoints, assessed sequentially under a multiplicity-control procedure, achieved statistical significance. 55 Table of Contents *Adolescent participants receive a non-attack dose for PK sampling prior to randomization. The efficacy analysis included paired attacks (one participant contributed one deucrictibant-treated attack and one placebo-treated attack) from 88 participants. Compared to placebo, deucrictibant demonstrated compelling and differentiating efficacy: the primary endpoint of time to symptom relief as measured by a PGI-C rating of at least “a little better” for two consecutive timepoints (1.28 hours vs. over 12 hours), time to End of Progression™ as measured by PGI-C (17.47 minutes vs. 228.67 minutes), time to substantial symptom relief as measured by a PGI-C rating of at least “better” for two consecutive timepoints (2.85 hours vs. over 12 hours), time to reduction in attack severity as measured by at least one level reduction in PGI-S from pre-treatment for two consecutive endpoints (2.41 hours vs. over 12 hours), and time to complete attack resolution as measured by a PGI-S rating of “none” (11.95 hours vs. over 48 hours). Additionally, most attacks were treated with a single capsule of deucrictibant. In RAPIDe-3, deucrictibant was well tolerated with no treatment-related serious adverse events and no participants discontinuing treatment due to treatment-emergent adverse events. 56 Table of Contents N: number of participants. n: number of participants with ≥1 event. % = n/N*100% Pharvaris remains on track to submit a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) in the first half of 2026 for the on-demand treatment of acute attacks of HAE. CHAPTER-1 Phase 2 Prophylaxis (C301) PHA022121-C301 is a double-blind, placebo-controlled Phase 2 study evaluating the efficacy as well as the safety and tolerability of deucrictibant for long-term prophylaxis against angioedema attacks in HAE-1/2. In the study, 34 participants were enrolled globally and randomized to receive one of two doses of deucrictibant (20 mg/day or 40 mg/day) or placebo for 12 weeks of treatment. Deucrictibant immediate-release capsule was dosed twice-a-day as a proof-of-concept for the once-daily deucrictibant extended-release tablet, which is the intended formulation for the prophylactic treatment of HAE. The open-label portion of the CHAPTER-1 study is ongoing at the 40 mg/day dose. *20 mg/day = deucrictibant immediate-release (IR) capsules 10 mg twice daily; †40 mg/day = deucrictibant IR capsules 20 mg twice daily. b40 mg/day = deucrictibant IR capsules 20 mg twice daily. The study’s primary endpoint measured the time-normalized number of investigator-confirmed HAE attacks during the treatment period. The monthly attack rate was reduced by 84.5% (p=0.0008) compared to placebo in participants who received 40 mg/day deucrictibant. In the analysis of the secondary endpoints, deucrictibant demonstrated clinically meaningful improvement in the severity of attacks (92.3% reduction in occurrence of moderate and severe attacks) and a decrease in the number of attacks treated with on-demand 57 Table of Contents medication (92.6% fewer attacks treated with on-demand medication). Participants on deucrictibant treatment also experienced a meaningful improvement in their quality of life. *20 mg/day = deucrictibant immediate-release (IR) capsules 10 mg twice daily; †40 mg/day = deucrictibant IR capsules 20 mg twice daily. *20 mg/day = deucrictibant immediate-release (IR) capsules 10 mg twice daily; †40 mg/day = deucrictibant IR capsules 20 mg twice daily. *20 mg/day = deucrictibant immediate-release (IR) capsules 10 mg twice daily; †40 mg/day = deucrictibant IR capsules 20 mg twice daily. 58 Table of Contents Throughout 12 weeks of treatment in CHAPTER-1, both dose regimens of deucrictibant (20 mg/day and 40 mg/day) were well-tolerated. There were no serious adverse events, no severe treatment-emergent adverse events, and no adverse events leading to treatment discontinuation. *20 mg/day = deucrictibant immediate-release (IR) capsules 10 mg twice daily; †40 mg/day = deucrictibant IR capsules 20 mg twice daily. Following the randomized portion of CHAPTER-1 (Part 1), participants were eligible to roll over to the open-label extension (OLE) of the study (Part 2), where they received deucrictibant 40 mg/day to evaluate the long-term safety and efficacy of deucrictibant administered for prophylaxis against HAE attacks. All 30 participants who completed CHAPTER-1 Part 1 enrolled in the ongoing OLE. Deucrictibant was well tolerated with no safety signals in the OLE. The mean treatment duration in the OLE was 22.2 months. Maximum deucrictibant exposure during the entire study was 33.8 months. b40 mg/day = deucrictibant IR capsules 20 mg twice daily. c20 mg/day = deucrictibant immediate-release (IR) capsules 10 mg twice daily; 59 Table of Contents The final data from the completed Phase 2 CHAPTER-1 OLE study provide further evidence on the long-term safety and efficacy of oral deucrictibant for prevention of HAE attacks. The attack rate was reduced by week 1 and remained low for up to ~34 months; the overall on-study attack rate during the OLE was 0.12 attacks/month. aBased on time normalized number of attacks per 4 weeks. b1 month = 4 weeks. cDeucrictibant IR capsule, 10 mg twice daily. dDeucrictibant IR capsule, 20 mg twice daily. XR Phase 1 Data In order to provide a differentiated product featuring more consistent exposure of deucrictibant for the prophylactic setting, we have developed an extended-release, or XR, formulation that features continuous slow release maintaining deucrictibant plasma concentrations above the levels we predict to provide protection against attacks. Deucrictibant has demonstrated properties favorable to the development of XR formulations, and we completed several human pharmacokinetics trials with deucrictibant to enable use of a to-be-marketed product candidate in the pivotal prophylactic trial CHAPTER-3. With the results of pharmacokinetic trials with the to-be-marketed XR formulation, we believe we have identified the to-be-marketed extended-release formulation of deucrictibant that enables once-daily dosing in a prophylactic setting. Future Development Path We intend to develop deucrictibant for bradykinin-mediated angioedema for the on-demand and prophylactic indications in parallel using two different product formulations. On-Demand The availability of an immediate-release capsule formulation provides a good pharmacokinetic profile for on-demand treatment: rapid oral absorption independent of fed status resulting in almost immediate onset of action with longer expected duration of efficacy than subcutaneous injections of icatibant. Based on the positive results of the RAPIDe-3 study, we are preparing marketing authorizations of deucrictibant for the on-demand treatment of HAE attacks. We also have an ongoing open-label extension study of deucrictibant for the on-demand treatment of HAE attacks. We also intend to file an sNDA of deucrictibant for the on-demand treatment of AAE-C1INH attacks following completion of the second part of the CREAATE pivotal Phase 3 study. Prophylaxis Currently there is not a bradykinin B2 receptor antagonist available for HAE prophylaxis. Icatibant has a very short half-life and would require multiple injections each day, making it generally unsuitable for prophylactic use, especially as most people report injection site pain. Based on the positive results of the primary analysis of CHAPTER-1, we have initiated the confirmatory global Phase 3 trial CHAPTER-3 for the efficacy and safety evaluation of deucrictibant, as described below, in prophylactic treatment of HAE. In December 2024, Pharvaris initiated a global, pivotal, randomized, double-blind, placebo-controlled Phase 3 study of orally administered deucrictibant extended-release tablet for the prophylaxis against angioedema attacks in adults and adolescents (12 years and older) with HAE. The study aims to enroll approximately 81 participants with HAE and randomize them in a 2:1 ratio to receive deucrictibant XR tablet (40 mg/day), which is the intended commercial dosage, or placebo, once daily for 24 weeks. The primary endpoint of the study is to evaluate the efficacy 60 Table of Contents of deucrictibant compared to placebo for prophylaxis against angioedema attacks as measured by the time-normalized number of investigator-confirmed HAE attacks during the 24-week treatment period. Other objectives of the study include evaluating additional clinically relevant outcomes, deucrictibant’s safety and tolerability, pharmacokinetics and its impact on health-related quality of life measures in the prophylactic setting. In addition, we also are running an open-label extension study, CHAPTER-4, in the prophylactic setting which will include participants from the CHAPTER-1 open-label extension, participants who have completed the randomized Phase 3 study, CHAPTER-3, and novel participants to collect long-time safety and efficacy data. Intellectual Property We seek to protect and enhance the proprietary technologies, inventions, product candidates, methods of manufacture and methods of usage of our product candidates, and improvements thereof that are commercially important to the development of our business. We protect our proprietary intellectual property by, among other things, filing patent applications in the United States and internationally covering our proprietary technologies, inventions, product candidates, methods of manufacture and use, and improvements that are important to the development and implementation of our business. We will also seek to rely on regulatory protection afforded by orphan drug designations, inclusion in expedited development and review, data exclusivity, market exclusivity and patent term extensions where available. As of December 31, 2025, we own five U.S. patents and 150 national/regional patents, including in Australia, China, India, Indonesia, Japan, Mexico, South Korea, France, Germany, Italy, Netherlands, Spain and United Kingdom, that expire on November 23, 2038 or later, and 85 pending patent applications worldwide, including 6 pending U.S. applications, 79 pending non-U.S. applications, including applications in China, Europe and Japan. The U.S. patents, 93 national/regional patents and 10 of our pending patent applications contain composition-of-matter claims to the deucrictibant small molecule and derivatives thereof; deucrictibant is the active pharmaceutical ingredient (API) in, and therefore extends our patents/patent applications to, our IR and XR product candidates. Each such patent application can generally be categorized into one of three patent families: (1) those relating to the novel bradykinin-B2-receptor antagonists, (2) those relating to the cyclic bradykinin-B2-receptor antagonists, and (3) those relating to the new cyclic bradykinin-B2-receptor antagonists. Two national/regional patents and 9 of our pending applications contain claims directed to the use of deucrictibant in on-demand treatment of HAE and in prophylaxis for HAE, and accordingly extend the patent applications to methods of use of the IR and XR product candidates. 53 granted patents, including in China, France, Germany, Italy, Netherlands, Spain and United Kingdom, and 18 of our pending patent applications, including an U.S. application, contain claims directed to the formulation of our IR product candidate. Two of our applications that are pending in the U.S. and Europe contain claims directed to the crystal form of the API. Two European patents and 46 pending national/regional patent applications are directly or indirectly directed to the formulation of our deucrictibant XR product candidate and its use in chronic or prophylactic treatment of HAE. Not accounting for any patent term adjustment, regulatory extension or terminal disclaimers, and assuming that all annuity and/or maintenance fees are paid timely, these patent applications, if granted, will not expire until November 24, 2038. We also rely upon trade secrets that may be important to the development of our business. Trade secrets are difficult to protect and provide us with only limited protection. There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any patents that may be issued in the future. The term of individual patents depends upon the legal term for patents in the countries in which they are obtained. In most countries in which we have filed, including the U.S., the patent term is 20 years from the earliest filing date of a non-provisional patent application. In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and 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 a drug or biological product may also be eligible for patent term extension when FDA approval is granted for a portion of the term effectively lost as a result of the FDA regulatory review period, subject to certain limitations and provided statutory and regulatory requirements are met. Any such patent term extension can be for no more than five years, only one patent per approved product can be extended, the extension cannot extend the total patent term beyond 14 years from approval and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended. We may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. In the future, if and when our product candidates receive approval from the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents we may obtain in the future covering deucrictibant, depending upon the length of the clinical trials for each product and other factors. As with other biotechnology and pharmaceutical companies, our ability to establish and maintain our proprietary and intellectual property position for our product candidates will depend on our success in obtaining effective patent claims and enforcing those claims if granted. There can be no assurance that any of our current or future patent applications will result in the issuance of patents or that our future issued patents (if any) will provide meaningful protection of our product candidates or technology. For more information regarding the risks related to our intellectual property, see “ITEM 3. KEY INFORMATION—D. Risk factors—Risks Related to Our Intellectual Property.” 61 Table of Contents License Agreement On March 31, 2016, we entered into a license agreement (the "BRAIN License"), and a research agreement with BRAIN to collaborate for the development of an orally available bradykinin B2 receptor antagonist. Pursuant to the BRAIN License, we acquired a worldwide, exclusive license from BRAIN to use (i) a certain proprietary substance class of bradykinin B2 receptor antagonists with the potential of oral activity ("OB2RA"), and (ii) any derivatives, improvements, analogs, isomers, metabolites, or conjugates therefrom (together, the "OB2RA Class"), in each case, for the purpose of developing, manufacturing and marketing compounds on a global basis from the OB2RA Class for the treatment of, among others, hereditary angioedema. Certain rights associated with deucrictibant, IR and XR are subject to the BRAIN License. In consideration for the license, we paid BRAIN a non-refundable up-front payment of approximately €0.3 million. Under the BRAIN License, we are required to make one-time payments in an aggregate amount of up to €11.7 million upon the achievement of certain development, regulatory, and sales milestones. To date, we have paid an aggregate amount of approximately €3.7 million (approximately €0.3 million up-front plus €3.4 million in milestone payments). Under the BRAIN License, up to €8.0 million in aggregate potential milestone payments remain outstanding. In addition, we will be required to pay low to medium single-digit tiered royalties on direct or indirect net sales of licensed products. The royalties that we are required to pay under this agreement may be reduced on a country-by-country and product-by-product basis if sales of a generic version of a product account for 1% or more of the relevant market. Our agreement with BRAIN will expire, on a product-by-product basis, upon (i) with respect to a royalty-bearing product, the expiry of the last valid claim of a royalty-bearing patent that claims such royalty-bearing product, and (ii) with respect to a licensed product that is not royalty-bearing, the expiry of the last valid claim of a non-royalty-bearing patent that claims such licensed product. Royalty-bearing patents comprise US Patent No. 10.836,748 and any patent or patent application that shares common priority with such patent. Each of deucrictibant, IR and XR is a royalty-bearing product. Not accounting for any regulatory extension or terminal disclaimers, and assuming that all annuity and/ or maintenance fees are paid timely, the applicable expiration date is November 23, 2038. Either party may terminate the agreement prematurely for cause, in particular, for the other party’s (i) uncured material breach, (ii) bankruptcy or insolvency, or (iii) challenge to the validity or ownership of the intellectual property rights relating to the compounds that form the object of the collaboration with BRAIN. If BRAIN were to (a) terminate the BRAIN License for cause and (b) exercise contractual remedies available to it thereunder, then we could be required to grant to BRAIN an exclusive worldwide license to our intellectual property generated under the collaboration with BRAIN for use in all applications, including HAE. In addition, we could be prevented from competing with BRAIN until five years after the commercial launch of any product containing a compound from the OB2RA Class. Manufacturing and Supply We currently have two CDMOs for the production of deucrictibant active pharmaceutical ingredient (API). A robust and scalable synthetic route has been established. All raw materials can be purchased from multiple suppliers. We also partner with a leading CDMO for the manufacturing of the on-demand treatment product, deucrictibant IR capsules. Another well-established CDMO produces the prophylactic treatment product, deucrictibant XR tablets. A CDMO with a global footprint is responsible for packaging and worldwide distribution of Clinical Trial Material. We partnered with a further Commercial Packaging Organization (CPO) with a global footprint for the packaging and labeling of commercial finished drug product. Sales and Marketing The Pharvaris team, including its founders, have experience developing and commercializing drug products for rare diseases including HAE specifically. We intend to develop a fully integrated sales and marketing organization ahead of marketing approval for deucrictibant IR or deucrictibant XR. Even though HAE is a competitive market, orphan product companies have demonstrated successful first launches with excellent preparation and execution. We believe that our products will provide patients with significant new treatment options, and we will evaluate options to optimize the commercial opportunity. Competition The biotechnology industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on intellectual property. We face competition from different sources, including from academic centers as well as from a number of large and specialty biotechnology and pharmaceutical companies. Currently, there are several approved therapies for HAE, including the following: •FIRAZYR: The bradykinin BR2 receptor antagonist FIRAZYR (icatibant) is approved for the treatment of acute attacks and is administered by subcutaneous administration. Seven generic forms of icatibant have been approved in the U.S. since July 2019 and more may be approved in the future. •C1INH: C1INH replacement therapy is available as an acute therapy (BERINERT, CINRYZE, and CETOR) and as a prophylactic therapy (HAEGARDA/BERINERT 2000/3000 and CINRYZE). These therapies are dosed subcutaneously and intravenously. Recombinant C1INH (RUCONEST) is also available as an acute therapy. •Kallikrein Inhibitors: KALBITOR (ecallantide) is a specific recombinant plasma kallikrein inhibitor that is dosed subcutaneously to treat acute HAE attacks. TAKHZYRO (lanadelumab-flyo) is a monoclonal antibody approved for prophylaxis of HAE attacks and can be self-administered as a subcutaneous injection. ORLADEYO (berotralstat) is a kallikrein inhibitor that was approved is dosed orally once daily for the prevention of HAE attacks. DAWNZERA (donidalorsen) is an RNA targeted plasma kallikrein 62 Table of Contents antisense oligonucleotide delivered subcutaneously either once or twice a month and was approved in the U.S. in the third quarter of 2025. EKTERLY (sebetralstat) is an oral kallikrein inhibitor that was approved for on-demand treatment of HAE attacks in the U.S. in the third quarter of 2025. •Anti-factor XIIa mAb: ANDEMBRY (garadacimab) is an anti-factor XIIa mAb delivered subcutaneously once a month and approved in the U.S. in the second quarter of 2025. •Other Medications: Prophylactic administration of synthetic attenuated androgens (generically available as danazol or stanozolol) has been utilized to reduce the frequency or severity of attacks. However, long-term use of danazol or stanozolol may result in liver damage, virilization and arterial hypertension. Six-month liver function tests, annual lipid profiles, and biennial hepatic ultrasound are recommended for patients on chronic androgen therapy. We are also aware of a number of HAE therapies in clinical development: STAR-0215 from Astria, a long-lived monoclonal antibody inhibitor of plasma kallikrein dosed subcutaneously, a gene therapy – NTLA-2002 from Intellia, using CRISPR technology to knock out the gene for prekallikrein, and ARD-324 from ADARx, an siRNA in development for the prophylactic treatment of HAE. Many of our competitors and potential competitors have substantially greater scientific, research and product development capabilities as well as greater financial, manufacturing, commercialization and human resources than we do. In addition, there is intense competition on the clinical trial sites and the enrollment of HAE patients for clinical trials. Many specialized biotechnology firms have formed collaborations with large, established companies to support the research, development and commercialization of products that may be competitive with ours, and many other biotech and pharmaceutical companies are competing for the same potential employees. Accordingly, our competitors may be more successful than we may be in developing, manufacturing, commercializing their products and in achieving widespread market acceptance. Government regulation and product approval In each country where we conduct our research and development, manufacture our products and intend to market our product candidates, if approved, we must comply with laws and regulations, including regulations issued by regulatory agencies and by other national or supra-national regulatory authorities, or collectively, the Competent Authorities, as well as industry standards, that govern nearly all aspects of our activities. Among others, the FDA, the EMA and the national Competent Authorities of each Member State of the European Union are the key regulatory agencies that exercise oversight over all aspects of our products. Our pharmaceutical product candidates are subject to substantial requirements that govern, among other things, their research, development, testing, manufacturing, quality control, approval, safety, efficacy, labelling, storage, record keeping, commercialization, distribution, import and export, post-approval monitoring and reporting, advertising, promotion, reimbursement and pricing. The process of maintaining continued compliance with the regulatory requirements requires the expenditure of substantial amounts of time and money. The nonclinical and clinical development paths for product candidates are broadly similar in the European Union and the United States. Nonclinical Studies Development of the product candidates starts with preclinical studies that enable the first-in-human clinical Phase I trial. The preclinical studies include tests for assessment of primary pharmacodynamics (the mode of action), secondary pharmacodynamics, safety pharmacology and general toxicity. Once in clinical development, additional nonclinical in vivo and in vitro studies are conducted until adequate proof of safety is established (e.g., animal testing for reproductive and general toxicity and carcinogenicity). The conduct of the nonclinical tests and formulation of the compounds for testing must comply with regulations and requirements set by the Competent Authorities, including compliance with GLP. Acceptance of the nonclinical study packages by regulatory agencies is necessary for the initiation and progression of the product candidate through Phase 1, Phase 2, and Phase 3 clinical trials. Chemical and Pharmaceutical development Chemical Development entails the development of the laboratory synthesis of the Drug Substance into a scalable process meeting the requirements of reproducibility, robustness, efficiency, and process safety, to manufacture the Drug Substance in high quality. Laboratory tests are conducted to develop a suitable formulation for clinical and commercial use. Pharmaceutical development includes the development of a formulation of the API, stability testing, and a robust Drug Product manufacturing process. The conduct of Chemical and Pharmaceutical development must comply with regulations and requirements set by the Competent Authorities, including compliance with cGMP. Clinical Studies Prior to obtaining approval to commercialize a drug candidate, sponsors typically must demonstrate with substantial evidence from well-controlled clinical trials, and to the satisfaction of the Competent Authorities, that such drug candidates are safe and effective for their intended uses. Clinical trials involve the administration of the investigational product to healthy volunteers or subjects under the supervision of a qualified investigator. Clinical trials must be conducted: (i) in compliance with the requirements of the Competent Authorities; (ii) in compliance with GCP, an international standard meant to protect the rights and health of subjects and to define the roles of clinical trial 63 Table of Contents sponsors, administrators, and monitors; as well as (iii) under protocols detailing the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. The number of clinical studies and trials that will be required for approval varies depending on, e.g., the drug candidate and the disease or condition that the drug candidate is designed to address. Prior to initiating clinical trials, a request for clinical trial authorization (national Competent Authorities in the European Union) or an IND application in the United States must be submitted to the relevant Competent Authorities. These submissions must be supported by an investigational medicinal product dossier or equivalent as detailed in applicable regulations and guidance documents from the Competent Authorities. Extensive information about the proposed clinical studies, as well as the results of the nonclinical tests, together with manufacturing information and analytical data, are included in these submissions. In the United States, a 30-day waiting period after the submission of an IND is required prior to the commencement of clinical testing in humans. If the FDA has neither commented on nor questioned the IND within this 30-day period, the clinical trial proposed in the IND may begin. Manufacturing of investigational products is subject to authorization and must be carried out in accordance with cGMP. Furthermore, a clinical trial may only be started after an IRB (United States) or a competent Ethics Committee (European Union) has issued a favorable opinion on the clinical trial application. During all phases of clinical development, Competent Authorities require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators. Annual progress reports detailing the progress of the clinical trials must be submitted to the Competent Authorities. Important new safety information, that suggests a significant risk for human patients, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure, must also be provided to clinical investigators. The Competent Authorities, sponsor or its data safety monitoring board may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research exposes patients 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 institutional requirements or if the drug candidate has been associated with unexpected serious harm to patients. The following section describes specific regulatory regimes and regulations applicable in certain jurisdictions. United States U.S. Food and Drug Administration In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FFDCA, and implementing regulations. These laws, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-marketing monitoring and reporting, sampling, and import and export of drug products. The process of obtaining regulatory approvals and the subsequent compliance with the many statutory and regulatory provisions require the expenditure of substantial time and financial resources. Failure to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to approve pending regulatory applications, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution. The FDA Approval Process Clinical trials to support NDAs for marketing approval are typically conducted in three sequential phases, but the phases may overlap. In Phase 1, the initial introduction of the product candidate is usually into healthy human subjects, and the product candidate is tested to assess metabolism, pharmacokinetics, pharmacological actions, side effects associated with increasing doses, and, if possible, early evidence on effectiveness. Phase 2 usually involves trials in a limited patient population to determine the effectiveness of the product candidate for a particular indication, dosage tolerance, and optimal dosage, and to identify common adverse effects and safety risks. If a product candidate demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2 evaluations, Phase 3 trials are undertaken to obtain additional information about clinical efficacy and safety in a larger number of subjects, typically at geographically dispersed clinical trial sites, to permit the FDA to evaluate the overall benefit-risk relationship of the product candidate and to provide adequate information for the labeling of the product candidate. In most cases, the FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the efficacy of the product candidate. A single Phase 3 trial may be sufficient in certain circumstances. During the development of a new product candidate, sponsors are given opportunities to meet with the FDA at certain points; specifically, prior to the submission of an IND, at the end of Phase 2 and before an NDA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date and for the FDA to provide advice on the next phase of development. Sponsors typically use the meeting at the end of Phase 2 to discuss their Phase 2 clinical results and present their plans for the pivotal Phase 3 clinical trials that they believe will support the approval of the new product candidate. The results of drug candidate development, nonclinical testing, clinical trials and proposed labeling are submitted to the FDA as part of the NDA. An NDA must include all information regarding and data from pertinent nonclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the drug’s chemistry, manufacturing and controls. The FDA will accept, as support for an IND or NDA a well-designed, well-conducted, non-IND foreign clinical trial if it was 64 Table of Contents conducted in accordance with GCP and the FDA is able to validate the data from the trial through an on-site inspection, if necessary. Regulatory applications based solely on foreign clinical data meeting these criteria may be approved if the foreign data are applicable to the U.S. population and U.S. medical practice, the trials have been performed by clinical investigators of recognized competence, and the data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means. Failure of an application to meet any of these criteria may result in the application not being approvable based on the foreign data alone. To support marketing approval and authorization, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational drug to the FDA’s satisfaction. The cost of preparing and submitting an NDA is substantial. The submission of most NDAs is additionally subject to a substantial application user fee payment to the FDA, and the manufacturer and/or sponsor under an approved NDA are also subject to certain annual program user fees. The FDA typically increases these fees annually. The FDA has 60 days from its receipt of an NDA to determine whether it will accept the application for filing based on the agency’s threshold determination that the application is sufficiently complete to permit substantive review. The FDA may refuse to file any NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the NDA must be resubmitted with the additional information and the resubmitted application also is subject to review before the FDA accepts it for filing. Once the FDA accepts the filing, the FDA begins an in-depth review. The FDA has agreed to certain performance goals in the review of NDAs. Under the Prescription Drug User Fee Act, the FDA has a goal of responding to standard review NDAs within ten months from the 60-day filing date. The review process may be extended by the FDA for three additional months to consider certain late-submitted information, or information intended to clarify information already provided in the submission. This late-submitted information is typically requested by the FDA. The FDA may also refer applications for novel drugs or product candidates that present difficult questions of safety or efficacy, to an FDA Advisory Committee. An Advisory Committee is an outside panel that typically includes clinicians and other experts in the field that will review and evaluate the questions posed by the FDA, and provide recommendations, sometimes including whether the FDA should approve the application. The FDA is not bound by the recommendation of an Advisory Committee, but it generally follows such recommendations. Before approving an NDA, the FDA will typically inspect one or more clinical study sites to assure compliance with GCP. The FDA may also inspect one or more nonclinical study sites. In addition, the FDA will inspect the facility or the facilities involved in the manufacture of the drug to determine if the facilities, processes and quality are compliant with cGMP. The FDA will not approve an NDA unless compliance with cGMP is satisfactory. After the FDA evaluates the NDA and the manufacturing facilities, it issues either an approval letter or a complete response letter. A complete response letter indicates that the FDA has completed its review of the NDA, and the agency has determined that it will not approve the application in its present form. A complete response letter generally outlines the deficiencies in the NDA, which may be minor or substantial, and may delineate the requirements needed to successfully progress the NDA to approval. This may require substantial additional clinical data and/or other significant, expensive, and time-consuming requirements related to clinical studies, nonclinical studies and/or manufacturing. If a complete response letter is issued, the applicant may either resubmit the NDA, addressing the deficiencies identified in the letter, or withdraw the application. The FDA has committed to reviewing resubmissions of the NDA addressing such deficiencies in two or six months, depending on the type of information included. Even if such data is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval. An approval letter authorizes commercial marketing of the drug, with specific prescribing information for specific indications. Even if FDA approves the NDA, the approval may be significantly limited to specific indications and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling. The FDA may impose restrictions and conditions on product distribution, prescribing, or dispensing in the form of a risk evaluation and mitigation strategy, or REMS, or otherwise limit the scope of any approval. REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use, or ETASU. ETASU can include, but is not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The requirement for a REMS can materially affect the potential market and profitability of the product. In addition, the FDA may require confirmatory post-marketing trials, sometimes referred to as “Phase 4” clinical trials, designed to further assess a product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized. Expedited Approval in the U.S. The FDA has a number of programs that are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition. These are: Fast Track Designation, Breakthrough Therapy Designation, Accelerated Approval and Priority Review Designation. Fast Track Designation can be requested early in the development process, if evidence of activity in a nonclinical model, a mechanistic rationale or pharmacologic data demonstrates the potential to address an unmet medical need. In the later stages of development, available clinical data should demonstrate the potential to address an unmet medical need. Fast Track Designation provides opportunities for applicants to have frequent interactions with the relevant FDA review teams. In addition, a fast-track product can be eligible 65 Table of Contents for priority review if supported by clinical data at the time of NDA submission. If the FDA determines that a fast-track product may be effective after preliminary evaluation of the NDA, it may consider reviewing portions of a marketing application before the sponsor submits the complete application. Fast Track Designation can be requested after the IND is first submitted but before receiving approval of the NDA. As a practical matter, the FDA should ordinarily receive a Fast Track Designation request no later than the sponsor’s pre-NDA meeting with the agency because many of the features of Fast Track Designation will not apply after that time. The FDA will respond to Fast Track Designation requests within 60 calendar days of receipt of the request. The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of drugs which may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. A drug that receives Breakthrough Therapy Designation is eligible for all Fast Track Designation features, intensive guidance from FDA on an efficient drug development program, beginning as early as Phase 1, and organizational commitment involving senior managers. Breakthrough Therapy Designation is requested by the manufacturer. A sponsor needs to submit a request to the agency for Breakthrough Therapy Designation, but in some cases the FDA may suggest that the sponsor consider submitting a request after reviewing submitted data and information (including preliminary clinical evidence), the FDA thinks the drug development program may meet the criteria for Breakthrough Therapy Designation; and the remaining drug development program can benefit from the designation. Ideally, a Breakthrough Therapy Designation request should be received by the FDA no later than the End-of-Phase 2 meetings if any of the features of the designation are to be obtained. The FDA will respond to Breakthrough Therapy Designation requests within 60 days of receipt of the request. Accelerated approval may be granted for a product based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments. For drugs granted accelerated approval, post-marketing confirmatory trials will be required to verify and describe the anticipated effect on the IMM or other clinical benefit. The accelerated approval pathway has been used primarily in settings in which the disease course is long, and an extended period of time would be required to measure the intended clinical benefit of a drug. Accelerated approval is also potentially useful in acute disease settings where the intended clinical benefit can be demonstrated only in a very large study because the clinical event that would need to be evaluated to demonstrate clinical benefit occurs rarely. The FDA may withdraw approval of a drug or indication approved under the accelerated approval pathway if e.g., the confirmatory trial fails to verify the predicted clinical benefit, the evidence demonstrates that the product is not shown to be safe and effective under the conditions of use, the applicant fails to conduct the post-approval trials with due diligence or the applicant disseminates false or misleading promotional materials related to the product. A priority review designation is intended to direct overall attention and resources to the evaluation of an application for a drug that treats, prevents or is used in the diagnosis of a serious condition and if approved would provide a significant improvement in safety or effectiveness. Eligibility for priority review is determined by the FDA at the time of an NDA or efficacy supplement filing. Where an application receives a priority review designation, the FDA’s goal is to take action on the marketing application within six months from the 60-day filing date (as compared to within 10 months under standard review). The FDA determines whether an application qualifies for priority review (versus standard review) for every application it reviews, not just when priority review is requested by the applicant. However, an applicant may expressly request priority review. The FDA will inform the applicant in writing of a priority review designation by day 60 of the review. Orphan Designation An orphan drug designation qualifies the manufacturer for certain tax credits and may lead to market exclusivity for seven years following the date of the drug’s approval by the FDA. The FDA provides that a drug shall be designated as an orphan drug if its manufacturer can establish that the drug is for a condition that affects fewer than 200,000 individuals in the United States or when there is no reasonable expectation that the cost of developing and making available the drug for the disease or condition will be recovered from sales of the drug in the United States. More than one manufacturer may receive orphan drug designation for the same drug for the same rare disease or condition, but each manufacturer seeking orphan drug designation must file a complete request for designation. In the United States, a manufacturer may request orphan drug designation of a previously unapproved drug or new orphan indication for a different use for an already marketed drug. In addition, a manufacturer of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug. FDA may grant the drug orphan exclusivity upon approval, if clinical superiority is demonstrated. Orphan drug exclusivity cannot otherwise be granted for the same drug made by another manufacturer for the same indication during the market exclusivity period unless the original manufacturer consents or the original manufacturer is unable to ensure the availability of sufficient quantities of the drug to meet the needs of persons with the disease or condition for which the drug was designated. An application for orphan drug designation can be made any time prior to the filing of an application for approval to market the product. The period of orphan exclusivity, if granted, begins on the date that the marketing application is approved. The exclusivity is limited to the indication for which the drug has been approved. 66 Table of Contents Post-Marketing Requirements FDA may withdraw approval of an NDA if compliance with regulatory requirements is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product may result in restrictions on the product, product recalls or even complete withdrawal of the product from the market. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further FDA review and approval; such changes may require the approval of a new NDA or an NDA supplement. An NDA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing NDA supplements as it does in reviewing new NDAs. As with new NDAs, the FDA often significantly extends the review process with requests for additional information or clarification. In addition, the FDA may, under some circumstances, require testing and surveillance programs to monitor the effect of approved products that have been commercialized, and the FDA under some circumstances has the power to prevent or limit further commercialization of a product based on the results of these post-marketing programs. In addition, drug products manufactured or distributed pursuant to the FDA approvals, are subject to additional and continuing regulation by the FDA, including, among other things: •record-keeping requirements; •reporting of adverse experiences associated with the product; •providing the FDA with updated safety and efficacy information; •distribution of drug samples; •notifying the FDA and gaining its approval of specified manufacturing or labeling changes; •drug establishment registration and drug listing requirements; and •complying with FDA promotion and advertising requirements, which include, among other things, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved labeling, limitations on industry-sponsored scientific and educational activities and requirements for promotional activities involving the internet. Drug manufacturers are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws. There are strict regulations regarding changes to the manufacturing process, and, depending on the significance of the change, it may require prior FDA approval before it can be implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon drug manufacturers. Drug manufacturers must also satisfy the product tracing, verification and reporting requirements in the Drug Quality and Security Act and have procedures in place to identify and properly handle suspect and illegitimate products. Accordingly, manufacturers must continue to spend time, money and effort in the area of production, distribution and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. Sponsors of clinical trials of FDA-regulated products are required to register and disclose certain clinical trial information. Information related to the product, patient population, phase of investigation, trial sites and investigators, and other aspects of the clinical trial is then made public as part of the registration. Sponsors are also obligated to disclose the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed in certain circumstances for up to two years after the date of completion of the trial. Competitors may use this publicly available information to gain knowledge regarding the progress of development programs. Although rare, the FDA may withdraw approval of an NDA if a company does not comply with its extensive regulatory requirements or if significant safety, efficacy or manufacturing issues arise after the drug reaches the market. More typically, if a company or the FDA discovers previously unknown problems with a drug, including adverse events of unanticipated severity or frequency or issues with manufacturing processes, the FDA may revise the approved labeling to add new safety information; require additional clinical studies to assess new safety risks; or impose distribution or other restrictions under a REMS program. Other potential consequences may include: •restrictions on the commercialization or manufacturing of the drug, market withdrawals or recalls; •fines, warning letters or holds on post-approval clinical studies; •the FDA refusal to approve pending NDAs or supplements to approved NDAs; •drug seizure or detention, or refusal to permit the import or export of drugs; or •injunctions or the imposition of civil or criminal penalties. From time to time, legislation is drafted, introduced and passed in Congress that could significantly change the statutory provisions governing the testing, approval, manufacturing and marketing of products regulated by the FDA. In addition to new legislation, FDA regulations and policies are often revised or interpreted by the agency in ways that may significantly affect our business and product candidates. It is impossible to predict whether further legislative changes will be enacted or whether FDA regulations, guidance, policies or interpretations will be changed or what the effect of such changes, if any, may be. 67 Table of Contents U.S. Patent Term Restoration A patent claiming a new product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost during product development and FDA regulatory review. The restoration period granted on a patent covering a product is typically one-half the time between the effective date of a clinical investigation involving human beings is begun and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved product and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. In addition, the application for the extension must be submitted prior to the expiration of the patent in question. A patent that covers multiple products for which approval is sought can only be extended in connection with one of the approvals. The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA. Other U.S. Healthcare Laws and Compliance Requirements In the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services (e.g., the Office of Inspector General), the U.S. Department of Justice, or DOJ, and individual U.S. Attorney offices within the DOJ, and state and local governments. For example, sales, marketing and scientific/educational grant programs are subject to anti-fraud and abuse provisions of the Social Security Act, the false claims laws, the privacy provisions of HIPAA, transparency reporting laws, and similar state laws, each as amended. Healthcare providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted marketing approval. Arrangements with providers, consultants, third-party payors and customers are subject to these broadly applicable healthcare laws and regulations that may constrain our business and/or financial arrangements. The applicable federal and state healthcare laws and regulations, include, without limitation, the following: •The Federal Anti-Kickback Statute – An intent-based federal criminal statute that prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order, recommendation, or arranging of, any item or service for which payment may be made, in whole or in part, by a federal health care program such as Medicare or Medicaid. The term “remuneration” has been interpreted broadly to include anything of value, including, without limitation, any kickback, bribe, or certain rebates. The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act ("the PPACA"), among other things, amended the intent requirement of the federal Anti-Kickback Statute to clarify that a person or entity need not have actual knowledge of this statute or specific intent to violate it. The Anti-Kickback Statute applies to arrangements between pharmaceutical manufacturers on the one hand and individuals, such as prescribers, patients, purchasers, and formulary managers on the other hand, including, for example,consulting/speaking arrangements, discount and rebate offers, grants, charitable contributions, and patient support offerings, among others. A conviction for violation of the Anti-Kickback Statute can result in criminal fines and/or imprisonment and requires mandatory exclusion from participation in federal health care programs (such as Medicare and Medicaid). Exclusion may also be imposed if the government determines that an entity has committed acts that are prohibited by the Anti-Kickback Statute. Although there are a number of statutory exceptions and regulatory safe harbors to the federal Anti-Kickback Statute that protect certain common industry activities from prosecution, the exceptions and safe harbors are drawn narrowly and arrangements may be subject to scrutiny or penalty if they do not fully satisfy all elements of an available exception of safe harbor. The Anti-Kickback Statute safe harbors are the subject of possible regulatory reforms. Any changes to the safe harbors may impact our future contractual and other arrangements with pharmacy benefit managers, group purchasing organizations, third-party payors, wholesalers and distributors, healthcare providers and prescribers, and other entities, as well as our future pricing strategies. •The Federal Civil False Claims Act—Imposes civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, false or fraudulent claims for payment to a federal health care program or knowingly making using or causing to be made or used a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties, currently set at $11,665 to $22,331 per false claim or statement for penalties assessed after June 19, 2020, with respect to violations occurring after November 2, 2015. Pharmaceutical companies have been investigated and/or subject to government enforcement actions asserting liability under the federal civil False Claims Act in connection with their alleged off-label promotion of drugs, purportedly concealing price concessions in the pricing information submitted to the government for government price reporting purposes (e.g., under the Medicaid Drug Rebate Program), and allegedly providing free product to customers with the expectation that the customers would bill federal health care programs for the product. In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act. As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S. government. In addition, manufacturers can be held liable under the federal False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. There is also the Federal Criminal False Claims Act, which is similar to the Federal Civil False Claims Act and imposes criminal liability on those that make or present a false, fictitious or fraudulent claim to the federal government. 68 Table of Contents •The Federal Criminal Statute on False Statements Relating to Health Care Matters—Makes it a crime to knowingly and willfully falsify, conceal, or cover up a material fact, make any materially false, fictitious, or fraudulent statements or representations, or make or use any materially false writing or document knowing the same to contain any materially false, fictitious, or fraudulent statement or entry in connection with the delivery of or payment for healthcare benefits, items, or services. •Criminal Health Care Fraud Statute—Enacted as part of the HIPAA, makes it a crime to knowingly and willfully execute, or attempt to execute, a scheme or artifice to defraud any health care benefit program or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program in connection with the delivery of or payment for healthcare benefits, items or services. •The Federal Civil Monetary Penalties Law—Authorizes the imposition of substantial civil monetary penalties against an entity, such as a pharmaceutical manufacturer, that engages in activities including, among others (1) knowingly presenting, or causing to be presented, a claim for services not provided as claimed or that is otherwise false or fraudulent in any way; (2) arranging for or contracting with an individual or entity that is excluded from participation in federal health care programs to provide items or services reimbursable by a federal health care program; (3) violations of the federal Anti-Kickback Statute; or (4) failing to report and return a known overpayment. •HIPAA Health Information Privacy and Security—HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 ("HITECH"), imposes privacy, security, and breach reporting obligations on certain covered entity healthcare providers, health plans, and healthcare clearinghouse as well as their business associates that perform certain services involving the use or disclosure of individually identifiable health information (referred to as “protected health information” under the law), including, among other requirements, mandatory contractual terms and technical safeguards to protect the privacy, security and transmission of individually identifiable health information, and require notification to affected individuals and regulatory authorities of certain breaches of security of individually identifiable health information. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in U.S. federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts. •The Federal Physician Payments Sunshine Act—Requires “applicable manufacturers” of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid or the State Children’s Health Insurance Program, among others, to track and report annually to the federal government (for disclosure to the public) certain payments and other transfers of value they make to “covered recipients.” The term covered recipients includes U.S.-licensed physicians, teaching hospitals, and, for reports submitted on or after January 1, 2022, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse midwives. Failure to submit required information may result in civil monetary penalties. •Analogous State Laws—There are state law equivalents of the above federal laws, such as the Anti-Kickback Statute and the False Claims Act, which may apply to items and services reimbursed by any third-party payor, including commercial insurers (i.e., so-called “all-payor anti-kickback laws”). •State Laws Regulating Pharmaceutical Manufacturer Compliance Programs, Drug Price Transparency, and Other Practices—Some state laws require pharmaceutical companies to implement compliance programs, comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or to track and report gifts, compensation, or other remuneration to physicians and other healthcare providers. Several U.S. states and localities have enacted legislation requiring pharmaceutical companies to establish marketing compliance programs, file periodic reports, and/or make periodic public disclosures on sales, marketing, pricing, clinical trials, and other activities. Other state laws prohibit certain marketing-related activities including the provision of gifts, meals or other items to certain healthcare providers, and restrict the ability of manufacturers to offer co-pay support to patients for certain prescription drugs. In addition, several recently passed state laws require disclosures related to state agencies and/or commercial purchasers with respect to certain price increases that exceed a certain level as identified in the relevant statutes. Some of these laws and regulations contain ambiguous requirements that government officials have not yet clarified. Given the lack of clarity in the laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent federal and state laws and regulations. •We are also required to satisfy the product tracing, verification and reporting requirements set out in the Drug Quality and Security Act. We expect that one or more of our products, if approved, may be eligible for coverage under Medicare, the federal health care program that provides health care benefits to the aged and disabled, including coverage for outpatient services and supplies, such as certain drug products, that are medically necessary to treat a beneficiary’s health condition. In addition, one or more of our products, if approved, may be covered and reimbursed under other federal health care programs, such as Medicaid and the 340B Drug Pricing Program. The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of the Department of Health and Human Services and pay quarterly rebates based on utilization of the manufacturer’s drugs under the program as a condition for states to receive federal matching funds for the manufacturer’s outpatient drugs furnished to Medicaid patients. Under the 340B Drug Pricing Program, the manufacturer must extend discounts to entities that participate in the program. As part of the requirements to participate in these government programs, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average manufacturer price and best price. 69 Table of Contents Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations, guidance, case law or other applicable law. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, individual imprisonment, exclusion from participation in federal health care programs, such as Medicare and Medicaid, disgorgement, reputational harm, additional oversight and reporting obligations pursuant to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with applicable laws and regulations, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to market our products, if approved, and adversely impact our financial results. Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws and regulations, these risks cannot be entirely eliminated. Any action against us for an alleged or suspected violation could cause us to incur significant legal expenses and could divert our management’s attention from the operation of our business, even if our defense is successful. If any of the physicians or other healthcare providers or entities with whom we expect to do business is found not to be in compliance with applicable laws, it may be costly to us in terms of money, time and resources, and they may be subject to criminal, civil or administrative sanctions, including exclusions from government-funded healthcare programs. U.S. Healthcare Reform In the United States, there have been and continue to be a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of our future collaborators, to effectively sell any drugs for which we, or they, obtain marketing approval. We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and additional downward pressure on the price that we, or our future collaborators, may receive for any approved drugs. For example, the PPACA substantially changed and continues to impact healthcare financing and delivery by both government payors and private insurers. Among the PPACA provisions of importance to the pharmaceutical industry, in addition to those otherwise described above, are the following: •an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs; •an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13.0% of the average manufacturer price for branded and generic drugs, respectively; •expansion of healthcare fraud and abuse laws, including the False Claims Act and the Anti-Kickback Statute, which include, among other things, new government investigative powers and enhanced penalties for non-compliance; •establishment of the Medicare Part D coverage gap discount program that, as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D, requires manufacturers to provide a now 70% point-of-sale discount off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period; •expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals, thereby potentially increasing manufacturers’ Medicaid rebate liability; •expansion of the types of entities eligible for discounts under the Public Health Service pharmaceutical pricing program (i.e., the 340B program); •reporting of certain financial arrangements between manufacturers of drugs, biologics, devices, and medical supplies and physicians and teaching hospitals under the Physician Payments Sunshine Act; •a requirement to annually report certain information regarding drug samples that manufacturers and distributors provide to licensed practitioners; and •creation of the Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research. Since its enactment there have been judicial and Congressional challenges to certain aspects of the PPACA to repeal or replace certain aspects of the PPACA. While Congress has not enacted legislation to comprehensively repeal the PPACA, at least two bills affecting the implementation of the PPACA have been signed into law, including the repeal, effective January 1, 2019, of the tax-based shared responsibility payment imposed by the PPACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year, which is commonly referred to as the “individual mandate.” In December 2018, a federal district court in Texas ruled that the PPACA’s individual mandate, without the penalty that was repealed effective January 1, 2019, was unconstitutional and could not be severed from the PPACA. As a result, the court ruled the remaining provisions of the PPACA were also invalid. The Fifth Circuit Court of Appeals affirmed the district court’s ruling that the individual mandate was unconstitutional, but it remanded the case back to the district court for further analysis of whether the mandate could be severed from the PPACA (i.e., whether the entire PPACA was therefore also unconstitutional). The Supreme Court of the United States granted certiorari on March 2, 2020, heard oral arguments on November 10, 2020, and on June 17, 2021, issued its opinion ruling that Texas and other states that initially challenged the individual mandate did not have standing. 70 Table of Contents During his tenure, President Trump also signed several Executive Orders, directives, and legislation affecting certain provisions of the PPACA. For example, effective January 1, 2019, the Bipartisan Budget Act of 2018, or the BBA, among other things, further amended portions of the Social Security Act implemented as part of the PPACA to increase from 50% to 70% the point-of-sale discount that pharmaceutical manufacturers who participate in the Medicare Part D Coverage Gap Discount Program must provide to eligible Medicare Part D beneficiaries during the coverage gap phase of the Part D benefit, commonly referred to as the “donut hole,” and to reduce standard beneficiary cost sharing in the coverage gap from 30% to 25% in most Medicare Part D plans. Additionally, on December 20, 2019, President Trump signed appropriations legislation for fiscal year 2020 that repealed the PPACA’s so-called “Cadillac” tax on certain high-cost employer-sponsored health insurance plans, for tax years beginning after December 31, 2019; the annual fee imposed on certain health insurance providers, for calendar years beginning after December 31, 2020; and the medical device excise tax on non-exempt medical devices, for sales after December 31, 2019. While the Biden administration has repealed or rolled-back certain of the actions taken by the Trump administration, in the future, there may be additional challenges and/or amendments to the PPACA. It remains to be seen precisely what any new legislation will provide, when or if it will be enacted, and what impact it will have on the availability and cost of healthcare items and services, including drug products. In addition, other legislative changes have been proposed and adopted since the PPACA was enacted. These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions to Medicare payments to providers of up to 2% per fiscal year effective April 1, 2013 and, due to subsequent legislation, will stay in effect through 2030 unless additional Congressional action is taken, with the exception of a temporary suspension of the payment reduction from May 1, 2020 through December 31, 2020 enacted as part of the CARES Act. Further, the American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments from providers from three to five years. These legislative changes may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used. Further, there has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed products in the United States. Congress is considering various legislative proposals to further increase transparency around prices and price increases, lower out-of-pocket costs for consumers, and decrease spending on prescription drugs by government programs. On September 13, 2020, President Trump issued an executive order directing the Secretary of Health and Human Services to pursue implementation of two new payment models under which Medicare would test whether paying no more than the “most-favored-nation” price for certain included drugs and biological products covered under Part B and Part D, respectively, would mitigate poor clinical outcomes and increased Medicare expenditures associated with high drug costs. If this executive order is implemented, the “most-favored-nation” price would generally reflect the lowest price, after certain adjustments, for a pharmaceutical product sold in an economically comparable member country of the Organisation for Economic Co-operation and Development. On December 28, 2020, the U.S. District Court for the Northern District of California issued a preliminary injunction halting implementation of the executive order nationwide pending completion of the notice and comment process, and on August 10, 2021, the CMS published a proposed rule that would rescind the “most-favored nation” pricing model for Medicare Part B drugs. However, the U.S. Congress continues to conduct inquiries into the prescription drug industry’s pricing practices, and at the state level in the United States, legislatures are also increasingly passing legislation and states are implementing regulations designed to control spending on, and patient out of pocket costs for, drug products. Recently, on August 16, 2022, President Biden signed into law the IRA, which included several measures intended to lower the cost of prescription drugs and limit out-of-pocket spending, including by requiring drug manufacturers to pay rebates to Medicare if they increase prices faster than inflation for drugs used by Medicare beneficiaries. We cannot be certain what impact, if any, such changes will have on the profitability of any of our drug candidates, if approved for commercial use in the future. At the state level, legislatures are increasingly passing legislation and states are implementing regulations designed to control spending on, and patient out-of-pocket costs for, drug products. Implementation of cost containment measures or other healthcare reforms that affect the pricing and/or availability of drug products may impact our ability to generate revenue, attain or maintain profitability, or commercialize products for which we may receive regulatory approval in the future. We expect that these, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and additional downward pressure on the price that we receive for any approved drug. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our drugs. Privacy and Information Security We may be subject to privacy and data security regulations and legal requirements in the United States and Europe. As we become more dependent on information technologies to conduct our operations, cyber incidents, including deliberate attacks and attempts to gain unauthorized access to computer systems and networks, may increase in frequency and sophistication. Our systems, servers and platforms and those of our service providers may be vulnerable to privacy and information security incidents such as data breaches, viruses or other malicious code, coordinated attacks, data loss, phishing attacks, ransomware, denial of service attacks, or other security or IT incidents caused by threat actors, technological vulnerabilities or human error. If we, or any of our vendors that support our IT or have access to our data, including any third-party vendors that collect, process and store personal data on our behalf, fail to comply with laws requiring the protection of personal information, or fail to safeguard and defend personal information or other critical data assets or IT systems, we may be subject to regulatory enforcement and fines as well as private civil actions. We may be required to expend significant resources in the 71 Table of Contents response, containment, mitigation of cybersecurity incidents as well as in defense against claims that our information security was unreasonable or otherwise violated applicable laws or contractual obligations. In the United States, numerous federal and state laws and regulations, including federal health information privacy laws, state data breach notification laws, state health information privacy laws and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure and protection of health-related and other personal information could apply to our operations or the operations of our collaborators. Domestic laws in this area are complex and developing rapidly. Many state legislatures have adopted legislation relating to privacy, data security and data breaches. Laws in all 50 states require businesses to provide notice to customers whose personally identifiable information has been disclosed as a result of a data breach. The laws are not consistent, and compliance in the event of a widespread data breach is costly. States are also frequently amending existing laws, requiring attention to frequently changing regulatory requirements. Additionally, the Federal Trade Commission, or FTC, and state attorneys general enforce consumer protection laws that prohibit unfair and deceptive acts and practices, including Section 5 of the FTC Act, which creates standards for the collection, use, dissemination and security of health-related and other personal information. Claims of unfair or deceptive trade practices regarding privacy and security can lead to significant liabilities and consequences, including regulatory investigations, penalties, fines and orders as well as civil claims, which could impact our data practices and operations or cause reputational damage. Further, HIPAA, as amended by the HITECH, and its implementing regulations, imposes requirements relating to the privacy, security and transmission of individually identifiable health information (also known as “protected health information”). Among other things, HITECH makes HIPAA’s security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity. HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts. It is important to note, however, that HIPAA and HITECH only apply directly to “covered entities” (healthcare providers, health insurance plans, and healthcare clearinghouses) and “business associates” (third parties providing services to covered entities). Pharvaris, as a private pharmaceutical company sponsoring clinical research, is itself neither a covered entity nor a business associate within the meaning of these laws and their associated regulations. With that in mind, in respect of HIPAA and HITECH, the risk to Pharvaris primarily lies in the potential lack of compliance by investigators and their service providers may result in the regulators invalidating the sharing of personal health information between investigators and Pharvaris. In other words, the failure of Pharvaris’s research partners to comply with these laws could lead to the exclusion of important data from Pharvaris studies. In addition, state laws in U.S. states, govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts. We also may be subject to privacy and data security requirements in Europe. Any clinical trial programs we conduct or research collaborations we enter into in the European Economic Area, or EEA, may subject us to European data protection laws, including the EU General Data Protection Regulation 2016/679, or GDPR. We are subject to the GDPR (as implemented by countries in the EEA), which applies extra-territorially and imposes onerous requirements on controllers (e.g., sponsors) and processors (e.g., CROs, laboratories, third-party vendors) of EEA personal data, including, for example: (i) accountability, transparency and accuracy requirements, and enhanced requirements for obtaining valid consent (separate and apart from informed medical consent); (ii) obligations to consider data protection as any new products or services are developed and to limit the amount of personal data processed; (iii) obligations to comply with data protection rights of data subjects; (iv) ensuring that all processors that process personal data on our behalf have adequate protections in place; and (v) reporting of personal data breaches to the supervisory authority without undue delay (and no later than 72 hours). The GDPR also prohibits the international transfer of personal data from the EEA to countries outside of the EEA unless made to a country deemed to have adequate data privacy laws by the European Commission or where a data transfer mechanism with appropriate safeguards has been put in place, such as the standard contractual clauses, or SCCs, and supplementary measures that provide privacy protections additional to those provided under SCCs. Further, the GDPR provides that countries in the EEA may establish their own laws and regulations further restricting the processing of certain personal data, including genetic data, biometric data, and health data. After assessing the severity and frequency of the EEA personal data processing activities we engage in, we appointed an external data protection officer that has expert knowledge of data protection law and practices and assists us with monitoring internal compliance with the GDPR. Failure to comply with the GDPR requirements could result in regulatory investigations, enforcement notices requiring us to stop or change the way we use personal data and/or fines of up to 20 million Euros or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, as well as compensation claims for financial or non-financial loss by affected individuals, negative publicity, reputational harm and a potential loss of business and goodwill. If our operations are found to be in violation of any of the data protection laws described above or any other laws that apply to us, we may be subject to penalties, including, but not limited to, criminal, civil and administrative penalties, damages, fines, disgorgement, individual imprisonment, possible exclusion from participation in government healthcare programs, injunctions, private qui tam actions 72 Table of Contents brought by individual whistleblowers in the name of the government, class action litigation and the curtailment or restructuring of our operations, as well as additional reporting obligations and oversight if we become subject to a corrective action plan or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect our ability to operate our business and our results of operations. The Foreign Corrupt Practices Act The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S. individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the Company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations. Additional Regulation In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, affect our business. These and other laws govern our use, handling and disposal of various biological, chemical and radioactive substances used in, and wastes generated by, our operations. If our operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines. We believe that we are in material compliance with applicable environmental laws and that continued compliance therewith will not have a material adverse effect on our business. We cannot predict, however, how changes in these laws may affect our future operations. European Union European Medicines Agency Marketing approvals under the European Union regulatory system may be obtained through a centralized or national marketing authorization procedures. The EMA and the European Commission administer the centralized authorization procedure. Pursuant to Regulation (EC) No. 726/2004 and Regulation (EC) 1394/2007, as amended, this procedure is compulsory for human medicines containing a new active substance to treat for which the therapeutic indication is the treatment of any of the following diseases: acquired immune deficiency syndrome, cancer, neurodegenerative disorders, diabetes, auto-immune diseases and other immune dysfunctions, viral diseases and all drugs that are designated as orphan drugs pursuant to Regulation (EC) No. 141/2000, as amended. Drugs for other indications may be granted a centralized authorization in accordance with Regulation (EC) No. 726/2004 if the drug contains a new active substance and is of a significant therapeutic, scientific or technical innovation or where the granting of authorization in accordance with Regulation (EC) No. 726/2004 is in the interests of patients or animal health at EU level. When a centralized authorization is granted, the authorization is automatically valid in all Member States of the European Union and by extension in the European Economic Area, or EEA, Norway, Iceland and Liechtenstein. According to Article 2 of Regulation (EC) No 726/2004, the marketing authorization holder must be established in the EEA. This means for the UK that as of the end of the transition period (end of 2020), a marketing authorization holder currently established in the UK has to have transferred its marketing authorization to a holder established in the EEA. The transfer of the marketing authorization must be fully completed and implemented by the marketing authorization holder before the end of the transition period. Also, any application for marketing authorizations must be made by applicants established in the EEA. Therefore, applications made by applicants established in the UK will need to change to an applicant established in the EEA. Under the centralized authorization procedure, the EMA’s Committee for Medicinal Products for Human Use, or CHMP, serves as the scientific committee that evaluates applications and renders opinions about the safety, efficacy and quality of human products on behalf of the EMA. The CHMP is composed of experts nominated by the Competent Authority of each European Union Member State, one of which is appointed to act as rapporteur for the coordination of the evaluation with the possible assistance of a further member acting as a co-rapporteur. The CHMP has 210 days to give its opinion to the EMA as to whether a marketing authorization should be granted. This period will be suspended until such time as the supplementary information requested by the CHMP has been provided by the applicant. Likewise, this time-limit will be suspended for the time allowed for the applicant to prepare oral or written explanations. The evaluation process is complex and involves extensive consultation with the Competent Authorities of the Member States of the European Union and a number of experts. It is possible to appeal the opinion within 15 days of receipt of the notification of the opinion. At the end of the re-examination, which lasts up to 60 active days, the CHMP adopts a final opinion. The European Commission usually takes its decision to grant a legally binding authorization within 67 days after obtaining the CHMP decision. A marketing authorization that has been granted in the European Union may be suspended or withdrawn if ongoing regulatory requirements are not met or if safety problems are identified. Among other things, marketing authorization holders are required to have risk management plans that use risk minimization strategies beyond product labeling to ensure that the benefits of certain prescription drugs outweigh their risks. 73 Table of Contents Accelerated Assessment Procedures When an application is submitted for a marketing authorization in the European Union in respect of drugs for human use which is of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure pursuant to Article 14 (9) of Regulation (EC) No. 726/2004, as amended. Based on the request, the justifications presented, and the recommendations of the rapporteurs, the CHMP will formulate a decision. Such a decision will be taken without prejudice to the CHMP opinion (positive or negative) on the granting of a marketing authorization. If the CHMP accepts the request, the timeframe for the evaluation will be reduced from the standard 210 days for the centralized procedure to 150 days, but it is possible that the CHMP can revert to the standard time limit for the centralized procedure if it considers that it is no longer appropriate to conduct an accelerated assessment. Conditional Marketing Authorization and Authorization under Exceptional Circumstances A conditional marketing authorization is valid for one year, can be renewed annually and may be requested by an applicant or proposed by the CHMP for medicinal products which aim at: •the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases; •medicinal products to be used in emergency situations in response to public health threats recognized either by the World Health Organization or by the European Union in the framework of Decision No. 1082/2013/EU (e.g. COVID-19 treatments); or •medicinal products designated as orphan medicinal products in accordance with Regulation (EC) No. 141/2000, as amended. A conditional marketing authorization may be requested by an applicant or proposed by the CHMP for medicinal products if all of the following requirements are met: •the risk-benefit balance of the medicinal product, as defined in Article 1(28a) of Directive 2001/83/EC, as amended, is positive; •it is likely that the applicant will be in a position to provide comprehensive clinical data; •unmet medical needs will be fulfilled (no existing satisfactory methods or the medicinal product provides major therapeutic advantage); and •the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required. The legal basis for a conditional marketing authorization is Article 14-a of Regulation (EC) No. 726/2004, as amended. The provisions for the granting of such an authorization are further elaborated in Regulation (EC) No. 507/2006. The holder will be required to complete ongoing studies or to conduct new studies within a specified period of time with a view to confirming that the benefit-risk balance is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data. In addition, authorization under exceptional circumstances may be requested when it is not possible to provide comprehensive data on the efficacy and safety under normal conditions of use, because: •the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence; •in the present state of scientific knowledge, comprehensive information cannot be provided; or •it would be contrary to generally accepted principles of medical ethics to collect such information. The legal basis for the marketing authorization under exceptional circumstances is Article 14 (8) of Regulation (EC) No. 726/2004, as amended, and the relevant documentation for applications in exceptional circumstances are laid down in Part II of Annex I of Directive 2001/83/EC, as amended. The authorization under exceptional circumstances is granted subject to a requirement for the applicant to meet certain conditions, in particular concerning the safety of the medicinal product, notification to the Competent Authorities of any incident relating to its use, and action to be taken. The renewal of the marketing authorization of a medicinal product under exceptional circumstances follows the same rules as a “normal” marketing authorization. After five years, the marketing authorization will then be renewed under exceptional circumstances for an unlimited period, unless the Competent Authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. Manufacturing and Manufacturers’ Authorization Directive 2003/94/EC, as amended, requires that the manufacturing of investigational medicinal products and approved drugs in the EEA is subject to a separate manufacturing authorization and must be conducted in strict compliance with GMP requirements, which mandate the methods, facilities, and controls used in manufacturing, processing, and packing of drugs to assure their safety and identity. Manufacturers must have at least one Qualified Person, or QP, permanently and continuously at their disposal. Although the ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the marketing authorization holder, the QP is responsible for ensuring that each batch of finished product released onto the market has been manufactured in accordance with GMP, in compliance with EU laws and the specifications set out in the marketing authorization or investigational medicinal product dossier. Certification can only be performed by a QP of the manufacturer and/or importer, which are described in the marketing 74 Table of Contents authorization. GMP requirements are enforced through mandatory registration of facilities and inspections of those facilities. Failure to comply with these requirements could interrupt supply and result in delays, unanticipated costs and lost revenues, and subject the applicant to potential legal or regulatory action, including but not limited to warning letters, suspension of manufacturing, seizure of product, injunctive action or possible civil and criminal penalties. Commercialization and Promotion The commercialization and promotion of authorized medicinal products, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs, are strictly regulated in the European Union, notably under, among others, Directive 2001/83/EC, as amended, guidance published by the European Commission and the EMA, laws, regulations and guidance set out by the Member States of the European Union and industry wide codes of conduct. The applicable regulatory framework aims to ensure that information provided by holders of marketing authorizations regarding their products is truthful, balanced and accurately reflects the safety and efficacy claims authorized by the EMA or by the Competent Authority of the authorizing Member State. Failure to comply with these requirements can result in adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Commercialization and promotion of prescription only medicinal products to consumers or patients (directly or indirectly) is strictly forbidden. Advertising of medicines pre-approval or off-label is also prohibited. Regulatory Data Protection and Market Exclusivity In the European Union, all new active substances approved on the basis of a complete independent data package benefit from an 8+2+1 -year data/market exclusivity regime. This regime consists of (i) a regulatory data protection period and market exclusivity period of eight years, (ii) a market exclusivity period of an additional two years after the eight-year period and (iii) an extended market exclusivity period of one year after the 10-year period if, during the first eight years of those 10 years, the marketing authorization holder obtains an approval for one or more new therapeutic indications which, during the scientific evaluation prior to their approval, are determined to bring a significant clinical benefit in comparison with existing therapies. Under the current rules, a third party may reference the nonclinical and clinical data of the original innovator beginning eight years after notification of the grant of the approval in the European Union, but the third party may market a generic version after only 10 or, where applicable, 11 years have lapsed from the notification of the grant of the approval. Orphan Designation Medicines that meet the criteria for orphan designation benefit from the incentive of 10 years of market exclusivity once they are approved for commercialization in the European Union. This protects them from market competition with similar medicines with the same indication once they are approved. Market exclusivity is awarded by the European Commission and is specifically linked to one specific orphan designation for which a marketing authorization has been granted. Each orphan designation carries the potential for one market exclusivity for a particular indication. A medicine that has several separate orphan designations for different indications can have several separate market exclusivities if these refer to separate designated conditions. A designated orphan medicinal product shall be removed from the European Union’s Community register of orphan medicinal products at the end of the period of market exclusivity. The period of market exclusivity is extended by two years for medicines that also have complied with an agreed pediatric investigational plan, or PIP. This period may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation, including among other things, if the product is sufficiently profitable so that market exclusivity is no longer justified. Notwithstanding the foregoing, a marketing authorization may be granted, for the same therapeutic indication, to a similar drug if: •the holder of the marketing authorization for the original orphan drug has given its consent to the second applicant; •the holder of the marketing authorization for the original orphan drug is unable to supply sufficient quantities of the drug; or •the second applicant can establish in the application that the second drug, although similar to the orphan drug already authorized, is safer, more effective or otherwise clinically superior. Regulation (EC) No 847/2000 lays down definitions of the concepts “similar drug” and “clinical superiority.” In order to be eligible for incentives made available by the European Union and by the Member States to support research into, and the development and availability of, orphan drugs, the medicinal product needs to be designated as an orphan drug pursuant to Regulation (EC)No. 141/2000, as amended. Regulation (EC) No. 141/2000, as amended, states that a medicinal product shall be designated as an orphan medicinal product if its manufacturer can establish: •that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10,000 persons in the European Union when the application is made or that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the European Union and 75 Table of Contents that without incentives it is unlikely that the commercialization of the medicinal product in the European Union would generate sufficient return to justify the necessary investment; and •that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the community or, if such method exists, the medicinal product will be of significant benefit to those affected by that condition. Small-or Medium-Sized Enterprise Status In the European Union, manufacturers may benefit from further incentives, including administrative and procedural assistance and fee reductions when they are classified as a small-or medium-sized enterprises, or SME. Within the SMEs, medium enterprises are defined as those which employ between 50 to 249 persons and which have an annual turnover not exceeding €50 million or an annual balance sheet total not exceeding €43 million; a small enterprise is defined as an enterprise which employs between 10 to 49 persons and whose annual turnover or annual balance sheet total does not exceed €10 million; and a microenterprise is defined as an enterprise which employs fewer than 10 persons and whose annual turnover or annual balance sheet total does not exceed €2 million. Administrative, regulatory and financial support is available to companies assigned the SME status by the EMA, including: •direct assistance by phone, email, teleconference or through briefing meetings on regulatory aspects of the pharmaceutical legislation; •fee exemptions and reductions for pre-and post-authorization regulatory procedures, including scientific advice, inspections and pharmaco-vigilance; •assistance with translations of product information into all official European Union languages; •inclusion in an online SME register, which is an important source of information on the EU-based SMEs involved in the manufacturing, development or marketing of medicines and promotes partnering and networking between the SMEs; •guidance on clinical data publication and a free redaction tool license; •liaison with academic investigators in pediatric-medicine research through the European Network of Pediatric Research at the EMA; and •workshops and training sessions. Development of Medicines for Children Several incentives for the development of medicines for children are available in the European Union: •medicines that have been authorized across the European Union with the results of PIP studies included in the product information are eligible for an extension of their patent protection by six months even when the studies’ results are negative; •for orphan medicines, the incentive is an additional two years of market exclusivity; •scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of medicines for children; and •medicines developed specifically for children that are already authorized but are not protected by a patent or supplementary protection certificate, can apply for a pediatric-use marketing authorization, or PUMA, which provides 10 years of market protection. Pediatric Regulation On January 26, 2007, the Pediatric Regulation (Regulation (EC) No. 1901/2006 and Regulation (EC) No. 1902/2006) came into force in the European Union. Its objective is to improve the health of children in the European Union by facilitating the development and availability of medicines for children from birth up to 18 years of age, ensuring that medicines for use in children are of high quality, ethically researched and authorized appropriately and improving the availability of information on the use of medicines for children. The aim is to achieve this without subjecting children to unnecessary trials or delaying the authorization of medicines for use in adults. The Pediatric Regulation established the Pediatric Committee, or PDCO, which is responsible for coordinating the EMA’s work on medicines for children. The Committee’s main role is to determine the studies that companies must carry out on children as part of PIPs. At least an approved PIP needs to be in place before applying for marketing authorization. The PDCO grants deferrals for some medicines, allowing a company to delay development of the medicine in children until there is enough information to demonstrate its effectiveness and safety in adults. The PDCO also grants waivers when development of a medicine in children is not needed or is not appropriate, such as for diseases that only affect the elderly population. When the approved PIP contains studies that need to be performed, the proposed study design and timelines need to be adhered to. 76 Table of Contents Pharmaceutical Coverage, Pricing and Reimbursement Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we obtain regulatory approval. Countries have different pricing and reimbursement schemes. In the European Union, the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend, in part, on the extent to which third-party payors provide coverage and establish adequate reimbursement levels for such products. In the European Union, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular product candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines but monitor and control company profits. Special pricing and reimbursement rules may apply to orphan drugs. Inclusion of orphan drugs in reimbursement systems tends to focus on the medical usefulness, need, quality and economic benefits to patients and the healthcare system as for any drug. The downward pressure on health care costs has become very intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country. In the United States, third-party payors include federal and state healthcare programs, private managed care providers, health insurers and other organizations. Even if our product candidates are approved, sales of our products will depend, in part, on the extent to which third-party payors provide coverage and establish adequate reimbursement levels for such products. The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price of a product or for establishing the reimbursement rate that such a payor will pay for the product. Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the FDA-approved products for a particular indication. Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of medical products, therapies and services, in addition to questioning their safety and efficacy. We may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our product candidates, in addition to the costs required to obtain the FDA approvals. Our product candidates may not be considered medically necessary or cost-effective. A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development. In addition, prices for drugs may be reduced by mandatory discounts or rebates required by federal health care programs (such as the Medicaid Drug Rebate Program and the 340B Drug Pricing Program) or discounts and rebates requested by private payors. In addition, any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States may also impact the pricing of drugs. It is difficult to predict how Medicare coverage and reimbursement policies will be applied to products for which the Company receives marketing approval in the future and coverage and reimbursement under different federal health care programs is not always consistent. Further, private payors often follow the coverage and reimbursement policies established under Medicare. If reimbursement is not available or is available only at limited levels, we may not be able to successfully commercialize our products for which we receive marketing approval. The containment of healthcare costs also has become a priority of federal, state and foreign governments and the prices of drugs have been a focus in this effort. Governments have shown significant interest in 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 a company’s revenue generated from the sale of any approved products. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future. The marketability of any product candidates for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care in the United States has increased and we expect will continue to increase the pressure on healthcare pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future. C.Organizational structure We were incorporated as a Dutch private company with limited liability (besloten vennootschap) and currently exist as a Dutch public company with limited liability (naamloze vennootschap) (after the conversion of our legal form in the first quarter of 2021), with operating subsidiaries in the Netherlands, Switzerland and the United States. 77 Table of Contents The following diagram illustrates our corporate structure: D.Property, plants and equipment We have offices in Leiden, the Netherlands, Lexington, Massachusetts (United States) and Zug, Switzerland. Our office space in Leiden measuring approximately 290 square meters is rented through November 30, 2025; our offices in Massachusetts measuring approximately 622 square meters is rented through December 31, 2029 and our office space in Zug measuring approximately 58 square meters is rented on a monthly basis.