Phathom Pharmaceuticals Inc

We are a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal, or GI, diseases. Our approved products, VOQUEZNA®, VOQUEZNA® TRIPLE PAK® and VOQUEZNA® DUAL PAK®, contain vonoprazan, an oral small molecule potassium-competitive acid blocker, or PCAB. PCABs are a novel class of medicines that block acid secretion in the stomach. Vonoprazan is the first gastric anti-secretory agent from a novel class approved in the United States, Europe, or Canada in over 30 years, and has shown rapid, potent, and durable anti-secretory effects. Vonoprazan has also demonstrated clinical benefits over the current standard of care as a single agent in the treatment of erosive gastroesophageal reflux disease, or Erosive GERD, and in combination with antibiotics for the treatment of Helicobacter pylori, or H. pylori, infection. Takeda Pharmaceutical Company Limited, or Takeda, developed vonoprazan and has received marketing approval in numerous countries in Asia and Latin America as well as Russia. Vonoprazan generated peak net sales of approximately $850 million and continues to achieve volume growth during its tenth full year on the market since its approval in 2014. In May 2019, we in-licensed the U.S., European, and Canadian rights to vonoprazan from Takeda.

In May 2022, the U.S. Food and Drug Administration, or FDA, approved the NDAs for vonoprazan triple therapy, under the brand name VOQUEZNA TRIPLE PAK, and vonoprazan dual therapy, under the brand name VOQUEZNA DUAL PAK. Subsequently, on November 1, 2023, the FDA approved vonoprazan, under the brand name VOQUEZNA, as a treatment for adults for the healing of all grades of Erosive GERD, maintenance of healing of all grades of Erosive GERD, and relief of heartburn associated with Erosive GERD, as well as in combination with amoxicillin, with or without clarithromycin, for the treatment of H. pylori infection in adults. We initiated commercial launch for VOQUEZNA for both the Erosive GERD and H. pylori indications, and VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK for treatment of H. pylori infection in the fourth quarter of 2023. In September 2023, we submitted an NDA seeking approval of vonoprazan as a once-daily treatment for heartburn symptoms associated with Non-Erosive GERD in adults. On July 17, 2024, the FDA approved VOQUEZNA 10 mg tablets for the relief of heartburn associated with Non-Erosive GERD, the largest category of GERD.

We are independently commercializing VOQUEZNA, VOQUEZNA TRIPLE PAK, and VOQUEZNA DUAL PAK in the United States. Our commercial launch continues to build momentum and early launch data shows strong physician and patient demand. As of February 21, 2025, over 300,000 prescriptions for VOQUEZNA tablets, VOQUEZNA Triple Pak, and VOQUEZNA Dual Pak have been filled since launch. These prescriptions were written by more than 20,000 prescribers. In addition, due to increasing commercial demand, we continue to make progress in securing broad commercial coverage for VOQUEZNA with over 120 million, or over 80%, of total U.S. commercial lives with access to VOQUEZNA tablets.

VOQUEZNA Commercial Launch Initiated in November 2023

We continue to evaluate potential commercial partnerships for vonoprazan in Europe and Canada, expand development of vonoprazan into other indications, dosing regimens and alternative formulations and packaging, and evaluate the in-license or acquisition of additional clinical or commercial stage product candidates for the treatment of GI diseases in a capital efficient manner.

In May 2021, the FDA granted qualified infectious disease product, or QIDP, designations for VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK and we thereby received an extension of five years of new chemical entity, or NCE, exclusivity based on the vonoprazan component in the applicable NDAs. We believe the extended NCE exclusivity should apply to any other approved or future products containing vonoprazan we develop and for which we obtain FDA approval. In December 2024, we submitted a citizen petition requesting that FDA update the Orange Book listings to reflect the same ten-year period of NCE exclusivity for

VOQUEZNA as reflected on the VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK Orange Book listings. For additional information, see the discussion in our risk factors related to non-patent regulatory exclusivity.

While we are initially focused on the commercialization of vonoprazan for the treatment of GERD and H. pylori infection, we believe there are opportunities to develop vonoprazan in other indications in our licensed territories. For example, we plan to expand the clinical development of vonoprazan in the U.S. into eosinophilic esophagitis, or EoE, the most common type of eosinophilic gastrointestinal disease. EoE is an autoimmune disease with significant unmet need and can result in trouble swallowing, chest pain, vomiting and impaction of food in the esophagus, a medical emergency. There are only two FDA-approved treatments for EoE. Although not approved for this indication, PPIs are often prescribed as a first-line therapy for the treatment of EoE. Given the limited choices of therapies for EoE and vonoprazan’s demonstrated potential, we believe EoE is an important indication for future study. We have obtained FDA feedback on the design of a Phase 2 study investigating VOQUEZNA as a potential treatment for EoE, in adults and adolescents, and plan to initiate the study in the first half of 2025.

GERD and H. pylori infection are two of the most common acid-related GI diseases and impact millions of people. The prevalence of GERD is estimated to be 20% of the U.S. population and 15% of the population in the five major countries in Europe (France, Germany, Italy, Spain and the United Kingdom), or collectively, the EU5. GERD is a disease that develops when the reflux of acidic stomach contents causes troublesome symptoms and/or complications. An estimated 20 million adults in the U.S. have Erosive GERD and more than twice that number, or an estimated 45 million adults, are believed to suffer from Non-Erosive GERD. H. pylori is a bacterial pathogen that infects approximately 35% of the U.S. population and 45% of the EU5 population. As a result of the chronic inflammation induced by H. pylori infection, approximately 20% of infected patients will develop a range of pathologies, including dyspepsia, peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue or MALT, lymphoma.

Over the last thirty years, the proton pump inhibitor, or PPI, class, has been the standard of care for the treatment of acid-related GI diseases. PPIs are generally used as a single agent for the treatment of GERD and in combination with antibiotics for the treatment of H. pylori infection. The PPI class includes drugs such as Prilosec (omeprazole), Nexium (esomeprazole), and Prevacid (lansoprazole). Prior to the introduction of generic and over-the-counter, or OTC, alternatives, annual PPI class sales reached approximately $12.5 billion in the United States, with peak sales for individual brands of approximately $3.7 billion for Prilosec, $3.5 billion for Nexium, and $3.4 billion for Prevacid.

While PPIs are the current standard of care and have experienced significant commercial success, they have significant limitations that result in a large unmet medical need. In GERD, PPI therapy is suboptimal for many patients due to the slow onset and insufficient duration of acid control which can lead to inadequate symptom relief. Less than 50% of patients are satisfied with their current treatment. In the treatment of H. pylori infection, the standard of care consists of a combination of a PPI and at least two oral antibiotics. However, increasing antibiotic resistance has resulted in declining eradication rates with PPI-based therapy. We believe these unmet medical needs are in part driven by limitations associated with the mechanism of action and pharmacokinetics of PPIs.

PPIs reduce gastric acid secretion by irreversibly binding to and inhibiting active proton pumps expressed on the parietal cells. Proton pumps of parietal cells become activated during a meal and thus, oral intake of PPIs prior to meal is required ideally to achieve maximal efficacy. PPIs also require activation by gastric acid, but they are unstable in the presence of acid and therefore enteric coating is necessary to protect them from degradation in the stomach when given orally. All these factors, combined with the short circulating half-life of PPIs, limits their efficacy. Additionally, because proton pumps continuously switch between active and inactive states, multiple doses of PPIs are required to inhibit enough proton pumps to achieve a clinical benefit. As a result, PPIs have a relatively slow onset of action and limited potency and duration of effect, which may result in patients experiencing only partial relief, increasing PPI dosage, and/or cycling through multiple PPIs seeking relief.

Vonoprazan has a differentiated mechanism of action from PPIs. Unlike PPIs, vonoprazan:

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is stable in the presence of acid;

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does not require activation by gastric acid;

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is designed to selectively concentrate in the parietal cells in both the resting and stimulated states, bind to the active pumps and remain associated with the active and inactive pumps;

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can be taken independent from meal intake;

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binds to the pumps in a noncovalent and reversible manner; and

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has a long plasma half-life that replenishes the drug at the site of action over the course of the day.

These factors have enabled vonoprazan to demonstrate more rapid and potent acid suppression versus the PPIs esomeprazole and lansoprazole in human subjects two to three hours after oral dosing and maintain target acid inhibition over a 24-hour period in randomized, open-label, crossover clinical trials. In contrast, PPIs require three to five days to reach steady state acid suppression and do not reliably maintain target acid inhibition over a 24-hour period. In addition, vonoprazan demonstrated approximately 10-to-100-fold better acid control compared to lansoprazole and esomeprazole.

Vonoprazan has demonstrated clinical advantages over the PPI lansoprazole in the treatment of Erosive GERD and H. pylori infection in completed Phase 3 clinical trials conducted in the United States and Europe, including:

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more complete healing of Erosive GERD in patients with moderate to severe disease after two weeks;

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more durable healing of Erosive GERD in patients with all grades of disease;

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higher H. pylori eradication rates in combination with antibiotics compared to standard of care triple therapy; and

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more flexible dosing, including dosing independent of food and time of day.

Moreover, we believe that vonoprazan’s anti-secretory mechanism has the potential to contribute to additional clinical advantages over PPIs such as rapid symptom relief through "as- needed" dosing in the treatment of patients with Non-Erosive GERD.

Erosive GERD. FDA approval of VOQUEZNA for the healing and maintenance of healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults was based on the results from PHALCON‑EE, our Phase 3 clinical trial conducted in the United States and Europe. This trial assessed vonoprazan versus lansoprazole in the healing and maintenance of healing of adult patients with Erosive GERD. In PHALCON-EE, vonoprazan met its primary healing endpoint demonstrating non-inferiority to lansoprazole in the number of patients who showed complete healing of Erosive GERD after eight weeks of treatment. Further, in a pre-specified secondary endpoint, vonoprazan demonstrated superior healing after two weeks of treatment in patients with moderate to severe Erosive GERD compared to lansoprazole. After two weeks of treatment, 70% of patients with moderate to severe Erosive GERD were healed after treatment with vonoprazan versus 53% with lansoprazole (p=0.0008). In the maintenance phase of the trial, both doses of vonoprazan (10 mg and 20 mg) met the primary endpoint of non-inferiority compared to lansoprazole in the number of all patients who maintained healing of Erosive GERD through week 24. Further, both vonoprazan doses also met a pre-specified secondary endpoint demonstrating superiority of maintenance of healing versus lansoprazole (79% for vonoprazan 10 mg, 81% for vonoprazan 20 mg compared to 72% for lansoprazole 15 mg) (p<0.0001 for both non-inferiority comparisons; p=0.0436 for vonoprazan 10 mg superiority comparison; p=0.0272 for vonoprazan 20 mg superiority comparison). Both vonoprazan doses also met the pre-specified secondary endpoint of demonstrating superiority of the percentage of patients with moderate-to-severe disease who maintained healing of Erosive GERD through week 24 (75% vonoprazan 10 mg, 77% vonoprazan 20 mg v. 61% lansoprazole 15 mg) (p=0.0490 for vonoprazan 10 mg superiority comparison; p=0.0196 for vonoprazan 20 mg superiority comparison).

In PHALCON-EE, vonoprazan 20 mg met the secondary endpoint of showing non-inferiority to lansoprazole 30 mg in the mean percentage of 24-hour heartburn free days over the healing period, and both vonoprazan doses met the secondary endpoint of showing non-inferiority to lansoprazole 15 mg in the mean percentage of 24-hour heartburn free days over the maintenance period. Finally, vonoprazan 20 mg was also compared to lansoprazole 30 mg in a superiority test for onset of sustained resolution of heartburn by day three of the healing phase but did not achieve statistical significance (p=0.2196).

Non-Erosive gastroesophageal reflux disease (Non-Erosive GERD). In PHALCON-NERD-301, a Phase 3 study evaluating the efficacy and safety of vonoprazan for the daily treatment of adults with Non-Erosive GERD, both doses of vonoprazan (10 mg and 20 mg) met the primary endpoint evaluating the mean percentage of 24-hour heartburn-free days through week four by demonstrating statistical significance versus placebo (mean 45% vonoprazan 10 mg, 44% vonoprazan 20 mg, compared to 28% for placebo; p<0.0001 for both vonoprazan 10 mg and 20 mg versus placebo). The median percentage of 24-hour heartburn-free days was 48%, 46% and 17% for vonoprazan 10 mg, vonoprazan 20 mg, and placebo, respectively. Patients randomized to vonoprazan 10 mg and 20 mg during the initial 4-week period remained on their blinded treatment assignment for a 20-week extension period. The mean percentage of heartburn free days reported over the 20-week extension period for these patients was 63% for vonoprazan 10 mg and 61% for vonoprazan 20 mg. Additionally, patients randomized to placebo during the initial 4-week period were re-randomized to either vonoprazan 10 mg or 20 mg for the 20-week extension period. For these patients, the mean percentage of heartburn free days reported over the 20-week extension period was 62% for vonoprazan 10 mg and 63% for vonoprazan 20 mg. Based on the results of PHALCON-NERD-301, on July 17, 2024, the FDA approved VOQUEZNA 10 mg tablets for the relief of heartburn associated with Non-Erosive GERD.

In PHALCON-NERD-201, a Phase 2 study evaluating three doses of vonoprazan (10 mg, 20 mg, and 40 mg) as an as needed therapy for relief of episodic heartburn in subjects with Non-Erosive GERD, all three vonoprazan doses successfully met the primary endpoint evaluating the percentage of heartburn episodes completely relieved within three hours with relief sustained for over 24 hours and were statistically significant (p<0.0001) when compared to placebo. Within three hours, vonoprazan 10 mg, 20 mg, and 40 mg achieved complete and sustained relief in 56%, 61% and 70% of evaluable heartburn episodes, respectively, as compared to 27% of episodes for placebo. An evaluable heartburn episode is a heartburn episode for which the participant completes a minimum of one timed assessment after taking study medication.

With our recent launch of VOQUEZNA for Non-Erosive GERD, we have begun generating real-world data which are being reviewed to understand consumer usage patterns and prescribing habits of healthcare providers. We believe these efforts will help assess the value and potential timing for advancing a Phase 3 program to evaluate the "as-needed" dosing of VOQUEZNA for active heartburn episodes, building on the positive results from our prior Phase 2 study.

H. pylori. The FDA’s approval of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK was based on the results from PHALCON-HP, our Phase 3 clinical trial in the United States and Europe studying two vonoprazan-based treatment regimens for the eradication of H. pylori infection, both of which successfully met their primary and all secondary endpoints. The trial studied vonoprazan triple therapy and vonoprazan dual therapy compared to lansoprazole in combination with amoxicillin and clarithromycin, or lansoprazole triple therapy. The objective of the PHALCON-HP trial was to compare eradication rates in all treated subjects as well as in two pre-identified subgroups of patients: those patients with clarithromycin resistant strains of H. pylori, and those patients who did not have clarithromycin or amoxicillin resistant strains of H. pylori. For regulatory purposes, the primary endpoint of this study was a non-inferiority comparison in the non-resistant subgroup for each of vonoprazan triple therapy and vonoprazan dual therapy compared to lansoprazole triple therapy.

In PHALCON-HP, both vonoprazan-based regimens successfully met their primary endpoints. In the modified intent-to-treat, or mITT, population, H. pylori eradication rates were 84.7% for vonoprazan triple therapy and 78.5% for vonoprazan dual therapy compared to 78.8% with lansoprazole triple therapy (p<0.0001 and p=0.0073, respectively, for non-inferiority). In the pre-specified per protocol population, a subset of the mITT population comprised of patients who were protocol compliant, H. pylori eradication rates were 90.4% with vonoprazan triple therapy and 81.2% with vonoprazan dual therapy compared to 82.1% with lansoprazole triple therapy (p<0.0001 and p=0.0155, respectively, for non-inferiority).

In PHALCON-HP vonoprazan triple therapy and vonoprazan dual therapy also met all secondary endpoints, demonstrating superior eradication rates versus lansoprazole triple therapy in all patients and in the subgroup of patients with clarithromycin resistant strains of H. pylori. Among all patients, the H. pylori eradication rate of vonoprazan triple therapy was superior to that of lansoprazole triple therapy in both the mITT population (80.8% vs. 68.5%; p=0.0001) and the per protocol population (85.7% vs. 70.0%; p<0.0001). In the subset of patients with H. pylori strains resistant to clarithromycin, the H. pylori eradication rate with vonoprazan triple therapy was superior to that of lansoprazole triple therapy in both the mITT population (65.8% vs. 31.9%; p<0.0001) and the per protocol population (67.2% vs. 29.0%; p<0.0001).

Among all patients, the H. pylori eradication rate of vonoprazan dual therapy was superior to that of lansoprazole triple therapy in both the mITT population (77.2% vs. 68.5%; p=0.0127) and the per protocol population (81.1% vs. 70.0%; p=0.0027). The H. pylori eradication rate of vonoprazan dual therapy was also superior to that of lansoprazole triple therapy in the subset of patients with H. pylori strains resistant to clarithromycin in both the mITT population (69.6% vs. 31.9%; p<0.0001) and the per protocol population (79.5% vs. 29.0%; p<0.0001).

Our Management

Our management team has deep expertise in developing and commercializing therapeutics, including anti-secretory agents, and direct experience developing vonoprazan at Takeda. Our Chief Executive Officer, Terrie Curran, has more than 25 years of experience in the biopharmaceutical industry. Ms. Curran served as President, Global Inflammation and Immunology (I&I) Franchise and as a member of the Executive Committee at Celgene Corporation from 2017 to 2019. Ms. Curran joined Celgene in 2013 as the

U.S. Commercial Head of the I&I Franchise, where she built the capabilities and recruited the teams that executed the successful launch of OTEZLA, which was sold to Amgen in November 2019 for $13.4 billion. Molly Henderson, our Chief Financial and Business Officer, has over 20 years of extensive financial experience in the biopharmaceutical industry. Ms. Henderson previously held the role of Chief Financial Officer at various companies such as UroGen Pharma and Iovance Biotherapeutics, Inc. where she oversaw all aspects of the corporate finance strategy, investor relations and capital raising. Martin Gilligan, our Chief Commercial Officer, has more than 30 years in the industry working at both large and small biopharmaceutical companies. His commercial experience includes launching specialty and primary care products, both in the U.S. and globally. Prior to joining Phathom, Mr. Gilligan worked at Celgene Corporation, and was Corporate Vice President in the I&I Franchise, responsible for marketing, market access, early product development, and business development. Azmi Nabulsi, M.D., M.P.H., our Chief Operating Officer, was Deputy Chief Medical and Scientific Officer at Takeda. Our Chief Development Sciences Officer, Tom Harris, was Senior Vice President and Head of Global Regulatory at Takeda. Both Dr. Nabulsi and Mr. Harris were extensively involved with the development of vonoprazan at Takeda and continue to lead our ongoing development efforts for VOQUEZNA.

Our Pipeline

The following chart summarizes our current development programs:

Our Strategy

Our mission is to improve the lives of people suffering from GI diseases. Our strategy is focused on continuing our commercial efforts of approved VOQUEZNA products and further developing vonoprazan as a first-in-class PCAB in the United States for the treatment of acid-related GI diseases. Key elements of this strategy include:

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Continue our efforts to ensure the successful commercialization of VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in the U.S. We have built a first-class commercial infrastructure including a national sales force to support the commercial launch of VOQUEZNA for treatment of Erosive GERD and H. pylori infection, and VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK for treatment of H. pylori infection, which commenced in the fourth quarter of 2023. Further, on July 17, 2024, the FDA approved VOQUEZNA 10 mg tablets for the relief of heartburn associated with Non-Erosive GERD and we launched vonoprazan in the U.S. for daily treatment of heartburn associated with Non-Erosive GERD in the third quarter of 2024. Our successful commercialization of these products in the United States includes a focused sales force targeting prescribers of treatments for GERD and H. pylori infection, particularly gastroenterologists and primary care physicians. Through our national sales force we are currently targeting approximately 52,000 core high volume PPI prescribers who, on average, have written close to 1,200 PPI prescriptions annually. We believe we have an opportunity to achieve significant share of voice and exposure to physicians given the scarcity of actively marketed anti-secretory medicines. Given the limitations of PPIs and current unmet need, we believe the commercial opportunity for VOQUEZNA is substantial. Moreover, we believe all our U.S. approved products containing vonoprazan, including VOQUEZNA, should benefit from the 10-year period of non-patent NCE exclusivity that commenced upon approval of our initial products for H. pylori infection in May 2022.

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Further expand the development of vonoprazan across indications, including EoE, and alternative formulations and packaging. We plan to pursue vonoprazan lifecycle extension strategies in areas with clear unmet need, clinical rationale, and commercial justification. For example, we have obtained FDA feedback on the design of a Phase 2 study investigating VOQUEZNA as a potential treatment for EoE, in adults and adolescents, and plan to initiate the study in the first half of 2025. Additionally, we believe that vonoprazan has the ideal profile for an OTC product because of the potential for rapid symptom relief and a well-tolerated safety profile. We plan to explore the economics and potential development in this market to determine the best strategy going forward. Potential indications for development in addition to EoE may include treatment of gastric and duodenal ulcers, and Barrett’s esophagus; and alternative formulations and packaging include orally disintegrating tablets and other oral dosage forms for patients with difficulty swallowing, and an intravenous formulation for in-hospital applications. We are also evaluating further development of vonoprazan as an “as needed” treatment of Non-Erosive GERD. With our recent launch of VOQUEZNA for Non-Erosive GERD, we have begun generating real-world data which are being reviewed to understand consumer usage patterns and prescribing habits of healthcare providers. These insights will help assess the value and potential timing for advancing a Phase 3 program to validate the "as needed" dosing of VOQUEZNA for active heartburn episodes.

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Evaluate commercial partnerships to maximize the vonoprazan opportunity outside of the United States. To address the opportunity for vonoprazan in Europe and Canada, we continue to evaluate potential partners with existing commercial infrastructure and expertise in these markets. We believe this strategy could allow us to realize the value of the market opportunity in Europe and Canada while focusing our resources on the U.S. market.

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In-license or acquisition of additional clinical or commercial stage product candidates for the treatment of GI diseases in a capital efficient manner. We plan to evaluate and to take advantage of our management team’s GI expertise to opportunistically in-license or acquire additional innovative therapies for diseases treated by gastroenterologists. We plan to leverage our development and commercial infrastructure to support multiple assets targeting GI indications.

Acid-Related GI Diseases

Gastric acid is a digestive fluid formed in the stomach. The highly acidic environment of the stomach causes the unfolding, or denaturing, of food proteins that are subsequently broken down by gastric enzymes. Gastric acid is secreted by the hydrogen potassium ATPase enzyme, which is known as the proton pump. Proton pumps are expressed on the channeled surfaces, or canaliculi, of parietal cells in the stomach, which secrete acid. Proton pumps are continuously synthesized and switch between active and inactive states in response to various stimuli, such as food. When activated, proton pumps increase acid secretion.

GI diseases where treatment is related to acid control, such as GERD, peptic ulcer disease, Zollinger Ellison syndrome, and H. pylori infection, are significant medical problems because of their high prevalence, chronic nature and clinical sequelae. GERD results from the effects of acid on compromised mucosal defenses in the gastrointestinal tract. The reflux of gastric acid into the esophagus produces frequent and/or severe heartburn, indigestion, and reflux symptoms. Chronic GERD may damage esophageal tissue and progress to more severe diseases including Erosive GERD, Barrett’s esophagus, and esophageal cancer. GERD and related diseases are associated with impaired quality of life and substantial costs to the healthcare system given their chronic nature and sequelae. In H. pylori infection, gastric acid limits the effectiveness of antibiotics used to eradicate infection. Chronic H. pylori infection can lead to dyspepsia, peptic ulcer disease, gastric cancer, and MALT lymphoma.

Prevalence

The prevalence of GI diseases is high. Approximately 20% of the U.S. population and 15% of EU5 population report chronic heartburn or regurgitation symptoms potentially related to GERD. We estimate that there are approximately 65 million individuals in the United States and 50 million individuals in the EU5 with GERD. In the United States, GERD is the most common gastroenterology-related outpatient diagnosis. Additionally, approximately 35% of the U.S. population and 45% of the EU5 population are infected with H. pylori. We estimate that there are approximately 115 million individuals in the United States and 145 million individuals in the EU5 infected with H. pylori.

Prevalence of GERD and H. pylori Infection

Treatments

Treatments of acid-related GI diseases aim to provide relief of acute symptoms, healing of damaged tissue, and prevention of long-term clinical sequelae associated with chronic acid exposure. Gastric acidity is measured by the pH scale, a logarithmic scale where 7.0 describes a neutral state and lower levels indicate a higher level of acidity. The pH of the stomach typically ranges from 1.5 to 3.5. In patients with acid-related GI diseases, increasing gastric pH has been shown to improve mucosal healing rates and provide more rapid symptom relief for patients. For example, the duration of time that intra-gastric acidity is greater than pH 3.0 correlates with the healing of duodenal and gastric ulcers, and pH greater than 4.0 is correlated with the healing of Erosive GERD. Similarly, in patients with H. pylori infection, a more neutral gastric pH of 6.0 to 8.0 preserves antibiotic function and is optimal for successful eradication.

Drug-induced gastric acid suppression is a key component of the management of acid-related GI diseases prior to the launch of VOQUEZNA. Three classes of drugs with distinct mechanisms of action were principally used for treatment in the United States and Europe: antacids, histamine receptor antagonists, or H2RAs, and PPIs.

Antacids

Antacids, first commercially available in the 1930s, directly neutralize gastric acid to raise intra-gastric pH and can alleviate intermittent, mild symptoms of acid-related GI diseases, such as heartburn, but they are only effective for a short duration and require frequent administrations per day. In addition, antacids do not significantly help heal or prevent complications of acid-related diseases. Antacids include commonly known OTC products, such as Alka-Seltzer, Pepto-Bismol, Rolaids, and TUMS.

Histamine Receptor Antagonists (H2RAs)

H2RAs, first commercially available in the 1970s, decrease gastric acid secretion in order to raise gastric pH. H2RAs represented a dramatic improvement over antacids in the control of gastric acid and consequently in the management of acid-related GI diseases. H2RAs are also generally safe and well-tolerated. Among the H2RA class were the first commercial blockbuster drugs, Pepcid (famotidine), Tagamet (cimetidine), and Zantac (ranitidine). Zantac was the world’s highest-selling prescription drug in the mid-1990s, with peak global sales of $3.7 billion and U.S. sales of $2.2 billion. Prior to the launch of generic H2RAs and increasing competition from PPIs, the H2RA class achieved sales of approximately $3.5 billion in the United States. H2RAs achieved commercial success despite clinical limitations, including unreliable 24-hour acid control, poor control of post-meal symptoms, and loss of efficacy over time.

Proton Pump Inhibitors (PPIs)

PPIs, first commercially available in 1989, offered improved acid control over H2RAs. Pharmacodynamic data demonstrated that PPIs maintain gastric pH above target levels for a longer duration than H2RAs. A commonly used benchmark of anti-secretory activity is the percentage of time in a 24-hour period that gastric pH exceeds 4.0, which we refer to as time above pH 4.0, which ranges from 40% to 71% for PPIs versus 33% for H2RAs.

Given this improved pharmacodynamic profile, PPIs demonstrated improved clinical symptom relief and healing over H2RAs. In a meta-analysis of results from 33 randomized clinical trials with over 3,000 GERD patients, a reduction in symptoms was achieved in 83% of patients taking PPIs versus 60% of those on H2RAs. In a second meta-analysis, the eight-week healing rate in patients with Erosive GERD was 82% for PPIs versus 52% for H2RAs.

The PPI class is currently the first-line treatment of acid-related GI diseases. Prior to the introduction and adoption of generic and OTC alternatives, annual PPI class sales reached approximately $12.5 billion in the United States, with peak sales for individual brands of approximately $3.7 billion for Prilosec, $3.5 billion for Nexium, and $3.4 billion for Prevacid. As recently as 2015, the last branded PPI, Dexilant (dexlansoprazole), reached approximately $530 million in sales in the United States despite limited differentiation from other PPIs. While Dexilant demonstrated a modest improvement in time above pH 4.0 compared to other PPIs, the approved dose did not demonstrate consistent superiority in Phase 3 trials against other PPIs for the healing of Erosive GERD and has not been tested against PPIs in other indications. We believe that the commercial success of Dexilant highlights the value to physicians and patients of even incremental improvements over other PPIs.

History of Pharmaceutical Agents for Control of Gastric Acid

PPI Limitations

While PPIs provide clinically meaningful symptom relief and healing for millions of patients suffering from acid-related GI diseases, they are inadequate for many patients. The suboptimal anti-secretory profile of PPIs results in slow onset of symptom relief, breakthrough nighttime or postprandial heartburn, and treatment failure. A recent population-based survey with over 70,000 participants in the United States showed that 55% of patients who reported having GERD symptoms were taking PPIs, with 68% taking them daily, and 54% of those daily PPI users reporting persistent symptoms. This is consistent with earlier studies that have shown that approximately 15% to 45% of GERD patients are inadequately treated with PPIs, experiencing persistent, troublesome symptoms, such as heartburn and regurgitation. In approximately two-thirds of symptomatic GERD patients, reflux symptoms are not adequately controlled after the first dose of a PPI, and nearly 50% of patients still suffer from symptoms three days later. Given these limitations, more than 20% of GERD patients on PPI therapy take their PPI twice daily, which is not FDA approved, or purchase OTC heartburn treatments in addition to their prescription medicine. In a survey of approximately 1,000 GERD patients and 1,000 physicians, approximately one third of GERD patients reported persistent symptoms and were dissatisfied with PPI therapy and 35% of physicians perceived patients as somewhat satisfied to completely dissatisfied with PPI treatment. In addition, in a real world study conducted in 2020 and 2021 evaluating the perspectives and unmet needs of over 400 physicians and patients in the U.S. in the management of acid related disorders, fewer than one-third of the physician participants were satisfied with current treatment options for their patients. Moreover, fewer than 50% of patients in the study reported they were satisfied with their current treatment.

In patients with more severe grades of Erosive GERD, studies with PPIs have reported failure rates of healing of esophageal erosions exceeding 25%. Additionally, recurrence of erosions is common in healed Erosive GERD patients receiving maintenance PPI therapy. One study reported recurrence in 15% to 23% of patients with less severe Erosive GERD and 24% to 41% of patients with more severe Erosive GERD. We believe that these limitations of PPIs are in part driven by their mechanism of action and pharmacokinetics.

As a result of these PPI limitations, real world data shows that up to 50% of GERD patients treated with a prescription PPI make therapy changes during their treatment journey. Real world data has also identified that 35% of patients treated with a prescription PPI switch to a different PPI after approximately 3 months.

Mechanistic Differences Between PPIs and Vonoprazan

PPIs

After oral dosing, PPIs reach the gastric parietal cells through the bloodstream. PPIs are prodrugs that are converted to their active form in the acidic environment of the secretory canaliculus of the parietal cell but degrade quickly because their active form is unstable in acid. For example, the half-life of omeprazole (Prilosec) is less than 10 minutes at pH 2.0. The active form of a PPI blocks acid production by covalently binding to active proton pumps that have moved to the surface of the secretory canaliculi after activation of the parietal cell with stimuli, such as a meal. Because PPIs bind only to actively secreting pumps, it is generally recommended that they be administered 30 to 60 minutes before a meal to achieve maximal efficacy. Once covalently bound to the proton pumps, the active PPI molecule is no longer available to bind to newly synthesized or activated proton pumps. Furthermore, given the relatively short plasma half-life of most PPIs of one to two hours, resupply of additional PPI molecules from the bloodstream is limited, and newly activated pumps are not inhibited. Due to this profile, PPIs must be dosed over several days to inhibit enough proton pumps to increase gastric pH to a clinically meaningful threshold. Moreover, PPIs have a limited window of efficacy leading to incomplete acid suppression over the 24-hour dosing interval. In addition, PPIs are primarily metabolized by CYP2C19, an enzyme which has significant interpatient metabolic variability based on genotype. As a result, PPI exposure levels in some patients may not achieve target levels, potentially reducing clinical efficacy.

Vonoprazan

Vonoprazan, a PCAB, has a differentiated mechanism of action relative to PPIs. Vonoprazan is designed to selectively concentrate in the parietal cell in both the resting and stimulated states. In contrast to most PPIs, vonoprazan does not require gastric acid for activation, remains stable in the presence of gastric acid, binds to the active proton pumps in a noncovalent and reversible manner, can be taken independent from meals and remains associated with the active and inactive proton pumps, and remains in the secretory canaliculus where it continues to inhibit acid secretion over an extended period. Vonoprazan’s prolonged effect is also maintained through a slow dissociation rate from the proton pumps and resupply from the bloodstream due to its approximate seven-hour half-life. These characteristics generally allow vonoprazan to rapidly achieve target 24-hour acid suppression within two to three hours of a single dose, unlike PPIs that require three to five days to achieve stable acid suppression. In addition, vonoprazan is primarily metabolized by CYP3A4/5, an enzyme which has less genetic variability than CYP2C19, and may exhibit more consistent activity than PPIs across U.S. and European populations.

The mechanistic and pharmacologic differences of PPIs and vonoprazan are summarized in the table below:

Vonoprazan Pharmacodynamics vs. PPIs

Vonoprazan’s more rapid, potent, and durable anti-secretory effects versus the PPI lansoprazole (Prevacid) were demonstrated in a randomized, open-label, crossover clinical trial comparing 20 mg of once daily, or QD, vonoprazan to 30 mg QD of lansoprazole for 7 days in 41 healthy volunteers. As shown below, vonoprazan had a significantly higher 24-hour holding time ratio than lansoprazole for pH>4.0 on Day 1 (62.4% vs. 22.6%) and Day 7 (87.8% vs. 42.3%) and for pH>6.0 on Day 1 (33.1 vs. 7.4) and Day 7 (62.5% vs. 16.4%). Mean 24-hour intragastric pH for vonoprazan and lansoprazole was 4.6 and 2.8, respectively, on Day 1, and 5.9 and 3.8, respectively, on Day 7. Gastric pH levels are measured on a logarithmic scale from 0.0 to 14.0, in which each point represents a 10-fold change in acidity and higher pH values represent less acidity. In this study, vonoprazan maintained an average pH approximately two points higher than lansoprazole at Day 7.

Improved Onset and Potency of pH Control of Vonoprazan vs. Lansoprazole at Day 1 and Day 7

This improved potency and duration of pH control with vonoprazan, as measured by 24-hour pH hold time and time above pH 4.0, was evident not only at Day 1, but also at Day 7 when lansoprazole had reached its steady state (see table below).

24-hr Hold Time > pH 4.0 and Mean pH of Vonoprazan vs. Lansoprazole at Day 1 and Day 7

Vonoprazan demonstrated similarly greater time above pH 4.0 versus the PPI esomeprazole (Nexium) in a randomized, open-label, crossover clinical trial comparing 20 mg QD vonoprazan to 20 mg QD of esomeprazole in 20 healthy volunteers. In that trial, greater duration of pH control with vonoprazan, as measured by time above pH 4.0 was observed both on Day 1 and Day 7 (see table below).

24-hr Hold Time > pH 4.0 of Vonoprazan vs. Esomeprazole at Day 1 and Day 7

Vonoprazan for the Treatment of Acid-Related GI Diseases

Given the shortcomings of PPI therapy, we believe that there is a significant unmet medical need for a safe and effective anti-secretory agent with rapid, potent, and durable anti-secretary effects. In May 2022, we received FDA approval for VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK, each for the treatment of H. pylori infection in adults. In November 2023, we received FDA approval of vonoprazan, under the brand name VOQUEZNA, for the healing and maintenance of healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults, and in September 2023, we submitted an NDA seeking approval of vonoprazan as a once-daily treatment of heartburn associated with Non-Erosive GERD in adults. On July 17, 2024, the FDA approved VOQUEZNA 10 mg tablets for the relief of heartburn associated with Non-Erosive GERD, the largest category of GERD. Before we developed and obtained our initial approvals for VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in the United States, vonoprazan was developed in markets outside of the United States by Takeda through an extensive clinical program, including 19 Phase 3 clinical trials. An estimate of over 60 million patients have received vonoprazan in Japan and other countries in Asia, Latin America and Russia since its launch. Vonoprazan received marketing approval in Japan in late 2014 and generated peak net sales of approximately $850 million and continues to achieve volume growth during its tenth full year on the market.

Vonoprazan in GERD

Based on the significant unmet medical need, previous Phase 3 trial results from Japan and elsewhere in Asia, and commercial potential, we prioritized the development and commercialization of vonoprazan in GERD, specifically for:

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the healing of all grades of Erosive GERD and relief of associated heartburn in adults;

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the maintenance of healing of all grades of Erosive GERD and relief of associated heartburn in adults; and

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the relief of heartburn associated with Non-Erosive GERD in adults.

GERD Disease Overview

GERD is one of the most prevalent diseases of any kind and is the most prevalent GI disease, affecting approximately 20% of the U.S. population and approximately 15% of the European population. We estimate there are approximately 65 million individuals with GERD in the United States and 50 million individuals with GERD in the EU5. GERD is a disease that develops when the reflux of acidic stomach contents into the esophagus causes troublesome symptoms and/or complications. The term covers a spectrum of diseases, the main categories of which are Erosive GERD, or EE, and Non-Erosive reflux disease, or Non-Erosive GERD. These diseases are detailed below:

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Erosive GERD: Approximately 30% of GERD patients have Erosive GERD, which is classified by erosions in the esophageal mucosa caused by acidic reflux of stomach contents into the esophagus. Erosive GERD is commonly graded by the Los Angeles (LA) classification system, which characterizes the extent of erosions in the esophagus and is graded on a scale of increasing severity from A to D, with D being the most severe. Approximately 20% to 30% of Erosive GERD patients have moderate-to-severe disease with LA grade C or D erosions. Erosive GERD can have serious consequences. If left untreated, esophagitis may develop into peptic stricture, Barrett’s esophagus or esophageal cancer.

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Non-Erosive gastroesophageal reflux disease (Non-Erosive GERD): Approximately 70% of GERD patients have Non-Erosive GERD, classified by abnormal gastric acid exposure in the esophagus and persistent symptoms without the presence of esophageal damage.

GERD patients typically present with heartburn and reflux symptoms. Based on these symptoms, patients are typically treated first-line with PPIs prior to a diagnostic endoscopy for specific disease classification of Erosive GERD or Non-Erosive GERD. Clinical guidelines suggest that endoscopy be performed in patients who continue to have symptoms despite an eight-week course of daily PPIs or have alarm symptoms, including GI bleeding, anemia, weight loss, chest pain, or difficult or painful swallowing. Our market research suggests that most patients are treated empirically based on symptoms rather than based on endoscopic characterization of disease.

GERD Treatment Paradigm

PPIs are currently the most widely used anti-secretory agents available in the United States and Europe for relieving GERD symptoms and healing erosions in gastric mucosa. Our market research suggests that approximately 80% of patients who are pharmacologically treated receive a PPI, and approximately 85% of PPI use is prescription rather than OTC. The majority of PPI use is chronic, with more than 70% of patients prescribed PPIs for daily use. According to IQVIA prescription data, approximately 110 million PPI prescriptions are written and filled annually across all indications.

There are few treatment options for GERD patients who are inadequately managed on PPI therapy. In a real world study conducted in 2020 and 2021 evaluating the perspectives and unmet needs of over 400 physicians and patients in the U.S. in the management of acid related disorders, only half of physicians reported that their patients are getting long-lasting relief from a PPI resulting in approximately 25% of patients taking a PPI more than once a day despite patients’ concerns about long term side effects of PPI use. A limited number of patients proceed to a surgical procedure, such as Nissen fundoplication. However, this procedure results in postoperative morbidity of 5% to 20%, as well as a two-to six-week recovery period and a median hospital stay of two days.

Our U.S. market research survey reported that 55% to 60% of physicians included in the survey believed that vonoprazan has demonstrated superior efficacy in the healing and maintenance of healed esophageal erosions compared to existing Erosive GERD treatments, provides faster onset of action compared to existing GERD treatments, and has superior duration and magnitude of gastric pH control compared to existing GERD treatments.

Clinical Data for Vonoprazan in GERD

Our Development Program in Erosive GERD

Five Phase 3 clinical trials have been completed comparing vonoprazan to PPIs in Erosive GERD: our healing and maintenance of healing trial in the United States and Europe; a healing trial in Japan; a maintenance of healing trial in Japan; a healing trial in Asia (China, Taiwan, and Korea); and a maintenance of healing trial in Asia. In addition to these Phase 3 trials, several published investigator-sponsored studies have compared vonoprazan to PPIs across dosing regimens and endpoints. Results of these clinical trials are summarized below.

Healing and Maintenance of Healing of Erosive GERD in the United States and Europe (PHALCON-EE)

In October 2021, we announced that vonoprazan successfully met its primary endpoints and key secondary superiority endpoints in PHALCON-EE, our pivotal Phase 3 trial evaluating vonoprazan versus lansoprazole for the treatment of Erosive GERD.

PHALCON-EE was a randomized, double-blind, two-phase, multicenter, Phase 3 trial that enrolled 1,024 patients with EE in the U.S. and Europe. PHALCON-EE was modeled after the successful Phase 3 clinical trials conducted in Japan and Asia with limited differences, including the combination of the healing and maintenance phases into one single study whereas in Japan and Asia separate clinical trials were conducted for each of these indications.

The first phase of the trial, the Healing Phase, evaluated the efficacy and safety of vonoprazan 20 mg QD compared to lansoprazole 30 mg QD for the healing of Erosive GERD for up to eight weeks. In the Healing Phase, patients were assessed via endoscopy to determine complete healing following 2 weeks of treatment and, if complete healing was not achieved, a second endoscopy occurred at 8 weeks of treatment. Patients who achieved complete healing were re-randomized into the second phase of the trial, the Maintenance Phase, where vonoprazan 10 mg and 20 mg were compared to lansoprazole 15 mg to assess maintenance of healing of Erosive GERD via endoscopy following 24 weeks of treatment. Heartburn symptom relief was assessed via secondary endpoints in both the Healing and Maintenance Phases of the study based on twice daily e-diary data collection.

Healing Phase

The primary endpoint analysis of the Healing Phase was non-inferiority of vonoprazan 20 mg compared to lansoprazole 30 mg in the percentage of all patients who have complete healing of Erosive GERD by Week 8. Vonoprazan met the non-inferiority criteria for the primary comparison with a healing rate of 93% compared to 85% for lansoprazole (p<0.0001). Based on a prespecified exploratory comparison test, the difference in healing rates in all patients between vonoprazan and lansoprazole was also significant (nominal p<0.0001). Non-inferiority analyses are conducted to evaluate whether the effect of an agent is not worse than the active control by more than a specified margin, while superiority analyses are conducted to evaluate whether an agent outperformed a comparator by a statistically significant margin.

Vonoprazan met the secondary superiority endpoint of healing in patients with moderate-to-severe disease, defined as patients with esophageal erosions classified as Grades C or D by the Los Angeles (LA) Classification System, at Week 2, demonstrating significantly faster healing than lansoprazole (70% for vonoprazan 20 mg and 53% for lansoprazole 30 mg) (p=0.0008). Vonoprazan also met the secondary endpoint of showing non-inferiority to lansoprazole 30 mg in the mean percentage of 24-hour heartburn free days over the healing period. In additional pre-specified secondary endpoint superiority comparisons, vonoprazan 20 mg healing rates were numerically greater than lansoprazole 30 mg in all patients at Week 2 (nominal p=0.0348) and in moderate-to-severe patients by Week 8 (nominal p<0.0001), although these superiority comparisons were not tested in the pre-specified testing hierarchy.

Vonoprazan 20 mg was also compared to lansoprazole 30 mg in a superiority test for onset of sustained resolution of heartburn by day 3 but did not achieve statistical significance (p=0.439).

Results of US/EU Phase 3 Clinical Trial in the Healing of Erosive GERD

Maintenance Phase

Vonoprazan met the primary and all secondary endpoints in the Maintenance Phase. The primary endpoint of the Maintenance Phase was non-inferiority of vonoprazan 10 mg and 20 mg compared to lansoprazole 15 mg in the percentage of all patients who maintained healing of Erosive GERD through Week 24.

Both vonoprazan doses met the Maintenance Phase primary endpoint of non-inferiority while also meeting the pre-specified secondary comparison demonstrating superiority of maintenance of healing versus lansoprazole (79% for vonoprazan 10 mg, 81% for vonoprazan 20 mg compared to 72% for lansoprazole 15 mg) (p<0.0001 for both non-inferiority comparisons; p=0.0438 for vonoprazan 10 mg superiority comparison; p=0.0136 for vonoprazan 20 mg superiority comparison).

Both vonoprazan doses also met the secondary endpoint of demonstrating superiority of the percentage of patients with moderate-to-severe disease who maintained healing of Erosive GERD through Week 24 (75% vonoprazan 10 mg, 77% vonoprazan 20 mg v. 61% lansoprazole 15 mg) (p=0.0490 for vonoprazan 10 mg superiority comparison; p=0.0196 for vonoprazan 20 mg superiority comparison). Additionally, both vonoprazan doses also met the secondary endpoint of showing non-inferiority to lansoprazole 15 mg in the mean percentage of 24-hour heartburn free days over the maintenance period.

Results of US/EU Phase 3 Clinical Trial in Maintenance of Healing of Erosive GERD

Healing and Maintenance of Healing of Erosive GERD Clinical Trials in Japan and Asia

The results of PHALCON-EE were consistent with the results of earlier Phase 3 trials of vonoprazan in healing and maintenance of healing of Erosive GERD after which it was modeled. These trials were conducted in Japan as well as other countries in Asia.

In two Phase 3 trials in healing of Erosive GERD comparing vonoprazan 20 mg QD to lansoprazole 30 mg QD for up to eight weeks, one conducted in Japan and the other in several countries in Asia, vonoprazan achieved the primary endpoint of non-inferiority versus lansoprazole on the percent of patients with healed Erosive GERD up to Week 8. Exploratory testing suggested higher healing rates for vonoprazan versus lansoprazole in the moderate to severe patients at Week 2 in both studies.

Similarly, in two Phase 3 trials in maintenance of healing of Erosive GERD comparing two doses of vonoprazan (10 mg and 20 mg QD) to lansoprazole 15 mg QD for 24 weeks, one conducted in Japan and the other in several countries in Asia, both vonoprazan doses achieved the primary endpoint of non-inferiority versus lansoprazole on the percent of patients with recurrence of Erosive GERD during the 24-week maintenance period. In both studies, exploratory testing suggested higher maintenance of healing rates for both vonoprazan doses versus lansoprazole in all patients and in the moderate to severe patients.

Our Development Program in Non-Erosive Gastroesophageal Reflux Disease (Non-Erosive GERD)

In July 2024, the FDA approved VOQUEZNA for the relief of heartburn associated with Non-Erosive GERD, the largest category of GERD. Non-Erosive GERD patients do not have esophageal erosions that require chronic treatment to prevent recurrence of erosions and their potential sequelae. Moreover, we believe the rapid onset of acid control of vonoprazan may enable as-needed use for the management of heartburn in Non-Erosive GERD patients as an alternative to chronic daily treatment.

Daily Dosing of Vonoprazan for the Treatment of Heartburn Associated with Non-Erosive GERD (PHALCON-NERD-301)

In January 2023, we reported positive topline data from the primary endpoint in PHALCON-NERD-301, our Phase 3 study evaluating the safety and efficacy of vonoprazan 10 mg and 20 mg as a daily dosing (QD) treatment, as compared to placebo (QD), in the relief of heartburn over four weeks in adult participants with Non-Erosive reflux disease, or Non-Erosive GERD. In this trial, patients in each vonoprazan treatment group, 10 mg and 20 mg, had a significantly higher mean percentage of 24-hour heartburn-free days (without daytime or nighttime heartburn as assessed by daily diary) compared to placebo after four weeks. This is the same endpoint used in other Phase 3 trials for PPIs that are approved in the U.S. for the treatment of Non-Erosive GERD.

PHALCON-NERD-301 also included a blinded 20-week long-term extension period to further evaluate the safety and efficacy of both doses of vonoprazan after six months of continuous use. A total of 772 patients with Non-Erosive GERD were enrolled, randomized and dosed in the multisite U.S. trial.

Design of PHALCON-NERD-301 Phase 3 Non-Erosive Daily Dosing Clinical Trial

Primary Endpoint of Phase 3 Clinical Trial in the Treatment of Non-Erosive GERD

The primary endpoint of the study, measured during the four-week, double-blind, placebo-controlled period, is the mean percentage of 24-hour heartburn free days. The topline results from the study showed both doses of vonoprazan, 20 mg and 10 mg, met the primary endpoint and demonstrated a significantly greater mean percentage of 24-hour heartburn-free days versus placebo (45% vonoprazan 10 mg, 44% vonoprazan 20 mg, 28% for placebo; p<0.0001 for both vonoprazan doses versus placebo). Additionally, the median percentage of 24-hour heartburn-free days was 48%, 46% and 17% for vonoprazan 10 mg, vonoprazan 20 mg, and placebo, respectively.

Vonoprazan was generally well tolerated in the initial four week double-blind, placebo-controlled phase of the trial. The overall adverse events for all vonoprazan arms were comparable to placebo and consistent with what was reported in previous studies. The most commonly reported adverse event was nausea (2.3% vonoprazan 10 mg, 3.1% vonoprazan 20 mg, 0.4% placebo) with no other events reported above 3.0% in either vonoprazan dose arm.

Results of Phase 3 Clinical Trial in the Treatment of Non-Erosive GERD

During the 20-week extension period, patients randomized to vonoprazan 10 mg and 20 mg during the initial 4-week period remained on their blinded treatment assignment. The mean percentage of heartburn free days reported over the 20-week extension period for these patients was 63% for vonoprazan 10 mg and 61% for vonoprazan 20 mg. Additionally, patients who were randomized to placebo during the initial 4-week period were re-randomized to either vonoprazan 10 mg or 20 mg for the 20-week extension period. For these patients, the mean percentage of heartburn free days reported over the 20-week extension period was 62% for vonoprazan 10 mg and 63% for vonoprazan 20 mg. The graph below shows the percentage of subjects without heartburn over the entire 24-week course of the study in the intent-to-treat subject set, which represents subjects who received at least one dose of study medication during randomized treatment.

Vonoprazan was generally well tolerated in the 20-week extension period. The most common adverse events reported for the two vonoprazan doses during that period were upper respiratory tract infection, sinusitis, influenza, urinary tract infection, nasopharyngitis, nausea, and gastroenteritis, each reported at or below 5%.

As Needed Dosing of Vonoprazan for the Treatment of Non-Erosive GERD

In February 2022, we announced that vonoprazan (10 mg, 20 mg and 40 mg), successfully met the primary endpoint in PHALCON-NERD-201, a Phase 2 trial evaluating three doses of vonoprazan versus placebo as an as needed treatment of Non-Erosive GERD.

PHALCON-NERD-201 was a Phase 2, randomized, double-blind, multicenter study that enrolled 458 subjects in the U.S. to evaluate the efficacy and safety of vonoprazan 10 mg, 20 mg, and 40 mg administered as needed for relief of episodic heartburn compared to placebo in subjects with Non-Erosive GERD (as confirmed by endoscopy). After an initial four-week vonoprazan 20 mg QD dose open-label run-in period, two hundred and seven subjects without a heartburn episode during the last 7 days of the run-in period and who also met drug and diary compliance requirements were randomized to receive vonoprazan 10 mg, 20 mg, 40 mg or placebo as needed for six weeks. Subjects completed an electronic diary to assess presence and severity of heartburn symptoms and use of rescue antacid (if needed).

In this Phase 2 proof-of-concept trial, the primary endpoint was the percentage of heartburn episodes completely relieved within three hours and with no further heartburn reported for 24 hours after taking study drug. All three vonoprazan doses met this primary endpoint and were statistically significant (p<0.0001) when compared to placebo. Within three hours, vonoprazan 10 mg, 20 mg and 40 mg achieved complete and sustained relief in 56.0%, 60.6% and 70.0% of evaluable heartburn episodes, respectively, as compared to 27.3% of episodes for placebo.

During the PHALCON-NERD open-label daily dosing run-in phase, where all enrolled participants received vonoprazan 20 mg QD for four weeks, the mean percentage of 24-hour heartburn free days observed was 65.4% (median 76.0%).

With our recent launch of VOQUEZNA for Non-Erosive GERD, we have begun generating real-world data which is being reviewed to understand consumer usage patterns and prescribing habits of healthcare providers. We believe these efforts will help assess the value and potential timing for advancing a Phase 3 program to evaluate the as needed dosing of VOQUEZNA for active heartburn episodes, building on the positive results from our prior Phase 2 study.

Results of Phase 2 Non-Erosive GERD As Needed Dosing Trial

Vonoprazan in Combination with Antibiotics for the Treatment of H. pylori Infection

Disease Burden and Outcomes

H. pylori is a bacterial pathogen that infects approximately 35% of the U.S. population, 45% of the EU5 population, and more than 50% of the global population. We estimate that there are approximately 115 million individuals in the United States and 145 million individuals in the EU5 infected with H. pylori, and we believe there are approximately 2.5 million patients treated for H. pylori infection in the United States each year. As a result of the chronic inflammation induced by H. pylori infection, approximately 20% of infected patients develop a range of pathologies including dyspepsia, peptic ulcer disease, gastric cancer, and MALT lymphoma. Gastric cancer is the third most common cause of cancer-related death worldwide, and over 80% of gastric cancers are attributed to H. pylori infection. Globally there are more than one million new cases of gastric cancer and approximately 782,000 deaths each year. Eradication of H. pylori infection has been proven to reduce the incidence of gastric cancer, and the American College of Gastroenterologists, or ACG, guidelines recommend treatment for all patients diagnosed with H. pylori infection.

Following the 2015 launch of vonoprazan in Japan not only did H. pylori eradication rates increase, vonoprazan-containing regimens rapidly became the most common first line treatment. One-year post launch, approximately 80% of all treated H. pylori-infected patients received vonoprazan-based regimens. In the study of H. pylori-infected patients, vonoprazan-based regimens overtook PPI-based regimens as the most common first-line treatment between 2015 and 2019. Within this Japanese database, the number of patients using vonoprazan-based regimens increased from 6,594 to 28,956 patients, while the number of patients using a PPI-based regimen decreased from 11,238 to 2,629, shown in the figure below.

Uptake of Vonoprazan-Based vs. PPI-Based Therapy for First Line Treatment of H. pylori Infection in Japan from 2015-2019

This same real-world study utilizing Japanese claims data also suggests that improved eradication rates have the potential to result in significant reductions of H. pylori-related healthcare costs and healthcare resource utilization. The results of this study showed that vonoprazan was associated with lower healthcare costs and healthcare resource utilization than PPI-based therapy for the treatment of H. pylori infection in Japan. Specifically, during the 12 months following initiation of treatment for H. pylori infection, all-cause healthcare costs and healthcare resource utilization were significantly lower for patients treated with vonoprazan-based triple therapy compared to a PPI-based triple therapy.

Given the clinical and post-marketing experience in the Japanese market, we believe that vonoprazan-based treatment regimens have the potential not only to restore eradication rates to their 1990s rates in the United States and Europe but also to significantly reduce H. pylori-related healthcare costs and healthcare resource utilization.

Current Treatment Paradigm in the United States and Europe

The ACG recently updated its clinical practice guideline to inform the evidence-based management of patients with H. pylori infection in North America. ACG noted that substantial changes were made to these updated guidelines based on increasing rates of resistance to key antibiotics used to treat H. pylori and new research on novel antibiotics and potassium-competitive acid blockers, or PCABs. As such the use of PCABs have been incorporated into these guidelines. In treatment naive patients, dual therapy with a PCAB and amoxicillin is suggested (moderate quality evidence) for empiric, first-line treatment. In patients with unknown clarithromycin susceptibility, PCAB-clarithromycin triple therapy is suggested over PPI-clarithromycin triple therapy (moderate quality evidence). Although PCAB based therapy is not specifically mentioned as a recommendation for treatment- experienced patients with H. pylori infection, the guidelines emphasize that it can be considered in certain patients with persistent H. pylori infection. Dual PCAB therapy may be considered in patients with no penicillin allergy and with unknown antibiotic susceptibility when optimized bismuth quadruple therapy or rifabutin triple therapy is not an option or in patients with known clarithromycin or levofloxacin resistance. Triple PCAB therapy may be considered in patients with confirmed clarithromycin sensitivity.

The use of anti-secretory agents enhances the effect of antibiotics in two ways. First, anti-secretory agents increase gastric pH, which in turn increases the stability of the antibiotics. For example, amoxicillin and clarithromycin are chemically unstable at the low pH typically found in the human stomach. Second, several antibiotics, including amoxicillin and clarithromycin, are most potent against H. pylori at the time of maximum bacterial replication, which occurs at pH 6.0 to 8.0. H. pylori is in a dormant state at lower pH values, which reduces the effectiveness of the antibiotics.

The table below shows the minimum inhibitory concentration of antibiotic required to eradicate 90% of H. pylori in vitro, or MIC90. As pH increases, the amount of antibiotic required for 90% eradication decreases substantially.

H. pylori MIC 90 Values as a Function of pH

A triple therapy regimen (PPI, clarithromycin, and either amoxicillin or metronidazole) is the regimen most commonly used in clinical practice for the first-line treatment of H. pylori infection. However, H. pylori eradication rates with PPI triple therapy in the 1990s have fallen to current levels of <80%, primarily due to increased resistance of H. pylori to clarithromycin and metronidazole. A recent meta-analysis indicates that U.S. resistance rates measured from 2012 to 2016 were 20% for clarithromycin, 29% for metronidazole, and 19% for levofloxacin. Additionally, in a U.S.-based study from 2021, 65.6% of tested H. pylori was resistant to at least one antibiotic currently used for treatment, with resistance rates of 33% for clarithromycin and approximately 30% for metronidazole and levofloxacin. These figures represent a marked increase from 2009 to 2011 for both clarithromycin and metronidazole, for which resistance was 9% for clarithromycin, 21% for metronidazole, and 11% for levofloxacin. H. pylori resistance to amoxicillin remains low despite its use in most triple therapy regimens; resistance is generally <2% among isolates in the United States and Europe. There is a similar trend of increasing resistance to key antibiotics in Europe.

Given the declining eradication rates for H. pylori, bismuth quadruple therapy is recommended as first-line treatment; however, our U.S. market research study reported that physicians prescribe quadruple therapy to only 17% of first-line patients. Due predominantly to considerations of convenience and patient compliance, approximately 75% of physicians surveyed in our market research expressed a preference for convenience, or combination packs compared to individual bottles for both dual and triple therapy. Further, geographic patterns of resistance in the United States are poorly understood and treatment is largely empiric, with susceptibility testing rarely conducted prior to first-line treatment. Our U.S. market research study reported that only 8% and 16% of physicians conduct resistance testing prior to prescribing treatment for first-line and second-line H. pylori infection, respectively.

In our U.S. market research study, physicians highlighted the need for more effective and simpler first-line treatment options. For the treatment of H. pylori infection, surveyed physicians highlighted the need for improved eradication rates and more convenient dosing as key unmet needs. In fact, on average, 53% and 52% reported a preference to use vonoprazan first line in patients with H. pylori infection, and in patients with refractory H. pylori infection, respectively.

Our H. pylori Phase 3 Clinical Trial in the United States and Europe – PHALCON-HP

In April 2021, we announced that in PHALCON-HP, our pivotal Phase 3 clinical trial for the eradication of H. pylori infection, both vonoprazan-based regimens successfully met their primary endpoints and met all secondary endpoints. The trial studied vonoprazan triple therapy and vonoprazan dual therapy compared to lansoprazole triple therapy. We believe PHALCON-HP was the largest U.S. Phase 3 registration trial ever conducted in H. pylori infection, randomizing 992 patients with confirmed H. pylori infection.

PHALCON-HP was a randomized, multicenter, Phase 3 trial that enrolled 1,046 patients of which 992 patients with a confirmed H. pylori infection were randomized to one of three arms:

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vonoprazan dual therapy: vonoprazan 20 mg BID and amoxicillin 1 g TID for 14 days (n=324);

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vonoprazan triple therapy: vonoprazan 20 mg BID, amoxicillin 1000 mg BID and clarithromycin 500 mg BID for 14 days (n=338); and

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PPI triple therapy: lansoprazole 30 mg BID, amoxicillin 1000 mg BID and clarithromycin 500 mg BID for 14 days (n=330).

The objective of the PHALCON-HP trial was to compare eradication rates in all treated subjects as well as in two pre-identified subgroups of patients: those patients with clarithromycin resistant strains of H. pylori, and those patients who did not have clarithromycin or amoxicillin resistant strains of H. pylori. For regulatory purposes, the primary endpoint of this study was a non-inferiority comparison in the non-resistant subgroup for each of vonoprazan triple therapy and vonoprazan dual therapy compared to lansoprazole triple therapy. All endpoints measured the percentage of patients with successful eradication of H. pylori infection as assessed by 13 C-urea breath test four weeks after completion of treatment. The primary analysis in the non-resistant population assessed the non-inferiority of vonoprazan dual therapy compared to lansoprazole triple therapy and vonoprazan triple therapy compared to lansoprazole triple therapy. Secondary analyses for superiority were conducted in all patients and in the subgroup of patients with clarithromycin-resistant H. pylori infection. Further efficacy analyses were conducted using the pre-specified per protocol population (n=822), which is comprised of patients who were protocol compliant as defined by FDA established criteria.

Primary endpoint analysis

Both vonoprazan-based regimens successfully met their primary endpoints in the subset of patients with H. pylori strains that were not shown to be resistant to clarithromycin or amoxicillin. In the mITT population, H. pylori eradication rates were 84.7% with vonoprazan triple therapy and 78.5% for vonoprazan dual therapy compared to 78.8% with lansoprazole triple therapy (p<0.0001 and p=0.0073, respectively, for non-inferiority).

In the per protocol population, H. pylori eradication rates were 90.4% with vonoprazan triple therapy and 81.2% with vonoprazan dual therapy compared to 82.1% with lansoprazole triple therapy (p<0.0001 and p=0.0155, respectively, for non-inferiority).

Secondary endpoint analysis

Vonoprazan triple therapy and vonoprazan dual therapy also met all secondary endpoints, and demonstrated superior eradication rates versus lansoprazole triple therapy in all patients and patients with clarithromycin resistant strains of H. pylori. Patients with clarithromycin resistant strains comprised 20.3% of the PHALCON-HP study population.

Vonoprazan triple therapy

The H. pylori eradication rate of vonoprazan triple therapy was superior to that of lansoprazole triple therapy among all patients in both the mITT population (80.8% vs. 68.5%; p=0.0003) and the per protocol population (85.7% vs. 70.0%; p<0.0001).

The H. pylori eradication rate of vonoprazan triple therapy was superior to that of lansoprazole triple therapy in the subset of patients with H. pylori strains resistant to clarithromycin in both the mITT population (65.8% vs. 31.9%; p<0.0001) and the per protocol population (67.2% vs. 29.0%; p<0.0001).

Vonoprazan dual therapy

The H. pylori eradication rate of vonoprazan dual therapy was superior to that of lansoprazole triple therapy among all patients in both the mITT population (77.2% vs. 68.5%; p=0.0127) and the per protocol population (81.1% vs. 70.0%; p=0.0027).

The H. pylori eradication rate of vonoprazan dual therapy was superior to that of lansoprazole triple therapy in the subset of patients with H. pylori strains resistant to clarithromycin in both the mITT population (69.6% vs. 31.9%; p<0.0001) and the per protocol population (79.5% vs. 29.0%; p<0.0001).

Results of US/EU Phase 3 Clinical Trial in H. pylori Infection

Primary Endpoint Analysis –Subjects without clarithromycin or amoxicillin resistant strains

Secondary Endpoint Analyses – All subject and subjects with clarithromycin resistant strains

Antibiotic resistance and declining eradication rates are significant clinical issues, and we believe that vonoprazan triple therapy and vonoprazan dual therapy have the potential to provide improvements over PPI-based therapies in addressing each of these issues. Vonoprazan dual therapy also has potential to spare the use of clarithromycin, representing an opportunity both for effective treatment and sound antibiotic stewardship through the avoidance of an additional antibiotic. As an alternative to multi-antibiotic drug regimens, vonoprazan dual therapy might also help to limit the spread of resistance among other pathogenic bacteria within populations. In addition, vonoprazan triple therapy and vonoprazan dual therapy will both be available in daily dosing blister cards inclusive of the appropriate antibiotic. We believe this convenience pack has the potential to enhance compliance in a category where full adherence to treatment regimen is often a challenge.

Convenience Packs for H. pylori

In December 2023, we launched VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK products which became available at retail pharmacies in the United States.

Convenience packs have the potential to improve patient adherence and treatment outcomes, and we believe there is a meaningful market opportunity for such a product. In the United States, PrevPac was formerly marketed as a pre-packaged convenience pack of lansoprazole, clarithromycin, and amoxicillin and achieved peak sales of $150 million. In Japan, vonoprazan is marketed both as a stand-alone medicine as well as in pre-packaged convenience packs with either clarithromycin and amoxicillin (Vonosap) or metronidazole and amoxicillin (Vonopion).

Summary of Vonoprazan Safety Data

Safety in Clinical Studies

As of December 2024, approximately 9,400 subjects have been exposed to vonoprazan in completed and ongoing Phase 1 to 3 clinical trials. The doses studied have ranged from 1 to 120 mg with durations up to one year.

In PHALCON-HP, both vonoprazan-based regimens were generally well tolerated with safety results comparable to patients who received lansoprazole triple therapy. The most common adverse events (≥2.0%) reported in the vonoprazan triple therapy, vonoprazan dual therapy, and lansoprazole triple therapy arms, respectively, were diarrhea (4.0%, 5.2%, and 9.6%), dysgeusia (4.3%, 0.6%, and 6.1%), abdominal pain (2.3%, 2.6% and 2.9%), headache (2.6%, 1.4%, 1.4%), vulvovaginal candidiasis (2.3%, 1.4%, 1.2%), hypertension (2.0%, 1.1%, 0.9%), and nasopharyngitis (0.3%, 2.0%, 0.9%). Overall rates of discontinuation due to adverse events were 2.3% for vonoprazan triple therapy-treated patients, 0.9% for vonoprazan dual therapy-treated patients, and 1.2% for lansoprazole triple therapy-treated patients.

Additionally, the safety results for vonoprazan observed in PHALCON-EE were consistent with the results observed in prior clinical studies. In the healing phase of the study, the most common adverse events (≥2%) were abdominal pain (2.1% for vonoprazan and 1.2% for lansoprazole), diarrhea (2.1% for vonoprazan and 2.5% for lansoprazole). Rates of discontinuation due to adverse events in the healing phase were 1% for vonoprazan 20 mg and 2.2% for lansoprazole 30 mg.

In the maintenance phase of the study, the most common adverse events (≥2%) were gastritis (2.7% vonoprazan 10 mg, 6.4% vonoprazan 20 mg, 2.7% lansoprazole), diarrhea (1.0% vonoprazan 10 mg, 2.7% vonoprazan 20 mg, 4.4% lansoprazole), abdominal pain (4.1% vonoprazan 10 mg, 5.4% vonoprazan 20 mg, 2.4% lansoprazole), dyspepsia (3.7% vonoprazan 10 mg, 4.1% vonoprazan 20 mg, 2.7% lansoprazole), gastroesophageal reflux disease (2.4% vonoprazan 10 mg, 3.7% vonoprazan 20 mg, 2.0 lansoprazole), hypertension (3.0% vonoprazan 10 mg, 3.4% vonoprazan 20 mg, 2.0% lansoprazole), liver function test (1.0% vonoprazan 10 mg, 2.0% vonoprazan 20 mg, 3.0% lansoprazole), and nausea (2.0% vonoprazan 10 mg, 1.4% vonoprazan 20 mg, 1.0% lansoprazole).

Rates of discontinuation due to adverse events in the maintenance phase were 0.7% for vonoprazan 10 mg, 2.7% for vonoprazan 20 mg, and 0.7% for lansoprazole.

Frequency of serious adverse events, or SAEs, in the healing phase were similar between vonoprazan 20 mg and lansoprazole at 0.6%. In the maintenance phase, SAEs were reported in 4.7% of patients for vonoprazan 20 mg, 3.4% for vonoprazan 10 mg and 2.4% for lansoprazole. Further, this clinical trial was conducted during the 2020-2021 global pandemic, and coronavirus infection was reported in 2.1% of the vonoprazan 20 mg-treated patients and 1.8% of the lansoprazole-treated patients in the healing phase whereas it was reported in 6.1% of the vonoprazan 10 mg-treated patients, 10.1% of the vonoprazan 20 mg-treated patients and 6.7% of the lansoprazole-treated patients in the maintenance phase. There were 2 deaths in the vonoprazan 20 mg-treated patients due to coronavirus infection. None of the coronavirus infection events reported were considered related by the investigator.

In PHALCON-NERD-301, vonoprazan was generally well tolerated in the initial four-week double-blind, placebo-controlled phase of the trial. The overall adverse events for all vonoprazan arms were comparable to placebo and consistent with what was reported in previous studies. The most commonly reported adverse event was nausea (2.3% vonoprazan 10 mg, 3.1% vonoprazan 20 mg, 0.4% placebo) with no other events reported above 3.0% in either vonoprazan dose arm. There was a total of three SAEs reported in the four-week period of the study, one in the vonoprazan 10 mg arm and two in the vonoprazan 20 mg arm. The most common adverse events reported for the two vonoprazan doses during the 20-week extension period were upper respiratory tract infection, sinusitis, influenza, urinary tract infection, nasopharyngitis, nausea, and gastroenteritis, reported at or below 5%.

In PHALCON-NERD-201, vonoprazan was generally well tolerated. In both phases of the trial, no adverse event was reported in more than three percent of the participants in a treatment group. There was a total of four SAEs in the daily dosing phase, only one of which was related to study drug, and no SAEs in the as needed phase. The safety data for all vonoprazan arms were comparable to placebo and consistent with what was reported in previous studies.

We also conducted a Phase 1, open-label study (VONO-401) to evaluate the pharmacokinetics, or PK, of vonoprazan in the breast milk of healthy lactating women following 20 mg once-daily or twice-daily regimens. The study enrolled women who had been breastfeeding or pumping for at least 4 weeks postpartum and temporarily discontinued breastfeeding during the treatment period. PK assessments demonstrated that the excretion of vonoprazan into breast milk was negligible, with less than 0.03% of the administered dose excreted and less than 0.3% of the weight-adjusted maternal dose potentially consumed by infants. Safety evaluations indicated that vonoprazan was well tolerated, with no significant safety concerns identified. These results suggest limited infant exposure to vonoprazan through breast milk.

Certain earlier generation PCABs previously under development by other companies may have been discontinued in-part due to their hepatic safety profile. These hepatic safety concerns may be compound-specific and not generalizable to the PCAB class. It is notable that vonoprazan is based on a pyrrole chemical structure and is chemically distinct from previously discontinued PCABs that were based on an imidazole structure. Vonoprazan has had a similar hepatic safety profile to lansoprazole across all clinical studies conducted by Takeda, in which 1.0% of subjects treated with vonoprazan 10 mg or 20 mg and 0.8% of subjects treated with lansoprazole 15 mg or 30 mg had alanine transaminase or ALT or aspartate transaminase or AST elevations greater than three times the upper limit of normal or bilirubin elevations greater than two times the upper limit of normal. Similarly, in the healing phase of PHALCON-EE, transient elevations in ALT or AST greater than 3 times the upper limit of normal were observed in 0.4% of subjects treated with vonoprazan 20 mg and 0.2% of subjects treated with lansoprazole. In the maintenance phase, transient ALT or AST elevations greater than three times the upper limit of normal were observed in 1% of subjects treated with vonoprazan 10 mg, 0.3% of subjects treated with vonoprazan 20 mg, and 2% of subjects treated with lansoprazole.

Vonoprazan Post-Marketing Safety in Japan and Asia

The most recent post-marketing safety report from December 2023 includes a worldwide cumulative estimate of over 60 million patients who have received vonoprazan since its approval in late 2014. Based on the post-marketing experience, the clinically significant adverse reactions section of the Japanese prescribing information for vonoprazan was updated to include shock, anaphylaxis, hepatic impairment, skin reactions such as toxic epidermal necrolysis, Steven-Johnson syndrome, and erythema multiforme; and events of pancytopenia, agranulocytosis, leukocytopenia, and thrombocytopenia. The incidence of these reactions was considered extremely rare (less than 1 in 100,000 patients) and a causal relationship to vonoprazan could not be ruled out. Although serious hepatic adverse events have been observed among patients exposed to vonoprazan in Japan in the post-marketing setting, these cases were typically confounded by comorbidities or other concomitant medications and believed to be idiosyncratic reactions. Post-marketing safety data, including the December 2023 post-marketing safety report, has been submitted to the Pharmaceuticals and Medical Devices Agency. Moreover, the final results from the VISION trial, a five-year randomized, open-label, multicenter study conducted by Takeda evaluating the long-term efficacy and safety of vonoprazan compared with the PPI lansoprazole in patients with EE, further demonstrate that the safety profile of vonoprazan is generally comparable to lansoprazole.

Vonoprazan Launch in Japan

Vonoprazan Regulatory Status

Vonoprazan first received approval in Japan on December 26, 2014, and was launched shortly thereafter in February 2015, as TAKECAB® for the following indications:

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Healing and maintenance of healing of erosive esophagitis;

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Adjunct to antibiotics in H. pylori treatment;

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Gastric ulcer;

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Duodenal ulcer;

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Prevention of recurrence of gastric ulcer or duodenal ulcer during low-dose aspirin administration; and

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Prevention of recurrence of gastric ulcer or duodenal ulcer during nonsteroidal anti-inflammatory drug (NSAID) administration.

Vonoprazan was subsequently approved in Japan in February 2016 for the treatment of H. pylori in combination packs with antibiotics (Vonosap Pack 400, Vonosap Pack 800, and Vonopion Pack), and has since been approved in numerous other countries in Asia and Latin America as well as Russia.

Vonoprazan Commercialization in Japan

Vonoprazan generated peak net sales of approximately $850 million and continues to achieve volume growth during its tenth full year on the market since its approval in 2014. Based upon sales during the 3-month period ending March 2024, vonoprazan had achieved a 34% share based on volume and a 63% market share based on sales among acid suppression therapies in Japan.

We believe that the market dynamic for anti-secretory agents in Japan is similar to that in the United States. In both countries, the anti-secretory market is largely genericized. Ahead of the vonoprazan launch in Japan, all PPIs, other than Nexium, were available as generics. As of September 2022, generic drugs in Japan represent approximately 80% of the market by volume, compared to the United States where generics are currently approximately 90% of the market by volume. Although vonoprazan and

Dexilant are priced at a premium to generic PPIs in Japan and the United States, respectively, both have experienced commercial success.

VOQUEZNA Commercial Opportunity and Strategy

The market for prevention and treatment of acid-related GI diseases in the United States and Europe is large. In the U.S., there were approximately 7.9 billion prescription PPI doses dispensed during the 12 months ended December 31, 2024.

Over many decades of use, multiple drug classes and individual drugs have demonstrated the substantial commercial opportunity for therapies treating acid-related GI diseases. H2RAs including Axid, Pepcid, Tagamet, and Zantac provided the first significant improvement in disease management over antacids and as a class reached approximately $3.5 billion in annual sales. After H2RAs, PPIs emerged as the new standard of care. Prior to the introduction of generic and OTC alternatives, annual PPI class sales reached approximately $12.5 billion in the United States, and peak sales for individual brands were approximately $3.7 billion for Prilosec, $3.5 billion for Nexium, and $3.4 billion for Prevacid.

We believe our success in securing broad market access and formulary positioning comes from our differentiated profile and superiority demonstrated in our Phase 3 clinical trials in Erosive GERD and H. pylori from the PPI-based standard of care. For example, following approval of VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK, we believe our interactions with payers highlight the favorable commercial coverage secured to date of these products. As of February 2025, approximately 120 million commercially covered lives in the United States have access to VOQUEZNA tablets, comprising an estimated 80% of total U.S. commercial lives. We believe our approved VOQUEZNA-based therapies have the potential to improve the standard of care for acid-related GI diseases by providing a safe and effective treatment option for the millions of patients not fully satisfied with their other current treatment options.

In May 2022, we conducted a U.S. market research study with 90 gastroenterologists, 90 primary care physicians and 45 advanced practice providers who treat GERD. Before seeing the vonoprazan clinical data, 82% of these clinicians strongly agreed that PPIs are the most potent class of acid suppressing agents. After review of vonoprazan clinical data and messages, only 34% strongly agreed that PPIs are the most potent class of acid suppressing agents.

Sales and Marketing

We have established robust marketing, sales, and distribution capabilities to support the launch of our approved products and we are independently commercializing VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in the United States through an experienced national sales force. We believe we can successfully commercialize our approved products in the United States with a focused sales force targeting high prescribers of PPIs, particularly gastroenterologists and primary care physicians. Our strategy is to target approximately 52,000 core high volume PPI prescribers in the treatment of GERD and H. pylori infection. According to IQVIA data, of these physicians, each write on average approximately 1,200 PPI prescriptions annually. We are not aware of any anti-secretory product that has been promoted to this core group of prescribers, nor to the broader medical community, for nearly a decade. In the United States, we sell primarily to pharmaceutical wholesale distributors, which are the principal means of distributing our products to healthcare providers.

We also market certain products through direct-to-consumer channels, including across streaming platforms, traditional broadcast and cable television, and consumer-facing digital channels including Facebook, Instagram, waiting room TVs in doctors’ offices, and digital banner ads. Since launch, the campaign has reached millions of GERD sufferers and is driving strong patient engagement, increasing prescription requests, and motivating patients to explore a treatment option that works differently than PPIs.

Additional Vonoprazan Development Opportunities

Eosinophilic Esophagitis and Other Indications

While we are initially focused on the commercialization of vonoprazan for the treatment of GERD and H. pylori infection, we believe there are opportunities to expand the use of vonoprazan to other indications in our licensed territories. For example, we plan to expand clinical development of vonoprazan in the U.S. into EoE, the most common type of eosinophilic gastrointestinal disease. EoE is an autoimmune disease with significant unmet need and can result in trouble swallowing, chest pain, vomiting and impaction of food in the esophagus, a medical emergency. There are only two FDA-approved treatments for EoE. Although not approved for this indication, PPIs are often prescribed as a first-line therapy for the treatment of EoE. Vonoprazan demonstrated similar efficacy to PPIs in an investigator-sponsored EoE clinical trial in Japan. In this clinical trial, 112 patients with EoE were treated with vonoprazan, or the PPI rabeprazole or esomeprazole. Of patients treated with vonoprazan, 82% had complete relief of symptoms compared to 70% for esomeprazole and 76-78% for rabeprazole. Similarly, 35% of patients treated with vonoprazan demonstrated complete remission of EoE by histology, compared to 37% for esomeprazole and 31-38% for rabeprazole. Given the limited choices of therapies for EoE and vonoprazan’s demonstrated potential, we believe EoE is an important indication for future study. We have obtained FDA feedback on the design of a Phase 2 study investigating VOQUEZNA as a potential treatment for EoE, in adults and adolescents, and plan to initiate the study in the first half of 2025.

In addition to EoE, Barrett’s esophagus and Zollinger Ellison syndrome are severe diseases related to acid secretion where PPIs are the current standard of care. The improved acid control of vonoprazan relative to PPIs may lead to use in these indications with improved results over PPIs.

Formulations and Packaging

Orally Disintegrating Tablet

Takeda currently commercializes an orally disintegrating tablet, or ODT, formulation for vonoprazan in Japan and we are in the process of developing our own ODT formulation. We plan to conduct one or more Phase 1 trials to support potential approval of this alternative formulation. We believe that an ODT formulation represents a meaningful commercial opportunity for patients with difficulty swallowing in adults as well as will provide more desirable dosing administration options for children. It is estimated peak U.S. sales of the lansoprazole ODT formulation were over $450 million.

Over the Counter Use

We believe that vonoprazan has the ideal profile for an OTC product, including the potential for as needed symptom relief and a well-tolerated safety profile. Sales of OTC heartburn relief products in the United States are substantial, constituting a multi-billion-dollar market. We plan to explore the economics and potential development in this market to determine the best strategy going forward.

Competition

The biopharmaceutical industry is characterized by rapidly advancing technologies, intense competition and strong emphasis on proprietary products. We face potential competition from many sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and government agencies and public and private research institutions. In the United States, VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK all compete, and if approved in Europe and/or Canada will compete, with existing therapies and new therapies that may become available in the future.

Some of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources and significantly greater experience in the discovery and development of product candidates, obtaining FDA and other regulatory approvals of treatments and commercializing those treatments. These same competitors may invent technology that competes with vonoprazan. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of our competitors. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and subject recruitment for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Outside the U.S., our competitors may obtain regulatory approval for, or initiate commercial launch of, their products more rapidly than we may obtain approval for or launch products containing vonoprazan, which could result in our competitors establishing a strong market position before we are able to enter the market. In addition, VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK, are priced at a premium over competitive generic products in the U.S., and our ability to compete may be affected in many cases by insurers or other third-party payers seeking to encourage the use of generic products.

We expect that, for the treatment of H. pylori infection, Erosive GERD and Non-Erosive GERD, VOQUEZNA will primarily compete with generic PPIs marketed by multiple pharmaceutical companies in both the prescription and OTC markets. In addition to generic PPI-based triple and quad therapies, we expect VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK will compete with Talicia, a co-formulated capsule comprising generic omeprazole, amoxicillin, and rifabutin for the treatment of H. pylori infection, launched in March 2020 by RedHill Biopharma Ltd.

We are aware of three PCABs in development in U.S. as well as additional PCABs in territories outside the U.S. If approved in our territories, these PCABs may compete with vonoprazan. In the U.S., Daewoong is seeking a partner to advance development of fexuprazan. Outside the U.S., fexuprazan is launched in five countries and under health authority review in nine countries or regions. In the U.S., Sebela initiated three tegoprazan Phase 3 studies in Erosive GERD, Non-Erosive GERD and long-term safety–with expected completion in 2025. Outside the U.S., tegoprazan is launched in 14 countries, registered but not launched in one country and under health authority review in four countries. In the U.S., Cinclus obtained FDA agreement on their linaprazan glurate pediatric plan and plans to initiate two linaprazan glurate Phase 3 studies in patients with severe Erosive GERD in 2025 and two H. pylori Phase 3 dual therapy (with amoxicillin) studies in 2026. Outside the U.S., Cinclus, via their local partner, received a 2024 approval in GERD for linaprazan glurate in China--facilitating a potential launch there in 2025. No other registration activities are noted for linaprazan glurate. In Europe, Cinclus agreed to a pediatric investigation plan with the European Medicines Agency and received regulatory advice on Phase 2 and Phase 3 study designs. Lastly, there are two additional PCABs with registrations outside the U.S.—Jiangsu Carephar’s keverprazan which launched in China and Jeil’s zastaprazan which launched in South Korea. To the best of our knowledge, none of the above compounds have demonstrated superiority to PPIs in a Phase 3 clinical trial.

Additionally, we are aware of two PPIs in territories outside of the U.S. that if developed and approved in our licensed territories may compete with vonoprazan. These include Dexa Medica’s DLBS-2411, launched in the Philippines and in Phase 3 in Indonesia and Sihuan Pharmaceutical’s anaprazole, launched in China.

Intellectual Property

Intellectual property, including patents, trade secrets, trademarks and copyrights, is important to our business. Our commercial success depends in part on our ability to obtain and maintain proprietary intellectual property protection for vonoprazan, as well as for future product candidates and novel discoveries, product development technologies, and know-how. Our commercial success also depends in part on our ability to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary rights. Our policy is to develop and maintain protection of our proprietary position by, among other methods, licensing or filing U.S. and foreign patents and applications relating to our technology, inventions, and improvements that are important to the development and implementation of our business.

Our patent portfolio, comprising patents and patent applications exclusively licensed to us, is built with a goal of establishing broad protection that generally includes, for the product candidate compound, claims directed to composition of matter, pharmaceutical compositions or formulations, methods of synthesis, and methods of treatment using such pharmaceutical compositions or formulations. As of December 31, 2024, our patent portfolio covering vonoprazan consists predominantly of exclusively licensed patents and patent applications from Takeda. Subject to the terms of the license agreement we entered into with Takeda on May 7, 2019, or the Takeda License, we have licensed from Takeda exclusive rights in the United States, Europe, and Canada to patents and patent applications covering the composition of matter, formulation, use and/or manufacture of vonoprazan. Our patent portfolio comprises 11 distinct patent families protecting the technology relating to the compound vonoprazan and its synthetic intermediates, methods of synthesizing vonoprazan and related compounds, various formulations of vonoprazan products, as well as methods of treating diseases with vonoprazan and related compounds. As of December 31, 2024, our portfolio consists of approximately 25 issued U.S. patents, 4 pending U.S. applications, 16 issued European patents subsequently validated in individual European countries, 2 pending European applications, 6 issued Canadian patents, and 3 pending Canadian applications. The issued patents and pending applications have nominal expiration dates ranging from 2024 to 2038 without accounting for any available patent term adjustments or extensions. The issued U.S. patent covering the composition of matter of vonoprazan is expected to expire in August 2028, not including patent term extension. The issued U.S. patent covering the formulation of vonoprazan is expected to expire in August 2030, not including patent term extension.

The term of individual patents in our portfolio depends upon the legal term of patents in the countries in which they are obtained. In most countries in which we file, including the United States, the patent term is 20 years from the earliest date of filing a non-provisional patent application. In the United States, the term of a patent may be eligible for patent term adjustment, which permits patent term restoration as compensation for delays incurred at the United States Patent and Trademark Office, or USPTO, during the patent prosecution process. In addition, for patents that cover an FDA-approved drug, the Drug Price Competition and

Patent Term Restoration Act of 1984, or the Hatch-Waxman Act, permits a patent term extension of up to five years beyond the expiration of the patent. While the length of the patent term extension is related to the length of time the drug is under regulatory review, patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, and only one patent per approved drug may be extended under the Hatch-Waxman Act. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug. We have applied for, and in the future, expect to apply for patent term extensions on patents covering our approved products, including vonoprazan. While we plan to seek any available patent term extension to any issued patents we may be granted in any jurisdiction where such extensions are available; however, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.

The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions. The relevant patent laws and their interpretation outside of the United States is also uncertain. Changes in either the patent laws or their interpretation in the United States and other countries may diminish our ability to protect our technology or product candidates and could affect the value of such intellectual property. In particular, our ability to stop third parties from making, using, selling, offering to sell or importing products that infringe our intellectual property will depend in part on our success in obtaining and enforcing patent claims that cover our technology, inventions and improvements. We cannot guarantee that patents will be granted with respect to any of our licensed pending patent applications or with respect to any patent applications we may file in the future, nor can we be sure that any patents that may be granted to us or Takeda in the future will be commercially useful in protecting our products, the methods of use or manufacture of those products. Moreover, issued patents do not guarantee the right to practice our technology in relation to the commercialization of our products. Issued patents only allow us to block potential competitors from practicing the claimed inventions of the issued patents.

Further, patents and other intellectual property rights in the pharmaceutical and biotechnology space are evolving and involve many risks and uncertainties. For example, third parties may have blocking patents that could be used to prevent us from commercializing vonoprazan and any future product candidates and practicing our proprietary technology, and any issued patents may be challenged, invalidated or circumvented, which could limit our ability to stop competitors from marketing related products or could limit the term of patent protection that otherwise may exist for vonoprazan and any future product candidates. In addition, the scope of the rights granted under any issued patents may not provide us with protection or competitive advantages against competitors with similar technology. Furthermore, our competitors may independently develop similar technologies that are outside the scope of the rights granted under any issued patents. For these reasons, we may face competition with respect to vonoprazan and any future product candidates. Moreover, because of the extensive time required for development, testing and regulatory review of a potential product, it is possible that, before any particular product candidate can be commercialized, any patent protection for such product may expire or remain in force for only a short period following commercialization, thereby reducing the commercial advantage the patent provides.

It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us, and for employees and consultants to enter into invention assignment agreements with us. These agreements provide that all confidential information developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. Where applicable, the agreements provide that all inventions to which the individual contributed as an inventor shall be assigned to us, and as such, will become our property. There can be no assurance, however, that these agreements will provide meaningful protection or adequate remedies for our trade secrets in the event of unauthorized use or disclosure of such information.

Further, we have filed for and have received trademark registrations for our company name “Phathom Pharmaceuticals” in the United States, European Union, and other foreign jurisdictions, and are pursuing trademark protection in certain other foreign jurisdictions.

License Agreement with Takeda Pharmaceutical Company Limited

On May 7, 2019, we and Takeda entered into an exclusive license, or the Takeda License, pursuant to which, Takeda granted us an exclusive, sublicensable (with Takeda’s reasonable consent) license under certain patents and know how relating to vonoprazan and owned or controlled by Takeda during the term of the Takeda License to commercialize vonoprazan products using specified formulations for all human therapeutic uses in the United States, Europe and Canada, and a non-exclusive license under such patents and know how to develop and manufacture such vonoprazan products anywhere in the world (subject to Takeda’s consent as to each country) for the purposes of commercializing the vonoprazan products in the United States, Europe and Canada.

We granted Takeda a non-exclusive, royalty-free, sublicensable license under our rights in any patents and know-how that are necessary or useful to enable Takeda to develop and manufacture vonoprazan products anywhere in the world for the purposes of commercialization outside United States, Europe and Canada. We also granted Takeda an exclusive, royalty-free license under our rights in certain patents and know-how owned or controlled by us and necessary for the exploitation of vonoprazan products, in each case for Takeda to commercialize any vonoprazan product outside of the United States, Canada, and Europe and for purposes other than human therapeutic use.

During the term of the Takeda License, we and our affiliates are not permitted to commercialize any pharmaceutical product, other than vonoprazan, that treats acid-related disorders, except for certain generic and OTC competing products in specified circumstances. We will be responsible, at our cost, for the development, manufacture and commercialization of the vonoprazan products. We are required to use commercially reasonable efforts to develop and commercialize the vonoprazan products in our licensed territory.

Under the Takeda License, Takeda has the sole right and authority, with our input, to prepare, file, prosecute, and maintain all Takeda and joint patents on a worldwide basis at its own cost. We are responsible, at our cost, for preparing, filing, prosecuting, and maintaining patents on inventions made solely by us in connection with vonoprazan, subject to input from Takeda. We have the first right to enforce the licensed patent rights with respect to certain infringing products in the United States, Europe and Canada.

We paid Takeda upfront consideration consisting of a cash payment of $25 million, 1,084,000 shares of common stock and a warrant to purchase 7,588,000 shares of common stock, or the Takeda Warrant. We agreed to make milestone payments to Takeda upon achieving certain tiered aggregate annual net sales of licensed products in the United States, Europe and Canada up to a total maximum milestone amount of $250 million. We also agreed to make tiered royalty payments averaging in the low double digits royalty rate on aggregate net sales of licensed products, subject to specified offsets and reductions. Royalties will be payable, on a product-by-product and country-by-country basis from the first commercial sale of such product in such country, until the latest of expiration of the licensed patents covering the applicable product, expiration of regulatory exclusivity in such country, or 15 years following first commercial sale in such country.

The Takeda License will continue until the expiration of the obligation to pay royalties in all countries and on all products. We may terminate the Takeda License in its entirety without cause upon six months’ prior written notice. We and Takeda may terminate the Takeda License in the case of the other party’s insolvency, or upon prior written notice within a specified time period for the other party’s material uncured breach. Takeda may terminate the Takeda License in its entirety if we challenge the licensed patents, or if we assist any third party in challenging such patents.

Manufacturing

We do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of vonoprazan. Vonoprazan is a small molecule that can be manufactured using commercially available technologies.

With respect to any future product candidates, we expect to continue to rely on third-party contract manufacturers to manufacture clinical supplies and commercial quantities of any approved products. Although we rely on contract manufacturers, we have personnel with manufacturing experience to oversee our relationships with Sandoz, Catalent and Evonik.

Sandoz Supply and Packaging Agreement

In December 2020, we entered into a Supply and Packaging Services Agreement with Sandoz GmbH, or the Sandoz Supply Agreement, pursuant to which Sandoz has agreed to supply commercial quantities of amoxicillin capsules and clarithromycin tablets, to package these antibiotics with vonoprazan drug product in finished convenience packs, and to supply us with these convenience packs.

Pursuant to the Sandoz Supply Agreement, we agreed to purchase certain quantities of convenience packs from Sandoz at an agreed upon price per pack. The price per pack is fixed for the first two (2) years following launch of the convenience pack in the United State and may be adjusted thereafter based on Sandoz’s cost increases, subject to an annual cap. The Sandoz Supply Agreement sets forth an annual minimum number of convenience packs that we must purchase each year following launch of the convenience pack product, and if we do not meet the minimum order in a given year, we are required to pay Sandoz the amount corresponding to the shortfall. Sandoz has no obligation to supply convenience packs above a maximum number of packs above a certain percentage of our forecasts. We have agreed to purchase convenience packs, amoxicillin capsules and clarithromycin tablets, in each case intended for sale in the United States, exclusively from Sandoz during the five-year period following launch.

The Sandoz Supply Agreement will continue for five years from launch of the convenience pack in the U.S. and may be terminated effective at the end of the initial five-year term upon written notice by either party prior to the end of the third year following launch. In the absence of such notice, the Sandoz Supply Agreement will extend automatically for an additional three-year period, and thereafter as mutually agreed upon by the parties. The Sandoz Supply Agreement may also be terminated at any time upon written notice by either party for uncured material breach following written notice of such breach.

Catalent Commercial Supply Agreement

In July 2021, we entered into a Commercial Supply Agreement, or the Tablet Supply Agreement, with Catalent Pharma Solutions, LLC, or Catalent, pursuant to which Catalent has agreed to supply us with commercial quantities of vonoprazan fumarate tablets.

Pursuant to the Tablet Supply Agreement, as amended, Catalent has agreed to supply us with, and we have agreed to purchase from Catalent, finished vonoprazan tablets at an agreed upon price per unit. The price per unit may be adjusted annually based on increases in costs incurred by Catalent. The Tablet Supply Agreement requires us to purchase a specified percentage of its requirements of finished vonoprazan tablets from Catalent, which percentage is subject to adjustment following January 1, 2027.

Unless terminated earlier, the term of the Tablet Supply Agreement extends for a period of five years from the Commencement Date. The Tablet Supply Agreement will extend automatically for additional two year periods unless terminated by either party upon at least 24 months prior written notice. The Tablet Supply Agreement may also be terminated at any time upon written notice by either party if the other party has failed to remedy a material breach of the terms of the Tablet Supply Agreement within a specified period following receipt of written notice of such breach.

Evonik Commercial Supply Agreement

In August 2022, we entered into a Commercial Supply Agreement, or the API Supply Agreement, with Evonik Operations GmbH, or Evonik, pursuant to which Evonik has agreed to supply us with commercial quantities of vonoprazan drug substance, or API.

Pursuant to the API Supply Agreement, Evonik has agreed to supply us with, and we have agreed to purchase, certain quantities of API at an agreed upon price which varies based on the volume of product ordered. The price may also be adjusted based on actual changes in costs incurred by Evonik. Subject to pre-existing purchase obligations to Takeda, we have agreed to purchase a percentage of our annual requirements of API from Evonik, for which the percentage of our annual API requirements is subject to adjustment based upon the price of API under the API Supply Agreement.

Unless terminated earlier, the API Supply Agreement has an initial period that expires in August 2027. This initial term was extended by two years from 2027 to 2029 upon Evonik's successful qualification of a second manufacturing facility to produce API in December of 2024. The API Supply Agreement may be terminated effective at the end of the initial period on at least 24-months written notice by either party. In the absence of such notice, the API Supply Agreement will extend automatically for additional 2-year periods which may be terminated upon 18 months’ notice. The API Supply Agreement may also be terminated at any time upon written notice by either party if the other party has failed to remedy a material breach of the terms of the Supply Agreement within a specified period following receipt of written notice of such breach.

Government Regulation

Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and export and import of products such as those we are developing. A new drug must be approved by the FDA through the NDA process before it may be legally marketed in the United States.

U.S. Drug Development Process

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or the FDCA, and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

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

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completion of certain preclinical laboratory tests, animal studies and formulation studies in accordance with Good Laboratory Practice, or GLP, regulations and other applicable regulations;

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

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

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performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice, or GCP, regulations to establish the safety and efficacy of the proposed drug for its intended use;

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submission to the FDA of an NDA;

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

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satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current Good Manufacturing Practice, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

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satisfactory completion of potential FDA inspection of selected clinical investigation sites to assess compliance with GCPs; and

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FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States.

Once a pharmaceutical candidate is identified for development, it enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for certain studies. Prior to beginning the first clinical trial with a product candidate in the United States, a sponsor must submit an IND to the FDA. The sponsor must submit the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational drug product to humans. The sponsor will also include a protocol detailing, among other things, the objectives of the first phase of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the first phase lends itself to an efficacy evaluation. Some preclinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, places the clinical trial on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about on-going or proposed clinical trials or non-compliance with specific FDA requirements, and the trials may not begin or continue until the FDA notifies the sponsor that the hold has been lifted. Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of one or more qualified investigators in accordance with GCP regulations, which include, among other things, the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, dosing procedures, subject selection and exclusion criteria and the safety and effectiveness criteria to be evaluated. Each protocol must be submitted to the FDA as part of the IND as well as any subsequent protocol amendments. While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing suggesting a significant risk to humans exposed to the drug, and any clinically important increased rate of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

Furthermore, an IRB at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations. The FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. In addition, some clinical trials are overseen by an independent group of qualified experts organized by the sponsor, known as a data safety monitoring board or committee. Depending on its charter, this group may determine whether a trial may move forward at designated check points based on access to certain data from the trial.

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

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Phase 1: The product candidate is initially introduced into healthy human volunteers or patients with the target disease or condition. These studies test for safety, dosage tolerance, absorption, metabolism, distribution and excretion and, if possible, to gain an early indication of its effectiveness.

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Phase 2: The product candidate is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

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Phase 3: The product candidate is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of the product’s effectiveness for its intended use(s) and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide, if appropriate, an adequate basis for product labeling.

Post-approval trials, sometimes referred to as Phase 4 studies, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

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

There are also requirements governing the reporting of ongoing clinical trials and completed trial results to public registries. Sponsors of certain clinical trials of FDA-regulated products are required to register and disclose specified clinical trial information, which is publicly available at www.clinicaltrials.gov. 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 disclosure.

NDA Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, preclinical and other non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the NDA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity. Under current PDUFA guidelines, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted.

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

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

After the FDA evaluates an NDA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical trials or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing to support the application. If a Complete Response Letter is issued, the sponsor must resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. In addition, the FDA may require a sponsor to conduct additional clinical studies to further assess a drug’s safety and effectiveness after NDA approval, and may require testing and surveillance programs to monitor the safety of approved products which have been commercialized. The FDA may also place other conditions on approval including the requirement for a risk evaluation and mitigation strategy, or REMS, to assure the safe use of the drug, which could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS. The FDA will not approve the NDA without an approved REMS, if required.

Furthermore, the Pediatric Research Equity Act, or PREA, requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, fails to keep a deferral current or fails to submit a request for approval of a pediatric formulation.

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates. The FDA has a Fast Track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria. Specifically, product candidates are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast Track designation applies to the combination of the product candidate and the specific indication for which it is being studied. The sponsor of a Fast Track product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA is submitted, the application may be eligible for priority review. A Fast Track product candidate may also be eligible for rolling review, where the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for Breakthrough Therapy designation to expedite its development and review. A product candidate can receive Breakthrough Therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the Fast Track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

Any marketing application for a drug submitted to the FDA for approval, including a product candidate with a Fast Track designation or Breakthrough Therapy designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review. A product candidate is eligible for priority review if it is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition. The FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review. The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

In addition, depending on the design of the applicable clinical trials, a product candidate may be eligible for accelerated approval. Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product candidate 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, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA will generally require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled confirmatory clinical trials verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit, and may require such confirmatory trials to be well underway prior to granting accelerated approval. Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required confirmatory studies in a timely manner, or if such studies fail to verify the predicted clinical benefit. In addition, the FDA requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast Track designation, Breakthrough Therapy designation, accelerated approval, and priority do not change the standards for approval but may expedite the development or approval process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Post-Approval Requirements

Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory standards 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 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, certain manufacturing changes and additional labeling claims, are subject to further FDA review and approval. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP regulations and other laws and regulations. In addition, the FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

Any drug products manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the drug, providing the FDA with updated safety and efficacy information, drug sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements. The FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market and imposes requirements and restrictions on drug manufacturers, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the Internet. Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling.

Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or post-approval, may subject an applicant or manufacturer to administrative or judicial civil or criminal sanctions and adverse publicity. FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical holds on post-approval clinical trials, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits, or civil or criminal penalties.

Non-Patent Data and Market Exclusivity

Data and market exclusivity provisions under the FDCA can delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a NCE if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an abbreviated new drug application, or ANDA, or an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA alternatively provides three years of non-patent market exclusivity for an NDA, or supplement to an existing NDA, if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Pediatric exclusivity is another type of market exclusivity available in the United States. Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of non-patent regulatory exclusivity or patent term if a sponsor conducts clinical trials in children in response to a written request from the FDA. The issuance of a written request does not require the sponsor to undertake the described clinical trials.

Additionally, under the GAIN Act, the FDA may designate a product as a QIDP. In order to receive this designation, a drug must qualify as an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections, including those caused by either (1) an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens, or (2) a so-called “qualifying pathogen” found on a list of potentially dangerous, drug-resistant organisms established and maintained by the FDA under the law. The FDA interprets QIDP designation to apply to a specific drug product, including a specific dosage form of the product. A sponsor must request such designation before submitting a marketing application, and the FDA will respond to a request for QIDP designation within 60 days of the date the FDA receives the request. The GAIN Act permits the FDA to revoke a QIDP designation if the request for such designation contained an untrue statement of material fact.

The benefits of QIDP designation include potential eligibility for priority review and Fast Track designation, and an extension by an additional five years of any non-patent exclusivity period awarded, such as a five-year NCE exclusivity period awarded for a new chemical entity. This extension is in addition to any pediatric exclusivity extension that may be awarded, and the extension will be awarded only to a drug first approved on or after the date of enactment. The GAIN Act provisions prohibit the grant of an exclusivity extension where the application is a supplement to an application for which an extension is in effect or has expired, is a subsequent application for a specified change to an approved product, or is an application for a product that does not meet a definition of QIDP based on the uses for which it is ultimately approved.

U.S. Healthcare Fraud and Abuse Laws and Compliance Requirements

In addition to FDA regulation of pharmaceutical products, U.S. federal and state healthcare laws and regulations restrict business practices in the pharmaceutical industry. These laws may impact, among other things, our current and future business operations, including our clinical research activities, and constrain the business or financial arrangements and relationships with healthcare providers and other parties. These laws include anti-kickback and false claims laws, civil monetary penalties laws, and transparency laws regarding drug pricing and payments or other items of value provided to physicians and other healthcare providers.

The federal Anti-Kickback Statute prohibits, among other things, individuals or entities from knowingly and willfully offering, paying, soliciting or receiving remuneration, directly or indirectly, overtly or covertly, in cash or in kind to induce or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. A person or entity does not need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation.

The federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws prohibit, among other things, any individual or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government, knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or from knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government. 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 civil False Claims Act.

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private third-party payers and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the U.S. federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the healthcare fraud statute implemented under HIPAA or specific intent to violate it in order to have committed a violation.

The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or CMS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other non-physician practitioners (physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists, anesthesiology assistants and certified nurse midwives), and teaching hospitals, and applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their immediate family members.

Similar state and local laws and regulations may also restrict business practices in the pharmaceutical industry, such as state anti-kickback and false claims laws, which may apply to business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payers, including private insurers, or by patients themselves; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information or which require tracking gifts and other remuneration and items of value provided to physicians, other healthcare providers and entities; and state and local laws that require the registration of pharmaceutical sales representatives.

Violation of any of such laws or any other governmental regulations that apply may result in significant criminal, civil and administrative penalties including damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, reputational harm, diminished profits and future earnings, disgorgement, exclusion from participation in government healthcare programs and the curtailment or restructuring of our operations.

U.S. Coverage and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any product candidate for which we may seek regulatory approval. Sales in the United States will depend, in part, on the availability of sufficient coverage and adequate reimbursement from third-party payers, which include government health programs such as Medicare, Medicaid, TRICARE and the Veterans Administration, as well as managed care organizations and private health insurers. Coverage and reimbursement for VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK and any future product candidates can be subject to challenge, reduction or denial by third-party payers.

The process for determining whether a third-party payer will provide coverage for a product is typically separate from the process for setting the reimbursement rate that the payer will pay for the product. In the United States, there is no uniform policy among payers for coverage or reimbursement. Decisions regarding whether to cover a product, the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. Third-party payers often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies, but also have their own methods and approval processes. Therefore, coverage and reimbursement for products can differ significantly from payer to payer. As a result, the coverage determination process is often a time-consuming and costly process that can require manufacturers to provide scientific and clinical support for the use of a product to each payer separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

Third-party payers are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product that receives approval. Third-party payers may not consider vonoprazan or any future product candidates to be medically necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure favorable coverage may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development. Additionally, decreases in third-party reimbursement for any product or a decision by a third-party payer not to cover a product could reduce physician usage and patient demand for the product.

Medicaid is a joint federal and state program administered by the states for low-income and disabled beneficiaries. Medicare is a federal program that is administered by the federal government covering individuals age 65 and over as well as those with certain disabilities. Under the Medicaid Drug Rebate Program, or MDRP, as a condition of having federal funds being made available to the states for covered outpatient drugs under Medicaid, and, if applicable, Medicare Part B, pharmaceutical manufacturers must enter into an agreement with the Secretary of Health and Human Services to pay a rebate to state Medicaid programs for each unit of covered outpatient drug dispensed to a Medicaid beneficiary and paid for by the state Medicaid program. Medicaid drug rebates are based on pricing data that pharmaceutical manufacturers report on a monthly and quarterly basis to CMS, which is the federal agency that administers the MDRP and Medicare programs. For the MDRP, these data include the average manufacturer price, or AMP, for each drug and, in the case of innovator products, the Best Price, or BP, which represents the lowest price available from the manufacturer to any entity in the United States in any pricing structure, calculated to include all applicable sales and associated rebates, discounts and other price concessions. If a manufacturer becomes aware that its MDRP government price reporting submission for a prior quarter was incorrect or has changed as a result of recalculation of the pricing data, the manufacturer must resubmit the corrected data for up to three years after those data originally were due. If a manufacturer fails to provide information timely or is found to have knowingly submitted false information to the government, the manufacturer may be subject to civil monetary penalties and other sanctions, including termination from the MDRP.

Federal law requires that a manufacturer that participates in the MDRP also participate in the Public Health Service’s 340B drug pricing program, or the 340B program, in order for federal funds to be available for the manufacturer’s drugs under Medicaid and, if applicable, Medicare Part B. The 340B program is administered by the Health Resources and Services Administration, or HRSA, and requires participating manufacturers to agree to charge statutorily defined covered entities no more than the 340B “ceiling price” for the manufacturer’s covered outpatient drugs used in an outpatient setting. These 340B covered entities include a variety of community health clinics and other entities that receive health services grants from the Public Health Service, as well as hospitals that serve a disproportionate share of low‑income patients. The 340B ceiling price is calculated using a statutory formula, which is based on the AMP and rebate amount for the covered outpatient drug as calculated under the MDRP. In general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement. Manufacturers must report 340B ceiling prices to HRSA on a quarterly basis, and HRSA publishes them to 340B covered entities. HRSA has finalized regulations regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities for 340B‑eligible drugs. HRSA has also finalized an administrative dispute resolution process through which 340B covered entities may pursue claims against participating manufacturers for overcharges, and through which manufacturers may pursue claims against 340B covered entities for engaging in unlawful diversion or duplicate discounting of 340B drugs. In addition, legislation may be introduced that, if passed, would further expand the 340B program, such as adding further covered entities or requiring participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.

In order to be eligible to have drug products paid for with federal funds under Medicaid and, if applicable, Medicare Part B, and purchased by certain federal agencies and grantees, a manufacturer must also participate in the U.S. Department of Veterans Affairs, or VA, Federal Supply Schedule, or FSS, pricing program. Under the VA/FSS program, a manufacturer must report the Non-Federal Average Manufacturer Price, or Non-FAMP, for its covered drugs to the VA and charge certain federal agencies no more than the Federal Ceiling Price, which is calculated based on Non-FAMP using a statutory formula. These federal agencies are the VA, the U.S. Department of Defense, the U.S. Coast Guard, and the U.S. Public Health Service (including the Indian Health Service). The manufacturer must also pay rebates on products purchased by military personnel and dependents through the TRICARE retail pharmacy program.

We are enrolled or participate in the MDRP, the 340B program, the VA/FSS program, and the TRICARE retail pharmacy program, and have price reporting and payment obligations under these and other programs. Pricing and rebate calculations vary among products and programs. The calculations are complex and are often subject to interpretation by us, governmental or regulatory agencies, and the courts. We cannot ensure that any submissions we are required to make under these programs will not be found to be incomplete or incorrect.

Individual states continue to consider and have enacted legislation to limit the growth of healthcare costs, including the cost of prescription drugs and combination products. A number of states have either implemented or are considering implementation of drug price transparency legislation. Requirements under such laws include advance notice of planned price increases, reporting price increase amounts and factors considered by manufacturers in taking such increases, wholesale acquisition cost disclosure to prescribers, purchasers, and state agencies, and new product notice and reporting. Such legislation could limit the price or payment for certain drugs, and a number of states are authorized to impose civil monetary penalties or pursue other enforcement mechanisms against manufacturers who fail to comply with drug price transparency requirements, including the untimely, inaccurate, or incomplete reporting of drug pricing information.

U.S. Healthcare Reform

In the United States, there has been, and continues to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect the profitable sale of product candidates.

Among policy makers and payers in the United States, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. In March 2010, the Patient Protection and Affordable Care Act, or the Affordable Care Act, was passed, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly affected the pharmaceutical industry. The Affordable Care Act increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs from 15.1% to 23.1%; required collection of rebates for drugs paid by Medicaid managed care organizations; required manufacturers to participate in a coverage gap discount program, which was replaced by a new manufacturer discount program on January 1, 2025 (as discussed below), in which manufacturers were required to offer point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs” to specified federal government programs; implemented a new methodology by which rebates owed by manufacturers under the MDRP are calculated for drugs that are inhaled, infused, instilled, implanted, or injected; expanded eligibility criteria for Medicaid programs; created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research; and established a Center for Medicare and Medicaid Innovation at the CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

Since its enactment, there have been judicial and political challenges to certain aspects of the Affordable Care Act. On June 17, 2021, the U.S. Supreme Court dismissed the most recent judicial challenge to the Affordable Care Act without specifically ruling on the constitutionality of the Affordable Care Act. Thus, the Affordable Care Act will remain in effect in its current form.

In addition, other legislative changes have been proposed and adopted since the Affordable Care Act was enacted. For example, beginning April 1, 2013, Medicare payments to providers were reduced under the sequestration required by the Budget Control Act of 2011, which will remain in effect through 2032, unless additional Congressional action is taken. Additionally, on January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. On March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap, beginning January 1, 2024. Previously, the rebate was capped at 100% of a drug’s AMP.

Moreover, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products.

Most significantly, on August 16, 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law. This statute marks the most significant action by Congress with respect to the pharmaceutical industry since adoption of the Affordable Care Act in 2010. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a new discounting program (which began on January 1, 2025). The IRA permits the Secretary of the Department of Health and Human Services, or HHS, to implement many of these provisions through guidance, as opposed to regulation, for the initial years. HHS has and will continue to issue and update guidance as these programs are implemented. CMS has published the negotiated prices for the initial ten drugs, which will first be effective in 2026, and the list of the subsequent 15 drugs that will be subject to negotiation, although the program is currently subject to legal challenges. The impact of the IRA on the pharmaceutical industry cannot yet be fully determined, but is likely to be significant. Individual states in the U.S. have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure, drug price reporting and other transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. Some states have enacted legislation creating so-called prescription drug affordability boards, which ultimately may attempt to impose price limits on certain drugs in these states. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine which drugs and suppliers will be included in their healthcare programs. Furthermore, there has been increased interest by third-party payers and governmental authorities in reference pricing systems and publication of discounts and list prices.

The likelihood of implementation of additional reform initiatives is uncertain. Moreover, in the coming years, additional legislative and regulatory changes could be made to governmental health programs that could significantly impact pharmaceutical companies and the success of our product candidates.

Foreign Regulation

In order to market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our products. Whether or not we obtain FDA approval for a product, we would need to obtain the necessary approvals by the comparable foreign regulatory authorities before we can commence clinical trials or marketing of the product in foreign countries and jurisdictions. Although many of the issues discussed above with respect to the United States apply similarly in the context of the European Union, or EU, the approval process varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods. The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

Regulation and Procedures Governing Marketing Authorization of Medicinal Products in the EU

Non-Clinical Studies and Clinical Trials

Similarly, to the United States, the various phases of non-clinical and clinical research in the EU are subject to significant regulatory controls.

Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances. Non-clinical (pharmaco-toxicological) studies must be conducted in compliance with the principles of good laboratory practice, or GLP, as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medicinal products, e.g., radio-pharmaceutical precursors for radio-labeling purposes). In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies. These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, or ICH, guidelines on good clinical practices, or GCP, as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative. The sponsor must take out a clinical trial insurance policy, and in most EU member states, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

The regulatory landscape related to clinical trials in the EU has been subject to recent changes. The EU Clinical Trials Regulation, or CTR, which was adopted in April 2014 and repeals the EU Clinical Trials Directive, became applicable on January 31, 2022. Unlike directives, the CTR is directly applicable in all EU member states without the need for member states to further implement it into national law. The CTR notably harmonizes the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.

While the EU Clinical Trials Directive required a separate clinical trial application, or CTA, to be submitted in each member state in which the clinical trial takes place, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB, respectively, the CTR introduces a centralized process and only requires the submission of a single application for multi-center trials. The CTR allows sponsors to make a single submission to both the competent authority and an ethics committee in each member state, leading to a single decision per member state. The CTA must include, among other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the medicinal product under investigation.

The assessment procedure of the CTA has been harmonized as well, including a joint assessment by all member states concerned, and a separate assessment by each member state with respect to specific requirements related to its own territory, including ethics rules. Each member state’s decision is communicated to the sponsor via the centralized EU portal. Once the CTA is approved, clinical study development may proceed.

The CTR foresees a three-year transition period. The extent to which ongoing and new clinical trials will be governed by the CTR varies. Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the EU Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the EU Clinical Trials Directive remain governed by said Directive until January 31, 2025. After this date, all clinical trials (including those which are ongoing) will become subject to the provisions of the CTR.

Medicines used in clinical trials must be manufactured in accordance with Good Manufacturing Practice, or GMP. Other national and EU-wide regulatory requirements may also apply.

Marketing Authorizations

In the EU, medicinal product candidates can only be commercialized after obtaining a marketing authorization, or MA. To obtain regulatory approval of a product candidate in the EU, we must submit a MA Application, or MAA. The process for doing this depends, among other things, on the nature of the medicinal product.

There are two types of MAs:

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"Centralized MAs" are issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and are valid throughout the EU. The centralized procedure is mandatory for certain types of products, such as (i) medicinal products derived from biotechnological processes, (ii) designated orphan medicinal products, (iii) advanced therapy medicinal products, or ATMPs, such as gene therapy, somatic cell-therapy or tissue-engineered medicines and (iv) medicinal products containing a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases. The centralized procedure is optional for any products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific or technical innovation or for which the granting of a MA would be in the interest of public health in the EU.

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"National MAs" are issued by the competent authorities of the EU member states, only cover their respective territory, and are available for product candidates not falling within the mandatory scope of the centralized procedure. Where a product has already been authorized for marketing in an EU member state, this national MA can be recognized in another member state through the mutual recognition procedure. If the product has not received a national MA in any member state at the time of application, it can be approved simultaneously in various member states through the decentralized procedure. Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the member states in which the MA is sought, one of which is selected by the applicant as the reference member state.

Under the above described procedures, before granting the MA, the EMA or the competent authorities of the EU member states make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

MAs have an initial duration of five years. After these five years, the authorization may be renewed for an unlimited period on the basis of a reevaluation of the risk-benefit balance. Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops. In exceptional cases, the CHMP might perform an accelerated review of a MA in no more than 150 days (not including clock stops).

Data and marketing exclusivity

The EU also provides opportunities for market exclusivity. Upon receiving MA, innovative medicinal products generally receive eight years of data exclusivity and an additional two years of market exclusivity. If granted, the data exclusivity period prevents generic or biosimilar applicants from relying on the pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized in the EU. The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU. The overall 10-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical (or biological) entity, and products may not qualify for data exclusivity.

Pediatric investigation plan

In the EU, MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO. The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the drug for which MA is being sought. The PDCO can grant a deferral of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults. Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data are not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Once the MA is obtained in all EU member states and study results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension (if any is in effect at the time of approval) or, in the case of orphan pharmaceutical products, a two-year extension of the orphan market exclusivity is granted.

Post-Approval Requirements

Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the member states. The holder of a MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance, or QPPV, who is responsible for the establishment and maintenance of that system, and oversees the safety profiles of medicinal products and any emerging safety concerns. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.

All new MAAs must include a risk management plan, or RMP, describing the risk management system that we will put in place and documenting measures to prevent or minimize the risks associated with the product. The regulatory authorities may also impose specific obligations as a condition of the MA. Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

The advertising and promotion of medicinal products is also subject to laws concerning promotion of medicinal products, interactions with physicians, misleading and comparative advertising and unfair commercial practices. All advertising and promotional activities for the product must be consistent with the approved summary of product characteristics, and therefore all off-label promotion is prohibited. Direct-to-consumer advertising of prescription medicines is also prohibited in the EU. Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each member state and can differ from one country to another.

Failure to comply with the aforementioned EU and member state laws may result in administrative, civil or criminal penalties. These penalties could include delays or refusal to authorize the conduct of clinical trials, or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

Coverage and Reimbursement

Outside of the United States, the pricing of pharmaceutical products and medical devices is subject to governmental control in many countries. In the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost effectiveness of a particular therapy to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval. Other countries may allow companies to fix their own prices for products, but monitor and control product volumes and issue guidance to physicians to limit prescriptions. Efforts to control prices and utilization of pharmaceutical products and medical devices will likely continue as countries attempt to manage healthcare expenditures. Historically, products launched in the EU do not follow price structures of the United States and generally prices tend to be significantly lower.

Data Privacy and Security Laws

As a pharmaceutical company, we are subject to federal, state and foreign data privacy, cybersecurity and data breach notification laws governing the collection, use, disclosure and protection of health-related and other personal information. For example, in the U.S., HIPAA imposes privacy, security and breach reporting obligations upon “covered entities” (health plans, health care clearinghouses and certain health care providers), and their respective business associates, individuals or entities that create, receive, maintain or transmit protected health information, or PHI, in connection with providing certain services for or on behalf of a covered entity. HIPAA mandates the reporting of certain breaches of protected health information to the HHS, to affected individuals, and if the breach is large enough, to the media. Entities that are found to be in violation of HIPAA as the result of a breach of unsecured personal health information, a complaint about privacy practices or an audit by the HHS may be subject to significant civil, criminal and administrative fines and penalties and/or additional reporting and oversight obligations if required to enter into a resolution agreement and corrective action plan with HHS to settle allegations of HIPAA non-compliance. While HIPAA does not create a private right of action allowing individuals to sue us in civil court for violations of HIPAA, its standards have been used as the basis for duty of care in state civil suits such as those for negligence or recklessness in the misuse or breach of PHI.

Even when HIPAA does not apply, according to the Federal Trade Commission or the FTC, failing to take appropriate steps to keep consumers’ personal information secure may constitute unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act. The FTC expects a company’s cybersecurity measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities. Individually identifiable health information is considered sensitive data that merits stronger safeguards. In addition, certain other federal, state laws, such as the California Consumer Privacy Act, as amended by the California Privacy Rights Act, or collectively, the CCPA and similar state laws in other U.S. states govern the privacy and security of personal information, including health-related information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

We are also subject to the European Union General Data Protection Regulation, or the EU GDPR, and to the United Kingdom General Data Protection Regulation and Data Protection Act 2018, or collectively, the UK GDPR (the EU GDPR and UK GDPR together referred to as the “GDPR”), which imposes comprehensive data privacy compliance obligations in relation to our collection, processing, sharing, disclosure, transfer and other use of data relating to an identifiable living individual or “personal data”, including a principle of accountability and the obligation to demonstrate compliance through policies, procedures, training and audit. Failure to comply with applicable data privacy and security laws can result in the imposition of significant civil and/or criminal penalties and private litigation. Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Human Capital

As of December 31, 2024, we had 427 full-time employees, some of whom hold a Ph.D., M.D. or other advanced degree in their field. Our number of employees continued to increase substantially in 2024 in support of our commercialization of VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider our relationship with our employees to be good.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and developing our existing and new employees, advisors and consultants. We maintain equity and cash incentive plans for, and offer a comprehensive benefit package to, every employee to attract, retain and reward personnel. The purpose of our cash and equity compensation plans is to increase stockholder value and the success of our company by motivating our employees to perform to the best of their abilities and achieve our objectives.

Corporate Information

We were originally incorporated under the laws of the state of Delaware on January 9, 2018 under the name North Bridge IV, Inc. On March 13, 2019, we changed our name to Phathom Pharmaceuticals, Inc. and merged YamadaCo IIA, Inc., a Delaware corporation, or YamadaCo, with and into our company, with Phathom Pharmaceuticals, Inc. as the surviving entity, or the Merger. Our principal executive offices are located at 100 Campus Drive, Suite 102, Florham Park, New Jersey 07932, and our telephone number is (877) 742-8466.

Available Information

Our internet address is www.phathompharma.com. Our investor relations website is located at https://investors.phathompharma.com. We make available free of charge on our investor relations website under “Financials and Filings” our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, our directors’ and officers’ Section 16 reports and any amendments to those reports as soon as reasonably practicable after filing or furnishing such materials to the SEC. They are also available for free on the SEC’s website at www.sec.gov.

We use our investor relations website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Investors should monitor such website, in addition to following our press releases, SEC filings and public conference calls and webcasts. Information relating to our corporate governance is also included on our investor relations website. The information in or accessible through the SEC and our website are not incorporated into, and are not considered part of, this filing.