Unless the context requires otherwise, references in this Annual Report on Form 10-K to “Aerovate”, “we”, “us” and “our” refer to Aerovate Therapeutics, Inc.
−Removed: We are a clinical-stage biopharmaceutical company focused on developing drugs that meaningfully improve the lives of patients with rare cardiopulmonary disease.
−Removed: Our initial focus is on advancing AV-101, our dry powder inhaled formulation of imatinib for the treatment of pulmonary arterial hypertension, or PAH, a devastating disease impacting approximately 70,000 people in the United States and Europe.
−Removed: Imatinib, marketed as Gleevec tablets, was originally developed for the treatment of multiple cancers.
−Removed: Oral imatinib also demonstrated statistically significant improvement on the primary endpoint, six-minute walk distance, and multiple secondary hemodynamic endpoints in PAH patients in an international Phase 3 trial conducted by Novartis but was poorly tolerated due to adverse events, or AEs, and never approved for the treatment of PAH.
−Removed: AV-101, delivered using a dry powder inhaler, is designed to provide lung concentrations at or above those observed with the oral dose while limiting systemic levels of the drug.
−Removed: We have completed a Phase 1 clinical trial in healthy volunteers and AV-101 was generally well-tolerated with no serious adverse events reported.
−Removed: In November 2023, we completed enrollment in the Phase 2b portion and enrolled the first patient in the Phase 3 portion of Inhaled iMatinib Pulmonary Arterial Hypertension Clinical Trial (IMPAHCT), our global Phase 2b/Phase 3 trial of AV-101 in adults with PAH.
−Removed: We have assembled a team with deep expertise in developing innovative PAH and inhaled therapies and commercializing novel drugs.
+Added: We are a biopharmaceutical company.
+Added: Our initial focus was on advancing AV 101, our dry powder inhaled formulation of imatinib for the treatment of pulmonary arterial hypertension, or PAH, a devastating disease impacting approximately 70,000 people in the United States and Europe.
+Added: On June 17, 2024, we announced topline results from the Phase 2b portion of our Phase 2b/Phase 3 Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial of AV-101, or IMPAHCT.
+Added: Topline data showed that, while AV-101 was generally well tolerated across all dose groups, the study did not meet its primary endpoint for improvement in pulmonary vascular resistance compared to placebo for any of the studied doses or show meaningful improvements in the secondary endpoint of change in six minute walk distance.
+Added: We also reviewed data from several additional secondary endpoints of the Phase 2b portion of IMPAHCT, which also failed to show meaningful improvements.
+Added: Based upon these results and in agreement with the independent study advisory committee, we halted enrollment and shut down the Phase 3 portion of IMPAHCT as well as the long-term extension study.
+Added: AV-101 for the treatment of PAH was our only product candidate in development.
+Added: At this time, we do not intend to resume development of AV-101 or any other product candidates.
+Added: In July 2024, we announced the decision to conduct a comprehensive review of strategic alternatives focused on maximizing shareholder value.
+Added: We also engaged Wedbush Securities Inc., or Wedbush PacGrow, as our exclusive strategic financial advisor to assist in the process of exploring strategic alternatives.
+Added: In June 2024, following our decision to halt further development of AV-101, we announced our plan to terminate nearly all of our workforce in the coming months, or the Workforce Reduction Plan.
+Added: As of December 31, 2024, 47 individuals, or approximately 92% of our workforce, have been terminated.
+Added: The affected individuals have been and will be provided severance benefits, including cash severance payments.
+Added: Each affected individual’s eligibility for severance benefits is contingent upon entering into a separation agreement, which includes a general release of claims against our company.
+Added: In connection with the Workforce Reduction Plan, we incurred costs (in consideration of releases) of approximately $6.7 million, which are primarily one-time severance benefits.
+Added: On October 30, 2024, we entered into an Agreement and Plan of Merger, or the Merger Agreement, by and among us, Caribbean Merger Sub I, Inc., a Delaware corporation and our wholly owned subsidiary, or Merger Sub I, Caribbean Merger Sub II, LLC, a Delaware limited liability company and our wholly owned subsidiary, or Merger Sub II and together with Merger Sub I, Merger Subs, and Jade Biosciences, Inc., a Delaware corporation, or Jade, pursuant to which, and subject to the satisfaction or waiver of the conditions set forth in the Merger Agreement, among other things, Merger Sub I will merge with and into Jade, with Jade surviving the merger as the surviving corporation, or the First Merger, and as part of the same overall transaction, Jade will merge with and into Merger Sub II, with Merger Sub II continuing as our wholly owned subsidiary and the surviving corporation of the merger, or the Second Merger and together with the First Merger, the Merger.
+Added: The Merger is intended to qualify for federal income tax purposes as a tax-free reorganization under the provisions of Section 368(a) of the Internal Revenue Code of 1986, as amended, or the Code.
+Added: In addition, in connection with the closing of the Merger, or the Closing, we expect to declare a cash dividend to our pre-Merger stockholders of approximately $65.0 million in the aggregate, or the Cash Dividend, provided such amount is subject to adjustment as set forth in the Merger Agreement.
+Added: Subject to the terms and conditions of the Merger Agreement, at the effective time of the Merger, or the Effective Time, (a) each then-outstanding share of Jade’s common stock, par value $0.0001 per share, or Jade Common Stock, will be converted into the right to receive a number of shares of our common stock, par value $0.0001 per share, or Aerovate Common Stock, based on a ratio calculated in accordance with the Merger Agreement, or the Exchange Ratio, provided that any unvested restricted shares of Jade Common Stock will be subject to the same terms and conditions (including, without limitation, vesting and repurchase provisions) that are otherwise applicable to such unvested shares as of immediately prior to the Effective Time, (b) each then-outstanding share of Jade’s preferred stock, par value $0.0001 per share, or Jade Preferred Stock, will be converted into the right to receive a number of shares of our newly authorized
+Added: convertible preferred stock, par value $0.0001 per share, equal to (x) the Exchange Ratio divided by (y) 1,000, (c) each then-outstanding option to purchase Jade Common Stock will be assumed by us, subject to adjustment as set forth in the Merger Agreement and (d) each then-outstanding warrant to purchase shares of Jade Common Stock or Jade Preferred Stock will be assumed by us, subject to adjust as set forth in the Merger Agreement.
+Added: We and Jade have each agreed to customary representations, warranties and covenants in the Merger Agreement, including, among others, covenants relating to (1) obtaining the requisite approval of our respective stockholders, (2) non-solicitation of alternative acquisition proposals and (3) the conduct of our respective businesses during the period between the date of signing the Merger Agreement and the Closing.
+Added: On October 30, 2024, Jade entered into a Securities Purchase Agreement, or the Purchase Agreement, with certain existing Jade stockholders and new investors, or the Investors.
+Added: Pursuant to the Purchase Agreement, and subject to the terms and conditions thereof, Jade agreed to sell, and the Investors agreed to purchase, immediately prior to the consummation of the Merger, shares of Jade Common Stock and pre-funded warrants for an aggregate purchase price of approximately $300.0 million, or the Concurrent Investment, which reflects the conversion of the previously issued $95 million of convertible notes.
+Added: The consummation of the Concurrent Investment is conditioned on the satisfaction or waiver of the conditions set forth in the Merger Agreement and in the Purchase Agreement.
+Added: Shares of Jade Common Stock and pre-funded warrants issued pursuant to this financing transaction will be converted into shares of Aerovate Common Stock and pre-funded warrants to acquire shares of Aerovate Common Stock, in accordance with the Exchange Ratio and the Merger Agreement.
+Added: Consummation of the Merger is subject to certain closing conditions, including, among other things, (1) requisite approval by our stockholders, (2) approval by the requisite Jade stockholders of the adoption and approval of the Merger Agreement and the transactions contemplated thereby, (3) Nasdaq’s approval of the listing of the shares of Aerovate Common Stock to be issued in connection with the Merger, and (4) an executed Purchase Agreement for the Concurrent Investment in full force and effect evidencing cash proceeds of not less than $80.0 million to be received by the combined company immediately prior to or following the Closing.
+Added: The Merger Agreement contains certain termination rights of each of us and Jade.
+Added: Upon termination of the Merger Agreement under specified circumstances, we may be required to pay Jade a termination fee of $2,340,000, and in certain other circumstances, Jade may be required to pay us a termination fee of $5,250,000.
+Added: At the Effective Time, our board of directors is expected to consist of six members, all of whom will be designated by Jade.
+Added: Concurrently and in connection with the execution of the Merger Agreement, (i) certain stockholders of Jade (solely in their respective capacities as Jade stockholders) holding approximately 99% of the outstanding shares of Jade capital stock have entered into support agreements with us and Jade to vote all of their shares of Jade capital stock in favor of the adoption and approval of the Merger Agreement and the transactions contemplated thereby and (ii) certain of our stockholders holding approximately 38.1% of the outstanding shares of Aerovate Common Stock have entered into support agreements with us and Jade to vote all of their shares of Aerovate Common Stock in favor of, among other things, the adoption and approval of the Merger Agreement and the transactions contemplated thereby.
+Added: Our Strategy to Date
PAH is an orphan disease with unmet medical need and is characterized by high pressure in the vessels transporting blood from the right side of the heart to the lungs.
1 unchanged sentence
The severe blood flow restriction and strain on the heart becomes increasingly severe over time and ultimately leads to heart failure that is often fatal.
−Removed: We estimate there are between 30,000-40,000 patients treated with approved PAH therapies in the U.S.
+Added: We estimate there are between 30,000 to 40,000 patients treated with approved PAH therapies in the U.S.
alone, many of whom are on two or more approved PAH therapies.
1 unchanged sentence
Despite the availability of multiple approved therapies, PAH has a five-year survival rate for newly diagnosed and prevalent patients between 61% and 65%.
−Removed: None of the approved therapies directly address the abnormal cellular hyperproliferation of the pulmonary vasculature that causes the increased resistance to blood flow.
+Added: None of the approved therapies directly address
+Added: the abnormal cellular hyperproliferation of the pulmonary vasculature that causes the increased resistance to blood flow.
We believe that novel treatments that primarily address abnormal cellular hyperproliferation may provide therapeutic benefit to PAH patients and lead to improved quality of life.
−Removed: Our focus on developing AV-101 is driven by historical results from the Phase 3 IMPRES clinical trial of oral imatinib for the treatment of PAH patients.
−Removed: Oral imatinib is a well-characterized targeted kinase inhibitor and approved oncology treatment, but clinical trials also supported its potential for the treatment of PAH.
−Removed: The Phase 3 IMPRES trial was a placebo-controlled clinical trial of oral imatinib, conducted globally by Novartis, in 202 PAH patients whose disease was not adequately controlled by two or all three classes of approved PAH therapies.
−Removed: After 24 weeks of treatment with oral imatinib, patients achieved on average an increase of 32 meters (p=0.002) compared to placebo in the distance they could walk in six minutes, a measure known as the 6MWD.
−Removed: A key secondary endpoint in the IMPRES trial was pulmonary vascular resistance, or PVR, which is an objective measure of hemodynamic disease severity in PAH patients.
−Removed: After 24 weeks of treatment with oral imatinib, patients achieved an average PVR improvement (reduction) of 32% (p<0.001) compared to placebo with a significant increase in cardiac output (p<0.001).
−Removed: The magnitude of improvement in both 6MWD and PVR is notable because no approved PAH drug has shown such an improvement in a Phase 3 trial on top of at least two background therapies.
−Removed: However, treatment with oral imatinib was also associated with significant tolerability issues and adverse events, including nausea, edema, diarrhea and vomiting.
−Removed: Patients taking oral imatinib also experienced serious adverse events, the most frequent of which were anemia (7%), worsening of pulmonary hypertension (6%), dyspnea (6%), peripheral edema (6%), presyncope (5%), diarrhea (3%), device-related infection (3%), subdural hematoma (2%) and syncope (1%).
−Removed: Despite the clinical effects of oral imatinib 26% of patients on oral imatinib, compared to 7% on placebo, discontinued due to AEs by 24 weeks.
−Removed: Our company was formed to develop an inhaled formulation of imatinib as a means of delivering therapeutically relevant drug concentrations to the lungs while minimizing systemic exposure, which we believe is the source of the observed intolerability of oral imatinib.
−Removed: We have brought together leaders both in the field of PAH drug development as well as in the area of inhaled drug formulation to invent AV-101, a drug/device combination designed to deliver imatinib directly to the lungs.
−Removed: We have completed a Phase 1 clinical trial of AV-101 in 82 healthy adults.
−Removed: Repeat inhaled doses of up to 90 mg were well-tolerated and resulted in systemic plasma levels that were below those observed with the 400 mg oral dose of imatinib (Gleevec) used in the IMPRES trial.
−Removed: According to pharmacokinetic models of lung exposure to imatinib as applied to our Phase 1 dose range, the predicted lung concentrations of imatinib delivered by AV-101 overlapped or surpassed those predicted from the 400 mg dose of oral imatinib in our Phase 1 clinical trial.
−Removed: There were no serious adverse events associated with AV-101.
−Removed: The most common adverse event was a transient cough primarily in the highest dose cohort, which was generally mild, and resolved within 30 minutes of dosing.
−Removed: There were no discontinuations due to cough.
−Removed: The intended Phase 2b dose range with AV-101 will only include doses that use 40% or less of the amount of dry powder that was inhaled at the highest Phase 1 dose and, based on the results of our Phase 1 clinical trial and our modeling, we expect lung concentrations of imatinib delivered by AV-101 in the 35 mg and 70 mg doses, both twice a day, or BID, selected for the Phase 2b portion of our Phase 2b/Phase 3 trial to overlap or surpass the lung concentrations predicted with the 400 mg oral dose in our Phase 1 clinical trial, which was the same target dose used in the Phase 3 IMPRES trial.
−Removed: In November 2023, we announced completion of enrollment with 202 patients in the Phase 2b portion and enrollment of the first patient in the Phase 3 portion of IMPAHCT, our global double-blinded, placebo-controlled, randomized Phase 2b/Phase 3 trial of AV-101 in adults with PAH on top of standard of care.
−Removed: We are enrolling patients in the Phase 3 portion of this trial and will announce the approximate number of patients we plan to enroll in the Phase 3 portion of the trial based on the topline results of the Phase 2b portion of the trial.
−Removed: The Phase 2b portion of the trial is designed to assess safety, tolerability and inform dose selection for the Phase 3 portion using changes in PVR, an objective measure of the effect of AV-101 on hemodynamic function in PAH patients, as the primary endpoint.
−Removed: We will measure 6MWD as a secondary endpoint in the Phase 2b portion of this trial.
−Removed: We anticipate that topline data from the Phase 2b portion of this trial will be available in June 2024.
−Removed: In the Phase 3 portion of the trial improvement in 6MWD will be the primary endpoint.
−Removed: If the results of the Phase 3 trial show a statistically significant increase in 6MWD, we plan to submit a New Drug Application, or NDA, with the United States Food and Drug Administration, or FDA, and Marketing Authorisation Application, or MAA, with the European Commission for AV-101 for the treatment of PAH.
−Removed: These applications will leverage the existing safety data for Gleevec oral tablets allowing the company to save time and money.
−Removed: If AV-101 is approved, we believe it has the potential to become an important addition to existing therapies for PAH in both the United States and Europe.
−Removed: We are pursuing a clinical development program utilizing established endpoints for development of previous PAH drugs, as well as enrollment criteria and dosing duration previously studied in oral imatinib PAH trials.
−Removed: At our April 14, 2021 end-of-Phase 1 meeting with the FDA, we received regulatory guidance that our clinical program could support an NDA submission;
−Removed: however, the process of clinical development is inherently uncertain and there can be no guarantee that we will obtain marketing approval.
−Removed: AV-101 has been granted orphan drug designation by the FDA and the EMA for the treatment of PAH.
−Removed: We own four issued U.S.
−Removed: patents and several U.S.
−Removed: and foreign patent applications for patent protection of the composition of the aerosol, drug product, manufacturing and methods of use.
−Removed: We retain worldwide commercial rights to AV-101.
−Removed: Our executive management team has extensive experience in the clinical development and the commercialization of orphan drug indications.
−Removed: Noyes, our Chief Executive Officer, was a senior executive at GelTex Pharmaceuticals, Inc., or GelTex, and Genzyme Corporation, or Genzyme, where he headed all launch planning and the commercialization of Renagel, a treatment for hemodialysis patients that resulted in Genzyme’s acquisition of GelTex for more than $1 billion.
−Removed: Dake, Ph.D., our Founder, President, Chief Operating Officer and Secretary, a cancer biologist, investor and entrepreneur, recognized the potential benefits of developing a lung-targeted imatinib and secured multiple rounds of funding to build the team at Aerovate with experts like Ralph Niven, Ph.D., our Chief Scientific Officer, who has over 30 years of expertise in translational medicine and inhalation dosage forms, and Hunter Gillies, M.B.Ch.B., our Chief Medical Officer, who has led Phase 2 and Phase 3 PAH trials at Pfizer Inc., or Pfizer, and Gilead Sciences, Inc., or Gilead, and has designed and executed PAH trials with several smaller biotechnology companies.
−Removed: Eldridge, our Chief Financial Officer, has served as CFO for several biotechnology companies, leading four of these companies to the public
−Removed: Marinus Verwijs, our Chief Technical Officer, has over 15 years of product development and manufacturing experience.
−Removed: He has worked on multiple commercial products, leading them from clinical product development to NDA filing and commercial launch.
−Removed: Timothy Pigot, our Chief Commercial Officer, has over 25 years of industry experience working to launch and commercialize a range of products over multiple therapeutic areas.
−Removed: Pigot gained significant experience in PAH during his 12 years at Gilead and 11 years at Pfizer, where his responsibilities included the launches of Revatio and Letairis for the treatment of PAH.
−Removed: Donna Dea, our Head of Regulatory Affairs, has over 30 years of global regulatory experience designing and implementing regulatory strategies resulting in the approval of treatments for asthma, COPD, rhinitis and others, for which several of these drugs involved inhaled formulations.
−Removed: Our Strengths
−Removed: We believe that our company and AV-101 possess the following attributes that may potentially increase the likelihood that we will be successful in developing and commercializing AV-101:
−Removed: ● Significant efficacy for oral imatinib .
−Removed: In the global Phase 3 IMPRES trial, oral imatinib demonstrated statistically and clinically significant efficacy following 24 weeks of treatment on top of PAH standard of care.
−Removed: These results were notable for achieving statistically significant improvements in the study’s primary efficacy endpoint, 6MWD, and a key secondary endpoint, PVR, but also for hitting statistical significance on other clinically relevant efficacy endpoints on top of standard of care, which included at least two background PAH therapies.
−Removed: The primary endpoint of the Phase 2b portion of our Phase 2b/Phase 3 trial is the change in PVR following 24 weeks of treatment.
−Removed: The primary endpoint of the Phase 3 portion of our Phase 2b/Phase 3 trial is the change in 6MWD following 24 weeks of treatment.
−Removed: Our Phase 2b/Phase 3 trial is designed to treat a similar patient population to the IMPRES trial, patients in WHO Functional Classes II-IV on top of standard of care background PAH therapies.
−Removed: ● Distinct PAH treatment mechanism .
−Removed: Unlike approved treatments for PAH, which act primarily through vasodilation (prostacyclin pathway, endothelin pathway, and nitric oxide pathway agents), AV-101 is designed to directly address the abnormal cellular hyperproliferation in the pulmonary vasculature that causes the increased resistance to blood flow and heart failure.
−Removed: We believe AV-101’s mechanism uniquely positions our product candidate, if approved, for combination therapy with existing vasodilator treatments.
−Removed: ● Adaptive development path .
−Removed: We have designed an innovative global Phase 2b/Phase 3 clinical trial based on an adaptive design that could lead to a potential NDA filing.
−Removed: Our development plan also benefits from our ability to leverage prior toxicology work done with oral imatinib.
−Removed: ● Improved tolerability based on route of administration .
−Removed: Our inhaled administration is designed to minimize systemic exposure and limit the safety and tolerability concerns observed in the IMPRES trial of oral imatinib in PAH.
−Removed: Our Phase 1 clinical trial results in healthy volunteers demonstrated that plasma levels of imatinib were significantly lower than those observed with the 400 mg oral dose of imatinib used in the IMPRES trial.
−Removed: ● Expected comparability of concentrations of drug delivered .
−Removed: Based on the results of our Phase 1 clinical trial and our modeling, we expect lung concentrations of imatinib delivered by AV-101 in the 35 mg and 70 mg doses, both BID, selected for the Phase 2b portion of our Phase 2b/Phase 3 trial to overlap or surpass the lung concentrations predicted with the 400 mg oral dose in our Phase 1 clinical trial, which was the same target dose used in the Phase 3 IMPRES trial.
−Removed: ● Powerful barriers to entry .
−Removed: We have generated strong intellectual property claims and other barriers to entry.
−Removed: We own four issued U.S.
−Removed: patent and several U.S.
−Removed: and foreign patent applications to protect our proprietary imatinib formulation, our drug product and methods of use.
−Removed: In addition, we have obtained exclusive access to a commercially available dry powder delivery device which we believe will create a substantial competitive advantage.
−Removed: ● Substantial and readily addressable market opportunity.
−Removed: If AV-101 is approved, we believe there is a substantial medical need and market opportunity for combining AV-101 with existing standard of care, which is often two or three background agents.
−Removed: Beyond this base case, we also believe that AV-101, if approved, could benefit a larger group of PAH patients with earlier-stage disease such as those patients receiving only one other PAH therapy.
−Removed: ● Strong leadership in PAH .
−Removed: Our executive management team has extensive experience in the clinical development of treatments for PAH, including Dr.
−Removed: Gillies who has been developing drugs for PAH for more than 20 years and recently ran the AMBITION trial that established the current first-line PAH combination therapy and Dr.
−Removed: Niven’s experience in manufacturing and development for inhaled small molecules.
−Removed: In addition, our Clinical Advisory Board includes several of the premier thought leaders in PAH who have extensive experience developing drugs and caring for patients suffering from PAH.
−Removed: Our strategy is to develop and commercialize AV-101 for patients suffering from PAH.
−Removed: Key elements of our strategy include our plans to:
−Removed: ● Complete regulatory discussions for AV-101 in the United States and Europe .
−Removed: At our April 14, 2021 end-of-Phase 1 meeting with the FDA, we received regulatory guidance that our Phase 2b/Phase 3 trial, if successful, could support a NDA submission using the change in 6MWD compared to placebo as the primary endpoint in the Phase 3 portion of the trial;
−Removed: however, the process of clinical development is inherently uncertain and there can be no guarantee that we will obtain marketing approval even if we successfully achieve our primary endpoint.
−Removed: We have been granted orphan designation for the treatment of PAH from the FDA and from the European Commission in the European Union.
−Removed: We completed the formal process of seeking scientific advice and regulatory guidance from the European Medicines Agency, or EMA, regarding its requirements for regulatory approval and we believe that, if successful, our existing clinical program could support an MAA submission for regulatory approval in Europe.
−Removed: ● Advance AV-101 through NDA submission .
−Removed: In November 2023, we announced completion of enrollment in the Phase 2b portion and enrollment of the first patient in the Phase 3 portion of IMPAHCT, our Phase 2b/Phase 3 trial of AV-101 in adults with PAH on top of standard of care PAH therapies.
−Removed: The Phase 2b portion of this trial will be a dose-ranging trial in which PVR will be the primary endpoint and we anticipate that topline data from the Phase 2b portion will be available in June 2024.
−Removed: The Phase 3 portion of the trial will be based on the optimal dose selected in the Phase 2b portion and 6MWD will be the primary endpoint.
−Removed: ● Commercialize AV-101 directly in the United States .
−Removed: If AV-101 is approved by the FDA, we intend to commercialize it ourselves in the United States with a specialty sales force focused primarily on pulmonologists and cardiologists treating adult patients suffering from PAH.
−Removed: We will consider entering into collaborations for the development and commercialization of AV-101 in Europe, Asia or other geographic regions, if approved by foreign regulatory authorities.
−Removed: ● Pursue additional indications for AV-101 .
−Removed: We believe that AV-101 could have clinical applications in other groups of PAH patients, such as those with earlier-stage disease who may be receiving only one other PAH therapy.
−Removed: We also may consider the potential use of AV-101 in other types of pulmonary vascular disease.
−Removed: ● Expand our pipeline by accessing additional product opportunities .
−Removed: We plan to search for additional product opportunities available for license or acquisition that could be supported by the commercial infrastructure we build to successfully launch AV-101 in the United States if it is approved for marketing.
−Removed: PAH Background and Limitations of Current Treatments
−Removed: PAH is a progressive, life-threatening orphan disease characterized by increased pressure in the pulmonary arteries, vessels responsible for carrying deoxygenated blood from the heart to the lungs.
−Removed: This increased pressure is caused by narrowing of these blood vessels as a result of dysregulation of cells of the arterial wall, leading to excessive growth and proliferation.
−Removed: Over time, blood flow worsens as inflammatory cells are recruited and inflammatory cytokines further stimulate the proliferation of blood vessel cells.
−Removed: This ultimately leads to tissue scarring, fibrosis and blood vessel remodeling, resulting in severe restriction of blood flow (as illustrated in the figure below) and increased risk of developing blood clots and heart failure.
−Removed: Increased pulmonary resistance is caused by cell proliferation that obstructs blood flow.
−Removed: This severe restriction of blood flow also causes the heart to work harder to circulate blood through the lungs causing abnormal strain on the right ventricle of the heart resulting in PAH symptoms that worsen over time;
−Removed: these commonly include breathlessness, fatigue, chest pain, fainting or light headedness, as well as abdominal distension.
−Removed: Four PAH functional classes categorize patient symptom severity and ability to carry out physical activity.
−Removed: Higher numbered functional classes indicate worsening symptoms and are associated with higher mortality.
−Removed: The four functional classes established by the World Health Organization, or WHO, are detailed in the figure below.
−Removed: WHO PAH FUNCTIONAL CLASSES
−Removed: FUNCTIONAL CLASS
−Removed: No limitation of physical activity, and ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.
−Removed: Slight limitation of physical activity, but patients are comfortable at rest.
−Removed: Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.
−Removed: Marked limitation of physical activity, but patients are still comfortable at rest.
−Removed: Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope.
−Removed: Patients are unable to carry out any physical activity without symptoms, and discomfort is increased by any physical activity.
−Removed: Signs of right heart failure manifest, and dyspnea and/or fatigue may even be present at rest.
−Removed: Prevalence of PAH and Unmet Need
−Removed: Based on third-party estimates, the number of PAH patients diagnosed is between 30,000 and 40,000 in the United States with an average age at diagnosis of 53 years old and 65% to 80% of those diagnosed being women.
−Removed: The exact prevalence of PAH worldwide is not known but it has been estimated to be between 10 to 52 cases per million.
−Removed: Many drugs have been developed and made commercially available for the treatment of PAH, such as vasodilators, and it is estimated that the combined global sales for PAH products in 2023 was $6.2 billion.
−Removed: While advances in the treatment of PAH using vasodilatory agents over the last two decades have markedly improved survival, PAH patients still face significant disease burden and premature death.
−Removed: The five-year survival rate for newly diagnosed and prevalent patients is between 61% and 65%.
−Removed: Clearly there is unmet need for new therapies beyond the standard of care.
−Removed: Limitations of Current Therapies for PAH
−Removed: The current standard of care in PAH consists of drugs that act primarily as pulmonary vasodilators, which relax the muscles in the pulmonary arterial walls, thereby reducing the degree of blood vessel constriction.
−Removed: Although the current standard of care provides some benefit to patients, it is clear from the pathology of PAH that abnormal cellular hyperproliferation causes progressive narrowing of the pulmonary vasculature.
−Removed: This abnormal hyperproliferation is not addressed by therapies currently used to treat PAH.
−Removed: Three classes of pulmonary vasodilators are currently used to treat PAH:
−Removed: endothelin receptor antagonists, nitric oxide pathway modulators and prostacyclins.
−Removed: ● Endothelin Receptor Antagonists .
−Removed: Some treatments currently approved for PAH work by blocking the action of endothelin-1, a potent vasoconstrictor, and are referred to as endothelin receptor antagonists, or ERAs.
−Removed: These drugs include bosentan, macitentan and ambrisentan.
−Removed: All three of these drugs are orally administered and improve blood flow to the lungs as determined by measures of hemodynamics such as pulmonary vascular resistance and cardiac output, which translates to improvements in exercisability as measured by the distance that patients can walk in a fixed period of time (6MWD).
−Removed: ● Nitric oxide pathway modulators such as PDE5 inhibitors and sGC’s .
−Removed: Nitric oxide is a naturally occurring molecule that is widely recognized as important in a number of biological processes.
−Removed: It causes blood vessels to relax and widen via the second messenger cGMP, resulting in an increase in blood flow.
−Removed: Two common modalities utilize the nitric oxide pathway to result in vasodilation:
−Removed: Phosphodiesterase type 5, or PDE5, inhibitors prevent the breakdown of cGMP and soluble guanylate cyclase stimulators, or sGC’s, increase the production of cGMP independent of nitric oxide.
−Removed: Several oral PDE5 drugs are available, such as sildenafil and tadalafil.
−Removed: Additionally, riociguat is the only sGC approved for PAH.
−Removed: ● Prostacyclin pathway modulators .
−Removed: Patients with PAH have been shown to have reduced levels of prostacyclin, a naturally occurring lipid that has the effect of relaxing the smooth muscles surrounding arteries, resulting in vasodilation.
−Removed: Prostacyclin analogues, such as iloprost, epoprostenol, and treprostinil, are approved therapies for PAH.
−Removed: Selexipag is an oral prostacyclin-like drug approved for PAH.
−Removed: In addition to the challenges associated with dosing, prostacyclin therapy can be difficult to tolerate.
−Removed: In clinical trials subcutaneous infusion of these agents has shown severe infusion site adverse events requiring narcotics for these symptoms.
−Removed: The oral prostacyclins also have a high incidence of headache and diarrhea, nausea, vomiting, and flushing, which can lead to discontinuations.
−Removed: PAH patients are often treated with more than one of these drugs and new therapies are typically added to existing therapies rather than replacing drugs that are providing insufficient benefit.
−Removed: Based on both primary research and third party sources, we estimate that a majority of patients are taking two or three FDA approved drugs for the treatment of PAH.
−Removed: Oral therapies are commonly prescribed first-line, typically consisting of an ERA and PDE5 inhibitor.
−Removed: As patients progress in their disease severity, a prostacyclin can typically be added as a third agent.
−Removed: Although these therapies have been shown to improve exercise capacity, quality of life, pulmonary pressure and short-term survival, none of the current treatments are curative
−Removed: and patients remain on life-long therapy.
−Removed: Despite the availability of multiple agents within each treatment pathway and efforts to treat PAH more aggressively, the long term prognosis for patients with PAH remains poor.
−Removed: Antiproliferative Medicines as a Novel Approach to Treating PAH
−Removed: Sotatercept is poised to be the first approved PAH therapy directly targeting the underlying cell proliferation that leads to increased pulmonary arterial pressure, although the concept behind targeting cell proliferation to treat PAH is not new.
−Removed: Sotatercept is a molecule that blocks signaling of members of the TGF-beta family of growth factors.
−Removed: Results from a Phase 3 clinical trial in PAH showed that in patients taking one, two or three standard PAH therapies, sotatercept led to a statistically significant improvement in 6MWD with a safety profile reported to be generally consistent with what was observed with sotatercept in the previous Phase 2 study, providing further support for the therapeutic potential of antiproliferative product candidates in PAH.
−Removed: We are encouraged by these results as they provide independent confirmation of the importance of antiproliferative products as a potentially broad class of PAH therapeutics to complement vasodilators.
−Removed: Despite the significant improvement with sotatercept therapy in multiple efficacy endpoints, it is notable that ~60% of patients did not meet the prespecified multi-component criteria for improvement, ~60% of patients did not achieve “low risk status” on the simplified French risk model and 70% of patients did not improve in New York Heart Association Functional Class status demonstrating the continued significant unmet need in PAH.
−Removed: Similar to the vasodilator field, we believe that PAH patients may benefit from treatment with multiple antiproliferative therapies directed against different targets.
−Removed: PAH Prescriber Interest in Novel Agents
−Removed: We conducted primary market research with approximately 150 PAH treating physicians to assess the demand for novel agents for the treatment of PAH.
−Removed: Respondents were presented on a blinded basis with three hypothetical novel agents with efficacy and safety profiles reflective of results seen in PAH clinical trials associated with actual novel agents currently being studied and/or under regulatory review.
−Removed: The majority of prescribers indicated a likelihood to utilize a therapeutic agent with characteristics similar to those of AV-101.
−Removed: Our Approach, AV-101
−Removed: We are developing AV-101 as a drug-device combination product that delivers imatinib directly to the lungs via inhalation.
−Removed: The product consists of capsules of particulate imatinib that will be used in conjunction with a dry powder inhaler device.
−Removed: We believe that delivery of imatinib directly to the lungs will maximize the amount of drug in the targeted tissues while minimizing systemic exposure.
−Removed: Furthermore, we believe that delivering imatinib in this way may improve the tolerability of treatment while maintaining imatinib’s known effects on exercise capacity and hemodynamics.
−Removed: AV-101 has been granted orphan drug designation by the FDA and the European Commission for the treatment of PAH.
−Removed: Potential of Imatinib to Treat PAH
−Removed: The molecule in AV-101, imatinib, has demonstrated improvement on the primary and multiple secondary endpoints in a global Phase 3 trial (IMPRES) conducted by Novartis in PAH patients on top of at least two standard of care PAH drugs.
−Removed: However, when administered orally, serious adverse events, and discontinuations were high and the oral version was never approved for PAH.
−Removed: We believe imatinib is unique amongst tyrosine kinase inhibitors for its specificity and potency.
−Removed: At pharmacologically achievable levels, it inhibits only a handful of kinases, such as PDGFR, KIT, DDR and ABL, which have been implicated in PAH disease processes.
−Removed: Other tyrosine kinase inhibitors that target the same binding pocket are more promiscuous.
−Removed: Recent academic focus on kinase inhibition in PAH has been on PDGFR.
−Removed: However, other kinase inhibitors that hit PDGFR also inhibit the closely related SRC and VEGFR kinases.
−Removed: These drugs have been shown to induce or exacerbate PAH.
−Removed: Thus, we believe clinical success with kinase inhibition in PAH is not dictated by inhibiting PDGFR alone, but rather by the overall kinase inhibition profile.
−Removed: We are encouraged that imatinib, the molecule in AV-101, has shown clinical effects in the IMPRES trial, and we believe inhaled delivery of AV-101 limits systemic exposure and may mitigate the tolerability issues observed with oral imatinib.
−Removed: Kinase inhibitors have been approved for the treatment of various cancers.
−Removed: Case reports of improvements in PAH in patients receiving oral imatinib, marketed as Gleevec by Novartis, led to several clinical trials designed to test the efficacy
−Removed: of imatinib for PAH.
−Removed: The IMPRES trial was a randomized, double-blind global Phase 3 trial conducted by Novartis that enrolled 202 PAH patients.
−Removed: Most of these patients had Functional Class II or Class III PAH and were already on at least two background therapies.
−Removed: Patients were randomized to receive oral imatinib or placebo for 24 weeks.
−Removed: Patients enrolled in the IMPRES trial had reduced exercise capacity compared to healthy adults as measured by the six-minute walk distance, or 6MWD, a simple test that has been used as a primary endpoint for the approval of multiple drugs to treat PAH.
−Removed: The mean baseline 6MWD for patients in this trial was 361 meters, whereas for healthy adults it has been reported to be approximately 600 meters The baseline 6MWD values in these patients upon enrollment was below normal for healthy adults despite the fact that they were all on treatment with at least two PAH therapies and 41% were on triple therapy, the maximal standard of care for PAH.
−Removed: Patients remained on their respective pre-trial PAH therapies throughout the trial.
−Removed: The target dose of oral imatinib in the IMPRES trial was 400 mg/day which is an approved dose of oral imatinib for the treatment of cancers such as chronic myelogenous leukemia, or CML, and metastatic malignant gastrointestinal stromal tumors, or GIST, containing specific genetic alterations.
−Removed: Treatment of PAH patients with 400 mg oral imatinib led to a significant improvement in 6MWD over baseline compared to placebo.
−Removed: This difference was significant at 12 weeks with significance observed at all consecutive timepoints through the end of the trial at 24 weeks, at which point the oral imatinib-treated patients achieved an average improvement of 32 meters vs placebo in the 6MWD (p=0.002).
−Removed: The magnitude of this improvement is notable because no approved PAH drug has shown such an improvement in a Phase 3 trial on top of at least two background therapies.
−Removed: The most recently approved oral PAH drug in the U.S., Uptravi (Selexipag), showed a 12-meter treatment effect in the Phase 3 GRIPHON trial.
−Removed: The patients in this trial were not as heavily treated as those in the IMPRES trial, with one third on double therapy and none on triple therapy.
−Removed: The figure below shows the improvement over time in 6MWD of PAH patients treated with oral imatinib on at least two standard of care therapies as compared to the placebo group in the Phase 3 IMPRES trial.
−Removed: Imatinib led to a significant increase in 6MWD on top of at least two standard of care therapies
−Removed: The improvement in 6MWD with oral imatinib treatment was observed across all patient subgroups regardless of treatment with other PAH therapies (as seen in the figure below).
−Removed: We believe this observation suggests that oral imatinib improved 6MWD through a mechanism that was independent of patients’ background therapies.
−Removed: Imatinib led to improvements in 6MWD compared to placebo regardless of patients being treated concurrently with at least two approved PAH therapies
−Removed: In addition to improvements in 6MWD, patients treated with imatinib had greater improvements in multiple secondary endpoints, including measures of hemodynamics.
−Removed: Importantly, there was a significant improvement at 24 weeks in PVR (p<0.001), a measure of how difficult it is for blood to circulate through the lungs.
−Removed: Damaged pulmonary blood vessels make it more difficult for the heart to pump blood through the lungs, leading to increased pulmonary arterial pressure, increased workload on the heart, and if not resolved, heart failure.
−Removed: PVR is frequently used as a quantitative measure in PAH Phase 2 trials to determine the appropriate dose for registrational Phase 3 trials that directly measure changes in patient exercise capacity, such as 6MWD.
−Removed: Patients treated with imatinib had a significant reduction in PVR at 24 weeks, as noted in the blue box in the figure below.
−Removed: PVR was virtually unchanged compared to baseline in placebo treated patients.
−Removed: Consistent with the improvements in PVR, significant improvements compared to placebo treated patients, as shown in the figure below, were also observed in mean pulmonary artery pressure, or mPAP, which was decreased by 5.2 mm Hg;
−Removed: cardiac output, or CO, which was increased by 0.88 liter/min;
−Removed: and right arterial pressure, or RAP, which was decreased by 1.7 mm Hg.
−Removed: An echocardiography sub-study of 74 IMPRES patients showed that patients randomized to oral imatinib showed significant improvements in certain measures of right ventricle function after 24 weeks compared with placebo.
−Removed: Significant and consistent changes across hemodynamic and echo measures suggest a benefit of imatinib for the treatment of PAH with the potential to result in long-term improvements in pulmonary and cardiac function.
−Removed: Imatinib treatment led to significant improvements across multiple secondary endpoints including PVR (highlighted), an endpoint frequently used in Phase 2 dose-finding trials (Patients included in analyses of hemodynamic parameters include those who completed the study plus those who discontinued early but had a right heart catheterization performed at discontinuation.)
−Removed: Long-Term Extension Study
−Removed: Patients who completed the 24 week trial were eligible to be enrolled in an open label long-term extension study.
−Removed: The improvements in 6MWD achieved at 24 weeks were sustained during this extension and the mean difference in 6MWD compared to baseline improved up to 144 weeks in patients that were able to tolerate the treatment.
−Removed: Although these results were very encouraging, data from the extension trial also highlighted the major limitation in using oral imatinib to treat PAH, which was drug tolerability.
−Removed: Of the 103 patients originally randomized to the imatinib arm of the core trial, only 21 remained on therapy after 180 weeks of dosing.
−Removed: The patients who were able to tolerate the drug long term showed a durable continued improvement in 6MWD.
−Removed: Safety and Tolerability
−Removed: The relatively poor tolerability of oral imatinib poses challenges for the potential use in PAH patients.
−Removed: The AEs observed in the IMPRES trial were consistent with the AE profile observed in cancer trials, with the exception of subdural hematoma, and led to a significant number of discontinuations, which limited oral imatinib’s potential as a therapy for PAH.
−Removed: Specifically, 44% of patients treated with oral imatinib in the IMPRES trial experienced fluid retention, which is of
−Removed: particular concern in PAH patients who suffer from heart failure.
−Removed: The figure below lists the AEs reported in the 24-week Phase 3 IMPRES trial of oral imatinib in PAH patients on two or more standard-of-care therapies.
−Removed: Adverse events reported in >10% of the Imatinib group in the 24-week IMPRES trial, not including the trial extension
−Removed: In the IMPRES trial, there were 45 serious adverse events reported in imatinib treated patients, including some that were of particular concern for PAH patients, who already have compromised cardiac function.
−Removed: These included worsening of PAH;
−Removed: dyspnea, or shortness of breath;
−Removed: peripheral edema;
−Removed: and presyncope, or lightheadedness.
−Removed: Of note, subdural
−Removed: hematoma occurred in eight patients (two in the core study (1.9%), six in the trial extension (4.2%)) receiving imatinib and anticoagulation.
−Removed: Serious adverse events reported in the IMPRES 24-week trial publication, not including the trial extension
−Removed: Patients enrolled in the IMPRES trial that were not able to tolerate 400 mg/day of imatinib did not see a significant improvement in 6MWD after 24 weeks.
−Removed: As shown in the figure below, those patients who were not dosed with 400 mg/day for more than half of the time did not achieve the improvements in 6MWD that were significantly distinguished from those achieved by placebo treated patients.
−Removed: These results suggest that addressing the adverse events and tolerability of imatinib in PAH patients cannot be achieved by lowering the oral dose without sacrificing this improvement.
−Removed: Further development of oral imatinib for the treatment of PAH was discontinued by Novartis.
−Removed: Patients who were dosed with 400 mg/day for less than half of the duration of the trial did not achieve a significant improvement in 6MWD
−Removed: AV-101, an inhaled formulation of imatinib
−Removed: AV-101 is designed to deliver imatinib directly to the lungs to maximize the amount of drug in the targeted tissues while minimizing systemic exposure.
−Removed: We believe that delivering imatinib in this way may maintain imatinib’s potential therapeutic benefits while improving the tolerability of treatment.
−Removed: The oral version of imatinib, marketed as Gleevec, is delivered as tablets containing imatinib mesylate which is a salt of imatinib.
−Removed: Imatinib mesylate is not readily amenable to being used in an inhaled formulation because it absorbs water from the atmosphere if not stored in a rigorously controlled environment.
−Removed: Moisture uptake would lead to potential stability concerns and a high likelihood of poor delivery performance when inhaled from any dry powder inhaler device.
−Removed: We also believe mesylate salt would be a poor choice for an inhaled PAH therapy for additional reasons:
−Removed: (i) the mesylate group introduces a genotoxic risk;
−Removed: (ii) it increases the formulation risk due to the existence of multiple crystal forms;
−Removed: and (iii) delivery using the mesylate salt has the potential to release the acidic mesylate upon deposition on the lung surface which could lead to transient irritation and increase the propensity for cough.
−Removed: We therefore explored other salt and polymorphs of imatinib to identify a more suitable formulation for an inhaled therapy without altering the active molecule.
−Removed: We discovered a form that exhibited what we believe to be almost ideal physical chemical properties for development as a dry powder for inhalation using capsules in a simple dry powder inhaler, or DPI.
−Removed: We also believe that dry powder inhalation is the most convenient mode of delivery to the lungs for patients.
−Removed: The prospective advantages of dry powder inhalation include that such formulations (i) can be delivered via a convenient, portable and easy-to-use delivery system;
−Removed: (ii) avoid the cords or batteries or bulky equipment that may be needed with nebulizers;
−Removed: (iii) carry less risk of microbial contamination due to the low moisture content powder;
−Removed: (iv) have better anticipated shelf stability of the drug product compared to a solution dosage form;
−Removed: and (v) can potentially improve lung retention of the powder imatinib compared to an aqueous nebulizer formulation, which may result in reduced dose, dose frequency and peak exposure in the circulation.
−Removed: AV-101 Phase 1 Clinical Trial
−Removed: We have completed a placebo-controlled, randomized, double-blinded, single ascending dose and multiple ascending dose Phase 1 clinical trial of AV-101 in 82 healthy adult volunteers.
−Removed: Doses tested in the single ascending dose, or SAD, portion ranged from 1 to 90 mg of AV-101.
−Removed: A 400 mg dose of oral imatinib was included as a comparator.
−Removed: The multiple ascending dose, or MAD, portion tested 10 mg, 30 mg and 90 mg BID ( bis in die ;
−Removed: or twice a day) for seven days.
−Removed: The purpose of the trial was to establish safety and tolerability of AV-101 and to demonstrate that systemic levels of AV-101 were lower than oral imatinib.
−Removed: All doses resulted in lower systemic plasma levels of imatinib compared to those observed following a single 400 mg oral dose.
−Removed: In the figure below, the blue dashed line shows simulated steady state levels of oral imatinib in the blood extrapolated from the 400 mg cohort in the SAD potion of our Phase 1 clinical trial.
−Removed: These levels are consistent with multiple publications on oral imatinib pharmacokinetics.
−Removed: The other lines show the blood concentrations following the final dose of AV-101 in the MAD portion of our Phase 1 clinical trial, on day 7, when steady state concentrations had been achieved.
−Removed: The dotted part of the 90 mg dose shows a simulated representation of an additional dose twelve hours later to illustrate steady state BID dosing.
−Removed: Phase 1 systemic exposure of AV-101 vs 400 mg oral imatinib.
−Removed: We also predicted lung exposures using a physiologically based pharmacokinetic, or PBPK, model built from a published method to extrapolate lung exposures from blood levels, which was informed by our Phase 1 plasma data.
−Removed: Although there is inherent uncertainty associated with all models that extrapolate data, we expect the exposures of imatinib obtained in the lungs at the dose range we intend to use in the Phase 2b portion of our Phase 2b/Phase 3 trial of 35 mg and 70 mg, all BID, to overlap or surpass lung levels predicted from 400 mg oral imatinib.
−Removed: The dashed blue line in Figure 11 shows lung
−Removed: exposures extrapolated from published steady state PK data and informed by our Phase 1 plasma data for oral imatinib at 400 mg.
−Removed: The solid lines show extrapolated lung levels of AV-101 doses using our PBPK model.
−Removed: Predicted Phase 2b lung exposures from dosing of 10, 35 and 70 mg AV-101.
−Removed: We expect the lung exposures of imatinib delivered by AV-101 in the dose range to overlap or surpass the predicted lung exposures from 400 mg oral imatinib
−Removed: Safety and Tolerability in Phase 1 Clinical Trial
−Removed: There were no serious adverse events reported in our Phase 1 clinical trial.
−Removed: Adverse events reported in the Phase 1 clinical trial were classified as mild or moderate.
−Removed: There were no changes in vital signs including pulmonary function testing and oxygen saturations.
−Removed: Of the less severe adverse events, there was one discontinuation at the highest dose due to vomiting and the most frequent adverse event was a cough that was reported in 55% of volunteers at the highest 90 mg dose.
−Removed: This cough was transient, predominantly mild in nature, resolved on its own within 30 minutes and did not lead to any discontinuations.
−Removed: We believe that the cough may be a function of the total amount of powder delivered in the high Phase 1 dose.
−Removed: The intended dosing for the Phase 2b/Phase 3 trial will use less than 40% of the amount of powder that was inhaled
−Removed: at the highest Phase 1 dose.
−Removed: The figure below shows the adverse events reported in our Phase 1 MAD trial of AV-101 in healthy volunteers.
−Removed: Adverse events reported in the Phase 1 MAD trial of AV-101 in healthy volunteers
−Removed: We submitted to the FDA summaries of the safety and tolerability findings from our Phase 1 clinical trial along with the systemic plasma levels for the participants from the trial.
−Removed: We also submitted information on our drug substance and drug product.
−Removed: At our April 2021 meeting, we reached alignment with the FDA that our Phase 2b/Phase 3 trial design was acceptable and could, if successful with strong results, support a NDA submission using the change in 6MWD compared to placebo over 24 weeks as the primary endpoint in the Phase 3 portion of our trial.
−Removed: AV-101 Phase 2b/Phase 3 IMPAHCT:
−Removed: Inhaled iMatinib Pulmonary Arterial Hypertension Clinical Trial
−Removed: In December 2021, we announced the initiation of IMPAHCT, our global Phase 2b/Phase 3 trial in adults with Functional Class II through Class IV PAH with inadequate disease control on top of standard of care PAH therapies.
−Removed: In November 2023, we announced completion of enrollment with 202 patients in the Phase 2b portion and enrollment of the first patient in the Phase 3 portion of IMPAHCT.
−Removed: We are enrolling patients in the Phase 3 portion of this trial and will announce the approximate number of patients we plan to enroll in the Phase 3 portion of the trial based on the topline results of the Phase 2b portion of the trial.
−Removed: We anticipate that topline data from the Phase 2b portion of this trial will be available in June 2024.
−Removed: This clinical trial will establish the target dose in the Phase 2b portion then continue into a Phase 3 efficacy trial using the selected dose.
−Removed: The Phase 2b portion of this double-blind, placebo-controlled randomized trial is designed to assess safety and tolerability using change in PVR, an objective measure of the effect of AV-101 on hemodynamic function in PAH patients, as the primary endpoint to inform the selection of the appropriate dose for the Phase 3 portion of the trial.
−Removed: Change in 6MWD compared to placebo will be a secondary endpoint, and all efficacy endpoints will be measured following 24 weeks of treatment.
−Removed: The Phase 3 portion of the trial will use the change in 6MWD compared to placebo at 24 weeks as the primary endpoint.
−Removed: Secondary endpoints in the Phase 2b/Phase 3 trial will include N-terminal pro B-type natriuretic peptide, or NT-proBNP, a biomarker associated with heart failure;
−Removed: hemodynamic parameters;
−Removed: clinical worsening;
−Removed: clinical improvement;
−Removed: change in functional class;
−Removed: change in risk score;
−Removed: and quality of life measures.
−Removed: All patients completing the Phase 2b or Phase 3 portions will be invited to enter a long-term extension trial of AV-101.
−Removed: Phase 2b/Phase 3 Enrollment and Timing
−Removed: The Phase 2b/Phase 3 trial employs an operationally seamless, adaptive design consisting of three parts.
−Removed: ● We completed Phase 2b enrollment with 202 patients across four treatment arms, which include three dose groups of AV-101 and one placebo group.
−Removed: The primary endpoint is the change in PVR compared to placebo at 24 weeks.
−Removed: Data from the Phase 2b portion will inform the selection of an optimal dose of AV-101 for Phase 3.
−Removed: We anticipate that topline Phase 2b data will be available in June 2024.
−Removed: ● Part 3 enrollment began in November 2023 with completion of enrollment in the Phase 2b portion of the trial.
−Removed: ● When the optimal dose is selected, Phase 3 will then only enroll across two treatment arms, the optimal dose of AV-101 and the placebo arm.
−Removed: Once the final patient enrolled in the Phase 3 portion has completed 24 weeks on study, the Phase 3 portion of the trial is complete.
−Removed: Design of the Phase 2b/Phase 3 trial of AV-101 in adults with PAH
−Removed: If the results of the Phase 3 portion of this trial show a statistically significant and potentially clinically meaningful benefit in 6MWD, we plan to submit a NDA, with the FDA for AV-101 for the treatment of PAH.
+Added: Our focus on developing AV-101 had been driven by historical results from the Phase 3 IMPRES clinical trial of oral imatinib for the treatment of PAH patients.
+Added: Oral imatinib is a well-characterized targeted kinase inhibitor and approved oncology treatment, but clinical trials had also supported its potential for the treatment of PAH.
+Added: On June 17, 2024, we announced topline results from the Phase 2b portion of the Phase 2b/Phase 3 IMPAHCT.
+Added: Results showed that, while AV-101 was well tolerated across all dose groups, the study did not meet its primary endpoint for improvement in pulmonary vascular resistance, or PVR, compared to placebo for any of the studied doses or show meaningful improvements in the secondary endpoint of change in 6MWD.
+Added: Primary Endpoint — ITT analysis of PVR (dynes*sec/cm ˄ 5)
+Added: Least-squares mean difference as compared with placebo (95% CI)d
+Added: 10mg BID (N=50)
+Added: 42.8 (-80.57 to 166.09)
+Added: 35mg BID (N=49)
+Added: -5.5 (-129.16 to 118.18)
+Added: 70mg BID (N=51)
+Added: -57.0 (-181.14 to 67.20)
+Added: Secondary Endpoint — ITT analysis of 6MWD (meters)
+Added: Least-squares mean difference as compared with placebo (95% CI)d
+Added: 10mg BID (N=50)
+Added: -11.7 (-34.75 to 11.26)
+Added: 35mg BID (N=49)
+Added: -4.2 (-27.74 to 19.37)
+Added: 70mg BID (N=51)
+Added: +1.3 (-22.09 to 24.60)
+Added: We also reviewed data from several additional secondary endpoints of the Phase 2b portion of IMPAHCT, which also failed to show meaningful improvements.
+Added: Based upon these results, we, in agreement with the independent study advisory committee, halted enrollment and shut down the Phase 3 portion of IMPAHCT as well as the long-term extension study.
+Added: We plan to release full data from the Phase 2b portion of IMPAHCT at a later date, the timing of which is to be determined.
Manufacturing and Supply
We use third-party contract manufacturers for the production of our combination product, AV-101.
−Removed: Our active pharmaceutical ingredient, or API, is generic and can be purchased from multiple commercial vendors in compliance with the FDA’s current Good Manufacturing Practice, or current GMP, regulations and European Pharmacopoeia, or EP, standards.
+Added: Our active pharmaceutical ingredient, or API, is generic and can be purchased from multiple commercial vendors in compliance with the U.S.
+Added: Food and Drug Administration’s, or the FDA’s, current Good Manufacturing Practice, or current GMP, regulations and European Pharmacopoeia, or EP, standards.
To be used in our inhaled product, the API requires an additional manufacturing step, which is completed at our contract manufacturing organization that complies with the FDA’s current GMP regulations.
2 unchanged sentences
Release and stability testing to date supports stability of at least 36 months for API under ambient conditions and supports stability of at least 36 months for drug product also under ambient conditions.
−Removed: Our API, finished product, and single-dose inhaler producers are accepted by the health authorities in all countries that are included in our ongoing global Phase 2b/Phase 3 clinical trial.
−Removed: We are routinely manufacturing clinical supplies to ensure sufficient supplies are positioned at our global distribution partner for distribution to the active clinical sites.
−Removed: In anticipation of a potential NDA filing, we are manufacturing a minimum of three batches of API, finished product, and single-dose inhaler devices for registration purposes and to test these batches for stability with a goal of establishing a commercial shelf life of at least two years for finished product and bulk API.
+Added: Our API, finished product, and single-dose inhaler producers are accepted by the health authorities in all countries that were included in our global Phase 2b/Phase 3 clinical trial.
+Added: We have paused manufacturing of AV-101 as we engage in our process to evaluate strategic alternatives, including the Merger.
Sales and Marketing
−Removed: Our commercialization strategy is to develop AV-101 into a leading therapy worldwide for the treatment of PAH.
−Removed: Our Chief Executive Officer and Chief Commercial Officer have significant commercial experience, but beyond that we have not yet established a sales and marketing organization.
−Removed: We intend to recruit our own specialty sales force in the United States focused on promoting AV-101.
−Removed: We plan to target our marketing and sales efforts to pulmonologists and cardiologists who specialize in treating PAH.
−Removed: We believe a specialty sales force of approximately 75-100 representatives, supported by reimbursement specialists and a medical affairs team, will enable us to call on the pulmonologists and cardiologists who specialize in treating PAH.
−Removed: We believe that the market for AV-101 in the five largest countries in the European Union represents the bulk of the potential European market and that China and Japan represent the bulk of the potential Asian market.
−Removed: We plan to enter one or multiple collaborations to commercialize AV-101 in Europe and Asia.
−Removed: We believe AV-101 will receive coverage and reimbursement by public and commercial payors, but we cannot guarantee this will happen.
−Removed: For more information regarding these risks, please see “Risk Factors—Risks Related to Commercialization—The successful commercialization of AV-101 will depend in part on the extent to which governmental authorities, private health insurers, and other third-party payors provide coverage and adequate reimbursement levels.
−Removed: Failure to obtain or maintain coverage and adequate reimbursement for AV-101, if approved, could limit our ability to market our product and decrease our ability to generate revenue.”
+Added: Our commercialization strategy was previously to develop AV-101 into a leading therapy worldwide for the treatment of PAH.
+Added: Should we resume product development activities and obtain approval for any products, we would need to establish a sales and marketing organization.
+Added: We cannot guarantee that AV-101 or any future product candidate will receive coverage and reimbursement by public and commercial payors.
Intellectual Property
5 unchanged sentences
We also rely on trademarks, trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain our proprietary position.
−Removed: Our intellectual property portfolio includes issued patents in the United States, pending patent applications in the United States, under the Patent Cooperation Treaty (PCT international applications), and in commercially relevant foreign jurisdictions for our products.
+Added: In June 2024, we announced our decision to halt enrollment and shut down the Phase 3 portion of IMPAHCT as well as the long-term extension study of AV-101 in PAH, and we do not intend to continue to seek or maintain intellectual property protection on the technology underlying AV-101.
+Added: Our intellectual property portfolio includes issued patents in the United States, pending patent applications in the United States, under the Patent Cooperation Treaty, or the PCT international applications, and in commercially relevant foreign jurisdictions for our products.
The PCT international applications preserve all of our rights to file patent applications in commercially relevant foreign jurisdictions for our products.
−Removed: As of March 20, 2024, we own six U.S.
−Removed: patents, eleven U.S.
−Removed: patent applications, no pending PCT international applications, and thirty foreign patent applications.
+Added: As of December 31, 2024, we own six U.S.
+Added: patents, seven U.S.
+Added: patent applications, no pending PCT international applications, and 19 foreign patent applications.
patent portfolio is expected to expire between May 14, 2040 and February 15, 2042, excluding any extension of patent term that may be available and assuming that the filed patent applications will issue as patents.
3 unchanged sentences
Our patent portfolio is summarized in the following table.
−Removed: APPLICATION/ PATENT NO.
+Added: EXPIRATION*
PROTECTION SOUGHT
−Removed: PROJECTED EXPIRATION*
+Added: EXPIRATION*
Composition of Matter;
89 unchanged sentences
In addition, patents, if granted, expire, and we cannot provide any assurance that any patents will be issued from our pending or any future applications or that any issued patents will adequately protect our products.
−Removed: We have conducted freedom to operate, or FTO, analyses of the current patent landscape with respect to our lead product candidates.
+Added: We have conducted freedom to operate analyses of the current patent landscape with respect to our lead product candidates.
In doing so, we have strived to ensure our ability to operate freely within the complex patent landscape of inhalable kinase inhibitors and the use of such products in the field of PAH.
−Removed: We are also working to develop new formulations of our drug products and new uses for such products, for which we intend to seek patent protection on our own to expand the layers of protection provided by our intellectual property estate.
+Added: New formulations of drug products and new uses for such products would require seeking patent protection on our own to expand the layers of protection provided by our intellectual property estate.
Patent Protection and Terms
4 unchanged sentences
There can be no assurance that any such patent term adjustment or extension will be obtained.
−Removed: The duration of foreign patents
−Removed: varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest effective filing date.
+Added: The duration of foreign patents varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest effective filing date.
However, the actual protection afforded by a patent varies on a product-by-product basis, from country to country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.
−Removed: Furthermore, the patent positions of biotechnology and pharmaceutical products and processes like those we intend to develop and commercialize are generally uncertain and involve complex legal and factual questions.
+Added: Furthermore, the patent positions of biotechnology and pharmaceutical products and processes are generally uncertain and involve complex legal and factual questions.
No consistent policy regarding the breadth of claims allowed in such patents has emerged to date in the United States.
The patent situation outside the United States is even more uncertain.
−Removed: Changes in either the patent laws or in interpretations of patent laws in the United States and other countries can diminish our ability to protect our inventions and enforce our intellectual property rights, can make it easier to challenge the validity, enforceability or scope of any patents that may issue, and, more generally, could affect the value of our intellectual property.
−Removed: Accordingly, we cannot predict the breadth of claims that may be allowed or enforced in our patents or in third-party patents.
+Added: Changes in either the patent laws or in interpretations of patent laws in the United States and other countries can diminish the ability to protect inventions and enforce intellectual property rights, can make it easier to challenge the validity, enforceability or scope of any patents that may issue, and, more generally, could affect the value of intellectual property.
+Added: Accordingly, the breadth of claims that may be allowed or enforced in our patents or in third-party patents cannot be predicted.
Third-Party Patent Filings
Numerous U.S.
−Removed: and foreign issued patents and patent applications owned by third parties exist in the fields in which we are developing products.
+Added: and foreign issued patents and patent applications owned by third parties exist in the fields in which we may resume developing products.
In addition, because patent applications can take many years to issue, there may be applications unknown to us, which may later result in issued patents that our products or proprietary technologies may infringe.
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However, we may not be able to obtain any required license on commercially reasonable terms or at all.
−Removed: Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed
+Added: Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us.
We could also be forced, including by court order, to cease commercializing the infringing product or technology.
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The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.
−Removed: We face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions.
−Removed: Some of our potential competitors have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.
+Added: We have faced potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions.
+Added: In June 2024, we announced our decision to halt enrollment and shut down the Phase 3 portion of IMPAHCT as well as the long-term extension study of AV-101 in PAH and will not advance development of AV-101 in PAH.
+Added: Some of our historical competitors have had significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we did.
Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
−Removed: The key competitive factors that will differentiate AV-101, if approved, are likely to be its efficacy, safety, convenience, price, and the availability of reimbursement from commercial, government and other third-party payors.
−Removed: We intend to seek approval for AV-101 initially in patients for the treatment of PAH as an add-on therapy to currently approved standard of care .
−Removed: We recognize that physicians have many treatment options for patients already on existing treatments for PAH, including prostanoids available in oral form as Orenitram (United Therapeutics Corporation, or United Therapeutics) and Uptravi (Janssen Pharmaceuticals, Inc., or Janssen), by inhalation as Tyvaso and Tyvaso DPI (United Therapeutics), Ventavis (Janssen), and by infusion as Remodulin (United Therapeutics), Flolan (GlaxoSmithKline plc) and Veletri (Janssen).
−Removed: We believe that AV-101, if approved, could be used prior to or in combination with prostanoids, and in combination with existing front-line agents such as the oral PDE5 inhibitors, including Revatio (Pfizer) and Adcirca (United Therapeutics);
−Removed: the sGC stimulator Adempas (Bayer AG);
−Removed: and oral ERAs, including Tracleer (Janssen), Letairis (Gilead) and Opsumit (Janssen).
−Removed: PAH is also an active indication for investigational drugs, and we may face competition in the future from sotatercept (Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc.) under review by the FDA and EMA, and/or seralutinib (Gossamer Bio, Inc.).
−Removed: To our knowledge, Aerami Therapeutics, Inc.
−Removed: is developing other formulations of imatinib for PAH, and have completed a Phase 1 clinical trial and indicated they intend to pursue further clinical development .
+Added: The key competitive factors that differentiate products, if approved, are likely to be efficacy, safety, convenience, price, and the availability of reimbursement from commercial, government and other third-party payors.
Government Regulation
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We, along with third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory authorities of the countries in which we wish to conduct studies or seek approval of our product candidates.
−Removed: Failure to comply with applicable United States requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending NDAs, withdrawal of an approval, warning or untitled letters, clinical holds, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, civil penalties, and criminal prosecution.
+Added: Failure to comply with applicable United States requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending New Drug Applications, or NDAs, withdrawal of an approval, warning or untitled letters, clinical holds, product recalls or withdrawals from the market, product seizures, total or partial suspension of production
+Added: or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, civil penalties, and criminal prosecution.
FDA approval is required before any new unapproved product or a product with certain changes to a previously approved product, including a new use of a previously approved drug, can be marketed in the United States.
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In such a case, the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.
−Removed: The FDA may also impose clinical holds on a product candidate at any time before or during clinical trials due to safety concerns, non-compliance or other issues affecting the integrity of the trial.
−Removed: Accordingly, submission of an IND application may or
−Removed: may not result in the FDA allowing clinical trials to commence and, once begun, issues may arise that could cause the trial to be suspended or terminated.
+Added: may also impose clinical holds on a product candidate at any time before or during clinical trials due to safety concerns, non-compliance or other issues affecting the integrity of the trial.
+Added: Accordingly, submission of an IND application may or may not result in the FDA allowing clinical trials to commence and, once begun, issues may arise that could cause the trial to be suspended or terminated.
Clinical trials involve the administration of the investigational drug product to human subjects under the supervision of a qualified investigator.
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The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product.
−Removed: Additionally, 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.
+Added: Additionally, appropriate packaging must be selected and
+Added: tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical study investigators.
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If regulatory approval of a product is granted, such approval will be granted for a particular indication(s) and may include limitations on the indicated use(s) for which such product may be marketed.
−Removed: Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the NDA
−Removed: on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-market testing or clinical trials and surveillance to monitor the effects of approved products.
+Added: Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-market testing or clinical trials and surveillance to monitor the effects of approved products.
As a condition of NDA approval, the FDA may require a risk evaluation and mitigation strategy, or REMS, to help ensure that the benefits of the drug outweigh the potential risks.
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Under the FDCA and its implementing regulations, the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product.
−Removed: The designation of a lead center generally eliminates the need to
−Removed: receive approvals from more than one FDA component for combination products, although it does not preclude consultations by the lead center with other components of FDA.
+Added: The designation of a lead center generally eliminates the need to receive approvals from more than one FDA component for combination products, although it does not preclude consultations by the lead center with other components of FDA.
The determination of which center will be the lead center is based on the “primary mode of action” of the combination product.
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The FDA may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards or is not maintained, if problems occur following initial marketing, or if previously unrecognized problems are subsequently discovered.
−Removed: Later discovery of previously unknown problems with a product, including adverse events of
−Removed: unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;
+Added: Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;
imposition of post-market studies or clinical trials to assess new safety risks;
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The USPTO, in consultation with the FDA, reviews and approves or denies the application for any patent term extension or restoration.
−Removed: In the future, we intend to apply for extension of patent term for one of our patents covering AV-101 to add patent life beyond its current expected expiration date.
Marketing Exclusivity
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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 applications for drugs that do not have the innovative change, such as generic copies of the original, unmodified drug product.
−Removed: Three-year exclusivity blocks approval of 505(b)(2) applications and Abbreviated New Drug Applications, or ANDAs, but will not delay the submission or approval of a full NDA.
−Removed: However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
+Added: Three-year exclusivity blocks approval of 505(b)(2) applications and Abbreviated NDAs, but will not delay the submission or approval of a full NDA.
+Added: However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the nonclinical studies and adequate and well-controlled clinical trials necessary to
+Added: demonstrate safety and effectiveness.
Orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.
−Removed: Pediatric exclusivity is another type of
−Removed: regulatory market exclusivity in the United States.
+Added: Pediatric exclusivity is another type of regulatory market exclusivity in the United States.
Pediatric exclusivity, if granted, adds six months to existing exclusivity periods, including exclusivity attaching to certain patent certifications.
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Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical substances.
−Removed: Non-clinical studies must be conducted in compliance with the principles of good laboratory practice, or GLP, as set forth in EU Directive 2004/10/EC.
+Added: Non-clinical studies must be conducted in compliance with the principles of GLP as set forth in EU Directive 2004/10/EC.
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.
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The CTR also makes it more efficient for EU Member States to evaluate and authorize applications together, via the Clinical Trials Information System.
−Removed: Medicines used in clinical trials must be manufactured in accordance with GMP.
+Added: Medicines used in clinical trials must be manufactured in accordance with Good Manufacturing Practices, or GMP.
Other national and EU-wide regulatory requirements may also apply.
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In the EU, medicinal products can only be placed on the market after obtaining a marketing authorisation, or MA.
−Removed: To obtain regulatory approval of a product in the EU, we must submit an MAA.
+Added: To obtain regulatory approval of a product in the EU, we must submit a marketing authorization application, or MAA.
The process for doing this depends, among other things, on the nature of the medicinal product.
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A medicinal product may be designated as orphan if (1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;
−Removed: (2) either (a) such condition affects no more than 5 in 10,000 persons in the EU when the application is made, or (b) it is unlikely that the marketing of the product, without the benefits derived from orphan status, would generate sufficient return in the EU to justify the necessary investment in its development;
+Added: (2) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) it is unlikely that the marketing of the product, without the benefits derived from orphan status, would generate sufficient return in the EU to justify the necessary investment in its development;
and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU or, if such a method exists, the product in question would be of significant benefit compared to products available for that condition.
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The grant of an MA for an orphan medicinal product leads to ten years of market exclusivity.
−Removed: During the ten-year market exclusivity period, the EMA cannot accept an MAA, or grant an MA, or accept an application to extend an MA, for the same therapeutic indication, in respect of a “similar medicinal product”.
−Removed: A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.
−Removed: An orphan medicinal product can also obtain an additional two years of market exclusivity in the EU for pediatric studies conducted in compliance with an agreed PIP.
+Added: During the ten-year market exclusivity period, the EMA cannot accept an MAA, or grant an MA, or accept an application to extend an MA, for the same therapeutic indication, in respect of a “similar medicinal product.” A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.
+Added: An orphan medicinal product can also obtain an additional two years of market exclusivity in the EU for pediatric studies conducted in compliance with an agreed pediatric investigation plan, or PIP.
No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.
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Pediatric Development
−Removed: 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.
+Added: In the EU, MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a 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 product for which an MA is being sought.
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In the United States no uniform policy of coverage and reimbursement for drug products exists.
−Removed: Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for any of our products will be made on a payor by payor basis.
+Added: Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for any products will be made on a payor by payor basis.
Private third-party payors tend to follow Medicare coverage policies and payment limitations in setting their own reimbursement rate to a substantial degree, but also have their own methods and approval process apart from Medicare determinations.
−Removed: As a result, coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.
+Added: As a result, coverage determination process is often a time-consuming and costly process that will require providing scientific and clinical support for the use of product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.
Factors payors consider in determining reimbursement are based on whether the product is:
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Increasingly, third party payors are implementing cost-cutting and reimbursement initiatives and likely will continue to do so in the future.
−Removed: These include establishing formularies that govern the drugs and biologics that will be offered and also the out-of-pocket obligations of member patients for such products.
−Removed: In addition, net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation
−Removed: of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
−Removed: It is possible that future legislation in the United States and other jurisdictions could be enacted which could potentially impact the reimbursement rates for the products we are developing and may develop in the future and also could further impact the levels of discounts and rebates paid to federal and state government entities.
−Removed: Any legislation that impacts these areas could impact, in a significant way, our ability to generate revenues from sales of products that, if successfully developed, we bring to market.
+Added: These include establishing formularies that govern the drugs and biologics that will be offered and also
+Added: the out-of-pocket obligations of member patients for such products.
+Added: In addition, net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
+Added: It is possible that future legislation in the United States and other jurisdictions could be enacted which could potentially impact the reimbursement rates for the products in development and that may be developed in the future and also could further impact the levels of discounts and rebates paid to federal and state government entities.
+Added: Any legislation that impacts these areas could impact, in a significant way, the ability to generate revenues from sales of products that, if successfully developed, are brought to market.
In addition, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.
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A company can make only those claims relating to safety and efficacy that are approved by the FDA in labeling.
−Removed: Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those tested by us and approved by the FDA.
+Added: Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those tested uses and uses approved by the FDA.
Such off-label uses are common across medical specialties, and often reflect a physician’s belief that the off-label use is the best treatment for the patients.
2 unchanged sentences
Healthcare Laws and Regulations
−Removed: Pharmaceutical companies are also subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business that may constrain the financial arrangements and relationships through which we research, as well as sell, market and distribute any products for which we obtain marketing authorization.
+Added: Pharmaceutical companies are also subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business that may constrain the financial arrangements and relationships through which products are researched, sold, marketed and distributed, when marketing authorization is obtained.
Such laws include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, and transparency laws and regulations related to drug pricing and payments and other transfers of value made to physicians and other healthcare providers.
−Removed: If our operations are found to be in violation of any of such laws or any other governmental regulations that apply, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations,
−Removed: integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and responsible individuals may be subject to imprisonment.
+Added: If operations are found to be in violation of any of such laws or
+Added: any other governmental regulations that apply, there may to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and responsible individuals may be subject to imprisonment.
Such laws include, but are not limited to:
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● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which impose requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses as well as their respective business associates, independent contractors or agents of covered entities, that perform services for them that involve the creation, maintenance, receipt, use, or disclosure of, individually identifiable health information relating to the privacy, security and transmission of individually identifiable health information.
−Removed: HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and
−Removed: seek attorneys’ fees and costs associated with pursuing federal civil actions.
+Added: HITECH also created new tiers of civil monetary penalties, amended HIPAA to
+Added: make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
In addition, there may be additional federal, state and non-U.S.
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Healthcare Reform and Legislation
−Removed: Payors, whether domestic or foreign, or governmental or private, are developing increasingly sophisticated methods of controlling healthcare costs and those methods are not always specifically adapted for new technologies such as gene therapy and therapies addressing rare diseases such as those we are developing.
−Removed: In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact our ability to sell our products profitably.
−Removed: In particular, in 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, was enacted, which,
−Removed: among other things, subjected biologic products to potential competition by lower-cost biosimilars;
+Added: Payors, whether domestic or foreign, or governmental or private, are developing increasingly sophisticated methods of controlling healthcare costs and those methods are not always specifically adapted for new technologies such as gene therapy and therapies addressing rare diseases.
+Added: In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact the ability to sell products
+Added: In particular, in 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, was enacted, which, among other things, subjected biologic products to potential competition by lower-cost biosimilars;
increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;
11 unchanged sentences
Additionally, in May 2019, CMS issued a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.
−Removed: The Inflation Reduction Act of 2022, includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket cap for Medicare Part D beneficiaries to $2,000 starting in 2025;
+Added: The Inflation Reduction Act of 2022, includes several provisions that may impact the healthcare industry to varying degrees, including provisions that reduce the out-of-pocket cap for Medicare Part D beneficiaries to $2,000 starting in 2025;
impose new manufacturer financial liability on certain drugs under Medicare Part D, allow the U.S.
3 unchanged sentences
The implementation of the IRA is currently subject to ongoing litigation challenging the constitutionality of the IRA’s Medicare drug price negotiation program.
−Removed: The effects of the IRA on our business and the healthcare industry in general is not yet known.
+Added: The effects of the IRA on the healthcare industry is not yet known.
There has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices.
4 unchanged sentences
Further, on May 30, 2018, the Right to Try Act, was signed into law.
−Removed: The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.
−Removed: Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access
+Added: The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical
+Added: trial and that are undergoing investigation for FDA approval.
+Added: Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.
There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.
1 unchanged sentence
In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.
−Removed: These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
+Added: These measures could reduce the ultimate demand for products or put pressure on product pricing.
Data Privacy and Security Laws
Numerous state, federal and foreign laws, including consumer protection laws and regulations, govern the collection, dissemination, use, access to, confidentiality, and security of personal information, including health-related information.
−Removed: In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws, including HIPAA and federal and state consumer protection laws and regulations (e.g., Section 5 of the Federal Trade Commission Act) that govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners.
+Added: In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws, including HIPAA and federal and state consumer protection laws and regulations (e.g., Section 5 of the Federal Trade Commission Act) govern the collection, use, disclosure, and protection of health-related and other personal information.
In addition, certain state and non-U.S.
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Other Laws and Regulatory Processes
−Removed: We will become subject to a variety of financial disclosure and securities trading regulations as a public company in the United States, including laws relating to the oversight activities of the SEC and, following the listing of our capital stock on The Nasdaq Global Market, we will be subject to the regulations of The Nasdaq Global Market.
+Added: We are subject to a variety of financial disclosure and securities trading regulations as a public company in the United States, including laws relating to the oversight activities of the SEC and, the regulations of The Nasdaq Global Market.
In addition, the Financial Accounting Standards Board, or FASB, the SEC and other bodies that have jurisdiction over the form and content of our accounts, our financial statements and other public disclosure are constantly discussing and interpreting proposals and existing pronouncements designed to ensure that companies best display relevant and transparent information relating to their respective businesses.
Our international operations are subject to compliance with the Foreign Corrupt Practices Act, or the FCPA, which prohibits corporations and individuals from paying, offering to pay, or authorizing the payment of anything of value to any foreign government official, government staff member, political party, or political candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity.
−Removed: We also may be implicated under the FCPA for activities by our partners, collaborators, CROs, vendors or other agents.
+Added: We also may be implicated under the FCPA for activities by our partners, collaborators, contract research organizations, or CROs, vendors or other agents.
Our present and future business has been and will continue to be subject to various other laws and regulations.
−Removed: Various laws, regulations and recommendations relating to safe working conditions, laboratory practices, the experimental use of animals, and the purchase, storage, movement, import and export and use and disposal of hazardous or potentially hazardous substances used in connection with our research work are or may be applicable to our activities.
−Removed: Certain agreements entered into by us involving exclusive license rights or acquisitions may be subject to national or supranational antitrust regulatory control, the effect of which cannot be predicted.
The extent of government regulation, which might result from future legislation or administrative action, cannot accurately be predicted.
Human Capital Resources
−Removed: As of March 22, 2024, we had 51 full-time employees, including 43 in research and development and eight in general and administrative functions.
−Removed: We also contract with a number of consultants to supplement the efforts and responsibilities of our employees.
+Added: As of March 24, 2025, we had four full-time employees, all in general and administrative functions.
+Added: We also contract with consultants to supplement the efforts and responsibilities of our employees.
None of our employees are subject to a collective bargaining agreement or represented by a labor or trade union.
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Our website address is https://www.aerovatetx.com.
−Removed: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we
−Removed: electronically file such material with, or furnish it to, the SEC.
+Added: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.
Information on our website is not part of this Annual Report on Form 10-K or any of our other securities filings unless specifically incorporated herein by reference.
7 unchanged sentences
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.