10-K
mt
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2024
OR
☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 FOR THE TRANSITION PERIOD FROM TO
Commission File Number 001-32157
Savara Inc.
(Exact name of Registrant as specified in its Charter)
1717 Langhorne Newtown Road, Suite 300 Langhorne, Pennsylvania 19047
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including area code: (512) 614-1848
Securities registered pursuant to Section 12(b) of the Act:
Title of each class TradingSymbol(s) Name of each exchange on which registered
Common Stock, par value $0.001 per share SVRA The Nasdaq Global Select Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes ☒ No ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐
If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No☒
The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant, based on the closing price of the shares of common stock on The Nasdaq Global Select Market on June 30, 2024, (the last business day of the registrant’s most recently completed second fiscal quarter), was $544,458,670.
The number of shares of Registrant’s Common Stock outstanding as of March 27, 2025 was172,633,140.
Portions of the Registrant’s Definitive Proxy Statement relating to the Annual Meeting of Shareholders, scheduled to be held on June 5, 2025, are incorporated by reference into Part III of this Report.
Table of Contents
Page
PART I
Item 1. Business 5
Item 1A. Risk Factors 28
Item 1B. Unresolved Staff Comments 48
Item 1C. Cybersecurity 49
Item 2. Properties 49
Item 3. Legal Proceedings 49
Item 4. Mine Safety Disclosures 49
PART II
Item 6. Reserved 50
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 57
Item 8. Financial Statements and Supplementary Data 57
Item 9A. Controls and Procedures 58
Item 9B. Other Information 58
PART III
Item 10. Directors, Executive Officers, and Corporate Governance 59
Item 11. Executive Compensation 59
Item 14. Principal Accounting Fees and Services 60
PART IV
Item 15. Exhibits, Financial Statement Schedules 61
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Cautionary Statement Concerning Forward-Looking Statements
This Annual Report on Form 10-K, particularly in Item 1. Business, and Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations, and the information incorporated herein by reference, include forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements are based on current expectations and beliefs and involve numerous risks and uncertainties that could cause actual results to differ materially from expectations. These forward-looking statements should not be relied upon as predictions of future events as we cannot assure you that the events or circumstances reflected in these statements will be achieved or will occur. When used in this report, the words “aim,” “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “indicate,” “intend,” “may,” “plan,” “predict,” “seek,” “should,” “target,” “will,” “would,” and similar expressions are intended to identify forward-looking statements, though not all forward-looking statements contain these identifying words. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements. For example, forward-looking statements include, but are not limited to, statements about:
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our plans, strategies, and objectives for future operations, including the execution and timing of those plans;
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our future financial condition or performance, including the accuracy of our estimates regarding expenses, future revenues, capital requirements, and needs for additional funding;
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the process, prospects, and timing for regulatory approval of our product candidate or any product candidates that we may develop;
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the timing, progress and results of clinical trials for our product candidate;
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our beliefs regarding the therapeutic benefits and efficacy of our product candidate;
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our beliefs regarding the treatment of conditions related to the indications targeted by our product candidate;
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our use of clinical research organizations and other contractors;
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our ability to successfully commercialize our product candidates and prospects for market success;
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our product candidate, including our ability to obtain and maintain intellectual property protection, third party payor coverage, and reimbursement;
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the size and growth of the markets for our product candidate and our ability to serve those markets;
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our competitive position, and developments and projections relating to both our competitors and our industry;
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our ability to establish and/or maintain future collaborations or strategic relationships or obtain additional funding;
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our ability to maintain compliance with our covenants under our long-term debt instruments;
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the impact of laws and regulations and/or regulatory developments in the U.S. and other countries;
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the performance of our third-party suppliers and manufacturers; and
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our ability to attract and retain key personnel.
Summary Risk Factors
The risk factors described below are a summary of the principal risk factors that may cause our actual results, performance, or achievements to differ materially from any future results, or performance or achievements expressed or implied in such forward-looking statements associated with an investment in us.
Risks Related to Development and Commercialization of our Product Candidate
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We are substantially dependent upon the clinical, regulatory, and commercial success of our sole product candidate, molgramostim inhaled solution ("MOLBREEVI"). If we are unable to successfully complete clinical development of, obtain regulatory approval for, and successfully commercialize MOLBREEVI, our business may be harmed.
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Clinical drug development involves a lengthy and expensive process, with an uncertain outcome. We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development of our product candidate. If development of our product candidate is unsuccessful or delayed, we may be unable to obtain required regulatory approvals and be unable to commercialize our product candidate on a timely basis, if at all.
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There is significant uncertainty regarding the regulatory approval process for any investigational new drug. Substantial further testing and validation of our product candidate and related manufacturing processes may be required, and regulatory approval may be conditioned, delayed, or denied, any of which could delay or prevent us from successfully marketing our product candidate and substantially harm our business.
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Our MOLBREEVI product candidate may cause undesirable side effects or adverse events or have other properties that could delay or prevent our clinical development, regulatory approval, or commercialization.
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Even if we receive regulatory approval for our product candidate, we may face regulatory difficulties that could materially and adversely affect our business, financial condition, and results of operations.
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If our product candidate receives regulatory approval but fails to achieve significant market acceptance among the medical community, patients, or third-party payers, the revenue we generate from its sales will be limited and our business may never achieve profitability.
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Even if we receive regulatory approval to market our product candidate in the U.S., we may never receive approval or commercialize our product outside of the U.S., which would limit our ability to realize the full commercial potential of our product candidate.
Risks Related to Our Capital Requirements and Financial Condition
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We have incurred significant losses since inception and expect that we will continue to incur losses for the foreseeable future, which makes it difficult to assess our future viability.
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We may require additional financing to obtain regulatory approval for MOLBREEVI and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce, or terminate our product development efforts or other operations.
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Our loan agreement contains covenants which may adversely impact our business; the failure to comply with such covenants could cause our outstanding debt to become immediately payable or accelerate principal payments.
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Any future acquisitions that we make could disrupt our business and harm our financial condition.
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We have in process research and development ("IPR&D") and future impairment of IPR&D may have an adverse impact on our future financial condition and results of operations.
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Adverse developments affecting financial institutions, companies in the financial services industry, or the financial services industry generally, such as actual events or concerns involving liquidity, defaults, or non-performance, could adversely affect our operations and liquidity.
Risks Related to Our Dependence on Third Parties
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We do not have, and do not have plans to, establish commercial manufacturing facilities. We completely rely on third parties for the manufacture and supply of our clinical trial drug and delivery device supplies and, if approved, commercial product materials. The loss of any of these vendors or a vendor’s failure to provide us with an adequate supply of clinical trial or commercial product material in a timely manner and on commercially acceptable terms, or at all, could harm our business.
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We rely significantly on third parties to conduct our nonclinical testing and clinical trials and other aspects of our MOLBREEVI development program, and if those third parties do not satisfactorily perform their contractual obligations or meet anticipated deadlines, the development of our MOLBREEVI product candidate could be adversely affected.
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Our employees, independent contractors and consultants, principal investigators, contract research organizations ("CROs"), contract manufacturing organizations ("CMOs"), other vendors, and any future commercial partners may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, which could cause significant liability for us and harm our reputation.
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The Company intends to establish a redundant supply chain with second sources of drug substance and drug product manufacture. If the product manufactured at the second sources of manufacture is not demonstrated to be comparable with materials used in the clinical program, we may not be able to commercialize from these second sources.
Risks Related to Competition, Retaining Key Employees and Managing Growth
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MOLBREEVI has received Orphan Drug Designation from the U.S. Food and Drug Administration (the "FDA") and the European Medicines Agency (the "EMA"). If a competitor obtains Orphan Drug exclusivity for a product with the same active ingredient and route of delivery as MOLBREEVI for autoimmune pulmonary alveolar proteinosis, we may be unable to market our product candidate until the exclusivity of the competing product expires.
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We expect competition in the marketplace for our MOLBREEVI product candidate should it receive regulatory approval.
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If we fail to attract and retain senior management and key scientific personnel and develop and maintain relationships with service providers, consultants and advisers, we may be unable to successfully develop and commercialize our product candidate.
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We currently have limited marketing capabilities and no sales organization. If we are unable to establish sales and marketing capabilities on our own or through third parties, we will be unable to successfully commercialize our product candidate, if approved, or generate product revenue.
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To establish a sales and marketing infrastructure and expand our manufacturing capabilities, we will need to increase the size of our organization, and we may experience difficulties in managing this growth.
Risks Related to Our Business Operations
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Our operations might be interrupted and financial results could be adversely impacted by the occurrence of a natural disaster, acts of war or terrorism, tariffs, information technology ("IT") system malfunction, telecommunication and electrical failures or other catastrophic event, or public health crises, such as a pandemic.
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Our business and operations would suffer in the event of third-party computer system failures, cyber-attacks on third-party systems, or deficiency in our cybersecurity.
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The Company’s remote working arrangements could significantly increase the Company’s digital and cybersecurity risks.
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If we or our vendors fail to comply with data protection laws and regulations, we could be subject to government enforcement actions (which could include civil or criminal penalties), private litigation, and/or adverse publicity, which could negatively affect our operating results and business.
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We must comply with the U.S. Foreign Corrupt Practices Act (the “FCPA”) and similar foreign anti-corruption laws.
Risks Related to Our Intellectual Property
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If we are unable to adequately protect our intellectual property rights related to our product candidate, it could have a material adverse effect on our business.
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We may not be able to enforce our intellectual property rights outside of the U.S.
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Third parties may claim that our product, if approved, infringes on their proprietary rights and may challenge the approved use or uses of a product or its patent rights through litigation or administrative proceedings, and defending such actions may be costly and time consuming, divert management attention away from our business, and result in an unfavorable outcome that could have an adverse effect on our business.
Risks Related to Our Industry
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We are subject to uncertainty relating to healthcare reform measures and reimbursement policies that, if not favorable to our product, could hinder or prevent our product’s commercial success, if our product candidate is approved.
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We face potential product liability exposure and, if successful claims are brought against us, we may incur substantial liability for a product or product candidate and may have to limit its commercialization. In the future, we anticipate that we will need to obtain additional or increased product liability insurance coverage and it is uncertain whether such increased or additional insurance coverage can be obtained on commercially reasonable terms, if at all.
Risks Related to our Common Stock
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Our stock price is expected to continue to be volatile.
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If we fail to satisfy all applicable Nasdaq continued listing requirements, including the $1.00 minimum closing bid price requirement, our common stock may be delisted from Nasdaq, which could have an adverse impact on the liquidity and market price of our common stock.
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We do not expect to pay any cash dividends in the foreseeable future.
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We may be unable to use certain of our net operating losses and other tax assets.
If any of these risks or uncertainties materialize or any of these assumptions proves incorrect, our results could differ materially from the forward-looking statements in this report. All forward-looking statements in this report are current only as of the date of this report. We do not undertake any obligation to publicly update any forward-looking statement to reflect events or circumstances after the date on which any statement is made or to reflect the occurrence of unanticipated events. Unless context requires otherwise, all references in this report to “Savara,” “our company,” “we,” “us,” “our,” or similar words refer to Savara Inc. together with its consolidated subsidiaries.
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PART I
Item 1. Business.
Business Overview
Savara Inc. (together with its subsidiaries “Savara,” the “Company,” “we,” “our” or “us”) is a clinical stage biopharmaceutical company focused on rare respiratory diseases. Our sole program, molgramostim inhalation solution ("MOLBREEVI" or "molgramostim"), is an investigational inhaled biologic, specifically an inhaled granulocyte-macrophage colony-stimulating factor ("GM-CSF") in Phase 3 development for autoimmune pulmonary alveolar proteinosis (“aPAP”). MOLBREEVIis delivered via a proprietary eFlow® Nebulizer System (PARI Pharma GmbH).
Corporate Strategy
Our goal is to become a leader in rare respiratory therapeutics through the development and commercialization of novel, best-in-class medicines that address unmet medical needs in this field. Key elements of our strategy include:
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Continued advancement of the MOLBREEVI aPAP program and the completion of the Phase 3 IMPALA-2 pivotal clinical trial of which the 96-week open-label period of the trial continues. The IMPALA-2 trial design was endorsed by regulatory authorities in the U.S. (U.S. Food and Drug Administration), Europe (European Medicines Agency), United Kingdom (Medicines and Healthcare Products Regulatory Agency), and Japan (Pharmaceuticals and Medical Devices Agency), and regulatory agencies and ethics committees in various countries and sites where the trial is being conducted. The first patient in the trial was dosed in June 2021. During the second quarter of 2023, patient enrollment in the trial was completed (target enrollment was 160, the trial enrolled 164 patients). In June 2024, positive top line results from the trial were reported that demonstrated a favorable risk benefit profile for MOLBREEVI in aPAP. The rolling submission of the MOLBREEVI biologics license application ("BLA") to the U.S. Food and Drug Administration ("FDA") was initiated in December 2024. On March 26, 2025, the Company announced that it had completed the BLA submission to the FDA.
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Ensuring all aspects of our manufacturing are validated and can produce product at commercial scale. To help ensure an uninterrupted drug supply and mitigate approvability risk, our goal is to establish a fully redundant supply chain with second source manufacturers for drug substance, drug product, and chemistry, manufacturing, and controls ("CMC") analytics. Starting with drug substance, we have invested in primary and secondary drug substance manufacturing partners. The primary drug substance manufacturer is GEMA Biotech S.A. (“GEMA”). In February 2024, we announced entry into a Master Services Agreement with a second source drug substance partner, Fujifilm Diosynth Biotechnologies UK Limited, Fujifilm Diosynth Biotechnologies Texas, LLC, and Fujifilm Diosynth Biotechnologies U.S.A., Inc. (collectively, “Fujifilm”). Drug product is currently manufactured by Patheon UK Ltd. (“Patheon”), a division of Thermo Fisher Scientific Inc. Following commercialization of MOLBREEVI, and pursuant to our strategy for a dual source supply chain, we plan to work to qualify a second source drug product partner as well as a second source CMC analytics vendor.
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Outsourcing capital-intensive operations. We will continue to pursue the development and manufacturing of our product candidate by outsourcing most clinical development work and manufacturing operations. We believe our business model enables the effective and capital-efficient development of our pipeline through the use of high-quality specialist vendors and consultants.
MOLBREEVI – aPAP
Our sole product candidate is an inhaled biologic. MOLBREEVI is an inhaled formulation of recombinant human GM-CSF and is being developed for the treatment of aPAP. Pulmonary alveolar proteinosis (“PAP”) is a rare lung disease characterized by the accumulation of surfactant in the alveoli (or air sacs) of the lungs. There are different types of PAP, of which aPAP is the most common.
In May 2019, the FDA granted Fast Track Designation to MOLBREEVI for the treatment of aPAP. Fast Track Designation facilitates the development and expedites the review of new drugs or biologics intended to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. In December 2019, the FDA granted Breakthrough Therapy Designation (“BTD”) for MOLBREEVI in aPAP based on data from the 24-week double-blind treatment period from our IMPALA Phase 2/3 trial. Additionally, MOLBREEVI was granted Orphan Drug Designation for the treatment of aPAP in the U.S. and the European Union (“EU”), which allows for seven and ten years of exclusivity from approval, respectively. Savara has exclusive access to the investigational, proprietary PARI eFlow® Nebulizer System for this indication along with a proprietary cell bank for the active drug substance of MOLBREEVI. Additionally, in the United Kingdom ("UK"), MOLBREEVI for the treatment of aPAP was granted Innovation Passport (June 2022) and
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Promising Innovative Medicine (August 2022) designations by the UK Medicines and Healthcare Products Regulatory Agency ("MHRA"). These designations provide the opportunity for enhanced dialogue and input from the MHRA and the Health Technology Assessment bodies in England, Scotland, and Wales.
In 2019, we announced that IMPALA, the Phase 2/3 clinical trial of MOLBREEVI for the treatment of aPAP did not meet its primary endpoint of improvement compared to placebo in the alveolar-arterial gradient, or (A-a)DO2, from baseline at week 24. While the trial did not meet its primary endpoint, the totality of data from the IMPALA trial gives us confidence that MOLBREEVI had the potential to address a significant unmet need in this rare lung disease. These data include:
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multiple key secondary and exploratory endpoints that either achieved statistical significance or trended in favor of the active drug arms;
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results from the open-label period of the trial that demonstrated a sustained treatment effect, or continued improvement, after longer term exposure to MOLBREEVI; additionally, patients who had been on placebo during the double-blind period of the trial and switched to treatment with MOLBREEVI during the open-label period showed improvements that eventually were generally similar to those seen in patients who received MOLBREEVI during the double-blind period; and
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MOLBREEVI being generally well tolerated, and its safety profile, when compared to placebo, was equal except for a few relatively non-serious outcomes that did not lead to discontinuations.
In September 2020, results from the IMPALA trial were published in the New England Journal of Medicine.
In June 2021, the Phase 3 IMPALA-2 pivotal trial, which built on the key learnings from the first IMPALA trial, was initiated and enrollment completed in June 2023.
In March 2024 and October 2024, respectively, the EU EMA and the UK MHRA accepted our MOLBREEVI Pediatric Investigational Plan (“PIP”) and trial initiation activities in Europe are currently ongoing.
In June 2024, we reported top line results from pivotal IMPALA-2 trial that demonstrated significant improvement in gas exchange, as measured by diffusing capacity of the lungs for carbon monoxide ("DLCO") and clinical benefit, as measured by St. George’s Respiratory Questionnaire ("SGRQ"). MOLBREEVIwas well tolerated throughout the 48-weeks and no unexpected safety signals were seen. A summary of results are as follows:
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statistically significant improvement in mean change from baseline in DLCO versus placebo at week 24 (primary endpoint) and week 48 (secondary endpoint), showing durability of effect;
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statistically significant improvement in mean change in baseline in SGRQ Total Score at week 24 (secondary endpoint);
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nominally significant improvements in mean change in baseline in SGRQ Activity Score at week 24 and Peak metabolic equivalents of task ("METs") (an established measure of exercise capacity) at week 48. We considered data with a p-value <0.05 to be nominally significant;
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97% of patients completed the double-blind treatment period through week 48 with no trial drug related adverse events leading to discontinuation; and
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100% of patients that completed the 48-week double-blind period of the trial elected to participate in the 96-week open-label period.
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In March 2024 and May 2024, respectively, the EMA and FDA conditionally accepted MOLBREEVI, the trade name for molgramostim inhalation solution. The MOLBREEVI trade name approval will not be finalized until our molgramostim inhalation solution is approved by the respective regulatory entities.
Detailed Program Description
MOLBREEVI
Background on aPAP
Autoimmune pulmonary alveolar proteinosis, known as aPAP, is a specific disease belonging to a family of distinct rare lung diseases collectively referred to as PAP. aPAP represents about 90% of all patients with PAP and the estimated diagnosed prevalence of PAP is six to seven cases per million people in the U.S., with similar or higher prevalence reported elsewhere in the world. For example, Japan, a country that undertakes a more centralized approach to diagnosing and treating PAP, has seen a consistent increase in patients being diagnosed with the disease. It is now estimated the diagnosed prevalence in Japan could be three to four times the original estimate of six to seven cases per million.
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aPAP is characterized by the accumulation of surfactant in the alveoli, or air sacs, of the lungs. The surfactant consists of proteins and lipids and is an important physiological substance that lines the inside of the alveoli to prevent the lungs from collapsing. The lungs continuously produce new active surfactant. In a healthy lung, the surfactant is cleared by immune cells called alveolar macrophages. However, in lungs of patients with aPAP, the macrophages fail to clear the surfactant from the alveoli, leading to gradual accumulation of surfactant in the alveoli. The root cause of aPAP is an autoimmune response against GM-CSF, a naturally occurring protein in the body. Pulmonary macrophages need to be stimulated by GM-CSF to function properly, but in aPAP, GM-CSF is neutralized by antibodies against GM-CSF, rendering the macrophages unable to perform their tasks, including the clearance of surfactant from the alveoli.
aPAP most commonly affects individuals in early middle age, but people of any age can be affected. As a result of the accumulation of surfactant, gas exchange in the lungs is obstructed, and patients start to experience shortness of breath, fatigue, and decreased exercise tolerance. Typically, shortness of breath is first observed upon exertion, but as the disease progresses, shortness of breath can be experienced even when a person is at rest. Patients may experience cough, sputum production, and episodes of fever, especially if secondary lung infection develops. In the long-term, the disease can lead to serious complications, including serious infections. Over time, aPAP can lead to pulmonary fibrosis and respiratory failure, which can be fatal and may require lung transplantation.
Current treatment options for aPAP
In the U.S. and Europe, there are no approved medicines for the treatment of aPAP. The current available therapy for aPAP is a non-standardized procedure called whole lung lavage (“WLL”), which entails the wash of the lung with saline, to physically remove excess surfactant from the lung. The invasive and inconvenient procedure is performed under general anesthesia and involves:
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insertion of a double-lumen endobronchial tube for lung separation;
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repeated filling of the treated lung with up to 15-50 liters of saline;
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percussion of the lung to emulsify the surfactant sediment; and
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draining the saline by gravity until the lavage fluid that is removed from the lung becomes clear.
Potential complications from WLL include rib fracture, hypoxia, pneumothorax (collapsed lung), hydrothorax (fluid in pleural cavity), superimposed infection, and acute respiratory distress syndrome ("ARDS").
WLLs are performed by highly experienced physicians at specialist sites and necessitate hospitalization. As WLL does not correct the underlying pathophysiology of the disease, or prevent abnormal surfactant accumulation, most patients who undergo the procedure may only experience temporary symptomatic relief. Once the lungs refill with surfactant, the WLL procedure needs to be repeated.
As there are no approved pharmaceutical treatments available for aPAP in the U.S. and Europe, there is an unmet need for a convenient and efficacious medicinal treatment. We believe that inhalation of MOLBREEVIactivates macrophages in the lung alveoli, thus potentially restoring the surfactant-clearing activity of the alveolar macrophages and considerably improving oxygenation and exercise tolerance. Sargramostim (Leukinecl), an injectable form of GM-CSF, is approved in the U.S. for intravenous and subcutaneous administration treatment of neutropenia caused by cancer chemotherapy and other related indications. In April 2024, sargramostim was approved in Japan for the treatment of aPAP. Currently, there are no approved inhalation formulations of GM-CSF in the U.S. or Europe, nor are there any investigational drugs in clinical development for aPAP in the U.S. or Europe, other than MOLBREEVI.
The potential benefits of inhaled GM-CSF in aPAP have prompted independent clinicians and academic researchers in the U.S., Japan, and countries in Europe to study the safety and efficacy of inhaled GM-CSF in aPAP patients. In addition to our two placebo-controlled clinical trials of MOLBREEVI in this patient population—the Phase 2/3 IMPALA trial (n=138) and the Phase 3 IMPALA-2 trial, the largest placebo-controlled trial in aPAP (n=164)—several investigator-sponsored, open-label clinical trials and case studies of inhaled GM-CSF treatment have been published, with promising results on the efficacy and safety of the treatment. In total, treatment of nearly 150 aPAP patients with inhaled GM-CSF has been reported in open-label trials or retrospective cohorts, as well as several individual case reports. A case series published in ERJ Open Research in January 2025 retrospectively evaluated 5 aPAP patients who received molgramostim through European single-patient access supplied by Savara. Following treatment with molgramostim (mean duration of 4.2 years), the real-world outcomes data suggest molgramostim addresses the underlying pathophysiology of aPAP, resulting in improved lung function, decreased disease burden, restored patient functionality, reduced clinical symptoms, and, at the
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time of publication, no need for WLL. For details on the results of the IMPALA-2 trial, please see the Clinical Development of MOLBREEVI – aPAP: Phase 3 IMPALA-2 Trialsection included in this report.
According to our review of published literature, few safety issues related with GM-CSF inhalation in patients with aPAP have been reported. However, there is still limited information available on the long-term safety of inhaled GM-CSF.
Product Description
MOLBREEVI is an inhaled formulation of a non-glycosylated form of recombinant human GM-CSF that we are developing for the treatment of aPAP. GM-CSF is an endogenous growth factor that stimulates the proliferation and differentiation of hematopoietic cells (blood immune cells), mainly granulocytic and monocytic cells, which defend against bacteria and viruses, and clear cellular debris and waste substances from the body. MOLBREEVI is produced in a strain of Escherichia coli bearing a genetically engineered plasmid containing a human GM-CSF gene.
Our product is a drug-device combination consisting of molgramostim (drug component) and a vibrating mesh nebulizer (device component). MOLBREEVI is supplied as a sterile formulation containing 300 μg of molgramostim in 1.2 mL solution. MOLBREEVI is administered once daily by inhalation via a high efficiency nebulizer, the investigational, proprietary eFlow® Nebulizer System (PARI Pharma GmbH). The eFlow®Nebulizer System is a reusable electronic inhalation system that has been optimized for administration of molgramostim. The eFlow® consists of a controller unit (AC or battery powered), a nebulizer handset, and a connection cord. The controller unit's lifespan is multiple years, and the handset is replaced monthly with a new unit.
MOLBREEVI was granted Orphan Drug Designation by the FDA in October 2012 and by the EMA in July 2013 for the treatment of aPAP. It was also granted Fast Track Designation and BTD by the FDA in May 2019 and December 2019, respectively. Further, it was granted Innovation Passport (June 2022) and Promising Innovative Medicine (August 2022) designations in the UK. Since 2014, molgramostim has been available in several European countries for the treatment of aPAP for named patients following unsolicited physician requests. In September 2024, we launched the Savara Early Access Program ("EAP") for molgramostim in patients with aPAP. The program enables physicians to request molgramostimfor eligible patients in select geographies where the product is not commercially available and in compliance with local regulatory requirements. The Savara EAP has been reviewed and allowed to proceed by the FDA and is open for requests from physicians, on behalf of aPAP patients, in North America and select countries in Europe. More information can be found on the program at www.clinicaltrials.gov, NCT06546098.
We anticipate that, if approved, MOLBREEVIwill be used as a long-term treatment in patients with aPAP. Once daily treatment with MOLBREEVI may reduce the need for WLL in patients with aPAP. In the IMPALA and IMPALA-2 trials, a reduced number of WLL procedures in the active treatment arms was seen compared to the placebo treatment arm, but the difference was not statistically significant, as the studies were not powered for statistical significance for WLL. Additionally, data from the real-world case studies (n=5) published in ERJ Open Research, noted above, suggest MOLBREEVI may reduce the need for WLL. While four of the five patients had at least one WLL prior to treatment with MOLBREEVI, none of the five patients required WLL after more than one year on treatment.
MOLBREEVI Key Advantages
Based on data from the completed Phase 2/3 IMPALA trial and the pivotal Phase 3 IMPALA-2 trial and building upon the published investigator-sponsored treatment experience with inhaled GM-CSF, we believe MOLBREEVI has the potential to become the treatment of choice for aPAP. The following characteristics of MOLBREEVI may contribute to the clinical profile of the investigational product candidate, as well as facilitate potential regulatory approval and successful commercialization.
Specifically, MOLBREEVI offers:
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a strong product foundation that applies both a previously approved active drug substance class and drug delivery technology;
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GM-CSF delivered directly to the lungs, the primary site of macrophage dysfunction in aPAP, which could result in clinical efficacy with limited systemic adverse effects;
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a portable nebulizer system that provides a fast and convenient method of administration (nebulization time of about 3 to 5 minutes each day); this is highly desirable for long-term treatment in a chronic disease, such as aPAP;
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eligibility for strong market protection via orphan drug status, potential eligibility for biologic exclusivity that provides twelve years of total market protection in the U.S.;
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a proprietary cell bank used in the production of the drug substance; and
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an exclusive agreement for the specific device that is optimized for administration of MOLBREEVI.
Clinical Development of MOLBREEVI – aPAP
Phase 3 IMPALA-2 Pivotal Trial
IMPALA-2 is a Phase 3, 48-week, randomized, double-blind, placebo-controlled pivotal clinical trial designed to compare the efficacy and safety of MOLBREEVI 300 μg administered once daily by inhalation with matching placebo in adult patients with aPAP. The primary endpoint was the change from baseline in percent predicted DLCO, a measure of gas transfer. Three secondary endpoints evaluated clinical measures of direct patient benefit: SGRQ Total Score, SGRQ Activity Component Score, and exercise capacity test using a treadmill. Other efficacy endpoints included (A-a)DO2 (another gas transfer measure), supplemental oxygen use, WLL frequency, patient and clinician global impression of disease severity and disease change, chest computed tomography (“CT”) scan to assess lung opacity, and blood biomarkers. Enrollment in IMPALA-2 was completed at the end of June 2023 with 164 patients, exceeding the expected trial enrollment of 160 patients. Patients were randomized to receive treatment for 48 weeks in one of two arms: MOLBREEVI 300 μg administered once daily or inhaled placebo administered once daily. The primary time point for efficacy assessment was at week 24; however, efficacy was assessed through week 48 to show durability of effect. Safety was assessed through week 48. Following the 48-week double-blind treatment period, patients had the option to transition to a 96-week open-label period where all patients receive MOLBREEVI300 μg administered once daily.
In June 2024, we announced positive top line results from the IMPALA-2 trial which enrolled 164 patients from 43 sites across 16 countries, making it the largest placebo-controlled trial conducted in aPAP. One hundred fifty-nine patients completed treatment during the 48-week double-blind period—which translates to a treatment discontinuation rate of only 3%, and 100% of patients who completed treatment during the double-blind period opted to enter the 96-week open-label MOLBREEVI treatment period.
Top line results from the trial are as follows:
PRIMARY ENDPOINT MET:
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Change from baseline to week 24 in hemoglobin adjusted percent predicted DLCO was the primary endpoint. DLCO is a lung function measurement that assesses the ability of the lungs to transfer gas from inspired air to the bloodstream. DLCO results showed a statistically significant treatment difference in mean changes of 6.0 percentage points in favor of MOLBREEVI compared to placebo (p=0.0007).
SECONDARY ENDPOINTS:
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Gas Transfer
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DLCO results were sustained through the double-blind period, with a treatment difference in mean changes of 6.9 percentage points at week 48 in favor of MOLBREEVI compared to placebo (p=0.0008)—indicating durability of treatment effect.
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Clinical Benefit
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SGRQ is a patient-reported outcome instrument that measures overall health, daily life, and a patient’s perceived well-being. SGRQ Activity, a subscale of the SGRQ, assesses the patient’s ability to carry out daily physical activity. A decrease from baseline in SGRQ indicates improvement (i.e. a lower number is better).
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SGRQ Total score showed a statistically significant treatment difference in mean changes from baseline of -6.59 points at week 24 in favor of MOLBREEVI compared to placebo (p=0.0072).
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At week 48, the treatment difference remained more favorable for MOLBREEVI compared to placebo at -4.87 points (p=0.1046).
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SGRQ Activity score demonstrated a nominally significant treatment difference in mean changes from baseline of -7.81 points at week 24 in favor of MOLBREEVI compared to placebo (p=0.0149) and remained numerically favorable with a treatment difference of -5.99 points at week 48 (p=0.1216).
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Exercise capacity expressed as peak METs is a controlled assessment that required patients to exercise through standardized increases in speed and grade on a treadmill.
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MOLBREEVI treatment resulted in an absolute mean increase in peak METs of 1.11 compared to a mean increase of 0.7 with placebo at week 24, with a treatment difference of 0.41 METs (p=0.0845). This improvement was maintained through week 48, with a nominally significant treatment difference of 0.55 METs (p=0.0234).
WLL, an invasive procedure intended to clean the lungs of excess surfactant, was allowed during the trial as rescue treatment in case of worsening of aPAP. During the double-blind period, 17 patients (~10%), underwent at least one lung lavage—6 patients (7%) in the treatment arm underwent WLL, and 11 patients (13%) in the placebo arm underwent WLL.
MOLBREEVI was generally well tolerated. The frequencies of adverse events were mostly similar in both arms. Common adverse events were generally mild or moderate in severity and balanced across groups in frequency and severity, except for COVID-19, which occurred more frequently in the MOLBREEVI group but only lead to discontinuation in one subject. None of the COVID-19 events was considered related to trial drug by the investigator. IMPALA-2 was initiated in 2021 during the peak of the COVID-19 pandemic.
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In December 2024, we initiated a rolling submission of a BLA to the FDA for MOLBREEVI for the potential treatment of aPAP. In 2019, MOLBREEVI was granted Fast Track and Breakthrough Therapy Designations for the treatment of patients with aPAP, therefore, we were allowed to submit individual modules of the BLA as they are completed, rather than waiting to submit the application once all modules were available. On March 26, 2025, the Company announced that it had completed the BLA submission to the FDA and it will request Priority Review.
Pediatric (PIP) Trial of MOLBREEVI – IMPACT
In March 2024 and October 2024, respectively, the EU EMA and the UK MHRA accepted our MOLBREEVI Pediatric Investigational Plan. Trial initiation activities for the IMPACT trial, which is a requirement from the EMA and MHRA as a function of the agreed-upon PIP, are currently ongoing. This open-label, multicenter clinical trial will evaluate the efficacy and safety of MOLBREEVI in pediatric patients with aPAP. The IMPACT clinical trial design is as follows:
Phase 2/3 IMPALA Trial
IMPALA was a Phase 2/3 randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of molgramostim in adult patients with aPAP. Patients with aPAP were randomly assigned to receive molgramostim (300 μg once daily by inhalation), either continuously or intermittently (once daily every other week), or matching placebo. The 24-week double-blind intervention period was followed by an open-label treatment-extension period during which patients were treated with molgramostim intermittently. The primary end point was the change from baseline in the alveolar–arterial difference in oxygen concentration (A-aDo2) at week 24.
Results from the double-blind period of the IMPALA trial, published in the New England Journal of Medicine in September 2020, demonstrated a positive treatment effect from daily continuous administration of molgramostim. In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. The primary endpoint, change from baseline in A-aDO2 was not statistically significant. This was due to 4 patients (1 in each molgramostimgroup and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement rendering the calculation of A-aDO2 invalid because the inspired oxygen content could not be determined. A post-hoc analysis treated these patients’ data as missing and were replaced
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by means of imputation. For the primary end point—the change from baseline in A-aDo2 at week 24—mean improvement was greater among patients receiving continuous molgramostimthan among those receiving placebo (−12.8 mm Hg vs. −6.6 mm Hg; estimated treatment difference, −6.2 mm Hg;P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater mean improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George’s Respiratory Questionnaire total score at week 24 (−12.4 points vs. −5.1 points; estimated treatment difference, −7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, mean improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain as investigated and deemed not related to cardiac effects, which was higher in the continuous molgramostim group.
In patients with aPAP, daily continuous administration of inhaled MOLBREEVI resulted in greater mean improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events.
Manufacturing and Supply
We do not own or operate manufacturing facilities to produce clinical or commercial quantities of MOLBREEVI. We have fee-for-service contracts with a drug substance manufacturer and drug product manufacturer that cover all steps of the manufacturing process of MOLBREEVI. We expect to continue with this outsourcing model for the foreseeable future. In order to reduce production risks and help ensure an uninterrupted supply, and mitigate approvability risk, we have engaged a second source manufacturer for drug substance. Following approval of MOLBREEVI, and as part of our longer-term strategy for a dual-source supply chain, we will engage a second source manufacturer for drug product. All of our manufacturing and supply vendors are certified by National Competent Authorities to operate under current Good Manufacturing Practices (“cGMP”), a regulatory standard for the manufacture of pharmaceuticals; however, certain manufacturing and supply vendors have not yet received an FDA inspection.
MOLBREEVIdrug substance is currently manufactured by GEMA in Buenos Aires, Argentina. All clinical and nonclinical trials to-date have used material sourced from GEMA and validation activities are ongoing to prepare for commercial manufacturing. Additionally, in February 2024, we entered into a master services agreement with Fujifilm in Billingham, UK, a well-established biologics manufacturer, pursuant to which Fujifilm will become our second source manufacturer and will provide manufacturing services related to MOLBREEVIdrug substance.
MOLBREEVI drug product is currently manufactured by Patheon in Ferentino, Italy. Technology transfer and process validation activities with Patheon have been completed and were re-executed in 2023 as Patheon moved the manufacturing of MOLBREEVI drug product to a new state-of-art filling line in the same facility. Following approval of MOLBREEVI, we expect to engage a second source drug product manufacturer for MOLBREEVI.
MOLBREEVIdrug product is currently tested by Selvita S.A. ("Selvita") and its affiliates, which are headquartered in Poland with additional offices in the U.S, the UK, and Croatia. Selvita is a drug discovery company engaged in provision of integrated drug discovery services, such as custom synthesis, medicinal chemistry, protein chemistry, molecular and cell biology, and analytical development, and its biology division specializes in certified testing conducted in GLP and GMP standards in areas such as pharmacodynamic testing, cytotoxicity testing, developing and validating biophysical, biochemical and cell-based assays as well as analytical methods.
MOLBREEVI is administered to the lungs using the eFlow® Nebulizer System, manufactured by PARI Pharma GmbH in Starnberg, Germany (“PARI”). The eFlow® Nebulizer System has been Conformité Européenne (“CE”) certified (CE 0123) according to the Medical Devices Directive 93/42/EEC (as amended by Directive 2007/47/EC) as a class IIa device. The device has a 510(k) clearance in the U.S. as a general device. We have an exclusive license and a long-term supply agreement with PARI, as further discussed below, covering the eFlow® Nebulizer System for the administration of MOLBREEVI.
Commercialization
Savara owns exclusive global rights to MOLBREEVI in aPAP. We continue to pursue clinical development and regulatory approvals for MOLBREEVI. We may engage with strategic partners to collaborate on implementing optimal sales and promotion activities. Our commercialization strategy will target key prescribing physicians and centers, as well as provide patients with support programs to ensure product access. Upon receipt of EMA approval, we expect to commercialize MOLBREEVI in the EU and may engage with strategic partners to optimize sales and promotion activities in other EU territories.
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Key License and Other Agreements
Parexel
We entered into a master services agreement ("Parexel MSA") with Parexel on March 5, 2021, pursuant to which Parexel provides contract research services related to our clinical trials. The Parexel MSA has an initial term of five years. We may terminate the Parexel MSA and/or any work order without cause on 60 days’ prior written notice to Parexel. Either party may terminate the Parexel MSA or any work order, and Parexel may suspend the performance of services for a material uncured breach by the other party. In addition, either party may immediately terminate the Agreement and/or any individual work order on prior written notice if (a) continuation of the services would pose an undue risk to the health and/or wellbeing of a study participant, (b) any certificate, authorization, approval or exemption from a regulatory authority required for the conduct of the services is revoked, suspended, or expires without renewal, (c) in the reasonable opinion of such party, the continuation of the services would be in violation of applicable law, or (d) the other party becomes insolvent. Concurrent with entering the Parexel MSA, we executed a work order with Parexel, under which Parexel provides services related to the IMPALA-2 pivotal trial.
Additionally, in the second quarter of 2024, the Company initiated an open-label, multicenter clinical trial, IMPACT, for pediatric subjects with aPAP under a separate work order with Parexel. Pursuant to the IMPACT trial, Parexel currently has the opportunity to earn various milestone payments primarily dependent upon patient enrollment, site management, project oversight, and the compliance with defined study protocols.
Please refer to Note 10. Commitments – Manufacturing and Other for additional detail on our financial obligations to Parexel.
PARI Pharma GmbH
We have a license and collaboration agreement related to MOLBREEVI with PARI Pharma GmbH ("PARI" and collectively the “PARI License Agreement”). Under the PARI License Agreement, we have a worldwide, exclusive license for use and commercialization of the mesh nebulizer system which was optimized for MOBREEVI, PARI’s eFlow Nebulizer System, for the pulmonary delivery of any liquid formulation containing recombinant human GM-CSF (“rhGM-CSF”) as the sole active pharmaceutical ingredient for nebulization for aPAP. Following an amendment in 2018 (the “PARI Amendment”), we have the option to add other pulmonary infections to the included indications in the future.
Under the terms of the PARI License Agreement, Savara is not permitted to work with third parties to develop any inhalation device or nebulizer for the pulmonary delivery of a pharmaceutical product containing GM-CSF as the sole active ingredient. This restriction extends (i) in the European Economic Area, until marketing approval of the product in Europe or the U.S., whichever is later, or (ii) in the rest of the world, until the termination of the PARI License Agreement.
In consideration of rights granted by PARI, a one-time fee was paid upfront, and we subsequently pay an hourly rate for work performed by PARI. Additionally, we are obligated to make future milestone payments to PARI based upon the first marketing approval for the product in the U.S., EU or Japan. The PARI Amendment expanded the development milestones in the agreement to include any additional pulmonary indications for which we use the device.
If we successfully commercialize any product candidate subject to the PARI License Agreement, we are responsible for royalty payments equal to a percentage of net sales. We are obligated to make such royalty payments until the later of (i) the expiration of the last valid claim in an issued patent covering a portion of the PARI device in the applicable country or (ii) 15 years after the first commercial sale of MOLBREEVI with the PARI device in that country (the “PARI Royalty Period”). If there is no such valid patent claim covering the applicable PARI device, the royalty owed to PARI will be decreased by a specified percentage.
The license term extends on a country-by-country basis until the end of the PARI Royalty Period or until mutually agreed by the parties. The PARI License Agreement may be earlier terminated by either party (i) upon 90 days’ notice (or 30 days’ notice by PARI in the event of uncured non-payment by Savara) due to a material uncured breach by the other party of its obligations or warranties thereunder or (ii) due to the other party initiating bankruptcy, reorganization or liquidation, or otherwise becoming insolvent. PARI may also terminate the PARI License Agreement in certain circumstances in which Savara transfers all or substantially all of its assets to a competitor of PARI.
We also have a commercial supply agreement with PARI (the “PARI Supply Agreement”) related to the supply of the PARI eFlow® Nebulizer System and related accessories for commercial use with our products after marketing approval is obtained. Pursuant to the PARI Supply Agreement, we are obligated to purchase from PARI (i) within the European Economic Area, (a) during the first five years from marketing approval, all of our requirements for the device and related accessories and (b) thereafter 80% and (ii) in the rest of the world, all of our requirements during the PARI Royalty Period. Pricing is on a per unit basis, with a reduction in price once certain purchasing volumes are met. The term of the PARI Supply Agreement extends until the end of the PARI Royalty Period and may be earlier terminated by either party (i) by
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mutual agreement, (ii) upon 90 days’ notice (or 10 days’ notice in the event of uncured non-payment by the other party) due to a material uncured breach by the other party of the PARI Supply Agreement, (iii) due to the other party initiating bankruptcy, reorganization or liquidation, or otherwise becoming insolvent, or (iv) upon termination of the PARI License Agreement.
GEMA Biotech S.A.
In April 2019, we entered into a manufacture and supply agreement with GEMA, which was amended on December 7, 2022 and December 13, 2023 (the “GEMA Agreement”), pursuant to which GEMA will supply the active pharmaceutical ingredient (“API”) for MOLBREEVI exclusively to us for commercial sale and continue to supply the API to us for clinical trials and research and development activities. Additionally, GEMA transferred and assigned to us all rights, titles, and interest in and to the master cell bank and working cell bank necessary to produce the API.
Pursuant to the terms of the GEMA Agreement, GEMA agreed to undertake the actions required to comply with the requirements of the FDA and other similar regulatory authorities and obtain the approvals necessary to manufacture and supply the API to us for commercial sale.
In addition to an agreed upon price of the API, we paid GEMA a milestone payment upon the effective date of the agreement and are required to make milestone payments upon (i) completion of certain developmental activities, (ii) successful completion of a mock pre-approval inspection, and (iii) marketing approval of a product containing the API. If we successfully commercialize a product containing the API in a country, we must pay GEMA a single digit percentage royalty on annual net sales. We are obligated to make such royalty payments until the earlier of (i) 10 years after the first receipt of marketing approval for the product in that country or (ii) the date a biosimilar of such product is first sold in that country.
Additionally, the Company is subject to a purchase obligation for ten years following the date of receipt of approval by a regulatory authority of the first regulatory filing for the marketing and sale of the first MOLBREEVI product in any country. Each year, the Company will purchase from the GEMA the API required to produce a percentage of such MOLBREEVI product it sells (the “Purchase Requirement”); provided, however, that the Purchase Requirement will no longer apply if (i) the price charged by GEMA exceeds a certain price charged by an alternative supplier, (ii) there is a shortage of supply, or (iii) GEMA at any time fails to materially fulfill a purchase order.
The term of the GEMA Agreement continues until the twentieth anniversary of the date of receipt of marketing approval for a product containing the API in any country and may be extended for additional twelve-month terms by the agreement of both parties. We may terminate the GEMA Agreement immediately if (i) products containing the API will not be sold or will be withdrawn from the market, (ii) the FDA or other regulatory authority withdraws marketing approval for or fails to approve products incorporating the API, (iii) three or more batches of API supplied in any six month period fail to conform to specifications, (iv) GEMA receives notice of deficiencies in its manufacturing and fails to adequately respond, or (v) GEMA fails to achieve compliance with the requirements of the FDA and other regulatory authorities necessary to manufacture and supply the API to us for commercial sale.
Fujifilm Diosynth Biotechnologies
In February 2024, we entered into a master services agreement with Fujifilm pursuant to which Fujifilm will continue to provide development and manufacturing services related to active pharmaceutical ingredient for MOLBREEVI in accordance with the terms of separate scope of work agreements to be entered into by the parties. In conjunction with execution of the master services agreement, the Company executed a scope of work between the parties, under which Fujifilm will perform a manufacturing campaign for process performance qualification of the active pharmaceutical ingredient of MOLBREEVI.
The master services agreement will continue until it is terminated by the Company or Fujifilm, which either party may do upon three months’ notice if no activities under a scope of work are in process. The Company may terminate activities under a scope of work at any time by providing written notice, subject to the payment of termination fees, as well as payment for services performed and non-cancelable costs. The master services agreement and any scope of work may also be terminated by either party due to a material uncured breach by the other party, and Fujifilm may terminate for certain unforeseen technical issues.
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Patheon UK Limited
We have entered into an agreement and related work orders with Patheon under which Patheon manufactures our MOLBREEVI product candidate for clinical trials. We may terminate the agreement at any time for any business reason.
In June 2019, we entered into a master manufacturing services agreement (the “Master Manufacturing Agreement”) with Patheon and expect in the future to enter into one or more related Product Agreements (each a "Product Agreement") to govern the terms and conditions of Patheon’s manufacture of commercial supplies of MOLBREEVI.
The Master Manufacturing Agreement had an initial term ending December 31, 2024, and will automatically renew after the initial term for successive terms of two years each if there is a Product Agreement in effect, unless a party has given notice of termination. Either party may terminate the Master Manufacturing Agreement upon the other party’s uncured material breach or insolvency. Patheon may terminate the Master Manufacturing Agreement if we assign such agreement to an assignee that is unacceptable to Patheon for certain reasons, for failure to timely pay invoices, or if we forecast zero volume for six months.
Selvita S.A.
We entered into a master services agreement with Selvita on January 17, 2024 (the "Selvita MSA") under which Selvita performs batch control testing and analyses of our MOLBREEVI drug product and drug substance through certain cell-based bioassays. The Selvita MSA has a term of five years, unless either party terminates the agreement upon ninety-day notification.
Diagnostic Testing
In December 2023, we launched aPAP ClearPath, a new serum-based blood test that can be used by physicians in the U.S. to help obtain a diagnosis of aPAP. The aPAP ClearPath test is a sensitive and specific quantitative immunoassay designed to detect aPAP GM-CSF autoantibodies in human serum. We partnered with TrilliumBiO, a modern health solutions provider and a Clinical Laboratory Improvement Amendments ("CLIA")-certified lab, to develop the simple, no-cost, and noninvasive test. A supporting disease awareness campaign was also launched to improve understanding of aPAP, highlight the hallmark signs and symptoms of the disease, and educate physicians about the need for early testing. In an effort to enhance testing, we are advancing development of a dried blood spot assay that we believe will further simplify blood sample collection and improve access to testing. We have launched the dried blood spot assay in the U.S. in the first quarter of 2025. In September 2024, we launched a disease state awareness campaign targeted at pulmonologists in Europe.
Expanded Access Program
In September 2024, we announced the Savara Early Access Program for patients with aPAP. The program enables physicians to request MOLBREEVI for eligible aPAP patients in select geographic areas where the product is not commercially available and in compliance with local regulatory requirements. The Savara Early Access Program has been reviewed and allowed to proceed by the FDA, and it is currently accepting requests from eligible patients in select countries in North America and Europe with plans to expand through 2026.
Expanded access programs are intended to serve as a potential pathway for a patient with a serious or immediate life-threatening disease or condition to gain access to an investigational medical treatment outside of clinical trials before it is commercially available, when no comparable or satisfactory alternative therapy options are available.
Government Regulation
The FDA and other regulatory authorities at federal, state, and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring, and post-approval reporting of drugs, such as the drug candidate we are developing. We, along with third-party contractors, will be required to navigate the various preclinical, clinical, and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidate. The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local, and global statutes and regulations require the expenditure of substantial time and financial resources.
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Government Regulation of Drugs
U.S.
The process required by the FDA before drug product candidates, like ours, may be marketed in the U.S. generally involves the following:
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completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices regulation;
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submission to the FDA of an Investigational New Drug application ("IND"), which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;
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approval by an independent Institutional Review Board (“IRB”) or ethics committee for each clinical site before a clinical trial can begin;
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performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed product candidate for its intended purpose;
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preparation of and submission to the FDA of a BLA, after adequate completion of all required clinical trials;
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a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;
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satisfactory completion of an FDA Advisory Committee review, if applicable;
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satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMPs and to assure that the facilities, methods, and controls are adequate to ensure the product’s quality attributes, and of selected clinical investigational sites to assess compliance with current Good Clinical Practices (“GCP”); and
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FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated annually and when significant changes are made.
The testing and approval process requires substantial time, effort, and financial resources, and we cannot be certain that any approvals for our product candidate will be granted on a timely basis, if at all. Prior to beginning the first clinical trial with a product candidate, we must submit an IND to the FDA. An IND is a request for authorization from the FDA to administer an investigational new drug product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials. The IND also includes results of animal and in vitro trials assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product candidate; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. An IND must become effective before human clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial. In such a case, the IND may be placed on clinical hold, and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin. Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. Furthermore, an independent IRB, for each site proposing to conduct the clinical trial, must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the trial until completed. Regulatory authorities, the IRB, or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some trials also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board, which provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.
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For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap. Additionally, in certain instances, a fourth phase, post approval, may be necessary or required.
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Phase 1. The drug product is initially introduced into healthy human subjects and tested for safety. In the case of some products for severe or life-threatening diseases, the initial human testing is often conducted in patients.
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Phase 2. The drug product is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.
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Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efficacy, and safety in an expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk to benefit ratio of the product and provide an adequate basis for product approval.
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Phase 4. In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product. Phase 4 trials may be required as a condition to approval of the BLA.
Phase 1, Phase 2, and Phase 3 testing may not be completed successfully within a specified period, if at all, and there can be no assurance that the data collected will support FDA approval or licensure of the product. Concurrent with clinical trials, companies may complete additional animal studies and develop additional information about the drug characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate acceptably maintains its quality attributes over its shelf life.
BLA Submission and Review by the FDA
Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies, and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications. The BLA must include all relevant data available from pertinent preclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including trials initiated by investigators. The submission of a BLA requires payment of a substantial user fee to the FDA, and the sponsor of an approved BLA is also subject to annual product and establishment user fees. These fees are typically increased annually. As noted previously, MOLBREEVI for the treatment of aPAP has been granted Orphan Drug Designation, and as such is exempt from the payment of user fees under current legislation.
We have completed the BLA submission to the FDA. Within 60 days following submission of the application, the FDA reviews a BLA to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. Once a BLA has been filed, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the FDA deems that the application sufficiently relates to an unmet medical need in a serious or life-threatening indication, six months after the FDA accepts the application for filing. The review process is often significantly extended by FDA requests for additional information or clarification. The FDA reviews a BLA to determine, among other things, whether a product is safe and effective for the indication being pursued, and the facilities in which it is manufactured, processed, packed, or held meets standards designed to assure the product’s continued safety and effectiveness. The FDA may convene an advisory committee to provide independent expert insight on application review questions. Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP. If the FDA determines that the application, manufacturing process, or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
The testing and approval process requires substantial time, effort, and financial resources, and each may take several years to complete. The FDA may not grant approval on a timely basis, or at all, and we may encounter difficulties or
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unanticipated costs in our efforts to secure necessary governmental approvals, which could delay or preclude us from marketing our product(s). After the FDA evaluates a BLA and conducts inspections they deem necessary to evaluate compliance with applicable regulations, the FDA may issue an Approval Letter or a Complete Response Letter. An Approval Letter authorizes commercial marketing of the product in compliance with specific prescribing information. A Complete Response Letter indicates that the review cycle of the application is complete, and the application is not ready for approval. A Complete Response Letter may request additional information or clarification. The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.
If regulatory approval of a product is granted, such approval may entail limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the BLA with a Risk Evaluation and Mitigation Strategy (“REMS”) to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing regulatory standards is not maintained or if problems occur after the product reaches the marketplace. The FDA may require one or more post-marketing trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing trials. In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of its products under development.
A sponsor may seek approval of its product candidate under programs designed to accelerate the FDA’s review and approval of new drugs that meet certain criteria. Specifically, new drug products are eligible for Fast-Track Designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition. For a fast-track product, the FDA may consider sections of the BLA for review on a rolling basis before the complete application is submitted if relevant criteria are met. A fast track designated product candidate may also qualify for priority review, under which the FDA sets the target date for FDA action on the BLA at six months after the FDA accepts the application for filing. Priority review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. If criteria are not met for priority review, the application is subject to the standard FDA review period of 10 months after the FDA accepts the application for filing. Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.
Under the accelerated approval program, the FDA may approve a BLA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Post-marketing trials or completion of ongoing trials after marketing approval are generally required to verify the biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.
In addition, the U.S. Food and Drug Administration Safety and Innovation Act, which was enacted and signed into law in 2012, established BTD. A sponsor may seek FDA designation of its product candidate as a breakthrough therapy if the product candidate is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the therapy may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Sponsors may request the FDA to designate breakthrough therapy at the time of, or any time after, the submission of an IND, but ideally before an end-of-phase 2 meeting with the FDA. If the FDA designates breakthrough therapy for a product candidate, it may take actions appropriate to expedite the development and review of the application, which may include holding meetings with the sponsor and the review team throughout the development of the therapy; providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable; involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review; assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor; and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller or more efficient clinical trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment. BTD also allows the sponsor to submit sections of the BLA for review on a rolling basis.
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Fast Track Designation, priority review and BTD do not change the standards for approval but may expedite the development or approval process.
Post-Approval Requirements
Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record keeping, reporting of adverse experiences, periodic reporting, distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing (as applicable) annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as potential new application fees for supplemental applications with clinical data. Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers. Changes to the manufacturing process are strictly regulated and, depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that we may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. We cannot be certain that we or our present or future suppliers will be able to comply with the cGMP regulations and other FDA regulatory requirements. If our present or future suppliers are not able to comply with these requirements, the FDA may, among other things, halt our clinical trials, require us to recall a product from distribution, or withdraw approval of the BLA.
Future FDA and state inspections may identify compliance issues at our facilities or at the facilities of our contract manufacturers that may disrupt production or distribution, or potentially require substantial resources to correct. In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer, or holder of an approved BLA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated, or judicial action that could delay or prohibit further marketing.
The FDA may withdraw approval of a BLA if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse 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-marketing trials or clinical trials to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:
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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;
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fines, warning letters, or holds on post-approval clinical trials;
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refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals;
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product seizure or detention, or refusal to permit the import or export of products; or
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injunctions or the imposition of civil or criminal penalties.
The FDA closely regulates the marketing, labeling, advertising, and promotion of drugs and biologics. A company can make only those claims relating to safety and efficacy that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising, and potential civil and criminal penalties. Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Such off-label uses are common across medical specialties. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.
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Government Regulation of Combination Products
Our product candidate under development will be regulated as a combination product, which means that it is comprised of two or more different components that, if marketed individually, would be subject to different regulatory paths and would require approval of independent marketing applications by the FDA. A combination product, however, is assigned to a center within the FDA that will have primary jurisdiction over its regulation on a determination of the combination product’s primary mode of action, which is the single mode of action that provides the most important therapeutic action. We believe our product candidate includes both a drug and medical device component, and will be regulated as a drug, subject to the review of the FDA’s Center for Drug Evaluation and Research which will have primary jurisdiction over premarket development and approval. The FDA’s Center for Devices and Radiological Health will provide support and review of the nebulizer component of our product candidate.
European Union
MAA
To obtain approval of a drug under the EU regulatory system, an application for a marketing authorization may be submitted under a centralized, a decentralized, or a national procedure. The centralized procedure, which is compulsory for medicines produced by certain biotechnological processes or for orphan drugs, provides for the grant of a single marketing authorization that is valid for all EU member states, which grants the same rights and obligations in each member state as a national marketing authorization. As a general rule, only one marketing authorization may be granted for drugs approved through the centralized procedure and the marketing authorization is also relevant for the European Economic Area countries.
Under the centralized procedure, the Committee for Medicinal Products for Human Use (“CHMP”) is required to adopt an opinion on a valid application within 210 days, excluding clock stops when additional information is to be provided by the applicant in response to questions. On day 120 of the procedure, once the CHMP has received the preliminary assessment reports and opinions from the Rapporteur and Co-Rapporteur designated by the CHMP, it adopts a list of questions, which are sent to the applicant together with the CHMP's overall conclusions. Applicants then have three months to respond (plus an additional three-month extension, if requested). The applicant's replies are assessed, and the assessment report is revised as necessary (and may include a prepared list of outstanding issues). By day 180 of the procedures, the revised assessment report and list of outstanding issues are sent to the applicant together with the CHMP's recommendation. Applicants then have one month to respond to the CHMP (and can request a one or two-month extension). The Rapporteur and Co-Rapporteur assess the applicant's replies and then submit them for review to the CHMP and prepare a final assessment report. Following their evaluation, the CHMP gives a favorable or unfavorable opinion as to whether to grant the marketing authorization. After the adoption of the CHMP opinion, a decision must be adopted by the European Commission, after consulting the Standing Committee of the Member States. The European Commission prepares a draft decision and circulates it to the member states; if the draft decision differs from the CHMP opinion, the Commission must provide detailed explanations. The European Commission adopts a decision within 15 days of the end of the consultation procedure.
Conditional marketing authorizations may be granted for products designated as orphan medicinal products if all of the following conditions are met: (1) the risk-benefit balance of the product is positive, (2) the applicant will likely be in a position to provide the required comprehensive clinical trial data, (3) the product fulfills unmet medical needs, and (4) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.
Conditional marketing authorizations are valid for one year, on a renewable basis, until the holder provides a comprehensive data package. Grant of conditional marketing authorization is dependent on the applicant's ability to fulfill the conditions within an agreed upon deadline. Applicants are subject to conditions, including the requirement to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance is positive or to fulfill specific obligations in relation to pharmacovigilance. Once a comprehensive data package has been supplied, the conditional marketing authorization is replaced by a regular marketing authorization.
Exclusivities
If an approved drug contains a new active substance, it is protected by data exclusivity for eight years from the notification of the Commission decision granting the marketing authorization and then by marketing protection for an additional two or three years. Overall, the drug is protected for ten or eleven years against generic competition, and no additional exclusivity protection is granted for any new development of the active substance it contains.
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During the eight-year period of data exclusivity, competitors may not refer to the marketing authorization dossier of the approved drug for regulatory purposes. During the period of marketing protection, competitors may not market their generic drugs. The period of marketing protection is normally two years but may become three years if, during the eight-year data exclusivity period, a new therapeutic indication is approved that is considered as bringing a significant clinical benefit over existing therapies.
Japan
Under the Japanese regulatory system administered by the Ministry of Health, Labor and Welfare (“MHLW”) and the Pharmaceutical and Medical Device Agency (“PMDA”) (which is responsible for product review and evaluations under the supervision of the MHLW), pre-marketing approval and clinical studies are required for all pharmaceutical products. The Law on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Act No. 145 of 1960) requires a license for marketing authorization when importing to Japan and selling pharmaceutical products manufactured in other countries. It also requires each manufacturing site of a foreign manufacturer to be certified as a manufacturing site of pharmaceutical products to be marketed in Japan.
To receive a license for marketing authorization, the manufacturer or seller must, at the very least, employ certain manufacturing, marketing, quality, and safety personnel. If the quality management methods and post marketing safety management methods applied with respect to the pharmaceutical product fail to conform to the standards stipulated by the MHLW license, marketing authorization may not be granted. A company must submit an application for approval to the MHLW with results of nonclinical and clinical studies to show the quality, efficacy, and safety of the product candidate to obtain manufacturing/marketing approval for a new product. A data compliance review, on-site inspection for GCP, and audit and detailed data review for compliance with current cGMP's are undertaken by the PMDA. The committees of the Pharmaceutical Affairs and Food Sanitation Council will discuss each application, and based on the results of these reviews, the final decision on approval is made by the MHLW. The approval process timeline significantly varies, but it can take years. Pricing approval for the product is required in order to be applied for redemption of health insurance. Once approved and marketable, the medical products are also subject to regular post-marketing vigilance of safety and quality under the standards of cGMP. In Japan, the National Health Insurance system maintains a Drug Price List specifying which pharmaceutical products are eligible for reimbursement, and the MHLW sets the prices of the products on this list. Upon marketing approval, the manufacturer or seller begins negotiations regarding the reimbursement price with the MHLW, which is generally determined within 60 to 90 days. The government generally introduces price cut rounds every other year and also mandates price decreases for specific products. New products judged innovative or useful, that are indicated for pediatric use, or that target orphan or small population diseases, however, may be eligible for a pricing premium. The government has also promoted the use of generics, where available.
Orphan Drug Status
Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation to drug candidates intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the U.S., or more than 200,000 individuals in the U.S. and for which there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the U.S. Orphan Drug Designation must be requested before submitting a BLA. After the FDA grants Orphan Drug Designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Although there may be some increased communication opportunities, Orphan Drug Designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.
If a drug candidate that has Orphan Drug Designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same drug for the same indication for seven years, except in very limited circumstances, such as if the second applicant demonstrates the clinical superiority of its product or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated. Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition. Among other benefits of Orphan Drug Designation are tax credits for certain research and a waiver of the BLA application user fee.
Orphan drug exclusivity could block the approval of our drug candidate for seven years if a competitor obtains approval of the same product as defined by the FDA or if our drug candidate is determined to be contained within the competitor’s product for the same indication or disease.
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As in the U.S., designation as an orphan drug for the treatment of a specific indication in the EU must be made before the application for marketing authorization is made. Orphan drugs in Europe enjoy economic and marketing benefits, including up to 10 years of market exclusivity for the approved indication unless another applicant can show that its product is safer, more effective, or otherwise clinically superior to the orphan designated product.
The FDA and foreign regulators expect holders of exclusivity for orphan drugs to assure the availability of sufficient quantities of their orphan drugs to meet the needs of patients. Failure to do so could result in the withdrawal of marketing exclusivity for the orphan drug.
Breakthrough Therapy Designation
In December 2019, the FDA granted the use of MOLBREEVI for the treatment of aPAP program BTD, which provides a process for expediting the development and review of drug candidates that are intended to treat a serious condition and for which preliminary evidence indicates that the drug candidate may demonstrate substantial improvement over the available therapy.
Other Healthcare Laws and Compliance Requirements
Our sales, promotion, medical education, clinical research, and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the U.S. in addition to the FDA, including potentially the Federal Trade Commission, the Department of Justice, the Centers for Medicare and Medicaid Services, other divisions of the U.S. Department of Health and Human Services and state and local governments. Our promotional and scientific/educational programs and interactions with healthcare professionals must comply with the federal Anti-Kickback Statute, the civil False Claims Act (“FCA”), physician payment transparency laws, privacy laws, security laws, and additional federal and state laws similar to the foregoing.
The federal Anti-Kickback Statute prohibits, among other things, the knowing and willing, direct or indirect offer, receipt, solicitation or payment of remuneration in exchange for or to induce the referral of patients, including the purchase, order, or lease of any good, facility, item or service that would be paid for in whole or part by Medicare, Medicaid, or other federal health care programs. Remuneration has been broadly defined to include anything of value, including cash, improper discounts, and free or reduced-price items and services. The federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, formulary managers, and beneficiaries on the other. Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases, or recommendations may be subject to increased scrutiny and review if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct illegal per se under the federal Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all its facts and circumstances. Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the federal Anti-Kickback Statute has been violated. The government has enforced the federal Anti-Kickback Statute to reach large settlements with healthcare companies based on sham research or consulting and other financial arrangements with physicians. Further, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it to have committed a violation. In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA. Many states have similar laws that apply to their state health care programs as well as private payers.
Federal false claims and false statement laws, including the FCA, impose liability on persons and/or entities that, among other things, knowingly present or cause to be presented claims that are false or fraudulent or not provided as claimed for payment or approval by a federal health care program. The FCA has been used to prosecute persons or entities that “cause” the submission of claims for payment that are inaccurate or fraudulent, by, for example, providing inaccurate billing or coding information to customers, promoting a product off-label, submitting claims for services not provided as claimed, or submitting claims for services that were provided but not medically necessary. Actions under the FCA may be brought by the Attorney General or as a qui tam action by a private individual, or whistleblower, in the name of the government. Violations of the FCA can result in significant monetary penalties and treble damages. The federal government is using the FCA, and the accompanying threat of significant liability, in its investigation and prosecution of pharmaceutical and biotechnology companies throughout the country, for example, in connection with the promotion of products for unapproved uses and other illegal sales and marketing practices. The government has obtained multi-million and multi-billion-dollar settlements under the FCA in addition to individual criminal convictions under applicable criminal statutes. In addition, certain companies that were found to be in violation of the FCA have been forced to implement
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extensive corrective action plans, and have often become subject to consent decrees or corporate integrity agreements, restricting the manner in which they conduct their business.
The federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payers; knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services; and willfully obstructing a criminal investigation of a healthcare offense. Like the federal Anti-Kickback Statute, the Affordable Care Act amended the intent standard for certain healthcare fraud statutes under HIPAA such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
Given the significant size of actual and potential settlements, it is expected that the government will continue to devote substantial resources to investigating healthcare providers’ and manufacturers’ compliance with applicable fraud and abuse laws. Also, many states have similar fraud and abuse statutes or regulations that may be broader in scope and may apply regardless of payer, in addition to items and services reimbursed under Medicaid and other state programs. Additionally, to the extent that our products, once commercialized, are sold in a foreign country, we may be subject to similar foreign laws.
In addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and other healthcare providers. The Physician Payments Sunshine Act, known as “Open Payments” and implemented as part of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the Affordable Care Act, among other things, imposed new reporting requirements on certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, for payments or other transfers of value made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Covered manufacturers are required to collect and report detailed payment data and submit legal attestation to the accuracy of such data to the government each year.
On October 24, 2018, then President Trump signed into law the “Substance Use-Disorder Prevention that Promoted Opioid Recovery and Treatment for Patients and Communities Act” which in part (under a provision entitled “Fighting the Opioid Epidemic with Sunshine”) extends the reporting and transparency requirements under Open Payments to physician assistants, nurse practitioners, and other mid-level practitioners (with reporting requirements going into effect in 2022 for payments made in 2021). Additionally, entities that do not comply with mandatory reporting requirements may be subject to a corporate integrity agreement. Certain states also mandate implementation of commercial compliance programs, impose restrictions on covered manufacturers’ marketing practices and/or require the tracking and reporting of gifts, compensation, and other remuneration to physicians and other healthcare professionals.
We are also subject to data privacy and security regulation by the federal government and the states in which we conduct our business and the EU with the General Data Protection Regulation rules, which became effective in May 2018. HIPAA, as amended by the Health Information Technology and Clinical Health Act (“HITECH”), and their respective implementing regulations, imposes specified requirements on certain health care providers, plans and clearinghouses (collectively, “covered entities”) and their “business associates,” relating to the privacy, security and transmission of individually identifiable health information. Among other things, HITECH makes HIPAA’s security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities that create, receive, maintain, or transmit protected health information in connection with providing a service for or on behalf of a covered entity. HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions. In addition, certain states have their own laws that govern the privacy and security of health information in certain circumstances, many of which differ from each other and/or HIPAA in significant ways and may not have the same effect, thus complicating compliance efforts.
If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to them, we may be subject to penalties, including, without limitation, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, imprisonment, contractual damages, reputational harm, and diminished profits and future earnings, any of which could adversely affect our ability to operate our business and our financial results.
In addition to the foregoing health care laws, we are also subject to the U.S. Foreign Corrupt Practices Act (“FCPA”) and similar worldwide anti-bribery laws, which generally prohibit companies and their intermediaries from making improper payments to government officials or private-sector recipients for the purpose of obtaining or retaining business. We have
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adopted an anti-corruption policy which mandates compliance with the FCPA and similar anti-bribery laws applicable to our business throughout the world. However, we cannot assure that such a policy or procedures implemented to enforce such a policy will protect against intentional, reckless, or negligent acts committed by our employees, distributors, partners, collaborators, or agents. Violations of these laws, or allegations of such violations, could result in fines, penalties, or prosecution and have a negative impact on our business, results of operations, and reputation.
Coverage and Reimbursement
Sales of pharmaceutical products depend significantly on the extent to which coverage and adequate reimbursement are provided by third-party payers. Third-party payers include state and federal government health care programs, managed care providers, private health insurers and other organizations. Although we currently believe that third-party payers will provide coverage and reimbursement for our product candidate, if approved, we cannot be certain of this. Third-party payers are increasingly challenging the price, examining the cost-effectiveness, and reducing reimbursement for medical products and services. In addition, significant uncertainty exists as to the reimbursement status of newly approved healthcare products. The U.S. government, state legislatures, and foreign governments have continued implementing cost containment programs, including price controls, restrictions on coverage and reimbursement, and requirements for substitution of generic products. Adoption of price controls and cost containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could limit our net revenue and results. We may need to conduct expensive clinical trials to demonstrate the comparative cost-effectiveness of our products. The product candidate that we develop may not be considered cost-effective and thus may not be covered or sufficiently reimbursed. It is time consuming and expensive for third-party payers to seek coverage and reimbursement. Thus, one payer’s decision to provide coverage and adequate reimbursement for a product does not assure that another payer will provide coverage or that the reimbursement levels will be adequate. Moreover, a payer’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Reimbursement may not be available or sufficient to allow third-party payers to sell our products on a competitive and profitable basis.
Healthcare Reform
The U.S. and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could materially affect our ability to sell our products profitably. Among policy makers and payers in the U.S. and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the U.S., the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.
By way of example, in March 2010, the Affordable Care Act was signed into law, intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for the healthcare and health insurance industries, impose new taxes and fees on the health industry, and impose additional health policy reforms. Among the provisions of the Affordable Care Act of importance to our product candidate are:
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an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs; however designated Orphan Drugs, such as MOLBREEVI, are generally exempt from these fees;
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an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13.0% of the average manufacturer price for branded and generic drugs, respectively;
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a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected;
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a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for a manufacturer’s outpatient drugs to be covered under Medicare Part D;
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extension of a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;
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expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;
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expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; and
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a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
In addition, other legislative changes have been proposed and adopted since the Affordable Care Act was enacted. These changes include, among others, the Budget Control Act of 2011, which mandates aggregate reductions to Medicare payments to providers of up to 2% per fiscal year effective April 1, 2013, and due to subsequent legislative amendments, will remain in effect through 2029 unless additional Congressional action is taken. In January 2013, former President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our product candidate, if approved, and, accordingly, our financial operations.
There have been judicial and Congressional challenges to certain aspects of the Affordable Care Act, and we expect additional challenges and amendments in the future. It is unclear how this such effort to repeal and replace the Affordable Care Act will impact the healthcare industry or our business operations. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payers. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our drugs.
Other Foreign Regulations
In addition to regulations mentioned above, we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of our products to the extent we choose to develop or sell any products outside of the U.S. The approval process varies from country to country and the time may be longer or shorter than that required to obtain FDA approval. The requirements governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary greatly from country to country.
Intellectual Property
We strive to protect the proprietary technology that we believe is important to our business, including our product candidate and our processes. We seek patent protection in the U.S. and internationally for our products, their methods of use and any other technology to which we have rights, as appropriate, such as device exclusivity. We also rely on trade secrets that may be important to the development of our business.
Our success will, in part, depend on the ability to obtain and maintain patent and other proprietary rights in commercially important technology, inventions and know-how related to our business, the validity and enforceability of our patents, the continued confidentiality of our trade secrets as well as our ability to operate without infringing the valid and enforceable patents and proprietary rights of third parties. We also rely on continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.
We cannot be sure patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may own or license in the future, nor can we be sure that any of our existing patents or any patents we may own or license in the future will be useful in protecting our technology and products. For this and more comprehensive risks related to our intellectual property, please see Risk Factors – Risks Related to Our Intellectual Property.
Trade Secrets
In addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position. For example, significant aspects of our processes and proprietary technology portfolio are based on unpatented trade secrets and know-how. Trade secrets and know-how can be difficult to protect. We seek to protect our proprietary technology and processes, in part, by confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors, and commercial partners. These agreements are designed to protect proprietary information and, in the case of the invention assignment agreements, to grant us ownership of technologies that are developed through a relationship with a third party. While we have confidence in our key individuals, consultants, partner organizations, and systems, agreements or security measures may be breached, and there may not be adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our contractors use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.
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Competition
The pharmaceutical industry is highly competitive and subject to continuous technological change. We compete in the segment of the pharmaceutical, biotechnology, and other related markets focused on rare respiratory diseases. Our potential competitors include large pharmaceutical and biotechnology companies, specialty pharmaceutical and generic drug companies, academic institutions, government agencies, and research institutions. We believe that key competitive factors affecting the commercial success of our product candidate will be efficacy, safety and tolerability profile, reliability, convenience of dosing, price and reimbursement. Many of our potential competitors, either alone or with their collaboration partners have substantially greater financial, technical, and human resources than us, and significantly greater experience in the discovery and development of product candidates, manufacturing, obtaining FDA and other regulatory approvals of products and the commercialization of those products. Accordingly, our competitors may be faster and more successful in obtaining FDA approval for therapies and achieving widespread market acceptance. Mergers and acquisitions in the pharmaceutical and biotechnology industry may result in even more resources being concentrated among a smaller number of very capable competitors. We anticipate facing intense and increasing competition as new drugs enter the market and advanced technologies become available. Our competitors’ products may be more effective, or more effectively marketed and sold, than any product candidate we may commercialize and may render our therapies obsolete or non-competitive before we can recover development and commercialization expenses.
A glycosylated GM-CSF product, sargramostim (Leukine), available in the U.S., is approved for intravenous or subcutaneous delivery in patients with neutropenia following cancer chemotherapy. Leukine has not been approved in the U.S. or Europe for the treatment of aPAP or any other acute or chronic lung disease but is sometimes used in the U.S. as an off-label, pharmacy-compounded product (injectable product compounded for inhalation delivery). The drug substance in Leukine, sargramostim, has been used in a nonclinical research project conducted by NIH/TRND in collaboration with the University of Cincinnati College of Medicine on the potential application of inhaled GM-CSF as a treatment for aPAP. No clinical trials have been conducted to date under this collaboration project. Additionally, in April 2024, sargramostim was approved by the Japanese Pharmaceuticals and Medical Device Agency ("PMDA") for the treatment of aPAP. The approval was based on a multicenter clinical trial of inhaled sargramostim in aPAP, using a standard commercially available nebulizer, which was conducted by a consortium of independent clinical investigators in Japan. Sargramostim, marketed in Japan by Nobelpharma Co. Ltd., has the potential to present a material competitive threat to the commercial success of MOLBREEVI in Japan. In addition, in November 2018 and June 2024, Partner Therapeutics, Inc., a commercial biotechnology company, was granted Orphan Drug Designation for Leukine for the treatment of PAP by the FDA and EMA, respectively. Except for the aformentioned treatments, we are not aware of any other companies developing an inhaled form of GM-CSF for aPAP in the U.S. or elsewhere
Employees and Human Capital
We are committed to attracting and retaining the best possible talent. As of March 27, 2025, we had 59 employees as well as several third-party consultants. None of our employees are represented by a labor union or covered by a collective bargaining agreement. We consider our relationship with our employees to be good.
Attraction, Development and Retention
We believe our future success will depend in large part on our continued ability to attract and retain highly skilled employees. Our compensation program, including salary, bonus, benefits as well as short and long-term incentives, is designed to help us to attract and retain individuals whose skills are important to our current and long-term success. Our total compensation package is generally positioned within the competitive ranges of our peer market, with differences generally based on tenure, skills, and performance needed to attract and retain key talent. We have also implemented a spot bonus program that allows employees to nominate their colleagues for cash awards in recognition of notable achievements.
We believe that continued professional growth and development are essential to helping our team stay on top of current rules, laws, trends, and events which impact their duties. We seek to develop our employee talent within the organization through access to training, continuous learning programs, and other development initiatives. We foster a culture of empowerment, transparency, and respect.
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Diversity and Inclusion
We value diverse backgrounds and viewpoints and are committed to equal opportunity. We aim to recruit, hire, place, develop, compensate, and advance people based on the needs of our organization and the qualifications, performance, skills, and experience of our people. We expect to continue to enhance our workforce diversity and advance the development of diverse talent. We consistently evaluate the opportunity for diversity for both our employee workforce and our board of directors. Upon beginning employment with Savara, all employees receive training on workplace diversity and inclusion.
Health and Safety
The health and safety of our employees is a top priority, and our goal is to provide a safe and healthy work environment for all personnel. We have provided our employees the ability to work remotely in order to best manage business and personal responsibilities. We will continue to manage our business with a focus towards the safety of our employees.
Corporate Information
Our company was incorporated in Delaware in December 1995. Our website is http://www.savarapharma.com. Information found on our website is not incorporated by reference into this annual report on Form 10-K. We make our filings with the U.S. Securities and Exchange Commission (“SEC”) including our annual report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and any amendments and exhibits to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (“Exchange Act”), available free of charge on or through our website, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC. The SEC maintains a website that contains reports, proxy and information statements, and other information regarding our filings at http://www.sec.gov.
Trademarks
“Savara Inc.,” "aPAP ClearPath," "MOLBREEVI," and the Savara logo are trademarks of Savara or its subsidiaries in the U.S. and other jurisdictions. Other third-party logos and product/trade names are registered trademarks or trade names of their respective companies. Use or display by us of other parties’ trademarks, service marks, trade names, trade dress or products is not intended to and does not imply a relationship with, or endorsements or sponsorship of, us by the trademark, service mark, trade name, trade dress or product owners.
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Item 1A. Risk Factors.
Investment in our common stock involves a high degree of risk and uncertainty. Our business, operating results, growth prospects and financial condition are subject to various risks, many of which are not exclusively within our control, that may cause actual performance to differ materially from historical or projected future performance. We urge investors to consider carefully the risks described below, together with all of the information in this report and our other public filings, before making investment decisions regarding our securities. Each of these risk factors, as well as additional risks not presently known to us or that we currently deem immaterial, could adversely affect our business, operating results, growth prospects or financial condition, as well as the trading price of our common stock, in which case you may lose all or part of your investment.
Risks Related to Development and Commercialization of our Product Candidate
We are substantially dependent upon the clinical, regulatory, and commercial success of our sole product candidate, MOLBREEVI. If we are unable to successfully complete clinical development of, obtain regulatory approval for, and successfully commercialize MOLBREEVI, our business may be harmed.
The success of our business is dependent on our ability to advance the clinical development of our sole product candidate, MOLBREEVI, an investigational inhaled GM-CSF for the treatment of aPAP. To date, we have never obtained regulatory approvals for or commercialized a product candidate, and we may never be able to develop a marketable product. We are devoting, and expect to continue to devote, substantially all our efforts and financial resources to the development of MOLBREEVI for aPAP, including clinical trials, regulatory approval, and, if approved, commercialization. Our business depends heavily on the successful completion of clinical development and subsequent regulatory approval of MOLBREEVI for aPAP.
We are conducting IMPALA-2, a global Phase 3 pivotal trial designed to compare the efficacy and safety of MOLBREEVI 300 μg administered once daily by inhalation with matching placebo in patients with aPAP. Although we may believe the trial demonstrates promising results, regulatory authorities may analyze or weigh trial data differently, resulting in delay or failure to obtain marketing approval or a requirement to conduct confirmatory studies.
We are not permitted to commercialize MOLBREEVI in the U.S. until we receive approval of a BLA, or in any other country until we receive the requisite approvals from the appropriate regulatory authorities. Failure to obtain such approvals could impair our ability to generate revenues from the product candidate, which would have a material adverse effect on our business, operating results, growth prospects or financial condition, as well as the trading price of our common stock.
Given the developmental nature of our product candidate, we are subject to risks associated with initiating, completing, and achieving positive outcomes from our current and future clinical trials.
If we successfully complete the necessary clinical trials for our product candidate, our success will be subject to the risks associated with obtaining regulatory approvals, product launch, and commercialization, including:
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rejection of our regulatory submissions for our product candidate by the FDA or other regulatory authorities;
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delays during regulatory review and/or requirements of additional chemistry, manufacturing, and controls, nonclinical, or clinical studies, resulting in increased costs and/or delays in marketing approval and subsequent commercialization of the product candidate in the U.S. and other markets;
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inability to consistently manufacture commercial supplies of drug and delivery devices resulting in slowed market development and lower revenue;
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poor commercial sales due to:
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the inability of our future sales organization or our potential commercialization partners to effectively sell the product candidate;
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our lack of success in educating physicians and patients about the benefits, administration, and use of our product candidate;
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the availability, perceived advantages, relative cost, relative safety, and relative efficacy of other products or treatments for the targeted indications of the product candidate;
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low patient demand for the product candidate; and
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poor prescription coverage and inadequate reimbursement for our product candidate;
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our inability to enforce our intellectual property rights in our product candidate; and
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reduction in the safety profile of our product candidate following approval.
Many of these clinical, regulatory, and commercial matters are beyond our control and are subject to other risks described elsewhere in this Item 1A, Risk Factors section. Accordingly, we cannot assure that we will be able to advance our product candidate further through final clinical development, or obtain regulatory approval of, commercialize, or generate significant revenue. If we cannot do so, or are significantly delayed in doing so, our business will be materially harmed.
Clinical drug development involves a lengthy and expensive process, with an uncertain outcome. We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development of our product candidate. If development of our product candidate is unsuccessful or delayed, we may be unable to obtain required regulatory approvals and be unable to commercialize our product candidate on a timely basis, if at all.
Pharmaceutical products are subject to stringent regulatory requirements covering quality, safety, and efficacy. Only after successfully completing extensive pharmaceutical development, nonclinical testing, and clinical trials may a product be considered for regulatory approval.
Clinical trials are expensive, difficult to design and implement, the outcome is inherently uncertain, and failure or delay may occur at any time. We may experience a number of unforeseen events that cause our clinical trials not commence or not be completed on schedule, if at all. Clinical trials can be delayed for a variety of reasons, including:
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inability to raise sufficient funding to initiate or continue a clinical trial;
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delays in obtaining regulatory approval to commence or extend a clinical trial;
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delays in identifying and reaching agreement on acceptable terms with prospective CROs, clinical trial sites, and investigators, which agreements can be subject to extensive negotiation and may vary significantly among trial sites;
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delays in obtaining regulatory approval in a prospective country;
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delays in obtaining ethics committee approval to conduct or extend a clinical trial at a prospective site;
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delays in reaching agreements on acceptable terms with prospective CMOs or other vendors for the production and supply of clinical trial material and, if necessary, drug administration devices, which agreements can be subject to extensive negotiation;
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delays in the production or delivery of sufficient quantities of clinical trial material or drug delivery devices from our CMOs and other vendors to initiate or continue a clinical trial;
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delays in distributing clinical trial material due to import restrictions or licenses in target countries;
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delays due to product candidate recalls as the result of stability failure, excessive product complaints, or other failures of the product candidate during its use or testing;
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invalidation of clinical data caused by premature unblinding or integrity issues;
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invalidation of clinical data caused by mixing up of the active drug and placebo through randomization or manufacturing errors;
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delays on the part of our CROs, CMOs, and other third-party contractors in developing procedures and protocols or otherwise conducting activities in accordance with applicable policies and procedures and in accordance with agreed upon timelines;
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delays in identifying and hiring or engaging, as applicable, additional employees or consultants to assist in managing clinical trial-related activities;
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delays in recruiting and enrolling individuals to participate in a clinical trial, which historically can be challenging in orphan diseases;
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delays caused by patients dropping out of a clinical trial due to side effects, concurrent disorders, difficulties in adhering to the trial protocol, unknown issues related to different patient profiles than in previous trials, or otherwise;
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delays in having patients complete participation in a clinical trial;
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delays resulting from clinical trial sites dropping out of a trial, providing inadequate staff support for the trial, problems with shipment of trial supplies to clinical sites, or focusing its staff’s efforts on enrolling trials that compete for the same patient population;
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suspension of enrollment at a trial site or the imposition of a clinical hold by the FDA or other regulatory authority following an inspection of clinical trial operations at trial sites or finding of a drug-related serious adverse event;
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delays in quality control/quality assurance procedures necessary for trial database lock and analysis of unblinded data;
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delays, inconsistencies, or negative results in statistical analyses of clinical trial data;
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delays in enrollment and the treatment of patients caused by global health risks; and
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delays due to supply chain disruptions as a result of global health risks, international conflict, or other unexpected event.
Clinical trials may not begin on time or be completed in the time frames we anticipate and may be costlier than we anticipate for a variety of reasons, including one or more of those described above. The length of time necessary to successfully complete clinical trials vary significantly and is difficult to predict accurately. We may make statements regarding anticipated timing for completion of enrollment in and/or availability of results from our clinical trials, but such predictions are subject to a number of significant assumptions and actual timing may differ materially for a variety of reasons, including patient enrollment rates, length of time needed to prepare raw trial data for analysis and then to review and analyze it, and other factors described above. If we experience delays in the completion of a clinical trial, if a clinical trial is terminated, or if failure to conduct a trial in accordance with regulatory requirements or the trial’s protocol leads to deficient safety and/or efficacy data, the regulatory approval and/or commercial prospects for our product candidate may be harmed, and our ability to generate product revenue will be delayed. In addition, any delays in completing our clinical trials likely will increase our development costs. Further, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials have in the past and may in the future ultimately lead to the denial of regulatory approval of a product candidate. Even if we ultimately commercialize a product candidate, the standard of care may have changed or other therapies for the same indications may have been introduced to the market in the interim and may establish a competitive threat to us or diminish the need for our products.
Failure at any stage of clinical testing is not uncommon and we may encounter problems that would require additional, unplanned trials or cause us to abandon a clinical development program.
In addition, a clinical trial may be suspended or terminated by us, an IRB, a data safety monitoring board, the FDA, or other regulatory authorities due to a number of factors, including:
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lack of adequate funding to continue the trial;
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failure to conduct the trial in accordance with regulatory requirements or the trial’s protocol;
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inspection of clinical trial operations or sites by the FDA or other regulatory authorities resulting in the imposition of a clinical hold;
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unforeseen safety issues, including adverse side effects; or
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changes in governmental regulations or administrative actions, such as lay-offs and staffing at regulatory agencies such as the FDA.
Changes in governmental regulations and guidance relating to clinical trials may occur and we may need to amend clinical trial protocols to reflect these changes, or we may amend trial protocols for other reasons. Amendments may require us to resubmit protocols to IRBs for re-examination and approval or renegotiate terms with CROs, clinical trial sites, and investigators, all of which may adversely impact the costs or timing of or our ability to successfully complete a trial.