Savara Inc

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”). MOLBREEVI is 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

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)DO 2, 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"). MOLBREEVI was 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.

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 MOLBREEVI activates 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 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 Trial section 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 molgramostim for 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, MOLBREEVI will 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.