Savara Reports Positive Phase 3 Results for Molgramostim in Rare Lung Disease

Rare Daily Staff

Savara reported positive results from the pivotal, phase 3 IMPALA-2 clinical trial evaluating molgramostim in patients with autoimmune pulmonary alveolar proteinosis, or aPAP.

Autoimmune PAP is a rare lung disease characterized by the abnormal build-up of surfactant in the alveoli (or air sacs) of the lungs. Surfactant consists of proteins and lipids and is an important physiological substance that lines the alveoli to prevent them from collapsing. In a healthy lung, excess surfactant is cleared and digested by immune cells called alveolar macrophages. Alveolar macrophages need to be stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) to function properly in clearing surfactant, but in autoimmune PAP, GM-CSF is neutralized by antibodies against GM-CSF, rendering the macrophages unable to adequately clear surfactant. As a result, an excess of surfactant accumulates in the alveoli, causing impaired gas exchange, resulting in clinical symptoms of shortness of breath, often with cough and frequent fatigue. Patients may also experience episodes of fever, chest pain, or coughing up blood, especially if secondary lung infection develops. In the long-term, the disease can lead to serious complications, including lung fibrosis and the need for a lung transplant.

“There is a high unmet need for effective, disease-specific pharmacotherapy for autoimmune PAP,” said Bruce Trapnell, professor of Medicine and Pediatrics at the University of Cincinnati College of Medicine and the lead clinical investigator of the IMPALA-2 trial. “Patients typically experience breathlessness, which begins slowly and progresses over time, often accompanied by cough and fatigue, and in some patients, serious infections, pulmonary fibrosis, and respiratory failure requiring lung transplantation. With convincing data from two large clinical trials, the evidence now clearly demonstrates molgramostim has the potential to be a safe and efficacious treatment option for these patients. This is a momentous day for the aPAP community.”

The trial met its primary endpoint which was the treatment difference between molgramostim and placebo for mean change from baseline to Week 24 in hemoglobin-adjusted percent predicted DLCO achieved statistical significance. This statistically significant treatment difference was sustained at Week 48, a secondary endpoint, which demonstrated durability of effect.

The treatment difference between molgramostim and placebo for mean change from baseline to Week 24 in SGRQ Total Score achieved statistical significance. Two additional secondary endpoints reached nominal significance: SGRQ Activity Score at Week 24 and exercise capacity using a treadmill test at Week 48.

SGRQ is a patient-reported outcomes instrument that measures overall health, daily life, and a patient’s perceived well-being. SGRQ Activity assesses the patient’s ability to carry out daily physical activity. With SGRQ, a negative change from baseline corresponds to improvement. Exercise capacity as measured by a treadmill is a cardiorespiratory health (CRH) measurement.

Molgramostim was well tolerated. The frequency of adverse events was generally similar between treatment groups. Two patients (2.5 percent) discontinued molgramostim treatment due to adverse events, both of which were considered unrelated to trial drug. The most commonly reported adverse events in the molgramostim group were COVID-19, cough, and pyrexia, with COVID-19 occurring more frequently with molgramostim than with placebo.

Molgramostim has been granted Orphan Drug, Fast Track, and Breakthrough Therapy designation from the U.S. Food and Drug Administration, Orphan Drug designation from the European Medicines Agency and Innovative Passport and Promising Innovative Medicine designation from the UK’s Medicines and Healthcare Products Regulatory Agency for the treatment of aPAP.

“The IMPALA-2 results not only met, but exceeded, our expectations, validating our hypothesis that molgramostim provides clear, durable improvement in gas exchange, and beyond that, clinical benefits that positively impact quality of life for aPAP patients,” said Matt Pauls, chair and CEO, Savara. “The strong efficacy data and favorable benefit-risk profile potentially position molgramostim to be the first and only approved therapeutic for aPAP in the U.S. and Europe. We extend our gratitude to the patients and their families, clinicians, and site personnel for their contributions and ongoing participation in the largest clinical trial in aPAP. We look forward to analyzing the full data from IMPALA-2 and anticipate submitting it for presentation at a scientific conference later this year.”

Photo: Matt Pauls, chair and CEO, Savara