Molgramostim

There is no approved drug for PAP in the United States or Europe, and the standard of care is whole lung lavage, a procedure under general anesthesia that washes surfactant out of the lungs and has to be repeated in many patients. Some pulmonologists already use GM-CSF products off label by inhalation or injection, and NORD reports that up to 95% of patients may respond to inhaled GM-CSF, but without an approved product supply and insurance coverage are uncertain. If approved, molgramostim would be the first drug that treats the cause of autoimmune PAP rather than its consequences. It is intended for the autoimmune form, which is confirmed by a GM-CSF autoantibody blood test; it does not address the hereditary form, in which the GM-CSF receptor itself is faulty.

In autoimmune PAP the body makes antibodies that neutralize GM-CSF, the protein that tells the lungs' cleanup cells, the alveolar macrophages, to clear away used surfactant. Without the signal, surfactant builds up in the air sacs and oxygen cannot get through. Molgramostim is a manufactured version of GM-CSF. Breathed in as a mist, it reaches the air sacs directly and supplies the signal the antibodies have blocked, so the macrophages start clearing surfactant again. Delivering it by inhalation puts the drug where it is needed and limits exposure to the rest of the body.

In the 48-week placebo-controlled part of IMPALA-2, the share of patients with at least 1 adverse event and with at least 1 serious adverse event was similar in the molgramostim and placebo groups, and no deaths occurred. Savara's patient summary lists cough and fever as the most common adverse events in people taking molgramostim. Events that were more frequent on molgramostim than placebo were symptomatic COVID-19 infection (22% versus 10%) and diarrhea (11% versus 2%), while worsening of PAP was less frequent (5% versus 14%). Only 2 adverse events led to discontinuation of molgramostim, and 97% of patients completed the double-blind period. There is no US label yet.

IMPALA-2 (NCT04544293) was a Phase 3, double-blind, placebo-controlled trial at 43 sites in 16 countries that randomized 164 adults with autoimmune PAP to inhaled molgramostim 300 micrograms or placebo once daily for 48 weeks; 81 received molgramostim and 83 placebo, with Japan, the United States, Turkey, South Korea and Germany the largest enrolling countries. The primary endpoint was the change at week 24 in DLCO, a breathing test of how well gas crosses from the lungs into the blood. DLCO improved by 9.8 percentage points on molgramostim versus 3.8 on placebo, a difference of 6.0 points (95% CI 2.5 to 9.4, p below 0.001), and by week 48 the gap was 11.6 versus 4.7 points. The St George's Respiratory Questionnaire, a quality of life measure, improved by 11.5 points versus 4.9 (p 0.007), although its activity subscore did not differ significantly. The results were published in the New England Journal of Medicine in 2025. An earlier Phase 2/3 trial, IMPALA, enrolled 138 patients and was published in NEJM in 2020.

Savara has developed molgramostim and run both IMPALA trials. The FDA granted Orphan Drug, Fast Track and Breakthrough Therapy designations, and the EMA granted orphan designation. Savara announced positive IMPALA-2 topline results in June 2024 and submitted the biologics license application. The FDA extended its review by 3 months and set a target action date of November 22, 2026. Applications are also under review in Europe, with a decision expected in the first quarter of 2027, and in the United Kingdom, with a decision expected in the fourth quarter of 2026. Molbreevi is the proposed trade name and the product is not approved anywhere.