Austin, Texas-based Savara announced that the U.S. Food and Drug Administration (FDA) granted its Molgradex Breakthrough Therapy designation for the treatment of autoimmune Pulmonary Alveolar Proteinosis (aPAP).

Molgradex is an inhaled formulation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). aPAP is a rare lung disease caused by a buildup of protein and other material in the air sacs, called alveoli. It affects about one person in 100,000 worldwide, with fewer than 10,000 in the U.S. It typically develops in adults, but some people are born with it. It is also sometimes called phospholipidosis or pulmonary alveolar lipoproteinosis.

The disease is the result of autoantibodies that neutralize GM-CSF in the lungs. Molgradex replenishes the lungs with a recombinant version of the protein.

The drug’s history has been something of a rollercoaster ride. In June 2019, the company announced that its Phase III IMPALA failed to hit the primary endpoint of improved lung function in aPAP. Savara indicated an average alveolar-arterial oxygen gradient A-aDO2 improvement was 12.1 mmHg in the continuous dosing arm. In the placebo group, the average A-aDO2 improvement was 8.8 mmHg. This was not deemed statistically significant.

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The company pointed to the secondary endpoints as a potential pathway forward for Molgradex. There was an average improvement of 12.3 points in a quality of life measures for patients receiving Molgradex compared to 3.7 points in the placebo cohort. This was statistically significant and about two times the generally accepted clinically meaningful difference of four points for this measure.

Another secondary endpoint, diffusing capacity of the lungs for carbon monoxide, was also statistically significant, with the continuous dosing arm showing mean improvement of 11.6% while two placebo arms showed 7.7% and 3.9% improvement.

Investors weren’t convinced, and company shares plunged 75%. And seemingly, the FDA wasn’t convinced either.

On October 2, Savara announced a response from a Type C meeting with the FDA over the drug. The agency indicated the data provided did not provide sufficient evidence of efficacy and safety and as a result, didn’t recommend Savara submit a Biologics License Application (BLA).

Unexpectedly, the Breakthrough Therapy designation was based on data from IMPALA.

“We are pleased that the FDA recognized Molgradex as a breakthrough therapy for the treatment of aPAP, a debilitating rare lung disease with no approved pharmacologic treatment options,” said Rob Neville, Savara’s chief executive officer. “We believe this designation reflects the significance of Molgradex as an investigational product that, based on the IMPALA study, has been demonstrated to improve patient outcomes. Breakthrough designation is designed to provide increased collaboration and more frequent dialogue with the FDA and is an important milestone as we work to determine the best path forward for this product.”

It’s not clear what the FDA is thinking in granting this designation, although investors were happy—at least temporarily—about it, with company shares tripling from $1.73 per share to $4.91 earlier this week at the news. That’s still not particularly close to its $10.57 share price on June 12.

The company’s release and slide presentation emphasized “a pattern of improvement” in the IMPALA trial based on several different metrics, arguing that the “totality of outcome data” suggested Molgradex was superior to placebo.



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