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IMPALA Phase 3 Study of Molgradex Does Not Meet Primary Endpoint

June 14, 2019 By americanpharmaceuticalreview

Savara announced top line data from IMPALA, a pivotal Phase 3 clinical study evaluating Molgradex, an inhaled formulation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of aPAP. A total of 138 patients were randomized and received treatment for 24 weeks in one of three arms: 1) Molgradex 300 µg administered once daily continuously over 24 weeks, 2) Molgradex 300 µg, and matching placebo, administered once daily in 7-day intermittent cycles of each, or 3) inhaled placebo administered once daily continuously over 24 weeks.

Primary Endpoint in the Intention-to-Treat (ITT) Population

An average A-aDO2 improvement of 12.1 mmHg was observed in the continuous dosing arm, compared to an average A-aDO2 improvement of 8.8 mmHg in the placebo arm. With an estimated 4.6 mmHg treatment difference (p=0.17), the study did not meet its primary endpoint.

Secondary Endpoints in the ITT Population

An average improvement of 12.3 points in the SGRQ (a patient-reported outcomes/quality-of-life measure) was observed in the continuous dosing arm compared to an average improvement of 4.7 points in the placebo arm. The estimated treatment difference was 7.6 points (p=0.01) which was statistically significant and approximately two times the generally accepted clinically meaningful difference of four points for this measure.

The other two key secondary endpoints, the six-minute walk distance (6MWD) and requirement for whole lung lavage (WLL), were numerically in favor of the continuous dosing arm, but the differences to placebo were not statistically significant. Patients in the continuous dosing arm showed a mean improvement of 39.6 meters in the 6MWD, while the intermittent and placebo arms showed improvements of 11.3 meters and 6.0 meters, respectively. Four patients in each of the active arms, and six patients in the placebo arm underwent a WLL during the treatment period. Given that some patients received more than one WLL, the total number of WLLs observed in the continuous dosing arm was 9, with 7 observed in the intermittent dosing arm and 17 in the placebo arm.

In addition to the A-aDO2, the diffusing capacity of the lungs for carbon monoxide (DLCO) was assessed as a secondary endpoint to evaluate the efficacy of Molgradex on gas transfer. Patients in the continuous dosing arm showed a mean improvement of 11.6% predicted in DLCO, whereas the intermittent dosing and placebo arms showed a 7.7% predicted and 3.9% predicted improvement, respectively. The estimated treatment difference of 7.9% predicted (p=0.007) between the continuous dosing arm and placebo was statistically significant.

 “Taken together, the trends in reduction of A-aDO2, as well as the improvement in the diffusion capacity, are very consistent with reduction of the surfactant burden that causes the clinical symptoms of aPAP,” said Bruce Trapnell, M.D., Lead Investigator of the IMPALA study in the U.S. and Professor of Medicine and Pediatrics, University of Cincinnati College of Medicine. “Most importantly, the impressive improvement in quality of life, as measured by the SGRQ, suggest that Molgradex not only improved objective measures of oxygenation, but also had a clinically meaningful therapeutic effect. I believe these data demonstrate that Molgradex can become an important pharmacological treatment option for patients with aPAP.”

The number of treatment emergent adverse events (TEAEs), including serious adverse events, occurred with similar frequency and severity in the active arms compared to placebo. The number of subjects discontinuing due to TEAEs was as follows: continuous dosing arm; n=2, intermittent dosing arm; n=1, placebo arm; n=1.

The Company plans to meet with the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the coming months to discuss these data and the path forward.

"Disappointingly, with the placebo effect stronger than anticipated, the study did not meet its primary endpoint,” said Rob Neville, Chief Executive Officer, Savara. “However, we remain encouraged about the results of IMPALA, most notably the significant improvement in SGRQ, the consistency of trends and improvements seen across the endpoints and the favorable safety profile. We are preparing to meet with the FDA and EMA to discuss the results from this study and to determine our options to seek approval based on the current data, and potentially conduct an additional study incorporating the learnings from IMPALA. It is with much gratitude that we acknowledge the patients participating in the study. It is on their behalf that we will continue to pursue our goal of bringing this important therapy to market.”

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