FDA Panel Votes 9-3 Against DMD Drug Amid Statistical Dispute

The approval outlook for Capricor Therapeutics’ cell therapy for Duchenne muscular dystrophy (DMD) has dimmed after a US Food and Drug Administration (FDA) advisory committee issued an overwhelming recommendation against the treatment.

According to biotech publication Fierce Biotech on the 29th local time, the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted on the efficacy of Capricor’s cell therapy deramiocel, recommending against approval by a vote of 3 in favor and 9 opposed.

The central issue at the advisory committee meeting was the statistical analysis method used for the phase 3 HOPE-3 trial data. Capricor and the FDA reached diametrically opposed conclusions of “success” and “failure” from the same clinical results by applying the statistical analysis plan (SAP) differently.

Deramiocel is administered intravenously every 3 months using cardiac cells derived from donated cadavers. The application sought approval to treat cardiomyopathy, a major complication of Duchenne muscular dystrophy.

During its presentation to the advisory committee, Capricor criticized the FDA for evaluating the data based on an early draft of the statistical analysis plan, SAP 1.1, that had not been formalized. Capricor CEO Linda Marban said, “It’s like grading a report draft that was never submitted,” and argued, “I cannot understand why the FDA is fixated on an unfinished draft.”

The FDA, however, said the analytical model in SAP 1.1 was consistent with later versions and pointed out that Capricor had changed the statistical method in a favorable manner immediately before analyzing the data. The final P value for the change in left ventricular ejection fraction (LVEF), the key endpoint for cardiomyopathy, was 0.09 and did not achieve statistical significance.

Advisory committee member John Tierney, a cardiologist at the San Francisco Veterans Affairs Medical Center, said, “The submitted analysis shows that the sponsor, Capricor itself, did not meet the endpoint statistically.” He also raised safety concerns about the observed increase in left ventricular volume among patients who received deramiocel.

The primary endpoint for skeletal muscle function, PUL 2.0, was also at the center of the dispute. Capricor said it confirmed a significant improvement, with a P value of 0.029 after changing the analysis method, but the FDA countered that under the original method, the P value was only 0.24, representing a clear failure.

Despite positive testimony from patients, the advisory committee members determined that the data lacked reliability. Acting committee chair Evan Snyder expressed mixed feelings, saying, “As a scientist, I would have voted no,” but adding, “As a clinician, I did not want methodological problems to close the door on a potentially promising treatment, so I cast a very limited yes vote.”

The FDA is not required to follow the advisory committee’s recommendation, but it typically makes decisions that respect the panel’s advice. The deadline for the final decision on deramiocel’s approval is Aug. 22.