An FDA panel said that trial data did not provide substantial evidence showing that investigational deramiocel was effective in treating cardiomyopathy among patients with Duchenne muscular dystrophy.
In a 9-3 vote, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee said deramiocel did not meet the cardiac endpoint, though the primary outcome of the drug’s phase III HOPE-3 trial was change in upper limb function.
Much of the meeting focused on how outcomes of the HOPE-3 trial should be interpreted.
Karim Mikhail, BPharm, MSc, acting director of the FDA’s Center for Biologics Evaluation and Research, said the meeting focused on cardiomyopathy because drug developer Capricor Therapeutics originally sought that indication in its marketing application for deramiocel.
For both upper limb and heart outcomes, “the data that we have is very fragile,” said committee member Steven Pavlakis, MD, of SUNY Downstate Health Sciences University in Brooklyn, New York, who voted against the drug.
“There are some glimpses there, but I would not be able to at this time consider it strong support,” added panelist John Teerlink, MD, of the University of California San Francisco, who also voted against the drug.
At the meeting, HOPE-2 investigator Craig McDonald, MD, of the University of California Davis in Sacramento, showed that the drug slowed upper limb functional decline in boys and young men with Duchenne muscular dystrophy in HOPE-3. At 12 months, the mean percent change from baseline in the Performance of Upper Limb 2.0 (PUL 2.0) total score was -3.86 in the deramiocel group and -8.41 in the placebo group, a difference of 4.55 (P=0.029).
The primary outcome findings were presented earlier this year at the American Academy of Neurology (AAN) meeting and published today in The Lancet.
At the AAN meeting, researchers also said deramiocel preserved left ventricular ejection fraction (LVEF), a key secondary endpoint, at 12 months. In the Lancet paper, however, McDonald’s team reported that the 12-month LVEF difference between the deramiocel and placebo groups was not significant (P=0.0935). The primary efficacy endpoint result and all other data were unchanged.
FDA reviewer Prateek Shukla, MD, said that the difference in mean change in PUL 2.0 total score from baseline to month 12 was actually 0.66 (95% CI -0.45 to 1.77, P=0.24). Shukla also said there was no significant difference between deramiocel and placebo on key secondary endpoints including LVEF (change of -0.04%, P=0.97).
The differences appeared to lie in the statistical analysis plan (SAP) used in the study. The FDA analysis used SAP version 1.1, which the agency said was prespecified. The plan used in Capricor’s analysis was a later version.
The 1.1 version of the plan was not prespecified, Capricor maintained. “This would be like your professor grading your term paper on an early draft you had never even submitted,” Capricor’s CEO Linda Marbán, PhD, said.
Duchenne muscular dystrophy is caused by mutations in the DMD gene. Loss of the protein dystrophin triggers a cascade of effects, including progressive degeneration of skeletal and cardiac muscle, a pro-inflammatory and pro-fibrotic immune response that impairs repair, and a steady decline in function that can culminate in life-threatening cardiac events. The condition primarily affects males.
Deramiocel is a novel cellular therapy that consists of allogeneic cardiosphere-derived cells that have been shown to confer immunomodulatory and anti-fibrotic properties. It was studied in the phase II HOPE-2 and phase III HOPE-3 trials.
HOPE-2 was limited by a small sample of 20 participants. HOPE-3 assessed the efficacy and safety of deramiocel in 106 late-ambulatory and non-ambulatory male Duchenne patients, randomizing Duchenne patients at least 10 years old to quarterly infusions of deramiocel or placebo. Mild to moderate adverse events were reported in the study.
The FDA does not always follow the advice of its advisory committees, though often it does.
