In briefing documents published Monday ahead of an advisory committee meeting for deramiocel, the FDA disagreed with Capricor’s assertion that a Phase 3 trial met its primary outcome measures.
The saga around Capricor Therapeutics’ Duchenne muscular dystrophy cell therapy deramiocel continues as the FDA disagreed with the company’s claim that a Phase 3 trial met the primary endpoints.
In December last year, Capricor reported that deramiocel hit both the primary and second endpoints in the pivotal HOPE-3 trial. However, in briefing documents released by the FDA prior to an advisory committee meeting on Wednesday, the agency wrote that this study “did not meet its pre-specified primary and secondary efficacy endpoints, showing no statistically significant difference between deramiocel and placebo at 12 months.”
After completion of the randomized, double-blind part of the Phase 3 trial, and during the trial’s open-label extension period where all patients were treated with the cell therapy, “changes were made to the pre-specified statistical analysis plan (SAP), generating at least two additional versions,” FDA reviewers wrote in the documents, which were published Monday morning.
The changes included modifications to the primary and key secondary endpoint definitions, the analytical methods, and the data imputation strategy for certain intercurrent events, according to the FDA.
The agency also raised questions about the effectiveness of blinding in HOPE-3. “The distinctive adverse event profile observed between treatment groups—hypersensitivity reactions seen in 42% of deramiocel-treated patients versus 15% of placebo-treated patients—raises the possibility that treatment assignment could be inferred even under formal blinding conditions,” according to the reviewers.
Capricor shares were down more than 65% to $6.53 per share at publication.
“It’s been very disconcerting to us,” Capricor CEO Linda Marbán told BioSpace in an interview on Monday afternoon. “We take great issue with how FDA analyzed the data using [SAP version 1.1].” The agency only received this particular SAP, she added, when it requested all draft SAPs during the information request process following Capricor’s biologics license application resubmission.
“So we were blown away that they would use something that was not even intended by us ever to be used,” Marbán said.
Capricor has attempted to speak with the FDA directly about these concerns, she continued. “They are refusing to meet with us.”
The path to potential regulatory approval for deramiocel has been paved with uncertainty. Capricor’s first application was rejected by the FDA last July after a planned adcomm was canceled—without the biotech first being informed.
Marbán told BioSpace last month that she was “surprised” when the FDA initially informed Capricor that an adcomm would be held on July 29 for the resubmission prior to the August action date.
“We really thought that it’s a very clean data set,” she said. “We have not gotten any issues that they want to discuss.”
Now, Capricor is in the know on those issues.
“Capricor has engaged fully and transparently with the FDA throughout the review process for our biologics license application for Deramiocel and has been responsive to every request from the FDA,” Marbán said in a statement responding to the FDA’s remarks late Monday morning. “Our results are governed by the final analysis plan, SAP version 3.0, which was finalized prior to unblinding.”
It is “critical,” Marbán continued, “to understand that the post-hoc analyses in the FDA’s briefing materials rely on SAP version 1.1,” which is an unsigned, incomplete internal draft that became obsolete with the addition of cohort B and did not include content specifically requested by FDA, according to the CEO.
The results from HOPE-3 “demonstrate a statistically significant benefit on the primary endpoint [upper limb performance], with supportive benefits in cardiac function,” Marbán added.
The CEO still has faith, however, in a positive outcome for deramiocel.
“I fundamentally believe that the adcomm will be able to see through the statistical analysis plans and not turn this into something mathematical, but actually look at the treatment effect that has been consistent [across Capricor’s trials],” Marbán said on Monday afternoon.
The advisory committee meeting for deramiocel will take place July 29.
Editor’s note (July 27): This story has been updated to include comments from Capricor CEO Linda Marbán.
