As outside experts gathered for a second day to discuss adding certain popular-yet-unapproved peptides to the U.S.’ bulk compounding list, the first to go up against a vote did not fare as well as those assessed Thursday.
On two votes concerning whether to recommend emideltide free base and emideltide acetate for the 503A Bulk Drug Substances list, the panelists on the FDA’s Pharmacy Compounding Advisory Committee (PCAC) voted the same way: Seven of the experts cast their lots behind ‘no,’ versus six ‘yes’ votes and one abstention.
In briefing documents released (PDF) ahead of the meeting, the FDA explained that it included both forms of the compound—and in turn two separate questions—as it wasn’t sure which version was intended from the nomination for inclusion on the list. The FDA also clarified that the “nominations were withdrawn” and that it is evaluating the substances “at its discretion”—a point that seemed to cause consternation among some PCAC members on Friday.
The recommendation against emideltide comes in contrast to the votes cast on the first day of the meeting, during which panelists ultimately backed the inclusion of all four other peptides considered so far for the compounding roster.
On Thursday, the PCAC members voted in favor of adding BPC-157, TB-500, KPV and MOTs-C to the positive list, in a move that would reverse restrictions placed on the unapproved compounds back in 2023. The FDA at the time cited safety concerns and a lack of evidence to support the use of a dozen peptides, which have nevertheless thrived on a gray market thanks to their popularity among fitness and wellness influencers, not to mention health secretary Robert F. Kennedy Jr.
The members did, however, come around by the second vote of Day 2, focused on the potential inclusion of epitalon free base and epitalon acetate to the 503A catalogue.
Reviewing that compound, used primarily for insomnia, the panelists tendered seven 'yes' votes to four 'no' votes, alongside one abstention, with the PCAC members sticking to their positions across both the free base and acetate form.
The final peptide up for deliberation, semax—popular for its ostensible cognitive benefits and evaluated by the FDA in cerebral ischemia, migraine and trigeminal neuralgia—also passed muster with the panelists.
In the concluding votes of the day, eight members of PCAC voted in favor of adding the compound to the bulk compounding list, overcoming five ‘no’ votes and one abstention.
The FDA isn’t beholden to the votes of its advisory committees. Conflict-of-interest concerns have been raised about the makeup of the panel given some members’ ties to clinics and other businesses that supply peptides. The FDA attempted to deflect some of that criticism earlier this week by adding eight new temporary voting members.
Vote by vote
In the case of emideltide, the compound is a reported nonapeptide that the FDA says has been evaluated for the treatment of opioid withdrawal, chronic insomnia and narcolepsy. The FDA itself continues to weigh against the inclusion of emideltide on the bulk compounding list, noting that, among other concerns, inconsistent naming standards pose patient safety risks, and that the peptide is not well characterized, and its purity profile cannot be easily confirmed.
On another point, the FDA noted that “[n]o outsourcing facilities have reported compounding drug products containing emideltide related [bulk drug substance] to the agency.” The websites of integrative neurology clinics, medical concierge services, med spas, wellness clinics and other online retailers marketing emideltide injections and nasal sprays in the U.S. often fail to describe or clearly state whether their products are compounded, the FDA added.
Regarding the panelists’ reasoning, Kevin Zacharoff, M.D., a clinical assistant professor and course director of pain and addiction from the Renaissance School of Medicine at Stony Brook University, explained that he cast his ‘no’ vote because, “as a clinician, as a member of another advisory committee, it’s impossible for me to not take the FDA’s recommendations at heart with respect to safety and efficacy.”
He also suggested that arguments in favor of the drug’s inclusion to help curb unregulated sales didn’t fully convince him “that there would be a diminishment of availability on the gray market.”
“I think it would end up being an economic situation,” he explained, “and if it was more expensive to be obtained on a compound pharmacy site, then people might still continue to purchase in a gray market situation.”
Todd Durham, Ph.D., SVP of clinical & outcomes research at the Foundation Fighting Blindness—who also voted ‘no’—said he cast his vote “primarily for low-quality evidence around efficacy, the poor characterization of the bulk drug substance and the fact that there are approved medical therapies for all proposed uses.”
That said, some who voted to include emideltide on the list suggested in their explanations that other panelists may have been straying from the purpose of the adcomm.
Tennessee state Senator Bobby Harshbarger, who voted ‘yes,’ suggested that he made his call “because our duty is to apply the 503A standards, not the Investigational New Drug Application standard.”
As for epitalon, the PCAC members seemed more assured of the compound's efficacy and safety on the whole, with many arguing that ultimate determinations about safety should come down to a discussion between doctor and patient.
One panelist who voted ‘yes,’ Gabriel Alizaidy, M.D., of Maximus Health, argued that there was a “mismatch in real-world data” on the peptide’s use versus what the FDA had presented, calling the disparity “immense.”
But on the other end of the spectrum, William Zamboni, Ph.D., a director and facility co-leader from the Immunotherapy and Drug Development Center of the University of Pittsburgh Medical Center Hillman Cancer Center, said he felt compelled to vote ‘no’ given “a significant lack of information and data to evaluate the product, and also how to prescribe it,” admitting he had more research to do on his own.
Meanwhile, as with most of the other votes issued in the past two days, the favorable semax verdict reflected a seeming disconnect between FDA career scientists and many of those on the committee, with that tension at times coming out during panelists explanations of their votes.
During the clarifying question section of the meeting focused on semax, one of the panelists asked just what the intended indication in ischemic stroke would be, to which an FDA staffer admitted that the agency itself is unclear from the materials it’s reviewed.
“We watched the FDA’s own review board lean on surface-level searches while hundreds of pages of research submitted on-time for these meetings went unaddressed,” Haleem Mohammed, M.D., global chief medical officer at men’s health clinic network Gameday Health, argued when presenting the rationale behind his vote for ‘yes’ on adding semax to the bulk compounding roster.
In framing the outcome of the vote, which still needs to be affirmed by the FDA, Mohammed suggested that the panelists were taking “a decision that patients are already making, and we try to keep it inside a system that has rules and regulations.”
But FDA staffers also defended their efforts, suggesting that the nominators of the peptides up for review led them through an opaque process in which attempts to glean more information were frequently unsuccessful.
Friedhelm Sandbrink, M.D., national program director for pain management specialty care services in the Veteran’s Health Administration—who voted ‘no’ on semax—said that while he understood the desire to provide medical care and access to treatments for patients, “I don’t think we can skip the rigorous scientific studies that are needed when we endorse any kind of product and make it available.”
Editor's note: This story has been updated with additional details on the final vote of the PCAC's Friday meeting.