A joint FDA advisory committee has voted in favor of approval of two long-acting buprenorphine formulations, though they expressed concerns about higher doses of both products.
The Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-1 in favor of approval of Indivior's RBP-6000 monthly buprenorphine depot and 17-3 in favor of approving some doses of Braeburn's CAM2038 weekly and monthly buprenorphine depot.
On Wednesday, the joint panel evaluated CAM2038, a subcutaneous injection that uses a novel "fluid crystal" technology for controlled release of buprenorphine, in weekly doses of 8, 16, 24, and 32 mg and monthly doses of 64, 96, 128, and 160 mg.
Braeburn conducted a phase III non-inferiority study of 428 patients with moderate-to-severe opioid use disorder that was done in two phases -- first weekly, then monthly, with each phase lasting 12 weeks. The drug was found to be non-inferior to Subutex in that trial.
The company also also conducted an opioid blockade study in 47 patients using the weekly 24 mg and 32 mg doses, and found those doses of the drug blocked the effects of hydromorphone.
Given the potential for serious adverse effects with intravenous injection, Braeburn proposed that the drug should be dispensed by a healthcare provider in a clinical setting and should have limited distribution. Both it and the FDA proposed a risk evaluation and mitigation strategy (REMS) for the product.
Panelists were given three choices for approval: (a) all of the doses; (b) some of the doses; and (c) none of the doses -- 17 voted for some of the doses and three voted for none of the doses. No one chose to approve all of the doses.
Most agreed that the data were just not there for the safety of the 160-mg dose, and that the evidence for the lowest doses suggest these may be effective for titration purposes only.
"I'm convinced by the data I've seen for the 24, 32, 96, and 128-mg doses," said Caleb Alexander, MD, of Johns Hopkins.
Steven Meisel, PharmD, of Fairview Health Services in Minneapolis, said the "higher monthly doses are problematic. For the 8-mg weekly dose, at best it's a supplement to get you through, though it hasn't been studied for that. The intermediate doses, I'm comfortable with."
Suzanne Robotti, founder of the MedShadow Foundation and a consumer representative who voted against approving the drug at any dosage, said many questions remained unanswered, including whether the depot can be removed if necessary, and about the pharmacokinetic properties of the "fluid crystal" technology.
"I don't think we should wait for postmarketing studies to come out," she said. "I don't think patients should be guinea pigs."
Kim Witczak, co-founder of Woodymatters and also a consumer representative who voted against approving any doses, said the data weren't strong enough to support approval, and that she was nervous about setting a precedent for future drug trials by relying on the fact that buprenorphine is already out on the market.
Panelists also voted separately on the drug's safety (one for all doses, 17 for some doses, and two for none of the doses) and effectiveness (two for all the doses, 17 for some doses, and one for none of the doses).
For safety, panelists were mostly concerned with the highest dose, though some also questioned the safety of the 128-mg dose, as both of these populations had small numbers in the study. Panelists mostly supported efficacy, but Almut Winterstein, RPh, PhD, of the University of Florida, noted that the study wasn't a pure efficacy trial but rather a non-inferiority trial.
Meisel cautioned that only 34% of patients at the end of the study had at least 50% of their drug screens turn up negative: "This is no wonder drug. I appreciate the stories we heard today, and for those whom it helps, it will be extremely helpful. But this 34% tells me this is far from a wonder drug at any dose."
Indivior's Monthly Injection
On Tuesday, the joint committee evaluated RBP-6000, a buprenorphine depot injected subcutaneously into the abdominal area once a month. It's made by Indivior, formerly part of Reckitt Benckiser before being spun off. The company is seeking approval for use in moderate-to-severe opioid use disorder in patients who have induction with a transmucosal buprenorphine product.
Indivior presented evidence from a single 24-week efficacy and safety study that had an extension phase, and it tested two doses of the drug: 300/300 mg and 300/100 mg. The higher dose version appeared to be less tolerated, with more discontinuations due to adverse events including elevated liver enzymes, injection site reactions, sedation, constipation, somnolence, lethargy, and withdrawal syndrome. The application also included data from a hydromorphone blockade study.
Like CAM2038, the drug would also have to be dispensed by a healthcare provider in a clinical setting, because of concerns that patients could administer it via the intravenous route, which at such a high dose could have lethal consequences. So the company also proposed a restricted distribution system as well as a risk evaluation and mitigation strategy (REMS).
Overall, the panel voted 18-1 in favor of approval, with Caleb Alexander, MD, of Johns Hopkins, casting the lone dissenting vote.
"A monthly product can be valuable, but we know nothing about real-world adherence and effectiveness," he said. "We need to learn a lot more about this product."
He added that there were "lots of arguments especially regarding the 300/300 mg dose that weren't based on any data. They were based on, 'we need this, we see this, people are dying.' That was the rationale for products already approved that are part of the problem, not the solution."
Several other panelists said they offered a qualified "yes" vote.
"Given the option, I would have voted no on the 300/300 mg dose, since we have zero data on safety and effectiveness," Meisel said.
"I do not love this product," said Robotti. "It's better than placebo, but I'm not convinced that it's better than the products that are out there today. We shouldn't be putting out secondary and tertiary products unless there's a need for them."
She added that if the drug is approved at any dose, there should be significant post-marketing data.
Panelists also voted 17-2 that the data support effectiveness of the drug, though several charged that the real-world experience will likely be very different from the highly controlled clinical trial data, and that the urine screens done in the trial didn't look for fentanyl, which is widely abused today.
They voted 13-6 that the data support the safety of the 300/300 mg high dose of the drug, though many raised concerns about elevated liver enzymes in a population that's already predisposed to hepatitis.
"It's adding toxicity without adding benefit," Meisel said, noting that the data didn't show much of an efficacy advantage over the lower dose.
Alexander raised concerns about diversion, asking whether people would be able to locate the depot and remove it. And other panelists raised a similar question of whether it can be removed in an emergency, like in the case of an overdose.
Some panelists felt that a higher dose would be needed for some patients, but complained that the company didn't provide information as to who, exactly, those patients are.
"We need label guidance that it can be limited to the people who really need it," said panelist Anne-Michelle Ruha, MD, of Banner University Medical Center in Phoenix.