SILVER SPRING, Md. -- With a pair of lopsided tallies, a joint FDA advisory committee voted against recommending approval of a buprenorphine-samidorphan combination (ALKS 5461), proposed as adjunctive therapy for the treatment of major depressive disorder.
On efficacy, the FDA panel voted against the agent 20-3, indicating that drugmaker Alkermes did not provide substantial evidence in support of the drug. The vote over whether the trial data demonstrated a favorable risk-benefit profile closely mirrored this (21 voting against and 2 voting for).
There was less agreement among the panel members -- comprised of the FDA's Psychopharmacologic Drugs Advisory Committee & Drug Safety and Risk Management Advisory Committee -- over whether the drug company adequately characterized the safety of the drug (13 said they did, 10 said they did not).
While panel members agreed that new treatments are needed for major depressive disorder, most said the effectiveness of the buprenorphine-samidorphan combination seemed modest at best.
"As someone who has prescribed opiates to patients with treatment-resistant depression and feels that they may have some benefit within our armamentarium, I still do not feel that the evidence presented by this sponsor was convincing of substantial effectiveness," said Felipe Jain, MD, of the University of California San Francisco.
Unease about the efficacy of ALKS 5461 was apparent from the start. In opening remarks, the FDA's director of the Division of Psychiatric Products, Mitchell Mathis, MD, explained that while Alkermes' position was that their two studies were positive, the FDA was not in agreement.
The concerns -- echoed by many FDA advisory committee members during voting -- focused on using sequential parallel comparison design (SPCD), depression scales the FDA did not agree with (including one that did not include suicidal ideation), and averaging endpoints instead of reporting improvements at the end of the treatment period.
The ALKS 5461 presentation marked the first time SPCD studies were presented to the Division of Psychiatry Products. The method is designed to reduce potentially high placebo response rates in psychiatry trials by filtering out placebo responders in stages. While Tiffany Farchione, MD, deputy director of the FDA's Division of Psychiatric Products, said the FDA had no objection to using SPCD in proof-of-concept trials, there has been "no analytical proof for the validity of associated statistical analyses when there are missing data" in phase III trials, she stated.
The FDA also took issue with one patient's response in a phase III trial that was so strong it warranted a look from the FDA Office of Scientific Investigations, which concluded that the patient's data should be removed. Doing so would change the P-value of the study and flip what Alkermes called a positive result to a failure -- a point that didn't sit well with several committee members.
"I was a little concerned about the single subject," said Rajesh Narendran, MD, of the University of Pittsburgh. "It gave me pause that one subject drove the results so strongly."
"That one outlier bothered me, too," said Anne-Michelle Ruha, MD, of the University of Arizona College of Medicine in Phoenix. "I don't feel very comfortable with any study where you eliminate one subject and it changes the significance of the study."
The consequences of bringing another opioid to market also weighed on committee members' minds. The potential harms of this drug would be subtle, observed Walter Dunn, MD, PhD, of the University of California Los Angeles. "They are long-term risks; they are not something that the patient is going to acutely notice," he said.
"Those types of risk are difficult to communicate to the patient," Dunn added. "That's why we have an opioid epidemic. That's why we have alcoholism. Those long-terms risks are hard for us to see."
To date, only three drugs have an indication for adjunctive treatment of major depressive disorder: aripiprazole (Abilify), quetiapine XR (Seroquel XR), and brexpiprazole (Rexulti). Unlike these atypical antipsychotics, the new drug would combine a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist (buprenorphine) and an investigational mu-opioid receptor antagonist to mitigate buprenorphine's abuse liability (samidorphan).
"We don't know the mechanism of action of this drug, just postulates about it," noted Steve Meisel, PharmD, of Fairview Health Services in Minneapolis. "We don't know if the impact we are seeing -- which is modest -- is that of an antidepressant or a narcotic euphoric effect."
If approved by the FDA, now highly unlikely following Thursday's votes, the oral buprenorphine/samidorphan combination would be the first in an entirely new class of drugs -- and the first opioid -- for major depressive disorder.