Not a single FDA advisory committee member said the benefits of an implant that delivers a GLP-1 receptor agonist for type 2 diabetes outweigh its risks.
In a unanimous 19-0 vote on Thursday, the Endocrinologic and Metabolic Drugs Advisory Committee came to the conclusion that they could not recommend Intarcia Therapeutics’ investigational ITCA 650, featuring exenatide (Byetta, Bydureon) in a DUROS device, due to its unfavorable risk-benefit profile for people with type 2 diabetes when paired with diet and exercise.
The downfall of the drug device was the safety signals highlighted in FDA briefing documents, mainly driven by four concerns: variability in drug delivery, acute kidney injury (AKI), major adverse cardiovascular event (MACE) risks, and gastrointestinal (GI) tolerability.
“The device itself has great, great potential. If operating at a very good level, I could really see it as a game changer,” said Robert Greevy, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee. “I’m also not convinced given the data we were presented that we’ve seen the best version of this device. And there appears to be evidence that the dispensing of the medication is not consistent and we didn’t see any data to explain why that could be or to convince us that it’s not the case.”
Jill Crandall, MD, of Albert Einstein College of Medicine in the Bronx, New York, noted that the “lack of clarity about the device and the variability of the drug delivery … really impacted my decision. I think those two issues outweigh the potential benefit at this point.”
This has been a lingering concern for years and was one of the reasons why the device was rejected by the FDA twice already — once in 2017 and again in 2019. The FDA’s Center for Drug Evaluation and Research (CDER) even recommended a total product redesign to address this issue.
If Intarcia continues testing the product, several panel members advised that trial participants wear continuous glucose monitors to better pinpoint potential low or high medication boluses. The widest individual variability seen during the first week of in vitro release testing ranged from 3 to 103 mcg/day of the study drug (there was a goal of 20 mcg/day during this period).
In addition to uncertainty about drug delivery, risk for AKI was another major deterrent for panel members.
“What has swayed my vote is with respect to the acute kidney injury risk,” said Patrick Nachman, MD, of the University of Minnesota in Minneapolis. “I do recognize that the absolute risk is low, and I do believe in my heart that there should be a way to mitigate it … But the time to figure out how to mitigate the risk is before approval, not afterwards.”
Echoing this sentiment, David Cooke, MD, of Johns Hopkins University School of Medicine in Baltimore, said that these “questions surrounding the AKI need to be clarified before approval.”
“That would best be assessed through an active comparator and I would recommend that it be another GLP-1 agonist,” he suggested. “Showing that, as the sponsor is hypothesizing, that the impact on AKI of this treatment is no different than that of any other GLP-1 agonist needs to be proven.”
The idea of testing ITCA 650 against an active comparator was a common suggestion from panel members. While all recommended that the active comparator be another GLP-1 receptor agonist, many suggested a head-to-head comparison against the injectable form of exenatide.
This suggestion of testing against an active comparator also extended to the concerns of MACE risk and GI tolerability.
In addressing GI tolerability, Greevy had a unique solution, suggesting a trial where participants uptitrate on the injectable form of exenatide and only those who could tolerate the GI side effects — a known GLP-1 class effect — could then be eligible for the implant.
Despite “no” votes across the board, a few panel members vocalized some positives with the device. No one questioned the efficacy of ITCA 650 on lowering HbA1c (-1.1% at week 39 on 60 mcg/day). Participants also lost weight with the device, but panel chair Cecilia Low Wang, MD, of the University of Colorado Hospital in Aurora, called both of these outcomes “modest.”
The biggest praise the device received was in regards to bolstering patient adherence to medication, since after implantation, the patient essentially forgets about the device for 6 months until it needs to be replaced again.
“I think that if it can be done safely, I think that this would be really favored by certainly many of my patients who would love to take one fewer pill or administer one less self-injection, so I think that there’s a lot of opportunity here,” said Brendan Everett, MD, MPH, of Brigham and Women’s Hospital in Boston.
Many said they felt extremely moved by testimonials given during the public hearing period. One point was made clear during that hour — patients need more options. During the hearing, one woman who participated in the clinical trial said it felt like “losing her best friend” when her device was removed at the end of the study.
“The folks who testified here deserve something along the lines that they’re asking for, is a signal to industry, that this company — they’re on to something — and now it behooves the industry to provide all of them with a solution to what they’re asking for,” said Marvin Konstam, MD, of Tufts University School of Medicine in Boston.
While the FDA is not required to follow the recommendations of its advisory committees, it typically does.