Unmet Need Is Not Enough: US FDA AdComm Rejects Levo’s Carbetocin For Prader Willi Syndrome
Executive Summary
Patient representative was lone ‘yes’ vote, and even she acknowledged using a broad interpretation of ‘substantial evidence.’ The only route forward for Levo may be a new trial, though expanded access could be an option in the near term.
Levo Therapeutics, Inc. may have to conduct another study if it wants to try to advance its nasal spray carbetocin for treatment of hyperphagia associated with Prader Willi Syndrome in light of the negative review of its data by a US Food and Drug Administration advisory committee.
The sponsor emphasized the intense unmet medical need for a treatment for the rare disease of unrelenting hunger, but the Psychopharmacologic Drugs Advisory Committee concluded 12-1 at its 4 November meeting that the two studies Levo conducted in support of approval did not show substantial evidence of efficacy.
The agency did not ask the committee to vote on whether the drug should be approved, or if another study was needed, but instead posed a very narrow question: “Has the applicant provided substantial evidence of effectiveness for carbetocin nasal spray (LV-101) in the treatment of hyperphagia associated with Prader Willi syndrome?”
The vote was not surprising given FDA’s analyses of the studies in a briefing document for the committee. The agency said there is “uncertainty about the effectiveness of carbetocin” given inconsistency in Phase II and Phase III study results, the lack of additional adequate and well-controlled substantiating studies, and the lack of robustness in the statistical findings. (Also see "Levo’s Carbetocin Faces Advisory Committee Hurdle Given FDA ‘Uncertainty’ About Its Effectiveness" - Pink Sheet, 2 Nov, 2021.)
Levo representatives stressed the lack of an approved therapy in presentations to the committee. And during the public hearing several parents and two Prader Willi Syndrome (PWS) support groups advocated for its approval citing the desperate need for treatment.
However, three parents spoke against approval, saying carbetocin did not help their children and one saying the drug actually made her child’s symptoms worse. Their testimony was highly unusual, as individuals and family members afflicted by a disease typically urge approval of a drug.
Charles Billington, professor of medicine at the University of Minnesota, said he was very moved by the compelling stories of family members who found the drug to be effective. But he said “given the question we’ve been asked, is there substantial evidence, I’m afraid the answer must be no. It is hard to find any evidence of a signal at all.”
James Troendle, a statistician in the Office of Biostatistics at the National Heart, Lung, and Blood Institute, agreed. “I don’t think that they met even a low bar for evidence, let alone substantial evidence. It’s far from that,” he said.
Walter Dunn, a professor at the University of California at Los Angeles, said he voted no based on a narrow interpretation of the question and the phrase “substantial evidence.” However, he said that if FDA had asked if there was modest evidence of effectiveness he would have to reconsider his vote.
Patient representative Alice Shapley, professor and vice chair for astronomy and astrophysics at UCLA, who cast the sole ‘yes’ vote, said she believed that substantial evidence was presented for the efficacy of carbetocin “with a liberal view of the term ‘substantial evidence.’” She cited the promising safety profile of carbetocin and said she was convinced of the treatment’s high ratio of benefit to risk.
Consumer representative Kimberly Witzcak, co-founder and executive director of Woodymatters, suggested an alternative path to approval, asking if expanded access is an option for the families who want carbetocin. She also encouraged the company to continue studying the drug.
Questions About Efficacy Of Lower Dose
Levo’s new drug application includes a Phase II proof-of-concept study (Study 114) that evaluated carbetocin 9.6 mg three times a day versus placebo in 37 subjects over 14 days, and an eight-week Phase III study (LV-101-3-01) that examined 9.6 mg and 3.2 mg doses of carbetocin three times a day versus placebo in 119 evaluable subjects followed by a 56-week long-term follow-up period.
Levo senior VP Jay Cormier told the committee that Study 114 showed statistically significant improvement in hyperphagia with the 9.6 mg dose. He said the Phase III study did not achieve statistical significance on its primary endpoints but the 9.6 mg dose showed numeric improvements in hyperphagia and the 3.2 mg dose achieved nominally significant improvements in hyperphagia. He said both studies demonstrate that carbetocin “provides clinically meaningful reductions in hyperphagia.”
FDA had a different take on the data. FDA clinical reviewer Paul Bossie said Study 114 provides preliminary evidence for the effect of the 9.6 mg dose on hyperphagia but the clinical meaningfulness of the treatment effect is unclear.
In the LV-101-3-01 Phase III study, he said there was no evidence of efficacy of 9.6 mg carbetocin on either primary endpoint. The two endpoints were change from baseline to week 8 in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score and the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Severity Rating total score. He said there was a potential efficacy signal for the 3.2 mg dose for HQ-CT.
However, FDA statistical reviewer Andrew Potter said the statistical inferences about the 3.2 mg dose are post hoc so it is unknown if the efficacy signal was due to chance. He said it is challenging to interpret the finding in the 3.2 mg dose because of the lack of evidence for the 9.6 mg dose.
The differing results with the two doses was an issue for committee members.
Panel member Dunn said the foremost question in his mind was whether the findings from the 3.2 mg dose were real, that is, whether the results were simply by chance. “The lack of replication and the absence of a clear pathway to formally evaluate the p value of that 3.2 mg group suggests that any interpretation of the findings should be conducted with extreme caution,” he stated.
Ensuring ‘Substantial Evidence’ Threshold Is Reached
Tiffany Farchione, director of FDA’s Division of Psychiatry in the Office of Neuroscience, addressed the considerations that are made in evaluating drugs for a rare disease when there are no approved therapies.
“This is absolutely an unmet need and there’s nothing available to treat hyperphagia in Prader Willi syndrome,” she stated. “But we’re also aware of the dangers of approving ineffective drugs that give [people] false hope, or could mislead them into using an ineffective drug and forego an opportunity to do something else, or to enroll in a future trial of something else.”
Farchione said the agency has flexibility when it comes to rare diseases, but it needs to balance that with “ensuring that we still do reach that substantial evidence threshold.” She noted that it’s not that FDA has a different requirement for rare diseases, or that it requires less evidence, but that it needs to be more flexible in how it looks at the data.
“The big question here,” she said, is “do we have enough to be able to pin our hopes on that 3.2 mg or not? In terms of exercising flexibility, that’s why we’re here today, because it’s not an easy question to answer.”
Farchione said the agency didn’t focus on safety during its presentations, noting that the agency’s review of that is ongoing and that it can manage whatever safety issues come up with information requests and postmarketing requirements or labeling.
“But when you’re balancing benefit and risk, you have to start with benefit,” Farchione said. “There’s no risk that is acceptable in the context of lack of benefit. So that’s why we’re focusing on that side of the equation.”