Livoletide

The FDA’s Psychopharmacologic Drugs Advisory Committee on Thursday voted 12 to 1 against approving Levo Therapeutics’ nasal spray for Prader-Willi syndrome, a difficult-to-treat disease that leaves patients with constant, insatiable hunger. Those who voted no raised concerns about a lack of substantial evidence, as a 9.6 mg dose of the drug failed the primary endpoints in a Phase III trial. Looking for a silver lining, Levo turned to a 3.2 mg dose which met the trial’s secondary endpoints. But adcomm members wondered whether Levo could replicate those positive results. “The thing that stuck out to me most was that the 9.6 dose study did not replicate,” committee member Satish Iyengar, chair of the University of Pittsburgh’s statistics department, said after the vote. “And given the fact that the 3.2 dose study didn’t really hold up strongly to the sensitivity analysis that they did, I just have no confidence — I have little confidence — that it will replicate.” Another panel member, UCLA psychiatry professor Walter Dunn, suggested that if the question had asked about “moderate evidence of effectiveness,” he would have reconsidered his vote. “I do think it’s interesting that this is worded this way, because it doesn’t talk at all about any possible risk-benefit trade-off,” said James Troendle, a mathematical statistician at the NIH. Levo’s candidate, dubbed LV-101, is an intranasal form of carbetocin, a drug used outside the US to control bleeding after childbirth. It’s an oxytocin receptor agonist that was originally being developed for PWS by Ferring Pharmaceuticals, until Levo snagged the rights in 2016. Oxytocin is a neurotransmitter that regulates social-emotional and feeding behaviors, and research shows that those with PWS don’t have enough of it. But despite what Ferring celebrated as positive Phase II results, Levo faced an uphill battle. Although the carbetocin arm showed statistically significant improvements over placebo, the FDA called the data weak and the study duration insufficient. Then, last August, Levo announced the 9.6 mg dose failed the primary endpoints in a Phase III study: changes in baseline in either Hyperphagia Questionnaire for Clinical Trials scores (HQ-CT) or Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) scores. Hyperphagia is another term for the extreme hunger experienced by PWS patients. Researchers describe it as a constant feeling of starvation, adding that patients will oftentimes seek food wherever they can get it. As there are no currently approved treatments, patients cope by limiting the type and amount of food they consume, and in some cases even locking refrigerator doors and trash bins. Levo approached the FDA with its 3.2 mg dose, which achieved statistical significance as evaluated by the HQ-CT scores in the Phase III trial. However, there was no meaningful difference seen in CY-BOCS scores. In their briefing ahead of the adcomm, the FDA noted that the secondary endpoint met with the 3.2 mg dose “must be considered in the context of the lack of efficacy of the higher dose (9.6 mg).” Levo suggested that the lack of efficacy seen in the 9.6 mg group may have been due to off-target vasopressin effects emerging with longer treatment duration. However, the FDA wrote: “If that were the case, one would expect to see a nominal difference versus placebo at Week 2 (consistent with the findings from Study 114); however, no difference between groups was observed at that earlier time point.” PWS has proved extremely difficult to treat. Millendo Therapeutics’ lead drug livoletide failed a pivotal trial for the treatment of PWS last April, sending shares plummeting. The drug didn’t improve hyperphagia or other eating-related behaviors. And Zafgen’s ZGN-1258, its second attempt to treat rare cases of obesity brought on by PWS, hit a brick wall after the FDA put a hold on the company’s PWS program in 2018, citing CV safety concerns. Multiple parents of children with PWS tuned in to the adcomm meeting, touting carbetocin as a miracle that has allowed their children to finally sleep through the night, or visit Disney World without obsessing over food. “You have the opportunity to change and possibly save an untold number of lives. Please take it,” one parent said. But multiple others argued against the drug, with one parent calling it “completely useless” and even claiming the treatment worsened her child’s behavior. Alice Shapley, a patient representative and the only adcomm member who voted in support of the drug, said: “In light of the promising safety profile of carbetocin, I’m convinced of the high ratio of benefit to risk for this treatment for the PWS community.” Charles Billington, an endocrinologist and professor of medicine at the University of Minnesota, said he was moved by the compelling stories by family members. But when it comes down to whether there’s substantial evidence to back the drug, the answer is no. “It’s hard to find any evidence of a signal at all,” he said.