Compelling testimony from parents who saw life-altering changes in their children who participated in Levo Therapeutics Inc.’s intranasal carbetocin clinical trial wasn’t enough to counter what the FDA’s Psychopharmacologic Drugs Advisory Committee saw as a lack of “substantial evidence” to support the drug’s effectiveness in treating hyperphagia associated with Prader-Willi syndrome (PWS).

Twelve committee members agreed with the FDA’s assessment Nov. 4 that the efficacy evidence doesn’t meet the regulatory bar, with only one member voting that it does. In explaining her yes vote, Alice Shapley, the committee’s patient representative, said that, encouraged by the drug’s safety profile, she took a “liberal view” of the term “substantial evidence.”

At the other end of the spectrum, James Troendle, deputy director of the Office of Biostatistics Research at the NIH’s National Heart, Lung, and Blood Institute, said the evidence Levo presented from a small phase II proof-of-concept study and a phase III study that failed to meet its primary endpoint didn’t meet even the lowest bar possible.

Given the critical unmet medical need in PWS, several adcom members said they would have liked to have seen substantial evidence that carbetocin works. “I would have loved to have been able to vote yes,” said James McGough, a clinical psychiatry professor at the University of California-Los Angeles’ David Geffen School of Medicine.

Currently, there are no approved treatments for hyperphagia, a life-threatening symptom marked by an insatiable, obsessive need to constantly eat. Patients often are treated with off-label psychiatric drugs, compounded oxytocin and supplements, for which there is no evidence of efficacy or safety, several parents pointed out in the public hearing session of the meeting.

Given the dearth of treatments, a number of adcom members encouraged Levo to continue studying carbetocin in PWS and to make the drug available through expanded use to those patients who have been helped by it in the phase III trial and long-term follow-up study. As of June, 89 people were still in the extension study, according to the FDA.

Even before Levo submitted its new drug application for carbetocin earlier this year, FDA reviewers had told the Chicago-based company that another study was needed. Although the agency has some flexibility with orphan drugs, the regulatory standard calls for two adequate and well-controlled trials to demonstrate efficacy.

Part of the issue with the carbetocin studies is dosage. The phase II trial, conducted as a proof-of-concept study by Ferring Pharmaceuticals Inc. in 2014, tested a 9.6-mg dose. That randomized, placebo-controlled trial enrolled 37 participants.

After licensing the drug from Ferring, Levo began a phase III trial in 2018 that was intended to enroll 178 patients. That trial was truncated by COVID-19 in March 2020, leaving only 119 participants evaluable. The phase III trial didn’t meet statistical significance in the primary endpoint for the 9.6-mg dose, but a second arm, using a 3.2-dose, did show improvement.

However, the FDA and several adcom members noted that the primary endpoint didn’t confirm the phase II results for the 9.6-mg dose, and the earlier trial didn’t test the lower dose. Thus, Levo doesn’t have evidence from two trials for either dose.

Another issue was the length of the trials. In the phase II study, carbetocin was tested over a two-week period, whereas the phase III trial was based on eight weeks of treatment. Even though there’s been a long-term extension study, some panelists and a few parents speaking during the hearing said longer studies are needed for drugs intended to treat chronic diseases such as PWS.

Challenges of another trial

Conducting another trial could be problematic in a condition that affects only 10,000 to 20,000 people in the U.S., especially when sponsors have to compete for participants. According to, more than 20 trials evaluating various aspects of PWS are recruiting or not yet recruiting and three are active but not recruiting.

Noting how regimented their children’s lives have to be and the difficulty they have coping with disruptions to routine, parents speaking at the meeting provided some insight into how challenging it is to participate in a trial. Large studies in this population are not realistic, said Susan Hedstrom, executive director of the Foundation for PWS Research. She urged the FDA to allow Levo to further study the drug while it’s being used, as it would be an undue burden to ask the community to undergo years of another clinical trial.

Diana Zuckerman, president of the National Center for Health Research, disagreed, noting that the FDA clearly told Levo what evidence would be needed, but the sponsor chose to ignore that advice. As a result, she said during her testimony, the evidence Levo presented at the adcom was among the worst she’s seen in the 100 adcoms she’s participated in. She feared it would set a bad precedence to approve the drug based on that evidence.

She encouraged Levo to spend “a few more months” to establish that carbetocin is safe and effective while maintaining patient access to the drug through the FDA’s extended access program.

“No one is asking for a perfect study,” Zuckerman said. “We’re asking for a good study” – one with an adequate number of participants studied for an appropriate length of time. It also should have more diversity. Zuckerman noted that all but one patient in the phase II trial was white.

Depending on the FDA’s next steps with carbetocin, it could be a while before there’s an approved drug to treat hyperphagia in PWS. Saniona AB, of plans to initiate a phase IIb trial for its hyperphagia candidate, Tesomet (tesofensine/metoprolol), yet this year, with top-line data expected in the first half of 2023. That’s the furthest development milestone the company has projected at this time, a Saniona spokesperson told BioWorld.

Saniona had hoped the upcoming study could serve as a single pivotal trial, but the FDA informed the company last year that it should consider a supportive phase IIb before beginning a phase III trial. The phase IIb study is designed to evaluate multiple Tesomet doses in adults and adolescents.