FDA Wants Additional Trial of LV-101 Nasal Spray to Confirm Efficacy

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by Patricia Inacio PhD |

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The U.S. Food and Drug Administration (FDA) has told Levo Therapeutics that an additional clinical trial will be necessary to confirm the efficacy of LV-101 (intranasal carbetocin), a nasal spray aimed at reducing insatiable hunger, called hyperphagia, in Prader-Willi syndrome (PWS) patients.

Levo Therapeutics had submitted a new drug application seeking approval of LV-101 based on data from two trials — the Phase 2 Study 114 (NCT01968187) and the Phase 3 CARE-PWS clinical trial (NCT03649477).

However, the FDA reported “a number of concerns” related to the efficacy findings in both studies to its advisory committee, which came down with an overwhelmingly negative vote on LV-101. That vote was 12-1 against, with all but one committee member saying that no substantial evidence supported the efficacy of LV-101.

Now, in a complete response letter to Levo, the FDA’s Division of Psychiatry stated that, while LV-101 appears to be safe and well-tolerated, the submitted efficacy data — at a dose of 3.2 mg — were insufficient and that an additional confirmatory trial will be required.

Levo is currently discussing with the FDA the new trial design. In the meantime, it continues to provide LV-101 to existing study patients.

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“We are disappointed by the outcome of FDA’s review of our application and the continued lack of treatments for the most significant symptoms of the syndrome,” Sara Cotter, Levo’s CEO, said in a press release. “We are hopeful that our discussions with FDA regarding the next study will be productive and that we can initiate enrollment of a confirmatory study later this year.”

Caregivers of PWS patients interested in receiving further information on the new trial as it becomes available can complete an interest form here.

“Currently, there are no therapies approved by FDA to treat the most challenging aspects of PWS, namely the constant hunger and distress that substantially impact patients and families,” said Paige Rivard, CEO of the Prader-Willi Syndrome Association USA.

“PWSA | USA remains committed to advocating for treatments for the PWS community and we urge the PWS community to consider enrollment in the next study of this important potential treatment,” she added.

LV-101 is a nasal spray form of carbetocin, a synthetic (lab-made) form of oxytocin, a hormone important for behaviors such as empathy, trust, and satisfaction from food. Oxytocin production is faulty in PWS patients, and leads to symptoms such as metabolic abnormalities, obesity, behavioral problems, and bone damage.

The experimental therapy was designed to ease insatiable hunger, and lessen social and emotional difficulties in PWS patients. The spray is given three times a day prior to meals.

In the Phase 2 study, children with PWS — 38 in total — were randomly assigned to receive either LV-101 (9.6 mg) or a placebo for two weeks. The results showed that LV-101 performed better than the placebo in significantly reducing hyperphagia and obsessive-compulsive behaviors. However, the FDA said these findings were of unclear significance and that the trial was too short to support chronic treatment of PWS.

Thus, the CARE-PWS trial was designed to confirm these first results in a large group of children and adolescents with PWS, and over a longer period. It also assessed other doses.

A total 130 patients were randomly assigned to receive one of two doses of LV-101 — 9.6 mg or 3.2 mg — or a placebo for eight weeks, or about two months.

Contrary to the Phase 2 study, top-line data from the CARE-PWS trial showed that, at the higher (9.6 mg) dose, LV-101 had no significant capacity to lessen hyperphagia or obsessive-compulsive behaviors compared with the placebo.

However, the lower dose 3.2 mg led to significant reductions in hyperphagia, as well as anxiety and distress. No effect was seen on obsessive-compulsive behaviors.

“As the highest enrolling site in both the phase 2 and phase 3 PWS studies of [the nasal spray], we have seen the exciting potential of this therapy,” said Elizabeth Roof, senior research specialist at Vanderbilt University. “We are committed to again being a part of the next study of carbetocin and look forward to collecting the data needed to enable access to this important treatment option.”