While privately held Levo Therapeutics Inc.’s phase III study of LV-101 (intranasal carbetocin) for treating Prader-Willi syndrome (PWS) failed to meet its primary outcome measurements, the company’s CEO told Bioworld the first secondary endpoint showed a statistical significance that raised her hopes the FDA might approve the selective oxytocin-receptor agonist for the indication.

Top-line data revealed first secondary endpoint data showing statistical significance with a 3.2-mg dose as evaluated by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score (p=0.016). In pooling the two dose arms of LV-101, the change in HQ-CT score from baseline to week eight resulted in a “p” value of 0.055.

The remaining secondary outcome measures were anxiety, as measured by the PWS Anxiety and Distress Questionnaire total score vs. placebo, and global impression as measured in the Clinical Global Impression of Change score vs. placebo. Both were measured from baseline to week eight.

Consistency in benefit/response was observed in the 3.2-mg dose arm across other key secondary endpoints, including clinical global impression of change (p=0.027) and anxiety and distress behaviors, as evaluated by the PWS Anxiety and Distress Behaviors Questionnaire (p=0.027).

The study was designed to enroll patients ages 7 to 18 of both genders who received two doses of LOV-101 with an even randomization (1-to-1-to-1) specifying a 9.6-mg dose as the primary endpoint and the 3.2-mg dose as the first secondary endpoint.

Neither dose demonstrated a statistically significant effect on the Children’s Yale-Brown Obsessive Compulsive Scale.

The safety data showed LV-101 was generally well-tolerated.

The study, CARE-PWS, was a randomized, double-blind study with an eight-week, placebo controlled-period. Its effectiveness was measured using caregiver- and clinician-reported measures of hyperphagia (extreme hunger), anxiety, and obsessive and compulsive behaviors. Primary outcome measures were the change in hyperphagia and the change in obsessive and compulsive behaviors as measured by the Children's Yale-Brown Obsessive-Compulsive Scale Total Score vs. placebo.

Chicago-based Levo wanted to see some dose ranging in the phase III, CEO Sara Cotter told BioWorld, so the 3.2-mg dose was added to the design. The secondary endpoint data were solid enough to encourage her to hope the FDA would approve LV-101 for the indication. With the fresh data, she plans to meet with the FDA when possible though she was unsure exactly when that would be.

In April, enrollment in the study was paused due to COVID-19 concerns. The pandemic came at a tough time, Cotter said, when the study was generating momentum. The anxiety and stress of the pandemic applied to the patients as well, Cotter added, as they thrive on routine and consistency.

The phase III study was initiated in December 2018. LV-101 received fast track designation in November 2019.

Cotter, a former biotech analyst at UBS Group AG, said she views PWS as a false state of starvation. Symptoms include anxiety, compulsivity, hyperphagia, mild to moderate levels of intellectual disability, growth hormone deficiency and a high risk of obesity.

“I was familiar with the space and work in the rare disease community,” Cotter said. “I felt a real responsibility to do my part.”

The condition occurs in about one in every 16,000 births, with the underlying cause being the lack of expression of paternally inherited genes on a small part of chromosome 15.

Others looking for answers

In June, Soleno Therapeutics Inc.’s phase III DESTINY PWS (C601) trial evaluating once-daily diazoxide choline controlled-release tablets for treating patients with PWS missed its primary endpoint of change from baseline in hyperphagia.

Also in June, Saniona AB, of Ballerup, Denmark, completed its IND meeting with the FDA to develop Tesomet (tesofensine + metoprolol), a beta 1 adrenoceptor antagonist for treating Prader-Willi. Saniona is following the 505(b)2 pathway in the phase IIb trial, set to start in the second half of 2020. The primary endpoint will be hyperphagia. In Saniona’s phase IIa trial, Tesomet significantly reduced hyperphagia in both adult and adolescent PWS patients.

In April, Millendo Therapeutics Inc. had a miss in a pivotal study of its PWS therapy, livoletide, an unacylated ghrelin analogue, which failed to show a statistically significant improvement in hyperphagia and food-related behaviors vs. placebo.

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