Levo Therapeutics’ Prader-Willi Drug Fails to Meet Primary Endpoint in Late Stage Study

Rare Daily Staff

Levo Therapeutics reported that its experimental treatment LV-101 for the treatment of Prader-Willi syndrome did not meet the primary endpoint of controlling hyperphagia, or extreme hunger.

Prader-Willi syndrome (PWS) in characterized by hyperphagia, a chronic feeling of insatiable hunger that severely diminishes the quality of life for PWS patients and their families. Additional characteristics of PWS include behavioral problems, cognitive disabilities, low muscle tone, short stature (when not treated with growth hormone), the accumulation of excess body fat, developmental delays, and incomplete sexual development. Hyperphagia can lead to significant stomach rupture, obesity, diabetes, and cardiovascular disease. It can also lead to accidental death as a result of choking, or food seeking behavior. There are currently no approved therapies to treat the hyperphagia/appetite, metabolic, cognitive function, or behavioral aspects of the disorder.

A deficiency of the neuroendocrine hormone oxytocin is believed to be contributory to the hyperphagia of PWS. LV-101 is an intranasal formulation of carbetocin, an analog of oxytocin and a selective oxytocin-receptor agonist. The U.S. Food and Drug Administration granted Orphan Drug and Fast Track designations to LV-101.

The phase 3 CARE-PWS study tested two doses of LV-101 versus placebo with an even randomization, specifying the 9.6 mg dose as the primary endpoint and the 3.2 mg dose as the first secondary endpoint. Levo expected to enroll 175 patients in the trial but enrollment was closed early due to COVID-19 with 119 evaluable patients in the primary analysis set.

While the study did not meet its primary outcome measurements evaluating the 9.6 mg dose of LV-101, statistical significance was achieved with the 3.2 mg dose as evaluated by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score as the first secondary endpoint. When pooling the two dose arms of LV-101, per a pre-specified analysis, the change in HQ-CT score from baseline to week 8 resulted in a p-value of 0.055. Consistency in benefit/response was observed in the 3.2 mg dose arm across other key secondary endpoints, including clinical global impression of change (CGI-C) and anxiety and distress behaviors, as evaluated by the PWS Anxiety and Distress Behaviors Questionnaire (PADQ). Neither dose demonstrated a statistically significant effect on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). LV-101 was generally well tolerated in the study.

After the 8-week placebo-controlled period, all patients were transitioned into the long-term follow-up period and received intranasal carbetocin. Greater than 98 percent of patients enrolled in CARE-PWS elected to enter the long-term follow-up period. The company says further improvements in scores were observed and subsequently maintained after week 8 in both dose arms. All patients actively participating in CARE-PWS will be transitioned to receive the 3.2 mg dose of LV-101 for the remainder of their long-term follow-up and extension periods.

Levo Therapeutics is trying to make the best of the results by focusing on the secondary endpoints.

“We are excited by these important results that were achieved after decades of interest in addressing the oxytocin deficiency in PWS,” said Sara Cotter, CEO of Levo Therapeutics. “We are also pleased that our efforts to develop new tools for clinical evaluation of this rare, neurodevelopmental disorder have enhanced our understanding of the real-world impact LV-101 has on anxiety and distress behaviors.”

Treatment for Prader-Willi has been fraught with failures. In April, Millendo Therapeutics said it would discontinue development of its experimental treatment livoletide after it missed the primary endpoints in a pivotal study. In June, Soleno Therapeutics said its experimental treatment failed in a late-stage study. Harmony Biosciences’ approved treatment for narcolepsy, pitolisant, is currently being studied as a treatment for the excessive sleepiness associated with PWS.

Photo: Sara Cotter, CEO of Levo Therapeutics

Editor’s note. The headline on this story was updated 8/12/20 to better reflect the outcome of the study.