Soleno Therapeutics Inc.’s phase III DESTINY PWS (C601) trial evaluating once-daily diazoxide choline controlled-release tablets for treating patients with Prader-Willi syndrome (PWS) missed its primary endpoint of change from baseline in hyperphagia, or insatiable hunger, which is the disease’s predominant syndrome.

The top-line results sent Redwood City, Calif.-based Soleno’s stock (NASDAQ:SLNO) into a downward spiral as shares closed 35% lower June 9 at $2.10.

Meanwhile, Saniona AB, of Ballerup, Denmark, completed its IND meeting with the FDA to develop Tesomet (tesofensine + metoprolol), a beta 1 adrenoceptor antagonist for treating PWS. 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.

The genetic disease is rare, with fewer than 20,000 cases diagnosed annually in the U.S.

Last October, the path looked clear for Soleno as the data safety monitoring board recommended the Destiny PWS trial continue without modification following review of data from more than 50% of patients enrolled and treated.

Anish Bhatnagar, Soleno’s CEO, said that despite the failure, the data encouraged the company to continue treating patients on C602, a long-term safety extension study of diazoxide choline controlled-release (DCCR) in PWS patients completing C601. More than 90% of those patients continue to be treated.

The Soleno study’s objective was to assess the safety and efficacy of once-daily DCCR tablets in subjects ages 4 and older, with genetically confirmed PWS. Patients who completed the double-blind study were eligible to enroll in study C602.

The primary endpoint, change from baseline in hyperphagia, was measured by the total score of a Hyperphagia Questionnaire for Clinical Trials (HQ-CT, 0‑36). An improvement in HQ-CT is represented by a decrease in the score. The mean (SE) change from baseline for DCCR was -5.94 (0.879) and for placebo was -4.27 (1.145). The least squares mean difference in HQ-CT score of DCCR compared with placebo was -1.67 (1.294); 95% confidence interval (-4.24, 0.89); p=0.1983.

Significant changes were observed in two of three key secondary endpoints from baseline to week 13 in subjects receiving DCCR as compared to placebo, showing an improvement in Clinical Global Impression of Improvement score as assessed by the investigator (p=0.029) and a reduction of body fat mass measured by DXA scan (p=0.025). In the prespecified subgroup of subjects (n=61) with more severe hyperphagia, as identified by a dichotomized median baseline HQ-CT score of >22, the mean (SE) change from baseline for DCCR (n=42) was -9.67 (1.429) and for placebo (n=19) was -4.26 (1.896). The least squares mean difference in HQ-CT score of DCCR compared with placebo was -5.41 (2.093); 95% confidence interval (-9.60, -1.22); p=0.0124.

That heartened analysts at Laidlaw & Co. Ltd., who wrote Tuesday that they were encouraged that DCCR has demonstrated to be a highly active drug.

“The robust efficacy outcome from the severe PWS patients is especially heartening, particularly given a much smaller patient size (n=61) could achieve statistically significant results,” they wrote. “The severe PWS patient size of the study is also meaningful enough, in our opinion, for being considered for approval. It is also encouraging that two out of three secondary endpoints with greater measurement stringency were met. Together with its acceptable safety profile, we believe DCCR has the potential being approved in severe PWS as we look forward to getting more visibility after the FDA meeting.”

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. The failure prompted the Ann Arbor, Mich.-based company to discontinue liveletide’s development in PWS, which Millendo had acquired at the end of 2017 by merging with the privately held French biotech Alizé Pharma SAS, the first in a trio of companies founded by entrepreneur Thierry Abribat.

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