Millendo Therapeutics Inc. in April decided to scrap work altogether with livoletide in Prader-Willi syndrome (PWS) after a phase IIb study fell short of statistical significance, but hope remains alive for – among others in the space – Soleno Therapeutics Inc., another recent newsmaker with once-daily diazoxide choline controlled-release (DCCR) tablets in PWS.
Livoletide, a cyclic peptide analogue of unacylated ghrelin, failed to show a statistically significant improvement in hyperphagia, or insatiable hunger, and food-related behaviors vs. placebo. The disappointing outcome caused Ann Arbor, Mich.-based Millendo to turn efforts to its candidate for congenital adrenal hyperplasia (CAH), nevanimibe, and a preclinical asset for menopausal vasomotor symptoms. Roth analyst Yasmeen Rahimi advised investors that the surprise fizzle of livoletide “does not mean anything” for nevanimibe, an acyl coenzyme A: cholesterol acyltransferase 1 inhibitor. In a report, she called the CAH prospect Millendo’s “ace in the hole” and said the “previously underappreciated asset will now come center-stage following the shelving of livoletide.” The NK3R antagonist MLE-301, MLND's preclinical asset for hot flashes and night sweats in menopausal women, isn’t slated for a phase I start until the second half of 2020.
In PWS, Soleno, of Redwood City, Calif., on Aug. 10 unveiled top-line phase III results that showed the Destiny study did not meet statistical significance on the primary endpoint of hyperphagia but showed encouraging improvements in a prespecified subgroup with a particularly severe form of the disease. Destiny also turned up positive changes in two of three key secondary endpoints in subjects given DCCR as compared to placebo. Those who completed Destiny PWS and enrolled in the open-label extension study will be treated for up to 36 months. Interim analysis of subjects who finished three months of treatment had continuing improvements in hyperphagia and other behaviors typical of PWS, Soleno noted. The safety profile was generally consistent with the known profile of diazoxide and prior experience with DCCR, and no serious unexpected adverse events turned up related to the study drug. Soleno plans to meet with the FDA later this year for a talk about next steps.
Overall positive Destiny
Laidlaw analyst Yale Jen likes the setup, calling the Destiny findings “overall positive” in an Aug. 11 report. The details explain why he feels that way. The mean change of Hyperphagia Questionnaire for Clinical Trials (HQ-CT) scores from baseline to visit seven between DCCR and placebo (the primary endpoint of the study) was -1.67 (DCCR: -5.94, placebo: -4.27; p=0.198 and n=124). In severe (HQ-CT score >22) PWS patients (n=61), the mean differences were -5.41 (DCCR: -9.67, placebo: -4.26; p=0.0124). The study also met two-thirds of secondary endpoints (Clinical Global Impression [CGI]-Improvement and dual-energy X-ray absorptiometry scan), and the lean body mass to fat mass ratio endpoint (p=0.001). Caregiver interviews at the end of the study (n=27) showed substantially more DCCR-treated patients (48% vs. 18-24%) experienced greater improvements in three categories: food-related, non-food-related, and daily life.
“As we examined the data in totality, the results suggested that DCCR is a highly active drug from a first placebo-controlled study,” Jen wrote. “The robust efficacy of the severe PWS patients is especially heartening, particularly given a much smaller patient size (n=61) achieved statistically significant results. The severe PWS patient size of the study is also meaningful enough, in our opinion, to be considered for approval,” in his view.
A rare genetic disease, PWS is characterized by decreased muscle tone and poor feeding in infancy, followed by the onset of hyperphagia in childhood, leading to morbid obesity and early death. Prevalence estimates for PWS vary from one in 12,000 to one in 77,000, differing depending on the country.
A more recent clinical blowup came Aug. 6 for privately held Levo Therapeutics Inc. with LV-101 (intranasal carbetocin), a selective oxytocin-receptor agonist that missed its primary endpoint but turned up statistical significance on the first secondary endpoint and may have a path forward. Secondary endpoint data showed statistical significance with a 3.2-mg dose as evaluated by the HQ-CT score (p=0.016). In pooling the two dose arms of LV-101, the change in HQ-CT 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 CGI-Change score vs. placebo. Both were measured from baseline to week eight.
Another, earlier stage player: Saniona AB, of Ballerup, Denmark, which completed its IND meeting in June 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 disease is fairly well understood but more findings continue to roll out. A paper published in Hormone Research in Pediatrics described how children with PWS bear high levels of a protein called LIGHT/TNFSF14, which may contribute to obesity and low bone mineral density. Data were presented at the European Society for Pediatric Endocrinology meeting last year in Vienna.