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DCCR development update (DESTINY PWS and extension studies)

SEPT 2021 – DCCR (Diazoxide Choline Controlled Release) is a once-daily treatment for hyperphagia and body composition being developed by Soleno Therapeutics for the PWS community. DCCR is thought to affect leptin pathways by opening KATP channels, and also to improve GABA signaling. (Leptin is a hormone that helps to regulate energy balance by inhibiting hunger and its pathway is thought to be disrupted in PWS.) DCCR activates hypothalamic POMC neurons which signal to MC4 receptors to inhibit food intake and increase energy expenditure. It also inhibits NPY neurons, a regulatory peptide (associated with the GABA neurotransmitter), which have a role in stimulating food intake.

Following a successful phase 2 trial, Soleno received Fast Track designation from the FDA in July 2018 to develop DCCR for PWS, due to the unmet treatment need in this patient group. A phase 3, placebo controlled trial (C601 / DESTINY PWS) was initiated in 2018 at 29 locations across the USA and UK, involving 127 participants with PWS, initially aged from 8 years, and later extended to 4 years plus. There were no serious or adverse events and Soleno announced phase 3 top-line results in June 2020.

Unfortunately, the results did not meet statistical significance for primary endpoint of change from baseline in hyperphagia, but they did show significant improvements in a prespecified subgroup with severe hyperphagia. Significant positive changes were also seen in 2 out of 3 key secondary endpoints: improvement in Clinical Global Impression of Improvement (CGI-I) score as assessed by the investigator, and reduction of body fat mass measured by DXA scan. In addition to the reduction in total body fat mass, other body composition changes included significant decreases in trunk fat mass and improvement in lean body mass to fat mass ratio. Fat mass changes were most pronounced in subjects in the highest weight band. In addition to improvements related to behaviours associated with hyperphagia, improvements were also observed in other behaviours typical of the PWS cognitive profile.

Over 95% of participants who completed the DESTINY PWS trial elected to continue treatment in Soleno’s long term open-label extension study (C602). At a 3 month interim analysis, continuing improvements in hyperphagia were noted, including in those who had switched from placebo to DCCR. The C602 trial also measures changes in behaviours related to PWS using a PWS Profile Questionnaire (PWS-P), consisting of caregiver responses to questions in six domains: aggressive behaviors, anxiety, rigidity-irritability, compulsivity, depression and disordered thinking. Improvements in most domains were seen in C601 and each domain showed further improvement in C602. Placebo subjects from C601 showed a similar change following three months of treatment in C602.

As a result of DESTINY PWS not meeting its primary endpoint, Soleno Therapeutics have been unable as yet to obtain a New Drug Application (NDA) from the FDA. In September 2020, Soleno announced updated phase 3 top-line results which included the interim analysis of C602. Soleno have also submitted additional C601 analyses of data from study visits completed prior to the disruptions caused by the COVID-19 pandemic. These showed statistically significant changes compared to placebo in the primary and key secondary endpoints. However, in March 2021, the FDA decided that an additional controlled clinical trial would be necessary to support an NDA submission. This decision led Soleno, PWSA(USA) and FPWR to launch an appeal requesting that the FDA reconsider the need for another trial to avoid delaying access to this treatment. They stated that the results of DESTINY PWS had been negatively skewed by the impact of Covid-19 and requested that robust pre-pandemic findings were not dismissed. To support their appeal, they collected and compiled the experiences of patients and caregivers during the DESTINY PWS trial and in the ongoing C602 study, and a petition was signed by more than 26,500 people. The appeal was supported by Dr Jennifer Miller, Prof of Paediatric Endocrinology and Principal Investigator, “DCCR therapy results in meaningful improvements in hyperphagia in severe patients, as well as various other positive impacts in behaviors and body composition, and if approved, could offer a safe and effective treatment to PWS patients struggling to manage their symptoms. My experience with DCCR in the largest cohort of patients in this study is consistent with the overall effects seen in DESTINY PWS.”
As a result of this appeal, the FDA did not rule out that an additional trial may be necessary, but they agreed to evaluate supplementary data from DESTINY PWS and C602, and to allow the inclusion of patient voice in their discussions.

Soleno continue to treat patients on C602 and evaluate the data from C601 and C602, whilst also meeting with regulatory authorities to discuss further analyses and data requirements. In September 2021, Soleno announced that they intend to submit comparison data from the ongoing C602 trial and PATH for PWS (an ongoing evaluation of the natural history of individuals with PWS by FPWR). The FDA had conveyed that despite statistical and other limitations, they would be open to reviewing this data which compared subjects who received DCCR for 26 and 52 weeks to results from matched subjects from the PATH for PWS study.

As previously indicated by the FDA, it is likely that another clinical trial will be needed, but Soleno are hopeful that the FDA will find the submitted data to be adequate enough to support an NDA for DCCR, or that they will agree to the use of C602 (with participants already enrolled) to generate any additional data necessary. It is Soleno’s hope to make DCCR available to the PWS community as expeditiously and cost effectively as possible.

Whilst DCCR has not worked significantly for every person in the trials, for those that it has helped, it has helped a great deal. We know that hyperphagia in PWS is not yet fully understood; it is extremely complex and presentation in individuals can vary. Therefore, hyperphagia drug trials for PWS have had mixed or varied results to date. There are several hyperphagia treatments currently being developed for PWS, each targeting different pathways or receptors, and perhaps, looking forward, the PWS community will continue to need a range of hyperphagia treatment options for PWS.

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Following FDA review of the adequacy of data submitted by Soleno Therapeutics in October 2021, the FDA indicated they were receptive to a study design involving participants currently enrolled in C602 to generate the additional control data necessary to support an NDA. Soleno expects to submit a study proposal shortly and to subsequently initiate this study, if acceptable.