Petition to request that the FDA file, grant priority review, and review the application for DCCR for people living with Prader-Willi syndrome (PWS).

If you agree with the information described in the community petition to FDA (below) and would like to see FDA review the New Drug Application for DCCR, please consider signing on to show your support. You can do so by completing the form on the next page.

Petition to request that the FDA file, grant priority review, and review the application for DCCR for people living with Prader-Willi syndrome (PWS).

We, the Prader Will syndrome (PWS) community, are at a point where our efforts to build a ‘research ready’ community, including the development of tools for drug development (such as our patient registry, natural history studies, cell and animal models, and clinical network), and investments in research are translating into a pipeline of new potential treatments for PWS. Diazoxide choline (DCCR) is an investigational drug being developed by Soleno Therapeutics, which has been shown to improve symptoms in people with PWS in well-controlled clinical trials. DCCR has the potential to improve hyperphagia, decrease fat mass, and improve challenging PWS-associated behaviors as rated both clinicians and caregivers.

Why are we sharing this, and why now? It is because we come to you with a call to action. The voice of the patient is critical to the drug development process. The 21st Century Cures Act requires drug developers to include, and FDA to consider, the patient perspective in making approval decisions for new drugs. The PWS community has been active in documenting the patient perspective and sharing the PWS patient voice with FDA over the last decade. Surveys of parents of those with PWS and individuals with PWS themselves have documented the profound impact of PWS on health and well-being, demonstrating the tremendous unmet need in this population. Treating PWS-associated symptoms including hyperphagia, anxiousness, and temper outbursts are the highest priority for the community. These symptoms make it so patients cannot live alone without significant supervision, cannot have jobs, and have limited friendships. Not surprisingly, there is high tolerance of risk for treatments that would reduce hyperphagia in PWS. These insights into PWS have been shared with FDA through on-site meetings with advocates, a Patient Listening Session (June 2021), and, most recently, through an externally-led Patient Focused Drug Development meeting (June 2023). This meeting showed that hyperphagia, anxiousness, temper outbursts, sleep disorders, obsessive-compulsive behaviors, and intellectual disability have tremendous negative impacts. We described to FDA that these symptoms greatly reduce the ability of the person with PWS to participate in community activities, gain independence, and reach their life goals. Further, we shared the reality that PWS is a life-threatening disease, whether from choking, accidents (e.g., running across a busy street to get food), stomach ruptures, or weight-related health events. This brings us to where we are today. With no approved treatments for any of these aspects of PWS, patients are left with no relief from hyperphagia or the other serious symptoms.

This is in stark contrast to the experiences reported by caregivers and those living with PWS who have had access to investigational DCCR. During two PWS community town halls (April and May 2021), members of the PWS community highlighted the impact that DCCR had on hyperphagia and other PWS-associated behaviors. For example, parents stated that DCCR treatment not enabled lessening of food controls but allowed participation in activities of daily life not previously possible, such as cooking or traveling. Others described DCCR treatment as changing their children’s eating behaviors from eating everything in sight (e.g., entire pound of cashews) to stopping once feeling full (e.g., leaving food on the dinner plate). These direct patient experiences provide a source of hope for the rest of the community that eagerly awaits the opportunity to try DCCR, should it be approved.

Studies to Evaluate the Efficacy and Safety of DCCR in the Treatment of People with PWS

Development of DCCR in patients with PWS began in 2014 with a Phase 2, single-center study conducted at UC Irvine Medical Center. The study showed improvements in hyperphagia as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) (Mean -4.32, p=0.006) and in behavioral and body composition parameters following 10 weeks of open-label treatment. Based on these data, a Phase 3 program was conducted starting in mid-2018. The Phase 3 study, a randomized, double-blind, placebo-controlled study of 127 patients at 29 sites in the US and UK, showed that while the primary analysis did not achieve statistical significance for change from baseline in hyperphagia (Mean 1.67, p=0.198), the trial was significantly impacted by COVID-19 pandemic and the analyses of hyperphagia excluding the COVID-19 -affected data showed significant improvements in hyperphagia (Mean -3.13, p=0.037).

The vast majority of subjects from the double-blind study enrolled in an open-label extension study. In that study, there were highly significant improvements from baseline in hyperphagia after one year of DCCR administration (Mean -9.9, p<0.0001) and in the final analysis at 3 years (Mean -10.7, p<0.0001), reflecting a more than 50% improvement from baseline in most patients. These long-term changes in hyperphagia were accompanied by improvements in all assessed PWS-associated behaviors, in body composition, in measures of disease severity, and in hormonal and metabolic parameters. Data from the long-term, open-label study of DCCR have also been compared with the Foundation for Prader-Willi Research (FPWR) PATH for PWS (PATH), a contemporaneous natural history study. In this comparison, highly statistically significant improvements in mean change in hyperphagia score compared to the PATH cohort at 6 months (Mean difference 5.9, p<0.001) and 12 months (Mean difference -6.2, p<0.001) was observed.

Seventy seven of the 83 patients in the open-label study, at the end of 2022, consented to a four-month double-blind randomized withdrawal period in which half of the patients remained on DCCR and half were randomized to placebo. The data showed highly significant worsening of hyperphagia in the placebo group compared to the DCCR group (Mean difference 5.0, p=0.0022), and were supported by corresponding differences in changes in mean weight and BMI (weight: Mean 1.6 kg, p=0.0353; BMI: Mean 0.6 kg/m2, p=0.034). In the placebo group compared to the DCCR group, trends towards worsening were observed for all PWS-associated behaviors and clinician-reported impressions of severity and improvement at four months.

The parent molecule of DCCR, diazoxide, has been approved for several decades and while used in a distinct indication, has an estimated 180,000 to 220,000 patient years of safety data showing a well-understood adverse event profile. In patients with PWS, the safety profile has been consistent with that for diazoxide at comparable doses. The most common adverse events have been hypertrichosis, blood glucose increase / hyperglycemia, and peripheral edema. A vast majority of these events have been Grade 1 or 2 and manageable with appropriate monitoring.

Overall, we believe these data support a favorable benefit-risk profile for DCCR.

Rationale

Given the clinical trial results, PWS patients, PWS families, and clinicians strongly encourage Soleno and the FDA to work together promptly to give people with PWS – who currently have no way to treat hyperphagia and other PWS-associated behaviors – access to DCCR as soon as possible.

FDA has emphasized the importance of the patient voice, especially for rare conditions without FDA-approved treatment options. The patients, families, and clinicians of the PWS community are fully aware of the clinical trial results evaluating the use of DCCR in PWS and are convinced that the results demonstrate meaningful benefit and low risk.

Since there are no FDA approved therapies for hyperphagia or other PWS-associated behaviors, DCCR would represent a significant improvement in the treatment of PWS as compared to the current standard of care. Time is of the essence for those living with PWS, so the NDA merits being given a Priority Review at time of filing.

We urge the FDA to consider the significant unmet need to reduce hyperphagia in PWS, allowing PWS individuals and their families to potentially dramatically improve their quality of life and perhaps longevity. We believe that the New Drug Application for diazoxide choline (DCCR) should be filed, designated for Priority Review, and reviewed in its entirety. We, as a community, have reviewed the benefit-risk of DCCR and believe that this option should be available as an option for people with PWS and their doctors as soon as possible.