Advocacy Groups Oppose Additional Trial for DCCR

The Foundation for Prader-Willi Research (FPWR) and the Prader-Willi Syndrome Association (PWSA) in the U.S. have asked the U.S. Food and Drug Administration (FDA) to reconsider its request for an additional clinical trial of diazoxide choline controlled release (DCCR) tablets in patients with Prader-Willi syndrome (PWS).

Last month, the FDA advised Soleno Therapeutics, the therapy’s developer, that another efficacy trial would be necessary to support any future application seeking DCCR’s approval, despite the significant therapeutic benefits seen in an analysis of pre-COVID-19 data from the DESTINY PWS Phase 3 study (NCT03440814), which was completed in June.

The decision has raised concerns “that access to this promising therapeutic will be unnecessarily delayed,” the patient advocacy groups wrote in their letter, which they said is supported by more than 26,500 people from 89 countries (79% were U.S. residents).

Most (81%) were PWS community supporters, and 15% were parents and caregivers of people with PWS, ages ranging from less than 1 to 62 years.

The sign-on survey, open online March 12–19, also showed that 97% of parents, caregivers, and healthcare providers would like the option to give DCCR to their loved one with PWS if approved by the FDA.

“Given the unanticipated impact of the COVID-19 pandemic, the life-threatening nature of PWS, the tremendous unmet medical need of this rare disease, and the extreme difficulties of performing traditional clinical trials in the PWS population, we are imploring the FDA to utilize its long-standing policy of applying reasonable, science-based regulatory flexibility in its evaluation of results from PWS clinical trials,” the organizations wrote.

“We believe that the robust pre-pandemic findings should not be dismissed, particularly given the unique circumstances of a global pandemic, paired with our community’s significant unmet medical need, which makes us accepting of less certainty of treatment benefit,” they added.

DESTINY PWS evaluated the safety and effectiveness of DCCR against a placebo in 127 PWS patients, ages 4 and older, living in the U.S. and the U.K. Following 13 weeks of treatment, 115 participants chose to enter an extension study (NCT03714373), in which all will receive the therapy for up to three years.

Top-line data showed that the trial failed to meet its main goal of significantly reducing hyperphagia (excessive eating), which was assessed with a caregiver-filled questionnaire. However, it did meet both objective, key secondary goals of significant clinical improvements, based on a clinician-filled scale, and significant decreases in body fat.

Suspecting that pandemic-induced routine disruptions may have influenced the study’s results, especially those based on subjective measures, Soleno analyzed participants’ data through March 1, 2020, when COVID-19 was declared a national emergency in the U.S.

Notably, a previous FPWR-conducted survey of 322 families of PWS patients living in the U.S. and the U.K., showed increased caregiver stress, and increased food-seeking behavior and anxiety among people with PWS due to COVID. Similar findings were obtained in a German survey of 108 caregivers.

Results of the pre-pandemic analysis showed that DCCR was significantly better than a placebo at easing hyperphagia from Jan. 15, 2020, to the middle of March, after which significance was lost — supporting the pandemic’s negative impact on the trial’s top-line results.

DCCR-treated patients also had significant reductions in nearly all evaluated behavioral symptoms, including aggressiveness, anxiety, rigidity, irritability, and compulsive behaviors, and significant improvements in communication and social interactions.

In addition, several measures have improved with continued use of DCCR in the extension study, consistent with reports from trial investigators and families of the participants — provided through the sign-on survey and subsequently added to the response letter.

“We have been able to stop locking up food because she has a better control over her hunger and her food seeking. She has stopped having outbursts and temper tantrums that disrupt our home and cause stress on our entire family. … The difference this medicine has made for our child is night and day in her behavior and her ability to have a more normal life,” wrote a parent of a 15-year-old girl.

Added a parent of a 17-year-old boy: “Our son no longer pushes, fights, argues, runs away or gets angry because he no longer experiences hyperphagia.”

Jennifer L. Miller, MD, one of the trial’s principal investigators and the director of the University of Florida’s PWS program, said: “It was abundantly clear to patients and [principal investigators] that the impact of COVID-19 directly negatively impacted the results of the study with regard to the [hyperphagia] questionnaire data.”

“Therefore, I ask that the FDA reconsider the request for an additional study with this life-changing medication, given the negative impact of the COVID-19 pandemic on the results of this study and, perhaps more importantly, the fact that there is currently no available treatment for the horrific symptoms of this syndrome,” Miller continued.

Thoughts from parents and caregivers of PWS patients in and outside the U.S. on what an approval of DCCR would mean for patients and their families also were added to the letter.

How DCCR works

DCCR works by suppressing the release of two appetite-stimulating proteins in the brain — neuropeptide Y and agouti-related protein — believed to drive hyperphagia.

Administered daily, it is an extended release version of diazoxide, an approved medication used for more than 40 years for low blood sugar in infants, children, and adults, and with a well-established safety profile.

“We believe our community’s risk tolerance is much higher than the risks presented by DCCR,” the organizations wrote, adding that initiating a new trial during the ongoing pandemic “is not advisable,” leaving “no path forward for the foreseeable future.”

“It is reasonable to expect that critical review of the DCCR data will establish that there are real and meaningful benefits with limited risk, and a degree of uncertainty that is appropriate for our community,” they added.

The advocacy groups also emphasized the importance of a “robust dialogue between the FDA and the PWS community” to clarify PWS families’ perspectives regarding the high unmet medical need, degree of tolerance to risk and uncertainty of benefit, and challenges in participating in clinical trials.

“We believe that such a discussion would advance the critical solutions needed for our community,” they concluded.