FPWR and PWSA|USA Request FDA Apply Regulatory Flexibility

FPWR and PWSA|USA have submitted a petition letter to the FDA requesting them to apply regulatory flexibility and to review a New Drug Application for DCCR (diazoxide choline extended-release).

Last month, the FDA advised Soleno Therapeutics that an additional efficacy trial for DCCR  would be needed prior to submitting a New Drug Application (NDA) for their review.  In our petition to the FDA, we are asking the FDA to reconsider this decision in light of the unprecedented circumstances of the past year (Covid-19) and to exercise the long-standing policy of regulatory flexibility when evaluating potential treatments for rare diseases, such as PWS. 

26,640 supporters signed on to our request that the FDA review a New Drug Application for DCCR and 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.

PWS is a rare neurodevelopmental and metabolic disorder and currently, there are no FDA-approved treatments for PWS-associated hyperphagia nor many of the other challenging symptoms of PWS. 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. We believe it is reasonable to expect that a 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. 

Our letter to the FDA is below. Download our package response to the FDA that includes comments and signatures to here.

PWS Community Response Letter to the FDA

April 7, 2021

Re: Request for Regulatory Flexibility & Review of NDA for DCCR, a Potential Treatment for Prader-Willi Syndrome; Unique Impact of COVID-19 on Prader-Willi Syndrome Clinical Trials

Dear FDA Leadership,

We represent the Foundation for Prader-Willi Research (FPWR) and the Prader-Willi Syndrome Association | USA (PWSA|USA), two patient advocacy groups that support thousands of individuals with Prader-Willi syndrome (PWS) and their families. We are writing on behalf of the patient community to bring to your attention a recent decision by FDA regarding a potential new therapy for PWS, and to request further dialogue and consideration. Specifically, the decision by the FDA advising Soleno Therapeutics that additional efficacy trial(s) for DCCR (diazoxide choline extended release) are needed prior to an NDA submission has raised concern that access to this promising therapeutic will be unnecessarily delayed. We are asking the FDA to reconsider in light of the unprecedented circumstances of the past year. More broadly, we appreciate that the FDA has a long-standing policy to exercise regulatory flexibility, and a history of doing so in rare disease; however, we propose that the full potential of regulatory flexibility to efficiently advance orphan product development in PWS has not been realized. We are asking for additional dialogue to convey the unique challenges of PWS clinical trials and to collaboratively work with the Agency to find solutions for Soleno’s product as well as other clinical packages before the Agency.

PWS is a rare neurodevelopmental and metabolic disorder caused by loss/inactivation of a contiguous set of imprinted genes on chromosome 15. Clinically, PWS is characterized as a constellation of symptoms including multiple endocrine deficiencies, a challenging behavioral phenotype, hyperphagia, and, in environments where food is not strictly controlled, morbid obesity. PWS is associated with increased mortality compared to the typical population, with a median age of death of 29 in the largest study to date (1). Common causes of death include complications of obesity (respiratory failure, cardiac issues), hyperphagia-related accidents (e.g., getting hit by a vehicle when running away to get food, choking while rushing to eat food), gastric rupture and pulmonary embolism. To keep children and adults with PWS safe and restrict food access, families must create a completely locked down environment, establishing an institution-like environment within the home, leading to a poor quality of life for the person with PWS and the entire family. Currently, there are no FDA approved treatments for PWS-associated hyperphagia.

Our community has worked diligently to build resources that address the FDA’s call for patient experience data, demonstrating high disease burden and the need for effective therapies addressing hyperphagia. We have demonstrated through family stories (2), surveys (3), and a more formal, best-worst scaling study (4) that hyperphagia is “the” aspect of PWS that families want addressed through new therapies, followed by other critical behavioral issues such as anxiety and aggression. We have demonstrated the tremendous unmet medical needs of individuals with PWS (2, 3), and the considerable burden of disease, showing that caregiver burden in PWS exceeds that of caregivers for traumatic brain injury and Alzheimer disease (5) and that higher levels of hyperphagia are associated with increased caregiver burden (6). We have also demonstrated that caregivers are willing to accept considerable risk in exchange for modest improvements in hyperphagia (7, 8). In the absence of a ‘cure’, families would welcome treatments that alleviate PWS symptoms. Finally, as suggested by the Agency during a Critical Path Innovation Meeting, we have also solicited input from individuals with PWS, speaking on their own behalf. Although this was challenging (not all individuals are capable of expressing their views), Dr. Elizabeth Dykens and her team elicited opinions from young adults with PWS on treatment preferences and disease burden, which nicely align with that of caregivers (9). This patient experience data is complemented by natural history studies that provide critical information to support clinical trials, including an NIH study funded 2006-2014 (10) as well as an ongoing registry-based prospective study of behavioral changes over time and serious medical events (11).

COVID-19 had a profound impact on the conduct and outcome of ongoing PWS clinical trials. Two large Phase 3 clinical trials evaluating new drugs for PWS were underway at height of the first COVID-19 wave of infections and related public health measures (e.g., stay at home orders). Beyond the cross-cutting issues that the clinical trial enterprise faced as a result of the pandemic (e.g., missed/delayed clinic visits), there were unique impacts on the PWS community that, we believe, could have led to confounding of clinical trial data upon the onset of the pandemic in the US (March 2020). PWS is defined by an extremely complex behavioral phenotype, with hyperphagia, anxiety, temper outbursts, rigidity and obsessive-compulsive behaviors interacting in the setting of social cognition and intellectual deficits (12). The primary outcome measure for most PWS clinical trials is the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), a caregiver-reported outcome measure assessing observable hyperphagia behaviors. While we believe this measure is appropriate for the PWS population and it has generally performed well in previous clinical trials, a limitation of the measure is its potential to be impacted by environmental changes. We believe this limitation became insurmountable in the face of the pandemic. Indeed, we have collected data on the impact of the COVID-19 pandemic on the US PWS patient community, with a survey administered through the Global PWS Registry. This survey documented increased caregiver stress, increased anxiety for individuals with PWS, as well as overall changes in food-related behaviors and activity due to COVID, with behaviors changing in sometimes unpredictable ways (13). These findings are corroborated by a similar study of PWS families in Europe (14). While the uncertainty and unexpected changes to routine that were experienced across the US had a profound impact on everyone, the particular sensitivity and inability of individuals with PWS to cope with unexpected change is well documented and would be expected to negatively impact the consistency and reliability of a measure such as HQ-CT.

In a Phase 3 trial by Soleno Therapeutics, pre-COVID data showed significant improvements in HQ-CT scores; families reported positive outcomes with continued improvement in the open label extension. Publicly released data from Soleno Therapeutics demonstrated that PWS participants receiving DCCR showed a drop in HQ-CT scores. While the reduction in HQ-CT scores did not reach statistical significance for the overall study, a significant improvement was detected for the prespecified, severe hyperphagia group [LS Mean Difference DCCR:Placebo -5.41 (2.09), p=0.0124]. In addition, significant improvement in hyperphagia was detected in the entire cohort when data from the pre-March 1, 2020 cut off (e.g., the start of the pandemic lockdown period) was considered [LS Mean Difference DCCR:Placebo -3.13 (1.48), p=0.037]. While we understand that prespecification of analyses protects against bias and improves reliability of findings, 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.

Importantly, objective secondary endpoints (DEXA scans, biochemical markers) showed significant improvements (e.g., p= 0.001 for change in body composition as assessed by lean body mass : fat mass ratio vs placebo), which continued to improve in the open label extension, while subjective measures trended consistently in the right direction. This is consistent with what we hear anecdotally from participants in the trial and their families. To this end, more than 26,000 comments from PWS families and supporters in the community were submitted to our organizations in a recent call for input regarding DCCR’s potential for treatment in PWS. Notably, site Principal Investigators and more than 80 family members of those enrolled in the trial provided their perspective (see appended comments for full quotes). Among these:

“As a PI, I have noticed considerable improvements in body composition, energy intake, hyperphagia, and quality of life for my patients participating in the DCCR trial…. Both patients and caretakers expressed a sense of relief from having less conflict and rigidity around food routines.  They expressed gratitude that they could now do things that families not living with PWS take for granted, such as go out to eat, travel, participate in after school activities, and socialize outside the home without the constant fear and anxiety surrounding unwanted food access….” P. Salehi, MD

“The effects of DCCR on the patients in the trial were multifactorial. While it definitively decreased the hyperphagia drive, it also significantly improved body composition and metabolism. Other changes that were noted by parents and patients, included decreased anxiety, both around food and overall, decreased compulsive behaviors, and improvements in socialization…. It was abundantly clear to patients and PIs that the impact of COVID-19 directly negatively impacted the results of the study with regard to the 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….” J. Miller, MD

“… Our son no longer pushes, fights, argues, runs away or gets angry because he no longer experiences hyperphagia. DCCR has given him the chance to graduate from high school and seriously consider college in his future. DCCR has allowed him freedom to no longer need supervision 24/7. He now has a chance to live a more healthy and productive life. Taking DCCR away will only cost him our family and society much more in the future…. (age 17) 

“Our son's entire physique has changed while taking DCCR. His endurance for physical activity has escalated and he's able to ride his bike for 5+ miles, take hour long walks, complete workout videos. It's night and day difference.”  (age 8) 

“We have noticed a remarkable difference with DCCR.  Our daughter's anxiety has decreased tremendously.  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.” (age 15)  

While we appreciate that these stories are anecdotal, they deviate remarkably from the documented natural history of PWS. Based on the publicly available data and feedback from our community, we are encouraged that DCCR is having a positive impact in PWS and propose that FDA review and analysis is warranted to speed access to this potentially impactful treatment.

This drug has a well characterized safety profile and no unexpected serious adverse events were reported. DCCR is an extended release version of diazoxide, which has been used clinically for more than 40 years in infants, children and adults. Importantly, diazoxide is well tolerated with a well characterized safety profile. The risks associated with this drug appear to be relatively low and can be readily monitored in the clinical setting. Given the serious consequences of PWS and the clear and significant unmet medical need, we believe our community’s risk tolerance is much higher than the risks presented by DCCR.

Additional large clinical trials for this drug in the PWS may not be feasible. While the FDA advised Soleno Therapeutics that additional DCCR clinical trial(s) are needed prior to NDA submission, as shared publicly in a March 8, 2021 press release, we are concerned that conducting an additional large efficacy study is not feasible in our population for the foreseeable future. COVID-19 disruptions continue and it is unclear how long it will take for our vulnerable population to be comfortable traveling to clinical trial sites. Further, the behavioral issues associated with the disruptions of routine will continue and are likely to be triggered again as vaccines become more widely available and daily routines change again, making the initiation of a new study in PWS susceptible to risk.

In addition, there has been widespread discussion about DCCR in the PWS community, further challenging placebo effect issues that can be difficult in any setting, but are particularly challenging in a close, rare disease community. Finally, our community is acutely aware that only a small number of clinical sites can effectively manage the challenging and sometimes extreme behaviors that characterize PWS. Potential trial participants are limited by the ability of their caregivers to manage these extreme behaviors during travel and at clinical trial sites.  

We request additional flexibility, consideration and dialogue, given this unprecedented situation. 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. We believe 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. Also, given that initiating a new trial during the ongoing COVID-19 pandemic is not advisable, there is no path forward for the foreseeable future. Therefore, we ask that you consider the full totality of the DCCR clinical trial results by conducting a fulsome and careful review of an NDA for this product.

Finally, we would welcome a robust dialogue between the FDA and the PWS community to convey the nuances and perspective of PWS families as it relates to unmet medical need, risk tolerance, acceptance of uncertainty of benefit, and challenges in the conduct of clinical trials, for DCCR as well as other products before the Agency for the treatment of PWS. We believe that such a discussion would advance the critical solutions needed for our community.

Sincerely,                                      

John Walter, CEO                                                        Paige Rivard, CEO
Foundation for Prader-Willi Research                    Prader-Willi Syndrome Association | USA    

Theresa Strong, PhD

Director of Research Programs

Foundation for Prader-Willi Research