COVID-19 Pandemic ‘Significantly’ Affected DCCR Phase 3 Trial, Soleno Says

The COVID-19 pandemic — which took a heavy toll on people with Prader-Willi syndrome (PWS) and their families, according to a recent webinar — likely influenced the results of the DESTINY PWS Phase 3 trial that was testing the investigational therapy diazoxide choline controlled release (DCCR) at its outbreak.

In the webinar, researchers from Soleno Therapeutics, which is developing DCCR, said a new analysis of pre-COVID-19 trial data revealed the therapy’s early results were better than those shown in the top-line analysis that followed the study’s completion last year at the height of the pandemic.

“Given the considerable impact of the COVID-19 pandemic, particularly for individuals with PWS and their families as highlighted during our webinar, it was critical for us to evaluate the data from our Phase 3 DCCR trial that was generated prior to the significant disruptions caused by the pandemic,” Anish Bhatnagar, MD, Soleno’s CEO, said in a press release.

“Our analysis of the data through March 1, 2020 found statistically significant differences between DCCR and placebo patients for the primary and all key secondary [goals],” distinct from June’s top-line analysis, Bhatnagar said.

As part of its previously announced plans, Soleno has submitted the results from this additional analysis to the U.S. Food and Drug Administration, which is evaluating whether the data to date are sufficient to support an application seeking DCCR’s approval for PWS patients.

“We will have to wait and see what they say,” Bhatnagar said in the webinar.

COVID-19’s ‘cataclysmic’ impact on PWS families

PWS is “an incredibly complex, difficult disease” associated with a severe burden for families, especially as patients reach adolescence, Jennifer L. Miller, MD, a pediatric endocrinologist and the director of the University of Florida’s PWS program, said in the webinar.

This burden becomes particularly heavy when patients start to develop hyperphagia, or excessive appetite — leading families to go into a nearly full-time crisis mode, Miller said.

Patients “have to be watched 24/7, they cannot be left unobserved,” she said. This results in many caregivers reporting “reduced sleep quality, anxiety, and depression,” she added.

Profound hyperphagia, combined with most patients’ rigid thinking and resistance to changes in activities or routines, can lead to severe problems, including temper tantrums and aggressive behavior.

Miller said that previous studies have shown that siblings of PWS patients have post-traumatic stress disorder symptoms, behavioral difficulties, and eating disorders.

As such, in addition to the everyday challenges of people with PWS and their families, the pandemic-induced routine disruptions in educational, social, and physical activities were “absolutely cataclysmic for these families,” Miller said.

These negative effects were clearly reflected in the results of the “Impact of COVID” survey, involving 322 families of PWS patients, that was conducted by the Foundation for Prader-Willi Research (FPWR). That survey involved PWS patients, ages 4 and older, living in the U.S. and the U.K., and their families; all were part of the Global PWS Registry.

Between May and August 2020, participating families were asked about caregiver stress, access to medical care and supportive therapies, and how patients were coping with changes.

The results showed that 85% of caregivers reported increased stress, with the main concern being that “their loved one with PWS would get sick with COVID,” said Theresa V. Strong, PhD, FPWR’s co-founder and director of research programs. Many people with PWS have comorbidities, or other concurrent disorders, that put them at a higher risk for COVID-19, she noted.

In addition, more than 40% said it was harder to manage the behavior of PWS patients, who showed increased food-seeking behavior and stress or anxiety.  While these results are “not a big surprise,” they do highlight that the pandemic and its lockdowns made it “exponentially” more difficult to care for patients with PWS, Strong said.

Strong added that the considerable reduction in patients’ physical and social activities likely contributed to their worse behavior and increased focus on food.

Notably, while most families felt they were getting the medical care that they needed, especially through telemedicine, they reported reduced or no access to therapeutic approaches such as physical therapy, occupational therapy, and speech therapy. Indeed, according to Strong, 60-80% of survey respondents said access to therapy was eliminated or severely reduced.

COVID-19 impact on DESTINY PWS trial

Given these profound effects on patients and their families, Soleno researchers began questioning COVID-19’s impact on the DESTINY PWS study (NCT03440814). Specifically, the team sought to assess whether the results of the trial, which took place in the U.S. and the U.K. — and was completed in June 2020 — also were negatively affected by the pandemic.

In the trial, also called C601, 127 PWS patients, ages 4 and older, received either DCCR or a placebo for 13 weeks. Following treatment completion, 115 of the participants chose to enter the C602 extension study (NCT03714373), in which all patients will receive the therapy for up to three years.

DCCR, an extended release formulation taken as a once-daily tablet, works by blocking the release of two appetite-stimulating proteins in the brain — neuropeptide Y and agouti-related protein — that are believed to drive hyperphagia.

With the last patient visit occurring in April, top-line data showed that the study failed to meet its main goal of significantly reducing hyperphagia.

Notably, hyperphagia was assessed with a caregiver-filled questionnaire.

The trial, however, did meet both objective, key secondary goals of significant clinical improvements, based on a clinician-filled scale, and significant reductions in body fat.

Additionally, no significant group differences were observed in the subjective key secondary goal — caregiver-reported clinical improvements. Subjective measures, those reported by patients or caregivers, are more susceptible to external influences, such as those caused by a pandemic, the researchers noted.

Now, an analysis of pre-pandemic data through March 1, 2020 — when COVID-19 was declared a national emergency in the U.S. — showed “statistically significant improvement in several subjective [goals], which were not positive in the top-line analysis,” said Bhatnagar.

Specifically, “primary, subjective key secondary, and several other efficacy variables that were not significant in the topline analyses, are significant with preMarch 1, 2020 analyses,” Soleno said in slides accompanying the webinar.

Notably, hyperphagia differences between the DCCR and placebo groups trended toward statistical significance as early as December 2019, became significant by Jan. 15, 2020, and remained so until the middle of March, after which significance was lost.

Significant reductions also were observed in nearly all evaluated behavioral symptoms, including aggressiveness, anxiety, rigidity, irritability, and compulsivity, while significant improvements were seen in communication and social interactions.

Meanwhile, there were no major differences between the pre-pandemic and top-line analyses in DCCR’s safety profile or in the trial’s patient population in terms of demographics.

DCCR’s meaningful benefits

These positive findings were in line with Miller’s observations of DCCR’s benefits in several patients taking part in the DESTINY PWS trial and its extension study, of which she is a principal investigator.

Currently following more than 550 PWS patients around the world, Miller said it was “truly stunning” to see the profound body composition improvements in DCCR-treated patients, while also observing “completely unexpected” reductions in some of PWS’ core symptoms, including hyperphagia.

“Food no longer was a top priority,” Miller said, with patients leaving food on their plate — which “never happened before” — and having less severe temper tantrums and fewer aggressive behaviors.

Many families also reported being able to unlock their refrigerators, turn off their surveillance cameras, and take their affected children to the grocery store or to restaurants without major issues.

Besides hyperphagia-related changes, DCCR treatment “tremendously improved” family dynamics and social interactions, and reduced patients’ anxiety, repetitive questioning, compulsive behaviors, and skin picking — all common symptoms in PWS patients.

Notably, the observed reductions in patients’ body fat resulted in increased strength, stamina, and exercise capacity, allowing them to do things “they normally wouldn’t do” and increasing their will to exercise and overall sense of well-being.

“I can’t even tell you the number of families that I heard say that they forgot their child had Prader-Willi syndrome, which was mind-blowing to me,” the pediatric endocrinologist said.

Still, “it does take a while” to go through the DCCR-induced biochemical and body composition changes that precede behavioral improvements, Miller said.

At this point, though, every patient at her trial site is showing positive effects, she said. 

“I actually had very little faith in this [therapy] before we started this trial and have really just been blown away by the effects that I’m seeing in my patients,” she said.

Miller emphasized, however, that her observations do not necessarily apply to every participant.

But if DCCR’s benefits are sustained over time — and up to 2.5 years of data so far have shown no signs of waning effects  — the therapy has the potential to “change the natural history of this syndrome,” Miller said.