DCCR Shows ‘Life-changing’ Potential in Troubled Trial, Doctor Says in Interview
Diazoxide choline controlled release (DCCR) tablets are an investigational therapy for Prader-Willi syndrome (PWS) that, according to data from a Phase 3 clinical trial and linked extension study, may be the first to control the disorder’s hallmark symptom: hyperphagia, or an insatiable hunger.
But the COVID-19 pandemic that upturned societies worldwide affected top-line trial data, Soleno Therapeutics, its developer, argues in the face of a decision by the U.S. Food and Drug Administration (FDA) for an additional study in people with this rare disease.
Patient advocacy groups — supported by the PWS community — are also asking the FDA to reconsider.
That DCCR appears to work effectively through a rather simple mechanism of action came as a surprise to Jennifer Miller, MD, a lead investigator of the DESTINY PWS Phase 3 clinical trial (NCT03440814) of DCCR. Miller, a pediatric neuroendocrinologist at the University of Florida, is currently following over 600 people with PWS from around the world.
“I’ve always said to patients, if hyperphagia was simple, we would have found the answer to treat it a long time ago,” she said in an interview with Prader-Willi Syndrome News.
DCCR’s parent molecule, diazoxide is used to treat low blood sugar that can suppress appetite. Diazoxide reduces levels of insulin and leptin, two hormones associated with hunger and metabolism. It also acts on fat cells in the liver, which indirectly affects body fat.
But studies evaluating diazoxide as a therapy for metabolic disorders tended to deliver inconsistent results. The need to administer it in high doses to provoke a therapeutic effect also led to significant side effects, and high dropout rates in clinical trials.
“DCCR was rationally designed to get around these problems,” Anish Bhatnagar, MD, Soleno’s CEO, said in a separate interview with Prader-Willi News.
Bhatnagar explained that DCCR is made to be more soluble and bioavailable, meaning that more of it dissolves into the bloodstream and is available for the body to use. The once-a-day tablet formulation also allows for fairly convenient administration.
“What it allows you to do is get the efficacy that you want, but without the problems that would be associated with the parent molecule,” Bhatnagar said.
DCCR works by opening ATP-dependent potassium channels. These channels are found on cell surfaces in many different tissues, such as the pancreas, liver, and fat cells. Most relevant to PWS, one of these tissues is the hypothalamus, a structure within the brain that controls appetite.
Some of the neurons found in the hypothalamus release peptides — short chains of amino acids, the building blocks of proteins — called neuropeptide Y and agouti-related protein, which stimulate appetite. Research has shown that these nerve cells make and secrete less of each peptide when KATP channels are open.
While top-line data from the main trial (completed in June 2020) showed no significant reduction in hyperphagia, an analysis of pre-pandemic findings revealed that DCCR did reduce excessive hunger, while also curbing some of the behavioral symptoms that accompany PWS, such as aggressiveness, compulsion, and anxiety.
Largely because of this wide array of physical and psychological symptoms extending from the gut to the brain, Miller expected it to be much more difficult to design an effective PWS therapy.
“There’s a gut-brain disconnect there, that is well known,” she said.
Psychological factors like obsessive-compulsive tendencies and anxiety also made Miller believe PWS to be too highly complicated a disorder to treat with any single medication.
Yet with DCCR, Miller reported having seen these symptoms dissipate. And, she added, this has been the case even for psychological manifestations unrelated to hunger.
A 13-year-old girl participating in DESTINY PWS, for instance, displayed compulsive behavior toward selecting her school outfit, a task where she would spend “three hours every night,” Miller said. To the neuroendocrinologist’s surprise, DCCR treatment was effective against both the girl’s hunger and her compulsive behavior.
Miller then began to ask her trial patients about other compulsive behaviors, such as collecting, hoarding, and arranging. All of these behaviors, Miller said, began to disappear.
“I was blown away,” she said, “that a single drug could have the efficacy that [DCCR] has.”
Throughout her career as an expert in PWS, Miller has seen how this disorder greatly impacts patients’ lives.
“It was just really touching to hear them say, ‘Well, if I didn’t have this, I would have been or I would have done [that],’ you know, because they couldn’t,” she said. “They were really amazing people who had a lot to offer but couldn’t because of the syndrome.”
The “life-changing” benefits Miller has been tracking with DCCR, which she said extended to less body fat and improved muscle mass, now give her hope.
“I just never thought that one drug … would make the degree of difference that this has made,” she said. “They’re on their high school football team, they’re on their high school basketball team, they are running track, they are running cross-country, they are bike riding, they are rollerblading.
“This crazy stuff that other kids can do no problem, these kids couldn’t do.”
She, with Bhatnagar, is waiting to see if the FDA might change, or in some way alter, its March new trial decision.
Soleno, meanwhile, is preparing to do whatever might be necessary, Bhatnagar said.
“We are continuing the conversation with the agency to see whether they would be willing to take a look at the full data set,” he said. “At the same time, we are also thinking through what a new trial might look like. There’s many challenges in designing a new study at this time with the pandemic going on.”