Diazoxide choline (DCCR) for Prader-Willi syndrome

Last updated Jan. 10, 2025, by Margarida Maia, PhD
Fact-checked by Marta Figueiredo, PhD

What is DCCR for Prader-Willi syndrome?

Diazoxide choline controlled-release (DCCR), also known as diazoxide choline extended-release, is an investigational oral therapy that Soleno Therapeutics is developing for people with Prader-Willi syndrome (PWS).

It is designed to ease certain symptoms of PWS, including excessive hunger, or hyperphagia, and behavioral problems.

DCCR has received orphan drug, fast track, and breakthrough designations in the U.S., as well as orphan drug status in the European Union, for PWS. These statuses are meant to accelerate the therapy’s clinical development and regulatory review by providing financial incentives and regulatory support.

It is currently under priority review by the U.S. Food and Drug Administration (FDA) for PWS patients, 4 years and older, with hyperphagia. A decision is expected by the end of March 2025.

Therapy snapshot

How does DCCR work in Prader-Willi syndrome?

Prader-Willi syndrome is a rare, complex genetic disorder caused by the loss of specific genes that control a wide range of bodily processes, including metabolism, growth, appetite, intellectual ability, and social behavior.

Symptoms include weak muscle tone and failure to thrive in infancy followed by the development of hyperphagia — marked by food obsession, aggressive food seeking, and lack of satiety — during childhood.

As a result, patients are at risk for obesity and associated conditions such as heart and lung disease, high blood pressure, diabetes, and gastrointestinal complications. This adds to a range of other symptoms such as developmental delays, cognitive impairment, sleep problems, and behavioral challenges like temper outbursts.

DCCR is an extended-release formulation of diazoxide choline that allows the therapy to be dissolved in a controlled way for up to 24 hours, beginning in the stomach and then continuing in the bowel. This helps maintain a steady amount of the therapy in circulation with once-daily dosing.

Diazoxide choline acts on ATP-sensitive potassium (KATP) channels, which are gate-like proteins that open and close in response to the amount of blood sugar, or glucose, in the bloodstream.

By keeping KATP channels open in a region of the brain called the hypothalamus, the therapy reduces the release of neuropeptide Y and agouti-related peptide, which are appetite-stimulating proteins in the brain that are thought to drive hyperphagia.

When it acts on KATP channels in the pancreas, DCCR blocks the release of insulin, a hormone that helps move glucose from the blood into the body’s cells. With less insulin, more glucose remains in circulation, which may increase the feeling of satiety and reduce the buildup of fat. There is also evidence that keeping KATP channels open in fat tissue may also be important for regulating body weight.

As such, DCCR’s effects on KATP channels are expected to help regulate appetite and lessen hyperphagia and associated aggressive and threatening behaviors, while limiting body fat buildup in people with PWS.

How will DCCR be administered in Prader-Willi syndrome?

In PWS clinical trials, DCCR is being tested in the form of tablets, at doses ranging from 75 to 545 mg, taken once daily by mouth.

DCCR in Prader-Willi syndrome clinical trials

Soleno’s application to the FDA is supported mainly by data from a Phase 3 clinical trial called DESTINY PWS (NCT03440814) and its open-label extension C602 study (NCT03714373).

DESTINY PWS

DESTINY PWS, also named C601, recruited 127 PWS patients, 4 and older, with moderate to severe hyperphagia at 29 sites in the U.S. and the U.K.

Participants were randomly assigned, in a 2:1 ratio, to receive an oral tablet of either DCCR, at doses ranging from 100 to 450 mg, or a placebo, once daily for 13 weeks (about three months). DCCR dosage was increased to a target of 3.3 to 5.8 mg per kg of body weight within the first six weeks.

The trial’s main goal was to assess how well DCCR worked compared with a placebo to ease hyperphagia. This was measured with the caregiver-reported Hyperphagia Questionnaire for Clinical Trials (HQ-CT), with scores ranging from 0 to 36, and higher scores reflecting more severe hyperphagia.

Secondary goals included changes in body fat, as well as caregiver and clinician evaluations of clinical progress. Exploratory goals included changes in other body composition parameters, certain hormones, and behavioral problems, as assessed with the Prader-Willi Syndrome Profile (PWSP) Questionnaire and the Developmental Behavior Checklist version 2 parent edition (DBC2-P).

Top-line data showed DCCR treatment was associated with a greater reduction in hyperphagia compared with the placebo, but this difference did not reach statistical significance, failing to meet the trial’s main goal.

Still, the therapy resulted in a significantly greater HQ-CT score reduction, by more than twofold, relative to the placebo in a subgroup of patients with more severe hyperphagia at the beginning of the study (HQ-CT scores higher than 22).

DDCR-treated patients also experienced significant clinical improvements, as assessed by the investigators, and a significant drop in body fat, compared with those given the placebo.

The therapy was also associated with a trend toward lessening in the anxiety, compulsivity, rigidity/irritability, and disordered thinking domains of the PWSP and a reduction in DBC2-P total scores, indicating less severe behaviors. But again, these differences failed to reach statistical significance.

However, further analyses suggested the COVID-19 pandemic greatly influenced the results, with pre-pandemic data showing significant reductions in hyperphagia and behavioral symptoms with DCCR.

C602

The majority of patients completing DESTINY PWS (90.6%) chose to enter its open-label extension study, called C602, where all would receive DCCR for up to three years.

Results showed one year of treatment significantly reduced hyperphagia and behavioral challenges, while significantly improving body composition (with greater lean body mass) and hormonal and metabolic profiles.

Data from interviews with caregivers of trial participants also supported the treatment’s beneficial effects for several behavioral symptoms.

Notably, all these trajectories were significantly different from what was seen over one year in untreated, matched patients participating in the PATH for PWS natural history study (NCT03718416).

In response to the FDA’s call for more clinical data, C602’s protocol was later changed to include a withdrawal period where patients were randomly assigned to either continue on DCCR or switch to a placebo for four months.

Results showed those who switched from DCCR to a placebo experienced greater hyperphagia worsening and weight gains compared with those who stayed on DCCR. Continuous DCCR treatment was also associated with a trend toward greater clinician-rated improvements and behavioral symptom reductions.

C614

Eligible C602 study participants could choose to enter another open-label extension study, called C614 (NCT05701774), in which all are receiving DCCR treatment for up to five years.

Common side effects of DCCR

​​In Phase 3 clinical testing so far, the most commonly reported adverse events in patients taking DCCR, and at higher rates relative to a placebo, included:

• excessive hair growth
• swelling of the lower legs or hands
• high blood sugar.

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