Game-changer drug is the first to tackle overeating in Prader-Willi syndrome

Appetite-suppressing GLP-1 inhibitors like Ozempic and Mounjaro have grabbed headlines for their efficacy in helping people who are overweight or obese shed pounds. People with the genetic condition Prader-Willi syndrome (PWS) also struggle with high body weight, but GLP-1 inhibitors appear to have no effect in reducing their hunger (1). A new drug approved by the FDA in March offers a solution. The compound, called Vykat XR, was developed by Soleno Therapeutics.

PWS is caused by the deletion or alteration of genes on chromosome 15 in a region called the Prader-Willi critical region (PWCR). These changes affect the hypothalamus, a brain area that regulates bodily processes like body temperature, hunger, and thirst (2). People living with PWS struggle to feed as babies and have low muscle tone. They also often have cognitive difficulties and learning delays. According to Maithé Tauber, a pediatrician at the University of Toulouse, the main challenge that people with PWS and their families grapple with is hyperphagia. This is an insatiable and lifelong hunger that begins when patients are around four years old. Around 90 percent of adults with PWS are obese, and their diet and access to food must be carefully monitored to make sure they don’t overeat. “It is really a core symptom — very, very difficult to live with for the patient — but also for the parents and all the carers,” said Tauber.

Families are really feeling hopeful for the first time in a long time.
- Lauren Schwartz, Foundation for Prader-Willi Research

Vykat XR did not have a straightforward path to approval. In an initial 13-week Phase 3 trial called C601, the drug reduced patients’ overeating, but the improvement wasn’t significantly different from placebo (3). Lauren Schwartz, a clinical psychologist at the Foundation for Prader-Willi Research, is also the mother to a young adult with PWS. She explained that the original trial’s results were thought to have been disrupted by the COVID-19 pandemic, which upended patients’ routines. “The pandemic added a lot of noise into the data,” said Schwartz.

Despite this initial disappointment, Soleno Therapeutics initiated an open-label follow-up trial, C602, to see how the drug performed over a longer period. Over the next three years, the patients’ scores on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) improved significantly over baseline at every timepoint measured. Moreover, the improvement deepened over the first year of dosing (4,5).

C602 concluded with a follow-up analysis that used a randomized withdrawal design. In this trial, researchers divided 77 patients into two groups. One subset maintained their usage of Vykat XR, while the other switched to placebo. Hyperphagia in the placebo group worsened significantly. After 16 weeks, the test group’s HQ-CT scores were on average five points better than the placebo group and 13 points better than their baseline scores from three years prior.

Maithé explained that the exact mechanism that causes hyperphagia in PWS is unknown, although it is likely related to abnormalities in hypothalamic development and function. Vykat XR is a formulation of a crystalline salt, diazoxide choline, which blocks potassium channels in the hypothalamus and suppresses appetite-stimulating hormones. Before the recent trials, the compound had been used in other rare diseases but not in PWS. Soleno’s modifications extended the bioavailability of the drug, meaning that patients only need to take it once per day. The drug has mild side effects, such as hypertrichosis, or excessive hair growth, and hyperglycemia.

Both Schwartz and Tauber were impressed with the drug’s performance. Schwartz, who called the drug a “game-changer,” added that there was a “lot of excitement” among the PWS community in the wake of Vykat XR’s approval. “Families are really feeling hopeful for the first time in a long time,” she said.

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