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Prader-Willi syndrome is a rare genetic condition that leads to physical and behavioral problems. A common feature of the condition is feeling hungry all the time, and people with Prader-Willi have an uncontrollable appetite. A new medicine was approved by regulators to address this uncontrollable appetite, also known as hyperphagia, earlier this year. Meanwhile, several treatments are being trialed in the clinic, all of which work differently and address different symptoms of the syndrome.
This year’s approval was for California-based Soleno Therapeutics’ VYKAT XR, which is made of diazoxide choline, a molecule that heightens satiety in people. It is now the first and only approved drug by the U.S. Food and Drug Administration (FDA) to treat hyperphagia, a big win for the Prader-Willi syndrome community.
Caused by an error in chromosome 15, Prader-Willi syndrome manifests through symptoms such as poor muscle tone, developmental delays, behavioral issues like hyperactivity and irritability, and insatiable appetite, which can lead to obesity if not managed.
Categorized as a rare disease, it affects one in 10,000 to 30,000 people worldwide, making it hard to treat due to a lower number of patients who can enroll for clinical trials. Nevertheless, there are many clinical trials assessing various medicines to address different symptoms of the condition, in particular hyperphagia. Let us take a look at five therapies climbing up the clinical ladder and poised for approval in the coming years.
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Aardvark Therapeutics’ ARD-101: small molecule nears finish line
As intense hunger is one of the major symptoms of Prader-Willi syndrome, California-based Aardvark Therapeutics’ ARD-101 is designed to treat hyperphagia-related behaviour in patients with the condition.
The small molecule ARD-101 is an oral candidate that targets the gut, specifically bitter-taste receptors present in the intestine. This stimulates the release of a hormone called cholecystokinin, which is responsible for promoting the release of bile to enable the digestion of fats and proteins. The hormone also signals feelings of fullness to the brain, curbing excessive appetite. Simultaneously, the drug also boosts the release of another hormone called glucagon-like peptide-1 (GLP-1), which helps double down on regulating satiety and food intake.
While it stimulates the production of GLP-1, ARD-101 is not a GLP-1 agonist like Ozempic or Wegovy, as its mechanism is more local and targeted and directly addresses hunger.
The drug promises much to the Prader-Willi syndrome community as it reaped encouraging results in phase 2 studies reported two years ago. The medicine showed strong efficacy signals such as reduced hunger as well as lower body fat composition in people with Prader-Willi syndrome. It was found that by aiding the release of both cholecystokinin and GLP-1, the effects were more pronounced. Moreover, in people who are obese, the drug managed weight better when compared to the placebo. It also showed a positive impact on hunger scores in people with Prader-Willi syndrome who had undergone weight-loss surgery.
The biotech presented these results at the 2025 United in Hope Conference for Prader-Willi syndrome in the U.S. in June this year.
Currently in phase 3 trials, Aardvark is set to publish topline results next year, following which, plans for regulatory submission and possible approval will be made. The drug is also being tested in the clinic for another metabolic condition called hypothalamic obesity, which is characterized by uncontrollable weight gain caused by damage to the hypothalamus, the region in the brain that regulates basic bodily functions like appetite, thirst, and sleep.
Rhythm Pharmaceuticals’ setmelanotide for Prader-Willi syndrome: can the pill beat the injectable?
Massachusetts-based Rhythm Pharmaceuticals’ goal is to treat conditions that lead to severe obesity and hyperphagia. As Prader-Willi syndrome is among these conditions, the American biotech is testing its candidate setmelanotide in people who are obese because of the genetic syndrome.
Rhythm created its peptide pill based on the understanding that not all obesity is the same, and that there are different targets that work for patients with various conditions. Unlike Aardvark’s ARD-101, which targets GLP-1 and cholecystokinin, setmelanotide targets a receptor called melanocortin-4 (MC4R). This particular receptor is known to regulate weight, and when it is impaired, it fails to do so. Setmelanotide is designed to turn on MC4R in the brain to restore the body’s natural regulation of hunger and energy metabolism.
For a phase 2 Prader-Willi syndrome study, Rhythm is recruiting patients aged between six and 65 at present. The first participant was dosed in April and early study results are expected later this year. It is evaluating the therapy over a period of around six months, during which the dosages will be gradually increased for patients.
This is following a shorter phase 2 trial that did well in the high dose groups. Setmelanotide was taken daily for two months, and it was found that those people on the higher doses experienced lower hyperphagia as well as had a reduction in body weight. However, those in the lower dose cohorts did not see these effects.
The injectable version of has already got the go-ahead from the FDA to treat Bardet-Biedl syndrome, a rare genetic disorder that affects many body systems, causing symptoms including obesity. Setmelanotide’s priority review was also accepted by the FDA for hypothalamic obesity, and now, the company awaits approval. This harbors hope for the Prader-Willi syndrome community as well.
Palobiofarma’s PBF-999 takes on brain signaling
Most small molecules essentially do similar things like cell signaling, enzyme inhibition, and altering the activities of target proteins and other molecules. Barcelona-based Palobiofarma’s Prader-Willi syndrome candidate PBF-999 is no different in that it inhibits the enzyme phosphodiesterase 10 (PDE10), which regulates the levels of cyclic nucleotides – a crucial signaling molecule in the brain.
The drug, which is the most advanced in Palobiofarma’s pipeline of cancer and inflammatory disease candidates, has had an effect on reducing appetite in people with Prader-Willi syndrome, which is why phase 2 trials to test its efficacy and safety are underway. Preclinical studies revealed that the drug had a potent and selective inhibition of PDE10 to help suppress appetite.
It was granted Orphan Drug designation by the European Medicines Agency (EMA) and the FDA last year as well as Rare Pediatric Disease designation by the FDA in 2023. Following this, it pocketed €7 million ($8.1 million) in a funding round to pursue the clinical development of PBF-999.
Although there is a long way ahead for PBF-999 to get in the good books of regulators, if approved, it would be the first of its kind to treat patients with Prader-Willi syndrome.
Tonix Pharmaceuticals’ TNX-2900 banks on the ‘love hormone’ to address Prader-Willi
Popularly known as the ‘love hormone’ as it plays a role in social bonding and childbirth, oxytocin has been found to be deficient in people with Prader-Willi syndrome. So, oxytocin is being investigated as a potential treatment for patients, and Tonix Pharmaceuticals’ TNX-2900 is on the top of the list.
The New Jersey-based biotech’s candidate is made up of oxytocin and formulated with magnesium to enhance oxytocin receptor binding and signaling. It is believed to enhance the potency of oxytocin as well as increase specificity for oxytocin receptors relative to vasopressin receptors – vasopressin being a hormone that regulates blood pressure and water balance in the body – potentially reducing unwanted side effects from activating vasopressin receptors.
The FDA approved the investigational new drug (IND) application of TNX-2900 two years ago, when it elevated the potency of oxytocin in animal models of Prader-Willi syndrome.
A phase 2 trial is scheduled to begin next year to treat hyperphagia in patients with Prader-Willi syndrome. The medicine will be administered through the nose. The goal is to find out how well the drug works and what the right dose might be.
Harmony Biosciences’ pitolisant: how close is it to approval for Prader-Willi syndrome?
Pitolisant was first greenlit by the FDA to treat patients with narcolepsy in 2019 and has been sold under the brand name Wakix since. But its journey in the clinic did not end with treating excessive sleepiness only in people with narcolepsy. It is currently being studied to address excessive daytime sleepiness in Prader-Willi syndrome, which affects many people with the condition.
It is a histamine-3 receptor (H3R) antagonist, meaning that it blocks H3R receptors in the brain, which increases the activity of neurons and other neurotransmitters – chemical messengers that transmit signals from a nerve cell to a target cell – like acetylcholine, norepinephrine, and dopamine. By doing so, it encourages wakefulness and alertness. Studies have shown that in patients with Prader-Willi, these inhibitor drugs can also relieve issues like irritability and hyperactivity.
At present, patients are being recruited for a phase 3 study testing pitolisant where the drug’s efficacy in address excess daytime sleepiness in those aged six years old and older with Prader-Willi syndrome will be evaluated. Moreover, the trial will find out to what extent irritability and other behavioral problems like social withdrawal and hyperactivity can be better managed.
Trial results are hoped to piggyback off positive phase 2 study outcomes from two years ago. The drug showed greater mean improvement from baseline in the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a measure for daytime sleepiness in children aged between 12 and 18. Those on the higher dose responded better to the drug – efficacy-wise – compared to those in the low-dose cohort.
Harmony is also assessing whether the drug could treat myotonic dystrophy type 1, a type of muscular dystrophy that causes progressive muscle loss and weakness, and pitolisant is in phase 2 trials for the condition.
Treating Prader-Willi: room for more therapies
It is rare for rare diseases to have a range of therapeutic options in the making, often because it’s hard to recruit patients for these conditions for small trials and due to financial constraints. But Prader-Willi syndrome is one condition that scientists are trying to address with several drugs that work differently from one another.
However, one of the most anticipated therapeutic candidates, the peptide analog carbetocin developed by California-based Acadia Pharmaceuticals, failed a phase 3 trial last month, in a major blow to the community.
That’s why the greater number of therapies in the clinic that have different mechanisms of actions, the better.
Along with the aforementioned therapies, people are also looking forward to how well Hungarian company Gedeon Richter’s melanin-concentrating hormone (MCH) blocker RGH-706 performs. The drug is in phase 2 trials, but no results have been published yet. Similarly, there is hype around a cannabinoid found in the cannabis plant called cannabidivarin in treating irritability, repetitive behaviors, and excessive eating in people with Prader-Willi. It is being developed by several collaborators, namely, the Foundation for Prader-Willi Research, Montefiore Medical Center in the U.S. and U.K.-based GW Pharmaceuticals.
Aside from medicines, a device that stimulates the vagus nerve – the longest nerve that aids body functions during rest and digestion – VNS4PWS, is in phase 3 trials to improve disruptive behaviors and temper outbursts for people with the rare disease.
New research related to Prader-Willi syndrome
