PWS Therapeutics in Development

Many drugs, devices, and other new PWS therapies are currently in development. The development phases range from very early discovery and preclinical studies to active clinical trials (Phase 1, 2, 3) or FDA-approved drugs or devices that are being studied for their safety and efficacy in PWS. The information below provides an overview of the therapeutics in development for PWS. More details of active PWS clinical trials can be found in our clinical trial directory.

Projects denoted with * have been funded through FPWR. We thank our many donors and fundraisers for your contributions to these research programs. You can get involved with FPWR and help fund the development of research tools and therapeutics – click here to learn how!

Approach	How It Works	Development Phase	Investigators / Company *= FPWR funded	Advantages	Potential Limitations
Genetic Therapies – These therapies seek to activate the PWS region genes on the silent maternal chromosome 15 OR provide critical missing genes OR provide a substitute function for PWS genes. These are early stage projects – optimizing approaches and examining feasibility / efficacy in cell and animal models of PWS. Learn more about genetic therapy for PWS >>
Gene activation by small molecules	Drugs targeting enzymes that establish / maintain epigenetic marks, activating the PWS genes on the maternal chromosome 15	Discovery / Preclinical	* Dr. Jiang	Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms. Would be applicable to all subtypes of PWS (del, UPD, imprinting)	Could activate other genes within or outside the PWS region; those consequences are not yet known There may be critical “windows" in which therapy would be effective
CRISPR-based activation	Delivery of a specialized gene/protein to specifically target and activate the PWS region on the normally silent maternal chromosome 15	Discovery	* Dr. Nicholls * Dr. Lalande * Dr. Iglesias	Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms Applicable to all subtypes. Specificity may be better. Potential for 1x therapy	Gene delivery likely to be challenging. Gene therapy is new, so FDA approval path may be difficult. Potential for ‘off target’ effects.
Oligonucleotide therapy	Use of small pieces DNA or RNA to modify gene expression	Preclinical	* Dr. Chamberlain	Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms Dosage may be better titrated than other gene therapy approaches Delivery may be more readily accomplished	Need for repeat therapy Oligonucleotide must be brain penetrant and will probably need to target a large number of cells – this will be challenging
AAV-Based Gene Activation	Delivery of specialized molecules to activate PWS genes	Discovery	Taysha Gene Therapies	Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms Applicable to all subtypes.	Gene delivery and targeting likely to be challenging.
Epigenome Editing	designer epigenome modifiers	Discovery	* Dr. Mussolino	Addresses the underlying cause of PWS, has the potential to profoundly impact symptoms. Applicable to all subtypes.	Development and delivery of epigenetic modifiers is at early stage; targeting and delivery will be challenging
Hyperphagia / Obesity Drugs – These drugs are being evaluated for their ability to curb appetite and/or induce weight loss in people with PWS.
Carbetocin (oxytocin analog)	Binds to oxytocin receptors, regulates trust, emotions, appetite	Phase 3 completed	Levo Therapeutics	Potential to address an underlying deficiency in PWS, Oxytocin analog may be more specific to oxytocin receptors, potentially less side effects than oxytocin	Not yet FDA approved, may act differently than oxytocin, Long term safety and efficacy in PWS population not yet known
Diazoxide Controlled Release (DCCR)	May affect leptin pathways	Phase 3 completed	* Essentialis, now Soleno Therapeutics	New formulation of FDA approved drug Well defined safety profile – has been used for decades in infants and children with hyperinsulinemia	Long term safety and efficacy in PWS population not yet know
Setmelanotide (RM-493)	Bypasses proposed POMC neuron defect	Phase 2 completed. Trial did not meet standards for efficacy.	Rhythm	Possibility of targeting underlying defect in hunger circuits Drug may also induce oxytocin release in the brain	Efficacy in PWS population not yet clear. Long term safety not yet known
Tesomet	A combination of tesofensine and metoprolol to reduce appetite and induce weight loss	Phase 2a completed, Phase 2b underway	Saniona	Proposed to act by reducing appetite, decreasing food craving and increasing fat utilization	Not yet FDA approved Long term safety not yet known
Cannabidivarin - CBDV	Works through endocannabinoid system	Phase 2 enrolling	* Dr. Hollander	May address both appetite and behavior	Not yet FDA approved Long term safety not yet known
Aardvark 101	Gut peptide stimulator	Phase 2 enrolling	* Aardvark	Potential to reduce appetite and obesity. Gut restricted.	Not yet FDA approved. Long term safety not yet known.
CBD	Hyperphagia and behaviors	Phase 2 enrolling	Radius Therapeutics	Defined formulation of CBD. Potential to address both hyperphagia and anxiety	Not yet FDA approved. Long term safety not yet known.
Peripheral Endocannabinoid (CB1R blocker)	Decrease activity of endocannabinoid system to decrease appetite	Phase 2 pending	* Inversago	CB1R induced weight loss in a small PWS study but had side effects; ‘peripheral’ version is expected to have decreased side effects	Not yet known if targeting this system peripherally will induce weight loss in PWS
Triple reuptake inhibitor (CSTI500)	Hyperphagia	Phase 2 pending	Consynance	Expected to reduce appetite	Not yet FDA approved. Long term safety not yet known.
GDD3898	Reduce excess body fat	Preclinical	Lipidio	Topical compound to reduce excess body fat	May not address hunger
GLP Receptor Agonists (exenatide, liraglutide, etc)	Suppresses appetite	FDA approved, pilot studies in PWS	Various	FDA approved May improve glucose metabolism, increase satiety	May slow gut motility, which can be problematic in PWS, small studies do not show significant weight loss
Behavior and Appetite – These drugs may cause weight loss and favorably impact behavior / social interaction.
Oxytocin	Binds to oxytocin receptors, regulates trust, emotions, appetite	Phase 1 ( Miller) AND Phase 2 (Tauber, Einfeld, Hollander, Hokken-Koelega)	Dr. Miller Dr. Tauber – infant * Dr. Tauber – adult * Dr. Einfeld *Dr. Hollander	Potential to address an underlying deficiency in PWS, may address behavior and appetite, FDA approved for other purposes	Complex biology, likely to be complex effects There may be specific therapeutic windows depending on age/stage Studies in other disorders (autism) have been mixed thus far
Mental Health
Mindfulness, Cognitive therapies	Adaptation of effective behavioral techniques to PWS population	Pilot studies	Various (see mental health workshop)	Safe approach to improve overall well-being	Impact may be restricted to a subset of symptoms and/or individuals
Miscellaneous
Pitolisant	Excessive daytime sleepiness	Phase 2 underway	Harmony Biosciences	Approved for Narcolepsy in the US and the EU. Potential to also impact behavior and cognition.	Long-term safety not yet known.
Oleoyl Serine	osteoperosis	Preclinical	Beryl	Addresses an important clinical issue (bone health) that is not fully addressed with current medications	Efficacy and long-term safety not yet known
Procedures / Devices – these devices may improve appetite and behavior in PWS
Transcranial Direct Current Stimulation	Treatment used for depression and other neurological disorders that could be applicable for PWS.	Pilot	* Dr. Butler	Used for some disorders (eg, headache). Noninvasive, generally thought to be safe	Does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals
Vagus Nerve Stimulation	Vagus nerve may not communication effectively with brain in PWS	Pilot complete - see results	* Dr. Holland	Approved for some mental health problems and epilepsy. New devices are noninvasive Degree of stimulation can be tightly regulated by device	Initial studies encouraging, but have been small to date.

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