Hyperphagia / Obesity Drugs for PWS (updated March 2022)
Weight loss drugs that are effective in the typical population have been found to have no effect in PWS. Developing a drug to treat the complexities of hyperphagia in PWS has been a challenge for pharmaceutical companies, but there are several drugs in clinical trial stages.
Exenatide and Liraglutide are both GLP Receptor Agonists, with the latter in phase 3 trial. GLP-1 is a gut derived hormone which reduces food intake and causes weight loss due to slowed gastric emptying and through direct central effects. There are some concerns around possibly slowing gut motility further, which can cause problems in PWS. Exenatide had some success in reducing appetite but without significant weight loss. Liraglutide (by NovoNordisk) is already FDA approved for improving glycemic control and reducing health risks associated with diabetes type 2, and whilst not funded in NZ, it is indicated to assist with weight management in obese adults by Medsafe NZ. Liraglutide is administered by daily subcutaneous injection and has recently been trialled in paediatric patients with PWS and obesity (but not diabetes) at various sites worldwide, including the Liggins Institute in Auckland. New Zealand’s trial investigator, Prof Paul Hofman, says that he has observed significant weight loss amongst patients he recruited. A results summary is yet to be published, but the trial is completed and result tables can be viewed.
DCCR (Diazoxide Choline Controlled Release) is thought to affect leptin pathways and improve GABA signalling. (Leptin is a hormone that helps to regulate energy balance by inhibiting hunger and its pathway is thought to be disrupted in PWS.) DCCR activates hypothalamic POMC neurons which signal to MC4 receptors to inhibit food intake and increase energy expenditure. It also inhibits NPY neurons, a regulatory peptide (associated with the GABA neurotransmitter), which have a role in stimulating food intake. The phase 2 trial results in PWS patients, presented here and here, observed a 35% improvement in hyperphagia with 4% reduction of body fat and about 5% increase in lean body mass, on average. There were also significant improvements in behaviours. In May 2018, Soleno Therapeutics (previously Essentialis) announced it is advancing DCCR into a phase 3 clinical development program (DESTINY PWS), receiving FDA Fast Track designation in July 2018. This phase 3 trial enrolled 127 patients and phase 3 top-line results were announced in June 2020. Unfortunately, the results did not meet statistical significance for primary endpoint of change from baseline in hyperphagia, but they did show significant improvements in a subgroup with severe hyperphagia. Significant positive changes were also seen in 2 out of 3 key secondary endpoints: improvement in Clinical Global Impression of Improvement score, and reduction of body fat mass measured by DXA scan. Unfortunately, the DESTINY PWS results were affected by the disruption caused by Covid-19 during 2020. To this date, participants of DESTINY PWS continue to receive DCCR in an extension study (C602), whilst Soleno continued to analyse old and new data and submit updated findings to the FDA in the hope of receiving an NDA (New Drug Application). The FDA had indicated that it is likely another trial would be needed, but in January 2022, following review of new data, the FDA suggested they were receptive to a study design involving participants currently enrolled in C602 to generate the additional control data necessary to support an NDA. Click to view further Soleno presentations.
Tesomet is a combination of tesofensine (a triple monoamine reuptake inhibitor) and metoprolol (a beta-1 selective blocker). Tesofensine blocks the reabsorption of 3 monoamine neurotransmitters: serotonin, noradrenaline and dopamine, increasing the levels of these neurotransmitters in the brain, which in turn reduces food cravings and appetite, and increases metabolic fat burn. It is being developed by Saniona who are recruiting for their phase 2b study taking place in multiple countries, including New Zealand. Phase 2a Step 1 demonstrated clinically meaningful weight loss (6.76%) and a statistically significant reduction in hyperphagia (43%) in adults with PWS at 0.5mg/day, but it was also discovered that plasma levels in PWS patients were higher compared to levels in non-PWS obese subjects, possibly causing the unwanted side effects observed. Therefore, a lower dose was recommended for adolescent PWS patients. Phase 2a Step 2 tested Tesomet in adolescents at lower dose (0.125mg) and was initially completed in January 2019, but a press release explained that a 24 week extension study was needed to obtain longer-term treatment data at a slightly higher dose for efficacy (0.25mg). Tesomet appeared to be well tolerated at lower doses. The phase 2b study aims to recruit 120 participants, aged 13-65 years (initially 18yrs+), who will randomly be given one of 3 different doses or placebo for the first 16 weeks. This initial period will be followed by a 36-week open-label extension where all participants will be treated with Tesomet at the highest tolerated dose as determined in the initial 16 weeks. Phase 2b is expected to be completed in December 2023. UPDATE March 2022: Unfortunately, Saniona have announced that they will be voluntarily pausing the Phase 2b clinical trials of Tesomet due to funding limitations. This is not related to the safety or efficacy of Tesomet. Saniona intend to continue evaluating strategic financing and business development options that could allow Tesomet to advance.
CSTI-500 is a triple monoamine reuptake inhibitor (similar to Tesomet), blocking the reuptake of serotonin, dopamine and norepinephrine. In phase 1 clinical trials it was found to be generally safe, well-tolerated and demonstrated weight loss effects that predict efficacy in patients. It is hoped that CSTI-500 will reduce symptoms of hyperphagia, obesity and behavioural issues such as social isolation, obsessive-compulsive disorder, cognitive disabilities and excessive daytime sleepiness. CSTI-500 is being developed by ConSynance Therapeutics and is phase II-ready.
Endocannabidoids – CB1R Blockers. The endocannabinoid system is a complex cell-signaling system involved in regulating processes such as appetite, metabolism, sleep, mood and pain. Endocannabinoids are molecules made by the body, similar to cannabinoids found in cannabis plants, which mainly bind to the CB1 or CB2 receptors. Endocannabidoids are thought to be involved with hyperphagia and the altered metabolism in PWS, but early trials in PWS with a CB1 Receptor antagonist, Rimonabant, were terminated due to psychiatric adverse events, although weight loss and reductions in body fat mass were observed. Investigators developed a new compound (JD5037) which would act peripherally (outside the brain) to block CB1 without causing behavioural effects. They tested JD5037 in Magel2-null mice and also measured circulating plasma levels of endocannabidoids in individuals with PWS. They found that eCB levels were significantly elevated in PWS and appeared to be correlated with the altered metabolic profile. JD5037 was successful in reducing body weight, hyperphagia and adiposity in PWS mouse models without affecting behaviour. This study demonstrated that treatment with a CB1R antagonist may be an effective strategy for the management of severe obesity in PWS. Inversago Pharma has developed a CB1 inverse agonist / antagonist compound, INV-202 for metabolic disorders, which also acts peripherally with CB1 receptors. A phase I study of INV-101 evaluated safety and tolerability, with encouraging INV-202 phase 1 results being announced in January 2022.
Cannabidoil (CBD oral solution) – RAD011
Unlike THC, Cannabidoil (CBD) is a non-psychoactive cannabidoid of the cannabis plant. It acts on cannabidoid receptors and it has the potential to address both hyperphagia and anxiety in PWS. A synthetic cannabidoil oral solution was developed for PWS by INSYS Therapeutics, but their phase 2 study examining its effect on hyperphagia-related behaviour was terminated early due to bankruptcy. However, the data was directionally supportive of reducing hyperphagia and there was a positive trend in reducing weight. The CBD assets of INSYS were acquired by Benuvia Therapeutics, and Radius Health acquired global development and commercialisation rights to Benuvia’s synthetic CBD oral solution, RAD011, in December 2020. RAD011 has demonstrated favourable safety and tolerability data, having been assessed in over 150 patients, and has FDA fast track designation. Radius are soon to start recruiting for their phase 2/3 trial, SCOUT-015, which aims to recruit 220 participants with PWS aged 8-65 years. The trial is expected to be completed in August 2024.
CBD oil is available to purchase in some countries, but is only available by prescription in NZ, at cost to patient.
Cannabidivarin (CBDV) is another non-psychoactive cannabinoid produced by the cannabis plant. It is very similar to cannabidoil, but appears to exert its effect on different membrane receptors. It is hoped that CBDV will address both hyperphagia and behaviour. Its efficacy and safety is being assessed for both ASD and PWS by Eric Hollander at Montefiore Medical Center. A phase 2 trial is currently recruiting participants with PWS aged 5 – 30 years.
ARD-101 is a gut-restricted, bitter taste receptor agonist that activates the secretion of gut peptide hormones, such as GLP-1 and GLP-2, which can lead to responses including appetite suppression, reductions in glucose and insulin, the lowering of LDL cholesterol, and an anti-inflammatory effect. It’s gut restriction enhances its safety profile. It is being developed by Aardvark Therapeutics and has shown good promise in preclinical studies (animal model). Aardvark CEO says ARD-101 “is differentiated from existing standard-of-care drugs in both its anticipated safety profile as well as its potential broad spectrum of effects….that impacts metabolic and inflammatory mediators.” A phase 2 study in a small group of patients with PWS aged 17 years+ is currently underway.
Oxytocin hormone treatment and Carbetocin, an oxytocin-like treatment, are also having positive effects on hyperphagia – read more by clicking the Oxytocin tab above.
A natural treatment being trialled for dietary management in PWS is caralluma fimbriata extract (CFE) which comes from an edible cactus plant and has been used for centuries in India as an appetite suppressant. Joanne Griggs found CFE to be effective in reducing hunger for her own child so conducted a study at Victoria University in Australia (involving some families in New Zealand) which saw an accumulative easing in appetite behaviour for one-third of the participants. Jo Griggs is happy to be asked questions about using CFE and can be contacted via email at email@example.com or firstname.lastname@example.org
Treatments No Longer Being Developed for PWS
RM-493 / Setmelanotide is an MC4R agonist targeting the MC4 receptors which reside in the hypothalamus and promote satiety. (A defect in the MAGEL2 gene in PWS impairs POMC neurons which are key components of the MC4 pathway.) It was in trial for other genetic obesity disorders and has now been FDA approved for patients 6 years+ with obesity caused by POMC, PCSK1 and LEPR deficiency. It has also been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4 receptor pathway. The trial involving patients with POMC-Deficiency, a very rare genetic form of obesity where patients also suffer from dysregulation of the hypothalamus resulting in intense hunger and weight issues, achieved positive results with regards to weight and hunger, as well as a marked improvement in insulin resistance. Unfortunately, a phase 2 study involving PWS patients produced modest effects on reducing hyperphagia, but had no effect on weight, although there was some evidence of weight loss in the subset of patients treated at the highest dose level for the longest duration. Whilst Rhythm Pharmaceuticals focused setmelanotide development on 6 other obesity disorders, they were also assessing opportunities to further evaluate it in PWS, which may be in parallel or in conjunction with their acquisition of RM-853, a ghrelin o-acyltransferase (GOAT) inhibitor which was in preclinical development for PWS. To date, there has been no further public indication that studies involving PWS patients will take place, but preclinical development could be ongoing.
Beloranib and ZGN-1258 – Beloranib is a MetAP2 inhibitor and these have other uses, but when indicated for obesity, they work to re-establish balance to the ways the body metabolises fat. Beloranib was one of the drugs showing the most encouraging results so far for hyperphagia and weight loss, but was halted from further development after 2 trial participants sadly and unexpectedly died from blood clots in the lungs during its phase 3 trial. Zafgen, the company who were developing Beloranib, had since worked to develop other MetAP2 inhibitors which should not cause the same thrombosis risk, and in January 2018, Zafgen announced the selection of ZGN-1258 as their new development candidate for PWS. Unfortunately, despite promising initial results demonstrating positive effects on appetite, weight and behaviour in various mouse models of hyperphagia, obesity and PWS-like characteristics in preclinical development phase, ZGN-1258 was found to have toxic effects on muscle tissue and its development programme was suspended. This was the first time an adverse event of this kind had been seen with a MetAP2 inhibitor, so researchers believed the effect to be specific to ZGN-1258. Zafgen were committed to evaluating ZGN-1258 further and exploring other potential options within their portfolio of MetAP2 inhibitors, but the successive failures of Beloranib and ZGN-1258 ultimately led to a necessary merger with Chondrial Therapeutics to form Larimar Therapeutics. We are unsure if Larimar have plans to continue a MetAP2 inhibitor programme, and they have another drug focus at present. Principal Investigator, Shawn McCandless states, “Alternative MetAP2 inhibitors without an effect on thrombotic parameters, as well as the proteins whose actions are altered by MetAP2 inhibition offer promising targets for treating the hyperphagia and obesity in PWS.”
AZP-531 / Livoletide by Alize Pharma, is an unacylated ghrelin analog which aimed to target and inhibit the metabolic effects of abnormally high acylated ghrelin (‘hunger hormone’) levels seen in PWS. It was described as having encouraging phase 2 trial results for reducing hyperphagia symptoms and was developed by Millendo Therapeutics in a phase 2b/3 trial (ZEPHYR) which recruited 8-65 yr olds at various international locations. Despite promising initial expectations (here and here), Millendo decided to discontinue its Livoletide programme in April 2020 after Livoletide failed to significantly reduce hunger and improve food-related behaviours. It is thought that the abnormally high levels of ghrelin in PWS may just be a marker of hyperphagia rather than what drives it.
GLWL-01 by GLWL Research Inc. also aimed to target elevated acylated ghrelin levels by decreasing AG levels circulating in plasma. It had been successfully tested in patients with type 2 diabetes and was found to reduce AG levels at doses of 150mg+ twice a day. Significant decreases had been observed with higher doses and in phase 2, GLWL-01 was tested in PWS at a dose of 450mg twice a day in adolescents and adults 16yrs+ at multiple sites in the USA and Canada. The phase 2 trial was completed with results tabled in 2020 – no news has been posted publically, but development is believed to be halted due to lack of significant effect.