Dwindling Prader-Willi Syndrome Drug Development Landscape And Hopeful Therapies

(RTTNews) - There are some diseases/disorders which lack a cure and Prader-Willi Syndrome is one of them.

Prader-Willi Syndrome, or PWS, is a rare genetic condition that affects one in 12,000 to 15,000 people in the U.S. This complex genetic neurobehavioral/metabolic disorder is caused due to the loss or lack of expression of a set of genes on chromosome 15. One of the main features of Prader-Willi Syndrome is hyperphagia or unregulated appetite.

Besides hyperphagia, the additional characteristics of PWS include behavioral problems, cognitive disabilities, low muscle tone, short stature (when not treated with growth hormone), the accumulation of excess body fat, developmental delays, and incomplete sexual development.

Although there are FDA approved therapies for the treatment of growth failure in children with PWS, say, Pfizer's (PFE) recombinant human growth hormone Genotropin (somatropin) and Sandoz/Novartis' Omnitrope, a biosimilar for Genotropin, there is no approved therapy yet to treat hyperphagia or excessive eating, the cardinal symptom of PWS.

The development of PWS drugs, particularly the ones that effectively modify hyperphagia in PWS patients has been facing many challenges and there has been a string of failures.

The latest to disappoint is Soleno Therapeutics Inc.'s (SLNO) Diazoxide Choline Controlled-Release tablet. In a phase III study, dubbed DESTINY PWS, the results of which were reported yesterday, DCCR did not meet its primary endpoint of change from baseline in hyperphagia.

Some of the recent headstones in the graveyard of PWS drugs are:

1. Millendo Therapeutics Inc.'s (MLND) Livoletide

In April of this year, Livoletide failed to achieve statistically significant improvement in the primary endpoint of change in hyperphagia and food-related behaviors relative to placebo in its pivotal phase IIb study, dubbed ZEPHYR. The Company has since discontinued its PWS program.

2. Zafgen Inc.'s (ZFGN) ZGN-1258 and Beloranib

The development of ZGN-1258 for PWS was discontinued last March, following concerns about the compound's safety profile in rodent toxicology studies. In July 2016, the Company had suspended the development of Beloranib, another potential treatment for Prader-Willi Syndrome, which was under phase III trial then, following two patient deaths.

Now let's take a look at some of the investigational drugs that are being explored to modify hyperphagia and food-related behaviors in PWS patients. (Please note this list is not exhaustive).

1. LV-101 (intranasal carbetocin) for the treatment of hyperphagia and behavior associated with Prader-Willi syndrome. This compound, developed by privately-held Levo Therapeutics Inc., is under a phase III study in subjects with Prader-Willi syndrome, dubbed CARE-PWS. Levo licensed the rights to LV-101 from Switzerland-based Ferring Pharmaceuticals.

2. Intranasal Oxytocin for the treatment of hyperphagia in PWS. Montefiore Medical Center is conducting a phase II study of intranasal Oxytocin.

3. Cannabidivarin (CBDV), which is being evaluated for its impact on irritability, restricted/repetitive behaviors, hyperphagia in PWS subjects. This non-psychoactive compound of GW Pharmaceuticals plc (GWPH) is under a phase II trial.

4. CSTI-500 for the treatment of hyperphagia in PWS is a phase II-ready compound. The exclusive global rights to CSTI-500, which was discovered and developed by Bristol-Myers Squibb and AMRI, are held by privately-held ConSynance Therapeutics Inc.

5. HM04 for the treatment of hyperphagia in PWS is in pre-clinical development. This compound, being developed by privately owned Helsinn Group, is a ghrelin receptor antagonist, which is designed to work by blocking ghrelin, the hormone that stimulates appetite.

6. GDD3898 that targets the metabolic conditions associated with PWS. Developed by privately-held Lipidio Pharmaceuticals Inc., GDD3898 is under phase II development.

7. NS200 that is designed to suppress not only food intake but also mood disorders in PWS. Developed by Korean biotech firm Neuracle Science, NS200 is in preclinical development.

8. OPN-300, being developed by OptiNose Inc. (OPTN), for the treatment of PWS, under pre-clinical development (Source: Company website).

9. RM-853, for the treatment of PWS, under pre-clinical development. This compound, being developed by Rhythm Pharmaceuticals (RYTM), is designed to block GOAT, the key enzyme involved in the production of the active form of ghrelin, with the expected effect of lowering active ghrelin levels. Ghrelin is the hormone that stimulates appetite.

10. Tesomet for the treatment of hyperphagia in PWS. Developed by Sweden-based Saniona AB, Tesomet is all set to advance into a phase IIb clinical trial in the second half of 2020.

Closing Thoughts

Although DCCR tablet, one of the PWS drug hopefuls, did not meet its primary endpoint of change from baseline in hyperphagia, Soleno has not given up. Rather, the Company is optimistic about DCCR, given the meaningful improvements in hyperphagia in severe patients, as well as various other positive impacts in behaviors and body composition in its phase III DESTINY PWS study.

Soleno plans to meet with regulatory authorities and determine the next steps.

But that said, the dwindling PWS drug development landscape begs the question "Will a drug that can effectively control appetite in PWS patients ever reach the pharmacy shelves?"