Kumar Budur, MD, MS
Prader-Willi syndrome (PWS) is a genetic multisystem dysfunction characterised throughout infancy by lethargy, diminished muscle tone, a weak suck and feeding difficulties with poor weight achieve and development, and different hormone deficiency. People with this syndrome could expertise extreme urge for food, resulting in an elevated danger for extreme weight problems, and thus, elevating problems with cardiac insufficiency, sleep apnea, diabetes, respiratory issues, and different critical circumstances that may trigger life-threatening issues.
People with PWS have been proven to expertise extreme daytime sleepiness (EDS) and emotional/behavioral disturbances. Apart from human development hormone, there aren’t any FDA-approved merchandise to deal with the syndrome.
On the 2023 SLEEP Annual Assembly, held June 3-7, in Indianapolis, Indiana, Concord Biosciences introduced late-breaking information from a part 2 proof-of-concept research assessing the remedy affect of pitolisant (Wakix; Concord Biosciences), an FDA-approved remedy for EDS and cataplexy, in grownup sufferers with narcolepsy. The trial featured sufferers with genetically confirmed PWS, aged 6-65 years, who have been randomly assigned 1:1:1 to low dose pitolisant, excessive dose pitolisant, or matching placebo primarily based on age.
On the conclusion of the 11-week trial, pitolisant-treated sufferers demonstrated improved EDS, as measured by the mother or father/caregiver model of the Epworth Sleepiness Scale for Kids and Adolescents (ESS-CHAD). Notably, a comparatively greater response fee was discovered within the excessive dose pitolisant group in contrast with the decrease dose group. As a part of a brand new iteration of NeuroVoices, Kumar Budur, MD, MS, Chief Medical Officer of Concord Biosciences, sat down to debate the outcomes, and the importance they maintain.
NeurologyLive®: Are you able to present an outline of the trial and the way it was performed?
Kumar Budur, MD: At a really excessive degree, it is a part 2 proof-of-concept research. It is a double blind, randomized placebo-controlled research wherein we evaluated the protection and efficacy of pitilosant in contrast with placebo within the remedy of extreme daytime sleepiness in sufferers with Prader-Willi syndrome. The topline information is absolutely attractive: pitolisant confirmed a clinically significant enchancment in decreasing the results of the daytime sleepiness from baseline to finish of remedy. The first endpoint was change in ESS, which measures the severity of daytime sleepiness. We noticed that pitolisant lowered the sleepiness wherever from 3.7 to five.5 factors from baseline to the top of remedy. To place this in perspective, a change of two factors is taken into account as clinically significant. And what’s vital is, we noticed this alteration throughout all of the age teams, and in addition throughout each a low dose group and excessive dose group. The protection profile of pitolisant was in step with the recognized security profile proven in sufferers with narcolepsy. We didn’t see any new hostile occasions, and we didn’t see any critical kind of occasions within the double-blind portion of the research associated to pitolisant.
Had been there any findings that stood out greater than others?
This research was not powered for statistical significance, as a result of it was a proof-of-concept research. Going into the research, the goals have been actually three-fold. First, is there a sign of efficacy in sufferers with PWS. The second, if there’s a sign, is there a dose response? And the third checked out security profile, as a result of that is essential. The reply to all these three questions was sure, sure, and sure. I wish to deal with security as a result of the sufferers with PWS even have a number of medical comorbidities. As talked about earlier than, the protection profile in these sufferers was in step with the recognized security profile of pitolisant in different circumstances. This profitable completion of this research and the deliberate subsequent steps exhibits that we’re dedicated to increase pitolisant’s profile past narcolepsy in indications the place it is smart.
How is Prader-Willi syndrome usually managed? Why is it so complicated?
Prader Willi syndrome is a uncommon genetic dysfunction. There are about 15,000 to twenty,000 sufferers in US. It has a really heterogeneous set of signs, characterised by hyperphagia, which is consuming extreme quantity of meals and meals searching for behaviors, extreme daytime sleepiness, behavioral issues, cognitive dysfunction, muscle hypotonia, amongst different issues. Administration of Prader Willi syndrome could be very complicated. Mother and father must collaborate with a number of specialists in endocrinology, neurology, and psychiatry to handle this complete array of signs.
What’s vital is there aren’t any authorized remedies for any of those signs, apart from development hormone dietary supplements. Underneath this context, now we have proven a sign in one of many core signs of PWS. We, together with the sufferers and the advocacy group, are very enthusiastic about it, and we’re trying ahead to provoke part 3 registration research within the second half of this 12 months. At present, we’re working with the FDA on the research design and different issues.Since this drug entered the market, how has our information on it expanded?
Pitolisant is a selective histamine 3 (H₃) receptor antagonist/inverse agonist, and we’re harnessing a mechanism-based strategy to the event of pitolisant. Our information of pitolisant continues to develop past narcolepsy as evidenced via our research in idiopathic hypersomnia (IH) and Prader-Willi syndrome and different actions associated to pitolisant.
We’re enthusiastic about our Section 3 registration research in IH. We accomplished enrollment 9 months forward of schedule and this represents the passion of the healthcare suppliers and sufferers alike for a novel mechanism of motion like pitolisant in IH. We’re anticipating the topline information within the 4Q of this 12 months.
We already talked about PWS. As well as, we accomplished the pitolisant lactation research (pharmacokinetics of pitolisant in breast milk and serum of wholesome lactating girls) and these information are additionally introduced on the SLEEP assembly. These information will assist girls with narcolepsy and their physicians to have a significant dialog concerning the remedy choices throughout breast feeding interval. We even have an ongoing research, a potential being pregnant registry with the target of measuring the outcomes of publicity to WAKIX throughout being pregnant and affect on maternal, fetal, and toddler outcomes.
Transcript edited for readability. Click on right here for extra protection of SLEEP 2023.
Observe: Pitolisant is marketed as WAKIX within the US and is FDA authorized to deal with EDS or cataplexy in grownup sufferers with narcolepsy. Pitolisant just isn’t authorized to be used in sufferers with PWS and is presently being evaluated as an investigational agent on this affected person inhabitants.