NeuroVoices: Kumar Budur, MD, on Pitolisant’s Impact in Excessive Daytime Sleepiness, Prader-Willi Syndrome

Kumar Budur, MD, MS

Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone, a weak suck and feeding difficulties with poor weight gain and growth, and other hormone deficiency. Individuals with this syndrome may experience excessive appetite, leading to an increased risk for severe obesity, and thus, raising issues of cardiac insufficiency, sleep apnea, diabetes, respiratory problems, and other serious conditions that can cause life-threatening complications.

Individuals with PWS have been shown to experience excessive daytime sleepiness (EDS) and emotional/behavioral disturbances. Besides human growth hormone, there are no FDA-approved products to treat the syndrome.

At the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, Harmony Biosciences presented late-breaking data from a phase 2 proof-of-concept study assessing the treatment impact of pitolisant (Wakix; Harmony Biosciences), an FDA-approved therapy for EDS and cataplexy, in adult patients with narcolepsy. The trial featured patients with genetically confirmed PWS, aged 6-65 years, who were randomly assigned 1:1:1 to low dose pitolisant, high dose pitolisant, or matching placebo based on age.

At the conclusion of the 11-week trial, pitolisant-treated patients demonstrated improved EDS, as measured by the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Notably, a relatively higher response rate was found in the high dose pitolisant group compared with the lower dose group. As part of a new iteration of NeuroVoices, Kumar Budur, MD, MS, Chief Medical Officer of Harmony Biosciences, sat down to discuss the results, and the significance they hold.

NeurologyLive^®: Can you provide an overview of the trial and how it was conducted?

Kumar Budur, MD: At a very high level, this is a phase 2 proof-of-concept study. It's a double blind, randomized placebo-controlled study in which we evaluated the safety and efficacy of pitilosant compared with placebo in the treatment of excessive daytime sleepiness in patients with Prader-Willi syndrome. The topline data is really enticing: pitolisant showed a clinically meaningful improvement in reducing the effects of the daytime sleepiness from baseline to end of treatment. The primary endpoint was change in ESS, which measures the severity of daytime sleepiness. We saw that pitolisant reduced the sleepiness anywhere from 3.7 to 5.5 points from baseline to the end of treatment. To put this in perspective, a change of 2 points is considered as clinically meaningful. And what's important is, we saw this change across all the age groups, and also across both a low dose group and high dose group. The safety profile of pitolisant was consistent with the known safety profile shown in patients with narcolepsy. We did not see any new adverse events, and we did not see any serious type of events in the double-blind portion of the study related to pitolisant.

Were there any findings that stood out more than others?

This study was not powered for statistical significance, because it was a proof-of-concept study. Going into the study, the objectives were really three-fold. First, is there a signal of efficacy in patients with PWS. The second, if there is a signal, is there a dose response? And the third looked at safety profile, because that's very important. The answer to all these three questions was yes, yes, and yes. I want to focus on safety because the patients with PWS also have multiple medical comorbidities. As mentioned before, the safety profile in these patients was consistent with the known safety profile of pitolisant in other conditions. This successful completion of this study and the planned next steps shows that we are committed to extend pitolisant’s profile beyond narcolepsy in indications where it makes sense.

How is Prader-Willi syndrome typically managed? Why is it so complex?

Prader Willi syndrome is a rare genetic disorder. There are about 15,000 to 20,000 patients in US. It has a very heterogeneous set of symptoms, characterized by hyperphagia, which is eating excessive amount of food and food seeking behaviors, excessive daytime sleepiness, behavioral problems, cognitive dysfunction, muscle hypotonia, amongst other things. Management of Prader Willi syndrome is very complex. Parents have to collaborate with multiple specialists in endocrinology, neurology, and psychiatry to manage this whole array of symptoms.

What's important is there are no approved treatments for any of these symptoms, except for growth hormone supplements. Under this context, we have shown a signal in one of the core symptoms of PWS. We, along with the patients and the advocacy community, are very excited about it, and we are looking forward to initiate phase 3 registration study in the second half of this year. Currently, we're working with the FDA on the study design and other things.

Since this drug entered the market, how has our knowledge on it expanded?

Pitolisant is a selective histamine 3 (H₃) receptor antagonist/inverse agonist, and we are harnessing a mechanism-based approach to the development of pitolisant. Our knowledge of pitolisant continues to expand beyond narcolepsy as evidenced through our studies in idiopathic hypersomnia (IH) and Prader-Willi syndrome and other activities related to pitolisant.

We are excited about our Phase 3 registration study in IH. We completed enrollment 9 months ahead of schedule and this represents the enthusiasm of the healthcare providers and patients alike for a novel mechanism of action like pitolisant in IH. We are anticipating the topline data in the 4Q of this year.

We already talked about PWS. In addition, we completed the pitolisant lactation study (pharmacokinetics of pitolisant in breast milk and serum of healthy lactating women) and these data are also presented at the SLEEP meeting. These data will help women with narcolepsy and their physicians to have a meaningful conversation about the treatment options during breast feeding period. We also have an ongoing study, a prospective pregnancy registry with the objective of measuring the outcomes of exposure to WAKIX during pregnancy and impact on maternal, fetal, and infant outcomes.

Transcript edited for clarity. Click here for more coverage of SLEEP 2023.

Note: Pitolisant is marketed as WAKIX in the US and is FDA approved to treat EDS or cataplexy in adult patients with narcolepsy. Pitolisant is not approved for use in patients with PWS and is currently being evaluated as an investigational agent in this patient population.