Pitolisant Shows Benefit for IH in Phase 3 Open-Label Trial, with Bruce Corser, MD

At SLEEP 2025, the 39th annual meeting of the Associated Professional Sleep Societies, in Seattle, HCPLive spoke with Bruce Corser, MD, FAASM, from Sleep Management Institute, on his team’s poster, “Effect of Pitolisant on Symptoms of Idiopathic Hypersomnia During an Open-Label Period in a Phase 3 Clinical Trial.”1

Although pitolisant (WAKIX) is not approved for idiopathic hypersomnia (IH), only for excessive daytime sleepiness in narcolepsy, the open-label phase of the INTUNE trial suggested potential benefit in IH.2 The 8-week open-label phase included 213 patients on daily 17.8 or 35.6 mg.

In February, the US Food and Drug Administration (FDA) issued a Refusal to File letter for Harmony Biosciences’ supplemental NDA for pitolisant in IH. Still, the company plans a phase 3 registrational trial, with pivotal data expected in Q4 2025.3

Corser shared his thoughts on the significance of the open-label findings.

HCPLive: What were the most significant improvements observed during the open-label period?

Corser: Over 80% of patients [who] enrolled actually completed the open-label phase and were responders.

There was a very large 7.5 reduction from baseline in the Epworth Sleepiness Scale, which is highly significant and clinically relevant, indicating a reduction in daytime sleepiness. Furthermore, there were a lot of parameters, including the idiopathic hypersomnia severity scale and various functional outcomes, as well as measures of sleep inertia, all of which improved from baseline and were clinically meaningful and highly significant.

Pitolisant appears to be very effective in this population in improving daytime wakefulness as well as reducing daytime symptoms, including sleep inertia and brain fog during the day. This was a very interesting and relevant study for patients [who] had idiopathic hypersomnia.

HCPLive: What symptom domains show the strongest response to pitolisant?

Corser: The primary endpoint that was evaluated was the Epworth Sleepiness Scale…the 7.5 reduction from baseline of the Epworth Sleepiness Scale was clinically meaningful. Greater than 3 is considered clinically meaningful, and the change from baseline was 7.5. This indicates a significant improvement in daytime sleepiness.

The other measures that were evaluated there were clinical global impression of change, both by the clinician and the patient, as well as the Idiopathic Hypersomnia Scale.

And then there were functional outcome scales indicating how well people were able to function during the day. All of these showed clinically significant and statistically significant improvement as compared to baseline.

HCPLive: Did improvements emerge early in the open-label phase, or did they build over time?

Corser: Improvement was seen immediately, within the first week or 2 during the titration period, but the maximum benefit was seen at the end of by the end of the 8-week trial. The last two weeks of the trial were a stable dose period, and that's where the maximum benefit was seen.

This is consistent with the prior information we know about the drug, that we typically see maximum efficacy after about 8 weeks.

HCPLive: Were the improvements in symptom severity reflected in both clinician-rated and patient-reported outcome measures?

Corser: Yes, the patient-reported outcome measures were highly significant and clinically meaningful. We captured these symptoms in a variety of different scales, including idiopathic hypersomnia scale, clinician rate of improvement, as well as patient-related improvement. And then there was the FOSS, which is a functional outcome measure. All these measures showed very significant improvement in daytime functioning and reduction in sleepiness.

HCPLive: Did the trial data suggest the certain that certain subgroups of patients with IH benefited more from pitolisant than others?

Corser: Over 80% of the patients enrolled in this trial were actually responders, and we don't have a responder analysis to analyze which patients responded and which didn't, but 80% is a very significant percentage of people [who] responded.

HCPLive: How did open-label findings expand your understanding of how pitolisant performs across heterogeneity of IH presentations?

Corser: Well, pitolisant seems to address many of the symptoms of idiopathic hypersomnia, the major symptoms being excessive daytime sleepiness, sleep inertia, brain fog, daytime fatigue. But again, it's not FDA approved for that indication.

HCPLive: Based on the open-label findings, how might pitolisant change the way clinicians approach symptom management in IH?

Corser: If pitolisant is used for [the] treatment of idiopathic hypersomnia, that would be off-label because it's not FDA approved for that indication. However, based on the open-label findings, it appears to be quite effective for treating many of the symptoms associated with it.

HCPLive: What did the results tell us about the potential of pitolisant?

Corser: I know Harmony is going to be evaluating higher doses of pitolisant for the indication of idiopathic hypersomnia. We'll see…what information [the] future study provides.

HCPLive: Is there anything else you'd like to highlight about this study?

Corser: [Pitolisant] is effective for this population. Unfortunately, the primary endpoints of the overall study were not met, and that may be more related to study design rather than the effect of the drug.

References

1. Corser B, Plante D, Drake C, et al. EFFECT OF PITOLISANT ON SYMPTOMS OF IDIOPATHIC HYPERSOMNIA DURING AN OPEN-LABEL PERIOD IN A PHASE 3 CLINICAL TRIAL. Presented at SLEEP 2025 the 39th annual meeting of the Associated Professional Sleep Societies, in Seattle.

2. Derman, C. FDA Approves Pitolisant for Excessive Daytime Sleepiness in Pediatric Patients. HCPLive. June 24, 2024. https://www.hcplive.com/view/fda-approves-pitolisant-for-excessive-daytime-sleepiness-in-pediatric-patients. Accessed June 18, 2025.

3. Johnson, V. FDA Rejects Pitolisant NDA for Idiopathic Hypersomnia. HCPLive. February 19, 2025. https://www.hcplive.com/view/fda-rejects-pitolisant-nda-idiopathic-hypersomnia. Accessed June 18, 2025.

4. Harmony Biosciences Provides Update on the Status of the Supplemental New Drug Application for Pitolisant in Idiopathic Hypersomnia. BioSpace. February 19, 2025. https://www.biospace.com/press-releases/harmony-biosciences-provides-update-on-the-status-of-the-supplemental-new-drug-application-for-pitolisant-in-idiopathic-hypersomnia. Accessed June 18, 2025.