Harmony Biosciences Provides Update on the Status of the Supplemental New Drug Application for Pitolisant in Idiopathic Hypersomnia

PLYMOUTH MEETING, Pa.--(BUSINESS WIRE)-- Harmony Biosciences Holdings, Inc. (Nasdaq: HRMY) today announced that it received a Refusal to File (RTF) letter from the U.S. Food and Drug Administration (FDA) for pitolisant for the treatment of excessive daytime sleepiness (EDS) in adult patients with idiopathic hypersomnia (IH). Harmony’s 2025 net revenue guidance of $820-$860 million remains unchanged.

“We are disappointed with this short-term setback, but our long-term strategy for pitolisant in IH remains firmly on track with our focus on Pitolisant HD,” said Jeffrey M. Dayno, M.D., President and Chief Executive Officer of Harmony Biosciences. “We made the decision to submit the sNDA based on our belief in pitolisant’s overall benefit-risk profile in IH and our deep commitment to the patient community, despite the challenge associated with this submission. Our long-term business strategy has always been to extend our leadership in sleep/wake through the development of Pitolisant HD, an enhanced and higher-dose formulation, which represents the more significant opportunity in IH given its optimized profile and provisional patent filed out to 2044. We are on track to initiate a Phase 3 registrational trial of Pitolisant HD in IH in Q4 2025, with a target PDUFA date in 2028.”

“Our planned Phase 3 registrational trial, a double-blind, randomized, parallel-group study in patients with IH, is based on input from the FDA,” said Kumar Budur, M.D., M.S., Chief Medical and Scientific Officer at Harmony Biosciences. “We believe this study design will effectively demonstrate the benefit of pitolisant in patients with IH based on the robust clinical response that was observed in the Phase 3 INTUNE Study. We are grateful to the patients and clinicians who participated in the INTUNE Study, and our commitment to these patients remains steadfast. With the initiation of this pivotal Phase 3 trial in Q4 2025, we will continue to advance pitolisant-based treatments to address their unmet needs.”

Although the primary outcome for EDS between pitolisant and placebo did not reach statistical significance in the randomized withdrawal phase of the Phase 3 INTUNE Study, the data from the open-label phase showed that patients experienced improvements on the Epworth Sleepiness Scale that were five times greater than what is recognized as clinically meaningful. Furthermore, the majority of patients in the long-term extension study achieved normal levels of wakefulness and sustained this response beyond one year.

Harmony’s diversified pipeline and commitment to advancing science in sleep/wake and rare neurological disorders remain key drivers of its long-term vision. The company continues to execute on its strategic priorities and is confident in its ability to deliver sustained growth.

Pitolisant is marketed as WAKIX® in the U.S. for the treatment of EDS or cataplexy in adult patients with narcolepsy, and for the treatment of EDS in pediatric patients 6 years of age and older with narcolepsy. Pitolisant is not currently approved for IH.

About WAKIX® (pitolisant) Tablets

WAKIX, a first-in-class medication, is approved by the U.S. Food and Drug Administration for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy and for the treatment of EDS in pediatric patients 6 years of age and older with narcolepsy. It was granted orphan drug designation for the treatment of narcolepsy in 2010, and breakthrough therapy designation for the treatment of cataplexy in 2018. WAKIX is a selective histamine 3 (H₃) receptor antagonist/inverse agonist. The mechanism of action of WAKIX is unclear; however, its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine, a wake promoting neurotransmitter. WAKIX was designed and developed by Bioprojet (France). Harmony has an exclusive license from Bioprojet to develop, manufacture and commercialize pitolisant in the United States.

Indications and Usage

WAKIX is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy and for the treatment of excessive daytime sleepiness (EDS) in pediatric patients 6 years of age and older with narcolepsy.

Important Safety Information

Contraindications

WAKIX is contraindicated in patients with known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported. WAKIX is also contraindicated in patients with severe hepatic impairment.

Warnings and Precautions

WAKIX prolongs the QT interval; avoid use of WAKIX in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval. Avoid use in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.

The risk of QT prolongation may be greater in patients with hepatic or renal impairment due to higher concentrations of pitolisant; monitor these patients for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment. WAKIX is contraindicated in patients with severe hepatic impairment and not recommended in patients with end-stage renal disease (ESRD).

Adverse Reactions

In the placebo-controlled clinical trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (≥5% and at least twice placebo) for WAKIX were insomnia (6%), nausea (6%), and anxiety (5%). Other adverse reactions that occurred at ≥2% and more frequently than in patients treated with placebo included headache, upper respiratory tract infection, musculoskeletal pain, heart rate increased, hallucinations, irritability, abdominal pain, sleep disturbance, decreased appetite, cataplexy, dry mouth, and rash.

In the placebo-controlled phase of the clinical trial conducted in pediatric patients 6 years and older with narcolepsy with or without cataplexy, the most common adverse reactions (≥5% and greater than placebo) for WAKIX were headache (19%) and insomnia (7%). The overall adverse reaction profile of WAKIX in the pediatric clinical trial was similar to that seen in the adult clinical trial program.

Drug Interactions

Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. Reduce the dose of WAKIX by half.

Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. Dosage adjustments may be required.

H1 receptor antagonists that cross the blood-brain barrier may reduce the effectiveness of WAKIX. Patients should avoid centrally acting H1 receptor antagonists.

WAKIX is a borderline/weak inducer of CYP3A4. WAKIX may reduce the effectiveness of sensitive CYP3A4 substrates, including hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuing treatment.

Use in Specific Populations

There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to WAKIX during pregnancy. Patients should be encouraged to enroll in the WAKIX pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-800-833-7460.

The safety and effectiveness of WAKIX have not been established for treatment of excessive daytime sleepiness in pediatric patients less than 6 years of age with narcolepsy.

The safety and effectiveness of WAKIX have not been established for treatment of cataplexy in pediatric patients with narcolepsy.

WAKIX is extensively metabolized by the liver. WAKIX is contraindicated in patients with severe hepatic impairment. Dosage adjustment is required in patients with moderate hepatic impairment.

WAKIX is not recommended in patients with end-stage renal disease. Dosage adjustment of WAKIX is recommended in patients with eGFR