Sleep Paralysis

WAKIX® (pitolisant) Net Revenue of $201.3 Million for Fourth Quarter and $714.7 Million for Full Year 2024; Representing Growth of 23% in Year-Five on the Market 2025 WAKIX Net Revenue Guidance Between $820 - $860 Million ; On Track toward a Potential $1 Billion+ Opportunity Committed to Leadership in Sleep/Wake with Next Generation Pitolisant Formulations and Orexin 2 Receptor Agonist; Phase 3 Registrational Trials with Pitolisant HD in Narcolepsy and IH to Initiate in Q4 2025 Topline Data Readout from Phase 3 Registrational Trial with ZYN002 in Fragile X Syndrome On Track for Q3 2025 Pitolisant Patent Position Strengthened with Favorable Settlement of First Generic Litigation Conference Call and Webcast to be Held Today at 8:30 a.m. ET PLYMOUTH MEETING, Pa. --(BUSINESS WIRE)--Feb. 25, 2025-- Harmony Biosciences Holdings, Inc. (Nasdaq: HRMY) today announced a record $201.3 million in net product revenues for the fourth quarter 2024, and full year 2024 net revenues of $714.7 million , ending the year with $576 million in cash, cash equivalents and investments on the balance sheet. The company has guided 2025 WAKIX® net revenues to $820 - $860 million , targeting a $1B+ opportunity with WAKIX in narcolepsy alone. “2025 is set up to be a transformational year for Harmony, as our robust, late-stage pipeline comes into focus and we advance our long-term growth strategy,” said Jeffrey M. Dayno , M.D., President and Chief Executive Officer of Harmony Biosciences . “This year will bring major milestones for Harmony, with the topline data readout from our Phase 3 registrational trial with ZYN002 in Fragile X syndrome expected in Q3 and the potential, if successful, to bring the first approved treatment to the Fragile X patient community. In Q4, we will be initiating two Phase 3 registrational trials with our next gen Pitolisant HD formulation in both narcolepsy and idiopathic hypersomnia, potentially extending the pitolisant franchise out to the 2040s and further solidifying our leadership in sleep/wake. Taken together, these catalysts underscore the importance of 2025 as a pivotal year in Harmony’s long-term growth strategy. With at least one new product candidate or indication launch each year over the coming years, our pipeline has the potential to deliver over $3 billion in net revenue as the leading CNS company focused on developing and delivering innovative treatments for patients with unmet needs.” Franchise Highlights Sleep/Wake Franchise WAKIX in Narcolepsy Net Sales were $201.3M for Q4 2024 and $714.7M for FY 2024 2025 Net Revenue projected between $820 to $860 million Settlement reached in first Abbreviated New Drug Application (ANDA) litigation, giving Novugen Pharma a license to sell its generic product beginning in January 2030 or earlier under certain circumstances This settlement reinforces the strength and durability of Harmony’s intellectual property portfolio and its vigorous defense of its patent estate On track to obtain pediatric exclusivity which, if granted, would add an additional 6 months of regulatory exclusivity This settlement reinforces the strength and durability of Harmony’s intellectual property portfolio and its vigorous defense of its patent estate Pitolisant HD (high-dose) Higher dose and optimized pharmacokinetic profile designed to address the need for greater efficacy in excessive daytime sleepiness (EDS) and other symptoms in patients with central disorders of hypersomnolence Phase 3 registrational trial in narcolepsy to include endpoint on narcolepsy-related fatigue in pursuit of differentiated label Trial to initiate in Q4 2025; topline data readout anticipated in 2027 with potential PDUFA date in 2028 Phase 3 registrational trial in IH to include endpoint on sleep inertia in pursuit of differentiated label Trial to initiate in Q4 2025; topline data readout anticipated in 2027 with potential PDUFA date in 2028 Provisional IP filed out to 2044 for narcolepsy and IH Trial to initiate in Q4 2025; topline data readout anticipated in 2027 with potential PDUFA date in 2028 Trial to initiate in Q4 2025; topline data readout anticipated in 2027 with potential PDUFA date in 2028 Pitolisant GR (gastro-resistant) Pivotal bioequivalence study on track to initiate Q1 2025 Topline data readout anticipated in Q3 2025 with potential PDUFA in 2026 Provisional IP filed out to 2044 Topline data readout anticipated in Q3 2025 with potential PDUFA in 2026 Orexin-2 receptor agonist (BP1.15205) Potential to be best-in-class orexin-2 receptor agonist based on a novel chemical scaffold, preclinical potency, selectivity and safety data, as well as its potential for once-a-day dosing Preclinical safety and efficacy data to be presented at SLEEP 2025 (June) IMPD submission on track for mid-2025; first-in-human study expected to initiate 2H 2025 Neurobehavioral Franchise ZYN002 Innovative product profile: pharmaceutically manufactured synthetic cannabidiol devoid of THC The RECONNECT study is designed to confirm the positive findings from the prespecified analysis of the primary outcome in the subgroup of patients with complete methylation from the Phase 2/3 CONNECT study Potential to be the first and only approved treatment for patients with Fragile X syndrome (FXS) (80,000 patients in the U.S. ), and also possess global rights Topline data readout from Phase 3 registrational trial of ZYN002 in FXS (RECONNECT study) in Q3 2025 with potential PDUFA date in 2026 Phase 3 registrational trial in 22q11.2 deletion syndrome (22q) to initiate in 2025 Rare Epilepsy Franchise EPX-100 (clemizole hydrochloride} Most advanced development program in the 5HT2 (serotonin) agonist class Topline data readout from Phase 3 registrational trial in Dravet syndrome (ARGUS Study) anticipated in 2026 Topline data for Phase 3 registrational trial in patients with Lennox-Gastaut syndrome (LIGHTHOUSE study) anticipated in 2026 EPX-200 (lorcaserin hydrochloride) Proven mechanism of action in developmental and epileptic encephalopathies (DEEs) confirmed via non-clinical and clinical data Currently in IND enabling stage Fourth Quarter 2024 Financial Results Net product revenues for the quarter ended December 31, 2024 , were $201.3 million , compared to $168.4 million for the same period in 2023. The 20% growth versus the same period in 2023 is primarily attributed to strong commercial sales of WAKIX driven by continued organic demand tapping into a large market opportunity (approximately 80,000 patients diagnosed with narcolepsy in the U.S. ) and the broad clinical utility of WAKIX across the approximately 9,000 HCPs that we call on (about 5,000 of whom do not participate in an oxybate REMS program). The average number of patients on WAKIX increased by approximately 300 sequentially to approximately 7,100 for the quarter ended December 31, 2024 . GAAP net income for the quarter ended December 31, 2024 , was $49.5 million , or $0.85 earnings per diluted share, compared to GAAP net income of $26.6 million , or $0.45 earnings per diluted share, for the same period in 2023. Non-GAAP adjusted net income was $63.0 million , or $1.08 earnings per diluted share, for the quarter ended December 31, 2024 , compared to Non-GAAP adjusted net income of $42.8 million , or $0.73 per diluted share, for the same period in 2023. Reconciliations of applicable GAAP financial measures to Non-GAAP financial measures are included at the end of this press release. Harmony’s operating expenses included the following: Research and Development expenses were $34.7 million in the fourth quarter of 2024, as compared to $30.3 million for the same quarter in 2023, representing a 14% increase; Sales and Marketing expenses were $27.6 million in the fourth quarter of 2024, as compared to $26.9 million for the same quarter in 2023, representing a 3% increase; General and Administrative expenses were $28.9 million in the fourth quarter of 2024, as compared to $27.9 million for the same quarter in 2023, representing a 4% increase; and Total Operating Expenses were $91.1 million in the fourth quarter of 2024, as compared to $85.1 million for the same quarter in 2023, representing a 7% increase. Full Year 2024 Financial Results Net product revenues for the year ended December 31, 2024 , were $714.7 million , compared to $582.0 million for the same period in 2023. The 23% growth versus the same period in 2023 is primarily attributed to strong commercial sales of WAKIX driven by continued organic demand tapping into a large market opportunity (approximately 80,000 patients diagnosed with narcolepsy in the U.S. ) and the broad clinical utility of WAKIX across the approximately 9,000 HCPs that we call on (about 5,000 of whom do not participate in an oxybate REMS program). GAAP net income for the year ended December 31, 2024 , was $145.5 million , or $2.51 earnings per diluted share, compared to GAAP net income of $128.9 million , or $2.13 earnings per diluted share, for the same period in 2023. Non-GAAP adjusted net income was $233.9 million , or $4.04 earnings per diluted share, for the year ended December 31, 2024 , compared to Non-GAAP adjusted net income of $188.4 million , or $3.12 per diluted share, for the same period in 2023. Reconciliations of applicable GAAP financial measures to Non-GAAP financial measures are included at the end of this press release. Harmony’s operating expenses included the following: Research and Development expenses were $145.8 million for the year ended December 31, 2024 , as compared to $76.1 million for the prior year, representing an 92% increase, primarily driven by a $25.5 million upfront licensing fee as part of the 2024 Bioprojet Sublicense Agreement for BP1.15205, an orexin-2 receptor agonist, and a $17.1 million IPR&D charge related to the acquisition of Epygenix Sales and Marketing expenses were $110.9 million for the year ended December 31, 2024 , as compared to $97.4 million for the prior year, representing a 14% increase; General and Administrative expenses were $110.4 million for the year ended December 31, 2024 , as compared to $95.3 million for the prior year, representing a 16% increase; and Total Operating Expenses were $367.1 million for the year ended December 31, 2024 , as compared to $268.8 million for the prior year, representing a 37% increase. As of December 31, 2024 , Harmony had cash, cash equivalents and investments of $576.1 million , compared to $425.6 million as of December 31, 2023 . 2025 Net Product Revenue Guidance Expect full year 2025 net product revenue of $820 million to $860 million . Share Repurchase Program The remaining amount of common stock authorized for repurchases as of December 31, 2024 , was $150 million . Conference Call Today at 8:30 a.m. ET We are hosting our fourth quarter and full year 2024 financial results conference call and webcast today, beginning at 8:30 a.m. Eastern Time . The live and replay webcast of the call will be available on the investor relations page of our website at https://ir.harmonybiosciences.com/. To participate in the live call by phone, dial 800-445-7795 (domestic) or 785-424-1699 (international), and reference passcode HRMYQ424. Non-GAAP Financial Measures In addition to our GAAP results, we present certain Non-GAAP metrics including Non-GAAP adjusted net income and Non-GAAP adjusted net income per share, which we believe provides important supplemental information to management and investors regarding our performance. These measurements are not a substitute for GAAP measurements, and the manner in which we calculate Non-GAAP adjusted net income and Non-GAAP adjusted net income per share may not be identical to the manner in which other companies calculate adjusted net income and adjusted net income per share. We use these Non-GAAP measurements as an aid in monitoring our financial performance from quarter-to-quarter and year-to-year and for benchmarking against comparable companies. Non-GAAP financial measures should not be considered in isolation or as a substitute for comparable GAAP measures; should be read in conjunction with our consolidated financial statements prepared in accordance with GAAP; have no standardized meaning prescribed by GAAP; and are not prepared under any comprehensive set of accounting rules or principles. In addition, from time to time in the future there may be other items that we may exclude for purposes of our Non-GAAP financial measures; and we may in the future cease to exclude items that we have historically excluded for purposes of our Non-GAAP financial measures. 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 <60 mL/minute/1.73 m2. Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers; these patients have higher concentrations of WAKIX than normal CYP2D6 metabolizers. Please see the Full Prescribing Information for WAKIX for more information. To report suspected adverse reactions, contact Harmony Biosciences at 1-800-833-7460 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. About Narcolepsy Narcolepsy is a rare, chronic, debilitating neurological disease of sleep-wake state instability that impacts approximately 170,000 Americans and is primarily characterized by excessive daytime sleepiness (EDS) and cataplexy – its two cardinal symptoms – along with other manifestations of REM sleep dysregulation (hallucinations and sleep paralysis), which intrude into wakefulness. EDS is the inability to stay awake and alert during the day and is the symptom that is present in all people living with narcolepsy. In most patients, narcolepsy is caused by the loss of hypocretin/orexin, a neuropeptide in the brain that supports sleep-wake state stability. This disease affects men and women equally, with typical symptom onset in adolescence or young adulthood; however, it can take up to a decade to be properly diagnosed. About Idiopathic Hypersomnia Idiopathic Hypersomnia (IH) is a rare and chronic neurological disease that is characterized by excessive daytime sleepiness (EDS) despite sufficient or even long sleep time. EDS in IH cannot be alleviated by naps, longer sleep or more efficient sleep. People living with IH experience significant EDS along with the symptoms of sleep inertia (prolonged difficulty waking up from sleep) and 'brain fog' (impaired cognition, attention, and alertness). The cause of IH is unknown, but it is likely due to alterations in areas of the brain that stabilize states of sleep and wakefulness. IH is one of the central disorders of hypersomnolence and, like narcolepsy, is a debilitating sleep disorder that can result in significant disruption in daily functioning. About ZYN002 ZYN002 is the first-and-only pharmaceutically manufactured synthetic cannabidiol devoid of THC and formulated as a patent-protected permeation-enhanced gel for transdermal delivery through the skin and into the circulatory system. The product is manufactured through a synthetic process in a cGMP facility and is not extracted from the cannabis plant. ZYN002 does not contain THC, the compound that causes the euphoric effect of cannabis, and has the potential to be a nonscheduled product if approved. Cannabidiol, the active ingredient in ZYN002, has been granted orphan drug designation by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of FXS and for the treatment of 22q. Additionally, ZYN002 has received FDA Fast Track designation for the treatment of behavioral symptoms in patients with FXS. About Fragile X Syndrome Fragile X syndrome (FXS) is a rare genetic disorder that is the leading known cause of both inherited intellectual disability and autism spectrum disorder. The disorder negatively affects synaptic function, plasticity and neuronal connections, and results in a spectrum of intellectual disabilities and behavioral symptoms, such as social avoidance and irritability. While the exact prevalence is unknown, upwards of 80,000 patients in the U.S. and 121,000 patients in the European Union and the UK are believed to have FXS, based on FXS prevalence estimates of approximately 1 in 4,000 to 7,000 in males and approximately 1 in 8,000 to 11,000 in females. There is a significant unmet medical need in patients living with FXS as there are currently no FDA-approved treatments for this disorder. FXS is caused by a mutation in FMR1, a gene which modulates a number of systems, including the endocannabinoid system, and most critically, codes for a protein called FMRP. The FMR1 mutation manifests as multiple repeats of a DNA segment, known as the CGG triplet repeat, resulting in deficiency or lack of FMRP. FMRP helps regulate the production of other proteins and plays a role in the development of synapses, which are critical for relaying nerve impulses, and in regulating synaptic plasticity. In people with full mutation of the FMR1 gene, the CGG segment is repeated more than 200 times, and in most cases causes the gene to not function. Methylation of the FMR1 gene also plays a role in determining functionality of the gene. In approximately 60% of patients with FXS, who have complete methylation of the FMR1 gene, no FMRP is produced, resulting in dysregulation of the systems modulated by FMRP. About Clemizole Hydrochloride (EPX-100) EPX-100, clemizole hydrochloride, is under development for the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). EPX-100 acts by targeting central 5-hydroxytryptamine receptors to modulate serotonin signaling. The drug candidate is administered orally twice a day in a liquid formulation and has been developed based on a proprietary phenotype-based zebrafish drug screening platform. DS is caused by a loss of function mutation in the SCN1A gene, and scn1 mutant zebrafish replicate the genetic etiology and phenotype observed in the majority of DS patients. The scn1Lab mutant zebrafish model that expresses voltage gated sodium channels has been used for high-throughput screening of compounds that modulate Nav1.1 in the central nervous system. About Dravet Syndrome Dravet syndrome (DS) is a severe and progressive epileptic encephalopathy that begins in infancy and causes significant impact on patient functioning. DS begins in the first year of life and is characterized by high seizure frequency and severity, intellectual disability, and a risk of sudden unexpected death in epilepsy. Approximately 85% of Dravet syndrome cases are caused by de novo loss-of-function (LOF) mutations in a voltage-gated sodium channel gene, SCN1A1. DS has an estimated incidence rate of 1:15,700. About Lennox-Gastaut Syndrome Lennox-Gastaut syndrome (LGS) is a rare and drug-resistant epileptic encephalopathy characterized by onset in children between 3-5 years of age. The underlying cause of LGS is unknown and can be related to a wide range of factors including genetic differences and structural differences in the brain. As a result, patients experience multiple seizure types, including atonic seizures, and developmental, cognitive, and behavioral issues. LGS affects approximately 48,000 patients in the U.S. About Harmony Biosciences Harmony Biosciences is a pharmaceutical company dedicated to developing and commercializing innovative therapies for patients with rare neurological diseases who have unmet medical needs. Driven by novel science, visionary thinking, and a commitment to those who feel overlooked, Harmony Biosciences is nurturing a future full of therapeutic possibilities that may enable patients with rare neurological diseases to truly thrive. Established by Paragon Biosciences, LLC , in 2017 and headquartered in Plymouth Meeting, Pa. , we believe that when empathy and innovation meet, a better future can begin; a vision evident in the therapeutic innovations we advance, the culture we cultivate, and the community programs we foster. For more information, please visit www.harmonybiosciences.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including statements regarding our full year 2024 net product revenue, expectations for the growth and value of WAKIX, plans to submit an sNDA for pitolisant in idiopathic hypersomnia; our future results of operations and financial position, business strategy, products, prospective products, product approvals, the plans and objectives of management for future operations and future results of anticipated products. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our commercialization efforts and strategy for WAKIX; the rate and degree of market acceptance and clinical utility of pitolisant in additional indications, if approved, and any other product candidates we may develop or acquire, if approved; our research and development plans, including our plans to explore the therapeutic potential of pitolisant in additional indications; our ongoing and planned clinical trials; our ability to expand the scope of our license agreements with Bioprojet Société Civile de Recherche (“Bioprojet”); the availability of favorable insurance coverage and reimbursement for WAKIX; the timing of, and our ability to obtain, regulatory approvals for pitolisant for other indications as well as any other product candidates; our estimates regarding expenses, future revenue, capital requirements and additional financing needs; our ability to identify, acquire and integrate additional products or product candidates with significant commercial potential that are consistent with our commercial objectives; our commercialization, marketing and manufacturing capabilities and strategy; significant competition in our industry; our intellectual property position; loss or retirement of key members of management; failure to successfully execute our growth strategy, including any delays in our planned future growth; our failure to maintain effective internal controls; the impact of government laws and regulations; volatility and fluctuations in the price of our common stock; the significant costs and required management time as a result of operating as a public company; the fact that the price of Harmony's common stock may be volatile and fluctuate substantially; statements related to our intended share repurchases and repurchase timeframe and the significant costs and required management time as a result of operating as a public company. These and other important factors discussed under the caption "Risk Factors" in our Annual Report on Form 10-K filed with the Securities and Exchange Commission (the " SEC ") on February 25, 2025 , and our other filings with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management's estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. HARMONY BIOSCIENCES HOLDINGS, INC. AND SUBSIDIARY CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE INCOME (LOSS) (In thousands, except share and per share data) Three Months Ended Year Ended December 31 , December 31 , December 31 , December 31 , 2024 2023 2024 2023 Net product revenue $ 201,267 $ 168,412 $ 714,734 $ 582,022 Cost of product sold 54,409 43,152 156,815 121,236 Gross profit 146,858 125,260 557,919 460,786 Operating expenses: Research and development 34,666 30,306 145,825 76,063 Sales and marketing 27,600 26,886 110,916 97,404 General and administrative 28,865 27,872 110,352 95,289 Total operating expenses 91,131 85,064 367,093 268,756 Operating income 55,727 40,196 190,826 192,030 Loss on debt extinguishment — — — (9,766) Other expense (income), net 160 193 (68) 159 Interest expense (4,209) (4,796) (17,496) (23,757) Interest income 4,477 4,096 18,542 14,730 Income before income taxes 56,155 39,689 191,804 173,396 Income tax benefit (expense) (6,680) (13,082) (46,311) (44,543) Net income $ 49,475 $ 26,607 $ 145,493 $ 128,853 EARNINGS PER SHARE: Basic $ 0.87 $ 0.46 $ 2.56 $ 2.17 Diluted $ 0.85 $ 0.45 $ 2.51 $ 2.13 Weighted average number of shares of common stock - basic 57,097,092 58,320,400 56,885,455 59,469,648 Weighted average number of shares of common stock - diluted 58,218,052 58,853,292 57,869,915 60,372,397 HARMONY BIOSCIENCES HOLDINGS, INC. AND SUBSIDIARIES CONSOLIDATED BALANCE SHEETS (In thousands, except share and per share data) December 31 , December 31 , 2024 2023 ASSETS CURRENT ASSETS: Cash and cash equivalents $ 453,001 $ 311,660 Investments, short-term 14,185 41,800 Trade receivables, net 83,033 74,140 Inventory, net 7,198 5,363 Prepaid expenses 13,714 12,570 Other current assets 8,121 5,537 Total current assets 579,252 451,070 NONCURRENT ASSETS: Property and equipment, net 1,257 371 Restricted cash 270 270 Investments, long-term 108,874 72,169 Intangible assets, net 113,263 137,108 Deferred tax asset 190,398 144,162 Other noncurrent assets 5,886 6,298 Total noncurrent assets 419,948 360,378 TOTAL ASSETS $ 999,200 $ 811,448 LIABILITIES AND STOCKHOLDERS’ EQUITY CURRENT LIABILITIES: Trade payables $ 13,744 $ 17,730 Accrued compensation 18,776 23,747 Accrued expenses 120,640 99,494 Current portion of long-term debt 16,250 15,000 Other current liabilities 5,672 7,810 Total current liabilities 175,082 163,781 NONCURRENT LIABILITIES: Long-term debt, net 163,016 178,566 Other noncurrent liabilities 1,947 2,109 Total noncurrent liabilities 164,963 180,675 TOTAL LIABILITIES 340,045 344,456 COMMITMENTS AND CONTINGENCIES (Note 13) STOCKHOLDERS’ EQUITY: Common stock—$0.00001 par value; 500,000,000 shares authorized at December 31, 2024 and December 31, 2023 , respectively; 57,144,887 and 56,769,081 shares issued and outstanding at December 31, 2024 and December 31, 2023 , respectively 1 1 Additional paid in capital 656,872 610,266 Accumulated other comprehensive (loss) income 66 2 Retained earnings (accumulated deficit) 2,216 (143,277) TOTAL STOCKHOLDERS’ EQUITY 659,155 466,992 TOTAL LIABILITIES AND STOCKHOLDERS’ EQUITY $ 999,200 $ 811,448 HARMONY BIOSCIENCES HOLDINGS, INC. AND SUBSIDIARIES RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL RESULTS (In thousands except share and per share data) Three Months Ended Year Ended December 31 , December 31 , December 31 , December 31 , 2024 2023 2024 2023 GAAP net income $ 49,475 $ 26,607 $ 145,493 $ 128,853 Non-GAAP Adjustments: Non-cash interest expense (1) 169 185 700 3,246 Depreciation 6 164 267 514 Amortization (2) 5,962 5,961 23,845 23,845 Stock-based compensation expense 9,856 8,894 42,701 31,205 Licensing fee and milestone payments (3) - - 26,500 750 Loss on debt extinguishment (4) - - - 9,766 Transaction related costs (5) - 9,804 17,095 9,804 Income tax effect related to non-GAAP adjustments (6) (2,442) (8,789) (22,657) (19,624) Non-GAAP adjusted net income $ 63,026 $ 42,826 $ 233,944 $ 188,359 GAAP reported net income per diluted share $ 0.85 $ 0.45 $ 2.51 $ 2.13 Non-GAAP adjusted net income per diluted share $ 1.08 $ 0.73 $ 4.04 $ 3.12 Weighted average number of shares of common stock used in non-GAAP diluted per share 58,218,052 58,853,292 57,869,915 60,372,397 (1) Includes amortization of deferred finance charges. (2) Includes amortization of intangible asset related to WAKIX. (3) Amount represents upfront licensing fee incurred upon closing the 2024 Bioprojet Sublicense Agreement, milestone payment related to HBS-102 in September 2024 and milestone payment related to HBS-102 in March 2023 . (4) Includes loss on extinguishment of the Blackstone Credit Agreement. (5) Includes IPR&D charge related to the acquisitions of Epygenix in April 2024 and Zynerba in October 2023 . (6) Calculated using the reported effective tax rate for the periods presented less impact of discrete items. View source version on businesswire.com: https://www.businesswire.com/news/home/20250225347698/en/ Harmony Biosciences Investor: Brennan Doyle 484-539-9700 bdoyle@harmonybiosciences.com Harmony Biosciences Media: Cate McCanless 202-641-6086 cmccanless@harmonybiosciences.com Source: Harmony Biosciences Holdings, Inc.

WAKIX® (pitolisant) Preliminary Net Revenue of ~$201 Million for Fourth Quarter and ~$714 Million for Full Year 2024; Representing Growth of ~23% in Year-Five of Launch 2025 WAKIX Net Revenue Guidance Between $820 - $860 Million; On Track to a Potential $1 Billion+ Opportunity Value-Creating Catalysts Anticipated Every Quarter in 2025: Q1 – FDA Decision on File Acceptance of Pitolisant sNDA for Idiopathic Hypersomnia; Potential Approval in 2025 Q2 – Orexin/BP1.15205 Data Presentation at SLEEP 2025 Conference Q3 – Pivotal Phase 3 Topline Data for ZYN002 in Fragile X Syndrome Q4 – Initiation of Pitolisant-HD Pivotal Phase 3 Trial in Narcolepsy Robust, Catalyst-Rich Pipeline Includes Up to Six Phase 3 Clinical Programs by Year End 2025 PLYMOUTH MEETING, Pa.--(BUSINESS WIRE)--Jan. 13, 2025-- Harmony Biosciences Holdings, Inc. (Nasdaq: HRMY) today announced strong preliminary, unaudited net product revenues for Q4 and full year 2024 of $201 million and $714 million, respectively. Building on this performance, the company is well positioned for a catalyst-rich 2025, with value-creating milestones anticipated every quarter. Harmony will be highlighting its catalysts for 2025 and other key milestones during its presentation at the 43rd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15, 2025, at 11:15 a.m. PT / 2:15 p.m. ET. “2025 is a pivotal year for Harmony Biosciences, as we focus on unlocking the full potential of our catalyst-rich neuroscience pipeline,” said Jeffrey M. Dayno, M.D., President and Chief Executive Officer of Harmony Biosciences. “Building upon our foundation of strong and continued revenue growth for WAKIX, our multi-franchise pipeline has come into focus with value-creating catalysts expected each and every quarter this year. We are entering 2025 with strong momentum and a clear path toward long-term growth, building a company with the potential to deliver over $3 billion in net revenue going forward." Fourth Quarter and Full Year 2024 Net Product Revenue for WAKIX (Preliminary and Unaudited) Preliminary, unaudited net product revenue for the quarter ended December 31, 2024, was approximately $201 million, compared to $168.4 million for the same period in 2023 Preliminary, unaudited net product revenue for the full year ended December 31, 2024, was approximately $714 million, compared to $582 million for the same period in 2023, representing ~23% growth in its fifth year on the market The average number of patients on WAKIX increased by approximately 300 sequentially to approximately 7,100 for the quarter ended December 31, 2024 2025 Net Revenue Guidance Net revenue projected between $820 to $860 million Key Catalysts for 2025 Q1 – FDA decision on file acceptance of pitolisant sNDA for Idiopathic Hypersomnia (IH) IH sNDA for pitolisant submitted in Q4 2024 Potential FDA approval in 2025 Q2 – Preclinical data for BP1.15205 (OX2R agonist) to be presented at SLEEP 2025 Data to include preclinical safety and efficacy BP1.15205 on track for first-in-human study in Q3 2025 Q3 – Topline data readout for ZYN002 from pivotal Phase 3 trial in Fragile X syndrome (FXS) Potential for first and only approved treatment for patients with FXS Estimated 80,000 people living with FXS in the US; worldwide rights Q4 – Initiation of Pitolisant-HD Pivotal Phase 3 trial in Narcolepsy Designed to address the largest unmet need in patients with narcolepsy by providing greater efficacy for both excessive daytime sleepiness and cataplexy Program to include novel endpoint to assess narcolepsy-related fatigue Preliminary IP filed out to 2044 to extend the pitolisant franchise IH sNDA for pitolisant submitted in Q4 2024 Potential FDA approval in 2025 Data to include preclinical safety and efficacy BP1.15205 on track for first-in-human study in Q3 2025 Potential for first and only approved treatment for patients with FXS Estimated 80,000 people living with FXS in the US; worldwide rights Designed to address the largest unmet need in patients with narcolepsy by providing greater efficacy for both excessive daytime sleepiness and cataplexy Program to include novel endpoint to assess narcolepsy-related fatigue Preliminary IP filed out to 2044 to extend the pitolisant franchise Robust, Multi-Franchise Pipeline Anticipates up to six phase 3 clinical development programs by year end 2025 Initiated pivotal phase 3 study in Lennox-Gastaut syndrome (LGS) for EPX-100 in Q4 2024 EPX-100 is the most advanced 5HT2 (serotonin) agonist in clinical development Initiation of Pitolisant-GR pivotal bioequivalence study in Q1 2025 with readout anticipated Q3 2025 Pipeline poised to deliver at least one new product or indication approval every year for the next four years (2028) Current pipeline has the potential to generate over $3B in net revenue Additional program updates to be provided during the Management presentation at the upcoming J.P. Morgan Healthcare Conference on January 15, 2025, at 11:15 a.m. PT / 2:15 p.m. ET. Presentation slides are available on the investor page of the Harmony Biosciences website: https://ir.harmonybiosciences.com/ Initiated pivotal phase 3 study in Lennox-Gastaut syndrome (LGS) for EPX-100 in Q4 2024 EPX-100 is the most advanced 5HT2 (serotonin) agonist in clinical development Initiation of Pitolisant-GR pivotal bioequivalence study in Q1 2025 with readout anticipated Q3 2025 EPX-100 is the most advanced 5HT2 (serotonin) agonist in clinical development The financial information included in this press release is preliminary, unaudited, and subject to change. It does not present all the information necessary for an understanding of the company's financial results for the fourth quarter or full year 2024. 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 <60 mL/minute/1.73 m2. Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers; these patients have higher concentrations of WAKIX than normal CYP2D6 metabolizers. Please see the Full Prescribing Information for WAKIX for more information. To report suspected adverse reactions, contact Harmony Biosciences at 1-800-833-7460 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. About Narcolepsy Narcolepsy is a rare, chronic, debilitating neurological disease of sleep-wake state instability that impacts approximately 170,000 Americans and is primarily characterized by excessive daytime sleepiness (EDS) and cataplexy – its two cardinal symptoms – along with other manifestations of REM sleep dysregulation (hallucinations and sleep paralysis), which intrude into wakefulness. EDS is the inability to stay awake and alert during the day and is the symptom that is present in all people living with narcolepsy. In most patients, narcolepsy is caused by the loss of hypocretin/orexin, a neuropeptide in the brain that supports sleep-wake state stability. This disease affects men and women equally, with typical symptom onset in adolescence or young adulthood; however, it can take up to a decade to be properly diagnosed. About Idiopathic Hypersomnia Idiopathic Hypersomnia (IH) is a rare and chronic neurological disease that is characterized by excessive daytime sleepiness (EDS) despite sufficient or even long sleep time. EDS in IH cannot be alleviated by naps, longer sleep or more efficient sleep. People living with IH experience significant EDS along with the symptoms of sleep inertia (prolonged difficulty waking up from sleep) and 'brain fog' (impaired cognition, attention, and alertness). The cause of IH is unknown, but it is likely due to alterations in areas of the brain that stabilize states of sleep and wakefulness. IH is one of the central disorders of hypersomnolence and, like narcolepsy, is a debilitating sleep disorder that can result in significant disruption in daily functioning. About ZYN002 ZYN002 is the first-and-only pharmaceutically manufactured synthetic cannabidiol devoid of THC and formulated as a patent-protected permeation-enhanced gel for transdermal delivery through the skin and into the circulatory system. The product is manufactured through a synthetic process in a cGMP facility and is not extracted from the cannabis plant. ZYN002 does not contain THC, the compound that causes the euphoric effect of cannabis, and has the potential to be a nonscheduled product if approved. Cannabidiol, the active ingredient in ZYN002, has been granted orphan drug designation by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of FXS and for the treatment of 22q. Additionally, ZYN002 has received FDA Fast Track designation for the treatment of behavioral symptoms in patients with FXS. About Fragile X Syndrome Fragile X syndrome (FXS) is a rare genetic disorder that is the leading known cause of both inherited intellectual disability and autism spectrum disorder. The disorder negatively affects synaptic function, plasticity and neuronal connections, and results in a spectrum of intellectual disabilities and behavioral symptoms, such as social avoidance and irritability. While the exact prevalence is unknown, upwards of 80,000 patients in the U.S. and 121,000 patients in the European Union and the UK are believed to have FXS, based on FXS prevalence estimates of approximately 1 in 4,000 to 7,000 in males and approximately 1 in 8,000 to 11,000 in females. There is a significant unmet medical need in patients living with FXS as there are currently no FDA-approved treatments for this disorder. FXS is caused by a mutation in FMR1, a gene which modulates a number of systems, including the endocannabinoid system, and most critically, codes for a protein called FMRP. The FMR1 mutation manifests as multiple repeats of a DNA segment, known as the CGG triplet repeat, resulting in deficiency or lack of FMRP. FMRP helps regulate the production of other proteins and plays a role in the development of synapses, which are critical for relaying nerve impulses, and in regulating synaptic plasticity. In people with full mutation of the FMR1 gene, the CGG segment is repeated more than 200 times, and in most cases causes the gene to not function. Methylation of the FMR1 gene also plays a role in determining functionality of the gene. In approximately 60% of patients with FXS, who have complete methylation of the FMR1 gene, no FMRP is produced, resulting in dysregulation of the systems modulated by FMRP. About Clemizole Hydrochloride (EPX-100) EPX-100, clemizole hydrochloride, is under development for the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). EPX-100 acts by targeting central 5-hydroxytryptamine receptors to modulate serotonin signaling. The drug candidate is administered orally twice a day in a liquid formulation and has been developed based on a proprietary phenotype-based zebrafish drug screening platform. DS is caused by a loss of function mutation in the SCN1A gene, and scn1 mutant zebrafish replicate the genetic etiology and phenotype observed in the majority of DS patients. The scn1Lab mutant zebrafish model that expresses voltage gated sodium channels has been used for high-throughput screening of compounds that modulate Nav1.1 in the central nervous system. About Dravet Syndrome Dravet syndrome (DS) is a severe and progressive epileptic encephalopathy that begins in infancy and causes significant impact on patient functioning. DS begins in the first year of life and is characterized by high seizure frequency and severity, intellectual disability, and a risk of sudden unexpected death in epilepsy. Approximately 85% of Dravet syndrome cases are caused by de novo loss-of-function (LOF) mutations in a voltage-gated sodium channel gene, SCN1A1. DS has an estimated incidence rate of 1:15,700. About Lennox-Gastaut Syndrome Lennox-Gastaut syndrome (LGS) is a rare and drug-resistant epileptic encephalopathy characterized by onset in children between 3-5 years of age. The underlying cause of LGS is unknown and can be related to a wide range of factors including genetic differences and structural differences in the brain. As a result, patients experience multiple seizure types, including atonic seizures, and developmental, cognitive, and behavioral issues. LGS affects approximately 48,000 patients in the U.S. About Harmony Biosciences Harmony Biosciences is a pharmaceutical company dedicated to developing and commercializing innovative therapies for patients with rare neurological diseases who have unmet medical needs. Driven by novel science, visionary thinking, and a commitment to those who feel overlooked, Harmony Biosciences is nurturing a future full of therapeutic possibilities that may enable patients with rare neurological diseases to truly thrive. Established by Paragon Biosciences, LLC, in 2017 and headquartered in Plymouth Meeting, Pa., we believe that when empathy and innovation meet, a better future can begin; a vision evident in the therapeutic innovations we advance, the culture we cultivate, and the community programs we foster. For more information, please visit www.harmonybiosciences.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including statements regarding our full year 2024 net product revenue, expectations for the growth and value of WAKIX, plans to submit an sNDA for pitolisant in idiopathic hypersomnia; our future results of operations and financial position, business strategy, products, prospective products, product approvals, the plans and objectives of management for future operations and future results of anticipated products. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our commercialization efforts and strategy for WAKIX; the rate and degree of market acceptance and clinical utility of pitolisant in additional indications, if approved, and any other product candidates we may develop or acquire, if approved; our research and development plans, including our plans to explore the therapeutic potential of pitolisant in additional indications; our ongoing and planned clinical trials; our ability to expand the scope of our license agreements with Bioprojet Société Civile de Recherche (“Bioprojet”); the availability of favorable insurance coverage and reimbursement for WAKIX; the timing of, and our ability to obtain, regulatory approvals for pitolisant for other indications as well as any other product candidates; our estimates regarding expenses, future revenue, capital requirements and additional financing needs; our ability to identify, acquire and integrate additional products or product candidates with significant commercial potential that are consistent with our commercial objectives; our commercialization, marketing and manufacturing capabilities and strategy; significant competition in our industry; our intellectual property position; loss or retirement of key members of management; failure to successfully execute our growth strategy, including any delays in our planned future growth; our failure to maintain effective internal controls; the impact of government laws and regulations; volatility and fluctuations in the price of our common stock; the significant costs and required management time as a result of operating as a public company; the fact that the price of Harmony's common stock may be volatile and fluctuate substantially; statements related to our intended share repurchases and repurchase timeframe and the significant costs and required management time as a result of operating as a public company. These and other important factors discussed under the caption "Risk Factors" in our Annual Report on Form 10-K filed with the Securities and Exchange Commission (the "SEC") on February 22, 2024, and our other filings with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management's estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. View source version on businesswire.com: https://www.businesswire.com/news/home/20250113795547/en/ Harmony Biosciences Investor: Brennan Doyle 484-539-9700 bdoyle@harmonybiosciences.com Harmony Biosciences Media: Cate McCanless 202-641-6086 cmccanless@harmonybiosciences.com Source: Harmony Biosciences

AXS-12 statistically significantly reduced the frequency of cataplexy attacks compared to placebo (p=0.017, primary endpoint) Statistically significant improvement in cognition compared to placebo (p=0.011, NSAQ) Statistically significant improvement in narcolepsy overall compared to placebo (p=0.024, PGI-C) Cataplexy response (≥50% improvement) achieved by 72% of patients at 1 month and 82% at 6 months Improvement in excessive daytime sleepiness (EDS), assessed by the CGI-C, achieved by 84% of patients at 1 month and 78% at 6 months Improvement in narcolepsy overall, assessed by the CGI-C, achieved by 90% of patients at 1 month and 90% at 6 months Well-tolerated with long-term safety profile consistent with previously completed trials and no new safety signals detected NEW YORK, Nov. 26, 2024 (GLOBE NEWSWIRE) -- Axsome Therapeutics, Inc. (NASDAQ: AXSM), a biopharmaceutical company developing and delivering innovative therapies for the management of central nervous system (CNS) disorders, today announced that AXS-12 (reboxetine), a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, achieved the primary endpoint in the ENCORE Phase 3 trial, demonstrating a statistically significant improvement in the frequency of cataplexy attacks compared to placebo. AXS-12 was also well tolerated with long-term dosing with a safety profile consistent with that observed in previously completed trials. ENCORE was a multi-center, two-period Phase 3 trial evaluating the long-term efficacy and safety of AXS-12 in patients with narcolepsy with cataplexy, consisting of a 6-month open-label AXS-12 treatment period, followed by a 3-week double-blind, placebo-controlled, randomized withdrawal period. The trial enrolled 68 patients in the 6-month AXS-12 treatment period. Patients (n=42) were then randomized in a 1:1 ratio to continue treatment with AXS-12 or to discontinue AXS-12 and switch to placebo for 3 weeks. AXS-12 met the primary endpoint of the change from randomization in the frequency of cataplexy attacks as compared to placebo at week 3 of the double-blind period. Patients randomized to switch to placebo experienced a statistically significant worsening in the average weekly number of cataplexy attacks compared with patients randomized to continue AXS-12 treatment, with an increase of 10.29 attacks per week with placebo versus 1.32 with AXS-12, at 3 weeks (p=0.017). “Clinical evidence continues to support AXS-12 as a novel treatment option for narcolepsy that has the potential to rapidly and durably ameliorate one of the most debilitating symptoms for patients, cataplexy, while also reducing the severity of excessive daytime sleepiness, and improving cognition and overall function,” commented Dr. Michael Thorpy, Director of the Sleep-Wake Disorders Center at the Montefiore Medical Center and Professor of Neurology at Albert Einstein College of Medicine. “Narcolepsy is a complex and heterogeneous condition defined by distinct symptom clusters and there remains great need for options that can address this variety in disease presentation. The results from the ENCORE study support AXS-12 as a potentially important new option for physicians and patients.” AXS-12 resulted in statistically significant benefit in cognition compared to placebo, as assessed by the Narcolepsy Symptom Assessment Questionnaire (NSAQ) and the Patient Global Impression of Change (PGI-C). A significantly greater proportion of patients randomized to switch to placebo experienced worsening on the NSAQ Ability to Concentrate item compared to those continuing on AXS-12 (52.6% versus 14.3%) at 3 weeks (p=0.011). A significantly greater proportion of patients randomized to switch to placebo also reported worsening in their ability to concentrate, as assessed by the PGI-C, compared to those continuing on AXS-12 (57.9% versus 22.2%) at 3 weeks (p=0.029). AXS-12 resulted in statistically significant benefit in narcolepsy overall compared to placebo, as assessed by the PGI-C. A significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy, as assessed by the PGI-C, compared to those continuing on AXS-12 (52.6% versus 16.7%) at 3 weeks (p=0.024). “The results of the ENCORE trial confirm the efficacy of AXS-12 in patients with narcolepsy with cataplexy, which has now been demonstrated in three positive controlled trials, and indicate that the potential benefits of AXS-12 are substantial and sustained with long-term treatment,” said Dr. Herriot Tabuteau, CEO of Axsome Therapeutics. “We are pleased by the improvements not only in cataplexy, but also in excessive daytime sleepiness and cognition reported by a majority of patients in the trial with long-term AXS-12 treatment. Importantly, these improvements were accompanied by a favorable long-term safety and tolerability profile. We plan to move expeditiously towards an NDA filing for AXS-12 and intend to request a pre-NDA meeting with the FDA.” During the long-term open-label treatment portion of the trial, patients experienced substantial and sustained improvement of cataplexy with AXS-12 treatment. Patients experienced a 71% reduction from baseline in mean weekly cataplexy attacks at 1 month with AXS-12 treatment, which was sustained with long-term treatment resulting in a 77% reduction at 6 months. Cataplexy response, defined as ≥50% reduction from baseline in weekly cataplexy attacks, was achieved by 72% of patients at 1 month, and by 82% of patients at 6 months with AXS-12 treatment. Treatment with AXS-12 also substantially increased the percentage of cataplexy-free days (days with zero cataplexy attacks) per week from 14% at baseline to 61% at 1 month and 70% at 6 months. Long-term open-label treatment with AXS-12 resulted in substantial improvements in excessive daytime sleepiness (EDS), assessed using the Epworth Sleepiness Scale (ESS) and the Clinician Global Impression of Change (CGI-C) scale. Mean ESS scores were reduced by 5.6 points at 1 month, with this improvement maintained with long-term treatment resulting in a mean reduction of 7.3 points at 6 months. Clinicians reported improvement in EDS in a substantial proportion of patients on the CGI-C scale, with 84% of patients achieving EDS improvement at 1 month and 78% of patients at 6 months with AXS-12 treatment. A substantial proportion of patients reported improvement in cognition with AXS-12 which was sustained with long-term open-label treatment. Improvement in cognition, assessed by the NSAQ Ability to Concentrate item, was reported by 55% of patients at 1 month and 59% at 6 months with AXS-12 treatment. Change in the ability to concentrate was also assessed using the PGI-C scale. The proportion of patients reporting improvement in the ability to concentrate on the PGI-C was 67% at 1 month and 70% at 6 months with AXS-12 treatment. Long-term open-label treatment with AXS-12 was also associated with improvement in overall narcolepsy status and patient functioning, assessed using the CGI-C, the PGI-C, and the Work Productivity and Activity Impairment Questionnaire (WPAI). On the CGI-C, clinicians reported overall improvement in narcolepsy in 90% of patients at 1 month and also 90% of patients at 6 months with AXS-12 treatment. Results were similar with the patient-reported PGI-C. Impairment due to narcolepsy while working was assessed after treatment with AXS-12 using the WPAI. The percentage of time impaired while working decreased substantially with AXS-12 treatment from 53% at baseline to 34% at 1 month and 24% at 6 months. AXS-12 was well tolerated with long-term dosing. The safety profile with long-term dosing was consistent with prior trials of AXS-12 with no new safety signals identified. During the 6-month open-label treatment period, the most common adverse events (≥5%) were nausea (5.9%) and tachycardia (5.9%). Over the 6-month treatment period, 17.6% of patients discontinued due to adverse events, with no individual adverse event leading to discontinuation by more than 1 patient. Treatment-related adverse events during the double-blind period were reported in 4.5% of patients in the AXS-12 group and 15% of patients in the placebo group. Rates of discontinuation due to adverse events in the double-blind period were 0% and 5% in the AXS-12 and placebo groups, respectively. AXS-12 has been granted Orphan Drug Designation for the treatment of narcolepsy. Orphan Drug Designation is granted to promising drugs intended for the safe and effective treatment of rare diseases, defined as those affecting fewer than 200,000 people in the U.S. This designation may entitle Axsome to a period of seven years of marketing exclusivity in the U.S. upon FDA approval and a waiver of the Company’s obligation to pay the FDA application user fees for the product as required by the Prescription Drug User Fee Act. AXS-12 is covered by issued patents providing protection to at least 2039. Double-Blind Efficacy Highlights A total of 42 patients were randomized, 22 to continued treatment with AXS-12, and 20 switched to placebo. The primary endpoint was the change from randomization to week 3 in the weekly frequency of cataplexy attacks.The primary endpoint was achieved with patients randomized to switch to placebo experiencing a mean increase of 10.29 cataplexy attacks per week compared to a mean increase of 1.32 attacks per week for patients randomized to continue AXS-12 treatment, at 3 weeks (p=0.017).A significantly greater proportion of patients randomized to switch to placebo experienced worsening on the NSAQ Ability to Concentrate item compared to those continuing on AXS-12 (52.6% versus 14.3%) at 3 weeks (p=0.011).A significantly greater proportion of patients randomized to switch to placebo also reported worsening in their ability to concentrate, as assessed by the PGI-C, compared to those continuing on AXS-12 (57.9% versus 22.2%) at 3 weeks (p=0.029).A significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy overall, as assessed by the PGI-C, compared to those continuing on AXS-12 (52.6% versus 16.7%) at 3 weeks (p=0.024). Long-Term Efficacy Highlights A total of 68 patients were treated with AXS-12 for up to 6 months in an open-label fashion. At baseline, the mean number of weekly cataplexy attacks was 31.3 and the mean ESS was 18. Efficacy results for this treatment period are summarized below: Cataplexy Treatment with AXS-12 resulted in a mean reduction from baseline of 22.3 cataplexy attacks per week at 1 month, corresponding to a decrease of 71%. The improvement in cataplexy was maintained with long-term AXS-12 treatment, resulting in a mean reduction of 24.1 cataplexy attacks per week at 6 months, corresponding to a decrease of 77%.Cataplexy response, defined as ≥50% reduction from baseline in the weekly frequency of cataplexy attacks, was achieved by 72% of patients at 1 month, and by 82% of patients at 6 months with AXS-12 treatment.AXS-12 increased the percentage of cataplexy free days (days with zero cataplexy attacks) per week from 14.3% at baseline to 61% at 1 month and 70% at 6 months. Excessive Daytime Sleepiness (EDS) Treatment with AXS-12 resulted in mean reductions from baseline in the ESS score of 5.6 points at 1 month and 7.3 points at 6 months.EDS, assessed by the Clinician Global Impression of Change (CGI-C), was improved in 84% of patients at 1 month, and in 78% of patients at 6 months with AXS-12 treatment. Cognition AXS-12 treatment was associated with an improvement in cognition, assessed by the NSAQ Ability to Concentrate item, with 55% of patients reporting improvement at 1 month, and 59% reporting improvement at 6 months.AXS-12 treatment was also associated with an improvement in the ability to concentrate, assessed by the PGI-C, with 67% of patients reporting improvement at 1 month, and 70% reporting improvement at 6 months. Narcolepsy Overall, Work Productivity Narcolepsy overall, assessed by the CGI-C, was improved in 90% of patients at 1 month and 90% at 6 months with AXS-12 treatment.AXS-12 treatment was associated with an improvement in narcolepsy overall, assessed by the PGI-C, with 78% of patients reporting improvement at 1 month, and 80% reporting improvement at 6 months.AXS-12 treatment was associated with improved patient function by substantially decreasing the time impaired due to narcolepsy while working, assessed by the WPAI, from 53% at baseline to 34% at 1 month and 24% at 6 months. Long-Term Safety and Tolerability Highlights Safety results are for all patients enrolled in the ENCORE trial (n=68). Safety results for the 6-month treatment and double-blind periods are summarized below. AXS-12 was well tolerated with a safety profile that was consistent with what was previously observed in completed, short-term controlled trials, with no new safety signals detected.The most commonly reported adverse events (≥5%) were nausea (5.9%) and tachycardia (5.9%).Discontinuations due to adverse events occurred in 17.6% of patients, with no individual event leading to discontinuation by more than 1 patient.During the double-blind period, the rates of treatment-related adverse events were 4.5% in the AXS-12 group and 15.0% in the placebo group. Discontinuations due to adverse events in the double-blind period occurred in no patients in the AXS-12 group and in 1 patient in the placebo group. About the ENCORE Study ENCORE (Evaluating Continued Treatment with Reboxetine) was a multicenter Phase 3 trial consisting of a 24-week open-label period followed by a 3-week, double-blind, randomized withdrawal period to evaluate the efficacy and long-term safety of AXS-12 in patients with narcolepsy. A total of 68 patients, who rolled over from the SYMPHONY Phase 3 trial of AXS-12, were enrolled into the open-label period and treated with AXS-12 (5 mg) once-daily for the first week, followed by twice daily dosing for the next 23 weeks. Patients who completed the open-label treatment period (n=42) were then randomized in a 1:1 ratio to continue on AXS-12 (n=22) or to switch to placebo (n=20). The mean number of cataplexy attacks at baseline was 31.3. The mean number of cataplexy attacks at randomization was 4.2 (AXS-12) and 6.9 (placebo). The prespecified primary efficacy endpoint was the change in frequency of weekly cataplexy attacks from baseline at randomization to week 3 of the double-blind period. Other symptoms of narcolepsy as well as safety and tolerability were assessed throughout the study. About Narcolepsy Narcolepsy is a serious and debilitating orphan neurological condition that causes dysregulation of the sleep-wake cycle and is characterized clinically by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nocturnal sleep.1-3 Cataplexy is seen in an estimated 70% of narcolepsy patients and is a sudden reduction or loss of muscle tone while a patient is awake, typically triggered by strong emotions such as laughter, fear, anger, stress, or excitement.4-5 Narcolepsy is a life-long condition that interferes with cognitive, psychological, and social functioning, increases the risk of work- and driving-related accidents, and is associated with a 1.5-fold higher mortality rate.6-8 About AXS-12 AXS-12 (reboxetine) is a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator under development for the treatment of narcolepsy. AXS-12 is thought to modulate noradrenergic activity to promote maintain tone during wakefulness, and noradrenergic and cortical dopamine signaling to promote wakefulness and enhance cognition. AXS-12 has been granted U.S. Food and Drug Administration (FDA) Orphan Drug Designation for the treatment of narcolepsy. AXS-12 is covered by issued patents providing protection to at least 2039. AXS-12 is an investigational drug product not approved by the FDA. About Axsome Therapeutics Axsome Therapeutics is a biopharmaceutical company leading a new era in the treatment of central nervous system (CNS) conditions. We deliver scientific breakthroughs by identifying critical gaps in care and develop differentiated products with a focus on novel mechanisms of action that enable meaningful advancements in patient outcomes. Our industry-leading neuroscience portfolio includes FDA-approved treatments for major depressive disorder and excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea and multiple late-stage development programs addressing a broad range of serious neurological and psychiatric conditions that impact over 150 million people in the United States. Together, we are on a mission to solve some of the brain’s biggest problems so patients and their loved ones can flourish. For more information, please visit the Company’s website at www.axsome.com. Forward Looking Statements Certain matters discussed in this press release are “forward-looking statements”. The Company may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s statements regarding trends and potential future results are examples of such forward-looking statements. The forward-looking statements include risks and uncertainties, including, but not limited to, the continued commercial success of the Company’s Sunosi® and Auvelity® products and the success of the Company’s efforts to obtain any additional indication(s) with respect to solriamfetol and/or AXS-05; the Company’s ability to maintain and expand payer coverage; the success, timing and cost of the Company’s ongoing clinical trials and anticipated clinical trials for the Company’s current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials (including the Company’s ability to fully fund the Company’s disclosed clinical trials, which assumes no material changes to the Company’s currently projected revenues or expenses), futility analyses and receipt of interim results, which are not necessarily indicative of the final results of the Company’s ongoing clinical trials, and/or data readouts, and the number or type of studies or nature of results necessary to support the filing of a new drug application (“NDA”) for any of the Company’s current product candidates; the Company’s ability to fund additional clinical trials to continue the advancement of the Company’s product candidates; the timing of and the Company’s ability to obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, the Company’s product candidates, including statements regarding the timing of any NDA submission; whether issues identified by FDA in the complete response letter may impact the potential approvability of the Company’s NDA for AXS-07 for the acute treatment of migraine in adults with or without aura, pursuant to the Company’s special protocol assessment for the MOMENTUM clinical trial; the Company’s ability to successfully defend its intellectual property or obtain the necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research and development programs and collaborations; the success of the Company’s license agreements; the acceptance by the market of the Company’s products and product candidates, if approved; the Company’s anticipated capital requirements, including the amount of capital required for the continued commercialization of Sunosi and Auvelity and for the Company’s commercial launch of its other product candidates, if approved, and the potential impact on the Company’s anticipated cash runway; the Company’s ability to convert sales to recognized revenue and maintain a favorable gross to net sales; unforeseen circumstances or other disruptions to normal business operations arising from or related to domestic political climate, geo-political conflicts or a global pandemic and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstance. Investors:Mark JacobsonChief Operating Officer(212) 332-3243mjacobson@axsome.com Media:Darren OplandDirector, Corporate Communications(929) 837-1065 dopland@axsome.com References American Academy of Sleep Medicine. The International Classification of Sleep Disorders. Third Edition (ICSD-3). 2014.National Institute of Neurological Disorders and Stroke. Narcolepsy.https://www.ninds.nih.gov/health-information/disorders/narcolepsy. Accessed September 2024.España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011 Jul 1;34(7):845-58.Narcolepsy Network. About Narcolepsy. https://narcolepsynetwork.org/about-narcolepsy/. Accessed September 2024.Swick TJ. Treatment paradigms for cataplexy in narcolepsy: past, present, and future. Nat Sci Sleep. 2015 Dec 11;7:159-69.Tadrous R, O'Rourke D, Mockler D, Broderick J. Health-related quality of life in narcolepsy: A systematic review and meta-analysis. J Sleep Res. 2021 Dec;30(6):e13383.Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. J Clin Sleep Med. 2019 Feb 15;15(2):301-334.Ohayon MM, Black J, Lai C, Eller M, Guinta D, Bhattacharyya A. Increased mortality in narcolepsy. Sleep. 2014 Mar 1;37(3):439-44.