Pitolisant Hydrochloride

​PLYMOUTH MEETING, Pa.--(BUSINESS WIRE)--Harmony Biosciences Holdings, Inc. (Nasdaq: HRMY) today announced strong year-over-year revenue growth for WAKIX® of 20% in the first quarter 2025, on its way to a potential $1B+ opportunity in narcolepsy alone and poised for additional growth from its next-gen pitolisant development programs. The company has demonstrated four consecutive years of profitability and has grown its cash and investments position to over $600M. “Building off of our strong foundation of commercial success, we are poised for significant momentum throughout the rest of the year, driven by the upcoming catalysts from our robust, late-stage pipeline,” said Jeffrey M. Dayno, M.D., President and Chief Executive Officer of Harmony Biosciences. “Our next major clinical milestone, topline data readout from our Phase 3 registrational trial of ZYN002 in patients with Fragile X syndrome, the RECONNECT Study, is on track for Q3. A positive readout could put us on a path toward the first ever approved treatment for this patient community. I am proud of the unique profile we have created at Harmony, a profitable, self-funding biotech company, with a robust pipeline, that has the potential to help hundreds of thousands of patients living with unmet medical needs while creating significant, long-term value.” Franchise Highlights Sleep/Wake Franchise WAKIX in Narcolepsy Net Revenue was $184.7 million for Q1 2025 2025 Net Revenue projected between $820 to $860 million The average number of patients on WAKIX increased to approximately 7,200 for Q1 2025 and we exited the quarter with approximately 7,300 patients Pitolisant HD (high-dose) Higher dose and optimized pharmacokinetic profile designed for greater efficacy in narcolepsy; development program to pursue multiple additional indications Phase 3 registrational trial in narcolepsy designed for greater efficacy in excessive daytime sleepiness and cataplexy; also to include endpoint on narcolepsy-related fatigue in pursuit of differentiated label Phase 3 registrational trial in IH to include endpoint on sleep inertia in pursuit of differentiated label On track to initiate Phase 3 registrational trials in both narcolepsy and IH in Q4 2025 with potential PDUFA dates in 2028 Utility patents filed out to 2044 for narcolepsy and IH Pitolisant GR (gastro-resistant) Pivotal bioequivalence study initiated in March 2025 Topline data readout anticipated in Q3 2025 with potential PDUFA date in 2026 Utility patents filed out to 2044 Orexin-2 receptor agonist (BP1.15205) Comprehensive preclinical safety and efficacy data to be presented at SLEEP 2025 (June) 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 IMPD submission on track for mid-2025; first-in-human study expected to initiate 2H 2025 with clinical data anticipated in 2026 Neurobehavioral Franchise ZYN002 Completed recruitment of Phase 3 registrational trial, the RECONNECT Study, in patients with Fragile X syndrome (FXS); on track for topline data readout in Q3 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 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 Promising new open-label extension (OLE) data shows benefit in patients with FXS Participants in the OLE trial demonstrated clinically meaningful improvements in behavioral symptoms as measured by the Aberrant Behavior Checklist – Community (ABC-C FXS Irritability) More than 60% of participants achieved clinically meaningful improvement of at least 9 points on the ABC-C FXS Irritability scores out to 3 years Participants in the OLE trial demonstrated clinically meaningful improvements in behavioral symptoms as measured by the Aberrant Behavior Checklist – Community (ABC-C FXS Irritability) More than 60% of participants achieved clinically meaningful improvement of at least 9 points on the ABC-C FXS Irritability scores out to 3 years Potential to be the first and only approved treatment for patients with FXS; 80,000 patients in the U.S. and Harmony possesses global rights Prepared to initiate Phase 3 registrational trial in 22q11.2 deletion syndrome (22q) in Q4 2025 (pending positive data from the RECONNECT Study) Rare Epilepsy Franchise EPX-100 (clemizole hydrochloride) Most advanced development program in the 5HT2 (serotonin) agonist class Recruitment ongoing for Phase 3 registrational trial in Dravet syndrome (ARGUS Study) with topline data anticipated in 2026 Recruitment ongoing for Phase 3 registrational trial in patients with Lennox-Gastaut syndrome (LIGHTHOUSE Study) with topline data 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 First Quarter 2025 Financial Results Net product revenue for the quarter ended March 31, 2025, was $184.7 million, compared to $154.6 million for the same period in 2024. The 20% growth versus the same period in 2024 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 quarter ended March 31, 2025, was $45.6 million, or $0.78 earnings per diluted share, compared to GAAP net income of $38.3 million, or $0.67 earnings per diluted share, for the same period in 2024. Non-GAAP adjusted net income was $60.4 million, or $1.03 earnings per diluted share, for the quarter ended March 31, 2025, compared to Non-GAAP adjusted net income of $50.7 million, or $0.88 per diluted share, for the same period in 2024. Reconciliations of applicable GAAP financial measures to Non-GAAP financial measures are included at the end of this press release. Harmony’s operating expenses include the following: Research and Development expenses were $34.5 million in the first quarter of 2025, as compared to $22.2 million for the same quarter in 2024, representing a 56% increase; Sales and Marketing expenses were $30.7 million in the first quarter of 2025, as compared to $27.2 million for the same quarter in 2024, representing a 13% increase; General and Administrative expenses were $31.2 million in the first quarter of 2025, as compared to $25.7 million for the same quarter in 2024, representing a 22% increase; and Total Operating Expenses were $96.5 million in the first quarter of 2025, as compared to $75.1 million for the same quarter in 2024, representing a 29% increase. As of March 31, 2025, Harmony had cash, cash equivalents and investments of $610.2 million, compared to $576.1 million as of December 31, 2024. 2025 Net Product Revenue Guidance Expect full year 2025 net product revenue of $820 million to $860 million. Conference Call Today at 8:30 a.m. ET We are hosting our first quarter 2025 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 https://ir.harmonybiosciences.com/. To participate in the live call by phone, dial 800-267-6316 (domestic) or 203-518-9783 (international), and reference passcode HRMYQ125. Non-GAAP Financial Measures In addition to our GAAP results, we present certain Non-GAAP measures 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 2025 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, including ZYN002 and EPX-100; 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 macroeconomic effects and changes in market conditions, including the impact of tariffs, inflation and the risk of recession. 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 (In thousands, except share and per share data) Three Months Ended March 31, 2025 2024 Net product revenue $ 184,733 $ 154,615 Cost of product sold 31,994 27,484 Gross profit 152,739 127,131 Operating expenses: Research and development 34,540 22,189 Sales and marketing 30,711 27,233 General and administrative 31,243 25,676 Total operating expenses 96,494 75,098 Operating income 56,245 52,033 Other expense, net (276 ) (141 ) Interest expense (3,836 ) (4,535 ) Interest income 5,044 4,428 Income before income taxes 57,177 51,785 Income tax expense (11,617 ) (13,451 ) Net income $ 45,560 $ 38,334 Unrealized income (loss) on investments 179 (173 ) Comprehensive income $ 45,739 $ 38,161 EARNINGS PER SHARE: Basic $ 0.79 $ 0.68 Diluted $ 0.78 $ 0.67 Weighted average number of shares of common stock - basic 57,309,938 56,771,251 Weighted average number of shares of common stock - diluted 58,524,566 57,597,627 HARMONY BIOSCIENCES HOLDINGS, INC. AND SUBSIDIARIES CONSOLIDATED BALANCE SHEETS (In thousands, except share and per share data) March 31, December 31, 2025 2024 ASSETS CURRENT ASSETS: Cash and cash equivalents $ 488,998 $ 453,001 Investments, short-term 17,955 14,185 Trade receivables, net 105,969 83,033 Inventory, net 6,384 7,198 Prepaid expenses 16,470 13,714 Other current assets 6,916 8,121 Total current assets 642,692 579,252 NONCURRENT ASSETS: Property and equipment, net 1,378 1,257 Restricted cash 270 270 Investments, long-term 103,245 108,874 Intangible assets, net 107,302 113,263 Deferred tax asset 194,709 190,398 Other noncurrent assets 5,939 5,886 Total noncurrent assets 412,843 419,948 TOTAL ASSETS $ 1,055,535 $ 999,200 LIABILITIES AND STOCKHOLDERS’ EQUITY CURRENT LIABILITIES: Trade payables $ 17,459 $ 13,744 Accrued compensation 7,582 18,776 Accrued expenses 112,701 120,640 Current portion of long-term debt 17,500 16,250 Other current liabilities 19,876 5,672 Total current liabilities 175,118 175,082 NONCURRENT LIABILITIES: Long-term debt, net 158,182 163,016 Other noncurrent liabilities 1,710 1,947 Total noncurrent liabilities 159,892 164,963 TOTAL LIABILITIES 335,010 340,045 COMMITMENTS AND CONTINGENCIES (Note 13) STOCKHOLDERS’ EQUITY: Common stock—$0.00001 par value; 500,000,000 shares authorized at March 31, 2025 and December 31, 2024, respectively; 57,393,673 and 57,144,887 shares issued and outstanding at March 31, 2025 and December 31, 2024, respectively 1 1 Additional paid in capital 672,503 656,872 Accumulated other comprehensive income 245 66 Retained earnings 47,776 2,216 TOTAL STOCKHOLDERS’ EQUITY 720,525 659,155 TOTAL LIABILITIES AND STOCKHOLDERS’ EQUITY $ 1,055,535 $ 999,200 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 March 31, March 31, 2025 2024 GAAP net income $ 45,560 $ 38,334 Non-GAAP Adjustments: Non-cash interest expense (1) 166 180 Depreciation 7 163 Amortization (2) 5,961 5,961 Stock-based compensation expense 12,450 10,434 Income tax effect related to non-GAAP adjustments (3) (3,776 ) (4,350 ) Non-GAAP adjusted net income $ 60,368 $ 50,722 GAAP reported net income per diluted share $ 0.78 $ 0.67 Non-GAAP adjusted net income per diluted share $ 1.03 $ 0.88 Weighted average number of shares of common stock used in non-GAAP diluted per share 58,524,566 57,597,627 (1) Includes amortization of deferred finance charges. (2) Includes amortization of intangible asset related to WAKIX. (3) Calculated using the reported effective tax rate for the periods presented less impact of valuation allowance release and discrete items.

MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)--Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced multiple presentations at the Society of Biological Psychiatry (SOBP) Annual Meeting, in Toronto, Canada, held April 24-26, 2025. “The biological and clinical insights we presented at SOBP support our precision psychiatry pipeline and mark important advancements for the field,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “To address the longstanding challenge of high placebo response in neuropsychiatric clinical development, we have successfully identified and prospectively replicated an EEG biomarker that captures placebo response patterns in patients with major depressive disorder. We believe this biomarker has the potential to reduce noise and improve the detection of true therapeutic effect.” Dr. Etkin continued, “We enhanced our understanding of the mechanistic link between ALTO-300 and the machine-learning derived, EEG biomarker used to identify patients who are more likely to respond to treatment. We showed that increasing 5-HT2C activity or directly depleting dopamine—both the opposite mechanistic effect of ALTO-300—resulted in greater EEG irregularity, consistent with a biomarker positive profile. Additionally, in a preclinical rescue study we demonstrated that ALTO-101 increased theta response, demonstrating its robustness as a translational biomarker for cognitive impairment associated with schizophrenia and potential pro-cognitive drug effect. We look forward to leveraging these findings to drive meaningful innovation in psychiatry and enhance clinical outcomes for patients.” Summary of Data Presentations Across Clinical Programs EEG-based biomarker for placebo response in MDD Background and Rationale: High placebo response is a major challenge in clinical trials for patients with major depressive disorder (MDD), yet no validated biomarker exists for reliably identifying high placebo responders. A shared predictor across diverse established antidepressant treatments was hypothesized to approximate a placebo response. Prospective replication was conducted in two randomized trials, including placebo and active arms. Within the two randomized trials, the ability to increase drug-placebo effect size was evaluated by incorporating placebo response predictions as sample weights. A shared predictor across diverse established antidepressant treatments was hypothesized to approximate a placebo response. Prospective replication was conducted in two randomized trials, including placebo and active arms. Within the two randomized trials, the ability to increase drug-placebo effect size was evaluated by incorporating placebo response predictions as sample weights. An EEG-based biomarker capable of predicting non-specific treatment response across multiple interventions and independent datasets​ was developed and validated. The placebo biomarker yielded significant predictions for the open-label ALTO-100 and sertraline treatment response, both analyzed prospectively. Additional prospective analyses in two randomized-controlled MDD studies were conducted to further validate the previously identified EEG-based placebo biomarker (ALTO-100 Phase 2b trial and the EMBARC sertraline trial) on both placebo response and drug-placebo differences. In the ALTO-100 placebo arm, the biomarker significantly predicted MADRS score change across all weeks with correlation ranging from 0.29 to 0.19 (p=0.001 to p=0.029; Cohen’s d=0.49 to d=0.41) at weeks 2 and 6 respectively. In the EMBARC placebo arm, the biomarker significantly predicted HAMD score change, with a partial correlation ranging from 0.24 to 0.31 (p=0.009 to p=0.001) at weeks 6 and 8 respectively. Drug-placebo treatment effect sizes were enhanced across diverse drug mechanisms when accounting for individual differences in predicted placebo response, as demonstrated by both the Phase 2b trial of ALTO-100 and EMBARC trial of sertraline. This biomarker has the potential to enable more precise identification of high placebo responders in MDD trials, reduce trial variability, and enhance detection of treatment effects. Alto has patent protection covering the use of EEG biomarkers to predict placebo response. ALTO-300 Background and Rationale: ALTO-300 is an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist. ALTO-300 has been shown to enhance dopaminergic and noradrenergic input to the frontal cortex and rescue anhedonia-like behavioral deficits. Greater gamma sample entropy (SE), or EEG irregularity, was previously shown to predict antidepressant response to ALTO-300 in MDD. Increasing 5-HT2C activity or directly depleting dopamine (both the opposite mechanism of ALTO-300) was hypothesized to increase gamma SE and create a more biomarker positive EEG pattern. Increasing 5-HT2C activity or directly depleting dopamine (both the opposite mechanism of ALTO-300) was hypothesized to increase gamma SE and create a more biomarker positive EEG pattern. Administered two different 5-HT2C agonists (R0-0175 and YM348) in independent preclinical studies and revealed a dose-related increase in SE. 5-HT2C agonism also led to an anhedonic phenotype as demonstrated by a sucrose preference test. In a double-blind, placebo-controlled, cross-over study, healthy participants consumed a nutritionally balanced amino acid mixture (placebo) and a mixture deficient in the dopamine precursors tyrosine and phenylalanine (APTD) in a counterbalanced order. SE was significantly larger in the APTD condition compared to the placebo condition (p<0.01, Cohen’s d=0.94), indicating that dopamine depletion drives a biomarker positive EEG pattern. The ALTO-300 biomarker signal likely reflects increased neural noise due to elevated 5-HT2C tone and reduced dopaminergic activity. The mechanism of action of ALTO-300 involves an increase in dopamine in part through 5-HT2C antagonism. These findings therefore provide a direct link between ALTO-300 and the EEG biomarker used to identify MDD patients who are more likely to be responders to treatment. ALTO-101 Background and Rationale: Cognitive Impairment Associated with Schizophrenia (CIAS) remains a high unmet need, with no approved treatments specifically targeting these deficits. Theta EEG response, measured by inter-trial coherence (ITC), is reproducibly disrupted in patients with schizophrenia and was previously identified as a promising marker for CIAS. Theta response strongly correlated with cognitive deficits in patients in multiple datasets. N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a key role in CIAS pathophysiology. A rodent model was used to evaluate the effects of ALTO-101 on theta response following administration of MK-801, an NMDAR antagonist. N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a key role in CIAS pathophysiology. A rodent model was used to evaluate the effects of ALTO-101 on theta response following administration of MK-801, an NMDAR antagonist. Administration of MK-801 reduced theta response, modeling neural and behavioral abnormalities in schizophrenia. Administration of ALTO-101 led to a dose-dependent rescue of the theta response abnormality induced by MK-801 and was statistically significant at the highest dose of 0.1 mg/kg (p<0.001). Results are consistent with the completed Phase 1 trial in healthy volunteers, where ALTO-101 demonstrated robust, dose-dependent effects on theta response and cognitive test performance. The effects on these two measures were also correlated. Taken together, results validate theta response as a robust translational biomarker and underscore the potential cognitive benefits of ALTO-101 for patients with CIAS. ALTO-203 Background and rationale: ALTO-203 is a novel, differentiated histamine H3 inverse agonist shown to increase dopamine release in the nucleus accumbens in rodents. This is a property not shared by pitolisant, the only FDA approved H3R inverse agonist, indicated for the treatment of excessive daytime sleepiness in narcolepsy. A dopamine-related anhedonic state can be induced in rats through dopamine depletion with α-methyl-p-tyrosine (AMPT). Rescue of this sucrose preference deficit was evaluated to further investigate the behavioral effect of ALTO-203 on accumbens dopamine. Rats received ALTO-203, pitolisant, or vehicle co-administered with AMPT. Sucrose preference was assessed at baseline, five hours, and 20 hours post-treatment. A dopamine-related anhedonic state can be induced in rats through dopamine depletion with α-methyl-p-tyrosine (AMPT). Rescue of this sucrose preference deficit was evaluated to further investigate the behavioral effect of ALTO-203 on accumbens dopamine. Rats received ALTO-203, pitolisant, or vehicle co-administered with AMPT. Sucrose preference was assessed at baseline, five hours, and 20 hours post-treatment. Key Takeaways: ALTO-203 (0.1 mg/kg) effectively reversed anhedonia-like behavior induced by dopamine depletion and demonstrated a significantly higher sucrose preference at five hours versus vehicle co-administered with AMPT (p=0.014). Pitolisant showed no significant effect at any dose. These findings underscore the distinct behavioral effects of ALTO-203, which may be driven by enhancing the function and control of dopamine in the reward system. The following posters presented at SOBP 2025 are available under “Publications” in the platform section of Alto’s website: An EEG Biomarker for Predicting Placebo Response in Major Depressive Disorder: Development and Validation Across Open-Label and Double-Blind Trials Poster First Author : Chao Wang, Ph.D. Poster First Author : Chao Wang, Ph.D. Prospective Replication and Application of an EEG-Based Placebo Response Prediction Biomarker in Randomized Controlled Trials in Depression Poster First Author: Akshay S. Ravindran, Ph.D. Poster First Author: Akshay S. Ravindran, Ph.D. Gamma Band EEG Sample Entropy, a Patient Selection Biomarker for ALTO-300, is Increased by Acute Dopamine Precursor Depletion in Humans Poster First Author: Guhan Sundar Poster First Author: Guhan Sundar Gamma Band EEG Sample Entropy, a Patient Selection Biomarker for ALTO-300, is Increased by 5-HT2C Agonists in Mice Poster First Author: Yueqi Guo, Ph.D. Poster First Author: Yueqi Guo, Ph.D. Translational Utility of ERP and Time-Frequency Features: Effects of the NMDA Antagonist MK-801 in Rats Poster First Author: Guhan Sundar Poster First Author: Guhan Sundar ALTO-203, a Novel Histamine H3 Inverse Agonist, Increases Sucrose Preference in Dopamine-Depleted Rats Poster First Author: Li Shen, Ph.D. Poster First Author: Li Shen, Ph.D. About Alto Neuroscience Alto Neuroscience is a clinical-stage biopharmaceutical company with a mission to redefine psychiatry by leveraging neurobiology to develop personalized and highly effective treatment options. Alto’s Precision Psychiatry Platform™ measures brain biomarkers by analyzing EEG activity, neurocognitive assessments, wearable data, and other factors to better identify which patients are more likely to respond to Alto product candidates. Alto’s clinical-stage pipeline includes novel drug candidates in bipolar depression, major depressive disorder, schizophrenia, and other mental health conditions. For more information, visit www.altoneuroscience.com or follow Alto on X. Forward-Looking Statements This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “expects,” “plans,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding Alto’s expectations about the potential benefits, activity, and effectiveness of its product candidates, biomarkers, and Precision Psychiatry Platform (“Platform”); and Alto’s expectations with regard to the design and results of its clinical trials. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including uncertainties inherent in the initiation, progress and completion of clinical trials and other important factors, any of which could cause Alto’s actual results to differ from those contained in the forward-looking statements, which are described in greater detail in the section titled “Risk Factors” in Alto’s Annual Report on Form 10-K for the fiscal year ended December 31, 2024 filed with the Securities and Exchange Commission (“SEC”) as well as in other filings Alto may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Alto expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as required by law. Availability of Information on Alto’s Website Alto routinely uses its investor relations website to post presentations to investors and other important information, including information that may be material. Accordingly, Alto encourages investors and others interested in Alto to review the information it makes public on its investor relations website.