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© 2025 Acadia Pharmaceuticals Inc. All rights reserved. Advancing Care for Underserved Neurological and Rare Diseases R&D Day • New York City June 25, 2025
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Opening Remarks Catherine Owen Adams CEO
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Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements other than statements of historical fact and can be identified by terms such as “may, ” “will, ” “should, ” “could, ” “would, ” “expects, ” “plans, ” “anticipates, ” “believes, ” “estimates, ” “projects, ” “predicts, ” “outlook, ” “potential” and similar expressions (including the negative thereof) intended to identify forward-looking statements. Forward-looking statements contained in this presentation, include, but are not limited to, statements about: (i) our business strategy, objectives and opportunities; (ii) plans for, including timing, development and progress of commercialization or regulatory timelines for our products, including NUPLAZID and DAYBUE, and our product candidates; (iii) benefits to be derived from and efficacy of our products, including the potential advantages of our products and our product candidates, and for trofinetide in jurisdictions outside the U.S. and Canada, including Europe; (iv) estimates regarding the prevalence of the diseases targeted by our products and product candidates; (v) potential markets for any of our commercial products or product candidates; and (vi) our estimates regarding our future financial performance, cash position, profitability or capital requirements. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. Such risks, uncertainties and other factors include, but are not limited to: our dependency on the continued successful commercialization of our products and our ability to maintain or increase sales of our products; the costs of our commercialization plans and development programs, and the financial impact or revenues from any commercialization we undertake; our ability to successfully develop our product candidates and to obtain necessary regulatory approvals for our product candidates and, if and when approved, market acceptance of our products; our dependence on third-party collaborators, clinical research organizations, manufacturers, suppliers and distributors; the impact of competitive products and therapies; our ability to generate or obtain the necessary capital to fund our operations; our ability to grow , equip and train our specialized sales forces; our ability to manage the growth and complexity of our organization; our ability to maintain, protect and enhance our intellectual property; and our ability to continue to stay in compliance with applicable laws and regulations. Given the risks and uncertainties, you should not place undue reliance on these forward-looking statements. For a discussion of these and other risks, uncertainties and other factors that may cause our actual results, performance or achievements to differ, please refer to our annual report on Form 10-K for the year ended December 31, 2024 as well as our subsequent filings with the Securities and Exchange Commission from time to time, including our quarterly report on Form 10-Q for the period ended March 31, 2025. The forward-looking statements contained herein are made as of the date hereof, and we undertake no obligation to update them after this date, except as required by law . This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Projections, assumptions and estimates of the future performance of the markets in which we operate are necessarily subject to a high degree of uncertaint y and risk. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. 3
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Driving Near-Term Shareholder Value Two Growing Brands Late-Stage Pipeline ACP-101 (P3-PWS) Data expected early Q4 2025 ACP-204 (P2-ADP) Data expected mid-2026 ACP-101 Accelerated Phase 3 Readout expected in 2025 for Prader-Willi Syndrome Positive and Growing Cash Flow to invest aggressively in pipeline developments Strong Balance Sheet $1 Billion+ U.S. Total Revenues expected in 2025 P RECIS ION MEDI CIN E | DATA IN N OVATION | G LOBAL IZ ATION | PATIEN T EMPO WERME NTPOWE RE D BY Advancing Care for Underserved Neurological and Rare Diseases
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Today We Are Sharing Our Strategy for Long-Term Value Creation NeurologicalRare ADP ACP-204 (new 5-HT2A inverse agonist) Essential Tremor ACP-711 (selective GABAA-α3 modulator) MDD ACP-211 (Deuterated R-norketamine) PWS ACP-101 (Intranasal Carbetocin) LBDP ACP-204 (new 5-HT2A inverse agonist) CORE FRANCHISE CORE PIPELINE EXPANSION AREAS TD/HD ACP-271 (GPR88 agonist) Rett/Fragile X ACP-2591 (cGP analogue) Expansion to other Rare Disease areas under evaluation Endocrine Metabolic Nephrology Cardiovascular Immunology Expanded pipeline via internal innovation and business development P RECIS ION MEDI CIN E | DATA IN N OVATION | G LOBA L IZ ATION | PATIEN T EMPO WERME NTPOWE RE D BY Neuro Psych Neuro Rare 5
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Additional Potential for Pipeline -Driven Growth From New Products 6 1. Previously provided 2025 fin ancial guidance (May 6, 2025) 2. Based on in ternal Acadia estimates for current products as of June 25, 2025. 3. Internal Acadia estimate for risk adjusted peak sales potential o f pipeline molecules as of Jun e 25, 2025. 4. Internal Acadia estimate for full potential peak sales for pipeline molecules as of June 25, 2025, assuming all are successfully approved and co mmercialized. Note: Peak sales used for calculations do not all occur within the same fiscal year. Potential Peak Sales of Current Products 2025 Guidance Risk-adjusted Peak Sales Potential Full Peak Sales Potential $1.5-$2 Billion2 >$1 Billion1 Current Commercial Outlook Building from a position of strength with NUPLAZID and DAYBUE Incremental Pipeline Potential Addressing high unmet needs with little competition $12 Billion4 $2.5 Billion3
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Pipeline Overview Elizabeth H.Z. Thompson, Ph.D. EVP , Head of R&D
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8 Motivated by the Everyday Moments Unaffected Families Take for Granted Minna, Living With Rett Syndrome Evan, Living With Prader-Willi Syndrome John, Living With Parkinson’s Disease Psychosis
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Building Long-Term Growth in Neurological and Rare Diseases PROGRAM INDICATION MOLECULE DESCRIPTION NEUROLOGICAL DISEASES NUPLAZID Parkinson's Disease Psychosis 5HT2A inverse agonist ACP-204 Alzheimer's Disease Psychosis New 5HT2A inverse agonist ACP-204 Lewy Body Dementia w/ Psychosis New 5HT2A inverse agonist ACP-711 Essential Tremor Selective GABAA-α3 modulator ACP-211 Major Depressive Disorder Deuterated R-norketamine ACP-271 Tardive Dyskinesia GPR88 agonist NUPLAZID (pimavanserin) is o nly app roved in the U.S . by the FDA for the treatment of hallucinatio ns and delusions asso ciated with Par kinson's disease psy ch osis. DAYBUE (trofinetid e) is only ap proved in th e U.S . and Canada for the treatment of Rett synd rome in adults and ped iatric patients two years of age and older. DISCO VERY IND ENABLING PHASE 1 PHASE 2 PHASE 3 LAUNCHED RARE DISEASES DAYBUE Rett Syndrome Analogue of GPE ACP-101 Hyperphagia in Prader-Willi Syndrome Intranasal Carbetocin ACP-2591 Rett Syndrome; Fragile X Syndrome cGP analogue ACP-271 Huntington’s Disease GPR88 agonist STOKE ASO SYNGAP1 Antisense oligonucleotide (ASO) + Multiple undisclosed discovery programs in neurological and rare disease 9
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Advancing care for underserved neurological and rare diseases We have a robust and active pipeline, gathering momentum over the next few years 2 Approved medicines 9 Disclosed and Multiple undisclosed programs 7 Phase 2 or Phase 3 study starts expected in 2025 and 2026 5 Phase 2 or Phase 3 study readouts anticipated 2025-2027
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Acadia R&D Day Agenda WELCOME AND INTRODUCTION Catherine Owen Adams CEO OPENING Elizabeth H.Z. Thompson, Ph.D. EVP , Head of Research and Development ACP-204 Sanjeev Pathak, M.D. SVP, Clinical Development ACP-211 Dragana Bugarski-Kirola, M.D. VP, Clinical Development Q&A ACP-711 Victor Abler , D.O VP, Medical Affairs ACP-271 TD Rachael Hawtin, Ph.D. VP, Translational Sciences Q&A BREAK ACP-271 HD Rachael Hawtin, Ph.D. VP, Translational Sciences ACP-101 Jim Youakim, M.D., VP, Clinical Development Susan Hedstrom, Foundation for Prader-Willi Research Shawn McCandless, M.D., University of Colorado DAYBUE Ponni Subbiah, M.D., M.P .H. SVP, Global Head of Medical Affairs & CMO RARE EPILEPSIES AND EXPANSION RARE AREAS Elizabeth H.Z. Thompson, Ph.D. EVP , Head of Research and Development ACADIA’S R&D STRATEGY Elizabeth H.Z. Thompson, Ph.D. EVP , Head of Research and Development Q&A CLOSING 11
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Neurological Disease – Neuro-Psych Introduction Elizabeth H.Z. Thompson, Ph.D. EVP , Head of R&D
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Neurological Disease – Neuro-Psych ACP-204: Alzheimer’s Disease Psychosis and Lewy Body Dementia with Psychosis Sanjeev Pathak, M.D. SVP , Clinical Development
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ACP-204 ACP-204: Alzheimer’s Disease Psychosis (ADP) and Lewy Body Dementia Psychosis (LBDP) 14 Alzheimer’s Disease & Lewy Body Dementia are severe neurodegenerative diseases, often marked by hallucinations and delusions (psychosis)1 Unmet Need No approved treatments specifically for ADP and LBDP1 Off-label treatments can impact cognition, motor, and autonomic functions, cause sedation, increase risks of falls and fractures2 High-need, complex patient populations benefited by easy, convenient dosing Rationale for Development ACP-204 is designed to build upon NUPLAZID (pimavanserin) experience, potentially optimizing the molecule and informing clinical space selection and execution 1. Cummings J, et al. J Prev Alzheimers Dis. 2018;5(4):253-258. 2. Schneider LS, et al. Am J Geriatr Psychiatry. 2006 Mar;14(3):191-210.2006
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ACP-204 ACP-204 Represents an Opportunity to Both Extend the NUPLAZID® Franchise With 5HT2A and Build Upon the Learnings 15 >1M Patients with Lewy Body Dementia2 50% - 75% experience psychosis3 ~7M Patients with Alzheimer’s Disease1* 30% experience psychosis3 A C P - 204 Patients living with psychosis across PDP , LBDP , and ADP in the US ~3M Please see NUPLAZID prescribing information for additio nal informatio n. Pimavanserin is not approved for the treatment of ADP or LBDP. 1. Alzheimer’s Dementia. 2024;20:3708–3821. 2. NINDS. 3. Cummin gs J, et al. J Prev Alzheimers Dis. 2018;5(4):253-258. 4. https://www.parkinson.org/understan ding-parkinsons/statistics. Accessed June 13, 2025. *American s 65 and older ~1M Patients with Parkinsons Disease4 50% experience psychosis3 P I M A V A N S E R I N
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ACP-204 ACP-204 Program Designed To Build Upon Lessons From Pimavanserin 16 ACP-204 Pimavanserin Minimize or eliminate QT prolongation Enable dose-ranging to higher exposures Speed time of onset Design study to robustly evaluate disease under study Acadia Pharmaceuticals Inc. Data on file.
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Data Suggest Reduced or No Risk for QTc Prolongation With ACP-204 – Permitting Exploration of Higher Doses • Unlike pimavanserin , ACP-204 demonstrates flat ∆∆QT cF(msec) curve with increase in plasma concentration • ∆∆QTcF (msec) confidence intervals does not exceed 10 msec at either dose currently under clinical investigation 17 ACP-204 No risk of significant QT prolongation at exposures under investigation in clinic (1x and 2x NUPLAZID marketed dose equivalent) Pimavanserin Acceptable level of QT prolongation at marketed dose, but noted risk is observed at higher concentrations Plasma Pimavanserin concentration (ng/mL) ΔΔQTcI (msec) -5 0 5 10 15 20 25 -10 196 ng/mL86 ng/mL 40mg 80mg 10.7 [8.5 -13] 7.8 [6.4 -9.1] 0 100 200 300 400 ΔΔQTcF (msec) Plasma ACP -204 concentration (ng/mL) ΔΔQTcF (msec) -10 -5 0 5 10 15 20 25 0 100 200 300 400 260 ng/mL130 ng/mL 2.0 (-1.3, 5.4) 0.76 (-4.7, 6.2) ΔΔQTcF = ΔΔQT interval using the Fridericia’s correction method; ΔΔQTcI = QT interval using an individual correction method; Phase 1 data. Acadia Pharmaceuticals In c. Data o n file. ACP-204
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ACP-204 Clinical Programs Chosen Through Prior Efficacy Signals in Both ADP and LBDP With Pimavanserin 18 ACP-204 ADP = Alzheimer’s Disease Psychosis; LBDP = Lewy Body Dementia with Psychosis; LCM = Least Squares Mean; NPI-NH PS = Neuropsych iatric Invento ry Nursin g Home Version Psycho tic Symptoms; SE = Standard Error 1. Ballard C, et al. J Prev Alzheimers Dis. 2019;6(1):27-33. 2. To rres-Yaghi Y, et al. Poster presented at: Psych Congress 2024; October 31, 2024; Bosto n, MA, USA. Relapses in Pimavanserin Withdrawal Study2NPI-NH PS Change from Baseline 1 -5 -4 -3 -2 -1 0 BL 2 4 6 Week 6 p = 0.045; Effect size = 0.32 LSM ± SE ADP 96.3 88.9 77.8 40.7 11.1 53.3 43.3 43.3 16.7 10.0 0 20 40 60 80 100 120 ≥20% ≥30% ≥50% ≥75% 100% % of patients % improvement from baseline Pimavanserin Placebo LBDP Week 6 Responder Analyses (Subgroup of NPI -NH PS ≥12) 1 55.0% (11 of 20 LBDP patients) receiving placebo relapsed 5.3% (1 of 19 LBDP patients) receiving pimavanserin relapsed
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Pimavanserin Data Demonstrate Positive Exposure-Response in ADP / LBDP Patients → Higher Doses of ACP-204 May Yield Better Efficacy 19 Increased Exposure (Higher Doses) Leads to a Greater Response -25 -20 -15 -10 -5 0 0 600 1200 1800 2400 3000 Change in Endpoint From Baseline Pimavanserin AUCO—24 (ngxh/mL) Increased Exposure (Higher Doses) Leads to a Greater Response in ADP and LBDP Patients in Prior Clinical Study ADP LBDP Median exposure for pimavanserin marketed dose (34 mg) Baseline Greatest Reduction from Baseline ADP = Alzheimer’s Disease Psychosis; AUC = Area Under Curve; LBDP = Lewy Body Dementia with Psychosis; Acadia Pharmaceuticals Inc. Data on file. ACP-204
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ACP-204 Achieves Higher Systemic Levels More Quickly, Potentially Yielding Faster and More Consistent Efficacy 20 Phase 1 Study - Median Maximum Concentration Versus Time in Elderly Subjects* Following 34 mg Daily Pimavanserin or 60 mg Daily ACP -204 0 10 20 30 40 50 60 70 80 90 100Maximum Concentration (ng/mL) Pimavanserin 34 mg daily ACP-204 60 mg daily 3 6 9 12 15 18 21 24 27 Steady State Steady State Time (days) *In normal healthy adults (age 18-45 years o ld), steady state of 5 days (ACP-204) vs 12 days (Pimavanserin); Acadia Pharmaceuticals Inc. Data on file. ACP-204
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ACP-204 Achieves Higher Free Drug Cerebrospinal Fluid (CSF) Concentrations vs. Pimavanserin in NHP • In NHP , drug exposure in cerebrospinal fluid (CSF) was ~5-fold higher for ACP-204 than pimavanserin • This also suggests potential for greater efficacy 21 CSF, cerebrospinal fluid. ACP-204 and pimavanserin were administered as intravenous bolus doses of 1.0 mg/kg and then drug concentratio ns in plasma and CSF were determined at the indicated time points. Kinetics and Uptake of ACP-204 and Pimavanserin in the Brain of NHP 2 8 1000 100 10 1 1 mg/kg 0 0.1 4 6 ACP-204 plasma Pimavanserin plasma ACP-204 CSF Pimavanserin CSF CSF Plasma Time (hours) Drug Concentration (ng/mL) NHP = non-human Primates Burstein ES, Dey M, Pathak S. Poster presented at: 63rd Annual Meeting of the American College of Neuropsychopharmacology 2024; December 8-11, 2024; Ph oenix, Arizona, USA. ACP-204
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ACP-204: Phase 1 Data Supports Convenient Once -Daily Dosing • No food effect – can be dosed with or without food • Half-life ~20 hours enabling QD dosing • Metabolized primarily by CYP3A4/5 • No drug-drug interactions with commonly used medications for Alzheimer's and Lewy Body Dementia (i.e., cholinesterase inhibitors and anti-amyloid monoclonal antibodies) 22 0.01 0.1 1 10 100 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Plasma Concentration (ng/mL) Time (hours) Evaluation of Food Effect Fasted Fed QD = Once daily Darwish M, et al. Poster presentation at: AAIC 2025 Annual Meeting. July 27-31, 2025; Toronto, Canada [poster accepted; to be presen ted]. Acadia Pharmaceuticals In c. Data o n file. ACP-204
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AD patients Treatment (N) Placebo (N) Weighted Mean Difference (WMD) WMD (95% CI) Pimavanserin 34 mg 280 268 0.29 (-0.34, 0.93) Antipsychotics1 T otal 950 614 -0.73 (-1.09, -0.38) Aripiprazole 87 82 -1.34 (-2.35, -0.33) Olanzapine 442 202 -0.64 (-1.36, 0.09) Quetiapine 124 125 -0.68 (-1.62, 0.26) Risperidone 297 205 -0.69 (-1.31, -0.07) Dopamine-Sparing Mechanisms May Spare Motor Function and Mitigate Cognitive Impairment • Dopamine blocking antipsychotics are associated with cognitive decline 1 • Dopamine blockade exacerbates movement disorders and risk of falls, and impairs cognition 1 23 Pimavanserin and ACP-204 lack affinity for dopamine (DA; including D2) 5-HT2A/D2 Selectivity2-3 Pimavanserin >1000 ACP-204 >1000 Haloperidol 0.002 Clozapine 7.1 Olanzapine 1.6 Quetiapine 0.1 Risperidone 2.5 In clinical studies, pimavanserin demonstrated: ✓ Lack of negative impact on motor function vs. placebo ✓ Lack of negative impact on cognitive function as demonstrated by MMSE vs. placebo (Forest Plot below) -3-2-10123 FAVORS PLACEBOFAVORS TREATMENT ADP = Alzheimer’s Disease Psychosis; APs = Antipsychotics; MMSE = Mini-mental State Examination 1. Schneider LS, et al. Am J Geriatr Psychiatry. 2006 Mar;14(3):191-210.2006. 2. Hacksell U, et al. Neurochem Res. 2014 Oct;39(10):2008-17. 3. Acadia Ph armaceuticals, Inc. Data on File. ACP-204
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ACP-204: RADIANT Phase 2 / Phase 3 Trial in ADP 24 52-WEEK DURATION OPEN-LABEL STUDY TWO PHASE 3 STUDIES of similar size PHASE 2 N=318, double-blind, randomized 1:1:1 Placebo ACP-204 (60 mg QD) ACP-204 (30 mg QD) Placebo ACP-204 (60 mg QD) ACP-204 (30 mg QD) Placebo ACP-204 (60 mg QD) ACP-204 (30 mg QD) 6-WEEKS 6-WEEKS PRIMARY ENDPOINT SAPS-H+D total score change from baseline to Week 6 Global, placebo -controlled, double-blind Phase 2 enrolling ADP = Alzheimer’s Disease Psychosis; QD = Once Daily; SAPS-H+D = Scale for Assessment of Po sitive Symptoms - Hallucinatio ns + Delusio ns. NCT06159673 ACP-204
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52-WEEK DURATION OPEN-LABEL STUDY SAFETY FOLLOW-UP 4 WEEKS DOUBLE-BLIND TREATMENT PERIOD RANDOMIZATION OF LBDP PATIENTS STRATIFIED BY DIAGNOSIS OF PDD-P OR DLB-P Placebo n=60 ACP-204 (60 mg QD) n=60 ACP-204 (30 mg QD) n=60 PDD-P (50% cap) DLB-P ACP-204: Phase 2 Randomized, Placebo -Controlled Trial in LBDP 25 6-WEEKS KEY SECONDARY ENDPOINT • CGI-S-LBDP EXPLORATORY BIOMARKER • Skin biopsy for neuronal α-synuclein disease PRIMARY ENDPOINT SAPS-LBDP at 6 Weeks CGI-I = Clinical Glo bal Impressions – Improvement; CGI-S = Clinical Global Impressions – Severity; DLB-P = Dementia with Lewy Bodies-Psychosis; LBDP = Lewy Body Dementia with Psychosis; PDD-P = Parkinson’s Disease Dementia - Psychosis; QD = Once Daily; SAPS = Scale for Assessment of Positive Symptoms Acadia Pharmaceuticals Inc. Data on file. NCT07029581 ACP-204
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TREND Community vendor engaged for patient & caregiver insights to shape recruitment efforts for ADP and LBDP programs Seamless Phase 2/3 design in ADP accelerates development Use of biomarkers ✓ Alzheimer’s disease: • p-Tau217 • Aβ42/Aβ40 ratio • APOE prototype ✓ Lewy Body Dementia: • Alpha-synuclein skin biopsy • Genetic assays for APOE ε4, GBA1, and LRRK2 ACP-204: Key Innovations in Clinical Development Program 26 ADP = Alzheimer’s Disease Psychosis; APOE = Apolipoprotein E; GBA1 = Glucocerebrosidase 1; LBDP = Lewy Body Dementia with Psychosis; LRRK2 = Leucine-Rich Repeat Kinase 2; p-Tau217 = phospho rylated-tau 217 ACP-204
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ACP-204 ACP-204: Key Takeaways 27 ✓ No approved treatments for ADP and LBDP; Current off-label treatments are often ineffective, are not dopamine-sparing, and can cause sedation, impact on cognition and motor function ✓ ACP-204 is a highly selective, potent inverse agonist of 5-HT2A and is believed to normalize dysregulation in brain networks implicated in psychosis, by modulating of serotonergic signaling ✓ ACP-204 program is designed to build upon lessons from Pimavanserin, minimizing or eliminating QT prolongation and enabling dose-ranging to higher exposures, and increasing potential for efficacy in both ADP and LBDP ✓ Key innovations incorporated in both Phase 2 trials, each designed to inform on dose-response, use of biomarkers, safety, efficacy, and caregiver burden ADP T opline Results Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2 0 2 5 2 0 2 6 LBDP First Patient In ✓ Alzheimer’s Disease & Lewy Body Dementia are severe neurodegenerative disorders, with significant proportions of patients suffering from hallucinations and delusions (psychosis)
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Neurological Disease – Neuro-Psych ACP-211: Major Depressive Disorder (MDD) Dragana Bugarski-Kirola, M.D. VP , Clinical Development
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ACP-211: Major Depressive Disorder (MDD) 29 ACP-211 Major Depressive Disorder is a common and serious medical illness that is marked by persistent sadness and loss of interest, often leading to emotional and physical problems1-2 Unmet Need Current approved treatments for MDD can be limited by extent and onset of efficacy, or show quick anti-depressant impact but require extensive in-office medical monitoring because of sedation and dissociation 3 Rationale for Development ACP-211 designed as an oral therapy with potential for ketamine-like efficacy, targeting minimal required in-office monitoring MDD = Major Depressive Disorder 1. https://www.mayoclinic.org/diseases-con ditions/depression/symptoms-causes/syc-20356007. Accessed Jun e 16, 2025. 2. Fekadu N, et al. J Depress Anxiety. 2017;6(1):255-7. 3. Karrouri R, et al. World J Clin Cases. 2021 Nov 6;9(31):9350-9367.
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Pervasive Disease Burden and Unmet Need in Major Depressive Disorder (MDD) 30 ACP-211 adults with MDD1 ~9M medically treated in the US2 ~21M MDD = Major Depressive Disorder 1. https://www.nimh.nih.gov/health/statistics/major-depression 2. Zhdanava M, et al. J Clin Psychiatry 2021; 82(2):20m13699. 3. JAMA 2013; 310:591; 4. Greenberg PE, et al. Pharmacoeconomics. 2021 Jun;39(6):653-665. *Ranked by years lived with disability in 2010 2nd economic burden in the US (2020 values)4 ~$326B ~3M highest cause of disability (all diseases)*3 Patients with treatment- resistant depression (TRD) in the US2
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Anti-depressant Effects • (R,S)-ketamine shows rapid reduction of depressive symptoms -- within 2 to 4 hours1-4 • S-ketamine (intranasal Spravato®) approved for Treatment Resistant Depression (TRD) in adults 5 (R,S)-Ketamine and S-Ketamine Use in Depression: Efficacy With Significant Side Effects Side Effects • Psychotomimetic and dissociative effects occur shortly after administration 6-8 Any Sedation (MOAA/s= 0 to 4) by Treatment6 Dissociation (CADSS increase >4) by Treatment6 31 CADSS = Clinician-Administered Dissociative States Scale; HDRS = Hamilton Depressio n Rating Scale; MDD = Majo r Depressive Disorder; MOAA/s = Modified Observer's Alertness/Sedation scale 1. Coyle CM and Laws KR. Hum PsychopharmacolClin Exp 2015; 30: 152–163. 2. DiazGranados N, et al. J Clin Psychiatry. 2010; 71(12): 1605–1611. 3. Murrough JW, et al.Am J Psychiatry. 2013 Oct;170(10):1134-42. 4. Zarate CA, et al. Arch Gen Psychiatry. 2006;63:856-864. 5. Registered trademark o f Johnson & Johnson, Spravato(esketamine) prescribing information. 2025. 6. US FDA. 2019. NDA 211243 Esketamine Treatment of Treatment-Resistant Depression (TRD). Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee. 7. Kleinloo g D, et al. Journal of Psychopharmacology. 2015 Apr;29(4):401-13. 8. Recourt K, et al. Frontiers in Neuroscience. 2025 Feb 3;19:1531375. ACP-211 Change in the 21-item Hamilton Depression Rating Scale4
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Neuroplasticity induced by NMDAR inhibition and increased AMPAR expression HEALTHY STATE Synaptic activity DEPRESSION Reduced synaptic activity, density. KETAMINE & ACP-211 Neuroplasticity, restored synaptic activity and density KETAMINE Non-oral, potent NMDAR antagonist High NDMAR potency – greater risk of sedation and dissociation ACP-211 Is a Deuterated Form of R-Norketamine With Potential to Retain Ketamine Efficacy With Reduced Sedation and Dissociation ACP-211 differentiated from Ketamine by reduced NMDAR activity Glu binds To AMP AR BDNF release ERK Akt mTORC1 AMPAR translation NMDAR AMPAR TrkB Glutamate Glycine Mg²+ Ketamine ACP-211 Oral, moderate potency NMDAR antagonist Moderate NMDAR potency – potential antidepressant activity with minimal side effects 32 Akt = AKT serine-threo nine protein kinase; AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazo lepropionic acid receptor; BDNF = brain-derived neurotrophic factor; ERK = extracellular signal-regulated kinase; mTORC1 = mammalian target of rapamycin complex 1; NMDAR = N-methyl-D-aspartate glutamate receptors. Adapted fro m Krystal JH, et al. Proc Natl Acad Sci U S A. 2023 Dec 5;120(49):e2305772120. Acadia Pharmaceuticals Inc. Data on file. ACP-211
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ACP-211: Anti-Depressant Activity in Rodents Is Equivalent to Ketamine Chronic stress test • ACP-211 (10 mg/kg) significantly increased sucrose consumption in stressed animals when administered 24 hours prior to testing with no effects on sucrose consumption in non-stressed animals 33 Rodent forced swim test • ACP-211 (10 mg/kg) significantly decreased immobility (i.e., showed antidepressant activity) in a forced swim test (FST) when administered 24 hours prior to testing 0 2 4 6 8 10 12 14 16 0 10 20 30 40 50 Vehicle Ketamine 10 mg/kg ACP-211 10 mg/kg Vehicle Ketamine 10 mg/kg ACP-211 10 mg/kg I M M O B I L E S W I M M I N G Frequency of Behavior STRESSED NON-STRESSED Baseline 1 2 24hr Post Drug 1 2 3 4 Stress (Weeks) Withdrawal (Weeks) Saline Control ACP-211 (5 mg/kg) ACP-211 (10 mg/kg) Sucrose Consumption (g) Acadia Pharmaceuticals Inc. Data on file. ACP-211
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ACP-211: Less Motor Impairment Than Ketamine in Animal Model Rat rotorod model • Rats treated with 150 mg/kg ACP-211 displayed similar latency to fall from a rotating rod when compared to vehicle control indicating no motor impairment • Rats treated with 100 mg/kg (R,S)- ketamine fell immediately, indicating significant motor impairment 34 Animals dosed with Ketamine (100 or 150 mg/kg) were unable to remain on rotorod 30 min post-dose 0 20 40 60 80 100 120 140 160 180 200 30 min 120 min Latency to fall (sec) Time post-dose Vehicle Ketamine (100 mg/kg) Ketamine (150 mg/kg) ACP-211 (50 mg/kg) ACP-211 (100 mg/kg) ACP-211 (150 mg/kg) 0 sec Acadia Pharmaceuticals Inc. Data on file. ACP-211
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ACP-211: In Phase 1 Study No Sedation and Dissociation Observed in Healthy Volunteers Potential adverse events of interest* ACP-211 SAD 8 cohorts (pooled, blinded data) N=64 ACP-211 MAD 2 cohorts (pooled, blinded data) N=16 Disturbances in consciousness None observed None observed Sedation None observed None observed Transient dissociative states and perception disorders Derealization, rare, mild, at higher doses only Derealization, rare, mild, at higher doses only Blood pressure and cardiovascular events • Orthostatic hypotension, rare, mild • Reflex tachycardia, rare, mild • Orthostasis with dizziness, rare, mild, at higher doses • Orthostatic hypotension, rare, mild • Reflex tachycardia, rare, mild • Orthostasis with dizziness, rare, mild, at higher doses Interstitial cystitis Cystitis, rare, mild Hematuria, rare, mild Mood changes and anxiety Euphoria, mild, transient Euphoria, mild, transient Cognitive disorders and memory impairment None observed None observed 35 Concentration-Time Profiles of ACP-211 0 1000 2000 3000 4000 0 4 8 12 16 20 24 Time (hours) Concentration (ng/mL) ACP-211 Concentration (mg) 900 600 400 200 100 60 30 SAD = single ascending dose; MAD = multiple ascending doses Acadia Pharmaceuticals Inc. Data on file. *Based on animal and literature data including similar compounds. ACP-211 Data are mean ± SD
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Phase 2, 4-week, randomized, double-blind, placebo-controlled, multi-center study ACP-211: Next-Stage Trial Designed to Inform on Ability To Meet TPP on Dissociation / Sedation 36 Double Blind TREATMENT PERIODSCREENING PERIOD Placebo ACP-211 low dose ACP-211 high dose 21- UP TO 42 DAYS 4-WEEKS MDD Patients with inadequate response to Anti-depressant treatment N =153 randomized 1:1:1 PRIMARY ENDPOINT Δ MADRS Total at week 4 MADRS = Montgomery-Åsberg Depression Rating Scale; MDD = Major Depressive Disorder; TPP = Target Product Profile Acadia Pharmaceuticals Inc. Data on file. PHASE 2 PROJECTED STUDY START Q4 2025T A K E A W A Y ACP-211
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ACP-211 ACP-211: Key Takeaways 37 ✓ Major Depressive Disorder (MDD) is a common and serious mood disorder impacting ~21M adults in the US with remaining unmet medical need despite approved therapies ✓ Currently approved therapies can be limited by extent and onset of efficacy, or show quick anti-depressant impact but require extensive in-office medical monitoring because of sedation and dissociation ✓ ACP-211 is an orally administered, selectively deuterated form of R-Norketamine ✓ ACP-211 data suggest comparable anti-depressant activity to ketamine with lower propensity for sedation in animal models. In healthy volunteers, a phase 1 study has also demonstrated the ability to reach high doses with no sedation and minimal dissociation ✓ Phase 2 MDD study designed to study efficacy and safety, specifically to rule out unacceptable rates of sedation or dissociation Phase 2 in MDD First Patient In Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2 0 2 5 2 0 2 6
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Neurological Disease – Neuro-Motor Introduction Elizabeth H.Z. Thompson, Ph.D. EVP , Head of R&D
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Neurological Disease – Neuro-Motor ACP-711: Essential Tremor Victor Abler, D.O. VP , Medical Affairs
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ACP-711: Essential Tremor (ET) 40 ACP-711 Unmet Need Current treatments for essential tremor are not always effective and can have significant side effects2,3 No new pharmacological therapies have been approved in >50 years Rationale for Development ACP-711 is a selective GABA A-α3 modulator targeting cerebellar GABA system dysfunction Phase 1 data to date support potential absence of cognitive or sedative effects, negative impact on sleep ET is a movement disorder with high- frequency postural and/or kinetic tremor, mainly affecting the upper limbs1 1. Olanow CW, et al. In: Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. 2. Ghanekar S, Zesiewicz T. Practical Neurology. 2023; September/October:20. https://practicalneurology.com/articles/2023-sept-oct/treatment-of-essential-tremor. 3. Lo uis ED, et al. Eur J Neurol. 2010;17:882-884
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Pervasive Burden and Unmet Need in Essential Tremor (ET) more prevalent than Parkinson’s disease2Up to 10X ~1M people From 2015 to 2019 who were diagnosedwith ET in the US sought treatment3* 41 1. Louis ED, Ottman R. Tremor Other Hyperkinet Mo v (N Y). 2014;4:259. 2. https://tremor.org.uk/essential-tremor. 3. Vetterick C, et al. Adv Ther. 2022 Dec;39(12):5546-5567. *In a retrospective, observational study of a large US insurance claims database ACP-711 or 2.2% of the US population is estimated to have ET1 ~7M
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ACP-711 GABA Hypothesis in ET: GABA Dysfunction 42 STEP 1 Cerebellar neurodegeneration (Purkinje cell loss) STEP 2 Cerebellar GABA system dysfunction STEP 3 Deep cerebellar neurons with pacemaker activity STEP 4 Thalamo-cortical activity TREMOR2 Reduced Purkinje Cell Dendritic Arborization and Loss of Dendritic Spines in Essential Tremor 1 Two adjacent Purkinje cells in a control One Purkinje cell in an ET case ET = Essential Tremor; GABA = Gamma-aminobutyric Acid 1. Adapted from Louis ED, et al. Brain. 2014 Dec;137(Pt 12):3142-8. 2. Adapted from: Gironell A. Tremor Other Hyperkinet Mo v (N Y). 2014 Jul 16;4:254.
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ACP-711 GABAA-α3 Located in All Layers of the Cerebellum; Staining is Intense in Purkinje Cells in Mouse Model In Complex Receptor System, GABAA-α3-Containing Receptors Most Likely Drive Tremor; GABAA-α3 Highly Concentrated in Purkinje Cells, Cerebellum • GABA exerts inhibitory activities through GABA receptors • Multiple GABA receptors, made up of different subunits (e.g., α1, α 2, α 3 and α 5) • Different receptors made up of different subunits can be located in different places in the brain, mediating different activities 43 Biser PS, et al. Dev Brain Res. 2000 Oct 28;123(2):165-72. Anti-α3 subunit antibody Confocal micrograph of 19-day-old rat cerebellum Purkinje cell layer Granular layer White matter Molecular layer ET = Essential Tremor; GABA = Gamma-aminobutyric Acid Schaefer SM, et al. Expert Rev Neurother. 2018 Feb;18(2):101-110.
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ACP-711 Highly Selective Activity for Alpha -3 Subunit GABAA-α3 subunit is expressed in key regions involved in essential tremor (cerebellar dentate, thalamus, and cortex)1-4 ACP-711 is a selective GABAA-α3 positive allosteric modulator (PAM) with potential to treat Essential Tremor Data on receptors containing different subunits implicate: • α3 in motoric control4 • α1 in hypnotic effects5 • α2 in mediating anxiolytic-like, reward-enhancing, and antihyperalgesic actions; antidepressant- like properties6 • α5 in memory and cognitive processes7 ACP-711: Selectively Activates α-3 Subunit- Containing Receptors 44 % modulation relative to reference8 Log [ACP-711] (M) High activity Low activity No activity GABA = Gamma-aminobutyricAcid 1. Waldvogel HJ, et al. J Chem Neuroanat. 2017 Jul;82:39-552017. 2. Sperk G, et al. J Comp Neuro l. 2020 Oct 15;528(15):2551-2568. 3. Stojanovic T,et al. J Comp Neurol. 2016 Jun 15;524(9):1805-24. 4. Schaefer SM, et al. Expert Rev Neurother. 2018 Feb;18(2):101-110. 5. Doble A. J Psychopharmacol. 1999;13(4 Suppl 1):S11-20. 6. Engin E, et al. Pharmacol Ther. 2012 No v;136(2):142-52. 7. Glykys J, et al. J Neurosci. 2008 Feb 6;28(6):1421-6. 8. Acadia Pharmaceuticals Inc. Data on file.
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ACP-711: Reduces Tremor in Harmaline Animal Model • Propranolol appeared to be more active but caused the animals to be recumbent from weakness • Current treatments for ET have limiting AEs such as sedation with primidone in humans 45 Harmaline Induces Kinetic Tremors in Frequency Range Similar to ET Patients 0 10 20 30 40 ACP-711 mg/kg,po Saline Vehicle Propranolol mg/kg,ip 0.3 1 330 Harmaline 5mg/kg,sc **** ** * #### % Motion power 0 10 20 30 40 ACP-711 mg/kg,po Vehicle Primidone mg/kg,ip 3 10 3060 Harmaline 5mg/kg,sc ** ** ** *** % Motion power One way ANOVA, Fisher's LSD post hoc test: ####p<0.0001 vs Saline, *p<0.05,**p<0.01, ***p<0.001, ****p<0.0001 vs Veh icle AE = Adverse Events; ET = Essential Tremor; LSD = Least Significant Difference Acadia Pharmaceuticals Inc. Data on file. ACP-711
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ACP-711: Phase 1 Demonstrated Adequate Exposure and High Receptor Occupancy • ACP-711 was absorbed rapidly • Mean T1/2 (approx. 10 h) was similar across all doses supporting 2x daily dosing • Most common CNS AEs include dizziness and headache 46 PET Scan Flumazenil PET Cohort: 1.16 - 2.23 mg/kg 0.6 hr. post ACP-711 ~24 hr. post ACP-711 PET receptor occupancy studies demonstrated up to 86% receptor occupancy T A K E A W A Y AE = Adverse Events; CNS = Central Nervous System; PET = Positron Emission Tomography Acadia Pharmaceuticals Inc. Data on file. A Phase 1 Study to Assess the Safety and Tolerability of Single Ascending Doses (SAD) an d Multiple Ascending Doses (MAD) of ACP-711 in Healthy Participants and to Determine GABAA Receptor Occupancy using PET (SAD n=48, MAD n=15, PET n =3) ACP-711
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ACP-711: Impact on EEGs in Phase 1 47 Specific, but preliminary, dose dependent effect of ACP-711 seen on EEG in line with clinical observations • EEG signature different from other GABA-A receptor agonists, namely benzodiazepines • ACP-711 appears to not cause sedation or negative attention or cognitive effects Compound Gamma Beta Alpha Theta Delta Benzodiazepines (lorazepam)1 ACP-711 (alpha 3) 2 - - - Higher frequencies Lower frequencies alpha, beta, gamma delta, theta Clinical Insights Attention, cognitive enhancement Drowsiness, reduced alertness ACP-711 EEG = Electroencephalogram 1. Chen X, et al. Br J Clin Pharmacol. 2014 Dec;78(6):1298-314. 2. Acadia Pharmaceuticals Inc. Data on file.
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ACP-711: Sleep Architecture Is Unchanged, Suggests ACP -711 May Not Impair Sleep 9 days of treatment had no effect on sleep architecture Percentage Stage N1 Percentage Stage N2 Percentage Stage N3 Spindle Rate Sleep macro – structure unchanged Sleep micro – structure unchanged 0 mg/kg 1.0 mg/kg 1.2 mg/kg 48 N=28 (2 PSGs of 14 subjects) Acadia Pharmaceuticals Inc. Data on file. ACP-711 BL Day 9 BL Day 9 BL Day 9 BL Day 9
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ACP-711: Next Steps in Clinical Development Phase 2 4-week, randomized, double-blind, placebo-controlled, multi-center study Phase 1 Elderly cohort underway Phase 2 Designed to assess safety and efficacy on ET and activities of daily living Double-Blind TREATMENT PERIODSCREENING PERIOD Placebo ACP-711 low dose ACP-711 high dose Day -28 to 0 4-WEEKS Essential Tremor Patients N =150 randomized 1:1:1 49 ENDPOINTS include Δ TETRAS-PS Score at week 4 Δ TETRAS-ADL Score at week 4 Δ CGI-I at week 4 PHASE 2 PROJECTED STUDY START 2026 ADL = Activities of Daily Living; CGI-I = CGI-Impro vement; PS = Performance Scale; TETRAS = Essen tial Tremo r Rating Assessment Scale ACP-711
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ACP-711 ACP-711: Key Takeaways 50 ✓ Essential Tremor (ET) is the most common movement disorder ✓ ACP-711 selectively enhances the effects of GABA on GABAA-α3 containing receptors, expressed in key brain regions involved in essential tremor ✓ Pre-clinical studies suggest ACP-711 may improve tremor without sedation. ACP-711 demonstrated high receptor occupancy with minimal impact on sleep, and limited or no evidence of sedation or cognitive impairment in a Phase 1 study ✓ Phase 1 study evaluating dosing in elderly cohort ongoing; Phase 2 trial designed to explore dose response, safety, efficacy, and impact on daily functioning ✓ Current treatment options remain suboptimal — fewer than 50% of patients experience meaningful benefit and no new pharmacological therapies have been approved in >50 years Phase 2 in ET First Patient In Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2 0 2 5 2 0 2 6
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Neurological Disease – Neuro-Motor ACP-271: Tardive Dyskinesia Rachael Hawtin, Ph.D. VP , Translational Sciences
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• Lead compound ACP-271 is an orally dosed GP88 agonist • ACP-271 is entering the clinic with target indications in Tardive Dyskinesia and Huntington’s Disease • Follow-on assets with increased potency and brain exposure in preclinical studies GPR88 Program Provides Unique Opportunities in Treatment of Neurological Disorders 52 ACP-271 ACP-271 GPR88 Graphical representatio n; not indicative o f actual binding site ACP-271 is an investigational agent, for which the safety and efficacy have not been establishedor approved by the FDA
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ACP-271: Tardive Dyskinesia (TD) 53 • ACP-271 Tardive Dyskinesia involves involuntary movements, typically of the lower face, resulting from treatment with dopamine-blocking antipsychotics1 Unmet Need Limited treatment options available Current treatments can cause sedation, have warnings for depression and suicide2-4 Given patients’ underlying diseases, TD treatment needs to spare antipsychotic activity of other drugs Rationale for Development ACP-271 is a GPR88 agonist with a dopamine- sparing mechanism, demonstrating durable efficacy in preclinical models without motor or motivational impairment 1. Hauser RA, Truong D. J Neurol Sci. 2018 Jun 15;389:1-3. 2. Austedo (deuterabenazine) prescribing info rmation. 2025. 3.Ingrezza(valbenazine) prescribing info rmation. 2025; 4.Xenazine(tetrabenazine) prescribing informatio n. 2025
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Pervasive Disease Burden and Unmet Need in Tardive Dyskinesia (TD) 54 1. Dhir A, et al. Mov Disord. 2017; 32 (suppl 2). 2. Carbo n M, et al. J Clin Psychiatry. 2017 Mar;78(3):e264-e278. ACP-271 treatable patients in US1 500-600K of patients receiving long-term dopaminergic antagonist/antipsychotics develop TD2 ~30%
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Questions for GPR88 agonism in TD: • Are symptoms of TD relieved and for how long? • Is activity of the antipsychotic affected by GPR88 agonism? • Are there benefits of GPR88 agonism compared to VMAT2 inhibitors? Rationale for GPR88 Agonists in Tardive Dyskinesia 55 VMAT2 inhibitor No / reduced involuntary movements Sedation, depression, suicidality GPR88 agonist Dopamine metabolism, D1& D2 blockade Balance of D1 & D2 signaling No / reduced involuntary movements Potential for no D1/D2 blockade- associated depression or sedation Tardive Dyskinesia due to long-term D2 antagonism Potential New Treatment Current Treatment ACP-271 GPR88 = G protein-coupled receptor 88; VMAT2 = vesicular monoamine transporter 2
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GPR88 Agonism: Significantly Reduces Oral Dyskinesia in a Rat Model 56 VCM are significantly and comparably reduced by the VMAT2 inhibitor tetrabenazine (TBZ) and GPR88 agonism The vacuous chewing movements (VCM) rat model is a standard model of Tardive Dyskinesia (TD) 0 2 4 6 8 10 12 Tetrabenazine (TBZ) GPR88 Agonist One way ANOVA/Post hoc: Tukey’s * p<0.05, **p<0.01 Baseline 0.3 0.5 1.0 TBZ (mg/kg) ~ 50% VCM Reduction VCM Count VCM Count 0 2 4 6 8 10 12 Baseline GPR88 Agonist (1 mg/kg) 69% VCM Reduction** GPR88 = G protein-coupled receptor 88; VMAT2 = vesicular monoamine transporter 2 Preclinical data generated with ACP-271 or alternative GPR88 ago nist. Acadia Pharmaceuticals. Data on File. ACP-271 **** T-test: ** p<0.01 vs Baseline
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GPR88 Agonism: Durable Reduction of Vacuous Chewing Movements in Rat Model of Oral Dyskinesia 57 24 124 224 324 424 524 0 2 4 6 8 10 12 14 16 0 2 4 6 24 120 288 456 Time Post Dose (Hours) ACP-271 Baseline VCM Count TBZ Baseline ACP-271 10 mg/kg vs TBZ 1 ACP-271 10 mg/kg TBZ 0.5 mg/kg TBZ 2 mg/kg TBZ 4 mg/kg Extended impact on VCM following a single dose may support infrequent dosing Currently approved VMAT2 inhibitors require daily dosing2-4 GPR88 = G protein-coupled receptor 88; TBZ = Tetrabenazine; VCM = Vacuous Chewing Movements; VMAT2 = vesicular mono amine transporter 2 1. Acadia Pharmaceuticals. Data on File. 2. Austedo (deuterabenazine) prescribing information. 2025. 3. In grezza (valbenazine) prescribing information. 2025. 4. Xenazin e (tetrabenazine) prescribing information. 2025. ACP-271
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GPR88 Agonism: Spares Antipsychotic Activity of Risperidone in a Mouse Model Pre-treatment: GPR88 agonist, TBZ or vehicle +/- antipsychotic (D2 antagonist) +/- psychomotor stimulation 30 min habituation 2-Hour locomotion monitoring Tetrabenazine 2 mg/kg; GPR88 agonist 10 mg/kg Dunnett's post hoc test ** p<0.01; *** p<0.001 vs Vehicle/Risperidone/MK-801 - treated group; ### p<0.001 vs Vehicle/Vehicle/MK-801 - treated group 58 Total Locomotor Duration Vehicle/ Vehicle/ Saline 3000 2500 Total Duration (seconds) 2000 1500 1000 500 0 Vehicle/ Vehicle/ MK-801 Vehicle/ Risp eridone/ MK-801 GPR88 agonist/ Risp eridone/ MK-801 Tetrabenazin e/ Risp eridone/ MK-801 ** ### *** ### ### ** ### GPR88 = G protein-coupled receptor 88; TBZ = Tetrabenazine Preclinical data generated with ACP-271 or alternative GPR88 ago nist. Acadia Pharmaceuticals. Data on File. ACP-271
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GPR88 Agonism: Dopamine-Sparing Mechanism Preserves Motor Function and Motivation in Wild Type Animal Models Preclinical data support depression-sparing activity of GPR88 agonism 59 Choice for Regular Chow or Lever Press to Obtain Pellet Reward 0 500 1000 1500 2000 2500 Locomotor Activity 0 100 200 300 400 500 0 20 40 60 80 100 120 ** GPR88 agonism did not reduce locomotor activity in WT mice, TBZ did 5 min time bins Cumulative Duration (S) GPR88 Agonist (30 mg/kg) TBZ (4 mg/kg) Vehicle Vehicle GPR88 Agonist (mg/kg) 1 3 10 2.5 TBZ (mg/kg) **** ** GPR88 agonism did not reduce reward motivation in WT rats, TBZ did Lever Presses (N) 0 5 10 15 20 Vehicle GPR88 Agonist (mg/kg) 1 3 10 2.5 TBZ (mg/kg) ** ** Pellet Intake (g) **** ** GPR88 = G protein-coupled receptor 88; TBZ = Tetrabenazine; WT = Wild Type Preclinical data generated with ACP-271 or alternative GPR88 ago nist. Acadia Pharmaceuticals. Data on File. ACP-271 Data are mean ± SEM One-way ANOVA/Post hoc: Tukey’s ** p<0.01; ****P<0.0001 vs TBZ **
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GPR88 Agonism: Mechanistically Differentiated From VMAT2 Inhibitors in Pre-Clinical Studies 60 Effects of TBZ and GPR88 on Striatal DA Metabolism No detectable effect on dopamine metabolism ✓ Locomotor activity retained in WT rodents ✓ Motivation retained in WT rodents ✓ Durable pharmacodynamic effect GPR88 agonism spares dopamine metabolism, TBZ does not DOPAC+HVA/DA 0 2 4 6 8 10 Vehicle GPR88 Agonist (mg/kg) 0.3 1 3 TBZ (mg/kg) 10 30 60 DA = Dopamine; DOPAC = 3,4-Dihydroxyphenylacetic acid; GPR88 = G protein-coupled receptor 88; HVA = homovanillic acid; TBZ = Tetrabenazine; VMAT2 = vesicular monoamine transport 2; WT = Wild Type Preclinical data generated with ACP-271 or alternative GPR88 ago nist. Acadia Pharmaceuticals. Data on File. ACP-271
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ACP-271 ACP-271: TD Key Takeaways 61 ✓ Tardive dyskinesia (TD) is a neurological movement disorder, involving debilitating and disfiguring involuntary movements, and is caused by prolonged use of dopamine-2 (D2) receptor antagonist antipsychotics ✓ ACP-271 is a potential first-in-class GPR88 agonist that may modulate the balance of D1 and D2 signaling without affecting dopamine levels. This may provide durable, sedative sparing relief to TD patients ✓ VMAT2 inhibitors are approved for treatment of TD but cause sedation and carry boxed warnings for depression and suicidality ✓ Preclinical studies of GPR88 agonists have shown promising effects in animal models, including reduction in involuntary movements, durable pharmacodynamic effect, no interference with antipsychotic treatment for the underlying psychiatric condition and avoidance of sedation Additional potential for ACP-271 in Huntington’s disease – after the break
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Neurological Disease – Neuro-Rare Introduction Elizabeth H.Z. Thompson, Ph.D. EVP , Head of R&D
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Neurological Disease – Neuro-Rare ACP-271: Huntington’s Disease Rachael Hawtin, Ph.D. VP , Translational Sciences
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ACP-271: Huntington’s Disease (HD) 64 ACP-271 Huntington’s Disease is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain1-2 Unmet Need There are no currently approved treatments to prevent or arrest HD Current treatments for the choreatic component can cause sedation and carry boxed warnings for sedation and suicidal behaviors3-5 Rationale for Development ACP-271’s mechanism of GPR88 agonism is potentially relevant in HD for treatment of both choreatic and psychiatric symptoms GPR88 is highly expressed in the striatum, a brain region severely affected in HD 1. Ro os RA. Orphanet jo urnal of rare diseases. 2010 Dec;5:1-8. 2. Rodrigues FB, et al. Movement disorders clinical practice. 2017 Sep;4(5):737-42. 3. Austedo(deuterabenazine) prescribing in fo rmation . 2025. 4. Ingrezza(valbenazine) prescribing info rmation. 2025. 5.Xenazine(tetrabenazine) prescribing informatio n. 2025
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Pervasive Burden and Unmet Need in Huntington’s Disease (HD) 65 ACP-271 per 100K global prevalence1 4.88 Currently diagnosed US patients ~21,0002 As many as Potentially undiagnosed US patients ~19,0002 As many as 1. Medina A, et al. Mov Disord. 2022 Dec;37(12):2327-2335. 2. Yohrling G, et al. Neurology. 2020 Apr; 94 (15).
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Rationale for GPR88 Agonists in Huntington’s Disease (HD) • HD patients have striatal loss and reduced expression of GPR88 receptor1-2 • Deleterious GPR88 mutation in non-HD patients is associated with clinical features reminiscent of HD3 such as choreatic-like movement, marked speech delay and learning disabilities • Animal models expressing mutant huntingtin protein (mHTT) have reduced expression of GPR884 • GPR88 involvement established in multiple phenotypic domains including motoric, impulsive, motivation and cognitive measures in animal studies5-7 66 Adapted from Fer M, et al. J Med Chem. 2024 Jul 11;67(13):11296-11325. Healthy brain Lateral ven tricles Caudate nucleus Putamen Huntington’s disease Enlarged ventricles Degeneration and atrophy of the dorsal striatum Inhibito ry Excitato ry Cortex Striatum D1 D1 GPe STN GPi Thal Excessive move ment Early HD Cortex Striatum D1 D1 GPe STN GPi Thal Inhibited move ment Late HD GPR88 agonism has the potential to ameliorate psychiatric and motor impairments in HD by balancing D1/D2 signaling 1. Ho dges A, et al. Hum Mol Genet. 2006 Mar 15;15(6):965-77. 2. Guo Z, et al. Movement Disorders. 2012 Sep 15;27(11):1379-86. 3. Alkufri F, et al. Neuro l Genet. 2016 Mar 9;2(3):e64. 4. Rocher AB, et al. Neurobiol Dis. 2016 Feb;86:131-9. 5. Spark DL, et al. Biol Psychiatry Glob Open Sci. 2022 Nov 11;3(4):1053-1061. 6. Ben Hamida S, et al. Mol Psychiatry. 2022 Nov;27(11):4662-4672. 7. Thomson DM, et al. Genes Brain Behav. 2021 Feb;20(2):e12710. ACP-271
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GPR88 Agonism: Significantly Improves Motor Control in a Zebrafish Model of Huntington’s Disease (HD) Supports hypothesis that restoring balance of dopamine activity enables healthier movement coordination, versus general sedation mHTT zebrafish show reduced locomotor activity and motor coordination, ameliorated by GPR88 agonism and not by Tetrabenazine (TBZ) 67 Locomotor Activity Motor Coordination One way ANOVA/Post hoc: Turkey’s *** * p<0.0001 v s mHTT Seconds 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Total Time in Motion (sec/min) WT mHTT TBZ (mg/kg) 4 1 10 100 GPR88 Agonist (mg/kg) One way ANOVA/Post hoc: Turkey’s ****p<0.0001 vs mHTT and vs TBZ WT mHTT 4 mg/kg 100 mg/kg TBZ GPR88 Agonist **** **** **** mHTT = mutant HD Gene. Preclinical data generated with ACP-271 or alternative GPR88 ago nist. Acadia Pharmaceuticals. Data on File. ACP-271 ****
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ACP-271 GPR88 Agonism: Drives HD Phenotype Toward Wild Type • The Q175 mouse is a genetically accurate model of HD, with initially slow-developing behavioral characteristics • Cloud plots show separation between treatment groups based on high content phenotypic data • 47% normalization of the HD phenotype was observed following 8 days of twice daily dosing 68 3 treatment groups of N=20 WT + vehicle Q175 + vehicle Q175+GPR88 agonist HD = Huntington’s Disease. Preclinical data generated with ACP-271 or alternative GPR88 ago nist. Acadia Pharmaceuticals. Data on File. 1 or 8 days dosing Multifactorial Phenotypic Data Collection Over 72hrs DISEASE WORSENS 8 DAY DOSING1 DAY DOSING 100% difference untreated vs WT 47% difference treatment vs WT HEALTHY WILD TYPE Separation of Q175 treatment group following 15 doses
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ACP-271: HD Key Takeaways 69 ACP-271 FIH Study Start Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2 0 2 5 2 0 2 6 ✓ Huntington’s Disease (HD) is a rare, inherited, fatal neurodegenerative disease characterized by loss of motor control and major psychiatric changes First introduction of mechanism into clinical trials in upcoming first-in-human study, with planned development in both TD and HD ✓ No approved treatments to prevent or arrest HD or broadly address symptomology.VMAT2 inhibitors approved for treatment Huntington's chorea but are effective in only ~50% of patients and carry box warnings for depression and suicidality ✓ ACP-271 is a potential first-in-class GPR88 agonist that may alleviate both motor and psychiatric disease symptoms, as demonstrated in preclinical analyses including HD disease models ✓ Atrophy of striatal medium spiny neurons and reduced GPR88 expression are hallmark features of HD. Deleterious GPR88 mutation in non-HD patients is associated with symptoms characteristic of HD
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Neurological Disease – Neuro-Rare Panel ACP-101: Hyperphagia in Prader-Willi Syndrome Shawn McCandless, M.D. University of Colorado Susan Hedstrom Foundation for Prader-Willi Research Jim Youakim, M.D. VP , Clinical Development
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Prader-Willi Syndrome (PWS) PWS Rare genetic disorder caused by a deletion or mutation on chromosome 15 Typically diagnosed during infancy based on characteristic lack of muscle tone1 Diagnosed in the US 8-10K2-3 Significant unmet need ~30 years average life expectancy1 with obesity and obesity-related complications leading to mortality 71 1. Butler MG, et al. Genet Med. 2017 Jun;19(6):635-642. 2. McCandless SE, et al. J Endocr Soc. 2020 May 8;4(Suppl 1):SUN-604. 3. Acadia Pharmaceuticals. Data on File. ACP-101
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Prader-Willi Syndrome (PWS): Complex Neurobehavioral Condition Rare and complex neurobehavioral disease characterized by a constellation of symptoms Most often managed by pediatric endocrinologists1 Caregivers and families are an essential support system Hyperphagia unrelenting hunger due to impaired neural response to food intake; inability to regulate food consumption in line with energy needs2 77% suffer with 2 or more Significant Comorbidities3 >25% Metabolic Condition4-5 >14% Renal or Liver Impairment3 72 1. https://www.ncbi.nlm.nih.gov/books/NBK553161/ Accessed June 18, 2025. 2. Bellis SA, et al. Eur J Med Genet. 2022 Jan;65(1):104379. 3. Based on ICD-10 coded claims data for distinct diagnosis-confirmed PWS patients (2018- 2025) from Komodo Health®. 4. Crinò A, Grugni G. Curr Diab Rep. 2020 Feb 6;20(2):7. 5. Butler JV, et al. Dev Med Child Neurol. 2002 Apr;44(4):248-55. ACP-101 ~50% Obstructive Sleep Apnea3
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Neurological Disease – Neuro-Rare Our Story Susan Hedstrom Foundation for Prader-Willi Research
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74 Jayden, Living With Prader-Willi Syndrome
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What Is ACP-101 (Intranasal Carbetocin)? • A natural hormone,oxytocin regulates several functions in the body1,2 • In Prader-Willi syndrome (PWS), there arefewer neurons that produce oxytocinin the brain3 • Oxytocin deficiencyis associated withhyperphagia and behavioral issues in patients withPWS1-3 • Carbetocin is a long-acting analogue of human oxytocin and binds to oxytocin receptors with greater selectivity, meaning potentially fewer side effects4 • Designed to overcome the functional deficit in oxytocin receptor agonism in PWS • ACP-101 is an investigationaldrug-device combinationproduct for intranasal administration 75 1. Sabatier N, et al. Front Endo crinol (Lausanne). 2013;4:35. 2. Jo nes C, et al. Dialogues Clin Neurosci. 2017;19(2):193-201. 3. Swaab DF. Acta Paediatr Suppl. 1997;423:50-54. 4. Passo ni I, et al. Neuro endocrinol. 2016;28:n/a. ACP-101
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ACP-101: CARE-PWS Phase 3 Trial Showed Some Evidence of Efficacy Multi-center, randomized, double-blind, placebo-controlled trial TREATMENT PERIODSCREENING PERIOD Placebo TID ( N=43) ACP-101 9.6 mg TID (N=44) ACP-101 3.2 mg TID (N=43) 8-WEEKS N =130 randomized 1:1:1 PRIMARY ENDPOINTS Change from baseline for 9.6 mg dose in: • HQ-CT total score • CY-BOCS total score PWS Patients 76 Change in HQ-CT From Baseline to Week 8 -2.2 -5.4 -3.4 -10.00 -8.00 -6.00 -4.00 -2.00 0.00 Placebo N=40 ACP-101 3.2 mg N=39 ACP-101 9.6 mg N=40 p=0.349* p=0.016** Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is a caregiver-reported outcome measure that has been widely used in interventional studies to assess changes in hyperphagia behavio rs in individuals with PWS. *Two-sided p-value; primary analysis; ** Nominal two-sided p-value; first secondary analysis. Roof E, et al. J Clin Endocrinol Metab. 2023;108(7):1696-1708. ACP-101
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ACP-101: Within the 3.2 mg Dose Data in CARE -PWS, Important Signs of Consistency -5.98 -5.37 -2.98 -2.24 -8 -6 -4 -2 0 0 2 4 6 8 3.2 mg ACP-101 (N=39) Placebo (N=40) Change in HQ-CT From Baseline Weeks p=0.0145 p=0.0162 Effects in HQ-CT Observed Early and Across Time Points CGI-Change = Clinician-rated Clinical Global Impression o f Chan ge; CY-BO CS = Children's Yale-Brown O bsessive-Compulsive Scale; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; PADQ = Prader-Willi Syndro me Anxiousness and Distress Behavio rs Questionnaire Ro of E, et al. J Clin Endocrinol Metab. 2023;108(7):1696-1708. Effects Across Various Endpoints with 3.2 mg of ACP -101 Endpoint 95% Cl of Placebo-adjusted Change (Baseline to Week 8) P Value HQ-CT 0.016 CY-BOCS 0.514 PADQ 0.027 CGI-Change 0.027 HQ-CT Subset 0.011 HQ-CT Question 9 0.114 FAVORS PLACEBOFAVORS TREATMENT 77 ACP-101 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 Acadia Pharmaceuticals, Inc. Data on File.
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ACP-101: Safety Profile Supportive of Continued Clinical Development • In CARE-PWS, no study drug discontinuations of participants in the 3.2 mg arm in placebo-controlled period; low rate of discontinuations due to adverse events in 9.6 mg arm (6.8%) • No serious adverse events were reported during the placebo- controlled period • No adverse events of edema • No required regular monitoring likely based on profile to date (1 transient event of hyperglycemia only) CARE-PWS: TEAEs in ≥5% of Participants in Any Treatment Group ACP-101 3.2 mg (N=43) n (%) ACP-101 9.6 mg (N=44) n (%) All placebo (N=43) n (%) At least 1 TEAE 26 (60.5) 29 (65.9) 24 (55.8) Flushing 6 (14.0) 9 (20.5) 0 Headache 7 (16.3) 4 (9.1) 3 (7.0) Epistaxis 1 (2.3) 6 (13.6) 1 (2.3) Diarrhea 4 (9.3) 2 (4.5) 1 (2.3) Upper respiratory tract infection 3 (7.0) 2 (4.5) 2 (4.7) Nasal discomfort 3 (7.0) 2 (4.5) 1 (2.3) Fatigue 3 (7.0) 1 (2.3) 0 Pyrexia 3 (7.0) 0 0 Nasopharyngitis 0 1 (2.3) 3 (7.0) 78 TEAEs = treatment-emergent adverse events ACP-101
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ACP-101: Explanations Exist for Bell -Shaped Dose Response Curve 79 • These outbursts may negate the beneficial behavioral effects of oxytocin receptor agonism1 ACP-101 Prior literature suggests that high doses of exogenous oxytocin in PWS may lead to increased emotional outbursts due to off-target vasopressin receptor agonism1 • Carbetocin has greater affinity for oxytocin receptors compared to vasopressin receptors and greater selectivity at oxytocin receptor than oxytocin itself 2-3 • While carbetocin's enhanced selectivity may reduce off-target effects, carbetocin still exhibits some activity on vasopressin receptors (e.g., V1aR) at higher doses2-3 • This activity may diminish its efficacy due to the overlapping nature of the behaviors being measured 1. Einfeld SL, et al. Am J Med Genet A. 2014:164A(9):2232‐2239. 2. Cid-Jo fré V, et al. Int J Mol Sci. 2021 Nov 8;22(21):12077. 3. Acadia Pharmaceuticals. Data on File. ACP-101
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ACP-101: COMPASS-PWS Phase 3 Study Designed to Maximize Success 80 Trial Design Builds On Previous Phase 3 Clinical Trial Experience • Focus on 3.2 mg dose • Training on primary endpoint • Larger sample size • Parallel arms Multi-center, randomized, double-blind, placebo-controlled trial LAST PATIENT ENROLLED Topline results expected Early Q4 2025 Potential US approval Q3 2026 TREATMENT PERIOD SCREENING PERIOD PRIMARY ENDPOINT Change in HQ -CT Placebo TID ( N=85) ACP-101 3.2 mg TID (N=85) 12-WEEKS N =170 randomized 1:1 PWS Patients PWS = Prader-Willi Syndro me; TID = three times a day. Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is a caregiver-reported outcome measure that has been widely used in in terven tional studies to assess changes in hyperphagia behavio rs in individuals with PWS. NCT06173531 ACP-101
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Potential US Approval ACP-101: Key Takeaways 81 ACP-101 T opline Results Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2 0 2 5 2 0 2 6 ✓ Prader-Willi Syndrome (PWS) is a rare and complex neurobehavioral disorder with hyperphagia as an important and impactful symptom ✓ ACP-101 (intranasal carbetocin) is a long-acting analogue of human oxytocin with greater selectivity for oxytocin receptors, targeting the functional deficit in oxytocin receptor agonismin PWS ✓ Data from the Phase 3 CARE-PWS study suggested potential benefit with a 3.2 mg dose of ACP-101, with a safety profile supportive of continued development ✓ The ongoing Phase 3 trial was designed for the potential to show results similar to the 3.2 mg dose arm from the prior Phase 3 trial ✓ Patient population with myriad and complex needs require treatment choices
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Neurological Disease – Neuro-Rare DAYBUE® Ponni Subbiah, M.D., M.PH. SVP , Global Head of Medical Affairs & CMO
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Synaptic Alterations in Rett Syndrome • Loss-of-function mutations in MECP2 occur in Rett syndrome; Animal models suggest loss of functional MeCP2 may result in deficits in synaptic maturation and neuronal maintenance in the brain • Trofinetide is a synthetic analog of the N -terminal Tripeptide of IGF -1, which is a potent pleiotropic regulator of central nerv ous system development, maturation, and plasticity • Increased branching of the dendrites that form synapses and synaptic plasticity signals were observed in studies of trofineti de in a MECP2 mouse model of Rett 83 Rett Syndrome Healthy Higher neuronal packing density Volumetric brain reduction Fewer branches Atypical dendritic spine Smaller soma Shorter dendrites Smaller neuronHealthy neuron Soma Dendrites Adapted from: Gold WA, et al. Nat Rev Dis Primers 10, 84 (2024).
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DAYBUE: First and Only Approved Therapy for Rett Syndrome ~1/3 of people with Rett in US ~1,800 Initiated treatment as of March 2025 >870 unique DAYBUE prescribers across a variety of specialties, as of March 2025 Percentage of DAYBUE prescriptions by age1 4% of Rx were for boys 2 years of age and older27% 20% 17% 28% 2-4 years 84 ≥21 years 16-20 years 11-15 years 5-10 years 8%DAYBUE is appro ved in the U.S. by the FDA and in Canada by Health Canada for the treatment of Rett syndrome in adults and pediatric patien ts two years of age and older 1. Acadia Pharmaceuticals Inc. Data on file. Q1 2025. 65% Of those currently on therapy, On treatment 12+ Months Of those ever on therapy, >50% Remain on treatment at 12 Months
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RSBQ T otal Score Change From Baseline to Week 12 CGI-I Score at Week 12 LAVENDER: Co-Primary Endpoint Results 1,2 93 90 92 85 91 90 83 76 90 92 86 90 83 77 Placebo, n= Trofinetide, n= -8 -6 -4 -2 0 -0.5 1.5 3.5 5.5 7.5 9.5 11.5BL Week 2 Week 6 Week 12 TrofinetidePlacebo Change from BL (LSM ± SE) -1.7 (0.90) -4.9 (0.94) LSM difference -3.2 (95% CI -5.7, -0.6); p=0.018; ES=0.37 Placebo, n= Trofinetide, n= 3 3.25 3.5 3.75 4 0 2 4 6 8 10 12BL Week 2 Week 6 Week 12 Score (LSM ± SE) LSM difference -0.3 (95% CI -0.5, -0.1); p=0.003; ES=0.47 3.8 (0.07) 3.5 (0.07) TrofinetidePlacebo BL = baseline; CGI-I = Clin ical Glo bal Impression-Impro vement; ES = effect size; LSM = least squares mean; PBO = placebo; RSBQ = Rett Syndrome Behaviour Question naire Full analysis set. Difference in LSM from the mixed-effect model for repeated measure analysis. 1. Neul JL, et al. Nat Med. 2023;29(6):1468-1475. 2. DAYBUE [package insert]. Acadia Pharmaceuticals In c., San Diego , CA. The common adverse reactions (≥5% for DAYBUE-treated patients and at least 2% greater than in placebo) reported in the 12-week study were diarrhea (82% vs 20%), vomiting (29% vs 12%), fever (9% vs 4%), seizure (9% vs 6%), anxiety (8% vs 1%), decreased appetite (8% vs 2%), fatigue (8% vs 2%), and nasopharyngitis (5% vs 1%). 85
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Slight and Gradual Decline in RSBQ T otal Score Observed With Increasing Age in Natural History Study Australian Rett syndrome database analysis: RSBQ total score over time, 2000-2019* RSBQ T otal Score (5-20 Years Subgroup; N=205) Time Interval (years) Mean Score at the beginning of the interval Score change within the interval Estimate (95% CI) 0-2 43.7 (41.7,45.8) -0.30 (-1.80,1.20) 86 RSBQ = Rett Syndrome Behaviour Question naire This research was supported by funding from Acadia Pharmaceuticals Inc. *Leonard et al. Presented at the World Rett Congress, 2024
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RSBQ T otal Score Change From LAVENDER Baseline to LILAC-2 Week 104 DAYBUE: Clinical Program Supports Efficacy, Provides Information on Long-Term Use Important Note: The descriptive data from LILAC-1 and LILAC-2 should be interpreted cautiously and may represent chance findings given the limitations of the open-label study design and lack of control arm. 36 35 28 11 40 40 39 11Trofinetide, n= 85 80 74 54 44 68 67 61 49 44 93 90 92 85 91 90 83 76 Change from DB baseline (mean ± SE) Placebo/crossover , n= -20 -15 -10 -5 0 -0.5 49.5 99.552 10412BL -20 -15 -10 -5 0 -0.5 9.5 19.5 29.5 39.52 26 4012BL -20 -15 -10 -5 0 -0.5 4.5 9.5BL 2 6 12 LILAC-2†3LILAC-1†2LAVENDER*1 -13.8 -9.8 Visit (week) Visit (week) Visit (week) -7.0 -7.3 -1.7 -4.9 Trofinetide in LAVENDER Placebo in LAVENDER Crossover from placebo to trofinetide in LILAC -1 Secondary endpoint Exploratory endpoint 87 BL = baseline; DB = double blind; LSM = least squares mean; RSBQ = Rett Syndrome Behaviour Question naire *Full analysis set. Difference in LSM from the mixed-effect model for repeated measure analysis. †Safety analysis set. Data are mean (SE) 1. Neul JL, et al. Nat Med. 2023;29(6):1468-1475. 2. Percy AK, et al. Med. 2024;5(9):1178-1189.e3. 3. Percy AK, et al. Med. 2024;5(10):1275-1281.e2.
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Rett Syndrome Behavior Questionnaire (RSBQ) – What Does It Measure? A validated composite endpoint, 45-item rating scale completed by the caregiver that assesses a range of symptoms in Rett syndrome:1,2 Lower scores reflect lesser severity in signs and symptoms 1. Mount HR, et al. J Child Psychol Psychiatry. 2002; 43(8):1099-110; 2. Barnes KV, et al. J Neurodev Disord. 2015; 7(1):30. Breathing Hand movements or stereotypies Repetitive behaviors Nighttime behaviors Vocalizations Facial expressions Eye gaze Mood 88
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Important Safety Information Diarrhea and vomiting are the most common side effects of Daybue that can sometimes be severe. Please see the full prescribing information for Daybue to learn about the complete risks and benefits of Daybue. Maddy's Experience with DAYBUE Maddie, Living With Rett Syndrome Maddy’s Diagnosis and symptoms • Maddy was diagnosed with Rett syndrome at age 3 —just a few years after the discovery of the MECP2 gene. • Some of her signs and symptoms have included: • Loss of purposeful hand use • Breath holding • Loss of communication abilities • Waking up in the middle of the night with laughing spells or night terrors Maddy started DAYBUE in 2020 in the phase 3 clinical trial and then transitioned to commercial drug after launch; visit Daybue.com for Maddy’s complete story and other caregiver stories 89
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DAYBUE: Total Number of Responders Increased With Length of Follow up (CGI-I) 90 56.9% 77.6% 98.3% 0 10 20 30 40 50 60 70 80 90 100 Month 0 Month 3 Month 6 Month 9 Month 12 % of Patients TTR Month 0-3 TTR Month 3-6 TTR Month 6-12 Estimated Time to Response (TTR) among Month 12 Responders per CGI -I (N=58) +20.7% +20.7% Of those who received trofinetide for 12 months in phase 3 clinical trials (N=80), 72.5% (n=58) were improved at month 12 per CGI-I CGI-I = Clinical Glo bal Impression-Impro vement No te: On e patien t (1.7% ) had missing CGI-I score at mo nth 6 and therefo re, TTR estimation was not possible. Peckham A, et al. Presented at the IRSF Rett Syndro me Scientific Meeting 2025, June 9-11, Bosto n, MA.
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LOTUS Real World Study: Areas of Improvement Up to Month 9 on DAYBUE 91 Pediatric Patients Adult Patients 53 50 36 55 55 48 61 56 47 62 56 46 64 56 49 64 69 5762 50 58 0 20 40 60 80 100 Non-verbal communication Alertness Social interaction/ connectedness Patients (%) 76 84 82 79 76 85 85 0 20 40 60 80 100 Any improvement Patients (%) Month 1 (N=66) Month 2 (N=73) Month 3 (N=71) Month 4 (N=66) Month 5 (N=63) Month 6 (N=58) Month 9 (N=26) Patients with caregiver-reported improvements* Top three areas of improvement reported† 44 33 26 41 50 3946 52 26 49 39 34 57 49 34 56 48 26 58 65 46 0 20 40 60 80 100 Non-verbal communication Alertness Social interaction/ connectedness Patients (%) 59 77 72 71 63 59 69 0 20 40 60 80 100 Any improvement Patients (%) Month 1 (N=39) Month 2 (N=44) Month 3 (N=46) Month 4 (N=41) Month 5 (N=35) Month 6 (N=27) Month 9 (N=26) Patients with caregiver-reported improvements* Top three areas of improvement reported† BIQ = Behavioral Improvement Questionnaire. Important Note: Findings from BIQ should be interpreted with caution given the study limitations. Caregiver observations may represent chance findings, and clinical conclusions cannot be drawn from these da ta. * Percentages are calculated using N at each timepoint. †Percentages are calculated using the number of patients whose caregiver's reported impro vements. Acadia PharmaceuticalsInc. Data on File. ACP-2566-014 Fourth Interim AnalysisTFLs. 2024.
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LOTUS Real World Study: GI Management Strategies 92 Patients (%) 45 10 0% 20% 40% 60% 80% 100% Patients (%) 19 14 6 4 Caregiver-Reported Diarrhea Management/Prevention Strategies After Initiation of Trofinetide Over the Past Week Caregiver-Reported Stool Type Over the Last 3 Days • Consistent stool type results were reported in both adults and pediatric patients1 • Both pediatric and adult patients had similar diarrhea mitigation strategies reported T A K E A W A Y 0% 20% 40% 60% 80% 100% No constipation medications Increased fluids Consumed supplementary fiber Took a lower dose of trofinetide Antidiarrheal medications Lower dose of constipation medications Avoided sugar alcohols Skipped dose(s) of trofinetide Specialized diet Did not take trofinetide this week due to previous diarrhea Hundreds Important Note: Diarrhea management considerations listed here may not be consistent with FDA approved recommendations in the Prescribing Information. 1. Acadia Pharmaceuticals Inc. Data on File. ACP-2566-014 Fourth Interim Analysis TFLs. 2024. 2. Cosand L, et al. Poster presented at the 53rd Child Neuro logy Society (CNS) Annual Meeting, November 11–14, 2024.
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DAYBUE: Expand Beyond North America 93 EU | Est 9,000-12,000 patients1 • MAA Submitted • Building out EU launch team for potential Q1 2026 approval PURSUING TARGETED FILINGS AND LAUNCHES JAPAN | Est 1,000 -2,000 patients 1 • Orphan Drug Designation status granted • JNDA will be based on global data with supplementary local data in Japanese patients with Rett syndrome • Study start anticipated by Q3 2025 1. Acadia Pharmaceuticals. Data on File.
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Next-Generation Investigational Approaches to Rett Syndrome 94 ACP-2591 LICENSED FROM NEUREN cGP analogue Better brain penetrance and potential impact on benefit-risk THE PROMISE Exploratory research-stage UNDISCLOSED PROGRAMS Build upon disease learnings to target and develop agents that provide different types of solutions for patients THE PROMISE
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DAYBUE: Key Takeaways 95 ✓ Rett Syndrome is a complex genetic disorder with a range of symptoms that require lifelong care ✓ DAYBUE is a synthetic analog of the N-terminal Tripeptide of IGF-1, which is a potent pleiotropic regulator of central nervous system development, maturation, and plasticity ✓ Looking to bring DAYBUE to more patients around the globe, through an MAA in Europe and a Phase 3 trial in Japan ✓ DAYBUE is the first and only approved treatment of Rett syndrome in adults and pediatric patients two years of age and older (U.S. and Canada). Its regulatory approvals have been based on clinical trials that demonstrated improvements in the co-primary endpoint of RSBQ and CGI-I with the most common adverse reactions of diarrhea and vomiting Potential EU Approval Phase 3 Japan First Patient In Q1 Q2 Q3 Q4 2 0 2 5 2 0 2 6 Q1 Q2 Q3 Q4 ✓ The LOTUS Real World Study continues to provide information on DAYBUE, including caregiver-reported improvements and GI management strategies employed by caregivers
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Rare Epilepsies and Expansion Rare Areas Elizabeth H.Z. Thompson, Ph.D. EVP , Head of R&D
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Our Early-Stage Pipeline Already Contains Interesting Neurological - Focused Innovation in Rare Epilepsies SYNGAP1-RELATED DISORDERS neurodevelopmental disorders marked by: • Childhood-onset epilepsy • Developmental delays • Motor impairments • Features of autism spectrum disorder WT = Wild Type Adapted from Carville et al., Neurotherapeutics 2021 Program data to date support dose-dependent target engagement, activity in patient-derived neurons Healthy subject Syngap1 patient Functional protein levels 100% WT 50% WT ASO-modulated target change in protein Target 50% increase • Decision-enabling data for Stoke collaboration expected in 2026 • Multiple additional undisclosed discovery -stage programs in rare epilepsies T A K E A W A Y 97
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In 2025 and Beyond Expand the Disease Areas We Seek to Target for Drug DevelopmentN E U R O P S Y C H Our Legacy and Foundation in Neurological Disease Our Neurological and Rare Disease Expansions Today Our Tomorrow Neuromotor Neurorare Expansion to other Rare Disease areas under evaluation Nephrology Immunology CardiovascularMetabolic Endocrine 98
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R&D Strategy
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Acadia Is Delivering a Robust, Sustainable Pipeline 100 Harness external innovation, supplemented with focused internal bets Continue to invest in the right people in the right places Creating pipeline balance by stage and risk/reward level Developing promising solutions that advance care, to their fullest extent Strong financial position provides flexibility to maximize current assets and pursue future business development opportunities T A K E A W A Y
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Building a Sustainable Pipeline: Acadia’s Approach To Research 101 Drive projects through external vendors • Maintain ability to drive projects in our areas of unique knowledge. Example: ACP-204.Acadia’s Approach To Research Without an Internal Lab Skews strongly towards external innovation Partnership with Axcelead • Access to high-class chemistry and innovation in areas of interest. Multiple undisclosed programs. Forge partnerships for unique capabilities • That enable us to harness multiple modalities and specialties. Example: Stoke Syngap-1.
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~$130M ~$610M We will take scientific risk when we see reason to believe: • First-in-class potential, backed by plausible hypothesis • Potential for Acadia’s proven commercial and development expertise to generate meaningful returns We Have a Track Record of Success in Business Development 102 DAYBUE economics already highly positive 2 years into launch At Risk R&D Spend: Upfront + Phase 3 and Related Costs1 Launch to Date Net Sales2 Low upfront investment yielding a high return Long growth runway ahead with patent protection to 2036 ~5x TLR = Topline Results 1. Includes expenses related to develo pment of trofinetide from deal signing through Phase 3 TLR including initial upfront payment to Neuren. 2. Based on Acadia financial results reported fro m 2Q 2023 through 1Q 2025.
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Acadia R&D Leadership Team Has Grown Their Careers at T op-Tier Companies 103 120 total approved drugs | 27 blockbuster status …And Has Developed Important Medicines in Neurology and Beyond
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Expanding Geographic Hubs To Attract Top Talent 104 San Diego, CA Princeton, NJ San Francisco, CA Switzerland
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2 Approved medicines 9 Disclosed and Multiple undisclosed programs 7 Phase 2 or Phase 3 study starts expected in 2025 and 2026 5 Phase 2 or Phase 3 study readouts anticipated 2025-2027 Advancing care for underserved neurological and rare diseases Expansion into certain rare disease adjacencies will increase our ability to build a sustainable pipeline while maintaining our “right to win” We have a robust and active pipeline, gathering momentum over the next few years
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