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Novel Mechanisms, Better Medicines R&D Day | October 27, 2025
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2 Forward-looking statements This presentation contains forward-looking statements about Neumora Therapeutics, Inc. (the “Company,” “we,” “us,” or “our”) within the meaning of the federal securities laws, including statements related to: Neumora’s intention to redefine neuroscience drug development by bringing forward the next generation of novel therapies that offer improved treatment outcomes and quality of life for patients; the timing, progress and plans for its therapeutic development programs, including the timing of clinical trial initiation and data readouts and upcoming milestones and catalysts; expectations and projections regarding future operating results and financial performance, including the sufficiency of its cash resources and expectation of the timing of its cash runway; intellectual property protection and exclusivity rights, and other statements identified by words such as “could,” “expects,” “intends,” “may,” “plans,” “potential,” “support,” “should,” “will,” “would,” or similar expressions and the negatives of those terms. Other than statements of historical facts, all statements contained in this presentation are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements are subject to risks and uncertainties that could cause the actual results to be materially different from the information expressed or implied by these forward-looking statements, including, among others: the risks related to the inherent uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals; risks related to the timely initiation and enrollment in our clinical trials; risks related to our reliance on third parties, including contract research organizations; risks related to serious or undesirable side effects of our therapeutic candidates; risks related to our ability to utilize and protect our intellectual property rights; and other matters that could affect sufficiency of capital resources to fund operations. For a detailed discussion of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to Neumora’s business in general, please refer to the risk factors identified in the Company’s filings with the Securities and Exchange Commission (SEC), including but not limited to its Quarterly Report on Form 10-Q for the quarter ended June 30, 2025 which was filed with the SEC on or about August 6, 2025. Forward-looking statements speak only as of the date hereof, and, except as required by law, Neumora undertakes no obligation to update or revise these forward-looking statements. Our results for the quarter ended June 30, 2025 are also not necessarily indicative of our operating results for any future periods.
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3 Today’s presenters Bill Aurora, Pharm.D. Chief Operating & Development Officer Helen Rubinstein VP, Investor Relations and Communications Nick Brandon, Ph.D. Chief Scientific Officer Joshua Pinto, Ph.D. President Anton P. Porsteinsson, M.D. William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine; Director, Alzheimer's Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry Paul Berns Chief Executive Officer
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4 Agenda Neumora’s Mission Paul Berns NMRA-215 for the Treatment of Obesity Josh Pinto, Ph.D. Nick Brandon, Ph.D. NMRA-511 in Alzheimer’s Disease Agitation Bill Aurora, Pharm.D. Fireside chat with Anton P. Porsteinsson, M.D., Director, University of Rochester Alzheimer’s Disease Care, Research and Education Program M4R Franchise Nick Brandon, Ph.D. Navacaprant in MDD Bill Aurora, Pharm.D. Closing Remarks Joshua Pinto, Ph.D. Q&A All Presenters
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5 Neumora’s Mission Paul Berns, Chief Executive Officer, Neumora
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6 6 Our Mission We are focused on redefining neuroscience drug development by bringing forward the next generation of novel therapies that offer improved treatment outcomes and quality of life for patients
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7 PROGRAM Target/Mechanism INDICATION U.S. Prevalence Preclinical Phase 1 Phase 2 Phase 3 Navacaprant KOR Antagonist Major Depressive Disorder 21M NMRA-511 V1aR Antagonist Agitation in Alzheimer’s Disease 7M NMRA-861 M4 Modulator Schizophrenia 3M NMRA-898 M4 Modulator Schizophrenia 3M NMRA-215 NLRP3 Inhibitor Obesity/Parkinson’s Disease 103M/1M NMRA-GCASE GCase Activator Parkinson’s Disease 1M NMRA-CK1δ CK1 Inhibitor ALS/Parkinson’s Disease 25K/1M Advancing a leading neuroscience pipeline Broad pipeline addressing some of the most prevalent diseases Targeting novel mechanisms across a broad range of centrally mediated indications ALS = Amyotrophic lateral sclerosis; CK1δ= Casein Kinase I Isoform delta; GCase = Glucocerebrosidase; IP = Intellectual Property; KOR = kappa opioid receptor; M4 = Muscarinic Acetylcholine Receptor M4; NLRP3 = Nucleotide-binding Domain, Leucine-rich–containing Family, Pyrin Domain–containing-3; V1aR = Vasopressin 1a Receptor; DIO = diet induced obesity mouse model.
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8 Multiple catalysts expected over next 12 months KEY MILESTONES Study Initiation Data Readout 2025 2026 Navacaprant KOASTAL-3 topline data (1Q26) Navacaprant KOASTAL-2 topline data (2Q26) NMRA-511 Phase 1b data (around year-end 2025) Provide M4 Franchise Update (mid-2026) NMRA-215 DIO data Advance NMRA-898 to the clinic Initiate Phase 1 studies of NMRA-215 (1Q26) Advance NMRA-861 to the clinic NMRA-215 Phase 1 human POC data (2026) TODAY
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9 NMRA-215 Program Overview Joshua Pinto, Ph.D., President, Neumora
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10 Obesity represents one of the greatest public health challenges 1.13 BILLION people worldwide will be living with obesity1 By 2030, $130 - $170 BILLION estimated obesity market size in 2030 Driving a significant market for obesity treatments Significant opportunity remains And yet, NLRP3 inhibition NLRP3 inhibition may offer benefit across monotherapy, combination therapy and maintenance paradigms: • Incretin-like weight loss • Increased response rates • Better tolerability • Convenience with no cold chain storage • Lower COGS with oral small molecule Approved incretin therapies offer weight loss, but come with challenges: • Significant AEs, such as nausea, vomiting, constipation and diarrhea • High discontinuation rates • Weight regain following discontinuation • Cold chain storage required Emerging oral treatments produce less weight loss and are burdened by the same intolerable side effects May address unmet needs 1World Obesity Federation. World Obesity Atlas 2025. London: World Obesity Federation, 2025. https://data.worldobesity.org/publications/world-obesity-atlas-2025-v7.pdf
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11 Pilot Study Full DIO Study Induction Confirming Study NMRA-215 demonstrated best-in-class monotherapy weight loss up to 19% 16% body weight loss with NMRA-215 monotherapy Monotherapy: 15% body weight loss with semaglutide- like induction Combination: 26% body weight loss; additive effect greater than semaglutide alone 19% body weight loss with semaglutide-like induction RESULTS Monotherapy • Evaluate of NMRA-215 weight loss potential Mono & Combination Therapy • Confirm weight loss & incretin-like induction • Demonstrate combination potential • Evaluate impact on metabolic biomarkers Monotherapy • Confirm incretin-like induction KEY DESIGN ELEMENTS Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022 Mar;21(3):201-223. doi: 10.1038/s41573-021-00337-8. Epub 2021 Nov 23. PMID: 34815532; PMCID: PMC8609996.
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12 NMRA-215 in Obesity Nick Brandon, Ph.D., Chief Scientific Officer, Neumora
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13 Multiple factors drive NLRP3-mediated inflammation resulting in disease NLRP3 ACTIVATION ASC NLRP3 Caspase-1 NLRP3 inflammasome complex pro-caspase-1pro-caspase-1 caspase-1 caspase-1 pro-IL-1β IL-1β IL-18 pro-IL-18 DRIVERS Diet (e.g., lipids) Environment Genetics Aging DISEASES Cardiometabolic (obesity) Neurodegeneration (Parkinson’s) Monogenic / autoimmune (CAPS) AdipoGen Life Sciences. https://adipogen.com/inflammasomes/rce
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14 CNS penetrant NLRP3 inhibition provides broad benefit System Drug Impact Outcome Periphery Protect organ and vascular system from inflammation-related damage CNS Reduce neuroinflammation in the brain Reduced appetite and drive body weight loss Reduce the risk of comorbidities. • Reduces heart disease: improved CV outcomes • Improves type II diabetes: reduced insulin resistance in mice Potential treatment benefits driven by both CNS and peripheral inhibition of NLRP3
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15 MDCK permeability: Unknown 14.0 P-gp efflux ratio: Unknown 1.1 NMRA-215 has an optimized pharmacological profile including best-in-class CNS exposure NMRA-215 is extensively characterized and optimized for brain exposure NMRA-215 is highly selective for NLRP3 NMRA-215 is highly potent with low nM potency across a range of assays • NMRA-215 is highly selective for NLRP3 versus other inflammasomes (NLRP1, NLRC4, AIM2) • >250-fold selective for NLRP3 versus a broad panel of targets (Eurofins SafetyScreen87) • Clean profile in cardiac ion channel and kinase screening panels 0.27 0.4 0.47 0.9 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 VTX-3232 NT-0796* VENT-02 NMRA-215 Rat Kpuu 1-4 Higher Brain Exposure NMRA-215 Assay Format IC50 THP-1 (IL-1β) 3 nM Target engagement (Nanobret) 5 nM iMicroglia (IL-1β) 8 nM Human whole blood (IL-1β) 16 nM *NT0796 = mouse Kpuu 1Neumora data on file. 2Thornton P, et al. JPET. 2024 Feb 15;388(3):813-826 . 3Ventus Data Presented at 5th Annual Inflammasome Summit. November 28 – 30, 2023. Boston, MA. 4Ventyx R&D Day Presentation. Published Jan 2023.
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16 Doses selected for DIO studies to determine target coverage necessary for weight loss NMRA-215 dose selection Semaglutide dose selection Goal: Sustained IC90 target coverage for 24 hours Goal: Select two doses that allow for evaluation of different treatment paradigmsDose (BID) IC Target Dose 90 Mid-Dose 50 Low Dose 20 • Ability to evaluate combination and dose sparing effects of NMRA-215 – Therapeutic dose: 3 nmol/kg – Sub-therapeutic dose (incretin-sparing): 1 nmol/kg • Similar dosing paradigm used by other sponsors allows for comparison across studies 1 10 100 1000 10000 100000 0 2 4 6 8 10 12 14 16 18 20 22 24 time (h) NMRA-215 Low Dose NMRA-215 Mid Dose NMRA-215 Target Dose free brain IC90 IC50 IC20 [Total Plasma] (log scale) Target dose drives IC90 in CNS and periphery over 24 hours based on human whole blood assay
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17 -20 -15 -10 -5 0 5 0 2 4 6 8 10 12 Monotherapy: Up to 19% weight loss with NMRA-215 with incretin-like induction -20 -15 -10 -5 0 5 0 2 4 6 8 10 Day Body Weight Change (%) Pilot StudySTUDY 1 -2% -10% -16% Day Body Weight Change (%) Induction Confirming Study*STUDY 3 -18% -2% -7% -20 -15 -10 -5 0 5 10 0 3 6 9 12 15 18 21 24 27 Day Body Weight Change (%) Full DIO StudySTUDY 2 -4% -6% -7% -7% -15% -17% Vehicle NMRA-215 Low Dose NMRA-215 Mid Dose NMRA-215 Target Dose semaglutide 1 nmol/kg semaglutide 3 nmol/kg -19% NMRA-215 administered subcutaneously in Studies 1 and 3 and administered orally in Study 2. Semaglutide administered subcutaneously in all studies. In Study 2 beginning on Day 22, mice underwent daily endpoint collections, including behavioral testing, MRI, and fasting on day 24 to support blood collection Days 25-27. *Study designed to run up to 28 days. Following achievement of study objectiveconfirming incretin-like induction at Day 13, study was stopped due to injection site irritation, which will not be present in the clinical setting, as NMRA-215 is being developed as an oral therapy.
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18 Class-leading weight loss demonstrated with NMRA-215 NMRA-215 VTX3232 VENT-02 BGE-102 NT-0796 NLRP3i (end of study) 15%–19% 2% 11% 6% 17% semaglutide (end of study) 17%–19% 12% 21%^ 5% 21% NLRP3i (Day 7) 9% / 14% (Study 2) (Study 3) 3% 8% 6% 7% semaglutide (Day 7) 9% / 14% (Study 2) (Study 3) 9% 15%^ 11% 11% NLRP3i + semaglutide (Day 28) 26% 19% 29%^ 21% 24%# NMRA-215 monotherapy demonstrates best-in-class weight loss NMRA-215 monotherapy matches semaglutide induction Combination demonstrates additive effects of NMRA-215 Studies in humanized transgenic obese mice are not directly comparable to other DIO studies ^Ventus semaglutide dose = 10 nmol/kg. #Nodthera combination study semaglutide dose = 5 μg/kg. Other market participant data obtained through company, scientific and Wall Street research publications
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19 -25 -20 -15 -10 -5 0 5 10 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 -30 -25 -20 -15 -10 -5 0 5 10 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Combination therapy: Up to 26% weight loss with NMRA-215 + semaglutide Day Body Weight Change (%) Combined with 3 nmol/kg semaglutideNMRA-215 + Day Body Weight Change (%) Combined with 1 nmol/kg semaglutideNMRA-215 + - 4% -17% -26% -21% - 4% -6% -18% -12% Additive weight loss with therapeutically active incretin dose Vehicle Combination with NMRA-215 Mid Dosesemaglutide Combination with NMRA-215 Target Dose Potential for incretin-sparing combination with better tolerability
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20 Class-leading weight loss demonstrated with NMRA-215 NMRA-215 VTX3232 VENT-02 BGE-102 NT-0796 NLRP3i 15%–19% 2% 11% 6% 17% semaglutide 17%–19% 12% 21%^ 5% 21% NLRP3i (Day 7) 9% / 14% 3% 8% 6% 7% semaglutide (Day 7) 9% / 14% 9% 15%^ 11% 11% NLRP3i + semaglutide (Day 28) 26% 19% 29%^ 21% 24%# NMRA-215 monotherapy demonstrates similar weight loss as semaglutide NMRA-215 monotherapy has best-in-class weight loss induction Combination demonstrates additive effects of NMRA-215 Studies in humanized transgenic obese mice are not directly comparable to other DIO studies ^Ventus semaglutide dose = 10 nmol/kg. #Nodthera combination study semaglutide dose = 5 μg/kg. Other market participant data obtained through company, scientific and Wall Street research publications
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21 NMRA-215 matches semaglutide weight loss with higher-quality outcomes Day Cumulative food intake (g) Reduced food intake equivalent to semaglutide Fat Mass (% to baseline) Vehicle NMRA-215 Target Dose semaglutide 3 nmol/kg Matches semaglutide weight loss, while preserving lean mass 0 10 20 30 40 50 60 70 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 -20 -15 -10 -5 0 5 10 15 20 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Lean Mass (% to baseline) 62.65 g 54.26 g 51.26 g * p<0.05 Neumora data on file. *Unpaired t-test, semaglutide 3 nmol/kg compared with NMRA-215 Target Dose
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22 NMRA-215 drove positive results across key biomarkers Improved liver health similar to semaglutide Improved cardiovascular/lipid profile relative to semaglutide Equiv. = equivalent. Neumora Data on File. Vehicle NMRA-215 Target Dose semaglutide 3 nmol/kgCytokine data from 28-day study available in early 2026Additional Data Improved insulin sensitivity 0 0 0 1 1 (nmol/mL) LDL 0 1 2 3 4 5 6 7 (mmol/L) TC Liver Weight 0 500 1000 1500 2000 2500 (mg) HDL 0 1 2 3 4 5 (mmol/L) Insulin Tolerance Test 0 200 400 600 800 1000 1200 AUC (0-150min) (mmol/L*min) equiv. p<0.0001 equiv. equiv. equiv. equiv. p<0.0001
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23 Data supports utility of NMRA-215 as monotherapy and combination therapy Upcoming 12-week DIO data to evaluate maintenance paradigm 1 2 3 NMRA-215 as weight loss monotherapy NMRA-215 as add-on to a GLP-1 NMRA-215 as weight maintenance treatment Up to 19% body weight loss with semaglutide- like induction Dose-dependent body weight loss confirmed Preserved lean mass and improved metabolic biomarkers Up to 26% body weight loss; additive to semaglutide alone Potential for incretin- sparing combination with better tolerability Report 12-week DIO mouse data in 1Q26 Initiate clinical program with NMRA-215 in monotherapy and combination settings in 1Q 2026 and deliver 12-week proof of concept by end of 2026Next Step
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24 NMRA-511 Overview Bill Aurora, Pharm.D., Chief Operating & Development Officer, Neumora
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25 Rationale Vasopressin plays a role in the regulation of aggression, affiliation, stress and anxiety response Indication Agitation in Alzheimer’s disease Status Phase 1b study underway with data anticipated around the end of 2025 Drug Profile Oral, BID dosing Strong IP Protection Expect exclusivity through 2042+, based on composition of matter protection and estimated patent term extension NMRA-511 is a best-in-class vasopressin 1a receptor antagonist with broad potential across neuropsychiatric disorders
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26 Alzheimer’s disease agitation represents large market opportunity with significant unmet need Agitation in Alzheimer’s disease impacts a significant portion of the U.S. population; that number is expected to increase as the population ages1 7 8 9 10 11 12 13 14 2024 2050 ~7M 13M >70% of people with AD experience agitation at some point in their disease2 Significant unmet medical need exists in this population3,4 Agitation is among the most disruptive symptoms of AD. It is associated with greater caregiver stress, increased morbidity and mortality and earlier placement in long-term care facilities. The only currently approved product carries a boxed warning for mortality in elderly people with dementia-related psychosis. U.S. Adults with Alzheimer’s Disease (M)1 1Alzheimer's Association. 2025 Alzheimer's Disease Facts and Figures. Alzheimer's Dementia 2025;21(5). 2Van der Mussele S, et al. Aging Ment Health 2015;19(3):247-257. 3Schein S, et al. J Alzheimers Dis. 2022;88(2):663-77. 4Rexulti, USPI May 2025.
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27 The vasopressin system modulates social-emotional, anxiety and threat-related behaviors across species • V1aR expression patterns critically affect social behavior1-5 • Rodents inbred for altered aggression or anxiety show dysregulated vasopressin release and HPA axis functioning6 • Vasopressin-deficient rodents display impaired responses to threat stimuli, reduced anxiety and depressive-like behaviors, and impaired aggression toward intruders7-9 Several lines of evidence indicate that V1a receptor antagonists have therapeutic potential for reducing symptoms of agitation Positive association between vasopressin and aggression in people with personality disorders11 Together, these data support the development of a V1a receptor antagonist for the treatment of symptoms of agitation, aggression, and anxiety In healthy volunteers, vasopressin enhances reactivity to threatening stimuli and disrupts emotional control1-2 • Exogenously administered vasopressin increases autonomic responsiveness to threat stimuli and increases anxiety2 • V1a antagonist administration suppresses anxiety induced by unpredictable threats10 In HD patients with irritability and aggressive behavior, an investigational V1a receptor antagonist reduced an exploratory endpoint measuring aggression12 1Ebstein et al., 2009, New York Academy of Sciences.; 2Thompson et al., 2006, PNAS.; 3Insel et al., 2010, Neuron Review, PNAS; 4Carter et al., 1995, Neuroscience Biobehavioral Review.; 5Wang et al., 1994, PNAS.; 6Veenema and Neumann, 2007, Brain behavior, evolution.; 7Zelena et al., 2009, Journal of Endocrinology.; 8Mlynarik et al., 2007, Hormones and Behavior.; 9Fodor et al., 2014, Psychoendocrinology.; 10Lago et al., 2021, Psychopharmacology.; 11Coccaro et al., 1998., Arch Gen Psychiatry.; 12Maibach et al., 2022, Personalized Medicine. HPA = hypothalamic-pituitary-adrenal
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28 NMRA-511 was safe and well-tolerated in healthy adults and healthy elderly participants Dose selected for Phase 1b to maximize receptor occupancy over 24 hours 40 mg QD in healthy adults compared to 20 mg BID in healthy elderly participants Phase 1 PK profile Healthy Adults 20 mg BID projected to achieve 97.7% to 99.3% receptor occupancy from trough to Cmax NMRA-511 was safe and well-tolerated No SAEs, or discontinuation due to treatment-related AEs was observed 15 mg QD 20 mg QD 40 mg QD 20 mg BID (Phase 1b) 40 mg QD (103 Study) Plasma Concentration of NMRA-511 (ng/mL) Plasma Concentration of NMRA-511 (ng/mL)
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29 NMRA-511 signal seeking study in Alzheimer’s disease agitation Part A: 2-Week Evaluation Period Enrolling Healthy Elderly Participants NMRA-511 Phase 1b Study Part A Inclusion Criteria: • Healthy elderly adult participants aged 65-80 years Part B Inclusion Criteria: • Adults aged 55-90 years with mild-severe dementia (MMSE score of 5-24) and clinically significant agitation (CMAI total score 45-100) Part B Primary Endpoint: • 𝚫 from baseline to Week 8 in CMAI total score Part B Other Endpoints Include*: 𝚫 from baseline to Week 8 in: • Ytotal score Statistics: • Study not powered to demonstrate statistical significance • Designed as a signal-seeking study; effect size will inform the potential future development of NMRA-511 in ADA Part B: 8-Week Evaluation Period Enrolling People with Alzheimer’s Disease Agitation (ADA) Randomized, double-blind treatment NMRA-511 20 mg BID (n=6) Placebo BID (n=2) R 1:1 Baseline WK 2 Randomized, double-blind treatment NMRA-511 20 mg BID (n=44) Placebo BID (n=44) R 1:1 Baseline WK 8 WK 4 WK 2 WK 7 WK 1 *Safety Assessments include adverse events, clinical laboratory, vital signs, physical examination, 12-lead electocardiogram (ECG), Columbia-Suicide Severity Rating Scale (C-SSRS). 𝚫 = Change; BID = twice daily; CMAI = Cohen-Mansfield Agitation Inventory; MMSE =Mini-Mental State Examinations; CGI = Clinical Global Impression of Change for Agitation; mADCS-CGIC = modified Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change for Agitation; NPI = Neuropsychiatric Inventory.
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30 Assumes efficacy confirmed via statistically significant separation from placebo in pivotal studies. AAD = Alzheimer’s disease agitation Significant opportunity for a product with a differentiated benefit/risk profile Rexulti and other atypical antipsychotics have a boxed warning for the risk of death in elderly individuals with dementia-related psychosis Auvelity is not FDA approved for AAD; 1 of 2 RCT demonstrated statistical separation of active over placebo There is a highly compelling opportunity if NMRA-511 demonstrates a differentiated benefit/risk profile Simplified market segmentation and opportunities Efficacy Safety CMAI Score Boxed Warning Moderate side-effects Mild side- effects
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31 Fireside Chat Anton P. Porsteinsson, M.D., William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine; Director, Alzheimer's Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry Bill Aurora, Pharm.D., Chief Operating & Development Officer 31
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32 M4 PAM Franchise Overview Nick Brandon, Ph.D., Chief Scientific Officer, Neumora
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33 M4 PAM franchise: Differentiated M4R PAMs for schizophrenia Pharmacology Neumora has multiple series of chemically distinct, highly selective M4 muscarinic receptor PAMs, including NMRA-861 and NMRA-898, designed for antipsychotic- like efficacy with the potential for improved tolerability profile Indication Schizophrenia Target Administration Oral, once-daily IP Composition of matter patent extending to 2044+* Epidemiology Estimated 3 million patients in the U.S. with schizophrenia1 Expected Milestones Provide M4 franchise update by mid-2026 M4 Franchise Target Profile 1Wander, C. Am J Manag Care. 2020;26:S62-S68. *Excluding any patent term adjustment or extension PAM = positive allosteric modulator
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34 Non-selective muscarinic agents are associated with a range of peripheral AEs PAMs offer the benefits of greater selectivity Why M4 PAMs Preclinical data and clinical data in acute schizophrenia supports M4 as a driver of antipsychotic activity 1 3 2 Validated Target Improvement over SOC Selectivity
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35 Preclinical and clinical data in acute schizophrenia support M4 as a driver of antipsychotic activity Placebo 20 mg NBI-1117568 Activity of xanomeline (active component of Cobenfy ) is dependent on M4R in mice Clinical activity shown with a M4 PAM and selective M4 agonist 1Digby GJ, et al. J Neurosci. 2012;32(25):8532-44. 2Dencker D, et al. J Neurosci. 2011 April 20;31(16):5905-8. 3Krystal JH, et al. Lancet. 2022 Dec 17;400(10369):2210-20. 4Neurocrine Biosciences. Q1 Earnings Presentation. April 14, 2025. www.neurocrine.com/documents/86/NBIX_Q1_2025_Earnings_Presentation_Final_05.05.25.pdf. 5Moran SP, et al. Trends Pharmacol Sci. 2019 Dec;40(12):1006-20. 6Tobin AB. Nat Rev Drug Discov. 2024 Oct,23(10);743-58. 7Paul SM, et al. Biol Psychiatry. 2024 Oct 15;96(8):627-37.
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36 Non-selective muscarinic agents are associated with a range of peripheral AEs Glands Increased salivation Increased lacrimation Increased sweating M1, M3 GI Tract Increased gastric secretion & gastric motility M1, M2, M3 M1, M2, M3 Cardiovascular Direct effect on cardiac function – increased BP & heart rate M4 Cardiovascular Transient increased BP & heart rate 1Digby GJ, et al. J Neurosci. 2012;32(25):8532-44. 2Dencker D, et al. J Neurosci. 2011 April 20;31(16):5905-8. 3Krystal JH, et al. Lancet. 2022 Dec 17;400(10369):2210-20. 4Neurocrine Biosciences. Q1 Earnings Presentation. April 14, 2025. www.neurocrine.com/documents/86/NBIX_Q1_2025_Earnings_Presentation_Final_05.05.25.pdf. 5Moran SP, et al. Trends Pharmacol Sci. 2019 Dec;40(12):1006-20. 6Tobin AB. Nat Rev Drug Discov. 2024 Oct,23(10);743-58. 7Paul SM, et al. Biol Psychiatry. 2024 Oct 15;96(8):627-37.
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37 PAMs offer the benefits of greater selectivity Targeting the allosteric site specifically allows for greater selectivity for M4 over other muscarinic sub-types than if targeting the orthosteric site due to binding site conservation To date the pharmacology of agonists targeting the orthosteric site are often thought to display ‘partial’ agonism which could contribute to variable clinical responses PAMs allow for more precise potentiation of M4, maintaining the spatial and temporal signaling dynamics of ACh
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38 NMRA-861 and -898 have potential best-in-class pharmacology and clinical differentiation NMRA-861 and -898 have potential best-in-class potency and optimized brain penetration NMRA-8611 NMRA-8981 Emraclidine M4 EC50 (human; cAMP)1 6 nM 13 nM 26 nM M4 EC50 (human; Ca2+)1 2 nM 8 nM 180 nM Selectivity at other muscarinic receptor subtypes (EC50)1 M1, M3, M5 > 10 µM, M2 0.7 µM M1, M2, M3, M5 > 10 µM M1, M3, M5 > 10 µM, M2 5.7 µM Brain exposure MDCK permeability (target >10) P-gp efflux ratio (target <2)1,2 High 45.5 1.26 High 36.7 0.93 Moderate 9.5 3, 6.021,2 Human half-life3 Pending Phase 1 Study Pending Phase 1 Study 9 – 12 hr Preclinical convulsions Not observed in rat, dog or rabbit Not observed in rat, dog or rabbit Unknown NMRA-861 and -898 potentially more potent than emraclidine across multiple assays Convulsions have not been observed with NMRA-861 or -898 NMRA-861 and -898 are selective for M4 over other muscarinic receptor subtypes Neumora M4 PAMs are optimized for once daily dosing Neumora M4 PAMs are optimized for high CNS exposure Note: Data on this slide is presented for illustrative purposes only. These molecules have not been studied in head-to-head clinical trials. cAMP = cyclic adenosine monophosphate; CNS = central nervous system; PAM = positive allosteric modulator 1Data generated by The Warren Center for Neuroscience Drug Discovery at Vanderbilt University on behalf of Neumora across NMRA-861, NMRA-898 and emraclidine. 2Butler CR, et al. J Med Chem. 2024 Jul 11;67(13):10831-47. 3Krystal JH, et al. Lancet. 2022 Dec 17;400(10369):2210-20.
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39 SAD/MAD studies evaluating NMRA-861 and NMRA-898 in healthy adults and people with stable schizophrenia Dose Cohorts Participants Randomization Part 1A Dose 1, Dose 2, Dose 3, etc. Healthy adults 6:2 active:placebo Part 1B (Fed- Fasted cohort) Dose to be determined Healthy adults 12 active SAD – Part 1 CSP Dose Participants Randomization Cohort 1 Dose to be determined Healthy adults 6:2 active:placebo Cohort 2 Dose to be determined Healthy adults Cohort 3 Dose to be determined Healthy adults OR with stable schizophrenia Cohort 4 Dose to be determined Healthy adults OR with stable schizophrenia Cohort 5 Dose to be determined Adults with stable schizophrenia MAD – Part 2 CSP Adults with stable schizophreniaHealthy adults Study Objectives • Confirm once-daily dosing – based on PK profile in humans • Evaluate tolerable doses in people with stable schizophrenia • Establish CNS penetration – based on CSF exposure
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40 Navacaprant Bill Aurora, Pharm.D., Chief Operating & Development Officer, Neumora
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41 The role of kappa opioid receptor antagonism in MDD Navacaprant • The kappa opioid receptor (KOR) / dynorphin system is a well- characterized pathway, and results from preclinical studies support its potential to modulate depression, anhedonia, and anxiety • KOR system overactivation in response to stress and mediation of depressive-like symptoms including anhedonia • KOR antagonism may allow DA and 5HT release to return to adaptive levels during reward processing
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42 Near-term clinical development plan focused on MDD with opportunity for further expansion KOASTAL-2 Conducted in U.S., Canada and Latin America KOASTAL-3 Conducted in U.S. and Europe KOASTAL-LT Open-label extension trial evaluating long-term safety of navacaprant in patients with MDD Additional indication opportunities include bipolar depression, substance use disorder, ADHD, Generalize Anxiety Disorder and Post-Traumatic Stress Disorder PHASE 3 DEVELOPMENT PROGRAM IN MDD KOASTAL-1 Conducted in U.S. Topline data announced 01/25 Placebo-controlled, double-blind RCTs evaluating efficacy and safety of navacaprant in MDD MDD = Major Depressive Disorder; RCT = Randomized Controlled Trial; ADHD = Attention-Deficit Hyperactivity Disorder
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43 KOASTAL pivotal study design Randomized, double-blind treatment Baseline WK 6 Navacaprant 80 mg QD Placebo QD R 1:1 Opportunity to enroll in KOASTAL-LT WK 1 WK 2 KOASTAL Pivotal Efficacy Studies KOASTAL-1, KOASTAL-2, KOASTAL-3 Summary Inclusion Criteria: • Adults ages 18 – 65 diagnosed with MDD • MADRS ≥ 25 at baseline Other Secondary Endpoints Include: 𝚫 from baseline to each timepoint in: • CGI-S and CGI-I • PHQ-9 • HAM-A • SDS Primary Endpoint: • 𝚫 from baseline to Week 6 in MADRS total score Key Secondary Endpoint: • 𝚫 from baseline to Week 6 in SHAPS total score Key Exploratory Endpoints*: 𝚫 from baseline to each timepoint in: • EQ-5D 5L • WPAI-GH Key Efficacy Assessments WK 4 *Safety Assessments include Change in Sexual Functioning Questionnaire (CSFQ-14) 𝚫 = Change; CGI-I = Clinical Global Impression-Improvement scale; CGI-S = Clinical Global Impression-Severity scale; EQ-5D 5L = EuroQol-5D 5L; HAM-A = Hamilton Anxiety Rating Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; MDD = Major Depressive Disorder; PHQ-9 = Patient Health Questionnaire-9; QD = once daily; SDS = Sheehan Disability Scale; SHAPS = Snaith-Hamilton Pleasure Scale; wk = week; WPAI-GH = Work Productivity and Activity Impairment Questionnaire – General Health.
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44 Optimizing KOASTAL-2 and -3 Phase 3 studies based on learnings from KOASTAL-1 Site Selection Adjusted clinical sites included in studies, with goal of including sites with demonstrated expertise in conducting MDD studies Medical Monitoring Using clinician-rated Massachusetts General Hospital Clinical Trials Network and Institute SAFER approach to verify the diagnosis and appropriateness of patient population Screening Tools Verified Clinical Trial (VCT) screening database complements the Clinical Trial Subject (CTS) database to screen for people who participate in multiple clinical trials Target Enrollment Option included in KOASTAL-2 and -3 protocols to overenroll the studies up to 25% MDD = major depressive disorder
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45 Closing Remarks Joshua Pinto, Ph.D., President, Neumora
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46 Multiple catalysts expected over next 12 months KEY MILESTONES Study Initiation Data Readout 2025 2026 Navacaprant KOASTAL-3 topline data (1Q26) Navacaprant KOASTAL-2 topline data (2Q26) NMRA-511 Phase 1b data (around year-end 2025) Provide M4 Franchise Update (mid-2026) NMRA-215 DIO data Advance NMRA-898 to the clinic Initiate Phase 1 studies of NMRA-215 (1Q26) Advance NMRA-861 to the clinic NMRA-215 Phase 1 human POC data (2026) TODAY
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47 Q&A Bill Aurora, Pharm.D. Chief Operating & Development Officer Helen Rubinstein VP, Investor Relations and Communications Nick Brandon, Ph.D. Chief Scientific Officer Joshua Pinto, Ph.D. President Anton P. Porsteinsson, M.D. William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine; Director, Alzheimer's Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry Paul Berns Chief Executive Officer MODERATER
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