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From Unmet Need to Reality Roluperidone is Potentially the First Treatment for Negative Symptoms of Schizophrenia KOL Event I February 3, 2026 1
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This presentation contains forward-looking statements which are subject to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. Forward- looking statements are statements that are not historical facts, reflect management’s expectations as of the date of this presentation, and involve certain risks and uncertainties. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this presentation include, but are not limited to, statements with respect to Minerva’s expectations regarding the potential of roluperidone to treat negative symptoms of schizophrenia and address unmet clinical and market needs; the design, timing conduct and anticipated results of the confirmatory Phase 3 trial of roluperidone; potential regulatory outcomes regulatory outcomes related to the Phase 3 trial and the development of roluperidone more broadly; and the anticipated financial resources to fund the planned Phase 3 trial and support Minerva’s corporate objectives. These forward-looking statements are based on our current expectations and may differ materially from actual results due to a variety of factors including, without limitation, trials and studies may be delayed and may not have satisfactory outcomes, and earlier trials and studies may not be predictive of later trials and studies; the design and rate of enrollment for clinical trials, including the current design of the Phase 3 confirmatory trial evaluating roluperidone may not enable successful completion of the trial(s); the commercial opportunity for roluperidone in negative symptoms of schizophrenia may be smaller than anticipated; Minerva may be unable to obtain and maintain regulatory approvals; Minerva may experience uncertainties inherent in the initiation and completion of clinical trials and clinical development; the need to align with collaborators or partners may hamper or delay development and regulatory efforts or increase costs; uncertainties of patent protection and litigation; and general economic conditions. Other factors that may cause our actual results to differ from those expressed or implied in the forward-looking statements in this presentation are identified under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2024, filed with the Securities and Exchange Commission on February 25, 2025, as updated by our Quarterly Report on Form 10-Q for the period ended September 30, 2025. Copies of reports filed with the SEC are posted on our website at www.minervaneurosciences.com. The forward-looking statements in this presentation are based on information available to us as of the date hereof, and we expressly disclaim any obligation to update any forward-looking statements, 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 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. Neither we nor any other person makes any representation as to the accuracy or completeness of such data or undertakes any obligation to update such data after the date of this presentation. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Forward-Looking Statement 2
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Welcome to Today’s Presentation: Introductions Professor Gregory Strauss, PhD Franklin Professor of Psychology Department of Psychology University of Georgia Professor Brian Kirkpatrick, MD, MSPH Peters Professor of Psychiatry University of Arkansas for Medical Sciences (UAMS) Department of Psychiatry Co-chaired the National Institute of Mental Health (NIMH)-sponsored Consensus Development Conference on Negative Symptoms Remy Luthringer, PhD Executive Chairman Chief Executive Officer Minerva Neurosciences, Inc. 3
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02 Defining Negative Symptoms of Schizophrenia and how they Impact Patients and their Families Professor Gregory Strauss The Challenge of Assessing Negative Symptoms of Schizophrenia in Clinical Trials Professor Brian Kirkpatrick 03 04 Roluperidone: Proposed Phase 3 Confirmatory Trial Design and Execution Dr. Remy Luthringer, CEO Minerva Q&A Agenda 01 02 03 04
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General alignment on FDA guidance, broad awareness in the psychiatry community, promising MOA and financial factors all combine to enable the confirmatory Phase 3 trial and a potential paradigm shift in the treatment of negative symptoms of schizophrenia February 2026: The Minerva Confluence Roluperidone FDA guidance on Phase 3 trial design following Public Meeting $200m raised Top Tier Investors SPRUCE STREET CAPITAL Broad understanding of unmet medical need 5
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General Alignment with FDA on Phase 3 Trial Design 6 General alignment reached on proposed design of a confirmatory Phase 3 study following extensive collaborative discussions with FDA throughout 2023- 2024 and the findings of an FDA Public Meeting in August 2024: Evaluating the Negative Symptoms of Schizophrenia in Clinical Trials 1 Excerpts from FDA Meeting Minutes • FDA acknowledges Minerva’s position that a population of people with schizophrenia can be identified with high negative symptoms and a low risk of relapses who can safely be withdrawn from antipsychotic treatment. • The Division is willing to discuss an additional study that provides robust, controlled data about the efficacy and safety of long-term monotherapy with roluperidone in subjects with negative symptoms of schizophrenia. • The Division agreed that it would consider a resubmission that included a double-blind, placebo- or active-controlled trial of roluperidone with a duration of at least 52 weeks. • The Division does not object to a 12-week primary efficacy endpoint for negative symptom. • To support a monotherapy indication, a comparison of relapse rates between patients on roluperidone monotherapy and similar patients maintained on antipsychotics would be important for regulatory decision making. • Would represent a new treatment paradigm. 1. FDA Meeting August 16, 2024
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Defining Negative Symptoms of Schizophrenia and How They Impact Patients and Their Families Dr. Gregory Strauss
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Positive Symptoms Often Ameliorate with Antipsychotic Treatment But Negative Symptoms Can Persist for Life and Drive Functional Impairment and Long-term Disability1 81 Fervaha G, et.al. Impact of primary negative symptoms on functional outcomes in schizophrenia. Eur Psychiatry. 2014 Sep;29(7):449-55
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Negative Symptoms of Schizophrenia are Underdiagnosed and Undertreated • KOL consensus that negative symptoms: − May have profound impact on patients’ quality of life (QOL) − Often present significant challenges for treatment − Antipsychotic treatment might worsen negative symptoms in some of the patients • Clinical practice and drug development have largely focused on treating the positive symptoms • No FDA approved therapies in the US for negative symptoms of schizophrenia Negative Symptoms1 Avolition AnhedoniaAsociality Blunted Affect Alogia • Lack of motivation • Reduced engagement with work/school • Poor self care • Reduced interest in relationships • Reduced social interactions • Limited friends • Reduced ability to experience and anticipate pleasure • Reduced frequency of pleasurable activities • Diminished facial & vocal expression of emotion • Reduced emotional expression in body gestures • Few gestures & little body language • Reduced quantity of speech • Less spontaneous elaboration Experiential Dimension Expressive Dimension 91 Kirkpatrick B, Fenton WS, Carpenter Jr WT, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia bulletin. 2006 Apr 1;32(2):214-9.
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All Domains are Not Created Equal: Avolition Acts as a Central Hub • Avolition (lack of motivation) acts as a central hub in schizophrenia's negative symptoms - Significantly impacts other domains of anhedonia (pleasure loss), asociality (social withdrawal), blunted affect (reduced emotional expression), and alogia (poverty of speech) • Disrupts goal-directed behavior and reward processing • Targeting avolition improves the entire constellation of symptoms & functional outcomes Avolition is a determinant of poor functional outcome Foussias & Remington, Schizophr Bulletin 2010 10
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Roluperidone Shows Pronounced Improvement in Avolition • Roluperidone targets key cortico-striatal circuits related to motivational deficits • Cascading improvement on other domains once motivation (avolition) improves Roluperidone Phase 2b: Avolition is most central for improvement (Strauss et al., 2020b) Roluperidone Phase 3 Replicated: Avolition is most central for improvement (James et al., 2024) 11
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Clinical Relevance: Improvement of Negative Symptoms with Roluperidone in Phase 2b Correlates to What Patients and Caregivers Deem Most Important • Self-perceptions study to determine clinical relevance1 - Patients and caregivers rated the magnitude of change in BNSS they believed was necessary for life to be meaningfully improved • Comparison to roluperidone Phase 2b data2 • Right two columns reflect the BNSS score that clinicians rated patients’ improvement - equated to a 1 or 2-point improvement on CGI • Tight correlation of actual roluperidone results5,6 to self perception study “clinically relevant”3,4 • Compelling evidence that roluperidone improves negative symptoms to a level that is meaningful to patients, caregivers and physicians 12 Self-Perceptions Study1 Roluperidone Phase 2b Data BNSS Domain Clin Rate – Self Ideal3 Clin Rate – Rel/Car Ideal4 ROL CGI-15 ROL CGI-26 MAP -0.65 -0.17 -0.72 -1.40 Anhedonia -0.38 -0.07 -0.67 -1.61 Asociality -0.53 -0.06 -0.71 -0.83 Avolition -1.10 -0.48 -0.69 -1.75 EXP -0.23 -0.33 -0.59 -1.68 Blunted Affect -0.87 -0.79 -0.59 -1.44 Alogia +0.46 +0.15 -0.60 -1.92 MAP: motivation-pleasure; EXP: emotional expressivity 1,2. GP Strauss; New Initiatives for Assessing Negative Symptoms: BNSS and Digital Phenotyping; presented at FDA public meeting 2024 3. Patient assessment of clinically meaningful; 4. clinician assessment of clinical meaningful; 5. 1-point improvement in CGI; 6. 2-point improvement in CGI
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The Challenge of Assessing Negative Symptoms of Schizophrenia in Clinical Trials Dr. Brian Kirkpatrick
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Why do Negative Symptom Trials Fail? Three Hurdles • Increased clinical attention by the research staff creates an expectation after previous positive trials & other supportive care (“nursing effect”) during the trial increase the placebo response rate • A widespread problem in all psychiatric trials – not just in schizophrenia studies Placebo response (the noise) • Improvement of a psychotic delusion by treatment with an antipsychotic changes the external perception of the patient, creating a misleading change in negative symptom ratings • However, this is not a true improvement in the primary illness-related negative symptoms Add-on to antipsychotics (the graveyard): • Antipsychotics interfere with dopaminergic neurotransmission, which in turn inhibits the brain’s reward system • Blocking dopamine receptors counteracts the effect of a therapy intended to improve negative symptoms • Hence trials as add-on therapy to antipsychotics are extremely challenging to show improvement in negative symptoms Pseudo-specificity (the false signal): 14
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Critical to Distinguish Between Primary and Secondary Negative Symptoms and Then Treat the Primary Negative Symptoms Primary vs secondary distinction (Kirkpatrick et al., 2001) Primary negative symptoms are a key factor in schizophrenia, often present prodromally, and may persist or even worsen throughout the patient’s lifetime Secondary negative symptoms result from intrinsic and environmental factors affecting patients with schizophrenia: • Positive symptoms (e.g. social withdrawal due to paranoia and delusions) • Depression • Side effects of antipsychotic treatment • Substance abuse • Social deprivation due to hospitalization or breakdown of family and social relationships Mosolov et al., 2022 15
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Prior Trials not Designed nor Sufficient for Negative Symptom Indication How to Best Evaluate Negative Symptoms of Schizophrenia in Clinical Trials?2 • Therapies in trials in patients with acute positive symptoms cannot demonstrate an effect on primary negative symptoms • Trial design as add-on to antipsychotics (blocking dopamine receptors) is not the solution because: − Signal obscured by ‘noise’ associated with antipsychotic-induced sedation, avolition, movement disorder − Blocking dopamine receptors in limbic structures involved in emotions and NS may be counterproductive − Not possible to discriminate between improvement of primary and/or secondary negative symptoms • Advantage of monotherapy trial design – Ideal to isolate the drug effect on primary negative symptoms – Include patients with stable positive schizophrenia symptoms and stable anxiety/depression symptoms FDA recently commented on Cobenfy marketing which claimed to show an “improvement across a range of symptoms” including negative symptoms FDA: “The pivotal trials supporting the schizophrenia indication for Cobenfy were not designed to capture changes in positive or negative symptoms as distinct groups…Additionally, the pivotal trials for Cobenfy were not designed to evaluate the efficacy of the drug in negative symptoms because the patients in the studies were experiencing acute exacerbations of schizophrenia, which can confound the assessment of improvement of negative symptoms. ”1 1. FDA letter, December 15, 2025; 2. Schizophrenia Bulletin Open, Volume 1, Issue 1, January 2020 16
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Importance of Function – Assessed by Personal and Social Performance Scale (PSP) Improving function • Regulators, payers and patients care about function and quality of life (QOL) • Improvement in functioning is a “lagging indicator” • Patients have often lived for years with negative symptoms, leading to diminished social networks, poor social skills, decreased opportunities, poor confidence Personal and Social Performance Scale (PSP) • A clinician-rated scale widely accepted as a measure of function in schizophrenia. • Four subscales: • Socially useful activities (including work and study). • Personal and social relationships. • Self-care. • Disturbing and aggressive behaviors. 17
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Phase 2b: Study Hit Primary Endpoint At Week 12 Roluperidone Separated from Placebo Throughout The Trial 18 ES = 0.61 ES = 0.78
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Phase 2b: Significant Improvement in PSP Total Score (Function) at 64 mg Dose PSP Total Score Change from Baseline (MMRM) (ITT Population) WEEK ES = 0.37 19 p = NS
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Phase 3: 64 mg Dose Meets Primary Endpoint NSFS (Negative Symptoms)* N=167 N=162 N=141 (84%) N=134 (82%) N=122 (75%) N=113 (70%) N=128 (77%) N=123 (74%) 20*mITT population (excludes 1 site for reasons of implausible data)
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Phase 3: Significant Improvement in PSP Total Score (Function) at 64 mg Dose* N=162 N=134 (83%) N=122 (75%) N=113 (70%) N=140 (84%) N=127 (77%) N=122 (74%) N=166 21*mITT population (excludes 1 site for reasons of implausible data)
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Discontinuation Rates in Combined Roluperidone Studies Outperforms Case-Matched Historical Database Controls 300 days = ~65% survival COMPARISON OF ALL-CAUSES DISCONTINUATION RATES BETWEEN ROLUPERIDONE AND EXISTING DATABASES 22 1. Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. NEJM 353:1209–1223, 2005 2. Winter-van Rossum, I., Weiser, M., Galderisi, S., et al. (2023). "Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST)." The Lancet Psychiatry, 10(3), 197–208 Red line: Roluperidone Blue line: CATIE1 & EULAST2 patients that met Minerva inclusion criteria 6 months
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Conclusions from Phase 2b and Phase 3* Trials • Roluperidone demonstrated clear statistical significance on multiple efficacy endpoints Improves primary negative symptoms Improves functioning Improves avolition No increase in positive symptoms or anxiety/depression Monotherapy was associated with a low relapse rate • No evidence of the well-known disabling side-effects regularly observed with atypical antipsychotic treatment Metabolic syndrome Sedation Motor symptoms (extra pyramidal symptoms; EPS) Prolactin elevation Nausea (for muscarinic antipsychotics) • Novel pharmacological profile that drives differentiated clinical benefit in all Minerva’s previous clinical trials 23*mITT population (excludes 1 site for reasons of implausible data)
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Roluperidone Proposed Phase 3 Confirmatory Trial Design and Execution Dr. Remy Luthringer
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Proposed Phase 3 Confirmatory Trial Design Screening (28 days) – to ensure patients meet eligibility criteria for stable symptoms prior to randomization Efficacy Assessment (12 weeks): Two parallel treatment arms randomized (1:1) to roluperidone or placebo using a double-blind study design Safety/Relapse Assessment (40 weeks following first 12 weeks): Two parallel treatment arms re-randomized (1:1) to roluperidone or one of three antipsychotics using a double-dummy study design 1 Patients re-randomized to either one of three atypical antipsychotics or roluperidone 25 SCREENING (N=380) ACTIVE-CONTROLLED SAFETY/RELAPSE ASSESSMENT PLACEBO-CONTROLLED EFFICACY EVALUATION 12-week efficacy analysis Primary endpoint (NSFS) Key secondary endpoint (PSP) Randomization Day -28 to Day -1 12 Weeks(1) Part A 40 Weeks (2) Part B Roluperidone 64 mg Antipsychotics1 Placebo 50% 50% 50% 50% 52-week end-of-study Safety analysis including qualitative relapse assessment Subject to ongoing feedback from the FDA
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Proposed Phase 3 Trial Design – Efficacy Endpoints for Part A Part A – 64 mg roluperidone vs. placebo for 12 weeks • N=380 randomized – following 28-day screening to ensure only patients with stable symptoms are enrolled • Primary endpoint: change from baseline in NSFS (Marder Negative Symptoms Factor Score) - Avolition drives negative symptoms and all prior studies show roluperidone has strong effect on avolition1 • Sole key secondary endpoint: - Change from baseline in PSP (Personal and Social Performance) total score – functional assessment - Avolition also closely correlated to function and daily performance • Statistical analysis: Mixed-effect Model Repeated Measurement (MMRM) 26 1. Strauss GP, Bartolomeo LA, Harvey PD. Avolition as the core negative symptom in schizophrenia: relevance to pharmacologica l treatment development. NPJ Schizophr. 2021 Feb 26;7(1):16. doi: 10.1038/s41537-021-00145-4. PMID: 33637748; PMCID: PMC7910596. Subject to ongoing feedback from the FDA
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Proposed Phase 3 Trial Design – Part B Safety/Relapse Assessment Part B: safety/relapse assessment to evaluate relapse rate in patients on roluperidone vs. SOC • Following 12-week efficacy endpoint, patients re-randomized to roluperidone or antipsychotics • 40-week treatment (52 weeks total) • Addresses FDA request to evaluate longer-term data on relapse rates in this population • Qualitative analyses of relapse rates as part of longer-term safety assessment 27Subject to ongoing feedback from the FDA
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Proposed Confirmatory Phase 3 Trial – Execution is Highest Priority 380 patients recruited from ~40 sites • US (target 25-30%) and 4 European countries • Rigorous inclusion/exclusion criteria to ensure correct patients • Reduces potential for variability to optimize statistical integrity Site selection based on quality performance metrics • Only working with the best sites with ability to recruit patients that meet inclusion criteria • Performance in Minerva’s previous negative symptoms trials and in other similar trials • Qualified training in PANSS rating, staff stability and access to high volume of appropriate patients Minimize potential placebo effect/maintain roluperidone improvement observed in two previous trials • Fewer assessment visits reduces the well-known “nursing effect” from enhanced clinical attention • Intensive PANSS rater training • Only one active drug dose (1:1 with placebo) reduces expectation bias that the patient was randomized to active drug • Careful attention to patient selection based on consensus of site and sponsor • Real time monitoring of rating quality by an independent expert service provider, with Minerva oversight from in-house personnel • Data collection using software on e-tablets with built in prompts to reduce rating errors • Single dose comparison to placebo obviating need for Type I correction (previous Phase 3 trial had two dose arms and Hochberg Type I correction) 28Subject to ongoing feedback from the FDA
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Proposed Confirmatory Phase 3 Trial – Status and Timelines Syneos appointed as CRO Multiple sites activated Topline results from 12-week primary efficacy endpoint expected 2H 2027 Relapse assessment expected 2H 2028 NDA resubmission strategy 29 First patient in (FPI) expected Q2 2026 Subject to ongoing feedback from the FDA
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Up to $200 Million Financing Announced October 21, 2025 30
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Summary: The Minerva Confluence 31 Only drug to date to demonstrate a significant and clinically relevant specific improvement on primary negative symptoms of schizophrenia Previous experience with two statistically significant (one nominally) trials + upcoming ‘high touch’ confirmatory Phase 3 trial improves probability of success FDA guidance on Phase 3 trial design + broad awareness of the unmet need in the psychiatry community + $200m investment from top tier investors Right Pharmacology and MOA Right Phase 3 Trial Design Right Moment
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Q&A A new approach to treating the unmet needs of schizophrenia patients