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SEPTEMBER 22, 2026 KOL CALL Unmet Need in Bipolar Mania and the RAP-219 Clinical Program
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This presentation contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward- looking statements contain these identifying words. These forward-looking statements include, but are not limited to, express or implied statements regarding: the clinical development of RAP-219 for the treatment of focal onset seizures, primary generalized tonic-clonic seizures, and bipolar mania, including the initiation, timing, progress and results of the ongoing and planned clinical trials; expectations for the efficacy, tolerability, and commercial potential of RAP-219; the potential multi-billion dollar market opportunity for RAP-219 in focal onset seizures, if approved; the potential multi-billion dollar market opportunity for RAP-219 in bipolar mania, if approved; expectations for the development of a long-acting injectable formulation of RAP-219; the prioritization of the Company’s α6β4 program, including the development candidate’s potential in chronic pain and migraine and the Company’s IND- enabling activities; the deferral of further investment in the RAP-219 diabetic peripheral neuropathic pain program; the potential of Rapport’s RAP technology platform; and expectations for Rapport’s uses of capital, including its cash runway into the second half of 2029. Forward looking statements are based on management’s current expectations and are subject to risks and uncertainties that could negatively affect Rapport’s business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to the Company’s research and development activities; Rapport’s ability to execute on its strategy including obtaining the requisite regulatory approvals on the expected timeline, if at all; uncertainties relating to preclinical and clinical development activities; the Company’s dependence on third parties to conduct clinical trials, manufacture its product candidates and develop and commercialize its product candidates, if approved; Rapport’s ability to attract, integrate and retain key personnel; risks related to the Company’s financial condition and need for substantial additional funds in order to complete development activities and commercialize a product candidate, if approved; risks related to regulatory developments and approval processes of the U.S. Food and Drug Administration and comparable foreign regulatory authorities; risks related to establishing and maintaining Rapport’s intellectual property protections; and risks related to the competitive landscape for Rapport’s product candidates; as well as other risks described in “Risk Factors,” in the Company’s Annual Report on Form 10-K and most recent Quarterly Report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in Rapport’s subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent Rapport’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Rapport expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in its expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law, and claims the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act. 2 Disclaimer
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3 Agenda Welcome, Company and RAP-219 Overview Abe Ceesay, Chief Executive Officer Bipolar Mania: Disease State & Treatment Landscape Mauricio Tohen, MD, DrPH, MBA, University of New Mexico Health Science Center RAP-219 Bipolar Mania Phase 2 Trial & Clinical Decision-Making Dr. Gary Sachs, MD, Massachusetts General Hospital, Harvard Medical School Closing Remarks Abe Ceesay, Chief Executive Officer Q&A 01 02 03 04 05
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4 Rapport: building a new class of precision neuroscience medicines Differentiated pharmacology with transformative potential Targeting receptor-associated proteins (RAPs) enables selectivity and neuroanatomical specificity Designed to address long-standing challenges in neuroscience FOCAL ONSET SEIZURES Positive Phase 2a results reported Sep 2025 Phase 3 program initiated • Q2 2026 OLE initial data • Q4 2026 → → RAP-219 Novel forebrain- restricted TARPγ8 AMPAR modulator PRIMARY GENERALIZED TONIC-CLONIC SEIZURES Phase 3 initiation expected • 2027 TARPγ8: transmembrane AMPA regulatory protein gamma-8; AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. LONG-ACTING INJECTIBLE Phase 1 PK data expected • 2027 BIPOLAR MANIA Phase 2 topline results expected • Oct 2026 NEUROSCIENCE PLATFORM →LEAD ASSET →RAP-219 PROGRAMS Pipeline-in-a-productDesigned for biological precision Multiple near-term catalysts
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RAP-219 selectively binds to TARPγ8, representing a potential first- in-class precision medicine for neurological and psychiatric disorders 5 TARPγ8 Clinical PET High expression in the neocortex and mesial temporal lobe, where nearly all seizures originate Low expression in hindbrain TARPs regulate the trafficking, subcellular localization and gating of AMPA receptors GluA1 GluA2 TARPγ8 Cryogenic Electron Microscopy of GluA1/2 + TARPγ8 Complex PET results confirm TARPγ8 is highly expressed in the MTL and neocortex
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6 Increased Cerebral Metabolism in Manic Patients Relative to Healthy Controls aBrooks III et al., Psychiatry Res (2010); bYüksel & Öngür, Biological Psychiatry (2010); cGigante et al., Bipolar Disord (2012); dTraynelis et al., Pharmacol Rev (2010); eDu et al., J Neurosci (2004); fLee et al., Epilepsia (2008) RAP-219 circuit-selective approach to bipolar mania Targets glutamatergic hyperactivity in cortico-limbic networks Bipolar mania is characterized by increased glutamate levels and hypermetabolism in cortico-limbic networksa,b,c Glutamate signaling is primarily mediated by AMPA receptors, which accounts for most fast excitatory transmission in the braind Lithium, valproate, and lamotrigine - approved therapies for bipolar - act in part by attenuating glutamatergic transmission, including reducing glutamate release and downregulating AMPA receptor function e,f RAP-219 selectively modulates TARPγ8-dependent AMPA receptor activity, potentially reducing excitatory glutamatergic drive in limbic neuronal populations that correspond to manic network hyperactivity
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7 $45B bipolar mania market underserved by current standard of care U.S. patient population Potential U.S. opportunity in bipolar maniaMetabolic and neurological side effects of SOC lead to lack of compliance and limit long-term chronic use ~3.6M Diagnosed patients ~1.6M Bipolar mania patients ~8M Adults with bipolar disorder $45B Merikangas et al. Arch Gen Psychiatry (2007); Kato et al., J Affect Disord (2019); Kessler et al., Int J Methods Psychiatr Res (2012); Ringeisen et al., Int J Methods Psychiatr Res (2023), Jain et al., Adv Ther (2022); Pompili et al., Acta Psychiatr Scand (2025); Internal Market Research 2026
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8 University Distinguished Professor & Chairman, Department of Psychiatry, University of New Mexico Health Science Center BIPOLAR MANIA Disease State & Treatment Landscape Mauricio Tohen, MD, DrPH, MBA
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Bipolar Disorders Mauricio Tohen MD, DrPH, MBA Service Chief, Behavioral Health University of New Mexico Hospitals Distinguished University & Regents’ Professor McMillian Endowed Faculty in Bipolar Disorders Research Chairman Dept. of Psychiatry & Behavioral Sciences University of New Mexico Health Sciences Center Albuquerque, New Mexico, USA President, America Association of Chairs of Depts Psychiatry
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Disclosures Dr. Tohen has received honoraria from or consulted for Abbott, AbbVie, AstraZeneca, Alkermes, Lilly, Johnson & Johnson, Otsuka, Merck, Gedeon Richter Plc, Sunovion, Intracellular Therapies, Rapport Therapeutics, Roche, Elan, Lundbeck, Teva, Minerva, Neurocrine, and Pfizer; Dr. Tohen was an employee at Lilly (1997– 2008), and his spouse was an employee at Lilly (1998–2013).
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Epidemiology • Affects ~1% population irrespective socioeconomic status, gender, race • Death by suicide (prevalence 20%) -the most in Psychiatric Conditions • 1/3 ➔ 1/2 attempt suicide, 20% attempts completed • Suicide attempts: FH suicide, female, young age, depressive polarity, co-morbid anxiety/substance use disorder • Completed suicides: male, first degree FH • Co-morbidities (Psychiatric, Substance use, Medical) • Accurate diagnosis is complicated – no valid biomarkers • Clinical assessment- identification of /mania/hypomania/depression/mixed features • Disability, cognitive/functional impairment • Mean delay illness onset to diagnosis = 5-10 years
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Course of illness Mood fluctuations are common – striking and persistent – impairment
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Bipolar I Diagnosis – DSM 5 Criteria A. Mood: Abnormal elevated, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 1 week and present most of the day, nearly every day (any duration if hospitalization is necessary) B. 3/7 sx including: 1. Grandiosity/self esteem 2. Decreased need for sleep 3. More talkative, racing thoughts/flight of ideas 4. Distractibility (attention drawn to unimportant stimuli) 5. Increase in goal directed activity (social, work, school, sexual) 6. Psychomotor agitation (purposeless non goal directed activity) 7. Impulsive behaviors/high potential for consequences (spending sprees, sexual indiscretions, substance) C. Impairment in social or occupational functioning/ hospitalization to prevent harm to self or others, psychosis D. Not resulting from substance, drug or medical condition • Specifiers: Rapid cyclers (4 mood episodes <12 mo), mixed (episodes 3 sx of opposite pole) Presence of a manic episode
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Pathophysiology • One of the most heritable • Genetics + environmental • Some alleles genome studies overlap with Schizophrenia • Imbalance in monoaminergic neurotransmitter systems – serotonergic, noradrenergic, dopaminergic, acetylcholine, Glutamatergic – no singular dysfunction • Neuronal interconnectivity: mitochondria • Post mortem brain tissue – Cortical/Limbic changes • Systemic neuroinflammation
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Mania Depression Maintenance Advantages Disadvantages Valproate +++ + ++ mixed features not recommended in women at childbearing age Lamotrigine --- - +++ Prevents Depression Slow titration Lithium ++ ++ +++ Anti-suicidal properties prevents mania Long term renal side effects Carbamazepine ++ + ++ Good tolerance Interaction with other drugs Oxcarbazepine + + + Fewer adverse effects than carbamazepine Better tolerated Chlorpromazine ++ --- + Rapid efficacy Risk of switch to depression, extrapyramidal symptoms Haloperidol +++ --- + IM, Rapid efficacy, LAI Risk of switch to depression, extrapyramidal symptoms Mood stabilizers Typical antipsychotics
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Mania Depression Maintenance Advantages Disadvantages Aripiprazole +++ - ++ Mania, good metabolic profile Intramuscular administration - 4 weeks Akathisia Asenapine +++ + + depressive symptoms Moderate metabolic syndrome Clozapine + + ++ Treatment Resistant patients Agranulocytosis, sialorrhoea, postural hypotension Lurasidone + +++ + Lack of anticholinergic effects Efficacy related to feeding, akathisia, sedation Olanzapine +++ +++ ++ Rapid efficacy Severe metabolic syndrome Paliperidone ++ - ++ intramuscularly every month High doses are often needed Quetiapine +++ +++ +++ Only antipsychotic indications mania Depression, maintenance Sedation Risperidone ++ - ++ Intramuscular administration - 4 weeks Risk of switch to depression, extrapyramidal symptoms Ziprasidone ++ - ++ Mania, good metabolic profile Efficacy related to feeding Cariprazine + +++ Lumateperone + +++ Antidepressants -- + + Applicable in resistant bipolar depression combined with mood stabilizers Risk of switch to mania Electroconvulsive TMS ++ ++ + Treatment Resistant, Pregnancy General anesthesia. Cognition Not FDA approved Atypical Antipsychotics
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Unmet Needs for Treatment of Mania • More effective & Better tolerated • New Mechanisms of Action • Faster onset of action • Effective mania/depression/mixed – Maintenance • Long lasting option Long Term • Curative not just symptom amelioration • Personalized Medicine
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BIPOLAR MANIA RAP-219 Phase 2 Trial Design & Defining Clinical Success 18 Gary Sachs, MD Founding Director, Bipolar Clinic & Research Program, Massachusetts General Hospital Associate Clinical Professor of Psychiatry, Harvard Medical School Clinical Vice President, Signant Health
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Acute Mania RCT Challenges: a Clinical Trialist Perspective Acute Mania RCTs • Overview/Need • Chance of Success • Lessons Learned Diagnostic Challenge • Achieving reasonable diagnostic confidence Outcome Assessment • Design issues • Primary Outcome Measure • -Clinically Meaningful Difference
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Conflict of Interest: Disclosure Past 36 Months 20 Full Time Employee: Consulting/DSMB: Equity/Options: Signant Health 4M Therapeutics, Abbvie, Beckley, BMS, Cognitiv, IntraCellular Therapies, Kintsugi, Neumora, Merck, Rapport, Seaport, Syntropic, Xenon Signant Health, Collaborative Care Initiative, Kintsugi
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Acute Mania RCTs Have a Good Track Record of Success! Efficacy of Antimanic Treatments: Meta-analysis of Randomized, Controlled Trials Forest plot of Hedges' g with its 95% upper and lower limits (confidence interval (CI)), based on mania score changes in 55 drug/placebo comparisons, based on random effects meta-analysis. Filled squares indicate pooled results of individual drugs (and their CI). Drugs are listed according to the magnitude of the pooled effect sizes (Hedges' g). Yildiz et al. Neuropsychopharmacology. 2011 Jan; 36(2): 375–389. Published online 2010 Oct 27. doi: 10.1038/npp.2010.192
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Rapid acting agent But, at the end of 3-4 weeks, the average participant in an acute mania trial experiences symptoms of sufficient severity to meet study entry criteria. Unmet needs Fully resolve mania Less burdensome agent (Weight/Metabolic, Cognition, Sedation, Lab monitoring, EPS, Tardive Dyskinesia)
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Signal in Successful Acute Mania Trials ΔYMRS Placebo and IP 10 8.5 7.2 10.5 4.8 3.4 5.6 8.1 4.1 14 15.5 12.5 22.7 10.6 8.2 11.1 14.8 13.9 Iloperidone 2024 Cariprazine 2015 Aripiprazole 2006 Risperidone 2005 Risperidone 2004 Aripiprazole 2003 Ziprasidone 2003 Olanzapine 2000 Olanzapine 1999 ΔPBO ΔIP
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NNT Likely Reflect Similar Effect Size but Some Interesting Differences Between Studies Number Needed to Treat (NNT)= 1/(Active Response Rate - Placebo Response Rate ) 2.7 4.0 4.5 4.8 4.8 5.3 5.9 6.7NNT Acute Mania Study Response Rate Tohen 19991 Olanzapine (OLZ)=49% Placebo=24% Tohen 20002 OLZ=65% Placebo=43% Khanna 20053 Risperidone (RIS)=73% Placebo=36% Hirschfeld 20044 RIS=43% Placebo=24% Vieta 20055 Quetiapine (QTP)=48% Placebo=31% Keck 20036 Ziprasidone (ZIP)=50% Placebo=35% Keck 20037 Aripiprazole (ARI)=40% Placebo=19% Sachs 20068 ARI=53% Placebo=32% 1. Tohen M et al. Am J Psychiatry. 1999;156:702-709; 2. Tohen M et al. Arch Gen Psychiatry. 2000;57:841-849; 3. Khanna S et al. Br J Psychiatry. 2005;187:229-234; 4. Hirschfeld RM et al. Am J Psychiatry. 2004;161:1057- 1065; 5. Vieta E et al. Curr Med Res Opin. 2005;21:923-934; 6. Keck PE Jr et al. Am J Psychiatry. 2003;160:741-748; 7. Keck PE Jr et al. Am J Psychiatry. 2003;160:1651-1658; 8. Sachs G et al. J Psychopharmacol. 2006;epub Feb 14. RIS3 OLZ1 OLZ2 ARI7 RIS4 QTP5 ZIP6ARI8 Comparisons across studies is not valid comparisons of efficacy!!!
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Brexpiprazole for the acute treatment of bipolar mania Two randomized, double-blind, placebo-controlled trials • In treatment-by-subgroup (sex, age, region, and race) interaction analyses, none of the subgroup interactions at day 21 were significant at the 0.05 level except for the treatment-by-region interaction term in study 081 (p = 0.0016). • There was a difference between brexpiprazole and placebo in change from baseline to day 21 in YMRS total score in patients from the EU in study 081 (LS mean difference: −6.42 (95% CLs −9.79, −3.05)), with a nominal p-value of 0.0003, but not in study 080 (LS mean difference: −2.38 (95% CLs −5.10, 0.34); nominal p-value = 0.0858; Study 080 Study 081 Mean change baseline to day 21 in YMRS total score Placebo Brexpiprazole
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Reliability of MDD and Anxiety Diagnoses is Moderate to Poor: Competent clinicians frequently differ 0.56 0.28 0.46 0.54 0.2 Bipolar I MDD Schizophrenia Borderline Personality GAD Pooled Kappa DSM 5 Field Trials Opportunity: Maximize chance of success by utilizing low burden checks on diagnostic reliability. Adapted from Regier DA, et al. Am J Psychiatry 2013;170:59-70. 10.1176/appi.ajp.2012.12070999 High reliability can be defined as two independent assessments with the same results. One of these assessments could be done by a computer
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Lessons from a Failed Study: Diagnosis Matters Study of adjunctive Ziprasidone vs Placebo for treatment of BP mania or mixed episodes Favors Active Favors Placebo ∆ YMRS Active- Placebo Tandem (High Confidence) n=201 ∆ Active-Placebo SBR Eligible Only (Low Confidence0 n= 303 ∆ Active-Placebo Meets DSM IV Mania or Mixed Criteria by Tandem Rating Sachs GS, Vanderburg D, Karayal ON, Kolluri S, Bachinsky M, Cavus I: Adjunctive Oral Ziprasidone in Patients With Acute Mania Treated With Lithium or Divalproex: 1. Results of a Randomized, Double-Blind, Placebo-controlled Trial. J Clin Psychiatry (in press)
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Despite all the advances in neuroscience, there are no lab tests for bipolar disorder What can be done now ?
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Validating Lifetime Mood Disorder Diagnosis: Five Dimensions 1. Index Episode Characteristics 2. Age of Onset 3. Course of illness 4. Family History 5. Response to Treatment Robins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 126:983-987, 1970. 20 Most convincing characteristic 15 Other convincing characteristics 10 Known associated feature suggestive of the disorder 5 Nonspecific feature suggestive of the disorder 0 No evidence of the disorder Sachs G. Strategies for improving treatment of bipolar disorder: integration of measurement and management. Acta Psychiatr Scand Suppl.;422:717. 2004 20 point scale for each dimension
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Bipolarity Index Clinical Practice Validation in US, Russia, and China
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RAP-219 Phase 2 Proof-of-Concept Trial in Bipolar Mania End of Treatment End of Trial Start of Treatment Day -7 to Day -1 1 Day 1 to Day 22 22 Day 22 to Day 77 1 Week 3 Weeks 8 Weeks Dischargea NCT07046494; aIf a participant does not meet all discharge criteria; the Investigator may reassess at their discretion for up to 1 week following the last dose or may transfer the participant to an appropriate care center in accordance with standard of care. Key Endpoints Change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score Change from baseline to Week 1 in YMRS total score Change from baseline to Week 3 in Clinical Global Impressions– Bipolar Version (CGI-BP) Severity of Illness-Mania score Population Bipolar mania N = ~250 Key Entry Criteria Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of bipolar I disorder, with or without mixed features, with or without psychotic symptoms, as confirmed by the Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT) At least one prior documented manic episode (with or without psychotic symptoms) that required treatment, within 5 years prior to Visit 1 Dose Regimen Participants randomized 1:1:2 (RAP-219 cohorts pooled for efficacy) RAP-219 with 2 or 4-day titration, then 0.75mg x 19 days RAP-219 with 4-day titration, 0.75mg x 17 days Placebo 21 Day Treatment Period RAP-219 or Placebo 56 Day Safety Follow up Period Weekly Following Last Dose Up to 7 Day* Screening Period (*may be extended with MM approval) 31
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Key Inclusion/Exclusion Criteria Inclusion • Age 18-65 • Meets DSM-5 diagnostic criteria for Bipolar I disorder, with or without psychotic features and with or without mixed features • YMRS total score ≥25 at Screening and Baseline, and no more than 20% improvement on YMRS score between Screening and Baseline • Score of ≥4 on at least 2 of the 4 core YMRS items (irritability, speech, content, disruptive/aggressive behavior) at Screening and Baseline • Score ≥50 on the Bipolarity Index at Screening • Current episode has been present for ≤12 weeks prior to Screening • MADRS total score <18 at Screening and Baseline • Meets criteria for inpatient hospitalization • Had at least one prior documented manic episode (with or without psychotic symptoms) that required treatment, within 5 years prior to Screening • Previously responded to at least one course of antimanic treatment Exclusion • History of schizophrenia or schizoaffective disorder, moderate or severe substance use disorders, cognitive disorders, or personality disorders • Rapid cycling (≥ 4 distinct mood episodes in the past 12 months) • Current manic episode results from treatment with a pharmacological agent or from recreational drug use per Investigator • Inability to reliably report symptoms of mania, as evidenced by ≥7 point discordance in YMRS total score between Investigator interview and computer simulated rater interview at Screening or Baseline • Suicidal ideation with intent within 6 months prior to screening or at baseline; history of a suicide attempt within the year prior to screening, or at risk of suicide per the Investigator
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Ensuring Data Quality 33 SCID-5-CT confirmed diagnosis, Bipolarity Index ≥ 50, and a documented history of a prior manic episode (within 5 years) with antimanic treatment Diagnostic Confidence YMRS ≥ 25 at both Screening and Baseline, ≥ 4 on 2 of 4 core YMRS items, and symptoms severe enough to require inpatient hospitalization Symptom Severity Threshold MADRS < 18 at Screening and Baseline, limiting enrollment of patients whose presentation is more depressive than manic Mania-Predominant Profile Blinded data analytics run throughout the study, with a CRO dedicated to trial quality tracking site-level variability — flagging issues early while preserving the blind Ongoing Blinded Monitoring No more than 20% YMRS improvement between Screening and Baseline — excludes patients whose mania is self- resolving Symptom Stability Screen YMRS ratings reviewed for concordance between patient computer administered assessments and site clinician ratings to ensure consistent and accurate reporting of mania symptoms Site Clinician/Rules Based AI concordance Eligibility was reviewed by the study team for each patient in the study to ensure they met inclusion/exclusion criteria and confirm the diagnostic accuracy of the Bipolar mania diagnosis Eligibility Review SCID-5-CT= Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version, MADRS= Montgomery-Åsberg Depression Rating Scale; YMRS= Young Mania Rating Scale
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Observed Concordance: Site Based Rater and Rules-based AI • Across all open phase visits, mean difference between computer/clinician MADRS was 0.48 • MADRS computer ratings were higher in 33% and lower in 19% MADRS Computer-SBR YMRS Computer-SBR • Across all open phase visits, mean difference between computer/clinician YMRS was 0.87 YMRS ratings were higher in 48% and lower in 12%. • % computer scores > 4 points higher < 4%
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35 Multiple anticipated catalysts over 12-18 months Cash balance of $436.1M1 (as of 6/30/26) supports Rapport into 2H 2029 RAP-219 Epilepsy Portfolio RAP-219 Phase 3 FOCUS 1 & FOCUS 2 trials enrolling RAP-219 FOS open-label long-term safety trial underway RAP-219 NDA-enabling activities progressing LAI IND-enabling activities progressing RAP-219 Bipolar Program RAP-219 Phase 2 bipolar mania trial full enrolled Oct 2026 RAP-219 bipolar mania Phase 2 topline results 4Q 2026 RAP-219 FOS open label long- term safety trial initial data Additional catalysts: RAP-641 (α6β4) Phase 1 trial initiation 1H 2027 RAP-219 PGTCS Phase 3 trial initiation 2027 RAP-219 long- acting injectable Phase 1 topline PK results 2027 2026 1Includes cash, cash equivalents, and short-term investments, excluding restricted cash.
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Questions & Answers