Slides
Page 1
November 2025 Corporate Presentation
Page 2
Disclaimer 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, bipolar mania and diabetic peripheral neuropathic pain, including the initiation, timing, progress and results of the Company's Phase 3 clinical trials in focal onset seizures, and a Phase 2 clinical trial of RAP-219 in bipolar mania, as well as other planned clinical trials; expectations for the activity, tolerability, and commercial potential of RAP-219; the future release of data from the ongoing 8-week follow-up period of the Phase 2a trial for RAP-219; expectations for a long-acting injectable (LAI) formulation of RAP-219 and the potential of a LAI to improve patient adherence; the Company's expectations for upcoming regulatory interactions; the potential of Rapport's RAP technology platform; the advancement of the Company's discovery programs; and expectations for Rapport's uses of capital, expenses and financial results, including its cash runway through the end of 2026. 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 of 1995. 2
Page 3
Leadership with track record of innovation and expertise Reid Huber, Ph.D. Director Partner, Third Rock Ventures; CEO, Merida Biosciences James Healy, M.D., Ph.D. Director Managing Partner, Sofinnova Investments Wendy Young, Ph.D. Director Former Head of Small Molecule Drug Discovery, Genentech Steve Paul, M.D. Founder and Board Chair Venture Partner, Third Rock Ventures John Maraganore, Ph.D. Director Former Founding CEO, Alnylam 1 Employee director. Robert Perez Director Operating Partner, General Atlantic, Former CEO, Cubist Pharmaceuticals Founder and Chairman, Life Science Cares Raymond Sanchez, M.D. Director Senior Advisor, Bain Life Sciences; Former CMO, Cerevel Therapeutics Paul Silva Director Former Chief Accounting Officer, Vertex Pharmaceuticals Management Team Board of Directors 3
Page 4
Company builders with industry-proven leadership Differentiated pharmacology we believe promotes high selectivity and specificity Potential to transform the treatment of neurological and psychiatric disorders with differentiated profile Strong Foundation & Differentiated Precision Approach Small molecule precision medicines for patients with neurological and psychiatric disorders TARP8: transmembrane AMPA regulatory protein gamma-8; AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. 1 Includes cash, cash equivalents, and short-term investments, excluding restricted cash. Robust Clinical & Discovery Pipeline Potential first-in-class programs leveraging receptor associated protein (RAP) science RAP-219 forebrain restricted TARP8 AMPAR modulator– significant opportunity in initial indication in focal onset seizures (FOS) Medicinal chemistry-enabled discovery portfolio with potential in additional indications Topline Phase 2a results in drug-resistant focal onset seizures announced September 2025; Phase 3 trials to begin Q3 2026 Topline Phase 2 results in bipolar mania in 1H 2027 Finalizing plans for Phase 2a in diabetic peripheral neuropathic pain RAP-219: Pipeline-in-a-Product with Multiple Catalysts Well Financed $513 million as of September 30, 20251 Cash runway expected to fund operations into 2H 2029 4
Page 5
Advancing precision therapeutics aimed at solving long-standing challenges in neuromedicine Drugs interact with receptors that are ubiquitous in the brain and body Drugs not designed with precision for disease-specific neuroanatomic sites / receptors Drug interactions and adverse events lead to noncompliance and discontinuation Drug discovery with conventional approaches (lacking RAPs) can miss high potential, previously unexplored targets RAPs are components of the broader neuronal receptor complexes and play critical roles in regulating receptor assembly and function RAPs serve as unique binding sites targetable by novel pharmacophores designed for increased selectivity, providing neuroanatomical specificity RAPs can enable differentiated pharmacology and potentially provide favorable efficacy, safety, and administration profiles RAPs can “unlock” drug targets previously inaccessible to study in vitro, allowing for potentially first-in-class drug discovery programs Conventional CNS drug discovery The potential of RAPs 5
Page 6
Precision neuroscience pipeline with opportunity to address large market opportunities a IND is currently on clinical hold with the FDA. AMPAR – α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor; nAChR – nicotinic acetylcholine receptor. Category Program Discovery Preclinical Phase 1 Phase 2 Phase 3 Next Expected Milestones RAP-219 TARPγ8 AMPAR Programs Focal Onset Seizures End-of-Phase 2 FDA Meeting 4Q 2025 Phase 3 Trials Begin 3Q 2026 Bipolar Mania Topline Results 1H 2027 Diabetic Peripheral Neuropathic Pain Trial Initiationa Long-acting Injectable Formulation Formulation Nomination nAChR Discovery Programs α6 Chronic Pain Development Candidate Nomination α9α10 Hearing Disorders Development Candidate Nomination Strong intellectual property with worldwide rights to all programs Topline Results Reported Trial Underway 6
Page 7
7 Unmet need in epilepsy highlights limitations of current antiseizure medications a Drug-resistant patients are those who continue to experience recurring seizures despite taking two or more ASMs; b Source: Epilepsy Foundation. ASM – antiseizure medication Limitations of antiseizure medications (ASMs) 3.0M U.S. Epilepsy Patients (ages 18+) 60% 1.8M Focal Seizure Patients 30-40% Drug-resistanta $11-15B market Limited Efficacy: Despite over 30 FDA approved ASMs, 30- 40% of patients are still drug-resistanta Tolerability Issues: Burdensome side-effects, such as sedation, ataxia, and cognitive problems Potential for Serious Adverse Events: Such as severe cutaneous reactions, serious hematological disorders, and hepatic failure Risk of Breakthrough Seizures: Missing doses of medicines with short half-lives create potential for breakthrough seizuresb Complicated Administration: Long titration, drug-drug interactions, overlapping mechanisms, and lab monitoring
Page 8
AMPAR inhibition is a clinically validated approach for epilepsy • ~50% of all focal onset seizures originate in the MTL, which includes the hippocampus and amygdala • Most of the remaining 50% originate in the cerebral cortex and spread into the mesial temporal structures • Focal onset seizures do not originate in hindbrain structures • AMPA type glutamate receptors at excitatory synapses can mediate the initiation and propagation of seizures • AMPAR target is clinically validated for the treatment of focal onset and generalized seizures AMPA receptors (AMPAR) in epilepsy Mesial temporal lobe (MTL) and cerebral cortex are the key brain areas associated with focal onset seizures Pre-synaptic neuron Post-synaptic neuron Na+ channel Action potential glutamate Ca2+ channel AMPAR Na+ Transmitter release Ca2+ Na+ perampanel EPSP K+ channel Depolarization Na+ Amygdala Cerebral cortex Brainstem Hippocampus Cerebellum 8
Page 9
TARPγ8 Clinical PET 9 Foundational science and supportive research established our early confidence in RAP-219 High expression in the neocortex and mesial temporal lobe, where nearly all seizures originate Relatively low expression in hindbrain Corneal Kindling Responders and Rotarod Failures in Mice Robust, dose-dependent seizure protection in gold-standard preclinical model Clear confirmation that TARPγ8 is broadly expressed in brain regions associated with the initiation and propagation of FOS
Page 10
RAP-219 dose-exposure-RO relationship Human PET RO data support lower dose levels, potentially increasing dose flexibility • Preclinical models demonstrated maximal seizure protection at 50- 70% RO (green band) • Human target RO (50-70%) achieved at doses/exposures lower than predicted from animal models (as low as 0.25 mg), and lower than the dose being used in Phase 2a FOS trial, potentially affording greater flexibility in dose selection • Phase 2a dose (green line) achieves target RO within 5 days and > 80% RO by day 28 Simulated RO based on Phase 1 PK and PET RO data RO: Receptor occupancy. 10 *Trough values calculated based on non-parametric superposition using data from the 101 and 102 studies 85% RO 80% RO 70% RO 60% RO 50% RO RAP-219 Trough* Concentration (ng/mL) 0.75 mg x 5 days, 1.25 mg/day x 23 days 0.75 mg x 28 days 0.25 mg x 28 days
Page 11
Phase 2a proof-of-concept trial in FOS patients using an objective electrographic biomarker for clinical seizure reduction • FDA-approved device for patients with drug-resistant focal onset seizures; approx. 6,500 RNS-treated patients in the U.S.1 • Two probes implanted into regions of the brain known to have epileptiform activity • Probes continuously detect and record epileptiform activity, including long episodes (LEs) & stimulate the region to attenuate seizure activity • ASMs resulting in a ≥ 30% reduction in LEs were associated with a ≥ 50% reduction in clinical seizures 2 1 Source: NeuroPace, January 2025. 2Gammaitoni et al, American Epilepsy Society (AES) 2024 Annual Meeting, Poster #1.494. Neuropace RNS System® 11
Page 12
Well-established relationship between long episode and clinical seizure responder rates 121 Skarpaas et al., Epilepsy & Behavior 83 (2018); 2 Quraishi et al., Epilepsia 61 (2020); 3 Gammaitoni et al, American Epilepsy Society (AES) 2024 Annual Meeting, Poster #1.494. • Skarpaas (2018)1: significant correlation exists between reduction in long episodes and clinical seizure frequency • Quraishi (2020)2: ASMs resulting in a ≥ 20% decrease in long episodes were clinical efficacious (≥ 50% reduction in seizures) • Gammaitoni (2024)3: ASMs resulting in a ≥ 30% reduction in LEs were associated with a ≥ 50% reduction in clinical seizures N=45 from three highly effective ASMs ASMs initiated: CLB (n=15), LEV (n=4), LCM (n=26)
Page 13
13 Phase 2a trial in drug-resistant focal onset seizure patients 1. Drug-resistant focal onset seizures 2. RNS® probe implanted in seizure onset zone within mesial temporal lobe (MTL) ≥15 months before screening 3. Stable RNS System settings and other therapies 4. ≥16 LEs during 8-week retrospective review period 5. ≥1 clinical seizure reported during 8-week retrospective review period 6. >50% concordance between LEs and electrographic seizures RAP-219 Washout0.75 mg x 5 days then 1.25 mg QD 4-week Prospective Baseline 12-week pre-treatment period 8-week open-label treatment period 8-week follow-up period End of treatment End of trial Start of treatment Key Entry Criteria a Patients with no clinical seizures during the prospective baseline period were allowed to enter the treatment period. b LE baseline was defined as the 12 weeks preceding the initiation of treatment (the combination of the 8-week retrospective, and 4-week prospective baseline periods) LE – long episode; MTL – mesial temporal lobe; RNS System – responsive neurostimulator; QD – once daily Key Endpoints 8-week Retrospective Baseline Clinical seizure baselinea Long Episode (LE) baselineb • LE reduction (power determinations based on this outcome measure) • Proportion of patients with ≥30% reduction compared with LE baseline • Median percent change from LE baseline • Clinical seizure reduction • Proportion of patients with ≥50% reduction compared with pre- treatment baseline; proportion of patients who achieved seizure freedom • Median percent change from baseline
Page 14
→ Safety population (N = 30) → mITT population for LE efficacy (N = 27) • Safety population minus 2 patients with <3 weeks of treatment and 1 patient with RNS setting change → mITT-CS population for clinical seizure efficacy (N=25) • mITT population minus 2 patients who did not have clinical seizures during prospective baseline 14 Patient disposition and analysis populations 30 Dosed with RAP-219 26 Completed Treatment Period 4 Discontinued Treatment • Adverse event (n=3) • Other (n=1) 38 Assessed for Eligibility 8 Excluded • Did not meet eligibility criteria (n=7) • Adverse event (n=1) Analysis Populations mITT – patients with ≥3 weeks or treatment, ≥70% adherence, and no RNS system detection or stimulation setting changes. mITT-CS – mITT with clinical seizures in prospective baseline. LE – long episode; RNS System – responsive neurostimulator.
Page 15
Patient demographic and baseline characteristics 15 Highly drug-resistant FOS patients are representative of those in registrational trials a ASMs in ≥20% of patients. ASM – maintenance baseline antiseizure medication; FOS – focal onset seizures; RNS System – responsive neurostimulator; SD – standard deviation; MTL – mesial temporal lobe Safety Population N=30 Age, years; mean (SD) 40.1 (10.4) Age at first seizure, years; mean (SD) 16.6 (9.4) Sex, male; n (%) 18 (60%) Years since RNS implantation; median (range) 4.6 (2-11) Number of patients with a lead outside of MTL (n) 5 No. of concomitant ASMs Median (range) 3 (1-4) 1, n (%) | 2, n (%) | 3, n (%) | 4, n (%) 2 (7%) | 7 (23%) | 14 (47%) | 7 (23%) Most frequently used ASMsa, n (%) Lamotrigine 15 (50%) Levetiracetam 12 (40%) Cenobamate 11 (37%) Zonisamide 9 (30%) Clobazam 7 (23%) Lacosamide 7 (23%)
Page 16
16 Efficacy analyses → Efficacy analyses for 8-week treatment period: • mITT population (N=27) for long episodes • mITT-CS population (N=25) for clinical seizures → 8-week follow-up period currently ongoing; full data will be presented at future medical meetings
Page 17
Primary endpoints achieved with high statistical significance 71% reduction in long episodes (LEs); 85.2% responder rate (≥30% LE reduction) a Median percent change statistical comparison used the Wilcoxon signed rank test to determine if the % change in LE was greater than 0%. b Responder analysis statistical comparison was based on a one-sample exact test to determine whether the proportion of responders is >10%. c Statistical comparisons were not made for other cut points. 95% confidence intervals for responder analysis -- Clopper- Pearson exact binomial: ≥50%, (61.9, 93.7); ≥75%, (28.7, 68.1); 100%, (0.9, 24.3). d Concordance at baseline was determined by an independent epileptologist reviewer. LEs – long episodes Weeks 1-8, N=27 Percent change Responder analysis 48 LEs at baseline (median, per 28 days); 92% electrographic seizure / LE concordanced 17
Page 18
10 clinical seizures at baseline (median, per 28 days) Clinical seizure secondary endpoints achieved with statistical significance 18 77.8% clinical seizure reduction; 72% achieved clinically meaningful response (≥50% reduction) a Statistical comparison for median percent change used the Wilcoxon signed-rank test to determine if the median % reduction from baseline in CS was greater than 20%. Responder analysis statistical comparison is based on a one sample exact test to determine whether the proportion of responders is, (b) >20%; (c) >7%; (d) >1.5% for the 50% responder, 75% responder, and seizure freedom groups, respectively. CS – clinical seizures. Responder analysis Percent change Seizure Freedom (weeks 1-8) Weeks 1-8, N=25
Page 19
RAP-219 was generally well tolerated 19 TEAEs: 79% were mild, 10% discontinuation rate TEAE – treatment emergent adverse event during treatment period; ECG – electrocardiogram. Safety Population (N=30) Any TEAE, n (%) 25 (83.3%) TEAE leading to study drug discontinuation 3 (10.0%) Grade 1 TEAE - Mild 15 (50.0%) Grade 2 TEAE - Moderate 10 (33.3%) Grade ≥3 TEAE - Severe 0 TEAEs reported in ≥10% of patients, n (%) Dizziness 8 (26.7%) Headache 5 (16.7%) Fatigue 4 (13.3%) Fall 3 (10.0%) Nausea 3 (10.0%) Somnolence 3 (10.0%) TEAE Summary → 25 patients reported a total of 65 TEAEs • 78.5% were mild, 21.5% were moderate • No serious adverse events or clinically significant laboratory, vital signs, or ECG abnormalities → 3 (10%) patients discontinued RAP-219 due to TEAEs • Grade 1 worsening of preexisting memory impairment • Grade 1 panic attack • Grade 2 worsening of preexisting anxiety
Page 20
20 Emerging best-in-class profile for RAP-219 in focal onset seizures, with multi-billion-dollar commercial opportunity, if approved Efficacy Data Phase 2a results demonstrated statistically significant reductions in long episodes and clinical seizures Tolerability Data RAP-219 was generally well-tolerated in Phase 2a Ease of Use Once daily dosing, low risk of drug-drug interactions, rational polypharmacy potential, and long half- life Long-acting Injectable Advancing first ever LAI for epilepsy patients, providing IP extension leading to potential commercial upside Initiation of Phase 3 registrational trials expected 3Q 2026 LAI – long acting injectable
Page 21
21 Robust Phase 2a results support advancing program Next steps → End of Phase 2 FDA meeting planned in 4Q 2025 → Open-label extension trial expected to begin in 4Q 2025 → Two Phase 3 trials expected to begin in 3Q 2026, using standard design and clinical seizure endpoint → Progressing registrational/NDA enabling activities
Page 22
Inflated self-esteem or grandiosity 22 Bipolar mania (bipolar 1 disorder) is characterized by episodes involving marked mood changes and increased energy Manic episode symptomsA single weeklong manic episode—or one requiring hospitalization—meets diagnostic criteria; disorder is considered lifelong, with most patients experiencing multiple episodes throughout life Bipolar disorder confers a high lifetime suicide risk of 10-20%; 5 times greater in males Patients also have higher risk of premature mortality as they are prone to coronary heart disease, chronic obstructive pulmonary disease, diabetes mellitus, and influenza or pneumonia Inflated self-esteem or grandiosity Decrease need for sleep More talkative Flight of ideas or racing thoughts Distractibility Increase in goal-directed actions Excessive involvement in risk taking activities
Page 23
~50% of bipolar patients are treated with ASMs in combination with lithium at first-line or used second-linec 23 Bipolar mania is a common psychiatric disease with significant need for well-tolerated, effective treatments Tolerability Issues: metabolic and neurological side effects including weight gain and cognitive impairment often lead to early discontinuation of medication Limited Efficacy: need for drugs with placebo-adjusted ≥6 YMRS reduction Potential for Serious Adverse Events: antipsychotics associated with extensive warnings and precautions—boxed and non-boxed—and confer risk of drug-drug interactions Low Adherence: medication intolerance leads to poor compliance with medication and high risk of relapse Limitations of standard of care ahttps://www.nimh.nih.gov/health/statistics/bipolar-disorder. bInternal market research (Trinity, 2023). chttps://pmc.ncbi.nlm.nih.gov/articles/PMC12404890/ ~7.2M U.S. Bipolar Prevalencea (ages 18+) ~2.9M Diagnosed Patientsb ~1.5M Bipolar Mania Patients
Page 24
24 RAP-219: A circuit-selective approach to bipolar mania Targets glutamatergic hyperactivity in cortico-limbic networks Increased cerebral metabolism in manic patients relative to healthy controls 1J.O. Brooks III et al. / Psychiatry Research: Neuroimaging 181 (2010) 136–140; Yüksel, C., & Öngür, D. (2010). Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biological Psychiatry, 68(9), 785–794. 2Traynelis et al., Pharmacol Rev 2010; 3Du J et al., J Neurosci 2008; Lee CY, Fu WM, Chen CC, Su MJ, Liou HH. Lamotrigine inhibits postsynaptic AMPA receptor and glutamate release in the dentate gyrus. Epilepsia. 2008 May;49(5):888-97. • Bipolar mania is characterized by increased glutamate levels and hypermetabolism in cortico- limbic networks1 • Glutamate signaling is primarily mediated by AMPA receptors, which accounts for most fast excitatory transmission in the brain2 • Lithium, valproate, and lamotrigine - approved therapies for bipolar - act in part by attenuating glutamatergic transmission, including reducing glutamate release and downregulating AMPA receptor function3 • RAP-219 selectively modulates TARPγ8- dependent AMPA receptor activity, potentially reducing excitatory glutamatergic drive in limbic neuronal populations that correspond to manic network hyperactivity Anterior Cingulate (BA 24/25) Hippocampal Complex Subgenual Prefrontal (BA 25)
Page 25
Phase 2 proof-of-concept trial in bipolar mania 56 Day Safety Follow up Period Weekly following last dose 21 Day Treatment Period RAP-219 or Placebo End of Treatment End of Study Start of Treatment Day -7 to Day -1 1 Day 1 to Day 22 22 Up to 7 Day* Screening Period (*may be extended with MM approval) Day 22 to Day 77 1 Week 3 Weeks 8 Weeks Discharge1 1If 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 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 to RAP-219 with 2-day titration, RAP-219 with 4-day titration, or placebo • 0.25mg x 1 day, 0.5mg x 1 day, 0.75mg x 19 days • 0.25mg x 2 days, 0.5mg x 2 days, 0.75mg x 17 days
Page 26
26 Multiple anticipated catalysts over next 24 months 2H 2025 RAP-219 FOS open label extension trial initiation 3Q 2025 RAP-219 bipolar mania Phase 2 trial initiated 2027 2026 2025 2026 RAP-219 FOS Phase 2a additional efficacy analyses and 8-wk follow-up results 3Q 2026 1H 2027 RAP-219 bipolar mania Phase 2 topline results 2H 2026 RAP-219 FOS open label extension interim results FOS – focal onset seizures; PK – Pharmacokinetics. 2027 RAP-219 long- acting injectable initial PK results Cash balance of $513Ma (as of 9/30/25) supports Rapport into 2H 2029 a Cash, cash equivalents and short-term investments, excluding restricted cash. RAP-219 FOS two Phase 3 trials initiation
Page 27
Appendix
Page 28
NatComm 2022 13:734 GluA1 GluA2 TARP8 Western blot JCB 2003 161:805 STG γ-3 γ-4 γ-8 tubulin RAP-219 target/TARPγ8 is selectively expressed in brain regions associated with focal onset seizures TARPs regulate the trafficking, subcellular localization and gating of AMPA receptors Cryogenic electron microscopy of GluA1/2 + TARPγ8 complex 28
Page 29
RAP-219 possesses potentially optimal drug properties for an ASM Potency at TARPγ8 IC50 ~ 100 pM Selectivity vs. other TARPs, NMDAR >4,000X target affinity Selectivity vs. CEREP and kinase panels >10,000X target affinity PK Orally bioavailable | %F = 80-100 Brain penetration Brain/plasma ~70% DDI/CYP inhibition/CYP induction >10,000 X target affinity. Not CYP substrate Solubility/permeability BCS Class I Target receptor occupancy 50% RO at <50 μg/kg oral dose in rodent Preclinical safety NOAEL in top dose of IND enabling studies Non-sedating No effects at exposures 1000X EC50 29NMDAR: N-methyl-D-aspartate receptor; DDI: drug-drug interactions; BCS: Biopharmaceutics Classification System; NOAEL: No Observed Adverse Effect Level.
Page 30
RAP-219 precision has the potential to significantly improve the therapeutic index Therapeutic Index = TD50 (toxic dose) on Rotarod/ED50 (effective dose) for efficacy. 1 Data on file, Rapport Therapeutics; https://panache.ninds.nih.gov/;2 Data based on published reports from different preclinical studies at different points in time, with differences in preclinical study design and subject population. As a result, cross-study comparisons cannot be made. No head-to-head studies have been conducted. >150 >44 25 9.5 5.6 5.5 5.3 4.9 > 4.6 3.1 <2.3 1.3 0 20 40 60 80 100 120 140 160Therapeutic Index Corneal kindling mouse model therapeutic index (TD50 rotarod/ED50 efficacy) for RAP-2191 and other ASMs2 30
Page 31
RNS measures and stores episode starts and long episodes in real time, all the time EEG RNS Progression of epileptiform activity to clinical seizures Seizure Diary Clinical Seizures Electrographic Seizures Increased amplitude, spread, and persist Epileptiform discharges Clinical SeizuresLong Episodes / Electrographic SeizuresEpisode Starts 31