Rapport Therapeutics, Inc. · NASDAQ:RAPP
Rapport Therapeutics — Investor Presentation (March 2025)
38 slides from Rapport Therapeutics's investor presentation, Mar 3, 2025
Slide 1: Corporate overview March 2025
Exhibit 99.1 Corporate overview March 2025
Slide 2: Disclaimer
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,” “
Slide 3: Leadership with track record of innovation and expertise
Leadership with track record of innovation and expertise Management Team Board of Directors Steve Paul, M.D. James Healy, M.D., Ph.D. Reid Huber, Ph.D. John Maraganore, Ph.D. Robert Perez Founder and Board Chair Director Director Director Director Partner, Third Rock Ventures Managing Partner, Partn
Slide 4: Ushering in a new era of precision neuroscience
Ushering in a new era of precision neuroscience Vision: To become a leader in precision neuroscience through the discovery and development of transformational small molecule medicines for patients suffering from central nervous system (CNS) disorders Potential for differentiated Accomplished scienti
Slide 5: Current limitations of neuromedicine compel the creation of Rapport
We believe the current state and limitations of neuromedicine compels the creation of Rapport RAPs are components of the broader neuronal receptor complexes and play critical roles in regulating receptor assembly and function Conventional CNS drug discovery The potential of RAPs Drugs interact with
Slide 6: Advancing our precision neuroscience pipeline
Advancing our precision neuroscience pipeline to potentially address large market opportunities Next Expected Category Program Discovery Preclinical Phase 1 Phase 2 Phase 3 Milestone Refractory Focal Topline Results Q3 2025 Trial Underway Epilepsy RAP-219 Trial Initiation Q3 2025 Bipolar Mania TARPγ
Slide 7: Focal epilepsy is a large market with high unmet need
Focal epilepsy is a large market with high unmet need Key highlights of U.S. focal epilepsy market Limitations of current therapies U.S. Epilepsy Patients Limited Efficacy: Despite over >20 FDA approved x 3.0M anti-seizure medications (ASMs), 30-40% of (ages 18+) 1 patients are drug-resistant Tolera
Slide 8: A "pipeline in a product" opportunity
RAP-219 is a “pipeline in a product” opportunity Focal epilepsy Peripheral neuropathic pain Bipolar disorder 1 2 3 U.S. patients: 1.8 million U.S. patients: ~5.6 million U.S. patients: ~7 million TARPγ8 is a preclinically and clinically validated target for epilepsy Once daily (QD) dosing | No evide
Slide 9: Overview
RAP-219 overview A. Mechanism of action and preclinical development B. Phase 1 trials C. Phase 2a proof-of-concept trial in refractory focal epilepsy D. Bipolar mania and diabetic peripheral neuropathic pain 9
Slide 10: AMPAR inhibition is a clinically validated approach for epilepsy
AMPAR inhibition is a clinically validated approach for epilepsy Hippocampus and cortex are important sites of AMPA receptors (AMPAR) in epilepsy focal onset seizure origination ISBN 978-0-07-129621-6 • AMPA type glutamate receptors at excitatory • Approximately 50% of all focal onset seizures synap
Slide 11: Transmembrane AMPA regulatory proteins (TARPs)
Transmembrane AMPA regulatory proteins (TARPs) TARPs: Auxiliary subunits that associate with AMPA receptors in the brain Crucial for regulating the trafficking, subcellular localization and gating of AMPA receptors Western Blot Cryogenic electron microscopy of TARPγ8 clinical PET GluA1/2 + TARPγ8 co
Slide 12: Highly potent and selective TARPγ8 AMPAR NAM
RAP-219 observed to be highly potent and selective TARPγ8 AMPAR NAM RAP-219 potency and selectivity TARPγ8-containing AMPA receptors (IC ) ~100 pM 50 vs. AMPA receptors (GluA1) lacking TARPs >100,000x vs. AMPA receptors containing other TARPs (γ2, γ3, γ4, γ7) >4,000x vs. NMDA receptors (2A, 2B, 2D)
Slide 13: Differentiated precision preclinical profile of RAP-219
Differentiated precision preclinical profile of RAP-219 Corneal kindling responders and Receptor occupancy (%) in rats rotarod failures in mice EC % Corneal Kindling Responders 70 % Rotarod Failures 7 ng/mL • Oral administration of RAP-219 (0.001-10 mg/kg) • Valid model in focal epilepsy • Plasma EC
Slide 14: Precision may improve the therapeutic index
RAP-219 precision has the potential to significantly improve the therapeutic index Corneal kindling mouse model therapeutic index 160 >150 1 2 (TD rotarod/ED efficacy) for RAP-219 and other ASMs 50 50 140 120 100 80 60 >44 40 25 20 9.5 5.6 5.5 5.3 4.9 > 4.6 3.1 <2.3 1.3 0 Therapeutic Index = TD (tox
Slide 15: TARPγ8 NAM effectiveness persists with repeat dosing
TARPγ8 NAM effectiveness persists with repeat dosing Antiseizure activity maintained after prolonged exposure Corneal Kindling Responders (%) • Efficacy in corneal kindling used to evaluate RTX-1738 (an analog of RAP- 219) • RTX-1738 (3 mg/kg) tested following either single day or seven consecutive
Slide 16: TARPγ8 AMPAR NAMs active in preclinical epilepsy models
TARPγ8 AMPAR NAMs active in preclinical epilepsy models Preclinical epilepsy models are highly translatable, with probabilities of clinical success up to 70%, according to epileptologist Jackie French • Robust efficacy across a broad array of preclinical Model focal and generalized seizure models *
Slide 17: Overview
RAP-219 overview A. Mechanism of action and preclinical development B. Phase 1 trials C. Phase 2a proof-of-concept trial in refractory focal epilepsy D. Bipolar mania and diabetic peripheral neuropathic pain 17
Slide 18: First-in-human Phase 1 trials
RAP-219 first-in-human Phase 1 trials PET receptor occupancy trial Single ascending dose (SAD) trial (RAP-219-103) (RAP-219-101) • Open label, multiple dose trial in healthy volunteers • Randomized, double-blind, placebo-controlled SAD • Objective: confirm neuroanatomical expression of and open labe
Slide 19: Phase 1 experience in healthy volunteers exposed to RAP-219
RAP-219 Phase 1 experience 100 healthy volunteers exposed to RAP-219 Data underscore the potential broad therapeutic index, differentiated tolerability profile, and dosing flexibility of RAP-219 RAP-219 tolerability • RAP-219 was generally well tolerated with no SAE’s and no TEAEs greater than Grade
Slide 20: Phase 1: PET trial results
RAP-219 Phase 1: PET trial results RAP-219 achieved and exceeded target RO and was generally well tolerated Restricted neuroanatomical expression of TARPγ8 was confirmed TARPγ8 clinical PET • TARPγ8-containing AMPA receptors were enriched in the hippocampus and cerebral cortex, and expression was mi
Slide 21: Phase 1: SAD vs. MAD exposures
RAP-219 Phase 1: SAD vs. MAD exposures * * * *Pending finalization 21
Slide 22: Phase 1: MAD-1 trial results
RAP-219 Phase 1: MAD-1 trial results At highest dose, no TEAEs above Grade 1 and no treatment-related TEAEs Dose in Phase 2a focal epilepsy trial 1 Possibly related or probably related 22
Slide 23: Potentially optimal target profile emerging for RAP-219 in focal epilepsy
Potentially optimal target profile emerging for RAP-219 in focal epilepsy Ideal Product Profile RAP-219 Emerging Profile Reduces seizures potently At low dose, reduced seizures in validated preclinical without evidence of sedation epilepsy models Displays no dose limiting Highest dose evaluated was
Slide 24: Overview
RAP-219 overview A. Mechanism of action and preclinical development B. Phase 1 trials C. Phase 2a proof-of-concept trial in refractory focal epilepsy D. Bipolar mania and diabetic peripheral neuropathic pain 24
Slide 25: Phase 2a proof-of-concept trial in refractory focal epilepsy
Phase 2a proof-of-concept trial in refractory focal epilepsy Key design considerations • Same patient population to be used in registrational trials – refractory FOS patients • Informs dose selection and effect size • Utilizes a recognized seizure biomarker demonstrated to predict clinical response
Slide 26: Phase 2a PoC trial: iEEG seizure biomarker
RAP-219 Phase 2a PoC trial in refractory focal epilepsy iEEG-recorded clinical seizure biomarker used to evaluate efficacy RNS System Principal investigator Jacqueline French, M.D. • FDA-approved implantable device continually Professor, Neurology monitors and records seizure activity (intracranial
Slide 27: Phase 2a PoC trial schema
RAP-219 Phase 2a PoC trial schema in refractory focal epilepsy 4-week 8-week open-label 8-week pre-treatment period treatment period follow-up period Eligibility criteria review 28-day Including review of 8 weeks of RAP-219 washout retrospective RNS system data prospective RAP-219 treatment period R
Slide 28: Focal epilepsy PoC model comparison
Focal epilepsy PoC model comparison Photosensitivity Transcranial Magnetic Stimulation Ideal Model RNS (PPR) (TMS) Uses focal epilepsy Yes No No patient population Long episode reduction Generalized Recognized seizure TMS-evoked EEG shown to predict clinical photoparoxysmal EEG biomarker potentials
Slide 29: Long episodes: objective biomarker for clinical seizure frequency
Long episodes (LEs) Objective and translatable biomarker for clinical seizure frequency Change in seizure activity recorded through intracranial EEG (iEEG) 2 1 predicted ASM clinical response • RNS detects a biomarker of clinical seizures – long episodes (LEs), which are considered subclinical seizu
Slide 30: Optimal cut point for reduction in LE frequency
Optimal cut point for reduction in LE frequency to predict meaningful change in CS frequency • A 30% reduction in LEs was associated with a 50% or greater reduction in CS in a post-hoc analysis, regardless of the antiseizure medication initiated • High positive predictive value -- LEs correlate with
Slide 31: Overview
RAP-219 overview A. Mechanism of action and preclinical development B. Phase 1 SAD/MAD trials C. Phase 2a proof-of-concept trial in refractory focal epilepsy D. Bipolar mania and diabetic peripheral neuropathic pain 31
Slide 32: Bipolar mania: strong mechanistic data for RAP-219
Bipolar mania Strong mechanistic data for RAP-219 Bipolar disorder Rationale for RAP-219 • Diagnosed prevalence is ~2.8 percent of the • Bipolar disorder is associated with hyperactivity adult population in the U.S. (~7 million adults) in the hippocampus, where TARPγ8 is enriched • Bipolar risk alle
Slide 33: Diabetic peripheral neuropathic pain
Diabetic peripheral neuropathic pain Strong mechanistic and compelling preclinical data for RAP-219 RTX-1738 (TARPγ8 NAM/RAP-219 analog) attenuates 1 • Diagnosed U.S. prevalence: ~5.6 million tactile allodynia in spinal nerve ligation (SNL) rat model • Incl. diabetic peripheral neuropathic pain, pos
Slide 34: nAChR discovery programs
nAChR discovery programs therapeutics
Slide 35: α6 nAChR program
α6 nAChR program Preclinically-validated approach to neuropathic pain • nAChR agonists have been observed to be efficacious Chrna6 WT Chrna4 WT 150 in third-party preclinical and clinical neuropathic pain Chrna6 KO Chrna4 KO studies; preclinical evidence in acute, inflammatory, 125 and neuropathic p
Slide 36: α9α10 nAChR program
α9α10 nAChR program Potential for first-in-class approach to hearing disorders • Potential for α9α10 nAChRs in hearing disorders demonstrated in preclinical studies • Engagement of α9α10 has been observed to mitigate hearing loss in preclinical models • Our RAP platform technology enabled Rapport to
Slide 37: Rapport Therapeutics: Charting new paths in neuroscience
Rapport Therapeutics: Charting new paths in neuroscience with groundbreaking precision Experienced leadership Lead asset in clinical development for the treatment of refractory focal epilepsy Proven track record of building companies, novel therapies, and development platforms Data demonstrate RAP-2
Slide 38: Thank you
& rapport therapeutics Thank you
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