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"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 drug-resistant focal epilepsy, peripheral neuropathic pain and bipolar disorder, including the initiation, timing, progress and results of our ongoing and
planned clinical trials; Rapport's ability to resolve a clinical hold with the FDA; the potential activity and tolerability of RAP-219; the potential of Rapport's RAP technology platform; the ongoing and planned development of RAP-199
and Rapport's discovery-stage 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 Rapport'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; Rapport'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 Rapport'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
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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, Partner, Third Rock
Ventures; Former Founding CEO, Operating Partner, General Atlantic Sofinnova Investments CEO, Merida Biosciences Alnylam Former CEO, Cubist Pharmaceuticals Founder and Chairman, Life Science Cares Raymond Sanchez, M.D. Paul Silva Wendy Young, Ph.D.
Director Director Director Senior Advisor, Bain Life Sciences; Former Chief Accounting Officer, Former Head of Small Molecule Drug Former CMO, Cerevel Therapeutics Vertex Pharmaceuticals Discovery, Genentech 1 Employee director 3
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 scientific innovators
Robust clinical & discovery Well financed approach to generate precision & company builders pipeline small molecule medicines Potential for first-in-class Road-tested capability of Pioneering programs leveraging receptor $320.7 million as of
identifying key mediators of 2 discovery team associated protein (RAP) September 30, 2024 receptor function science RAP-219 clinical program Cash runway expected to fund Differentiated pharmacology Non-sedative forebrain restricted Company builders
with 1 operations through end of we believe promotes high TARP 8 AMPAR modulator - industry-proven leadership 2026, including multiple selectivity and specificity significant opportunity in initial development catalysts indication in
focal epilepsy Potential to transform the Discovery programs treatment of neurological Medicinal chemistry-enabled disorders with portfolio with potential in differentiated profile additional indications 1 AMPAR
-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 2 Includes cash, cash equivalents, and short-term investments, excluding restricted cash 4
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 receptors that are
RAPs serve as unique binding sites targetable by ubiquitous in the brain and body novel pharmacophores designed for increased selectivity Drugs not designed with precision for disease- RAP targeting can provide tissue / neuroanatomical specific
neuroanatomic sites / receptors specificity RAPs enable differentiated pharmacology and Drug interactions and adverse events lead to potentially provide optimal efficacy, safety, and noncompliance and discontinuation administration profiles Drug
discovery with conventional approaches RAPs can "unlock" drug targets previously (lacking RAPs) can miss high potential, previously inaccessible to study in vitro, allowing for unexplored targets potentially first-in-class drug discovery
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 TARP 8 AMPAR
Topline Results 1H 2027 Programs Diabetic Peripheral Trial Initiation* Neuropathic Pain 6 Development Candidate Chronic Pain nAChR Discovery Programs 9 10 Development Candidate Hearing Disorders Strong intellectual property with
worldwide rights to all programs Note: We have conducted two Phase 1 trials supportive of multiple RAP-219 indications * Subject to resolution of clinical hold with the FDA 6
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 Tolerability Issues:
Especially CNS side-effects, x % Focal Epilepsy 60% such as sedation, ataxia, and cognitive problems Potential for Serious Adverse Events: Such as x Focal Epilepsy Patients 1.8M severe cutaneous reactions, serious hematological disorders, and
hepatic failure 1 Complicated Administration: Long titration, drug- x % Drug-Resistant 30-40% drug interactions, and lab monitoring 1 Drug-resistant patients are those who continue to experience recurring seizures despite taking two or more ASMs
Internal Market Research, 2023 7
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 TARP 8 is a preclinically and clinically validated target for epilepsy Once daily (QD) dosing | No
evidence of sedation or motoric impairment | No observed drug-drug interactions (DDI) Compelling data supporting potential in peripheral neuropathic pain and bipolar disorder Long acting injectable (LAI) opportunity Potency and metabolic profile
positions RAP-219 as the first potential ASM in a depot formulation 1 2 Internal Market Research, 2023. Diagnosed prevalence. Diagnosed prevalence across diabetic peripheral neuropathy (~2.8 million), post-herpetic neuralgia (~1.8 3 million),
trigeminal neuralgia (~1.0 million). True prevalence (diagnosed prevalence divided by the diagnosis rate) 8
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
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
synapses can mediate seizure initiation and originate in the mesial temporal lobe, which includes spread the hippocampus and amygdala. AMPAR target is clinically validated - perampanel Most of the remaining 50% originate in the
(FYCOMPA ) is an FDA/EMA approved pan- cerebral neocortex and often spread into and are AMPAR antagonist for the treatment of focal propagated by the mesial temporal structures. onset and generalized seizures 10
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 TARP 8 clinical PET GluA1/2 + TARP 8
complex STG GluA1 -3 GluA2 TARP 8 -4 -8 NatComm 2022 13:734 tubulin JCB 2003 161:805
RAP-219 observed to be highly potent and selective TARP 8 AMPAR
NAM RAP-219 potency and selectivity TARP 8-containing AMPA receptors (IC ) ~100 pM 50 vs. AMPA receptors (GluA1) lacking TARPs >100,000x vs. AMPA receptors containing other TARPs ( 2, 3, 4, 7) >4,000x vs. NMDA
receptors (2A, 2B, 2D) >500,000x vs. GPCRs/ion channels/enzymes (panel of 52) >10,000x vs. kinases (panel of 373) >100,000x NAM = Negative allosteric modulator 12
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 's of 7 ng/mL in rats (shown above) and Oral administration of RAP-219 resulted in significant seizure 70 plasma EC 's of 3 ng/mL in mice reduction in kindled mice at low plasma levels (<7 ng/mL) 70 corresponding to
a projected 50-70% receptor occupancy (RO) No motoric impairments observed at highest doses tested EC = effective concentration achieving 70% occupancy of target receptor 70 13
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 (toxic
dose) on Rotarod/ED (effective dose) for efficacy 50 50 1 Data on file, Rapport Therapeutics; https://panache.ninds.nih.gov/ 2 Data are based on published reports from different preclinical studies at different points in time, with differences in
preclinical study design and subject population. 14 As a result, cross-study comparisons cannot be made. No head-to-head studies have been conducted. Therapeutic Index
TARP 8 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
days of oral administration Antiseizure activity was maintained or became more potent after 7-day dosing Single oral administration, tested 2 hours post dose Seven-day oral administration, tested 2 hours after last dose 15
TARP 8 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 *
Corneal Kindling - mouse Potent activity in kindling model has been observed to * PTZ - mouse predict efficacy in focal epilepsy * Rotarod Activity not seen in maximal electroshock (MES) Amygdala kindling - mouse model,
consistent with performance of levetiracetam and some other effective ASMs Hippocampal kindling - mouse 6Hz stimulation - mouse Chronic seizure models [like corneal kindling] offer Frings audiogenic seizure - mouse the most
etiologically relevant platform on which to accurately replicate clinical epilepsy and are thus GAERS absence epilepsy - rat deserving of more use earlier in ASD identification." - Barker-Haliski, Expert Opinion on Drug Discovery *
Used RAP-219; where not noted, used other TARP 8 NAM CNS & Neurological Disorders - Drug Targets (2017) 16:1099; J Pharmacol Exp Ther (2016) 357:394; J Amer Soc for Exper NeuroTherapeutics (2007) 4:12; Jackie French AES Presentation,
Professor, Neurology, NYU Grossman School of Medicine; Director, The Epilepsy Study Consortium (TESC); Barker-Haliski, M. (2019) Expert Opinion on Drug Discovery, 14(10), 947-951. 16
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
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
label food effect study TARP 8 and establish relationship between PK and Objective: evaluate safety and tolerability brain target receptor occupancy (RO) 5 cohorts, n=8 per cohort (6 active & 2 placebo) 3 cohorts,
n=3-6 per cohort 0.25 mg QD to 3 mg QD doses 0.25 mg QD to 1.25 mg QD doses; over 14 days Multiple ascending dose trial (MAD-1) Multiple ascending dose trial (MAD-2) (RAP-219-102) (RAP-219-104) Randomized, double-blind,
placebo-controlled MAD Randomized, double-blind, placebo-controlled MAD Objective: evaluate safety and tolerability with dose Objective: evaluate safety and tolerability with escalation continued dose escalation and shorten
time to 5 cohorts, n=8 per cohort (6 active & 2 placebo) reach predicted therapeutic levels Up to 1.25 mg QD doses; over 2 to 4 weeks 3 cohorts, n=8 per cohort (6 active & 2 placebo) Up to 1.75 mg QD doses; up
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 2
Unlike with many anti-seizure medications, no sedation or motoric impairments were observed, consistent with target biology and preclinical observations Three treatment discontinuations occurred (3%) that were attributed to TEAEs
RAP-219 receptor occupancy PET trial confirmed restricted neuroanatomical expression of TARP 8 RAP-219 achieved and exceeded target RO associated with maximal efficacy in preclinical models (50%-70%), while maintaining a
differentiated tolerability profile Target RO can be achieved within five days of dosing SAE = Serious adverse event; TEAE = Treatment emergent adverse events; ECG= electrocardiogram 19
RAP-219 Phase 1: PET trial results RAP-219 achieved and exceeded target
RO and was generally well tolerated Restricted neuroanatomical expression of TARP 8 was confirmed TARP 8 clinical PET TARP 8-containing AMPA receptors were enriched in the hippocampus and cerebral cortex, and expression was
minimal in the cerebellum and brain stem Cohort 1 (Phase 2a focal epilepsy trial dosing regimen) exceeded the target RO range associated with maximal efficacy in preclinical models (50%-70%) while maintaining tolerability
Collectively, PET and MAD-2 trials demonstrated that target plasma concentrations and associated RO could be achieved within 5 days Note: Results are based on preliminary analysis of the data. Clinical conduct of the PET and MAD-2 trials is
complete, and the clinical study reports for both are in progress. 20
RAP-219 Phase 1: SAD vs. MAD exposures * * * *Pending finalization
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
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 considered to
be generally toxicities well tolerated Potential for reduced Low DDI potential as RAP-219 not observed to interact drug-drug interactions with CYP enzymes No treatment related TEAEs above Grade 2 in Phase 1 Generally well tolerated trials; no