Ep160: Abe Ceesay on Precision Neuroscience

Episode Summary

Executive Summary: Abe Cisse explains how Rapport Therapeutics emerged from a chance Traverse connection with Third Rock’s Reid Huber and a long-running J&J neuroscience program centered on RAPs/TARPs that enable region-selective AMPA receptor modulation. The company’s lead drug, RAP219, aims to treat focal epilepsy with a wider therapeutic window and fewer sedating/motor side effects, while potentially extending to pain, bipolar disorder, and a long-acting injectable format.

Main Topics: Origin of Rapport Therapeutics through the Timmerman Traverse (Priority: 5/5): Cisse describes how an early Traverse hike connected him with Reid Huber, sparking a relationship that later fed into company creation and broader collaboration with Life Science Cares and Project OnRamp. Scientific foundation: AMPA receptors and receptor-associated proteins (RAPs/TARPs) (Priority: 5/5): The conversation centers on the biology of AMPA receptors, the problem of non-selective modulation, and the discovery that specific accessory proteins are expressed in different brain regions, enabling precision targeting. From J&J internal program to startup formation (Priority: 4/5): Cisse explains how J&J’s long investment in the biology and chemistry of the target was externally spun out as a strategic externalization, rather than simply being deprioritized. RAP219 development and epilepsy proof-of-concept strategy (Priority: 5/5): The lead compound RAP219 showed encouraging preclinical and phase 1 signals, supporting advancement into focal epilepsy patients and positioning epilepsy as the clearest initial indication. Selectivity, tolerability, and therapeutic window as the differentiator (Priority: 5/5): The key value proposition is to preserve antiseizure efficacy while reducing sedation, ataxia, and motor impairment seen with broad AMPA antagonism and many existing epilepsy drugs. Pipeline expansion and long-acting injectable ambition (Priority: 4/5): Beyond epilepsy, Rapport is exploring neuropathic pain and bipolar disorder, and is also considering a monthly long-acting injectable version of RAP219. Platform vision for precision neuroscience (Priority: 4/5): Cisse argues that RAP biology may underpin a scalable discovery engine for multiple ion-channel targets, potentially making Rapport a leading precision neuroscience company.

Key Arguments: The Traverse was not just networking; it catalyzed both a friendship and the eventual creation of Rapport by connecting Cisse and Huber around neuroscience and mission-driven biotech. AMPA receptors are central to synaptic transmission, but direct broad modulation creates unacceptable on-target side effects because the receptors are widely expressed throughout the brain. RAPs/TARPs provide a way to achieve regional selectivity by targeting receptor-associated proteins expressed in specific neuroanatomic regions, especially the forebrain. J&J’s work was a deep, decade-long effort in biology, chemistry, structural biology, and imaging, and it was intentionally externalized to a focused startup to maximize patient impact. Preclinical epilepsy models are highly translatable, making them a strong proof-of-concept setting for RAP219 compared with many other neuroscience areas. RAP219 showed a potentially unprecedented therapeutic index in animals: seizure control without motor impairment on the rotor rod. Phase 1 healthy-volunteer data supported on-target pharmacology, receptor occupancy, and good tolerability, strengthening confidence before patient studies. The company believes the same biology may apply to other indications where excitability matters, including neuropathic pain and bipolar disorder. A long-acting injectable could be especially meaningful in epilepsy because adherence is difficult and breakthrough seizures have major life consequences. Rapport’s broader ambition is a repeatable platform, not a one-off asset, using RAP biology to unlock previously hard-to-drug nervous-system targets.

Data Points: Series A financing: $100 million - Rapport Therapeutics’ initial financing in March 2023 Series B financing: $150 million - Follow-on financing raised after emerging clinical/preclinical data Implied total capital raised: $250 million - Combined Series A and Series B described in the interview AbbVie acquisition of Cerevel: $8.7 billion - Cisse’s prior company, Cerevel Therapeutics, was acquired last year Initial public offering: Filed paperwork - Transcript notes Rapport has since filed for an IPO Annual dosing frequency: Once daily (QD) - RAP219’s current oral dosing profile Therapeutic occupancy target: 50% to 70% receptor occupancy - Target range cited from preclinical modeling for RAP219 Healthy-volunteer study size: 5 cohorts; 8 subjects per cohort; 6 active and 2 placebo - MAD study design in phase 1 Total healthy volunteers in MAD study: 40 - Derived from 5 cohorts of 8 participants each Observational dose finding: No serious adverse events; all grade 2 or less - Phase 1 single-ascending-dose findings Target concentration: Single-digit nanograms per mL - Cisse described RAP219 as highly potent with very low therapeutic concentrations Patient population: 1.8 million - Estimated U.S. patients living with focal epilepsy Treatment resistance: 30% to 40% - Proportion of focal epilepsy patients still having breakthrough seizures despite available medications Program breadth: 2 named late-stage programs - Rapport said it has two named programs plus additional discovery efforts Timeline to patient data: Data expected in the middle of 2025 - Expected readout from the phase 2A proof-of-concept epilepsy study

Pivotal Quotes: "The first guinea pig." — Abe Cisse: He joked about being in the inaugural Timmerman Traverse class "Strategic externalization." — Abe Cisse: His description of J&J’s decision to spin the program into Rapport rather than simply abandon it "That would be transformational for patients." — Abe Cisse: He explains the significance of controlling seizures without sedation or motor impairment

Implications: Rapport could validate a new precision-neuroscience model: region-selective modulation of core brain receptors with fewer side effects. If RAP219 succeeds, it may reshape epilepsy treatment and open a platform for other CNS diseases.