In the PET trial, RAP-219 achieved and exceeded target receptor occupancy, increasing support for the dosing regimen utilized in the ongoing Phase 2a trial in focal epilepsy; restricted neuroanatomical expression of TARP8 was confirmed
In the MAD-2 trial, RAP-219 was observed to be generally well tolerated with faster titration and higher exposures than in the initial MAD trial
Data underscore the potential broad therapeutic index of RAP-219 and dosing flexibility
Ongoing Phase 2a trial of RAP-219 in focal epilepsy is on track and topline data is expected in mid-2025
Jan. 09, 2025 -- Rapport Therapeutics, Inc. (Nasdaq: RAPP), a clinical-stage biotechnology company dedicated to the discovery and development of small molecule precision medicines for patients suffering from central nervous system (CNS) disorders, today announced results from its positron emission tomography (PET) trial and second multiple ascending dose (MAD-2) trial for RAP-219. Data from the trials demonstrated that RAP-219 achieved target receptor occupancy (RO) associated with maximal efficacy in prior preclinical models within five days of dosing while maintaining a differentiated tolerability profile.
“These Phase 1 results reinforce our belief in RAP-219’s distinct profile and potential to deliver transformative outcomes for patients,” said Steve Paul, M.D., Rapport cofounder and chair of the board of directors. “The data demonstrate that neuroanatomical specificity can be achieved through RAP-219’s selective targeting of a receptor-associated protein, and RAP-219 was able to quickly achieve target engagement and therapeutic exposures in the brain while maintaining a generally favorable tolerability profile. Additionally, the data provide further support for the dosing regimen selected for our ongoing Phase 2a trial in focal epilepsy.”
A total of four Phase 1 trials have been conducted to date, with 100 healthy volunteers exposed to RAP-219. In these trials, RAP-219 was generally well tolerated in multiple repeat-dose studies with up to 28 days of dosing, with no serious adverse events (SAEs), no treatment emergent adverse events (TEAEs) greater than Grade 2, and no clinically relevant laboratory or electrocardiogram (ECG) abnormalities. Three treatment discontinuations occurred (3%) that were attributed to TEAEs. The trials also showed that favorable tolerability was achieved with various dosing and titration regimens. Rapport believes the pharmacokinetic (PK) and tolerability outcomes from these clinical trials provide compelling translational evidence of selectively targeting TARP8 associated AMPA receptors to significantly enhance the therapeutic index of AMPA receptor modulation.
“Due to the non-specific nature of currently available and other investigational treatments, many patients continue to endure significant side effects, which limit therapeutic efficacy and diminish their quality of life,” said Abe Ceesay, chief executive officer of Rapport. “RAP-219 was designed to overcome such limitations, and we believe these compelling new data support our approach as we advance our Phase 2a trial in focal epilepsy, with topline results expected in mid-2025.”
Also announced today, Bradley Galer, M.D., has stepped down as chief medical officer of Rapport. A search for his successor is underway, and the Company is confident that the transition will not disrupt progress across its clinical programs. Dr. Galer will be assisting the transition, and the Company is grateful for his support and contributions to Rapport over the past two years.
Results from the recent PET and MAD-2 trials are below, 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.
The PET trial (RAP-219-103) was an open label trial in healthy volunteers designed to confirm neuroanatomical expression of TARP8 and establish the relationship between PK and brain target RO with RAP-219. The trial included three cohorts: Cohort 1 was given the same dosing regimen currently being used in the Phase 2a trial in focal epilepsy (0.75 mg daily for 5 days, followed by 1.25 mg daily for 9 days), and lower doses were used in the other two cohorts to better characterize the plasma concentration versus RO relationship. Cohort 2 was given 0.25 mg daily for 14 days and Cohort 3 was given 0.25 mg daily for 7 days, followed by 0.5 mg daily for 7 days.
The PET data demonstrated that Cohort 1 (the dosing regimen utilized in the ongoing Phase 2a trial in focal epilepsy) exceeded the target RO range associated with maximal efficacy in prior preclinical models (50%-70%) within five days of dosing, while maintaining a differentiated tolerability profile generally consistent with prior Phase 1 trial findings.
The trial confirmed that the expression of TARP8-containing AMPA receptors is enriched in the hippocampus and cerebral cortex and is minimal in the cerebellum and brain stem.
Collectively, data from the PET and MAD-2 trials demonstrated that plasma concentrations and associated target RO could be achieved within 5 days.
The MAD-2 (RAP-219-104) trial was a double-blind, placebo-controlled trial in healthy volunteers and was the second MAD trial of RAP-219. The trial was designed to further evaluate safety and tolerability with continued dose escalation, as well as to shorten time to reach predicted therapeutic levels of RAP-219. The trial included three cohorts: Cohort 1 (0.75 mg for 3 days, 1.25 mg for 3 days, 1.75 mg for 2 days), Cohort 2 (0.75 mg for 2 days, 1.25 mg for 2 days, 1.75 mg for 4 days), and Cohort 3 (0.5 mg for 2 days, 1 mg for 2 days, 1.75 mg for 24 days).
RAP-219 was generally well tolerated. All TEAEs were Grade 1 or 2 and generally consistent with tolerability observed in prior Phase 1 trials.
Unlike with many anti-seizure medications, no sedation or motoric impairments were observed with RAP-219, consistent with target biology and preclinical observations.
Target exposures and RO were achieved within 5 days of dosing across various dosing regimens.
A Phase 2a proof-of-concept trial is currently underway to evaluate RAP-219 in patients with refractory focal epilepsy, with topline results expected in mid-2025.
RAP-219 is a clinical-stage AMPA receptor negative allosteric modulator designed to achieve neuroanatomical specificity through its selective targeting of AMPA-associated protein, TARP8. AMPA receptors are present throughout the brain, including in the cerebellum and brain stem, where their non-selective targeting has resulted in poor tolerability. In contrast, TARP8 expression is enriched in the hippocampus and cerebral cortex and is minimal in the cerebellum and brain stem. RAP-219 is designed to be highly potent and selective for TARP8. It has been observed to have a long half-life (8–14 days) and minimal drug-drug interactions, making it potentially well-suited for polypharmacy. With this profile, RAP-219 has the potential to provide improved activity, tolerability, and a higher therapeutic index, potentially providing more patients with sustained therapeutic benefits without intolerable side effects, as compared to traditional neuroscience medications. As AMPA receptors play critical roles in numerous neurological disorders, selective targeting of TARP8 may provide a pipeline-in-a-product opportunity. The Company is currently pursuing RAP-219 as a potentially differentiated treatment for patients with focal epilepsy, diabetic peripheral neuropathic pain, and bipolar mania.
Rapport Therapeutics is a clinical-stage biotechnology company dedicated to discovering and developing small molecule precision medicines for patients suffering from central nervous system (CNS) disorders. The Company’s founders have made pioneering discoveries related to the function of receptor associated proteins (RAPs) in the brain. Their findings form the basis of Rapport’s RAP technology platform, which enables a differentiated approach to generate precision small molecule product candidates with the potential to overcome many limitations of conventional neurology drug discovery. Rapport’s precision neuroscience pipeline includes the Company’s lead clinical program, RAP-219, designed to achieve neuroanatomical specificity through its selective targeting of a RAP expressed in only discrete regions of the brain. The Company is currently advancing RAP-219 in clinical trials in focal epilepsy, diabetic peripheral neuropathic pain, and bipolar mania. Additional preclinical and late-stage discovery stage programs are also underway, targeting CNS disorders including chronic pain and hearing disorders.
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