Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders
Rapport Therapeutics (NASDAQ: RAPP) has announced positive Phase 1 data for RAP-219, its CNS disorder treatment candidate. The PET trial demonstrated that RAP-219 achieved and exceeded target receptor occupancy within five days of dosing, supporting the dosing regimen in the ongoing Phase 2a focal epilepsy trial.
Key findings from trials involving 100 healthy volunteers showed RAP-219 was generally well-tolerated with no serious adverse events, and only 3% treatment discontinuations. The drug demonstrated favorable tolerability across various dosing regimens, with no sedation or motoric impairments observed.
The PET trial confirmed TARP8-containing AMPA receptors are enriched in the hippocampus and cerebral cortex, with minimal presence in the cerebellum and brain stem. The MAD-2 trial showed successful dose escalation and faster therapeutic level achievement. The company expects topline data from the ongoing Phase 2a trial in focal epilepsy by mid-2025.
Rapport Therapeutics (NASDAQ: RAPP) ha annunciato dati positivi della Fase 1 per RAP-219, il suo candidato trattamento per i disturbi del CNS. La sperimentazione PET ha dimostrato che RAP-219 ha raggiunto e superato l'occupazione del recettore target entro cinque giorni dalla somministrazione, supportando il regime di dosaggio nella sperimentazione in corso di Fase 2a per l'epilessia focale.
I risultati chiave degli studi condotti su 100 volontari sani hanno mostrato che RAP-219 è stato generalmente ben tollerato, senza eventi avversi gravi e solo il 3% di interruzioni del trattamento. Il farmaco ha dimostrato una tollerabilità favorevole attraverso vari regimi di dosaggio, senza osservare sedazione o impairments motorie.
La sperimentazione PET ha confermato che i recettori AMPA contenenti TARP8 sono arricchiti nell'ippocampo e nella corteccia cerebrale, con una presenza minima nel cervelletto e nel tronco cerebrale. La sperimentazione MAD-2 ha mostrato un'adeguata escalation del dosaggio e un raggiungimento più rapido dei livelli terapeutici. L'azienda prevede di ricevere dati preliminari dalla sperimentazione di Fase 2a in corso per l'epilessia focale entro metà 2025.
Rapport Therapeutics (NASDAQ: RAPP) ha anunciado datos positivos de la Fase 1 para RAP-219, su candidato a tratamiento para trastornos del SNC. La prueba PET demostró que RAP-219 alcanzó y superó la ocupación del receptor objetivo dentro de los cinco días posteriores a la dosificación, respaldando el régimen de dosificación en el ensayo en curso de la Fase 2a para la epilepsia focal.
Los hallazgos clave de los ensayos que involucraron a 100 voluntarios sanos mostraron que RAP-219 fue generalmente bien tolerado sin eventos adversos graves, y solo el 3% de las interrupciones en el tratamiento. El fármaco demostró una tolerabilidad favorable en varios regímenes de dosificación, sin sedación ni deterioro motor observado.
La prueba PET confirmó que los receptores AMPA que contienen TARP8 están enriquecidos en el hipocampo y la corteza cerebral, con una presencia mínima en el cerebelo y el tronco encefálico. La prueba MAD-2 mostró una exitosa escalada de dosis y un logro más rápido del nivel terapéutico. La empresa espera datos preliminares del ensayo en curso de la Fase 2a en epilepsia focal para mediados de 2025.
랩포트 테라퓨틱스 (NASDAQ: RAPP)는 CNS 질환 치료 후보인 RAP-219의 긍정적인 1상 데이터를 발표했습니다. PET 시험에서는 RAP-219가 투여 후 5일 이내에 목표 수용체 점유율에 도달하고 이를 초과했다고 보여주며, 진행 중인 2a상 국소 간질 시험에서의 투여 요법을 지지합니다.
100명의 건강한 자원봉사자를 대상으로 한 시험에서 RAP-219는 일반적으로 잘 견뎌졌으며 심각한 부작용이 없었고, 단 3%의 치료 중단이 있었습니다. 이 약물은 다양한 투여 요법에서 우호적인 내약성을 보여주었으며, 진정이나 운동 장애는 관찰되지 않았습니다.
PET 시험에서는 TARP8을 포함한 AMPA 수용체가 해마와 대뇌 피질에 풍부하게 존재하며, 소뇌와 뇌줄기의 존재는 최소한으로 확인되었습니다. MAD-2 시험에서는 성공적인 용량 증가와 더 빠른 치료 수준 달성을 보여주었습니다. 이 회사는 진행 중인 2a상 국소 간질 시험의 주요 데이터를 2025년 중반까지 기대하고 있습니다.
Rapport Therapeutics (NASDAQ: RAPP) a annoncé des données positives de Phase 1 pour RAP-219, son candidat traitement pour les troubles du SNC. L'essai PET a démontré que RAP-219 a atteint et dépassé l'occupation des récepteurs cibles en cinq jours après l'administration, soutenant le schéma posologique dans l'essai en cours de Phase 2a sur l'épilepsie focale.
Les résultats clés des essais impliquant 100 volontaires sains ont montré que RAP-219 était généralement bien toléré sans événements indésirables graves, et seulement 3 % des traitements ont été interrompus. Le médicament a montré une tolérance favorable à travers divers schémas posologiques, sans aucune sédation ni impairments moteurs observés.
L'essai PET a confirmé que les récepteurs AMPA contenant TARP8 sont enrichis dans l'hippocampe et le cortex cérébral, avec une présence minimale dans le cervelet et le tronc cérébral. L'essai MAD-2 a montré une augmentation réussie des doses et un atteinte plus rapide des niveaux thérapeutiques. L'entreprise s'attend à obtenir des données préliminaires de l'essai en cours de Phase 2a sur l'épilepsie focale d'ici mi-2025.
Rapport Therapeutics (NASDAQ: RAPP) hat positive Phase-1-Daten für RAP-219, seinen Kandidaten zur Behandlung von Erkrankungen des zentralen Nervensystems (ZNS), bekannt gegeben. Die PET-Studie zeigte, dass RAP-219 die Zielrezeptorbelegung innerhalb von fünf Tagen nach der Dosis erreicht und überschreitet, was das Dosierungsschema in der laufenden Phase-2a-Studie zur fokalen Epilepsie unterstützt.
Wesentliche Ergebnisse aus Studien mit 100 gesunden Freiwilligen zeigten, dass RAP-219 im Allgemeinen gut vertragen wurde, ohne schwerwiegende unerwünschte Ereignisse, und nur 3 % der Behandlungen abgebrochen wurden. Das Medikament zeigte eine günstige Verträglichkeit über verschiedene Dosierungsschemata hinweg, ohne dass sedierende oder motorische Beeinträchtigungen festgestellt wurden.
Die PET-Studie bestätigte, dass TARP8-haltige AMPA-Rezeptoren im Hippocampus und Kortex angereichert sind, mit minimalem Vorhandensein im Kleinhirn und Hirnstamm. Die MAD-2-Studie zeigte eine erfolgreiche Dosiserhöhung und schnellere Erreichung therapeutischer Werte. Das Unternehmen erwartet, dass bis Mitte 2025 Daten zur laufenden Phase-2a-Studie zur fokalen Epilepsie verfügbar sind.
- Achieved target receptor occupancy within 5 days of dosing
- High tolerability with only 3% treatment discontinuation rate
- No serious adverse events or significant side effects observed
- Successfully demonstrated neuroanatomical specificity of drug targeting
- Chief Medical Officer Bradley Galer stepped down, successor search ongoing
Insights
The Phase 1 data for RAP-219 reveals compelling evidence of successful target engagement and a favorable safety profile. Key findings demonstrate target receptor occupancy above 50-70% within 5 days, precisely in brain regions relevant for epilepsy treatment while sparing areas associated with adverse effects. The 3% discontinuation rate across 100 participants is notably low for CNS drug development.
The PET study validates RAP-219's selective targeting mechanism through TARP8-containing AMPA receptors, predominantly in the hippocampus and cerebral cortex - critical areas for seizure control. This neuroanatomical specificity, combined with minimal presence in the cerebellum and brain stem, supports a potentially wider therapeutic window than current anti-epileptic drugs.
The MAD-2 trial's successful acceleration of dosing titration without compromising tolerability is particularly significant for clinical application. The absence of sedation and motoric impairments - common limitations of existing treatments - suggests a potentially differentiated clinical profile that could translate to better quality of life for patients.
This data release strengthens RAP-219's commercial potential in the $6.5 billion focal epilepsy market. The demonstrated ability to achieve target engagement while maintaining favorable tolerability addresses a important unmet need in epilepsy treatment, where side effects often limit therapeutic efficacy.
The successful Phase 1 results significantly de-risk the ongoing Phase 2a trial, with topline data expected in mid-2025. The CMO departure appears manageable given the clinical program's current momentum and established dosing protocol. The comprehensive Phase 1 program, involving 100 healthy volunteers across four trials, provides robust safety data that supports advancement into patient populations.
For investors, these results validate Rapport's platform technology focusing on receptor-associated proteins as therapeutic targets. The potential for improved therapeutic index through selective targeting could position RAP-219 as a preferred treatment option, particularly for patients who struggle with current medications' side effects.
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
BOSTON and SAN DIEGO, Jan. 09, 2025 (GLOBE NEWSWIRE) -- 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 (
“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.
PET trial results are summarized below:
- 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).
MAD-2 trial results are summarized below:
- 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.
About RAP-219
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.
About Rapport Therapeutics
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.
Forward-Looking Statements
This press release 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,” “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 broad therapeutic index of RAP-219 and its ability to deliver transformative outcomes for patients; the clinical development of RAP-219 for the treatment of drug-resistant focal epilepsy, peripheral neuropathic pain and bipolar acute mania, including expected dosing flexibility; the expected timing of the results from ongoing clinical trials; the activity and tolerability of RAP-219, including its neuroanatomical specificity; and Rapport’s RAP technology platform.
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, including that interim, topline and preliminary data from our clinical trials that we announce or publish from time to time are subject to audit and verification procedures that could result in material changes in the final data; 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 Registration Statement on Form S-1, 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. 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.
FAQ
What were the key findings from RAPP's Phase 1 trials for RAP-219?
When will Rapport Therapeutics (RAPP) release Phase 2a results for RAP-219?
How many participants were involved in RAPP's RAP-219 Phase 1 trials?
What is the safety profile of RAPP's RAP-219 based on Phase 1 data?
What distinguishes RAP-219 from other CNS disorder treatments?
