CORRECTION -- Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders
Rapport Therapeutics (NASDAQ: RAPP) announced new 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 while maintaining good tolerability. The MAD-2 trial showed favorable results with faster titration and higher exposures than the initial MAD trial.
Key findings from four Phase 1 trials involving 100 healthy volunteers showed RAP-219 was generally well-tolerated with no serious adverse events, no TEAEs greater than Grade 2, and only three treatment discontinuations (3%). The PET trial confirmed TARPγ8-containing AMPA receptors are enriched in the hippocampus and cerebral cortex, with minimal presence in the cerebellum and brain stem.
The company announced that Bradley Galer stepped down as chief medical officer, with a search for successor underway. A Phase 2a proof-of-concept trial for focal epilepsy is ongoing with topline results expected in mid-2025.
Rapport Therapeutics (NASDAQ: RAPP) ha annunciato nuovi dati della Fase 1 per RAP-219, il suo candidato per il trattamento dei disturbi del SNC. Il trial PET ha dimostrato che RAP-219 ha raggiunto e superato l'occupazione del recettore target entro cinque giorni, mantenendo una buona tollerabilità. Il trial MAD-2 ha mostrato risultati favorevoli con una titolazione più rapida e esposizioni più elevate rispetto al trial MAD iniziale.
I risultati chiave di quattro trial di Fase 1 che coinvolgono 100 volontari sani hanno mostrato che RAP-219 è stato generalmente ben tollerato, senza eventi avversi gravi, nessun TEAE superiore al grado 2 e solo tre interruzioni del trattamento (3%). Il trial PET ha confermato che i recettori AMPA contenenti TARPγ8 sono arricchiti nell'ippocampo e nella corteccia cerebrale, con una presenza minima nel cervelletto e nel tronco encefalico.
L'azienda ha annunciato che Bradley Galer si è dimesso dal ruolo di chief medical officer e che è in corso la ricerca di un successore. Un trial di prova di concetto di Fase 2a per l'epilessia focale è in corso, con risultati preliminari attesi per la metà del 2025.
Rapport Therapeutics (NASDAQ: RAPP) anunció nuevos datos de Fase 1 para RAP-219, su candidato para el tratamiento de trastornos del SNC. El ensayo PET demostró que RAP-219 logró y superó la ocupación del receptor objetivo en cinco días, manteniendo una buena tolerabilidad. El ensayo MAD-2 mostró resultados favorables con una titulación más rápida y mayores exposiciones en comparación con el ensayo MAD inicial.
Los hallazgos clave de cuatro ensayos de Fase 1 que involucraron a 100 voluntarios sanos mostraron que RAP-219 fue generalmente bien tolerado, sin eventos adversos graves, sin TEAEs superiores a Grado 2 y solo tres interrupciones del tratamiento (3%). El ensayo PET confirmó que los receptores AMPA que contienen TARPγ8 están enriquecidos en el hipocampo y la corteza cerebral, con una presencia mínima en el cerebelo y el tronco encefálico.
La compañía anunció que Bradley Galer renunció como director médico, y se encuentra en búsqueda de un sucesor. Un ensayo de Fase 2a para la prueba de concepto de epilepsia focal está en curso y se esperan resultados preliminares para mediados de 2025.
Rapport Therapeutics (NASDAQ: RAPP)는 CNS 질환 치료 후보인 RAP-219의 새로운 1상 데이터를 발표했습니다. PET 연구에서 RAP-219는 목표 수용체 점유율에 도달하고 이를 초과했으며, 좋은 내약성을 유지했습니다. MAD-2 연구는 초기 MAD 연구보다 더 빠른 적정과 더 높은 노출로 유리한 결과를 보였습니다.
100명의 건강한 자원봉사자를 대상으로 한 4개의 1상 연구에서 주요 발견은 RAP-219가 일반적으로 잘 내약되었으며, 심각한 부작용이 없고, 2등급 이상의 TEAE가 없으며, 단 3건(3%)의 치료 중단이 있었던 것입니다. PET 연구는 TARPγ8이 포함된 AMPA 수용체가 해마와 대뇌 피질에 풍부하게 존재하며, 소뇌와 뇌간에서는 미미하게 존재한다는 것을 확인했습니다.
회사는 브래들리 갤러가 최고 의학 책임자로서 사임했으며 후임자를 찾고 있다고 발표했습니다.초점 간질에 대한 2a상 개념 증명 연구가 진행 중이며, 2025년 중반에 주요 결과가 예상됩니다.
Rapport Therapeutics (NASDAQ: RAPP) a annoncé de nouvelles données de Phase 1 pour RAP-219, son candidat au traitement des troubles du SNC. L'essai PET a montré que RAP-219 a atteint et dépassé l'occupation des récepteurs cibles en cinq jours tout en maintenant une bonne tolérance. L'essai MAD-2 a montré des résultats favorables avec une titration plus rapide et des expositions plus élevées que l'essai MAD initial.
Les résultats clés de quatre essais de Phase 1 impliquant 100 volontaires en bonne santé ont montré que RAP-219 était généralement bien toléré, sans événements indésirables graves, sans TEAE supérieure au Grade 2 et seulement trois interruptions de traitement (3%). L'essai PET a confirmé que les récepteurs AMPA contenant TARPγ8 sont enrichis dans l'hippocampe et le cortex cérébral, avec une présence minimale dans le cervelet et le tronc cérébral.
L'entreprise a annoncé que Bradley Galer a démissionné de son poste de directeur médical, et une recherche de successeur est en cours. Un essai de preuve de concept de Phase 2a pour l'épilepsie focale est en cours, avec des résultats préliminaires attendus pour la mi-2025.
Rapport Therapeutics (NASDAQ: RAPP) hat neue Phase-1-Daten für RAP-219, seinen Behandlungskandidaten bei ZNS-Erkrankungen, veröffentlicht. Die PET-Studie zeigte, dass RAP-219 innerhalb von fünf Tagen die Zielrezeptorbelegung erreichte und übertraf, während eine gute Verträglichkeit aufrechterhalten wurde. Die MAD-2-Studie zeigte günstige Ergebnisse mit schnelleren Dosierungen und höheren Expositionen als die ursprüngliche MAD-Studie.
Wichtige Ergebnisse aus vier Phase-1-Studien mit 100 gesunden Freiwilligen zeigten, dass RAP-219 allgemein gut vertragen wurde, ohne schwerwiegende unerwünschte Ereignisse, ohne TEAEs über Grad 2 und nur drei Therapieabbrüche (3%). Die PET-Studie bestätigte, dass TARPγ8-haltige AMPA-Rezeptoren im Hippocampus und in der Großhirnrinde angereichert sind, mit minimaler Präsenz im Kleinhirn und im Hirnstamm.
Das Unternehmen gab bekannt, dass Bradley Galer als Chief Medical Officer zurückgetreten ist und die Suche nach einem Nachfolger läuft. Eine Phase-2a-Konzeptnachweisstudie zur fokalen Epilepsie ist im Gange, und die ersten Ergebnisse werden Mitte 2025 erwartet.
- Achieved target receptor occupancy within 5 days of dosing
- Strong safety profile with no serious adverse events in Phase 1 trials
- Low discontinuation rate of 3% in clinical trials
- Successfully demonstrated neuroanatomical specificity of drug target
- Multiple dosing regimens showed favorable tolerability
- Chief Medical Officer Bradley Galer stepping down
- Phase 2a results not expected until mid-2025
Insights
The Phase 1 data for RAP-219 reveals several critical developments in CNS drug development. The achievement of target receptor occupancy within 5 days while maintaining favorable tolerability represents a significant advancement in the treatment landscape for CNS disorders. The drug's selective targeting of TARPγ8-containing AMPA receptors, particularly in the hippocampus and cerebral cortex, with minimal presence in the cerebellum and brain stem, suggests a highly precise mechanism of action.
The safety profile is particularly noteworthy - only 3% treatment discontinuation rate across 100 healthy volunteers, with no serious adverse events and no TEAEs above Grade 2. This contrasts sharply with traditional CNS medications that often have significant side effect profiles. The absence of sedation and motoric impairments typically associated with anti-seizure medications is a major differentiator.
The data strengthens RAP-219's commercial potential in the competitive CNS therapeutics market. Several key factors enhance the investment thesis: First, the demonstrated neuroanatomical specificity through selective targeting suggests potential for reduced off-target effects, a major hurdle in CNS drug development. Second, the faster titration schedule and higher exposures achieved in MAD-2 could translate to quicker onset of therapeutic benefit - a significant commercial advantage.
The mid-2025 Phase 2a readout in focal epilepsy represents a important catalyst. With a market cap of
BOSTON and SAN DIEGO, Jan. 09, 2025 (GLOBE NEWSWIRE) -- In a release issued under the same headline earlier today by Rapport Therapeutics, Inc. (Nasdaq: RAPP), please note the references to the AMPA-associated protein, TARP8 have been updated to the correct term, TARPγ8. The omission was due to a conversion issue when the release was formatted for distribution. The revised release follows:
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 TARPγ8 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
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 TARPγ8 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 TARPγ8-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, TARPγ8. 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, TARPγ8 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 TARPγ8. 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 TARPγ8 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.
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