Septerna Announces Dosing of the First Participants in Phase 1 Clinical Trial of SEP-631, an Oral Small Molecule MRGPRX2 Negative Allosteric Modulator for the Treatment of Mast Cell-Driven Diseases
Septerna (NASDAQ:SEPN) has initiated its Phase 1 clinical trial for SEP-631, an oral small molecule MRGPRX2 negative allosteric modulator (NAM), marking a significant milestone in their drug development program. The trial will evaluate the drug's safety, tolerability, and pharmacological properties in up to 150 healthy adult volunteers.
The study focuses on treating chronic spontaneous urticaria (CSU) and other mast cell-driven diseases. SEP-631 works by selectively blocking MRGPRX2, a GPCR crucial in mast cell activation and degranulation. The trial consists of both single-ascending dose (SAD) and multiple-ascending dose (MAD) components, with SAD dosing already underway.
This development represents a potential breakthrough for patients with CSU, a systemic inflammatory skin disease characterized by persistent itchy hives and angioedema, where current antihistamine treatments often prove inadequate.
Septerna (NASDAQ:SEPN) ha avviato la sperimentazione clinica di Fase 1 per SEP-631, un modulatore allosterico negativo (NAM) orale della MRGPRX2, segnando una tappa importante nel suo programma di sviluppo. Lo studio valuterà la sicurezza, la tollerabilità e le proprietà farmacologiche del farmaco in fino a 150 volontari adulti sani.
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Questo sviluppo potrebbe rappresentare una svolta per i pazienti con CSU, una malattia infiammatoria sistemica della pelle caratterizzata da orticaria pruriginosa persistente e angioedema, per la quale gli antistaminici attuali spesso non sono sufficienti.
Septerna (NASDAQ:SEPN) ha iniciado su ensayo clínico de Fase 1 para SEP-631, un modulador alostérico negativo (NAM) oral de MRGPRX2, marcando un hito importante en su programa de desarrollo. El ensayo evaluará la seguridad, tolerabilidad y propiedades farmacológicas del fármaco en hasta 150 voluntarios adultos sanos.
El estudio se centra en el tratamiento de la urticaria crónica espontánea (CSU) y otras enfermedades mediadas por mastocitos. SEP-631 actúa bloqueando selectivamente MRGPRX2, un GPCR crucial en la activación y desgranulación de los mastocitos. El ensayo incluye componentes de dosis única ascendente (SAD) y de dosis múltiple ascendente (MAD), y la administración SAD ya está en curso.
Este avance puede suponer un posible cambio para los pacientes con CSU, una enfermedad inflamatoria sistémica de la piel caracterizada por habones pruriginosos persistentes y angioedema, en la que los antihistamínicos actuales a menudo resultan insuficientes.
Septerna (NASDAQ:SEPN)가 경구용 소분자 MRGPRX2 음성 알로스테릭 조절제(NAM)인 SEP-631의 1상 임상시험을 시작하며 약물 개발 프로그램에서 중요한 이정표를 세웠습니다. 본 임상시험은 최대 150명의 건강한 성인 자원자를 대상으로 약물의 안전성, 내약성 및 약리학적 특성을 평가합니다.
연구는 만성 자발성 두드러기(CSU) 및 기타 비만세포 유발 질환 치료에 중점을 두고 있습니다. SEP-631은 비만세포 활성화와 탈과립에서 중요한 역할을 하는 GPCR인 MRGPRX2를 선택적으로 차단합니다. 임상은 단회 용량 상승(SAD)과 다회 용량 상승(MAD)으로 구성되며, 현재 SAD 투여가 진행 중입니다.
이 개발은 지속적인 가려움증성 두드러기와 혈관부종을 특징으로 하는 전신 염증성 피부 질환인 CSU 환자들에게 잠재적인 획기적 치료가 될 수 있습니다. 현재 항히스타민제가 종종 불충분한 상황에서 의미가 큽니다.
Septerna (NASDAQ:SEPN) a lancé son essai clinique de phase 1 pour SEP-631, un modulateur allostérique négatif (NAM) oral de MRGPRX2, marquant une étape importante dans son programme de développement. L'essai évaluera la sécurité, la tolérabilité et les propriétés pharmacologiques du médicament chez jusqu'à 150 volontaires adultes sains.
L'étude vise le traitement de l'urticaire chronique spontanée (CSU) et d'autres maladies induites par les mastocytes. SEP-631 agit en bloquant sélectivement MRGPRX2, un récepteur GPCR crucial pour l'activation et la dégranulation des mastocytes. L'essai comporte des volets dose unique ascendante (SAD) et dose multiple ascendante (MAD), la phase SAD étant déjà en cours.
Cette avancée pourrait représenter une percée pour les patients atteints de CSU, une maladie inflammatoire systémique de la peau caractérisée par des plaques prurigineuses persistantes et de l'angio-œdème, pour laquelle les antihistaminiques actuels sont souvent insuffisants.
Septerna (NASDAQ:SEPN) hat die Phase‑1‑Studie für SEP-631, einen oralen kleinen Molekül-MRGPRX2-negativen allosterischen Modulator (NAM), gestartet und damit einen wichtigen Meilenstein im Entwicklungsprogramm erreicht. Die Studie wird die Sicherheit, Verträglichkeit und pharmakologischen Eigenschaften des Wirkstoffs bei bis zu 150 gesunden erwachsenen Probanden untersuchen.
Der Schwerpunkt liegt auf der Behandlung der chronischen spontanen Urtikaria (CSU) und anderer mastzellvermittelter Erkrankungen. SEP-631 wirkt durch selektive Blockade von MRGPRX2, einem GPCR, das für die Aktivierung und Degranulation von Mastzellen zentral ist. Die Studie umfasst Single‑Ascending‑Dose (SAD)‑ und Multiple‑Ascending‑Dose (MAD)‑Teile; die SAD‑Dosisierung läuft bereits.
Diese Entwicklung könnte einen Durchbruch für Patienten mit CSU darstellen, einer systemischen entzündlichen Hauterkrankung, die durch anhaltenden, juckenden Nesselausschlag und Angioödem gekennzeichnet ist, bei der aktuelle Antihistaminika häufig unzureichend sind.
- First-in-human trial initiated for novel oral treatment SEP-631
- Potential to address significant unmet medical needs in mast cell-driven diseases
- Large market opportunity with multiple potential disease applications including CSU, asthma, and atopic dermatitis
- Convenient oral administration compared to existing treatments
- Early-stage Phase 1 trial with no efficacy data yet
- Will require extensive clinical testing and regulatory approvals before commercialization
Insights
Septerna's entry into Phase 1 trials with SEP-631 marks an early but significant milestone for their GPCR platform targeting mast cell diseases.
Septerna has initiated its first-in-human Phase 1 trial for SEP-631, signaling an important early-stage milestone in the company's clinical pipeline development. The compound represents a novel approach to treating mast cell-driven diseases through a unique mechanism - it's a negative allosteric modulator (NAM) targeting MRGPRX2, a G protein-coupled receptor involved in mast cell activation and degranulation.
The scientific rationale is compelling as MRGPRX2 plays a critical role in mast cell biology, and targeting this pathway could potentially address the significant unmet needs in conditions like chronic spontaneous urticaria (CSU), where many patients don't respond adequately to antihistamines. The oral delivery route could provide a convenience advantage over injectable biologics in this space.
This Phase 1 trial follows the standard early clinical development approach with both single-ascending dose (SAD) and multiple-ascending dose (MAD) components to evaluate safety, tolerability, and pharmacokinetics. The inclusion of an icatibant skin challenge as a pharmacodynamic readout is particularly noteworthy, as it may provide early evidence of target engagement and biological activity.
The planned enrollment of approximately 150 healthy volunteers is relatively large for a Phase 1 study, suggesting a comprehensive dose-finding and safety evaluation approach. While this represents just the beginning of clinical development (typically a 12-18 month process before efficacy data), it validates Septerna's Native Complex Platform™ technology and demonstrates progress in translating their GPCR-focused drug discovery approach into clinical candidates.
Trial Designed to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SEP-631 in Healthy Volunteers
SOUTH SAN FRANCISCO, Calif., Aug. 21, 2025 (GLOBE NEWSWIRE) -- Septerna, Inc. (Nasdaq: SEPN), a clinical-stage biotechnology company pioneering a new era of G protein-coupled receptor (GPCR) drug discovery, today announced the dosing of the first participants in its Phase 1 clinical trial of SEP-631, a selective oral small molecule Mas-related G protein-coupled receptor X2 (MRGPRX2) negative allosteric modulator (NAM) being developed for the treatment of chronic spontaneous urticaria (CSU) and other mast cell-driven diseases. The Phase 1 single-ascending dose (SAD) and multiple-ascending dose (MAD) clinical trial will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SEP-631 in healthy adult volunteers.
“Mast cell-driven diseases represent significant unmet medical needs worldwide, affecting millions of patients who often struggle with inadequate symptom relief with current therapies,” said Jae Kim, M.D., chief medical officer of Septerna. “We are excited to initiate the first-in-human trial for SEP-631, a small molecule NAM that aims to inhibit mast cell activation by selectively blocking MRGPRX2, a GPCR that plays a critical role in mast cell activation and degranulation. SEP-631 has the potential to provide a convenient oral treatment option for patients with CSU and other mast cell-driven diseases. As we initiate this Phase 1 trial, we look forward to further demonstrating the potential of our Native Complex Platform™ to discover new ways to modulate GPCR targets to develop novel medicines for patients in need of better treatment options."
One of the most common mast cell-driven diseases, CSU is a systemic inflammatory skin disease characterized by the spontaneous and persistent recurrence of itchy, painful hives and angioedema. While there is no known trigger, the activation and degranulation of mast cells and release of histamine and other inflammatory mediators lead to these debilitating symptoms. While patients are initially treated with antihistamines, a significant portion do not respond to therapy, underscoring the need for new oral treatment options. Mast cells are also implicated in multiple other diseases, including asthma, atopic dermatitis, interstitial cystitis, and migraine, representing additional potential opportunities for an MRGPRX2-targeted therapy.
The randomized, placebo-controlled Phase 1 SAD / MAD clinical trial is expected to enroll up to approximately 150 healthy adult volunteers. Dosing is underway in the SAD portion of the trial, which will evaluate the safety and tolerability of SEP-631 at escalating oral doses. The MAD portion of the trial will evaluate the safety and tolerability of oral doses of SEP-631 over the treatment period, and PD will be assessed through an icatibant skin challenge.
About SEP-631
Septerna is developing SEP-631, a selective oral small molecule Mas-related G protein-coupled receptor X2 (MRGPRX2) negative allosteric modulator (NAM) for the treatment of patients with chronic spontaneous urticaria (CSU) and other mast-cell driven diseases. MRGPRX2 is known to play an important role in mast cell activation and degranulation which, in combination with other inflammatory mediators, lead to debilitating symptoms for patients. In addition to CSU, MRGPRX2 is highly and uniquely expressed on mast cells implicated in multiple diseases, including asthma, atopic dermatitis, interstitial cystitis, and migraine. In preclinical studies, SEP-631 demonstrated potent and long-lasting inhibition of MRGPRX2 and blocked mediator-induced skin extravasation in mice engineered to express the human MRGPRX2 receptor.
About Septerna
Septerna, Inc. is a clinical-stage biotechnology company with a world-class team of GPCR experts and drug developers advancing cutting-edge science to unlock the full potential of GPCR therapies for patients with significant unmet needs. The company’s proprietary Native Complex Platform™ is designed to enable new approaches to GPCR drug discovery and has led to the development of a diverse pipeline of novel oral small molecule drug candidates. Septerna is advancing programs in endocrinology, immunology and inflammation, metabolic diseases and additional therapeutic areas, both independently and with partners. For more information, please visit www.septerna.com.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Septerna’s beliefs and expectations regarding: the continued advancement of its MRGPRX2 NAM program, including the potential of SEP-631 to provide a convenient oral treatment option for patients with CSU and other mast cell-driven diseases; the role of MRGPRX2 in mast cell-driven diseases; the ability to enroll patients and complete the Phase 1 clinical trial for SEP-631; the safety and efficacy results from conducting its research and development programs, including potential outcomes from the clinical development of SEP-631; and the potential of its proprietary Native Complex Platform™. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “predict,” “project,” “potential,” “should,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward looking statements contain these identifying words.
Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: clinical development outcomes including unexpected safety or efficacy findings; the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the scope of protection Septerna is able to establish and maintain for intellectual property rights covering its Native Complex Platform™ and its product candidates, including SEP-631; and general economic, industry and market conditions. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Septerna’s Annual Report on Form 10-K for the year ended December 31, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Septerna’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Septerna explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
Investor Contact:
Renee Leck, THRUST
renee@thrustsc.com
Media Contact:
Carly Scaduto
carly@carlyscadutoconsulting.com
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