Solid Biosciences has achieved a significant regulatory milestone with the approval of its Investigational New Drug (IND) application by the U.S. Food and Drug Administration and clinical trial application (CTA) by Health Canada for SGT-501, a first-in-class gene therapy targeting catecholaminergic polymorphic ventricular tachycardia (CPVT). The company expects to initiate a Phase 1b clinical trial evaluating the safety, tolerability and efficacy of SGT-501 in the fourth quarter of 2025.
Addressing a Critical Unmet Medical Need
CPVT represents a particularly devastating genetic heart condition that has remained without approved therapies despite being identified nearly 50 years ago. The disorder is characterized by abnormal heart rhythms, specifically ventricular tachycardia, triggered by adrenergic stimulation such as physical activity or emotional stress. These arrhythmias can cause unexplained fainting, seizures, cardiac arrest and sudden death.
"Despite being identified nearly 50 years ago, CPVT still lacks FDA-approved therapies - this announcement reflects a critical development in the treatment of this underserved, often fatal, cardiac disease," said Gabriel Brooks, M.D., Chief Medical Officer of Solid Biosciences.
The condition affects approximately 1 in 10,000 individuals globally, though it is often misdiagnosed, and typically manifests in children and young adults. CPVT is primarily caused by mutations in the RYR2 and CASQ2 genes, which disrupt calcium regulation in heart muscle cells, impairing proper heart contraction and relaxation.
Novel Therapeutic Mechanism
SGT-501 is an AAV-based gene therapy candidate designed to deliver a functional, full-length, codon-optimized copy of the human cardiac calsequestrin (CASQ2) gene to heart muscle cells. In the context of RYR2 variants, increasing CASQ2 protein levels enhances buffering of free calcium in the sarcoplasmic reticulum, stabilizing the RYR2 and resulting in reduced diastolic calcium leak into the cytosol.
The stabilization of the RYR2 in its closed conformation supports the maintenance of normal cardiac rhythm with the potential to protect against ventricular tachycardia. This precision genetic approach targets the underlying pathophysiology of the disease by addressing abnormal calcium releases from the sarcoplasmic reticulum in an otherwise structurally sound heart.
"SGT-501 offers a precision genetic approach targeting the underlying pathophysiology of the disease," Brooks explained. "We believe SGT-501 has the unique potential to provide durable protection and may be capable of liberating patients from the ever-present threat of lethal arrhythmias and life-limiting prohibitions on exercise."
Scientific Foundation and Development
The AAV-CASQ2 gene therapy approach utilized by SGT-501 was pioneered by Dr. Silvia Priori and the IRCCS ICS Maugeri lab in Pavia, Italy. Dr. Priori, a globally recognized leader in inherited arrhythmias, has been at the forefront of translational cardiac research for decades.
"After decades during which we, the clinical community, have been limited in our ability to treat people living with CPVT, I have long hoped for the day when a genetic-modifying therapy becomes available," said Silvia Priori, M.D., Ph.D., Professor of Cardiology at the University of Pavia and Director of the Molecular Cardiology Unit at the IRCCS Maugeri.
Solid Biosciences in-licensed this innovative therapeutic in 2023 and subsequently advanced it into IND-enabling preclinical development. The fundamental work from the Maugeri labs demonstrated that calsequestrin overexpression can have a therapeutic impact on multiple forms of CPVT in both cellular and mouse models of disease.
Regulatory Recognition and Clinical Path Forward
SGT-501 has received both Orphan Drug Designation and Rare Pediatric Disease Designation from the U.S. FDA, recognizing its potential as a first-in-class therapy to correct the underlying RYR2 instability and calcium dysregulation that causes CPVT.
The upcoming Phase 1b clinical trial represents a crucial step toward bringing this potential treatment to individuals living with CPVT. The study will evaluate the safety, tolerability and efficacy of SGT-501 in patients with this life-threatening condition.
Expanding Cardiac Portfolio
This regulatory approval marks Solid Biosciences' expansion into cardiac indications, building on the company's expertise in precision genetic medicines for rare diseases. The company's broader pipeline includes gene therapy candidates targeting rare neuromuscular and cardiac diseases, including Duchenne muscular dystrophy, Friedreich's ataxia, TNNT2-mediated dilated cardiomyopathy, BAG3-mediated dilated cardiomyopathy, and additional fatal genetic cardiac diseases.
The development of SGT-501 represents a significant advancement in the treatment landscape for CPVT patients, who currently face limited therapeutic options and must often restrict their physical activities to avoid potentially fatal arrhythmic episodes. The gene therapy approach offers the potential for a disease-modifying treatment that could fundamentally change the management of this devastating condition.
