Gene therapy for catecholaminergic polymorphic ventricular tachycardia (CPVT): IND-enabling data and design of the ARTEMIS Phase 1b clinical trial

Background

CPVT is a rare, inherited disorder characterized by life-threatening ventricular arrhythmias triggered by exercise or emotional stress. Current treatments fail to address the underlying cause, are associated with significant side effects, and require strict compliance.

CPVT is most commonly caused by mutations in the ryanodine receptor 2 (RYR2) gene, which regulates calcium (Ca2+) release from the sarcoplasmic reticulum (SR) during excitation–contraction coupling. Arrhythmias in CPVT occur due to diastolic leak of Ca2+ through RYR2 into the cytosol leading to delayed afterdepolarizations, which cause ventricular tachycardia (VT) or fibrillation. Calsequestrin 2 (CASQ2) is a closely associated protein in the SR that stabilizes the RYR2 channel in the closed state and increases buffering of Ca2+, thus preventing abnormal Ca2+ leak during diastole.

We hypothesized that augmentation of CASQ2 levels may reduce diastolic Ca2+ flow through RYR2 and lead to a decrease in ventricular arrhythmias in a mouse model of CPVT as well as in CPVT patients with RYR2 mutations.

Methods

A gene therapy candidate (SGT-501) was developed using an AAV8 capsid to express human CASQ2 in cardiomyocytes (rAAV8-CASQ2). Cardiac efficacy was evaluated in RYR2 mutant mice (RYR2 R4496C/+) 3-months after a single IV infusion at a low, mid, or high dose. Long-term safety and biodistribution were assessed in non-human primates (NHPs) 6-months post-dosing.

The planned first-in-human ARTEMIS trial aims to evaluate the safety, tolerability, and efficacy of a single IV dose of SGT-501 in patients with pathogenic or likely pathogenic mutations in RYR2 associated with CPVT. The primary objective will be to assess the incidence of treatment-emergent adverse events. Other objectives include measuring changes in the Ventricular Arrhythmia Score (VAS) during exercise. This multicenter open-label study will have 2 adult cohorts followed by a pediatric cohort.

Results

In RYR2 R4496C/+ mice, bioanalytical analysis demonstrated a clear dose-responsive impact on vector genomes, CASQ2 mRNA, and CASQ2 protein expression. Following a beta-adrenergic challenge (2mg/kg epinephrine and 120mg/kg caffeine), ECG analysis revealed an SGT-501 dose-dependent decrease in the incidence of VT. A significant decrease in VT incidence was observed at the mid dose (4/25, 16%) and high dose (1/28, 4%) compared to vehicle (13/25, 52%), with cardiac CASQ2 protein levels measured at 1.6-fold and 6-fold above vehicle levels, respectively. In NHPs, SGT-501 was well tolerated across all dose levels with no adverse observations.

Conclusions

A single administration of SGT-501 is effective in rescuing electrophysiological abnormalities in a mouse model of CPVT and is well-tolerated in NHPs. This is the basis of the ARTEMIS trial, a first- in- human clinical trial evaluating the safety, tolerability, and preliminary efficacy of SGT-501 in patients with CPVT.