FDA Grants RMAT Designation to Lexeo’s LX2020 Gene Therapy for PKP2-ACM

The U.S. Food and Drug Administration has granted Regenerative Medicine Advanced Therapy (RMAT) designation to Lexeo Therapeutics’ investigational gene therapy LX2020 for the treatment of plakophilin-2-associated arrhythmogenic cardiomyopathy (PKP2-ACM). The designation is supported by recent interim clinical data from the ongoing HEROIC-PKP2 Phase I/II trial, highlighting the therapy’s potential to address a serious inherited cardiovascular disease with no approved disease-modifying treatment.

The regulatory milestone strengthens LX2020’s expedited development pathway. In addition to RMAT designation, the therapy has already received Orphan Drug and Fast Track designations from the FDA, providing multiple avenues for closer regulatory engagement as clinical development progresses.

Gene Therapy Targets the Genetic Cause of PKP2-ACM

LX2020 is an adeno-associated virus (AAV)-based gene therapy that delivers a functional full-length PKP2 gene to heart muscle cells using the AAVrh10 vector. Mutations in the PKP2 gene account for approximately half of all arrhythmogenic cardiomyopathy (ACM) cases and are estimated to affect around 60,000 people in the United States.

Loss of functional PKP2 disrupts the desmosomal protein complex responsible for maintaining cell-to-cell adhesion in cardiac tissue. Progressive damage can result in myocardial cell death, fibrosis, ventricular dysfunction, life-threatening arrhythmias, and sudden cardiac death. By restoring PKP2 expression in cardiomyocytes, LX2020 aims to improve cellular integrity and address the underlying genetic defect rather than only managing symptoms.

HEROIC-PKP2 Trial Continues to Evaluate Safety and Clinical Activity

LX2020 is currently being investigated in the HEROIC-PKP2 study (NCT06109181), a Phase I/II, single-arm, open-label, multicenter clinical trial enrolling patients with PKP2-associated arrhythmogenic cardiomyopathy.

The FDA based its RMAT decision on interim clinical findings from the ongoing study. Lexeo did not disclose detailed efficacy or safety results in the announcement, but the available data were considered sufficient to support the therapy’s potential to address an unmet medical need in a serious condition.

RMAT designation is reserved for regenerative medicine therapies that demonstrate preliminary clinical evidence of potential benefit. The program offers enhanced opportunities for early and frequent interactions with the FDA on clinical development, manufacturing, and regulatory strategy. Eligible products may also qualify for accelerated approval, priority review, and rolling review, when appropriate.

Regulatory Recognition Reflects Growing Clinical Momentum

Narinder Bhalla, MD, Chief Medical Officer of Lexeo Therapeutics, said the RMAT designation represents an important regulatory milestone that reflects the emerging clinical evidence generated from the HEROIC-PKP2 trial. He noted that PKP2-ACM currently lacks approved disease-modifying therapies and said the designation will facilitate continued collaboration with the FDA as the company advances LX2020 through clinical development.

Bhalla added that Lexeo expects to provide additional clinical and regulatory updates on the program before the end of the year.

Path Forward

With RMAT, Fast Track, and Orphan Drug designations now in place, LX2020 enters the next stage of development with access to multiple FDA expedited programs intended to streamline regulatory interactions. Lexeo will continue enrolling and following participants in the HEROIC-PKP2 Phase I/II trial while generating additional evidence to support future regulatory discussions and potential late-stage development of the one-time gene therapy for PKP2-associated arrhythmogenic cardiomyopathy.

Reference

Lexeo Therapeutics Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for LX2020 for the Treatment of PKP2 Arrhythmogenic Cardiomyopathy – Lexeo Therapeutics