Taysha AAV Therapies Achieves FDA Alignment on Pivotal Trial Design and Reports Positive Phase 1/2 Data for TSHA-102 in Rett Syndrome

DALLAS, May 28, 2025 – Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a clinical-stage biotechnology company focused on advancing adeno-associated virus (AAV)-based gene therapies for severe monogenic CNS diseases, today announced key advancements for its AAV gene therapy, TSHA-102, for Rett syndrome. The Company has secured written alignment from the U.S. FDA on the planned pivotal Part B trial design, a decision supported by extensive analysis of the International Rett Syndrome Foundation’s (IRSF) natural history study data and positive clinical results from the ongoing REVEAL Phase 1/2 trials.

“Our analysis of robust natural history data showed minimal likelihood of developmental milestone gains after six years of age in Rett syndrome. It is therefore striking that TSHA-102 achieved a 100% responder rate in all pediatric, adolescent, and adult patients, who gained or regained one or more developmental milestones,” said Sean P. Nolan, Chairman and CEO of Taysha. “This validates our pivotal trial design and strengthens our conviction in the transformative potential of this AAV therapy. This progress sets us on an efficient path to potentially deliver TSHA-102 to patients.”

Dr. Jeffrey Neul and Laura Hameed of IRSF highlighted the critical role of natural history data in shaping meaningful clinical outcomes and advancing therapeutic development for Rett syndrome, particularly for AAV-based interventions.

Pivotal Part B Trial Design (FDA Alignment via RMAT Pathway): The planned single-arm, open-label trial (N=15) will enroll females ≥ 6 years of age in the developmental plateau population. The primary endpoint is defined as the gain/regain of ≥ one developmental milestone, with video-based assessment by independent, blinded central raters. Safety will be evaluated in younger patients (2-6 years), with efficacy data extrapolated. This AAV gene therapy trial aims for a 12-month primary analysis and a 6-month interim analysis, with protocol submission to the IND this quarter.

Positive Clinical Data from Part A (REVEAL Phase 1/2 Trials): Efficacy data from 10 females (aged 6-21 years) treated with TSHA-102 (high or low dose) showed 100% of patients gained ≥ one defined developmental milestone across fine motor, gross motor, and communication domains. This contrasts with a ~0% likelihood without treatment, based on natural history data. Dose-dependent improvements were observed, with the high dose cohort achieving the responder rate 25% faster and outperforming the low dose cohort across multiple clinician-assessed measures. TSHA-102, an AAV-mediated treatment, was generally well tolerated, with no treatment-related SAEs or DLTs, and all related AEs were mild to moderate.

Taysha anticipates submitting the pivotal Part B trial protocol this quarter, presenting TSHA-102 data at the 2025 IRSF Rett Syndrome Scientific Meeting (June 9-11), and initiating the pivotal trial in Q3 2025.

About TSHA-102:

TSHA-102 is a self-complementary intrathecally delivered AAV9 investigational gene transfer therapy for Rett syndrome. Designed as a one-time treatment, this AAV therapy aims to deliver a functional MECP2 gene using novel miRARE technology for regulated expression. TSHA-102 holds RMAT, Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the FDA, along with other international designations, recognizing its potential as an AAV-based therapeutic.

About Rett Syndrome:

Rett syndrome is a rare neurodevelopmental disorder primarily affecting females, caused by MECP2 gene mutations. It leads to severe intellectual disability, loss of communication and motor function, and other impairments. There are no approved disease-modifying therapies for the genetic root cause, highlighting the urgent need for AAV gene therapies like TSHA-102.