Rett Syndrome Gene Therapy Trial Recommended to Dose Second Patient

The phase 1/2 REVEAL clinical trial (NCT05606614), which is evaluating Taysha Gene Therapies’ investigational adeno-associated virus (AAV) vector-based gene therapy TSHA-102 for the treatment of Rett syndrome, has received a recommendation from its Independent Data Monitoring Committee (IDMC) to proceed with dosing of the second patient.¹

Taysha previously reported the dosing of the first patient in REVEAL in June 2023.² Later in June, Taysha announced that the first patient, who was treated at CHU Sainte-Justine, the Université de Montréal mother and child university hospital center in Montreal, Canada, had been discharged from the hospital in accordance with study protocol and had completed several follow-up visits.³ The IDMC’s recommendation was based on a prespecified examination of clinical results carried out after the first patient had reached the end of a posttreatment evaluation period lasting 42 days.¹

“We thank the IDMC members for their guidance and are pleased with their recommendation to continue the REVEAL phase 1/2 trial,” Sukumar Nagendran, MD, the president and head of R&D at Taysha Gene Therapies, said in a statement.¹ “This recommendation was based on the analysis of initial clinical data from the first adult patient with Rett syndrome to receive TSHA-102. A second patient is expected to be dosed in the third quarter of this year. We are highly encouraged by the initial clinical observations, which support the transformative potential of TSHA-102 and mark important progress in our efforts to bring a gene therapy to patients and families living with Rett syndrome. We look forward to providing an initial clinical update on the first patient at our second quarter corporate update conference call in mid-August."

The REVEAL trial, which is being conducted under a clinical trial application (CTA) cleared by Health Canada in March of last year, is currently taking place at a single site in Canada and is recruiting women aged 18 years or older. Taysha is working to expand the trial to other countries, with a CTA planned for submission to the United Kingdom’s Medicines and Healthcare products Regulatory Agency in mid-2023 and an investigational new drug application planned for submission to the FDA before the end of the year. Notably, the planned UK trial will evaluate the gene therapy in children with Rett syndrome.² Nagendran noted in a June 28, 2023, statement that the company would provide updates on REVEAL quarterly after the IDMC’s review of the initial clinical data.

TSHA-102, which is administered intrathecally, delivers a copy of miniMECP2, a truncated version of the disease-targeted MECP2 gene, via an AAV9 vector.^2,4 The gene therapy product also incorporates use of the company's novel miRNA-Responsive Auto-Regulatory Element (miRARE) platform, which is intended to enable regulation of cellular expression for both endogenous and exogenous MECP2. The gene therapy has previously been granted orphan drug designation (ODD) and rare pediatric disease designation from the FDA and ODD from the European Commission.¹

Taysha Gene Therapies is also developing TSHA-120, an investigational AAV9 gene therapy intended to treat giant axonal neuropathy (GAN).⁵ In late June, the company reported that TSHA-120 demonstrated a positive benefit in disease progression modeling in patients with GAN treated in a phase 1/2 clinical trial (NCT02362438). Investigators found that participants treated with TSHA-120 had a 99% probability of positive treatment effect on slowing disease progression, with an estimated average treatment effect of 31% on the Modified Friedreich’s Ataxia Rating Scale and an estimated treatment effect of 28% on Motor Function Measure 32 Domain 3 (distal motor function – hands) compared to natural history data.

REFERENCES
1. Taysha Gene Therapies announces positive recommendation from independent data monitoring committee of REVEAL phase 1/2 trial in Rett syndrome. News release. Taysha Gene Therapies, Inc. July 31, 2023. Accessed July 31, 2023. https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-positive-recommendation
2. Taysha Gene Therapies announces first patient dosed with TSHA-102 in the reveal phase 1/2 trial under investigation for the treatment of Rett syndrome. News release. Taysha Gene Therapies, Inc. June 5, 2023. Accessed July 31, 2023. https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-first-patient-dosed-tsha-102
3. Taysha Gene Therapies provides clinical updates for investigational programs TSHA-120 in giant axonal neuropathy (GAN) and TSHA-102 in Rett syndrome at R&D day. News release. Taysha Gene Therapies, Inc. June 28, 2023. Accessed July31, 2023. https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-provides-clinical-updates-investigational
4. Pipeline. Taysha Gene Therapies. Website. Accessed June 6, 2023. https://tayshagtx.com/pipeline/