Second Patient Dosing Recommended for TSHA-102 Gene Therapy Trial in Rett Syndrome

Sukumar Nagendran, MD

This content originally appeared on our sister site, CGTLive.

In recent news, the phase 1/2 REVEAL clinical trial (NCT05606614) investigating Taysha Gene Therapies’ adeno-associated virus (AAV) vector-based gene therapy TSHA-102 for Rett syndrome, has received direction from its Independent Data Monitoring Committee (IDMC) to continue with dosing the second patient.¹

In June 2023, the company reported news of the first patient dosed with the gene therapy.² Later that month, the company declared that the first patient treated was discharged from the hospital in accordance with the study protocol. The patient, treated at CHU Sainte-Justine, the Université de Montréal mother and child university hospital center in Montreal, Canada, had also completed many follow-up visits.³ The recommendation from the IDMC was specifically based on the prespecified examination results from the first patient that had reached the end of a posttreatment evaluation period, which lasted 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."

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In March 2022, Health Canada cleared the clinical trial application (CTA) for the REVEAL trial. The trial is currently taking place at a single site in Canada and is recruiting adult women with Rett syndrome. Taysha is working toward expansion of the trial to other countries, with a CTA in the planning for submission to the United Kingdom’s Medicines and Healthcare products Regulatory Agency in mid-2023. Also the company plans to submit an investigational new drug application to the FDA before the end of the year. The potential UK trial plans to explore the gene therapy among pediatric patients with Rett syndrome.² In June 2023, Nagendran noted that the company would offer updates on REVEAL quarterly following the IDMC’s review of the initial clinical findings.

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

The company is also in the development of another investigational AAV9 gene therapy, TSHA-120, which is intended to treat giant axonal neuropathy (GAN).⁵ In late June of 2023, Taysha announced that findings from a phase 1/2 clinical trial (NCT02362438) exploring TSHA-120 demonstrated a positive benefit in disease progression modeling in patients with GAN. In the trial, investigators observed that patients treated with TSHA-120 had a 99% probability of a positive treatment effect for slowing disease progression. Notably, those treated with the gene therapy also had an estimated average treatment effect of 31% on the Modified Friedreich’s Ataxia Rating Scale and 28% on Motor Function Measure 32 Domain 3 (distal motor function – hands) compared with 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 July 31, 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/