Giant Axonal Neuropathy Gene Therapy Needs Double-blind Trial Before BLA Submission


The dosing of additional patients in a double-blind, placebo-controlled design will help support a BLA submission for TSHA-120.

The FDA has recommended Taysha Gene Therapies to dose additional patients with TSHA-120, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat giant axonal neuropathy (GAN), in order to support a biologics license application (BLA) submission.1

The recommendation, which came out of a Type B end-of-Phase 2 meeting between the company and the FDA, includes the stipulation that the dosing of the additional patients be carried out in a double-blind, placebo-controlled design. Taysha Gene Therapies has submitted follow-up questions regarding the design and necessary evidence for a BLA submission and is awaiting a response from the FDA. In addition to the recommendation, the FDA noted that the 32-item Motor Function Measure (MFM32) score is an acceptable end point for the trial. Pending a review of a Chemistry, Manufacturing, and Controls data package, which the company is planning to submit, the agency has deemed the manufacturing approach for the gene therapy product to be appropriate for pivotal-stage and commercial production.

TSHA-120 utilizes an AAV9 vector intended to deliver a functional copy of gigaxonin, the disease-targeted gene, and is administered intrathecally.2 It was previously evaluated in a phase 1 clinical trial (NCT02362438). In January 2022, Taysha Gene Therapies announced that TSHA-120 was well-tolerated in this trial’s highest dose cohort (3.5x1014 total vg).3 It was additionally reported that it had demonstrated efficacy in this cohort, including a 5-point improvement in the change in rate of decline in MFM32 score by 1 year compared with a natural history decline of 8 points (n=3; P = .04). TSHA-120 previously received orphan drug designations from the FDA and European Commission and rare pediatric disease designation from the FDA.2

In addition to TSHA-120, Taysha Gene Therapies is also developing TSHA-102, an AAV9 vector-based gene therapy intended to treat Rett syndrome.1 TSHA-102 is intended to deliver a copy of the miniMECP2 gene and is administered intrathecally. A phase 1/2 clinical trial (NCT05606614) for the therapy is currently recruiting in Canada. Taysha Gene Therapies expects that the dosing of the first patient will take place in the first half of this year, with initial clinical data also anticipated in the first half of 2023. Submissions of a clinical trial application (CTA) to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and an investigational new drug (IND) application to the FDA are expected in mid-2023 and the second half of 2023, respectively.

“We expect to deliver on several key milestones in 2023, including the generation of first-in-human adult clinical data in Rett syndrome, CTA submission to MHRA to enable initiation of our pediatric Rett syndrome program and submission of an IND for Rett syndrome in the United States to further expand our clinical study footprint,” Sean P. Nolan, chairman and chief executive officer, Taysha Gene Therapies, said in a statement.1 “For our GAN program, we received the formal FDA meeting minutes and recently submitted follow up questions to clarify some of their recommendations including the feasibility of a proposed study design and the totality of evidence required for BLA submission. Their feedback will help inform next steps for the program in this ultra-rare indication with no approved treatments. I believe that the operational, structural, and personnel actions recently implemented position us well to execute across our near-term milestones and deliver on our commitments to key stakeholders, especially patients.”

1. Taysha Gene Therapies provides update on TSHA-120 program in giant axonal neuropathy and a 2023 corporate outlook. News release. Taysha Gene Therapies, Inc. January 31, 2023. Accessed February 1, 2023. 
2. Taysha Gene Therapies receives orphan drug designation from the European Commission for TSHA-120 for the treatment of giant axon neuropathy (GAN). News release. Taysha Gene Therapies. May 3, 2022. 
3. Taysha Gene Therapies Reports Positive Clinical Efficacy and Safety Data for High Dose Cohort and Long-term Durability Data for TSHA-120 in Giant Axonal Neuropathy. News release. Taysha Gene Therapies. January 31, 2022. 

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