Gene Therapy Modifies Disease Progression in Patients With Giant Axonal Neuropathy


Taysha also provided updates on its gene therapy program for Rett syndrome.

Taysha Gene Therapies’ TSHA-120 has shown a positive benefit in disease progression modeling (DPM) in patients with giant axon neuropathy (GAN) treated in a phase 1/2 trial (NCT02362438).

“Late last year, the company submitted and discussed with the FDA a subset of available evidence supporting the potential therapeutic benefit and safety profile for TSHA-120 in patients with GAN, an ultra-rare disease with currently no approved treatments. FDA feedback included the need to address the heterogeneity of disease progression in GAN and the effort-dependent nature of MFM32 as a primary endpoint, considering the unblinded study design,” Sean P. Nolan, chairman and chief executive officer, Taysha, said in a statement. “Given the FDA also indicated it is open to regulatory flexibility in a controlled trial setting and willing to consider alternative study designs, we undertook an extensive analysis of the totality of data available to determine a feasible regulatory path forward for TSHA-120.”

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 (mFARS) and an estimated treatment effect of 28% on Motor Function Measure 32 (MFM32) Domain 3 (distal motor function – hands) compared to natural history data. Participants also had a 100% probability of positive treatment effect on slowing disease progression in visual acuity, as measured by Logarithm of the Minimum Angle of Resolution (LogMAR), with an estimated treatment effect of 70% in the right eye and 51% in the left eye.

Investigators also founda 100% probability of positive treatment effect on slowing progression, with an estimated treatment effect of 189% and 152% for Ulnar Sensory Nerve Action Potential (SNAP) and median SNAP amplitude, respectively, and a94% probability on slowing progression with an estimated 29% treatment effect. Four of 5 patients that improved or stabilized in SNAP had regenerative clusters on nerve biopsy. Five patients stabilized or increased in nerve fiber density in at least 1 location of the proximal or distal leg at 12 months.

READ MORE: Giant Axonal Neuropathy Gene Therapy Well-Tolerated With Some Clinical Benefit

“We believe the new analyses may help support an approval pathway for TSHA-120 for the treatment of GAN. Our newly developed disease progression model demonstrates predictable and homogenous disease progression in classic GAN, which in our view supports the use of natural history data as an external control. Additionally, we identified objective functional, electrophysiological and biological measurements that demonstrated a clinically meaningful treatment effect, which is also accompanied by over seven years of clinical data supporting the safety profile,” Nolan added. “We’ve requested a formal FDA meeting to discuss these new developments to support a potential regulatory path forward for TSHA-120. We expect the meeting to take place in the third quarter of this year.”

TSHA-120 has demonstrated a tolerable safety profile in patients over 7 years of follow-up. There have been no dose-limiting toxicities and no serious adverse events (AEs) have been related to therapy infusion. The therapy has also been dosed safely in participants with neutralizing antibodies.

TSHA-120 is a self-complimentary AAV9 gene therapy delivered intrathecally that utilizes a novel miRNA-Responsive Auto-Regulatory Element (miRARE) platform. The trial is anongoing and recruiting open-label, dose-escalation, non-randomized study. Taysha plans to meet with the FDA in the third quarter of 2023 for this indication. Taysha also provided updates onthe REVEAL Phase 1/2 trial (NCT05606614) evaluating TSHA-102 for Rett syndrome.

Taysha has dosed the first patient with Rett syndrome. More data will be provided in the third quarter of 2023. The second potential patient has been identified. The company plans tosubmit a clinical trial application to the United Kingdom’s Medicines and Healthcare products Regulatory Agency for pediatric patients in mid-2023 and an investigational new drug application for the FDA in the second half of 2023.

“For our TSHA-102 program in Rett syndrome, we are encouraged by the initial clinical observations of the first adult patient recently dosed in the REVEAL Phase 1/2 trial,” Sukumar Nagendran, MD, president, and head, research and development, Taysha, added. “We look forward to providing further clinical updates on the safety and efficacy observations for the first patient early in the third quarter of this year, following the required IDMC adjudication of the initial clinical data. Subsequent REVEAL trial updates will be provided quarterly, thereafter. We remain on track to submit a CTA to the UK MHRA in pediatric patients in mid-2023 and to submit an IND application to the FDA in the second half of 2023.”

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. June 28, 2023.
Related Videos
Nathan Yozwiak, PhD, on Researching AAV Gene Therapy Delivery to the Brain
Salvador Rico, MD, PhD, on Informing Clinical Trials With Natural History Studies in Dravet
Zheng-Yi Chen, DPhil, on International Collaboration on Clinical Trials
Maria Escolar, MD, the chief medical officer of Forge Biologics
Leigh Ramos-Platt, MD, on Allowing Access and Ensuring Preparation for Gene Therapies
Erika Fullwood Augustine, MD, MS, the associate chief science officer of the Kennedy Krieger Institute
Maria Escolar, MD, the chief medical officer of Forge Biologics
Shankar Ramaswamy, MD, the cofounder, chairman, and CEO of Kriya Therapeutics
Kevin Campbell, PhD, a Howard Hughes Investigator at the University of Iowa
Travis Drow, BS, a research scientist at Seattle Children's Research Institute
© 2024 MJH Life Sciences

All rights reserved.