Phase 1/2 Studies Highlight Durable Impacts of Gene Therapy TSHA-102 in Rett Syndrome


Initial data from a few pediatric and adult patients with Rett syndrome showed that treatment with TSHA-102 resulted in numerous positive enhancements across multiple efficacy measures and clinical domains.

Sean P. Nolan, chairman and chief executive officer at Taysha

Sean P. Nolan

Taysha Gene Therapies has announced positive data from its pivotal phase 1/2 REVEAL studies assessing TSHA-102, an adeno-associated (AAV)-based gene therapy for patients with Rett syndrome. All told, treatment with the therapy resulted in durable improvements across clinical domains in a small group of both adult and pediatric patients, including motor skills, communication/socialization, autonomic function, and seizures, in addition to demonstrating a safe profile.1

Designed as a one-time lumbar intrathecal treatment, TSHA-102 aims to address the genetic root cause of Rett by delivering a functional form of MECP2 to cells in the central nervous system. Following an independent data monitoring committee review of safety data from the first high dose patient in the adolescent and adult trial, dosing for a high-dose cohort is expected to commence in Q3 2024.

"We are highly encouraged by the safety profile and broad clinical response observed across multiple domains in both the adult and pediatric patients with different genetic mutation severity treated with the low dose of TSHA-102," Sean P. Nolan, chairman and chief executive officer at Taysha, said in a statement.1 "The longer-term follow up data indicate a durable response with sustained and new improvements across multiple clinical domains in both adult patients, and importantly, both pediatric patients showed initial improvements across consistent clinical domains, with early evidence of developmental gains following treatment with TSHA-102. We believe these improvements in adult and pediatric patients further reinforce the potential of TSHA-102 to be transformative for a broad range of patients with Rett syndrome."

Both the adolescent/adult and pediatric portions of REVEAL were open-label, dose-escalation and dose-expanding, and included those with Rett syndrome due to MECP2 loss-of-function mutation. In the adolescent/adult population, the therapy was generally well tolerated in 2 patients who received low doses of 5.7 x 1014, with no serious adverse events at 52-week assessment for patient 1 and 36-week assessment for patient 2. Patients also saw improved motor skills, including hand function and gained ability to sit unassisted for the first time in over a decade (patient 1), as well as improved hand stereotypies for the first time since regression at age 3 and improved posture and stability (patient 2).

Among the 2 patients in the adolescent/adult cohort, investigators observed enhanced social interest vocalization, and ability to use eye-gaze driven communication device (patient 1), as well as improved social interest with increased response to spoken words and eye contact (patient 2). Both patients saw improvements in breathing patterns and circulation, while patient 1 also saw benefits in normalized sleep quality/duration.

In terms of seizures, patient 1 had seizure events stabilized, whereas patient 2 saw significant reductions in seizure events. At 52 weeks, patient 1 experienced stable seizure events at lower levels of antiseizure medication relative to baseline, while patient 2 showed a 25% reduction in seizure events at week 36 post-treatment. Notably, patient 2 reported 8.5 months of seizure freedom.

"TSHA-102 was well-tolerated in both adult patients treated, with no serious adverse events or dose-limiting toxicities as of week 52 and week 36 post-treatment for the first and second patient, respectively. It’s encouraging that we continue to see improvements across multiple clinical domains in the longer-term assessments with no diminution of effect,” principal investigator Elsa Rossignol, MD, FRCP, FAAP, associate professor in Neuroscience and Pediatrics at the University of Montreal, said in a statement.1 "We believe these longer-term clinical data support the durability and broad clinical benefits of TSHA-102 in adult patients with the most advanced stage of Rett syndrome."

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On the pediatric side, results included 2 dosed patients, both 6- and 7-years-old, who had MECP2 deletion (associated with moderate phenotype) and missense MECP2 mutation (associated with milder phenotype), respectively, with pseudo stationary symptoms. To date, patient 1 had been followed for up to 22 weeks while patient 2 only had data for 11 weeks post-baseline. Overall, results were similar to the adult population, with no serious AEs related to TSHA-102 observed thus far. Of note, there was 2 serious AEs in the second patient (both related to underlying disease and 1 attributed to immunosuppression) and were resolved; however, the company noted significant challenges with AEs because of immunosuppressive regimen.

Similar to the adolescent/adult patients, investigators saw improvements in motor skills, communication/socialization, autonomic function, and seizures, for up to 12-weeks post-treatment for patient 1 and 8-weeks post-baseline for patient 2. Patient 1 saw clinical improvements in Clinical Global Impression-Improvement (CGI-I), Parental Global Impression-Improvement (PGI-I), Revised Motor Behavior Assessment (R-MBA), Adapted Mullen Scales of Early Learning, and Seizure Diaries, while Patient 2 saw enhancements in CGI-I, PGI-I, Rett Syndrome Behavior Questionnaire (RSBQ), R-MBA, and seizure diaries.

In terms of motor skills, patient 1 demonstrated improved hand function with the ability to hold an object for 3 minutes vs up to 12 seconds at baseline, improved truncal stability and balance with the gained ability to move her leg on her own to better take a step with assistance and sit unassisted for longer duration, and improved swallowing and oral intake relative to gastrostomy tube feeding. Patient 2 showed improved hand function and gait, speed and stability when walking with some new skills gained, including standing up from a chair and walking up a stair.

"Following treatment with TSHA-102, both pediatric patients with different genotypes and disease severity had challenging side effects related to immunosuppressant treatment but showed a well-tolerated safety profile with no SAEs or DLTs related to TSHA-102 as of week 22 and week 11 post-treatment for the first and second pediatric patient, respectively, as well as some initial improvements across multiple clinical domains and early evidence of new developmental gains," Colleen Buhrfiend, MD, assistant professor of pediatrics at RUSH University Medical Center, said in a statement.1 "The initial improvements observed across multiple areas of disease in both pediatric patients are encouraging early signs of possible benefit."

1. Taysha Gene Therapies Announces Positive Clinical Data Across Adult and Pediatric Patients from Low Dose Cohort in Ongoing REVEAL Phase 1/2 Trials Evaluating TSHA-102 in Rett Syndrome. June 18, 2024. Accessed June 18, 2024.
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