Taysha Seeks to Overturn Natural History Trends With Rett Syndrome Gene Therapy in Dual Phase 1/2 REVEAL Studies
The REVEAL adolescent and adult trial and the separate phase 1/2 REVEAL Pediatric Study are both evaluating the gene therapy TSHA-102 in Rett syndrome populations.
Taysha Gene Therapies’ TSHA-102, an investigational adeno-associated virus (AAV) vector-based gene therapy, is currently being evaluated for the treatment of Rett syndromein both the phase 1/2 REVEAL adolescent and adult clinical trial (NCT05606614) and the separate phase 1/2 REVEAL Pediatric Study clinical trial (NCT06152237).1 In honor of Rett Syndrome Awareness Month, which is observed annually in the month of October by the patient and clinician communities, CGTLive® has decided to take a look at the 2 trials evaluating this novel therapy.
TSHA-102, which is administered intrathecally (IT), delivers a copy of miniMECP2, a truncated version of the disease-targeted MECP2 gene, via an AAV9 vector.2,3 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.
REVEAL Adolescent and Adult Clinical Trial
The REVEAL adolescent and adult trial was initiated on March 6, 2023, and takes the form of a dose escalation and dose expansion study. The trial is expected to enroll approximately 18 patients in total and includes 2 dose level cohorts. Meredith Schultz, MD, MS, the chief medical officer of Taysha Gene Therapies, is serving as the study director. According to the clinicaltrials.gov page, which was most recently updated on October 8, 2024, the REVEAL adolescent and adult is currently recruiting at locations in Quebec, Canada and Chicago, Illinois. Additional locations in La Jolla, California; Boston, Massachusetts; Sain Paul, Minnesota; and Dallas, Texas are listed as not yet recruiting.
The trial’s primary end points include the proportions of participants who experience any treatment-emergent adverse events (TEAEs) and serious AEs; and the change in a patients’ statuseson the Clinical Global Impressions-Improvement (CGI-I) scale as adapted to Rett syndrome, the Revised Motor Behavior Assessment (R-MBA), and the Rett Syndrome Hand Function Scale (RSHFS). All of these end points will be assessed from baseline to 52 weeks posttreatment.
Secondary end points for the study include the change in patients' statuses on the CGI-I scale, seizure frequency, adaptive behavior as measured via Vineland-3, as well as quantitative EEG findings with visual evoked potentials and quantitative EEG findings with auditory evoked potentials. All these secondary end points will also be assessed from baseline to 52 weeks posttreatment.
The study is open to women and girls aged 12 years and older who have been clinically diagnosed with classical/typical Rett syndrome with a loss-of-function mutation in the gene for the methyl-CpG-binding protein 2 (MECP2). Patients who have another neurodevelopmental disorder unrelated to the MECP2 mutation or any other genetic syndrome with a progressive course; patients with atypical Rett syndrome; patients with a history of neurological problems resulting from brain injury; and patients who had grossly abnormal psychomotor development prior to reaching 6 months of age will be excluded from participation. Additional criteria for exclusion are a need for invasive ventilatory support; unwillingness to receive blood products for AE treatment if needed; contraindications to the IT or lumbar puncture administration procedure, including contraindication to any medications needed for the procedure; and uncontrolled seizures or status epilepticus in the 3 months before being enrolled.
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REVEAL Pediatric Study
The design of the REVEAL Pediatric Study is largely similar to that of the adolescent and adult trial. It similarly takes the form of a dose escalation and dose expansion study, and is evaluating TSHA-102 in a lower dose and higher dose cohort. The trial, which was initiated on December 12, 2023, is expected to enroll approximately 20 participants in total. Schultz is also serving as the study director for this trial. According to the clinicaltrials.gov page, which was most recently updated on October 3, 2024, the study is currently recruiting at locations in Saint Louis, Missouri; Saint Paul, Minnesota; and Chicago Illinois. Locations in La Jolla, California; Boston, Massachusetts; Philadelphia, Pennsylvania; Nashville, Tennessee; Dallas, Texas; Quebec, Canada; and London, United Kingdom are listed as not yet recruiting.
The primary end point for the REVEAL Pediatric Study is the incidence of TEAEs and SAEs. Secondary end points include change in CGI-I status, R-MBA status, Rett Syndrome Behavior Questionnaire status, Clinical Global Impressions-Severity status, quantitative EEG findings with auditory evoked potential and visual evoked potentials, and the percent change in monthly countable seizure frequency. All end points will be assessed from baseline to 52 weeks posttreatment.
The study is open to girls aged 5 years to 8 years who have who have been clinically diagnosed with classical/typical Rett syndrome with a loss-of-function mutation in MECP2. Participants are required to have received all relevant locally-required vaccines within 42 days or more of starting the study’s immunosuppression regimen. Exclusion criteria are largely similar to the REVEAL adolescent and adult trial, with additional criteria excluding patients who require noninvasive ventilatory support and patients who have acute or chronic hepatitis B or C infections. Although, the clinicaltrials.gov page for the Pediatric Study does not list an exclusion criteria related to uncontrolled seizures or status epilepticus history.
The Big Picture
CGTLive has previously spoken to Sukumar Nagendran, MD, the president and head of research and development at Taysha, about the clinical development of TSHA-102. At the time, early promising results from the first 2 adult patients treated with the gene therapy had been announced.
"What actually excites me and my team is that given that we have such a good clinical response in adults, we think the clinical response in the pediatric population could be even better,” Nagendran told CGTLive. “This now gives us the gamut of the age range from pediatrics to adults to treat in a very difficult to treat central nervous system disorder.”
In January 2024, Taysha clarified that further clinical development of TSHA-102 is its main focus at the moment.4 More recently, in June 2024, Taysha announced early results from the first 2 pediatric patients to have been treated in the REVEAL Pediatric Study clinical trial, along with updated results from the adolescent and adult clinical trial.5
“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 dose-limiting toxicities 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, an assistant professor of pediatrics at RUSH University Medical Center, said in a June 2024 statement.5
