First Pediatric Patient Dosed in Phase 1/2 REVEAL Trial of Gene Therapy TSHA-102
The pediatric REVEAL trial assesses THSA-102 in 2 cohorts of pediatric patients with Rett syndrome due to MECP2 loss-of-function mutation, with results expected in mid-2024.
Elizabeth Berry-Kravis, MD, PhD
According to a recent announcement, the first pediatric patient has been dosed in the phase 1/2 REVEAL trial (NCT06152237) assessing Taysha’s gene therapy candidate TSHA-102 in individuals with Rett syndrome. The company expects to complete dosing in the low-dose cohort 1 and report initial safety and efficacy data in mid-2024.1
Initial dosing of the adeno-associated vector 9 (AAV9) gene transfer therapy took place at RUSH University Medical Center in Chicago under principal investigator Elizabeth Berry-Kravis, MD, PhD, a professor of pediatrics, neurology, and anatomy/cell biology at RUSH University Medical Center. Administered as a single lumbar intrathecal injection, TSHA-102 utilizes a novel miRNA-Responsive Auto-Regulatory Element (miRARE) technology designed to mediate levels of MECP2, the genetic cause of Rett, in the central nervous system.
"Designed as a one-time, disease-modifying treatment with the ability to mediate MECP2 expression on a cell-by-cell basis, TSHA-102 holds the potential to address a significant unmet medical need for the Rett syndrome community," Berry-Kravis said in a statement.1 "By intervening early in disease, we believe TSHA-102 may provide significant therapeutic impact for pediatric patients. I look forward to evaluating this promising gene therapy and its impact on the lives of patients and their caregivers in the clinic."
The REVEAL Pediatric study, an open-label, dose-escalation and dose-expansion study assessing TSHA-102, is split into cohort A, which includes 6 pediatric females aged 5 to 8 years, and cohort B, which includes patients aged 5-8 years and 3-5 years. Patients in the study have a diagnosis of Rett syndrome due to MECP2 loss-of-function mutation. The study excludes those with another neurodevelopmental disorder independent of MECP2 loss-of-function mutation, a history of brain injury, grossly abnormal psychomotor development, or a diagnosis of atypical Rett syndrome.
"Dosing the first pediatric patient with Rett syndrome marks an important step forward in our efforts to broaden the clinical evaluation of TSHA-102 to younger patients with earlier stages of Rett syndrome," Sukumar Nagendran, MD, president and head of R&D at Taysha, said in a statement.1 "We are pleased with our progress on expanding the study of TSHA-102 across a broad population of ages and stages of Rett syndrome to bring a potentially transformative treatment option to all patients and families suffering from this devastating disease."
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In August 2023, the company announced positive initial data from its adolescent and adult version of REVEAL, with findings that showed tolerability in low doses and efficacy in several key measures. The data included 1 single adult with Rett, who showed no treatment-emergent serious adverse events over the 6-week treatment period. Additionally, there were no quantifiable seizure events through 5 weeks and no marked changes in the Revised Motor Behavior Assessment, a 24-question clinician-reported scale measuring disease behaviors of Rett syndrome.2
In addition to showing a positive safety and tolerability profile, treatment with the gene therapy resulted in improvements in multiple domains, including vocalization with increased social interest. The treated individual also improved autonomic function, as demonstrated by enhanced breathing patterns and sleep quality/duration. Furthermore, investigators observed positive benefits in gross motor skills, with the patient showing a gained ability to sit unassisted for 3 minutes, and fine motor skills, as the patient gained the ability to hold an object, unclasp her hands, and use her fingers to touch a screen.
Taysha expects to have additional updates from the low-dose cohort of the adolescent and adult REVEAL trial in the first quarter of 2024. In addition, the company also announced the UK Medicines and Healthcare products Regulatory Agency authorized the Clinical Trial Application for THSA-102 in pediatric patients, enabling expansion of the ongoing US REVEAL pediatric trial into the UK.
Currently, Acadia’s trofinetide (Daybue), a novel synthetic analog of the amino-terminal tripeptide of IGF-1, remains the only FDA-approved therapy for patients with Rett syndrome. The supporting data from the pivotal phase 3 LAVENDER study (NCT04181723) demonstrated statistically significant improvement compared with placebo on both co-primary efficacy end points, as measured by the change from baseline in Rett Syndrome Behavior Questionnaire (RSBQ) total score (P = .018) and the Clinical Global Impression-Improvement (CGI-I) scale score (P = .003) at week 12.
