Promising Phase 1/2 Data Released on Rett Syndrome Gene Therapy Agent TSHA-102
At 6 weeks post-treatment, the patient saw clinical improvements in multiple domains, including autonomic function, vocalization, gross motor skills, and fine motor skills and hand function.
Elsa Rossingnol, MD, FRCP, FAAP
Newly announced positive data from a phase 1/2 study (NCT05606614) assessing Taysha Therapeutic’s investigational gene therapy TSHA-102 showed that treatment in low doses was safe with efficacy observed in several key measures 4 weeks posttreatment in a single adult with Rett syndrome. The company also announced that the FDA has cleared its investigational new drug application for the agent to be assessed in pediatric patients with the condition.1,2
Otherwise known as the REVEAL trial, findings showed a safe and tolerable profile with no treatment-emergent serious adverse events as of the 6-week posttreatment assessment. Investigators observed 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.
"The efficacy response observed following treatment with TSHA-102 in the first adult with an advanced stage of Rett syndrome is promising," principal investigator Elsa Rossingnol, MD, FRCP, FAAP, associate professor of neuroscience and pediatrics, CHU Sainte-Justine, an affiliate of the University of Montreal, said in a statement.1 "Prior to treatment, the patient was in a constant state of hypertonia, had limited body movement, required constant back support, and had lost fine and gross motor function early in childhood. Following treatment, we have observed improvements in breathing patterns, vocalization and motor skills. The patient was able to sit unassisted for the first time in over a decade, and she demonstrated the ability to unclasp her hands and hold an object steadily for the first time since infancy."
THSA-102, an adeno-associated virus (AAV) vector gene transfer therapy, utilizes a novel miRNA-Responsive Auto-Regulatory Element (miRARE) platform designed to regulate cellular MECP2 expression, otherwise known as the root genetic cause of Rett syndrome. At 4 weeks, the treated patient showed efficacy in key measures of Clinical Global Impression (CGI)-Improvement scale adapted to Rett syndrome, CGI-Severity scale, and Rett Syndrome Behavior Questionnaire.
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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.
Rossingnol added, "Prior to treatment, the patient was in a constant state of hypertonia, had limited body movement, required constant back support, and had lost fine and gross motor function early in childhood. Following treatment, we have observed improvements in breathing patterns, vocalization and motor skills. The patient was able to sit unassisted for the first time in over a decade, and she demonstrated the ability to unclasp her hands and hold an object steadily for the first time since infancy."1
The positive patient data comes weeks after the company announced it will continue dosing the gene therapy in a second patient based on recommendations from an Independent Data Monitoring Committee. The recommendation from the IDCM was specifically based on the prespecified examination results from the first patient that had reached the end of a posttreatment evaluation period, which lasted 42 days. Continued dosing for the adult patients is expected to occur in the second half of 20223, with further updates on available clinical data expected quarterly.2
Taysha also gave an update on its other AAV9 gene therapy, TSHA-120, for the treatment of giant axonal neuropathy, a genetic neurodegenerative disorder with no approved treatments. At R&D (research and development) Day in June 2023, the company provided an overview of new comprehensive data analysis and development of disease progression model (DPM), which the company believes has the potential to address FDA feedback regarding the heterogeneity of GAN and effort-dependent nature of MFM32 as the primary end point in an unblinded study. The company submitted a new data analysis using the DPM as a meeting request to the FDA, with feedback for a potential regulatory pathway expected in Q3 of 2023.
