Taysha Gene Therapies, Inc. 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

Taysha Gene Therapies, Inc. announced positive longer-term clinical data from the ongoing REVEAL Phase 1/2 adolescent and adult trial and initial clinical data from the REVEAL Phase 1/2 pediatric trial evaluating TSHA-102 in Rett syndrome. Elsa Rossignol, M.D., FRCP, FAAP, Associate Professor in Neuroscience and Pediatrics at the Université de Montréal and Principal Investigator of the REVEAL adolescent and adult trial. REVEAL Phase 1/2 Adolescent and Adult Trial (Canada and U.S.): a first-in-human, open-label, randomized, dose-escalation and dose-expansion study evaluating the safety and preliminary efficacy of TSHA-102 in adolescent and adult females aged 12 years and older with Rett syndrome due to MECP2 loss-of-function mutation.

TSHA-102 is administered as a single lumbar intrathecal injection. Dose escalation will evaluate two dose levels of TSHA-102 sequentially. The maximum tolerated dose (MTD) or maximum administered dose (MAD) established in Part A will then be administered during dose expansion in Part B of the study.

Completed dosing in cohort one (low dose, n=2) of 5.7x1014 total vg Dosed first patient in cohort two (high dose, n=3) of 1x1015 total vg in the second quarter of 2024 Initial available safety and efficacy data from cohort two expected in the second half of 2024 Longer-term data from the first adult patient (20 years old; large MECP2 deletion; associated with severe phenotype) and second adult patient (21 years old; missense MECP2 mutation; associated with milder phenotype) with late motor deterioration, stage four Rett syndrome dosed with TSHA-102 in the low dose cohort: Generally well-tolerated with no serious adverse events (SAEs) related to TSHA-102 or dose-limiting toxicities (DLTs) as of 52-week assessment post-treatment for patient one and 36-week assessment post-treatment for patient two Sustained and new improvements observed across multiple clinical domains relative to baseline, as of 52-weeks post-treatment for patient one, based on clinical observations reported by the Principal Investigator (PI), including: Motor skills: improved hand function and gained ability to sit unassisted for first time in over a decade and move legs (patient one), and improved hand stereotypies for the first time since regression at age three and improved posture and stability (patient two) Communication/Socialization: improved social interest, vocalization and ability to use eye-gaze driven communication device (patient one), and improved social interest with increased response to spoken words and eye contact (patient two) Autonomic function: improved breathing patterns, normalized sleep quality/duration for first time in 20 years and improved circulation (patient one), and improved breathing patterns and circulation (patient two) Seizures: stable seizure events (patient one), and significantly reduced seizure events (patient two) Seizure Diary and caregiver reports: Patient one at week 52 post-treatment: stable seizure events at lower levels of anti-seizure medication relative to baseline Patient two at week 36 post-treatment: significantly reduced seizure events at 25% lower levels of anti-seizure medication relative to baseline (2-4 seizures per week), with 8.5 months reported seizure-free Clinical improvements seen across multiple efficacy measurements relative to baseline include: Patient one at week 52 post-treatment: Sustained improvement in Clinical Global Impression?Improvement (CGI-I), Clinical Global Impression?Severity (CGI-S) and Seizure Diaries, with new improvement in Revised Motor Behavior Assessment (R-MBA), Parental Global Impressions?Improvement (PGI-I) and Rett Syndrome Behavior Questionnaire (RSBQ) following completion of steroid and sirolimus taper Patient two at week 25 post-treatment: Sustained improvement in CGI-I and PGI-I, with new improvement in R-MBA and Seizure Diaries following completion of steroid taper REVEAL Phase 1/2 Pediatric Trial (U.S. and U.K.): an open-label, randomized, dose-escalation and dose-expansion study evaluating the safety and preliminary efficacy of TSHA-102 in pediatric females with Rett syndrome due to MECP2 loss-of-function mutation. TSHA-102 is administered as a single lumbar intrathecal injection. Part A of the study will focus on determining MAD and MTD in patients aged 5 to 8 years old.

Part B is the dose expansion phase and will evaluate TSHA-102 at the MAD or MTD in two age cohorts (5 to 8 years and 3 to 5 years). Completed dosing in cohort one (low dose, n=2) of 5.7x1014 total vg Received IDMC approval of Company?s request to advance early to cohort two (high dose, n=3) evaluating 1x1015 total vg, with dosing to occur following IDMC review of the 42-day safety data from the first high dose patient in the adolescent and adult trial Dosing of first pediatric patient in cohort two expected in the third quarter of 2024 Initial available safety and efficacy data from cohort two expected in the second half of 2024. Longer-term data from the first adult patient (20 years old; large MECP2 deletion; associated with severe phenotype) and second adult patient (21 years old; missense MECP2 mutation; associated with milder phenotype) with late motor deterioration, stage four Rett syndrome dosed with TSHA-102 in the low dose cohort: Generally well-tolerated with no serious adverse events (SAEs) related to TSHA-102 or dose-limiting toxicities (DLTs) as of 52-week assessment post-treatment for patient one and 36-week assessment post-treatment for patient two Sustained and new improvements observed across multiple clinical domains relative to baseline, as of 52-weeks post-treatment for patient one, based on clinical observations reported by the Principal Investigator (PI), including: Motor skills: improved hand function and gained ability to sit unassisted for first time in over a decade and move legs (patient one), and improved hand stereotypies for the first time since regression at age three and improved posture and stability (patient two) Communication/Socialization: improved social interest, vocalization and ability to use eye-gaze driven communication device (patient one), and improved social interest with increased response to spoken words and eye contact (patient two) Autonomic function: improved breathing patterns, normalized sleep quality/duration for first time in 20 years and improved circulation (patient one), and improved breathing patterns and circulation (patient two) Seizures: stable seizure events (patient one), and significantly reduced seizure events (patient two) Seizure Diary and caregiver reports: Patient one at week 52 post-treatment: stable seizure events at lower levels of anti-seizure medication relative to baseline Patient two at week 36 post-treatment: significantly reduced seizure events at 25% lower levels of anti-seizure medication relative to baseline (2-4 seizures per week), with 8.5 months reported seizure-free.