Taysha Gene Therapies(TSHA) - 2020 Q4 - Annual Report

Gene Therapy Pipeline - The company has a pipeline of 25 gene therapy product candidates targeting neurological indications, with the potential to address over 500,000 patients in the U.S. and EU[20] - The product portfolio currently consists of 25 gene therapy product candidates targeting various CNS indications, with exclusive options to acquire four additional development programs from UT Southwestern at no cost[41] - The company is advancing four new undisclosed programs focused on neurodevelopmental disorders and genetic epilepsies into preclinical development in 2021[20] - The company plans to advance four undisclosed programs into preclinical development in 2021[41] Clinical Trials - TSHA-101 is in development for GM2 gangliosidosis, with a Phase 1/2 clinical trial initiated in Canada, and preliminary safety data expected in the second half of 2021[25] - TSHA-118, targeting CLN1 disease, plans to initiate a Phase 1/2 clinical trial in the second half of 2021 under an open IND[26] - TSHA-102, for Rett syndrome, is set to submit an IND/CTA in the second half of 2021 and initiate a clinical trial by the end of 2021[27] - The company anticipates submitting INDs for multiple product candidates in the second half of 2021, including TSHA-102 and TSHA-104[20] - The company plans to submit an IND/CTA for TSHA-104 in the second half of 2021 and initiate a Phase 1/2 clinical trial by the end of 2021[29] - A Phase 1/2 clinical trial of TSHA-101 was initiated by Queen's University, with preliminary safety and biomarker data expected in the second half of 2021[41] - The global Phase 1/2 trial for TSHA-118 is expected to enroll up to 18 patients, focusing on safety, tolerability, and developmental milestones[93] - The Phase 1/2 clinical trial for TSHA-101 is expected to report preliminary safety and biomarker data in the second half of 2021 and preliminary clinical data by the end of 2021[82] Manufacturing and Facilities - The company is establishing a commercial-scale, GMP-compliant manufacturing facility in Durham, North Carolina, to meet clinical demand[19] - The manufacturing process utilizes scalable suspension HEK293 cell culture, which is expected to support the full pipeline of product candidates[19] - The company intends to utilize scalable manufacturing technologies, including a 187,000-square-foot commercial-scale cGMP manufacturing facility in Durham, North Carolina, expected to meet clinical and commercial demand[41] - An approximately 187,000-square-foot commercial-scale cGMP manufacturing facility is being configured in Durham, North Carolina, to support commercial scale manufacturing of pipeline programs[198] Partnerships and Collaborations - The partnership with UT Southwestern allows for exclusive, royalty-free access to develop and commercialize gene therapies, enhancing the speed and scale of development[21] - The company has established a strategic partnership with UT Southwestern, providing access to a GMP viral vector manufacturing facility capable of supporting multiple preclinical and early clinical development efforts[34][36] - The company has entered into a Sponsored Research Agreement with UT Southwestern to fund the discovery and development of novel gene therapy candidates[39] - The company has entered into a research, collaboration, and license agreement with UT Southwestern, which includes 15 product candidates and options for additional indications[199] - Under the UT Southwestern Agreement, the company issued 2,179,000 shares of common stock to UT Southwestern, with no future milestone or royalty obligations other than patent maintenance costs[201] - The Queen's University Agreement includes a one-time upfront fee of $3.0 million and potential milestone payments totaling up to $20.0 million, along with royalties on net sales of licensed products[205] Preclinical Studies and Efficacy - In preclinical studies, TSHA-101 demonstrated a significant improvement in survival rates, with high, medium, and low doses increasing survival by 3.4-fold, 2.3-fold, and 1.5-fold, respectively, compared to vehicle control[74] - Preclinical studies showed a dose-dependent decrease in GM2 ganglioside accumulation, indicating restoration of Hex A enzyme activity[78] - TSHA-118 has shown significant improvements in survival rates in preclinical studies, with treated CLN1 knockout mice surviving an average of 18.7 months compared to approximately 8 months for untreated mice[90] - TSHA-118 treatment resulted in supraphysiological levels of active PPT1 enzyme in serum, indicating effective restoration of enzyme activity[92] - Preclinical studies for TSHA-104 demonstrated restoration of mitochondrial function and reduction of elevated blood lactate levels in SURF1 knockout mice[102] - Preclinical studies for TSHA-111 showed effective knockdown of GYS1 expression and reduced insoluble glycogen in brain tissue[111] - TSHA-119 demonstrated a dose-dependent reduction of GM2 gangliosides in preclinical studies, indicating potential efficacy for the GM2 AB variant[120] - In preclinical studies, TSHA-102 extended survival in MECP2 knockout mice by 56%[144] - TSHA-102 demonstrated a favorable tolerability profile with no deaths associated with treatment in wild type mice[141] Regulatory Designations - The company has received orphan drug designation and rare pediatric disease designation from the FDA for TSHA-101[71] - The company has received orphan drug designation and rare pediatric disease designation from the FDA for both TSHA-103 and TSHA-105[169][172] Targeted Therapies and Conditions - TSHA-101 is designed to express the HEXA and HEXB genes in a 1:1 ratio to ensure therapeutic efficacy, addressing the critical threshold for normal hydrolysis of GM2 ganglioside[65] - TSHA-106 is being developed for Angelman syndrome, which affects approximately 55,000 patients in the United States and European Union[147] - TSHA-114 is being developed for Fragile X syndrome, with an estimated prevalence of 100,000 patients in the United States and European Union[151] - TSHA-116 is being developed for Prader-Willi syndrome, with an estimated prevalence of 40,000 patients in the United States and European Union[156] - TSHA-117 is being developed for FOXG1 syndrome, which has an estimated prevalence of 20,000 patients in the United States and European Union[157] - The company is also developing TSHA-103 for SLC6A1 haploinsufficiency disorder and TSHA-105 for SLC13A5 deficiency[162] - Approximately 81% of patients with SLC6A1 haploinsufficiency disorder have epilepsy, with 91% exhibiting developmental delays and over 80% characterized as having mild or moderate intellectual disability[165] - The estimated prevalence of SLC6A1 haploinsufficiency disorder is 17,000 patients in the United States and European Union, with an incidence of approximately 1 in 36,000 live births[167] - TSHA-103 is a gene replacement therapy for SLC6A1 haploinsufficiency disorder, currently in preclinical studies[168] - TSHA-105 is being developed for SLC13A5 deficiency, with an estimated prevalence of 1,900 patients in the United States and European Union[170] - TSHA-110 is planned for development targeting KCNQ2 Developmental and Epileptic Encephalopathy, with an estimated prevalence of 37,000 patients in the United States and European Union[176] Innovative Technologies - The company is utilizing a novel AAV dosing platform that allows for redosing by administering therapies directly to the vagus nerve, showing promising results in preclinical studies[55] - The company is developing a novel AAV capsid platform using machine learning and directed evolution to improve targeted delivery of gene therapies[58] - AAV9 delivery to the vagus nerve has shown efficient targeting of vagal neurons in preclinical studies, facilitating potential redosing of gene therapies[179] - The company is developing a novel miRNA target panel, miRARE, to regulate transgene expression levels in the brain for disorders requiring dose-sensitive gene replacement[183] - The company has access to a state-of-the-art AAV production facility through collaboration with UT Southwestern, equipped for both research-grade and GMP-grade AAV vector production[195][196]