Dados do Trabalho

Título

ASPIRO Gene Therapy Trial In X-Linked Myotubular Myopathy (XLMTM): Update on Preliminary Efficacy and Safety Findings

Introdução

X-linked myotubular myopathy (XLMTM) XLMTM, an ultra-rare, life-threatening myopathy is caused by mutations in MTM1 gene, leading to absent or dysfunctional myotubularin.

Objetivo

We present updated results from ASPIRO (NCT03199469), a Phase 1/2/3 clinical trial investigating gene replacement therapy, AT132 for XLMTM.

Métodos

Participants were genetically confirmed XLMTM patients, required ventilator support and had no clinically significant underlying liver disease (>5x ULN ALT or AST, or hepatic peliosis by imaging). As of Jul2020, efficacy data were analyzed for 16 participants (n=6, 1x1014 vg/kg (age 0.8–4.1 years at dosing); n=10, 3x1014 vg/kg (age 1.3–6.8 years at dosing) vs control (n=7).

Resultados

At baseline, all participants required ventilator support (mean [SD] 22.4 [3.34] hours/day), and missed critical motor milestones. Treated participants had significant reductions in daily hours of ventilator dependence vs control (p<0.0001 for both doses); 5/6 participants at 1x1014 vg/kg achieved ventilator independence. Treated participants showed significant improvements in motor function vs control; acquired and maintained several major motor milestones. Muscle biopsies demonstrated durable myotubularin expression with improved pathology scores at 48 weeks. Three participants at 3x1014 vg/kg, who were relatively older and heavier vs others, experienced fatal sepsis or gastrointestinal bleeding with ongoing severe cholestatic liver dysfunction. Present understanding is that these events are related to a combination of underlying XLMTM process and gene replacement therapy. Three patient deaths are currently investigated to ensure appropriate safety monitoring of AT132.

Conclusões

XLMTM patients treated with AT132 demonstrated significant improvements vs control in neuromuscular and respiratory function. Assessment of safety and efficacy is on-going.


This abstract has been submitted at the World Muscle Society Congress 2021.

Palavras Chave

XLMTM, congenital myopathy, gene replacement therapy, clinical trial

Declaração de conflito de interesses de TODOS os autores

PBS has received grants or personal fees from Audentes, Sarepta, AveXis, PTC Therapeutics, Pfizer, Biogen, Argenx, Catalyst, Roche, Ra Pharma, Grifols, Alexion, CSL Behring, Fulcrum Therapeutics, Fibrogen, Acceleron, Reveragen, Sanofi, Santhera. JJD has received research grants from Astellas Gene Therapies, Inc and has participated in advisory boards at Dynacure, Kate Therapeutics, and RYR1. AB has received grants or personal fees from Biogene and Sanofi Genzyme. ARF is part of an advisory or other board at Dynacure and CMD Scientific and Medical. LS has received consultancy fees from Astellas Gene Therapies and Dynacure. MWL has received research grants from Solid Biosciences, Kate Therapeutics, Taysha Therapeutics, and Prothelia; part of an advisory board or has received consultancy or other fees from Solid Biosciences, Taysha Therapeutics, Astellas Gene Therapies, Inc., Encoded Therapeutics, Modis Therapeutics, Lacerta Therapeutics, AGADA Biosciences, Dynacure, Affinia, and BIomarin. MN, SP and SR are former employees of Astellas Gene Therapies. WM is an employee and stockholder of Astellas Gene Therapies. NK, WM-F, AMS, CGB have nothing to disclose.