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

Background/Purpose: XLMTM, an ultra-rare, life-threatening myopathy is caused by mutations in MTM1 gene, leading to absent or dysfunctional myotubularin. We present updated results from ASPIRO (NCT03199469), investigating gene replacement therapy, AT132 for XLMTM.

Methods: Participants were genetically confirmed XLMTM patients, required ventilator support and had no clinically significant underlying liver disease (>5× ULN ALT or AST, or hepatic peliosis by imaging). As of July 2020, efficacy data were analyzed for 16 participants (n = 6, 1 × 10¹⁴ vg/kg (age 0.8–4.1 years at dosing); n = 10, 3 × 10¹⁴ vg/kg (age: 1.3–6.8 years at dosing) versus control (n = 7).

Results: 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 1 × 10¹⁴ 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 3 × 10¹⁴ 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.

Conclusion: XLMTM patients treated with AT132 demonstrated significant improvements vs control in neuromuscular and respiratory function. Assessment of safety and efficacy is ongoing.

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

Publication History

Article published online:
28 October 2021