AT132 Gene Therapy Shows Early Phase Safety and Efficacy in X-Linked Myotubular Myopathy


Preliminary data from the ASPIRO study of Audentes Therapeutics resamirigene bilparvovec gene therapy suggests it is safe with improvements in neuromuscular and respiratory function.

Dr Perry Shieh

Perry B. Shieh, MD, PhD, department of neurology, Ronald Reagan UCLA Medical Center

Perry B. Shieh, MD, PhD

A data report from the ongoing phase 1/2 ASPIRO study (NCT03199469) of the investigational gene therapy AT132 (resamirigene bilparvovec) in the treatment of X-linked myotubular myopathy (XLMTM) suggests that the delivery of the therapy was manageably safe across a number of cohorts.

Thus far, the investigators have observed clinically meaningful improvements in neuromuscular and respiratory function, which have maintained through 72 weeks post-dose. Additionally, muscle biopsies have shown a robust and dose-dependent tissue transduction and myotubularin expression accompanying gains in histopathology through 48 weeks.

The data on were presented virtually by Perry B. Shieh, MD, PhD, department of neurology, Ronald Reagan UCLA Medical Center, due to the cancellation of the on-site portion of the 2020 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference.

The study included 4 to 72 weeks follow-up for 12 patients in 3 cohorts: Cohort 1 (n = 6; 1x1014 vg/kg), Cohort 2 (n = 4; 3x1014 vg/kg); and Cohort 3 (n = 2; untreated controls). Muscle biopsy data are available for 9 treated patients, 6 in Cohort 1 and 3 in Cohort 2.

“We’re seeing rapid CHOP-INTEND improvements in a lot of our patients, and we’re really seeing meaningful changes in motor skills—sitting, crawling, standing, walking, and even running,” Shieh explained. “A lot of them are eating normal food, they’re speaking and they’re vocalizing normally. We’ve really been seeing unprecedented reductions in ventilator dependence.”

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Shieh noted that this significant and rapid reduction in ventilator use occurred in all but 1 treated patient, which was in contrast of the 2 controls in ASPIRO as well as the pre-phase 1 INCEPTUS study (NCT02704273) contemporaneous external control subjects. In the controls, there were no gains in motor skills nor independence from ventilation observed.

As well, the adverse events (AEs) in reaction to resamirigene bilparvovec treatment—from September 2017 to August 2019, there were 82 considered related or possibly related to treatment (serious AEs: 14; non-serious AEs: 68)—have been comparable to those that have been described in other systemic gene therapy programs. Shieh said that the reactions observed were liver-related, thrombocytopenia, and occasional tropinemia, though the majority were manageable.

“There is also another concern that we have, that muscle tissues close to motor neurons potentially have turnover, so there may be a potential dilution effect of the transgene in the future,” Shieh said. “There is interest in exploring possible re-dosing strategies.”

In 2018, Audentes Therapeutics, the developer of the gene therapy, announced that the FDA granted regenerative medicine advanced therapy (RMAT) designation to AT132 for the treatment XLMTM. It was also granted rare pediatric disease, fast track, and orphan drug designations by the FDA, as well as priority medicines and orphan drug designations by the European Medicines Agency. The RMAT designation was granted based on early data from the ASPIRO study.2

ASPIRO is being conducted in 2 parts: a dose-escalation phase that is evaluating the preliminary safety and efficacy of AT132 at doses of 1x1014 vg/kg and 3x1014 vg/kg (Part 1); and a pivotal expansion cohort designed to confirm the safety and efficacy of AT132 at a dose of 3x1014 vg/kg (Part 2).

Part 2 is set to include 8 subjects in age-matched pairs, each randomized to receive a single dose or act as a delayed treatment control, the latter of which will receive AT132 after 24 weeks, when the primary efficacy end point measures will be assessed. The cohort will be followed for a total of 5 years post-administration.


1. Shieh P, Dowling J, Kuntz N, et al. ASPIRO phase 1/2 Gene Therapy Trial in X-Linked Myotubular Myopathy (XLMTM): Update on Preliminary Safety and Efficacy Findings. Presented at: 2020 MDA Clinical & Scientific Conference; March 24, 2020. Poster 31.

2. Audentes Therapeutics Reports Second Quarter 2018 Financial Results and Provides Update on ASPIRO, the Phase 1/2 Clinical Trial of AT132 in Patients with X-Linked Myotubular Myopathy [news release]. San Francisco, CA: Audentes; Published August 7, 2018. Accessed March 26, 2020.

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