AT132 Granted RMAT Designation for X-Linked Myotubular Myopathy


The designation is backed by positive interim data from ASPIRO, which has demonstrated significant improvements in neuromuscular and respiratory function at week 24.

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The FDA has granted regenerative medicine advanced therapy (RMAT) designation to AT132 for the treatment of X-linked myotubular myopathy, announced Audentes Therapeutics, the developer of the gene therapy.

The RMAT designation is supported by positive interim clinical data from ASPIRO, an ongoing phase I/II clinical study evaluating the safety and preliminary efficacy of AT132 in 12 patients less than 5 years of age with X-linked myotubular myopathy. The study included 9 AT132-treated subjects and 3 delayed-treatment concurrent control subjects.

A 24 week assessment was recently provided for patient 3 in the study. Overall, the CHOP-INTEND score increased from 34 at baseline to 48 at week 24, representing a 41% increase. Ventilator support decreased from continuous (24 hours a day) to just during night (8 hours a day). Across all 6 patients, interim results have shown neuromuscular function improvements, with respiratory function improvements for 5 of 6 patients. Other analyses remain ongoing.

“We are pleased that the FDA has granted RMAT designation to AT132, an important regulatory milestone that highlights the transformative potential of AT132 as a therapy to treat X-linked Myotubular Myopathy, a rare, congenital disease characterized by extreme muscle weakness, respiratory failure and early death,” Mary Newman, PhD, senior vice president, regulatory affairs, Audentes, said in a statement. “This news follows our recent announcement of the priority medicines, or PRIME, designation received from the European Medicines Agency, and we look forward to collaborating closely with the FDA, EMA, our X-linked Myotubular Myopathy clinical experts and the patient community as we seek to rapidly advance the AT132 development program toward global regulatory approvals.”

The data show promising initial evidence of safety and efficacy in the first dose cohort, including significant improvements in neuromuscular function, assessed by the CHOP-INTEND scale, increased respiratory function demonstrated by reductions in ventilator dependence and gains in maximal inspiratory pressure.

At the 24-week mark, muscle biopsy results from the first 3 patients treated in the study demonstrate highly efficient tissue transduction indicated by vector copy number, robust myotubularin protein expression as assessed by western blot, and significant improvement in histology. Based on these findings, the independent Data Monitoring Committee for ASPIRO recommended continuing with dose escalation per protocol, from 1x1014 vg/kg, for Cohort 1 to 3x1014 vg/kg for Cohort 2.2 Patient screening is underway, and dosing is expected to begin in coming weeks.

Primary endpoints of the study include safety (adverse events and certain laboratory measures) and efficacy (assessments of neuromuscular and respiratory function), and secondary endpoints include the burden of disease and health-related quality-of-life, and muscle tissue histology and biomarkers.

The primary efficacy analysis is expected to be conducted at 12 months, with interim evaluations conducted at earlier times, and afterward, subjects are expected to be followed for an additional 4 years to assess long-term safety, durability of effect and developmental progression.

There have been a total of 24 adverse events reported, 6 of which were determined to be serious adverse events, and an additional 11 non-serious adverse events all determined to be non-treatment related. There have been no significant treatment-related adverse events identified to date in patients 5 to 7, referred to as the Cohort 1 expansion patients.

The data set now includes safety and efficacy results through 24 weeks for patients 1 to 4 of Cohort 1, and up to week 4 data for the Cohort 1 expansion patients (patients 5 to 7), and week 24 muscle biopsy data for patients 1 to 3. All patients show clinically meaningful improvements in neuromuscular and respiratory function. Data show that patients 1 to 3 show significant reductions in ventilator dependence, with patient 1 achieving ventilator independence by week 24.

AT132 has been granted RMAT, rare pediatric disease, fast track and orphan drug designations by the FDA, priority medicines and orphan drug designations by the European Medicines Agency.

Audentes plans to meet with the FDA map out the development plan for AT132.

The next update on the trial will be presented at the 23rd International Congress of the World Muscle Society, October 2—6.


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, Calif.: Audentes; August 7, 2018. Accessed August 21, 2018.

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