FDA Grants RMAT Designation to AT132 for Patients with X-Linked Myotubular Myopathy

The US Food and Drug Administration (FDA) has granted a regenerative medicine advanced therapy (RMAT) designation to Audentes Therapeutics to their product AT132 for the treatment of patients with X-linked Myotubular Myopathy (XLMTM), an ultra-rare, congenital disease.

“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 XLMTM, a rare congenital disease,” said Mary S. Newman, Audentes’ senior vice president of Regulatory Affairs in a recent statement.

XLMTM is caused by mutations in the MTM1 gene which lead to dysfunction of the protein myotubularin, which is required for the development, maturation, and maintenance of skeletal muscle cells. According to Audentes, the goal of their gene therapy, AT132, is to achieve long-term expression of myotubularin via the administration of a AAV8 vector carrying a functional copy of the MTM1 gene.

RMAT designation is an important acknowledgement by the FDA that Audentes’ product candidate could have potential benefit in patients who have a high unmet medical need, like those with XLMTM, according to the biotechnology company.

This kind of designation is one of the newest of the FDA’s programs that have been developed to accelerate treatment development for serious and often deadly diseases; the designation was created specifically for cell and gene therapy products.

The RMAT designation for AT132 was based on positive interim clinical data collected from an ongoing phase 1/2 trial referred to as ASPIRO, which is assessing the use of the drug in patients with the disease. In the first dose cohort of the trial, investigators noted improvements in neuromuscular function—as assessed by the CHOP-INTEND scale—as well as greater respiratory function, as demonstrated by a decrease in ventilator dependence. They also reported an increase in respiratory muscle strength.

Furthermore, muscle biopsies conducted on the first 3 patients treated with the investigational drug at the 24-week timepoint showed “highly efficient” tissue transduction and robust myotubularin protein expression; a significant improvement in histology was also reported in these participants.

Before the ASPIRO trial, the gene therapy demonstrated positive results in mice and dog models. In mice, the therapy resulted in increased expression of myotubularin protein, improvement in muscle architecture, reversal of muscle hypotrophy, improvement in muscle strength as well as overall survival. In dogs, the therapy was found to boost muscle strength, improve respiratory function, and prolong survival.

“The designation highlights the potential of this gene therapy to improve neuromuscular and respiratory function as well as reduce ventilator dependence in patients with this rare, congenital disease characterized by extreme muscle weakness, respiratory failure, and early death,” Matthew R. Patterson, Audentes’ chief executive officer, told Rare Disease Report^®. “We look forward to working closely with the FDA to discuss the AT132 development program and to determine how we can accelerate the pathway for making AT132 available to XLMTM patients.”