Audentes Therapeutics Inc. (NASDAQ:BOLD) ended the week at $38.24, up $4.04 (12%), after an oral presentation of updated interim data from the first cohort of the dose-escalation Phase I/II ASPIRO trial testing AT132 in patients with X-linked myotubular myopathy (XLMTM).
The Wednesday presentation at the American Society of Gene and Cell Therapy meeting in Chicago included additional follow-up from three patients and data from additional patients since the company first reported results in January (see BioCentury Extra, Jan. 4).
AT132 is an adeno-associated viral serotype 8 (AAV8) vector delivering the myotubularin 1 (MTM1) gene.
Among five patients assessed at least four weeks after treatment, AT132 led to improvements of 4-35 points on the 64-point Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale from baseline to the most recent assessment. CHOP-INTEND compares neuromuscular functioning to the expected abilities of a healthy baby aged 3-6 months.
Those same patients saw maximal inspiratory pressure (MIP) increase by 80-170% over baseline. A delayed-treatment control patient had no change in CHOP-INTEND score and a 21% decrease in MIP from baseline.
The two patients who had been followed the longest - 24 weeks - also acquired new first-year motor milestones. One went from 12-hour ventilator support per day to no ventilator support, and the other reduced the time he required daily ventilator support from 22 to 12 hours.
There were 24 adverse events including six serious adverse events (SAEs). Five of the SAEs occurred in the same patient, of which four were considered “probably” or “possibly” related to treatment. These were hospitalization for gastrointestinal infection, elevated creatine kinase levels, elevated troponin levels and hospitalization for monitoring of atrial tachycardia. The patient’s history included an episode of tachycardia before enrolling in ASPIRO.
President and CEO Matthew Patterson told BioCentury that Audentes will apply for regenerative medicine advanced therapy (RMAT) designation and discuss with FDA whether ASPIRO is sufficient to seek accelerated approval of AT132. It has Fast Track and rare pediatric disease designations in the U.S. and Orphan Drug designation in the U.S. and EU.
All patients dosed in ASPIRO so far have received a 1x10^14 vector genomes per kg (vg/kg) dose of AT132. Next quarter, Audentes expects to complete muscle biopsy analyses of MTM1 expression levels, which it will use to decide whether to enroll more patients in ASPIRO at the same or an escalated dose.
“From the first three patients treated, we did three more at the same dose because the efficacy was better than we had anticipated, plus we wanted the biopsy data to help decide,” said Patterson.
Earlier this year, a report in Human Gene Therapy raised safety concerns about giving AAVs systemically at high doses after researchers saw transaminase elevations and one case of acute liver failure in non-human primates and degeneration of dorsal root ganglia sensory neurons in piglets (see BioCentury, Feb. 2).
Patterson said Audentes’ programs use the AAV8 vector serotype, whereas the papers described an AAV9 variant, and that Audentes did not see events of concern in preclinical studies that tested AT132 at doses of up to 8x10^14 vg/kg in non-human primates.