The Phase I/II ASPIRO study of Audentes Therapeutics' experimental gene replacement therapy AT132 for patients with X-linked myotubular myopathy (XLMTM) has been placed on clinical hold by the FDA. The move, which was detailed in a letter to patient groups, including the Myotubular Trust, follows the death of a second patient in the trial.
According to the letter, preliminary information suggests the immediate cause of death was sepsis, with the patient having progressive liver dysfunction characterised by hyperbilirubinaemia that occurred within the first four to six weeks following AT132 dosing, and which did not respond to standard treatment.
Similar clinical course
Audentes noted that similar to a patient death detailed last month, this second subject was one of three older patients who had received AT132 at the higher dose of 3×1014 vg/kg in whom serious adverse events (SAEs) of hepatobiliary disease have recently been observed. Investigations are ongoing, but Audentes said preliminary reports indicate the "clinical course was similar" in both cases.
The company noted that in consultation with ASPIRO's data monitoring committee, it had, prior to both of these deaths, stopped further dosing of patients currently enrolled in the study. ASPIRO was formally put on clinical hold after discussions with the FDA.
"We continue to follow and actively monitor those patients who are enrolled in the trial," Audentes stated, adding "it should be noted that among the six patients treated at 1x1014 vg/kg, including four with a previous history of hepatobiliary disease, none have developed liver SAEs, despite being years out from treatment."
Planned filings on hold
In October, the company reported data from the trial showing that the first seven treated patients with XLMTM were ventilator-independent and able to rise to a standing position or walk, while "continued significant and durable improvements in respiratory function and developmental motor milestones" were seen in all treated patients. At the time, Audentes indicated that AT132 was "generally well-tolerated with a manageable safety profile across both dose cohorts."
The study, which has an estimated enrollment of 24 patients, is assessing the primary endpoints of treatment-emergent adverse events, as well as change from baseline in hours of ventilation support over time through week 24.
The company, which was acquired by Astellas earlier this year for about $3 billion, said Monday that it is currently assessing the impact of the latest news on potential regulatory filings for AT132, which will now not go ahead in mid-2020 as previously planned.
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