On 15 November, The Lancet Neurology announced a new publication of preliminary data analysis from the recent ASPIRO trial. ASPIRO is Astellas Pharmaceutical’s Gene Therapy Study for the treatment of patients with x-linked Myotubular Myopathy (XLMTM). The trial was put on hold by the FDA (US Foods & Drug Administration) in late 2021, after a fourth patient tragically died following dosing. This, along with other efficacy and safety findings during the trial, are discussed in the publication.
Please scroll to read the key statements from Astellas Pharmaceutical’s Press Release, or you may like to read the full publication, here. Also, towards the bottom of The Lancet Neurology article you will find a video presentation summary by Dr Perry Shieh one of the authors, and a Principal Investigator on the study.
Key statements from the Press Release include:-
Perry B. Shieh, M.D., Ph.D., Professor of Neurology and Pediatrics,University of California Los Angeles, and Principal Investigator for ASPIRO, who states
“There is a real need for treatments for these patients. These preliminary data document for the first time that there is potential for gene therapy to provide clinical improvements in patients with XLMTM, including improvement in ventilator dependence and achievement of major motor milestones. Additionally, important issues related to liver health in participants with XLMTM receiving gene therapy have been identified and will continue to require careful evaluation.”
Richard Wilson, Senior Vice President, Primary Focus Lead, Genetic Regulation, Astellas, states
“We are grateful for the opportunity to share this important analysis. We are focused on patients and the potential impact of gene therapy and are driven to deliver transformational benefits for people living with rare genetic diseases. While we continue our efforts to address the ongoing clinical hold for ASPIRO, this publication serves to provide information that may guide efforts aimed at advancing promising therapies for XLMTM.”
The manuscript reports data as of February 28, 2022. At the time of this data cut, the study included 24 boys with XLMTM dosed with AT132. An exploratory analysis was conducted of two dosing cohorts (lower-dose at 1.3 x 1014 vg/kg and higher-dose at 3.5 x 1014 vg/kg) who received a single infusion of AT132, compared with a control group comprised of two subjects who were enrolled but not dosed and 12 children from a natural history study.
At baseline, all participants were ventilator dependent, three were able to sit independently for 30 seconds, and none had achieved more advanced milestones. By 24 weeks post-dosing, the lower-dose cohort demonstrated an estimated 77.7% (95% CI: 40.22, 115.24) greater reduction in mean hours of ventilator support from baseline compared with controls (p=0.0002). The higher-dose cohort demonstrated an estimated 22.8% (95% CI 6.15, 39.37) greater reduction from baseline compared with controls (p=0.0077). Of the 24 boys dosed in the study, 16 participants, including six at the lower-dose and 10 at the higher-dose, achieved ventilator independence as of the data cut. Five participants at the lower-dose and three participants in the higher-dose cohort were able to walk independently; several other major motor milestones were achieved after gene therapy.
There were three deaths in the higher-dose cohort (18%), followed by one death in the lower-dose cohort (14%). All four participants had ongoing hepatic and hepatobiliary serious adverse events (SAEs), which had progressed to cholestatic liver failure at the time of death. Treatment-emergent SAEs were observed in two of the seven participants at the lower-dose, and nine of 17 at the higher-dose. Five of the 20 surviving dosed participants had hepatobiliary SAEs.
Of the 14 participants in the non-treated cohort (two in the control group and 12 from a natural history study), none achieved ventilator independence while five were able to sit unassisted for 30 seconds by the end of the 48-week period. No other motor milestones were achieved.
These data demonstrate the potential of a therapeutic approach for myotubularin replacement using recombinant AAV gene therapy.
(Source: Astellas Pharmaceutical)
