O.06 Long term outcomes for X-Linked myotubular Myopathy (XLMTM) with gene replacement therapy, resamirigene bilparvovec: Preliminary results from ASPIRO

ASPIRO (NCT03199469) is a first-in-human clinical study of resamirigene bilparvovec (AT132), an AAV-mediated, muscle-directed gene replacement therapy in boys with ventilator-dependent XLMTM, a devastating congenital myopathy. We previously reported study outcomes through 48 weeks following dosing, including 4 participants with treatment-related, fatal, hepatobiliary toxicity. Here we report long-term outcomes among the 20 surviving dosed participants (new data cut of 01MAR2022): n=6 at 1.3 x 1014 vg/kg AT132, (dosing age, median 0.9 [range, 0.8–4.1] years; post-dose follow-up period age, 4.1 [3.9–4.4] years); n=14 at 3.5 x 1014 vg/kg AT132 (dosing age, 1.9 [0.6–6.0] years; post-dose follow-up period, 2.5 [1.9–5.6] years). All participants were ventilator dependent at baseline (mean: 22.8 hours/day). Currently, 6/6 lower- and 10/14 higher-dosed participants are ventilator independent, and 4/6 lower-, and 5/14 higher-dosed patients have been decannulated. At baseline, 1/6 lower-dose and none of higher-dose participants were able to sit independently; none had achieved more advanced milestones. At data cut, all participants have achieved major motor milestones: 5/6 lower-and 4/14 higher-dose participants achieved and maintained independent walking (achieved mean 38.8 [SD, 14.1] months); 4/6 lower-and 2/14 higher-dose participants have achieved the ability to ascend stairs. Among the surviving participants, 2/6 lower- and 7/14 higher-dose experienced treatment-related serious adverse events (SAEs); 5/20 had hepatobiliary related SAEs. Overall, significant improvements and maintenance of ventilator independence, respiratory muscle strength and skeletal muscle function were observed compared to untreated controls. These substantial long-term durable improvements must be weighed against the occurrences of fatal serious adverse events, for which the ASPIRO program is on clinical hold while relevant clinical information is being gathered and reviewed. ASPIRO (NCT03199469) is a first-in-human clinical study of resamirigene bilparvovec (AT132), an AAV-mediated, muscle-directed gene replacement therapy in boys with ventilator-dependent XLMTM, a devastating congenital myopathy. We previously reported study outcomes through 48 weeks following dosing, including 4 participants with treatment-related, fatal, hepatobiliary toxicity. Here we report long-term outcomes among the 20 surviving dosed participants (new data cut of 01MAR2022): n=6 at 1.3 x 1014 vg/kg AT132, (dosing age, median 0.9 [range, 0.8–4.1] years; post-dose follow-up period age, 4.1 [3.9–4.4] years); n=14 at 3.5 x 1014 vg/kg AT132 (dosing age, 1.9 [0.6–6.0] years; post-dose follow-up period, 2.5 [1.9–5.6] years). All participants were ventilator dependent at baseline (mean: 22.8 hours/day). Currently, 6/6 lower- and 10/14 higher-dosed participants are ventilator independent, and 4/6 lower-, and 5/14 higher-dosed patients have been decannulated. At baseline, 1/6 lower-dose and none of higher-dose participants were able to sit independently; none had achieved more advanced milestones. At data cut, all participants have achieved major motor milestones: 5/6 lower-and 4/14 higher-dose participants achieved and maintained independent walking (achieved mean 38.8 [SD, 14.1] months); 4/6 lower-and 2/14 higher-dose participants have achieved the ability to ascend stairs. Among the surviving participants, 2/6 lower- and 7/14 higher-dose experienced treatment-related serious adverse events (SAEs); 5/20 had hepatobiliary related SAEs. Overall, significant improvements and maintenance of ventilator independence, respiratory muscle strength and skeletal muscle function were observed compared to untreated controls. These substantial long-term durable improvements must be weighed against the occurrences of fatal serious adverse events, for which the ASPIRO program is on clinical hold while relevant clinical information is being gathered and reviewed.