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Zolgensma Shows Safety and Durability of Efficacy in Long-Term Follow-Ups for SMA Type 1

LT-001 and LT-002 followed up patients treated with onasemnogene abeparvovec from the START, STRONG, STR1VE, and STR1VE-EU studies.

Data from a recent study suggest that onasemnogene abeparvovec (Zolgensma; Novartis) has a favorable benefit-risk profile in patients with spinal muscular atrophy (SMA) type 1, with no evidence of new or emerging safety signals in long-term studies.

Two long-term studies of onasemnogene abeparvovec, LT-001 and LT-002, found that no serious adverse events (SAEs) led to study discontinuation or death. No previously achieved motor milestones were lost during follow-up.

These findings were presented virtually at Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2021, March 15-18, by first author Jerry R. Mendell, MD, attending neurologist, Nationwide Children’s Hospital, and professor, pediatrics and neurology, The Ohio State University. 

“In the phase 1 study (START; NCT02122952), patients [with SMA type 1] who received a one-time high-dose (therapeutic dose) infusion (n = 12) of onasemnogene abeparvovec demonstrated improvements in ventilation-free survival and motor milestone achievement that were unprecedented in the untreated natural history of SMA,” Mendell and colleagues wrote.

READ MORE: Zolgensma Continues to Show Therapeutic Benefit in SMA Type 1

LT-001 (NCT03421977), an ongoing long-term follow-up study of patients that completed the START study, focuses on long-term safety, as well as assessing survival and durability of efficacy. LTT-002 (NCT04042025), an ongoing long-term follow-up study of patients participating in other phase 1 and phase 3 studies of SMA (STRONG, STR1VE, and STR1VE-EU), focuses on additional efficacy end points as well as assessing long-term safety and durability of efficacy.

Mendell and colleagues analyzed data from 13 patients in LT-001 with a mean age of 36.42 months (standard deviation [SD], 8.523) and 31 patients in LT-002 with a mean age of 33.6 months (SD, 12.92). LT-001 patients were 46% male (n = 6), and LT-002 patients were 45.2% male (n = 14). 

In LT-001, 8 patients reported SAEs, none of which led to study discontinuation or death and all of which were considered unrelated to treatment. The most common were acute respiratory failure, pneumonia, and dehydration. In LT-002, 2 patients reported SAEs and 1 AE of special interest was reported. 

As of data cutoff dates, 2 of 3 patients (66.7%) remained free of permanent ventilation in the low-dose cohort of LT-001, and all patients in the therapeutic dose cohort were alive and free of permanent ventilation. Half the patients (n = 5) in the therapeutic dose cohort did not use respiratory support and 1 required it only when ill. The mean age at data cutoff was 5.2 years (range, 4.7-6.1) and mean time since dosing was 5.0 years (range, 4.6-5.6) as of data cutoff, June 11, 2020.

Among patients in LT-002 from the STR1VE studies, none of the 16 patients required permanent ventilation while 9 reported baseline respiratory support. The intravenous (IV) cohort had a mean age of 2.3 years (range, 1.6-3.2) at data cutoff and the mean time since dosing was 2.0 years (range, 1.5-2.7). The intrathecal cohort had a mean age of 4.3 years (range, 2.8-6.1) at data cutoff and the mean time since dosing was 2.4 years (range, 1.8-2.8).

No previously achieved motor milestones were lost during long-term follow-up in LT-001, with 2 patients gaining the milestone of standing with assistance without ever receiving nusinersen. In LT-002, 11 new milestones were achieved during long-term follow-up in 4 patients in the IV cohort, the highest of which was sitting without support, achieved without nusinersen or risdiplam (Evrysdi; Genentech) support in 3 patients and with risdiplam in 1.

“Evidence from several completed and ongoing clinical studies of onasemnogeneabeparvovec for patients with SMA1, SMA2, or presymptomatic SMA with multiple copies of SMN2 continues to demonstrate its efficacy,” Mendell and colleagues wrote.

For more coverage of MDA 2021, click here.

Mendell JR, Finkell RS, Mercuri E, et al. Long-term follow-up (LTFU) of onasemnogene abeparvovec gene therapy in spinal muscular atrophy. Presented at: MDA Clinical and Scientific Conference 2021; March 15-18.