Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study
Basil Darras1, Eugenio Mercuri2, Kevin Strauss3, John Day4, Yin-Hsiu Chien5, Ricardo Masson6, Melissa Wigderson7, Iulian Alecu8, Nicolas Ballarini8, Lesa Mehl9, Jonathan Marra8, Anne Connolly10
1Boston Children’s Hospital, Harvard Medical School, 2Department of Paediatric Neurology and Nemo Clinical Centre, Catholic University, 3Clinic for Special Children, 4Stanford University School of Medicine, 5National Taiwan University Hospital, 6Fondazione IRCCS Istituto Neurologico Carlo Besta, 7Novartis Gene Therapies, Inc., 8Novartis Pharmaceuticals, 9Novartis Institutes for BioMedical Research, 10Center for Gene Therapy, Nationwide Children's Hospital
Objective:
Examine the long-term safety and durability of intravenous or intrathecal onasemnogene abeparvovec in symptomatic and presymptomatic patients with spinal muscular atrophy (SMA) who enrolled into the LT-002 study (NCT04042025).
Background:
Patients who received intravenous (STR1VE-US; STR1VE-EU; STR1VE-AP; SPR1NT) and intrathecal (STRONG) onasemnogene abeparvovec demonstrated improved survival and motor function versus natural history.
Design/Methods:
Long-term safety was assessed by medical history/record review, physical examination, laboratory evaluation, and pulmonary/cardiac assessments. Efficacy was assessed by developmental milestones and Hammersmith Functional Motor Scale Expanded (HFMSE).
Results:
As of May 23, 2022, 81 patients (intravenous, n=63 [symptomatic, n=38; presymptomatic, n=25]; intrathecal, n=18) were enrolled in LT-002, with a mean (range) follow-up of 3.4 (1.0–4.3) and 3.6 (2.6–4.3) years for the intravenous and intrathecal cohorts, respectively. There were no deaths or treatment-emergent adverse events (TEAEs) resulting in discontinuation. The most frequently reported TEAEs were gastroenteritis, nasopharyngitis, pneumonia, respiratory distress, and viral infection. All patients survived and maintained developmental milestones with a mean (range) age at cutoff of 3.7 (2.4–4.7) and 5.3 (3.4–7.4) years for the intravenous and intrathecal cohorts, respectively. Only one patient required permanent ventilation. Twenty-seven patients achieved new developmental milestones (presymptomatic-intravenous, n=6; symptomatic-intravenous, n=16; intrathecal, n=5); more than half (n=16) did so without add-on therapy. Improvements in HFMSE were clinically significant (≥3 points; presymptomatic-intravenous, 81.25%; symptomatic-intravenous, 66.6%; intrathecal, 50%). No patients treated presymptomatically required ventilatory/nutritional support; few symptomatic patients required ventilatory (intravenous-symptomatic, 32%; intrathecal, 5.6%) or feeding (intravenous-symptomatic, 20%; intrathecal, 0%) support at cutoff. Most patients fed orally (intravenous, 95%; intrathecal, 100%). The majority (57/81) never received add-on therapy. Of those receiving add-on therapy, half did not achieve a new developmental milestone after initiation of add-on therapy.
Conclusions:
Intravenous/intrathecal onasemnogene abeparvovec demonstrates consistent, substantial, and durable efficacy and no new safety signals in symptomatic and presymptomatic patients with SMA.