Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

Abstract

Importance: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy.

Objective: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained.

Design, setting, and participants: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020.

Exposures: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort.

Main outcomes and measures: The primary outcome measure was the incidence of serious adverse events (SAEs).

Results: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen.

Conclusions and relevance: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose.

Trial registration: ClinicalTrials.gov Identifier: NCT03421977.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mendell reported receiving personal compensation for clinical trial consulting and for serving on scientific advisory boards, as well as research support from Novartis Gene Therapies outside the submitted work. Dr Al-Zaidy reported receiving personal compensation for consulting from Novartis Gene Therapies, license/royalty payment from Milo Biotech, research funding from Novartis Gene Therapies and Catalyst, grants from AveXis Inc during the conduct of the study, and personal fees from AveXis Inc outside the submitted work. Ms Lehman reported receiving nonfinancial support from Sarepta and AveXis outside the submitted work; in addition, Ms Lehman had a patent and received licensing fees for Gene Therapy Immersion Training Program licensed to Sarepta. Dr Lowes reported receiving personal compensation for employment, consulting, scientific advisory board participation, speaking, or other activities from ATOM International; and licensing fees or royalties from Nationwide Children’s Hospital. Dr Shell reported receiving personal compensation for consulting from Novartis Gene Therapies during the conduct of the study. Dr Alfano reported receiving personal compensation for employment, consulting, scientific advisory board participation, speaking, or other activities from ATOM International; and licensing fees or royalties from Nationwide Children’s Hospital. Dr Reash reported receiving personal compensation for employment, consulting, or other activities from ATOM International and personal fees from Casimir, LLC outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Disposition of Patients in the START LTFU Study

aNo patient was treated with concomitant nusinersen during the START phase 1 trial. bTwo patients who did not enroll in the START long-term follow-up study are being followed up at the Nationwide Children’s Hospital Spinal Muscular Atrophy Clinic in Columbus, Ohio. Note that no visits were conducted in the START LTFU clinical trial from December 31, 2019, through June 11, 2020.

Figure 2.. Greatest Development Milestones Achieved During the START Long-term Follow-up Study

Milestones are shown for the 10 patients in the therapeutic-dose cohort who received dosing early and had low baseline motor function (blue quadrant), those who received dosing early and had high motor function (orange quadrant), and those who received dosing late (gray quadrant). Values in parentheses are the age at which the milestone was achieved (in months). Patients were grouped according to baseline motor function (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores