Novartis and AveXis (a Novartis company) announced that an investigation is underway into whether a second trial death could be related to gene therapy candidate Zolgensma (onasemnogene abeparvovec-xioi), under development for Spinal Muscular Atrophy (SMA). It was previously reported that one patient died from respiratory failure after receiving treatment in the STR1VE U.S trial. The death was deemed by the trial investigator and independent Data Safety Monitoring Board to be unrelated to treatment. Last week, the companies reported the death of a second patient, a 6-month-old with Type 1 SMA, enrolled in the company’s European trial, STRIVE-EU. A company spokesperson said that the infant died of severe respiratory infection followed by neurological complications after receiving Zolgensma.
AveXis reported interim data from the phase III STR1VE trial on April 16, 2019. STR1VE is an ongoing, open-label, single-arm, single-dose, multi-center trial designed to evaluate the efficacy and safety of a one-time intravenous infusion of Zolgensma in patients with SMA Type 1 who are less than six months of age at the time of gene therapy. The study was designed to enroll the broadest possible population of SMA Type 1 patients with one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations. As of the September 2018 data cut-off date, 21 of 22 (95%) patients were alive and event-free. The median age was 9.5 months, with 6 of 7 (86%) patients who could have reached 10.5 months of age or older surviving event-free. Untreated natural history indicates that 50% of babies with SMA Type 1 will not survive or will require permanent ventilation by the time they reach 10.5 months of age. In addition, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores increased by an average of 7.0 points one month after gene transfer and 11.8 points three months after gene transfer, reflecting improvement in motor function from baseline. STR1VE is projected to complete in 2020.
The U.S. FDA accepted AveXis’ Biologics License Application (BLA) for Zolgensma in December 2018. The BLA was granted Priority Review, with a target action date in May 2019. The drug previously received Breakthrough Therapy designation by the FDA. Approval is expected to be granted in Japan and the European Union later this year.
About Spinal Muscular Atrophy (SMA)
SMA is a severe neuromuscular disease characterized by the loss of motor neurons leading to progressive muscle weakness and paralysis. SMA is caused by a genetic defect in the SMN1 gene that codes SMN, a protein necessary for survival of motor neurons. The incidence of SMA is approximately one in 10,000 live births and is the leading genetic cause of infant mortality. The most severe form of SMA is Type 1, a lethal genetic disorder characterized by rapid motor neuron loss and associated muscle deterioration, which results in mortality or the need for permanent ventilation support by 24 months of age for more than 90 percent of patients.
About Zolgensma (onasemnogene abeparvovec-xioi)
Zolgensma (onasemnogene abeparvovec-xioi; AVXS-101) is an investigational gene therapy developed as a one-time infusion for SMA Type 1. Zolgensma is designed to address the monogenic root cause of SMA and prevent further muscle degeneration by providing a copy of the human SMN gene to halt disease progression through rapid and sustained SMN protein expression. Zolgensma introduces a functional copy of the SMN gene using the adeno-associated viral vector 9 (AAV9). AAV9 is a common virus not known to cause disease in humans, and there is a low prevalence of anti-AAV antibodies in young children, lowering the probability of immunological reaction to the AAV9 vector.