SMA is a severe neuromuscular disease caused by a mutation in the SMN1 gene, which codes for SMN, a protein necessary for motor neuron function.
It was only a few weeks ago that AveXis, a Novartis company, announced interim data from its Phase III STR1VE clinical trial of Zolgensma (onasemnogene abeparvovec-xioi) in spinal muscular atrophy (SMA) Type 1. Yesterday, they released more data, in this case, interim data from the Phase I STRONG trial, additional data from the STR1VE trial, and the first data from the Phase III SPR1NT trial.
SMA is a severe neuromuscular disease caused by a mutation in the SMN1 gene, which codes for SMN, a protein necessary for motor neuron function. The disease is noted by the loss of motor neurons, which leads to progressive muscle weakness and paralysis. It is rare, occurring in about one in 10,000 live births. Type 1 is lethal and typically results in death by the age of two years.
Zolgensma is a gene therapy in development as a one-time infusion for SMA Type 1. It uses a virus vector to deliver a copy of the human SMN gene.
In December, the U.S. Food and Drug Administration (FDA) accepted AveXis’ Biologics License Application (BLA) for Zolgensma, with a target action date in May 2019. It is also expected to be approved in Japan and the European Union later this year.
The STRONG Phase I trial evaluated the safety and tolerability of one-time intrathecal (IT) administration of the gene therapy in patients with SMA Type 2 who have three copies of the SMN2 gene who are able to sit but can’t stand or walk. They were split into two groups based on age at time of dosing—6 to 24 months of age and 24 to 60 months.
In the 6-24-month group’s primary efficacy endpoint was ability to stand without support for more than 3 seconds; for the older group, it was change in Hammersmith Functional Motor Scale-Expanded (HFMSE) score from baseline.
“With an average of just over six months of data available for these Type 2 patients following treatment with Zolgensma, we are pleased to see they are achieving motor milestones, including the ability to stand and walk,” stated Olga Santiago, AveXis’ chief medical officer. “Based on these early promising data, we plan to approach regulators to define the path to registration for intrathecal administration of Zolgensma.”
The purpose of the STR1VE trial is to evaluate the efficacy and safety of Zolgensma in SMA patents less than six months of age at the time of the therapy. It enrolled the broadest possible population of SMA Type 1 patients who had one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations.
The new data is updated as of March 8, 2019 (compared to an earlier announcement reported with a data cutoff of September 27, 2018).
Of 15 patients who could have reached 13.6 months of age or discontinued the study previous to that age, 13 survived without need for permanent ventilation. Statistically, untreated natural history indicates that only 50 and 25% of babies with SMA Type 1 will survive event-free by the time they reach 10.5 months and 13.6 months of age, respectively.
SPR1NT is a Phase III trial to evaluate the safety and efficacy of Zolgensma in pre-symptomatic patients with SMA and two or three copies of SMN2 who are younger than six weeks of age. The primary outcome measure for patients with two copies of the gene is independent sitting for more than 30 seconds by 18 months. The primary measure for babies with three copies of the gene is standing without support for at least 3 seconds by 24 months.
As or March 8, 2019, all patients were alive and event-free. In the 2-copy group, a mean 8.9-point improvement from baseline in CHOP-INTEND was seen one month after dosing and a mean score of 8.4 points in Bayley-III Gross Motor was achieved by the second month.
“SMA is rapidly progressive, and we know that intervening as early as possible in the disease course is critical to rescue motor neurons and preserve motor function,” stated Santiago. “Patients treated with Zolgensma before the onset of symptoms are achieving age-appropriate motor milestones in line with normal development. These SPR1NT data reinforce the potential Zolgensma has as a foundational treatment for patients with SMA.”
Currently, the only approved drug for SMA is Biogen’s Spinraza (nusinersen). Spinraza is priced at $750,000 for the first year and $375,000 for every year after. It is approved for all forms of SMA, types 0 through 5. Zolgensma, if approved, will only be for patients with Type 1. Zolgensma is also believed to be a one-and-done gene therapy that will not require more than a single treatment.
