Dr Olga SantiagoOlga Santiago, MD
Interim data from a phase 3 trial suggest that treatment with Zolgensma (AVXS-101; onasemnogene abeparvovec) is associated with prolonged event-free survival, quick and prompt increases in neuromuscular scale scores, and milestone achievement in spinal muscular atrophy (SMA) type 1 compared to untreated natural history.1

Presented at the 2019 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Orlando, Florida, the findings of the STR1VE trial are consistent with previous results observed in the phase 1 START trial. This new, individual case study data is the first-in-human biodistribution data from STR1VE to show the AveXis product has successfully transduced intended targets in the central nervous system (CNS) as well as provided widespread SMN protein expression in comparison with tissue from an unaffected individual.

“These STR1VE data reinforce what was seen in the pivotal phase 1 START trial, including trends toward prolonged survival and milestone achievement never seen in the natural history of the untreated disease,” Olga Santiago, MD, chief medical officer at AveXis, said in a statement. “With a patient population and baseline characteristics closely matched to the START trial, these data build upon the body of evidence supporting the use of Zolgensma for SMA type 1.”

The gene replacement therapy is designed to address the genetic root of SMA, for which there are very few treatment options available to patients. Previously, it received a breakthrough therapy designation from the FDA, and in December 2018 was granted priority review, with a regulatory decision expected by May 2019.2

STR1VE is an assessment of Zolgensma’s intravenous administration in 15 to 20 presymptomatic infants with SMA types 1, 2, and 3. The open-label, single-arm, single-dose study is evaluating the therapy with primary outcome measures of independent sitting and event-free survival.

As of September 2018, 95% of patients (21 of 22) in STR1VE were alive and event-free. The median patient age was 9.5 months, with 86% of patients (6 of 7) capable of reaching 10.5 months of age—the point at which 50% of babies with SMA type 1 will not survive or will require permanent ventilation—or older surviving event-free.

Additionally, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores went up by a mean 7.0 points at 1-month post-gene transfer and 11.8 points at 3 months. Early CHOP-INTEND increases seem to be linked with eventual milestone achievement, according to AveXis. In total, 3 patients could sit unassisted for ≥30 seconds as of September 2018, with that number jumping to 8 patients by December 2018.

In the START phase 1 study (NCT02122952), data showed that a single intravenous infusion of the therapy in 15 patients with SMA type 1 resulted in longer survival, superior achievement of milestones of motor function, and better motor function compared to historical data. In that trial, 12 patients received the full 2.0×1014 vg/kg dose, with 11 sitting unassisted for ≥5 seconds, a milestone previously unachieved in the natural history of SMA type 1.3

Additionally, 9 patients could roll over, 11 were fed orally and could speak, and 2 walked independently. Data also showed that at 20 months of age, all 15 patients were alive compared to a historical event-free survival rate of 8% to that point. CHOP-INTEND scores increased 9.8 points from 1 month of age and 15.4 points at 3 months, compared to historical rates of score declines.

AveXis is also currently assessing the treatment in an intrathecal delivery method in a phase 1 trial, STRONG (NCT03381729). This additional method would allow treatment access for those with SMA types 2, 3, and 4.
REFERENCES
1. AveXis data reinforce effectiveness of Zolgensma® in treating spinal muscular atrophy (SMA) Type 1 [press release]. Basel, Switzerland; Novartis; Published April 17, 2019. hugin.info/134323/R/2241833/884431.pdf. Accessed April 17, 2019.
2. Novartis announces FDA filing acceptance and Priority Review of AVXS-101, a one-time treatment designed to address the genetic root cause of SMA Type 1 [press release]. Basel, Switzerland; Novartis; Published December 3, 2018. novartis.com/news/media-releases/novartis-announces-fda-filing-acceptance-and-priority-review-avxs-101-one-time-treatment-designed-address-genetic-root-cause-sma-type-1. Accessed April 17, 2019.
3. Mendell JR, Al-Zaidy S, Shell R. Single-dose gene-replacement therpay for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-1722. doi: 10.1056/NEJMoa1706198