Zolgensma Defying SMA Type 1 Natural History in STR1VE, Helping Treated Babies to Breathe and Sit, Early Data Show

Zolgensma (AVXS-101), an investigational gene therapy for patients with spinal muscular atrophy (SMA), improves motor function and prolongs survival in infants with SMA type 1 under six months of age, Phase 3 trial interim data show.

These findings from the ongoing, multicenter and open-label Phase 3 STR1VE trial (NCT03306277) in the U.S. were presented at the recent 2019 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Orlando, Novartis, which is now developing the therapy, announced  in a press release.

Zolgensma is thought to be a one-time gene therapy that works by delivering a functional copy of the SMN1 gene, which is defective in SMA patients, to motor neurons — nerve cells responsible for controlling voluntary muscles. The treatment aims to allow patients to produce the SMN protein in necessary amounts, thereby preventing the loss of motor neurons and subsequent muscle weakness and wasting.

It is currently awaiting regulatory approval decisions in the U.S., Europe, and Japan for infants with type 1, the disease’s most severe form, up to 9 months old.

The STR1VE trial (NCT03306277) — sponsored by AveXis, the company that first developed Zolgensma and was acquired by Novartis in 2018 — is designed to assess the safety and efficacy of a single intravenous infusion of Zolgensma in 22 type 1 babies under six months of age.

Its primary outcome is changes in measures of their ability to sit independently for 30 seconds or longer at 18 months of age, and event-free survival, defined as death or needing permanent ventilation for breathing, at 14 months of age.

Secondary outcomes include assessing these children’s ability to thrive (maintain a healthy body weight and not requiring nutritional support) and the need for ventilatory support at 18 months of age.

Exploratory outcomes include changes in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score of motor function, and the Bayley Scales of Infant and Toddler Development score, which compares a child’s development to a standardized norm.

Positive outcomes in these measure would contrast strongly with SMA type’s 1 natural history, or how it progresses without treatment in  a child. That natural history would have lead either to death or permanent ventilation in 50% of type 1 infants by the time they were 10.5 months old, Novartis noted.

As of Sept. 27, 2018, 21 out of the 22 (95%) infants enrolled and treated in the trial were alive and event-free. Their median age was 9.5 months when data were assessed.

If untreated, only 50 and 25% of babies with SMA type 1 will survive event-free by the time they reach 10.5 months of age and 13.6 months of age, respectively.

As of March 8, 2019, of the 20 patients who could have reached 10.5 months of age 95% (19 patients) survived without permanent ventilation. Of the 15 patients who could have reached 13.6 months of age 87% (13 patients) survived without permanent ventilation.

Results showed the CHOP-INTEND scores increased by an average of 7.0 points one month after the infusion, 11.8 points three months after treatment, and by 14.3 points five months after gene transfer, reflecting a significant improvement in infants’ motor function from the beginning of the study.

In addition, preliminary assessments found that treated infants showed significant improvements in motor milestones. As of March 8 2019, half the children treated with Zolgensma were able to sit without support for more than 30 seconds, an event that occurred at a mean age of 11.9 months and at a mean 8.2 months after treatment.

Other motor improvements were also seen: a rise in the percentage of infants able to hold their head erect for more than three seconds, able to stand without assistance, or able to turn right or left while on their back. One patient could crawl and one could pull to a stand.

Adverse events associated with treatment included low platelet count and high levels of liver transaminases (enzymes that when elevated may indicate liver inflammation or damage). However, they were temporary and did not cause permanent injury.

One child died from respiratory failure, which was deemed by the study’s lead investigator and an independent monitor to be unrelated to treatment. This patient had shown significant motor improvement prior to the event, with a 27-point increase in CHOP-INTEND at five months after treatment.

The early improvements motor function and skills improvements reported in STR1VE were in agreement with previous data from the pivotal Phase 1 START trial (NCT02122952), showing that treatment with Zolgensma also led to significant gains in survival and motor function, without significant side effects.

“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 for AveXis, said in the release. “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.”

More than 150 patients have been treated with Zolgensma so far, and only 5% had to stop treatment due to the production of antibodies against the adeno-associated viral vector 9 (AAV9), the viral vector used in Zolgensma to deliver the functional SMN1 gene to motor neurons, Novartis said.

STR1VE is due to conclude next year.