• Treatment with Novartis’ experimental gene therapy Zolgensma helped to keep alive nearly all infants with a severe form of spinal muscular atrophy who enrolled in a pivotal study called STR1VE, the Swiss pharma said Tuesday.
• Interim results from the trial, which enrolled SMA patients younger than 6 months of age, found a similar benefit to Zolgensma as was shown in a Phase 1 study Novartis used last year to support an application for U.S. approval of the potentially one-time treatment.
• One patient of the 22 enrolled in the study died six months after infusion of Zolgensma, from respiratory failure that an independent safety board judged unrelated to treatment with the gene therapy. However, another patient death in a still-enrolling European version of STR1VE was recently reported, according to a Novartis statement, and preliminary findings suggest a possible link to treatment.

Novartis is weeks away from a decision by the Food and Drug Administration on approval of Zolgensma (onasemnogene abeparvovec). In the run-up to what would make for another gene therapy milestone, much of the focus has on what Novartis might charge.

Yet the Swiss pharma is also working to build out the clinical case for the treatment, which to date has been primarily supported by results from just 15 patients.

STR1VE, a study which began enrolling patients in late 2017, more than doubles that data set — albeit with shorter follow-up.

Like the earlier study of Zolgensma, called START, this (slightly) larger trial looked at infants with SMA Type 1, a severe form of the inherited neuromuscular condition. Most babies diagnosed with Type 1 die before age two, and typically are incapable of sitting without support, crawling or standing.

Zolgensma proposes to change that by delivering a functional copy of the gene which encodes for a needed protein, called SMN, that’s missing in individuals with SMA.

Results from STR1VE showed that, as of Dec. 31, eight of the 22 patients could sit without support for more than 30 seconds. One could even stand with assistance.

On a measure of motor milestones known as CHOP-INTEND, average scores increased by 7 points at one month post-Zolgensma infusion and by nearly 12 points at three months. SMA Type 1 patients experience steady declines on the 64-point scale, with scores usually dropping by 10.5 points between six and 12 months, noted Brian Kaspar, the chief scientific officer at AveXis, Zolgensma’s developer before Novartis paid $8.7 billion to acquire the biotech last year.

Those increases, which are associated with eventual achievement of motor milestones, are similar — although slightly smaller — than the 10- and 15-point increases seen at the same time points in START.

However, the reports of two deaths could invite some fresh caution.

For the case reported in STR1VE, a child treated with Zolgensma at two months was hospitalized last spring with a respiratory illness and abnormal weight gain, said Kaspar, speaking to BioPharma Dive in an interview.

After the infant was discharged, investigators evaluated the child on CHOP-INTEND, measuring a 27-point increase suggestive of substantial functional benefit from Zolgensma. The respiratory illness returned, unfortunately, leading to the infant’s death.

“We’re deeply saddened by this loss,” Kaspar said.”These children sometimes don’t recover from respiratory illnesses and other complications.”

Post-mortem tissue analysis revealed no “untoward findings” on safety. Further data showed widespread expression of SMN protein at levels comparable to those of an unaffected individual, indicating that Zolgensma accomplished what it’s supposed to do.

Less details are available on the other death, confirmed by Novartis as occurring in STR1VE-EU, a similar study of SMA Type 1 patients in Europe.

“Preliminary findings indicate this occurred in the context of a severe respiratory infection followed by neurological complications, and was deemed possibly related to treatment by the investigator,” Novartis said in a statement.

Results from an autopsy are pending and a report has been submitted to regulatory authorities.

In the START study, all 15 treated patients were alive and without need of permanent ventilation at two years.

According to Novartis, more than 150 patients to date have been dosed with Zolgensma across all clinical studies testing the therapy.

The Food and Drug Administration granted Zolgensma a Priority Review last December, setting up a decision on approval next month. If cleared, the therapy would only be the second DNA-based treatment for an inherited disorder in the U.S., after Spark Therapeutics’ Luxturna (voretigene neparvovec).

Such treatments are closely watched, both for their possibly significant benefit for patients with previously limited or no options and for their potentially outsized impact on how medicines are priced and paid for.

Novartis has said Zolgensma would be cost-effective at prices as high as $4 million to $5 million per patient, a conclusion disputed by the Institute for Clinical and Economic Review, a cost watchdog. No price has been set.

At such costs, Zolgensma’s benefit over a longer time frame is a critical question, one not yet fully answered by the clinical data generated by AveXis and Novartis to date.

Novartis plans to present further results from STR1VE, as well as other updates from Zolgensma’s clinical programs, at the upcoming annual meeting of the American Academy of Neurology.