Novartis to Open, at FDA Request, New Trial of Zolgensma for Older Patients

Novartis will open a new clinical trial investigating Zolgensma, given via an injection directly into the spinal canal, after the U.S. Food and Drug Administration (FDA) recommended a “pivotal confirmatory study” into the gene therapy’s use in older spinal muscular atrophy (SMA) patients.

Findings from this future trial of Zolgensma as a single intrathecal (IT) injection will supplement existing data from Novartis’ Phase 1 STRONG trial in SMA type 2 children up to 5 years old, which was placed on an FDA clinical hold last year, and an animal study of IT use.

“This guidance provides clarity on the path to registration for AVXS-101 [Zolgensma] IT,” the company said in a press release issued by its subsidiary, Novartis Gene Therapies.

It also likely pushes back by years a U.S. regulatory decision on Zolgensma’s IT use in older SMA patients.

Vasant Narasimhan, Novartis’ CEO, spoke in a recent investor update of the company’s plans to file for FDA approval of intrathecal Zolgensma use in 2021. Those plans, he said, came on the heels of “very positive” discussions with agency officials.

After reviewing documents given at that meeting, however, the FDA returned with its request for an additional trial to “further support the regulatory submission” for IT administration, while acknowledging the therapy’s “potential … in this [older] patient population,” the release stated.

The trial’s design and possible testing sites “are being evaluated and a comprehensive update on the overall Novartis SMA clinical development program will be provided at a future time,” the company added, after “further discussions with health authorities.”

The STRONG trial (NCT03381729), which opened in December 2017, was testing three ascending doses of Zolgensma, given by a one-time spinal cord injection, when the study was put on hold in October 2019 due to concerns seen in an earlier animal study using IT injection.

This hold is still in effect, and a new study of Zolgensma’s IT use will not include U.S. sites until the hold is lifted, Novartis said.

Zolgensma, when given by intravenous (IV) infusion, or treatment directly into the bloodstream, was approved by the FDA in May 2019 for infants and toddlers up to age 2 with any type of SMA. Its continued commercial IV use is not affected in any way by ongoing considerations of IT administration.

In STRONG, 32 type 2 children, 6 months to 5 years old and able to sit unassisted for at least 10 seconds, were treated by intrathecal injection before the hold was announced. Most were in the low (6 x 10¹³  vector genomes or vg; given to three patients) and medium (1.2 x 10¹⁴ vg; 25 patients) dose groups, and results were promising.

The four patients treated at the trial’s high dose (2.4 x 10¹⁴ vg) are a small portion of this dose’s intended group. Once the hold was in place, the study — which aimed to recruit 51 children in total — stopped enrollment.

Reported benefits included meaningful improvements in motor function, as measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE), in STRONG’s oldest patient group, those ages 2 to 5.

A previous primate study led to the FDA hold. It was said to involve 12 monkeys, divided into three groups and given the gene therapy by IT injection. Inflammation appeared in dorsal root ganglia of monkeys in each group; such an inflammatory reaction can damage nerve cells and lead to their loss.

No unusual safety concerns, like those seen in this preclinical study, have been found in any STRONG trial patients. The FDA, in announcing the trial’s hold, also affirmed Zolgensma’s safety in its approved IV use.

IT injection directly to the cerebral spinal fluid, which bathes the brain and spinal cord, is favored for those beyond toddler age. Researchers see it as a way of better targeting in older patients the motor neurons damaged and lost to this disease.

In its investor report, Novartis also announced plans to give the FDA one-year data from a separate and more recent primate study, likely assessing the safety of IT injections in these animals. The regulatory agency, the company had noted, was willing to accept six-month data.

“We have taken the decision to go to the one-year [study] readout … just to ensure that we have a very robust data package so that when we move to a hopeful [approval] filing in [the] next year, we’ll have the best possible data to support our filing,” Narasimhan said in the update.

Further details on this primate study were not made available.

“Novartis Gene Therapies reaffirms its commitment to the SMA community and to pursuing solutions for patients with all types of SMA, including older children and adults,” the company stated in this week’s release. “All patients deserve a gene therapy designed to address the genetic root cause of their disease with a single dose.”

Other clinical studies into Zolgensma by IV infusion were never affected by the STRONG hold: STR1VE-EU (NCT03461289), a Phase 3 study in infants up to 6 months old; STRIVE-AP (NCT03837184), an equivalent study in three Asian-Pacific countries; and the SPR1NT Phase 3 study (NCT03505099) in pre-symptomatic infants up to 6 weeks old. STR1VE-EU concluded this month, and other two are due to end in mid-2021.

A separate trial (NCT04042025) — a long-term safety and efficacy monitoring study in SMA type 1, 2, or 3 children treated in any previous Zolgensma study — runs through December 2035.

To date, more than 600 children worldwide have been given the one-time gene therapy, either through clinical trials, managed access programs, or commercial use, Novartis stated.

In Europe, Zolgensma in IV administration is approved for infants and young children up to 21 kg (about 46 lbs) with most types of SMA. The disease is caused by mutations in the SMN1 gene that affect the amount and quality of the SMA protein it produces. This protein is essential for motor neuron health and survival, and the gene therapy brings a working version of SMN1 to these nerve cells.