The U.S. Food and Drug Administration (FDA) has placed a partial hold on a Phase 1/2 clinical trial testing AVXS-101, given by intrathecal (IT) injection to young children with spinal muscular atrophy (SMA), citing concerns seen in an early animal study using this method of delivering the gene therapy directly into the spinal canal, Novartis announced in a press release.
AVXS-101, when given by intravenous (IV) infusion, is known as Zolgensma and approved by the FDA to treat all SMA patients up to age 2. Zolgensma’s commercial use and its use in ongoing clinical trials with IV infusion delivery is not affected by this hold, Novartis added.
Rather, the partial hold affects the enrollment of SMA type 2 and 3 patients for high-dose testing in the open-label STRONG trial (NCT03381729), the company said. The study is assigning up to 51 children, ages 6 months to 5 years, to three dosing groups — low (6.0 X 10^13 vg), medium (1.2 X 10^14 vg) and high (2.4 X 10^14 vg). Dosing in the first two groups (A and B) is complete.
A trial in older SMA patients, extending to adults and called REACH, is also on hold, a representative for AveXis said in an email response to questions. “We have paused dosing of any new patients in the STRONG study and will not dose any patients in the REACH study until the partial hold is lifted,” read the statement from AveXis, which developed Zolgensma and is now part of Novartis.
AveXis informed regulatory authorities and trial investigators of possibly troubling findings seen in “a small, AveXis-initiated pre-clinical study,” the Novartis release states.
Specifically, “animal findings showed dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss.”
What this means is that animals in a model of SMA given the gene therapy by IT injection showed inflammation — a sign of immune system reaction against something viewed as a threat — in a cluster (a ganglia) of sensory nerve cell bodies at the dorsal root of spinal nerves. These cells bodies help to transmit sensory messages of pain and touch.
The inflammation was traced to “mononuclear cells,” different types of immune blood cells like T-cells, B-cells, NK-cells, or monocytes that, when found in tissues at high levels, are synonymous with inflammation. Such an inflammatory reaction can damage nerve cells and lead to their loss.
“The clinical significance of the DRG inflammation observed in this pre-clinical animal study is not known and was not seen in prior animal studies with AVXS-101,” Novartis said in its release, adding that no reasons for safety concerns in people have been found.
“Of note, we have completed a thorough review of human safety data from all available sources to date and no adverse effects related to sensory changes have been seen in AVXS-101 intrathecal or Zolgensma,” it said.
Novartis is “working with health authorities” to address this concern and determine next steps for the STRONG study.
To date, 32 children have been treated in STRONG, Novartis and AveXis said in email exchanges, including “a small number” in the high-dose group.
In a May update for 24th World Muscle Society (WMS) International Annual Congress in Copenhagen, Novartis announced that 31 STRONG patients had been given a low, middle or high dose of AVXS-101 via IT injection. Evidence of significant motor gains in six of 12 older children (ages 2–5) were seen as early as one month after treatment.
IV infusion was used in the pivotal Phase 1 trial (NCT02122952) that enrolled type 1 infants up to 6 months old, and in its long-term extension study called START (NCT03421977) that supported Zolgensma’s approval.
This type of delivery is also being used in the SPR1NT Phase 3 trial (NCT03505099) in presymptomatic types 1–3 babies up to 6 weeks of age, and in the STR1VE (NCT03306277) Phase 3 study in type 1 infants up to 6 months old.
AveXis researchers favored IT infusion as a way of better targeting spinal motor neurons for older SMA patients, because the need for high and system-wide levels of the SMN protein drops after infancy.
“Our approach in using IV early in infants is to try to replicate the biological situation by giving high levels of SMN expression throughout the body,” Dave Lennon, president of AveXis, said in a May interview with SMA News Today. Older patients are being treated with the more targeted IT infusion to deliver SMN “where it’s needed most, which is in the motor neurons of the spine.”
SMA is caused by mutations in the SMN1 gene, which affect the amount of SMN protein available to motor neurons — specialized cells that control muscle contraction — leading to symptoms that include progressive muscle weakness. Zolgensma and AVXS-101 work by bringing a functional copy of SMN1 to motor nerve cells of treated patients, increasing the levels of this protein that’s essential to their survival.
AveXis, and Novartis by extension, have the FDA’s attention because of possible “data manipulation issues” that led to inaccuracies in its application to the regulatory agency for Zolgensma’s approval. AveXis was reported to know of manipulated data and inaccuracies in early animal tests that were included to support its approval request months before it informed the FDA of these issues, which it did after approval came in May.
Zolgensma’s quality is not in question, both the FDA and Novartis said in announcing the data manipulation finding in August.