Zolgensma Intrathecal Trial on Partial Hold Amid Safety Concerns


The drug, which is currently approved for single-dose intravenous administration in patients with SMA type 1, is currently being investigated as intrathecal therapy in SMA type 2.

US Food and Drug Administration

Novartis’ tussle with the FDA appears to be far from over. After receiving a scathing letter from the agency back in August regarding data manipulation in preclinical assessments of Zolgensma (AVXS-101; AveXis), the FDA has now placed a partial hold on an ongoing clinical trial assessing intrathecal administration of the drug in patients with spinal muscular atrophy (SMA).

The announcement comes after AveXis disclosed findings from a small, preclinical study that showed dorsal root ganglia mononuclear cell inflammation, which was sometimes accompanied by neuronal cell degeneration or loss.

Notably, this partial hold by the agency does not affect the intravenous form of Zolgensma, an adeno-associated viral vector-based gene therapy, that is currently on the market or ongoing intravenous clinical trials.

“The clinical significance of the DRG inflammation observed in this preclinical animal study is not known and was not seen in prior animal studies with AVXS-101. DRG inflammation can be associated with sensory effects,” Novartis, parent company of AveXis, said in a statement. “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. We are working with health authorities to confirm further guidance to clinical investigators.”

The affected study is the ongoing, open-label, phase 1 STRONG trial assessing one-time administration of intrathecal AVXS-101 in patients with SMA type 2. The study is evaluating 3 doses, of which only the highest dose is affected by the FDA hold. Notably, the study, which is exploring safety and dosing endpoints, as well as 2 functional endpoints, includes patients aged 6 months to 5 years. The FDA approved form of intravenous Zolgensma is restricted to patients less than 2 years old.

“We will continue to closely monitor for any reports of related safety events in patients. We remain confident that the overall benefit-risk profile for patients on treatment is favorable and we continue to advance our AVXS-101 intravenous clinical studies,” the company said. “We will work diligently with FDA to identify any additional actions necessary to resume dosing in the AVXS-101 intrathecal clinical trials.”

Zolgensma has repeatedly made headlines since its approval in May, with a single dose priced at $2.125 million. The drug’s approval was based on data from the phase 3 STR1VE trial as well as the phase 1 START trial, which included patients with SMA type 1 who showed symptoms at <6 months. Patients enrolled in STR1VE have shown prolonged event-free survival, motor function increase, and ongoing milestone achievement as observed in START, including those never before seen in the natural history of the disease, including sitting, talking, and walking in some patients.


Novartis announces AVXS-101 intrathecal study update [press release]. Basel, Switzerland: Novartis. October 30, 2019. novartis.com/news/media-releases/novartis-announces-avxs-101-intrathecal-study-update. Accessed October 30, 2019.

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