FDA Places Partial Clinical Hold on Zolgensma Trial Over Safety Concerns

The U.S. Food and Drug Administration (FDA) placed a partial clinical hold on clinical trials for intrathecal administration of Zolgensma, Novartis’ multi-million dollar gene therapy treatment for spinal muscular atrophy due to safety concerns.

The Swiss giant announced the hold in a filing with the U.S. Securities and Exchange Commission this morning. Novartis said the announcement follows a communication its subsidiary AveXis, the developer of Zolgensma, made to health authorities and clinical trial investigators. The communication was made after AveXis found a small hitch in a preclinical study. The company discovered animal findings that showed dorsal root ganglia (DRG) mononuclear cell inflammation, which were sometimes accompanied by neuronal cell body degeneration or loss. What this means clinically is not yet known, Novartis said in its filing. Novartis said this had not been seen in prior animal studies with Zolgensma.

“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,” Novartis said in its filing.

Novartis said it will work diligently with the FDA to resolve the partial clinical hold and resume the study. If Zolgensma is successful in the clinical trial with older patients, it could begin to compete with Biogen’s marketed Spinraza in this indication. Success could also put the company ahead of rival Roche and its investigational risdiplam, which will likely be submitted to regulators later this year.

Zolgensma has a list price of $2.1 million for the one-and-done treatment. It has been approved for all types of spinal muscular atrophy. The FDA recently announced there was some data manipulation in the preclinical efforts of AveXis but opted to keep the gene therapy on the market. The FDA said the data manipulation was “limited to only a small portion of the product testing data that was contained in the marketing application.”

The partial hold impacts enrollment in the high dose cohort of the ongoing STRONG trial, which is seeking to boost the use of the gene therapy in older SMA patients. The STRONG trial is an open-label, dose-comparison, multi-center trial designed to evaluate the efficacy, safety and tolerability of one-time intrathecal administration Zolgensma in patients with spinal muscular atrophy Type 2. Patients with Types 2 and 3 typically live into adulthood and could potentially have a normal life expectancy, although with a great deal of healthcare services. The low and mid-dose cohorts have completed enrollment and Novartis already presented interim results, Novartis said.

Novartis was quick to note that the partial clinical hold does not impact Zolgensma that is currently marketed, nor does the hold impact any of the intravenous clinical trials being conducted by AveXis with Zolgensma.

“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,” Novartis said. “We will work diligently with FDA to identify any additional actions necessary to resume dosing in the AVXS-101 intrathecal clinical trials.