FDA places partial hold on studies investigating intrathecal administration of Novartis' SMA gene therapy Zolgensma

Novartis announced Wednesday that the FDA placed a partial hold on trials investigating intrathecal administration of the gene therapy Zolgensma (onasemnogene abeparvovec), also known as AVXS-101. The company noted that the action was taken after its AveXis unit informed regulators of dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss, in preclinical animal studies.

According to Novartis, intrathecal administration of Zolgensma is currently being evaluated in patients aged up to five years with spinal muscular atrophy (SMA) Type 2 in a Phase I/II trial. Intravenous administration of the therapy gained US approval earlier this year for the treatment of paediatric patients under two years of age with SMA with bi-allelic mutations in the SMN1 gene. The drugmaker indicated that the partial hold does not impact marketed Zolgensma or ongoing intravenous clinical studies.

Novartis said that the partial hold impacts enrolment in the high dose cohort of the STRONG trial, while recruitment into the low and mid dose cohorts has previously been completed. The company noted that while DRG inflammation can be associated with sensory effects, the clinical significance of this finding in the preclinical animal study is not known and was not seen in prior animal studies. Novartis added that is has completed a review of human safety data from all available sources and no adverse effects related to sensory changes have been seen with either intrathecal or intravenous administration of Zolgensma.

The drugmaker said it remains "confident that the overall benefit-risk profile for patients on treatment is favourable," adding that it will work with the FDA to determine next steps to release the partial hold and resume dosing studies using intrathecal administration.

Commenting on the news, Vontobel analyst Stefan Schneider said "we need to better understand, what the issues are and whether there really is a read-through to the human trial." In September, AveXis disclosed that the death of a patient who received Zolgensma was deemed not to have been caused by brain inflammation, but rather from hypoxic-ischaemic brain damage with respiratory tract infection as the underlying cause.

The latest news comes as Novartis has faced criticism over how it dealt with a recent data manipulation controversy involving Zolgensma, including delays in informing the FDA about the problem. Last week, the company announced that Zolgensma generated sales of $160 million in the third quarter, coming in above analyst expectations of around $98 million.

For related analysis, see ViewPoints: Novartis' Zolgensma hits a speed bump.

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