- The Food and Drug Administration partially suspended a trial of Zolgensma in older children with spinal muscular atrophy because of an inflammatory response observed in a small animal study. The hold affects only a high-dose group in the STRONG trial, which delivers the gene therapy through a spinal injection known as "intrathecal" infusion.
- The partial hold is another blow to the Zolgensma program, which since launch has been criticized by the FDA for data manipulation in a preclinical trial. Two senior employees of AveXis, the company Novartis bought to access Zolgensma, were ousted in the wake of that scandal.
- Zolgensma may face tough competition in the less severe, older patients from Biogen's Spinraza and Roche and PTC Therapeutics' risdiplam, so any delay to the intrathecal program may give its rivals the upper hand.
The issue flagged by the FDA has been known generally for at least a year and a half, when gene therapy pioneer James Wilson published a paper identifying the risk of inflammation in certain neurons after exposure to an SMA-related gene delivered virally.
Wilson's findings, which stirred debate in the field, came from a study of non-human primates and pigs.
The dose used by Wilson was 200 trillion genome copies per kilogram delivered intravenously, similar to the high dose in the STRONG trial of intrathecal Zolgensma (onasemnogene abeparvovec), which is 240 trillion genome copies per kilogram.
Novartis reported the clinical hold was placed after AveXis communicated "findings from a small, AveXis-initiated pre-clinical study" to the FDA and clinical trial investigators. Novartis did not confirm whether the communication to the FDA was related to that Wilson-authored study, nor when it identified the safety concern.
Inflammation of the neurons in question — dorsal root ganglia sensory neurons — can lead to sensory changes, Novartis said in a press release.
"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 Zolgensma through any delivery method, the company said.
Novartis has already presented data on the lower two doses studied in STRONG, one of which is half as much as the high dose just put on partial hold. In this trial, Zolgensma was injected into patients with at least three copies of the SMN gene, between 6 months and five years of age and who were able to sit independently but not stand or walk.
The partial hold will probably delay Novartis' FDA filings to treat older, less severe patients with the intrathecal dose, RBC Capital Markets analyst Brian Abrahams wrote in a note to clients.
Biogen's rival therapy Spinraza (nusinersen) is approved to treat spinal muscular atrophy in pediatric and adult patients. Roche and PTC Therapeutics, meanwhile, are expected to submit their oral drug risdiplam to the FDA by the end of 2019, a filing that could ask permission to treat the less severe patients targeted by Novartis in the STRONG study.
Shares of PTC rose 5% in morning trading. Ionis, which licenses Spinraza to Biogen, rose 3%.