Another Zolgensma red flag, another delay in data reporting at Novartis' AveXis

Turns out, there was another delayed data reporting at Novartis’ AveXis for Zolgensma, once again putting the gene therapy unit’s data management into serious question.

Wednesday, Novartis said the FDA had halted enrollment in a phase 1/2 trial testing Zolgensma’s spinal-injection delivery after preclinical data showed a safety red flag. The thing is, the signal wasn’t so new—seven months old to be exact.

The issue was in fact uncovered in March and should have been included in the investigator brochure in a planned annual update in September. However, “a mistake was made” and the information was left out, a Novartis spokesperson confirmed to FiercePharma.

Once the missing data were identified, Novartis notified investigators and the FDA “in a timely manner” at the end of last week, the spokesperson said.

According to analysts at Guggenheim Partners, the preclinical trial in question was carried out to examine the potential impact of a contrast agent used to guide injections into the spine. It involved 12 monkeys and it turned up spinal-cord inflammation and neuronal cell degeneration, the Swiss drugmaker said. The condition can be associated with sensory changes.

The FDA’s Wednesday order stopped enrollment in the Strong trial's high-dose group, but only because the low- and mid-dose cohorts are already fully recruited. So far, 32 patients have received Zolgensma via spinal injection in the study, including a small number of patients in the high-dose cohort. So far, none of those patients have symptoms of the problems found in monkeys, Novartis said.

RELATED: Zolgensma safety scare hits Novartis again as FDA halts spinal injection trial

The study is key to Novartis’ plan to expand Zolgensma into patients older than 2 years of age. Zolgensma as an intravenous infusion is currently only approved in spinal muscular atrophy patients younger than 2, and older patients represent a bigger market.

As Evercore ISI analyst Umer Raffat sees it, the high dose is the key focus for Zolgensma’s success for older patients via spinal injection. In patients between 2 to 5 years of age, clinical improvement was “more marginal” on the two lower doses, versus a “clear” improvement with the two dosing strengths in younger patients, he said in a Wednesday note to clients.

New safety findings are not uncommon during the drug development process. That’s why the FDA is asking trial sponsors—usually drug companies—to alert the agency and investigators with new important safety information and to update their investigator brochures on an ongoing basis, as mandated by federal regulations.

While new findings that represent a significant risk to study subjects require an immediate update, other changes can be made on an annual basis.

Novartis found out about the missing update during its ongoing investigation of AveXis data integrity, as it promised the FDA in the wake of the Zolgensma data manipulation scandal and the Form 483 posted by the FDA soon after.

RELATED: Novartis to put AveXis into protective custody after data manipulation scandal

As the FDA announced in August, some mouse testing data in Zolgensma's application package were falsified. Rather than immediately alert the FDA when it confirmed the data-tampering, Novartis sat on the information while it continued investigating for more details. The company finally told the FDA a month after the drug was approved.

The delay raised eyebrows as critics suggested the company deliberately withheld the intel so that Zolgensma could be approved on time.

In response to the Form 483 issued in August, Novartis said it is addressing the gaps in AveXis’ data integrity and documentation practices. It started a data integrity remediation plan, including a “comprehensive investigation into the extent of the inaccuracies in data records and reporting.”

At least this time, the company’s alert to the FDA came in the middle of a clinical trial and before any regulatory decision is made. The company said it’s working with the agency to confirm further guidance to clinical investigators.