More than three years after Novartis’ plan for a speedy approval for intrathecal Zolgensma was thwarted by an FDA requirement for a pivotal phase 3 trial, the company is back with a positive readout from that study, which could give the gene therapy a much-needed boost.
The one-time therapy, coded OAV-101 IT, helped Type 2 spinal muscular atrophy (SMA) patients aged 2 to less than 18 years achieve a significantly better motor function than a sham treatment did after one year, Novartis said Monday.
The findings mean the randomized phase 3 trial, dubbed Steer, met its primary endpoint, which is measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE) score, an industry scale that assesses the motor ability of patients with SMA. Trial participants hadn't received any prior SMA treatments and were able to sit but couldn’t walk independently when entering the study.
Zolgensma as an intravenous infusion has been approved in the U.S. for children under 2 years with SMA since 2019. The intrathecal version injects the gene therapy directly into the spinal cord, thereby allowing for a smaller dose needed to have enough therapeutic payload reaching the motor neurons, Daniel Grant, VP & global program head of some of Novartis’ gene therapy projects, explained in an interview with Fierce Pharma.
The goal is to get Zolgensma into a larger, older patient population. As the IV version is dosed based on a patient’s weight, toxicity doesn’t allow it to be given in older individuals.
Liver toxicity is a known side effect that appears as a boxed warning on Zolgensma’s U.S. label. The intrathecal route of administration could reduce liver exposure to the adeno-associated virus capsid that’s used to deliver the gene therapy, Grant said, citing biodistribution studies in monkeys.
In its Monday release, Novartis described the safety profile of OAV101 IT as “favorable,” citing "similar" overall adverse events and serious adverse events between the trial arms.
Because of Zolgensma’s age—or weight in Europe—limitation, more than 70% of patients living with SMA have never had a shot at the gene therapy, Grant observed.
“The meaningfulness of this study for me is that it allows us to take an AAV and make gene replacement an option for patients all the way across the spectrum of one specific disease,” he said. “That’s kind of a landmark from the AAV front.”
Novartis said it plans to share the Steer results with regulators, including the FDA, to seek approvals for OAV-101 IT. Grant said a submission is expected in the first half of 2025.
Novartis had originally aimed to file intrathecal Zolgensma for FDA approval in 2021 based on data from a phase 1/2 trial in patients aged 2 to less than 5 years old. But a temporary partial clinical hold caused by toxicology findings from a preclinical study and a following FDA requirement to run a phase 3 trial delayed Novartis’ regulatory plan.
By Novartis’ estimate, OAV-101 IT represents a multibillion-dollar opportunity in peak sales, CEO Vas Narasimhan said during an investor event in November.
The intrathecal version comes at a time when Zolgensma sales have become stagnant, relying mainly on new geographic expansions. In the first nine months of 2024, sales from the one-time gene therapy reached $952 million, up 3% year over year.
Besides the 125 subject-strong Steer trial in treatment-naïve patients, Novartis also anticipates an upcoming readout from another study called Strength, which includes about 30 treatment-experienced patients. The open-label study is meant to show how patients do after switching from existing chronic treatment to a one-time therapy, and therefore is not expected to prompt any major changes in motor function scores, Grant explained.
The approval of OAV-101 IT will be solely dependent on the phase 3 Steer trial, Grant said.
Outside of Zolgensma, Novartis has recently made several investments in gene therapies for neuromuscular diseases, including a $100 million-upfront deal with Voyager Therapeutics and a pending $1.1 billion acquisition of Kate Therapeutics.
Novartis is “at a place where we think our gene therapy capabilities […] we brought in-house with the various vectors from Regenxbio and other partners will allow us to solve the biology that we did solve with Zolgensma but then struggled to solve for other monogenic or polygenic neuromuscular diseases,” CEO Narasimhan said at the November event.