Novartis’s Zolgensma has had a bumpy journey to expanding its access to older patients with spinal muscular atrophy (SMA) with an intrathecal (spinally administered) version of the therapy, OAV-101 IT. Now the firm’s plans are back on track after the US Food and Drug Administration (FDA) lifted an almost two-year hold.

Novartis can now commence a new Phase III trial, named STEER, in SMA type 2 that will enroll “treatment naïve patients who are between two and 18 years of age, able to sit, but have never walked” now that data from its non-human primate toxicology study has quashed all safety concerns regulators had, including any potential risks of dorsal root ganglia (DRG) injury caused by spinal administration of Zolgensma.

Zolgensma in older SMA patients

The one-time gene therapy, known as the most expensive drug in the world at nearly $2.5m a dose, has already been approved for Type 1 SMA in children under two years old in the US and 40 other countries via intravenous injection. It is in this age group that the rare genetic disease that causes irreversible loss of motorneurons is most deadly.

Zolgensma represents huge hope for patients and parents of those with SMA and is one of only two treatments for the rare neuromuscular disorder. Four years ago there were no treatments for SMA, highlighting the huge unmet medical need in this patient population.

Many patients living with SMA have either type 2 or type 3 SMA, which shows up in later life and can either stop people from ever being able to walk or strip them of the ability at a later stage.

Younger SMA patients need the muscle-boosting protein that Zolgensma promotes the expression of throughout the body, while older patients require a more targeted approach, hence why Novartis is developing the intrathecal version.

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This spinally administered version of the therapy could more than double Zolgensma’s eligible patient pool.

Safety concerns and clinical hold

The pharma giant’s plan to expand access to older patients via intrathecal administration was thwarted back in October 2019 after the firm’s subsidiary AveXis highlighted concerns to regulators over an animal study pointing to “DRG mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss”. This led to the FDA putting a hold on the trials assessing OAV-101 IT.

Novartis responded that the company had seen no evidence of this in any patients that had been treated with the therapy – around 600 patients have been treated with Zolgensma through clinical trials, expanded access programs and commercially.

The firm then came under fire as the safety concerns actually emerged in March 2019 but authorities were not made aware of these until two months later.

After the data manipulation scandal that followed, Novartis admitted to delaying notifying authorities of the concerns and swiftly sacked brothers Brian and Allan Kaspar, founders of AveXis, publicly blaming them for hindering an internal investigation. The brothers denied the claims. Novartis has now renamed the AveXis unit Novartis Gene Therapies.

The FDA’s abrupt hold included the STRONG study arm assessing the intrathecal administration of the gene therapy and the REACH study assessing the intrathecal formulation for other types of SMA.

The approved use of Zolgensma and IV administration was not affected by the hold.

Forging ahead with Zolgensma IT trials

Novartis says the Phase III STEER trial will build on the Phase I/II STRONG study, which showed that treatment with OAV-101 IT led to significant increases in Hammersmith Functional Motor Scale-Expanded (HFMSE) scores and a clinically meaningful response in older patients between two and five years old with SMA Type 2.

“We are very pleased that our comprehensive nonclinical data package has addressed all issues identified related to DRG toxicity and the FDA has reached the decision that we may proceed with our OAV-101 IT clinical trial program and initiate the STEER trial,” said Novartis Gene Therapies Chief Medical Officer, Shephard Mpofu.

“We believe that all patients diagnosed with SMA should be able to benefit from the transformative impact of gene therapy and we remain confident that investigational OAV-101 IT is a viable potential treatment path for older patients who often have ongoing unmet needs, and for whom a one-time treatment could be especially compelling.”

As can be seen on the firm’s listing, Novartis has recently pushed back the expected completion data of the STRONG study from 2021 to 2024. A completion date for the STEER study has not yet been forecast.

Cell & Gene Therapy Coverage on Clinical Trials Arena supported by Cytiva.

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