- Novartis on Tuesday said it will begin a new study of its gene therapy Zolgensma in older patients with spinal muscular atrophy following the Food and Drug Administration's clearance of administration via a spinal infusion. The regulator had suspended testing of that dosing in October 2019 due to safety concerns.
- The Swiss pharma said toxicology data from animal studies resolved the FDA's questions, specifically around the potential for inflammation in clusters of nerve cells within vertebrae. In babies, Zolgensma is administered intravenously, but researchers are using spinal injection, or "intrathecal" infusion, in older patients.
- While Zolgensma is the only one-time treatment approved for SMA, its use has been restricted to children under 2 years old. Roche's oral drug Evrysdi is approved for children older than 2 months, while Biogen's Spinraza can be used for patients at any age.
Zolgensma is designed to be given once, with benefits meant to extend over many years or, in theory, a lifetime. But the more permissive labels of Spinraza and Evrysdi have meant a wider group of patients can receive those treatments.
The two drugs must be given chronically and Spinraza requires the invasive intrathecal delivery that Novartis is using for Zolgensma in older patients.
Delays for gene therapies have become more common as the FDA reviews an increasing number of experimental candidates entering clinical testing or advancing into later trial stages. Closely followed programs like BioMarin Pharmaceuticals' gene therapy for hemophilia and Sarepta Therapeutics' treatment for Duchenne muscular dystrophy have progressed more slowly than company executives planned because of FDA actions.
Some of the recent delays have been the result of FDA questions over manufacturing and study reproducibility, while others, like the one that set back Novartis, have centered on safety issues.
Novartis now calls the intrathecal version of Zolgensma "OAV-101," because it uses a lower dose of the adeno-associated viral vectors used to deliver corrective genes to cells than does the approved intravenously infused version. The FDA's hold had affected primarily a high-dose group in a trial named STRONG, the first to test intrathecal administration of Zolgensma.
With full STRONG results in hand, along with FDA permission to proceed, Novartis now is initiating a study called STEER that will enroll patients between the ages of 2 and 5 who have the less severe "Type 2" version of SMA. The FDA's approval of Zolgensma is currently only for the severest patients with "Type 1" SMA, which becomes symptomatic soon after birth and frequently leads to death in infancy.
Data from the STRONG trial were encouraging enough for Novartis to begin STEER, the company said. In the two lower doses of STRONG, 16 SMA patients who could sit but were unable to stand saw their scores on a functional motor scale climb 5.9 points on average. Two patients gained the ability to stand and two were able to walk independently.
With progress underway for the intrathecal dose, Novartis appears to be advancing past some of the setbacks that have weighed on its development of Zolgensma. The biggest hit was the FDA's finding that animal data used to measure the gene therapy's potency had been manipulated before submission to the agency, a scandal which resulted in the firing of two executives of the Zolgensma's original developer, AveXis, which Novartis acquired in 2018.