RARE Daily

FDA Clears Novartis to Start Phase 3 Study of Intrathecal Zolgensma in Older Patients with SMA

August 3, 2021

Rare Daily Staff

The U.S. Food and Drug Administration has determined that clinical trials of Novartis’ experimental OAV-101 IT gene therapy for spinal muscular atrophy patients may proceed, thereby lifting the partial clinical trial hold initiated in October 2019.

OAV-101 IT is an intrathecal delivery (IT) formulation of Zolgensma, under investigation as a one-time, single-dose, treatment option for older patients with SMA.

The decision to lift the hold was based on data from Novartis’ comprehensive nonclinical toxicology study in non-human primates that addressed all issues identified, including questions of dorsal root ganglia (DRG) injury following IT administration.

Following this decision and input from the FDA and European Medicines Agency, Novartis now plans to initiate STEER, a global pivotal Phase 3 registration-enabling study to evaluate the clinical efficacy, safety, and tolerability of OAV-101 IT (intrathecal Zolgensma gene therapy) in treatment naïve patients who are between two and 18 years of age, able to sit, but have never walked. While disease progression is slower in patients with later-onset SMA, there are significant unmet needs.

“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 Shephard Mpofu, chief medical officer, Novartis Gene Therapies. “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.”

SMA is a rare, genetic neuromuscular disease caused by a lack of a functional SMN1 gene, resulting in the irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement. The severity of SMA varies across a spectrum of types that each correspond to the copy number of the SMN2 gene, which produces a small fraction (approximately 10 percent) of functional SMN protein compared with SMN1. Left untreated, patients with SMA Type 2 are unable to walk and will require a wheelchair, and more than 30 percent will die by age 25. Loss of motor neurons cannot be reversed, so SMA patients with symptoms at the time of treatment will likely require some supportive respiratory, nutritional and/or musculoskeletal care to maximize functional abilities.

The STEER study will build upon the phase 1/2 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 ≥2 years and <5 years old with SMA Type 2.

Additionally, STEER will add to the clinical data and emerging real-world evidence for the use of gene therapy to treat SMA. Novartis’ Intravenous formulation Zolgensma is approved in 41 countries. More than 1,400 patients have been treated with Zolgensma IV globally, including in the European Union, South Korea and Canada, where regulatory approval includes dosing guidance for babies and young children up to 21kg.

“We are very pleased to see that a plan has been reached from Novartis, the FDA and EMA working together to move this IT approach forward,” said Kenneth Hobby, president, Cure SMA. “This route of administration has the potential to open up access for older patients to all the benefits of gene therapy. We have seen the interest among our symptomatic patients and their families in gene therapy, and this study is an important step in understanding its potential to address unmet needs that remain in the SMA community.”

Photo: Kenneth Hobby, president, Cure SMA

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