SMA Gene Therapy Cleared to Proceed Following FDA Clinical Hold

Shephard Mpofu, MD

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According to a recent announcement, Novartis' intrathecal (IT) gene therapy OAV-101 (formerly AVXS-101; onasemnogene abeparvovec) had its partial clinical hold lifted by the FDA and may proceed with the phase 1 STRONG trial (NCT03381729). The decision comes after the company presented data from a comprehensive nonclinical toxicology study that addressed toxicity issues observed in preclinical studies.

The therapy is the IT version of Zolgensma, its intravenous gene therapy which received approval for the treatment of SMA in pediatric patients less than 2 years of age in March 2019. Questions about inflammatory responses and dorsal root ganglia (DRG) following IT administration of OAV-101 observed in animal studies prompted the hold of the study.

"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, MD, senior vice president and chief medical officer, Novartis Gene Therapies, in a statement.¹ "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."

The company also announced plans to initiate the phase 3 STEER trial which will evaluate efficacy, safety, and tolerability of OAV-101 IT in treatment-naïve patients with SMA type 2 who are aged 2 to 18 years and are able to sit but have never walked. The company plans for the trial to build on the results of the STRONG trial, which, before its hold, demonstrated significant increases in Hammersmith Functional Motor Scale Expanded (HFMSE) for SMA scores and clinically meaningful responses in patients aged 2 to 5 years.

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The randomized, double-blind, sham-controlled study will compare OAV-101 to sham treatment over a 52-week period. Primary end points will be the change in HFMSE score and safety, and the secondary end point will evaluate change on the Revised Upper Limb Module (RULM) scale. The trial plans to enroll more than 100 patients, all of whom will receive OAV-101 after the blinded treatment period.

"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."

Novartis previously announced plans to initiate the phase 3b global SMART (NCT04851873) study of IV Zolgensma.2 The study will evaluate the safety and efficacy of Zolgensma in children with SMA weighing between 8.5 kg and 21 kg following a 1-time IV infusion. The company hopes the study will supplement real-world evidence of the treatment’s merits.

The study plans to enroll 24 symptomatic children with SMA across Europe, North America, Australia, and Taiwan, with follow-up through 12 months. The primary end point consists of key safety assessments including the evaluation of adverse events, laboratory data, vital signs, and cardiac safety monitoring. Secondary efficacy end points will assess motor milestone achievements according to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS), Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) criteria, HFMSE scores, and the Revised Upper Limb Module (RULM).

"SMART is a study designed to expand the clinical evidence for Zolgensma in children up to 21 kg,” said Nicole Gusset, PhD, president, SMA Europe, in a statement.² “We have seen the interest in Zolgensma among physicians and families across Europe and believe this additional safety and efficacy data will help the community better understand its potential and inform treatment decisions for young children with SMA.”

REFERENCES

1. Novartis announces lift of partial clinical trial hold and plans to initiate a new, pivotal Phase 3 study of intrathecal OAV-101 in older patients with SMA. News release. Novartis. August 3, 2021. Accessed Augut 9, 2021. https://www.novartis.com/news/media-releases/novartis-announces-lift-partial-clinical-trial-hold-and-plans-initiate-new-pivotal-phase-3-study-intrathecal-oav-101-older-patients-sma
2. Novartis to initiate SMART Phase 3b global study of Zolgensma in children up to 21 kg, building on real-world experience. News release. Novartis. April 23, 2021. Accessed August 9, 2021. https://www.novartis.com/news/media-releases/novartis-initiate-smart-phase-3b-global-study-zolgensma-children-21-kg-building-real-world-experience