FDA Lifts Clinical Hold on Novartis’ Zolgensma Intrathecal Formulation, Paving Way for Pivotal Phase 3 Trial in Older SMA Patients

Compiled by | Tom Li

This Tuesday, Novartis announced that the FDA has lifted the partial clinical hold on the intrathecal formulation of Zolgensma. The company stated that with this regulatory hurdle removed, Novartis plans to initiate a registrational Phase 3 trial to evaluate the therapeutic efficacy of Zolgensma in patients with spinal muscular atrophy (SMA) aged 2 to 18 years.

Zolgensma, currently administered via intravenous infusion, is the first FDA-approved AAV vector gene therapy for the treatment of spinal muscular atrophy (SMA). Designed as a one-time treatment, it is intended to address the genetic root cause of SMA by replacing the function of the missing or non-functional SMN1 gene. In the United States, the drug is currently approved only for pediatric patients under two years of age. If the new intrathecal formulation is approved, it could more than double the eligible patient population for Zolgensma, representing a "multi-billion-dollar" market, as stated by Novartis CEO Vas Narasimhan.

However, since receiving FDA approval for market launch in May 2019, the drug's progress has not been as smooth as expected. In addition to the considerable controversy sparked by its price tag of over $2.1 million, in July 2019, the FDA alleged potential falsification of the drug's preclinical data. At the time, the U.S. FDA issued a firm statement: "We will take full enforcement action and do not rule out civil or criminal penalties." However, after a seven-month investigation, the U.S. FDA ultimately did not impose substantial sanctions on Novartis for the data manipulation, nor did it revoke Zolgensma's market approval. Following its review, the FDA concluded that although Novartis had engaged in data falsification, the issue remained within an acceptable "compliance level." Meanwhile, numerous U.S. insurance companies have limited Zolgensma's coverage to infants under six months of age.

In October 2019, the drug faced another setback. In an animal study, Zolgensma triggered a mononuclear inflammatory response in the dorsal root ganglia (DRG) and resulted in neuronal degeneration or loss in the test animals. Given that the safety of human trial data could not be fully assured, the FDA required Novartis to discontinue the clinical trials of Zolgensma in the United States. Although Novartis had sought approval for an expanded indication based on existing Phase 1/2 data, the FDA rejected the proposal in September 2020, requiring the company to conduct a Phase 3 clinical trial with a controllable safety profile.

Novartis has consistently aimed to expand the indication for Zolgensma to children under five years of age and to complete the marketing authorization application by 2021. During a conference call two weeks ago, Marie-France Tschudin, Head of Novartis Pharmaceuticals, stated that Novartis is actively promoting newborn screening to identify SMA patients as early as possible prior to symptom onset. In the United States, where 80% of newborns are currently screened, this enables patients to initiate Zolgensma treatment within weeks of birth. Novartis aims to achieve an overall screening rate of 20% in the European Union by the end of 2021.

Sales of Zolgensma in the second quarter increased by 48% year-over-year, reaching $315 million. In the first half of 2021, sales of the drug reached $634 million, representing a year-over-year growth of nearly 70%. According to forecasts in Novartis's 2020 financial report, Zolgensma is expected to be covered by medical insurance reimbursement programs in 15 countries or regions by 2022. However, competition in this therapeutic area is also intensifying. In 2020, the FDA approved Roche's oral medication Evrysdi (risdiplam) for the treatment of spinal muscular atrophy (SMA) in infants aged two months and older, as well as in adults. Furthermore, Biogen's SMA-targeted therapy Spinraza, which received FDA approval in 2016, remains a major competitor to Novartis in this field.

Source: Novartis back with bid for 'multibillion-dollar' Zolgensma expansion in older SMA patients as FDA lifts clinical hold