Novartis' Zolgensma Expansion Hits FDA Roadblock, Benefiting Biogen and Roche

Compiled by: Keke

“—Leveraging the latest animal safety data, Novartis had originally planned to submit a marketing application for a new formulation of Zolgensma to the U.S. FDA in 2021, aiming to expand the use of its gene therapy to older patients with spinal muscular atrophy. However, this hope has now been dashed, as the animal studies were far from sufficient.”

On September 23, Novartis issued a statement announcing that it had recently received feedback from the U.S. Food and Drug Administration (FDA). The FDA indicated that it could not accept an application based on Phase 1/2 clinical trial data for the intravenous (IV) formulation of AVXS-101, and recommended conducting a pivotal Phase 3 confirmatory study of the intrathecal (IT) formulation to supplement the existing robust data and further support regulatory submission.

The previously FDA-approved intravenous (IV) formulation of Zolgensma is indicated for children under two years of age, whereas Novartis aims to expand the indication to patients under five years of age with its new intrathecal (IT) injection formulation and had hoped to complete the marketing application in 2021. However, the FDA’s latest recommendations will delay the application timeline to at least 2023.

In the fall of 2019, the intrathecal (IT) formulation of Zolgensma encountered setbacks during the FDA review process. Preclinical testing revealed safety concerns associated with spinal inflammation and neuronal cell degeneration, prompting the FDA to halt enrollment in the high-dose cohort of the Phase 1/2 clinical trial for this drug formulation.

Novartis CEO Vas Narasimhan stated in a July conference call that Novartis conducted a year-long animal (monkey) study to “ensure we have the best possible data” to support its 2021 regulatory submission. It turned out that these additional animal safety data were insufficient by FDA standards.

In its latest statement, Novartis expressed continued confidence in the overall risk profile of its gene therapy and stated that this would not affect Zolgensma, which is already on the market. The company will continue to advance regulatory applications for the drug as well as clinical studies of its intravenous (IV) formulation. Furthermore, it is understood that Novartis’s research and development efforts for spinal muscular atrophy (SMA) are not limited to gene therapy but also include branaplam (LMI070), an oral, once-weekly RNA splicing modifier currently under development.

The FDA’s feedback clarified the regulatory pathway for the intrathecal (IT) formulation of AVXS-101. Novartis stated that the trial design and other details are currently under evaluation, and a comprehensive update on Novartis’ overall clinical development plan for spinal muscular atrophy (SMA) will be provided following further discussions with regulatory authorities. Meanwhile, the company noted that the FDA’s request for additional clinical studies is unrelated to the partial clinical hold placed on certain studies of the AVXS-101 IT formulation; new studies will not be initiated in the United States until the FDA lifts the hold. However, no specific details were provided regarding the potential design or duration of the confirmatory studies.

Jefferies analyst Peter Welford’s latest analysis indicates that the delayed launch represents a clear setback for Novartis. In his projections, Zolgensma’s peak global sales are estimated at $2.8 billion, with the intrathecal (IT) formulation accounting for $1 billion of that total. Furthermore, the U.S. FDA’s feedback delaying the approval of Zolgensma’s new formulation is welcome news for its two major competitors: Biogen’s Spinraza and Roche’s newly approved Evrysdi. Both products are approved for use across age groups and SMA subtypes.

SVB Leerink analyst Mani Foroohar recently predicted that Evrysdi could capture a meaningful share of Spinraza’s market, given Spinraza’s broad label, convenient oral administration, and lower cost. As for Zolgensma, if its curative potential as a one-time gene therapy gains recognition among the target patient population, it is highly likely to attract some patients away from slower-acting treatment options.

Now, with the delayed adoption of Zolgensma in children under five years of age, Spinraza has gained greater market space and a better opportunity to focus on competition from Evrysdi, as Roche still has a long way to go in establishing Evrysdi’s position in the market. However, during an investor event last week, Teresa Graham, Global Head of Product Strategy at Roche Pharmaceuticals, stated that approximately two-thirds of Evrysdi patients had prior treatment experience with either Spinraza or Zolgensma. Evrysdi has already found its market. Analyst Welford currently projects that peak sales for Evrysdi will reach $2.4 billion.

Reference Sources:

1.Novartis Provides Update on AVXS-101 Intrathecal Clinical Development Program

2.Novartis' Zolgensma expansion hits FDA roadblock, giving Biogen and Roche a reprieve