FDA Rejects Two Spinal Muscular Atrophy Therapies Citing Manufacturing Concerns

In a surprising turn of events, the U.S. Food and Drug Administration (FDA) has denied approval for two separate spinal muscular atrophy (SMA) therapies within the same week, both due to manufacturing-related issues. These regulatory actions have sent ripples through the pharmaceutical industry, highlighting the critical importance of manufacturing processes in drug development and approval.

Biogen's High-Dose Spinraza Faces Setback

Biogen, a leading player in the SMA treatment landscape, received an unexpected rejection from the FDA for its higher-dose formulation of Spinraza (nusinersen). The company's application sought approval for a new dosing regimen involving two 50-mg intrathecal injections for initiation, followed by 28-mg maintenance doses. This is a significant increase from the currently approved 12-mg dose with four loading doses.

The FDA's decision was not based on concerns about the drug's efficacy or safety profile. Instead, the regulator has requested updated technical information in the chemistry manufacturing and controls (CMC) portion of the application. Biogen has stated its intention to address these requests promptly and resubmit the application.

Despite the setback, industry analysts remain optimistic about the drug's prospects. BMO Capital Markets characterized the rejection as a "quickly resolvable setback" and maintained that there are "no true concerns to high-dose nusinersen's ultimate approval."

The higher-dose formulation of Spinraza has shown promise in clinical trials. The Phase II/III DEVOTE study demonstrated significantly higher improvements in motor skills compared to a sham control, and outperformed the standard-dose formulation, although the latter effect did not reach statistical significance.

Scholar Rock's Apitegromab Faces Similar Fate

In a parallel development, Scholar Rock received a complete response letter from the FDA for its myostatin inhibitor, apitegromab, also intended for SMA treatment. The rejection stemmed from manufacturing issues at a third-party fill-finish site managed by Novo Nordisk.

A report made public last month detailed concerning observations at the facility, including persistent bacterial contamination and pest infestations. These findings underscore the stringent quality control measures required in pharmaceutical manufacturing and the potential consequences of failing to meet these standards.

Implications for the SMA Treatment Landscape

These dual rejections represent a significant moment in the development of SMA therapies. Spinraza, first approved in 2016, works by promoting the production of the SMN protein, which is typically deficient in SMA patients. The proposed higher-dose formulation aimed to build on this established mechanism of action, potentially offering improved efficacy.

While these setbacks may temporarily slow the progress of new SMA treatments reaching patients, they also reinforce the FDA's commitment to ensuring the quality and safety of manufactured drugs. As both Biogen and Scholar Rock work to address the identified issues, the SMA community awaits the potential availability of these promising new treatment options.