FDA knocks back Biogen's high-dose Spinraza

A big part of Biogen's efforts to defend its spinal muscular atrophy (SMA) business has been dealt a setback by the FDA, which declined to approve a high-dose version of its flagship Spinraza product.

Spinraza (nusinersen), an antisense oligonucleotide (ASO) developed with Ionis that is delivered by intrathecal injection, is still a big earner for Biogen, but has been facing increased competition from rival SMA therapies, including Roche's orally-delivered Evrysdi (risdiplam) and Novartis' one-shot gene therapy Zolgensma (onasemnogene abeparvovec).

The new formulation of Spinraza is designed to reduce the number of lumbar puncture injections into the cerebrospinal fluid needed by patients, reducing the burden on patients and healthcare costs, and at the same time help Biogen defend its franchise while it works on newer therapies for the devastating neurodegenerative disease.

Biogen has been sent a complete response letter (CRL) for the high-dose regimen of nusinersen, requesting an update to the technical information be included in the chemistry, manufacturing, and controls (CMC) module of its application.

In a statement, Biogen stressed that there were no issues with the clinical data submitted in support of the new version, which is based on two 50 mg loading doses of nusinersen given 14 days apart, followed by a higher maintenance dose of 28 mg every four months.

At the moment, Spinraza requires four loading doses, the first three given two weeks apart and the fourth administered 30 days later, before the four-monthly maintenance phase starts.

According to a head-to-head trial called DEVOTE, which underpins the application, the high-dose of nusinersen slowed neurodegeneration faster at day 64 than the current 12 mg regimen, based on measurements of the neurofilament light chain biomarker.

If the problems are restricted to CMC queries, Biogen should be able to resubmit fairly promptly.

"While this outcome was unexpected, we remain committed to bringing the high-dose regimen to people living with SMA," said Priya Singhal, Biogen's head of development. "We are working diligently to provide the necessary information to the FDA."

The high-dose formulation is just one way that Biogen is trying to fight back against its rivals in the SMA space. Last week, it firmed up an alliance with Alcyone Therapeutics to develop a version of nusinersen that would allow long-term delivery of the drug in a single intrathecal administration by agreeing to acquire the company outright.

It is also working with Ionis on a new-generation ASO candidate for SMA, salanersen (BIIB115/ION306), which could offer dosing just once a year and is in early-stage clinical testing.

Spinraza sales were $817 million in the first half of this year, while Evrysdi has now overtaken it with a turnover of almost $1.1 billion in the period, and Zolgensma brought in $624 million.

Earlier this week, another potential SMA therapy – Scholar Rock's apitegromab – was also sent a CRL by the FDA because of manufacturing compliance issues at a facility run by a contract manufacturing organisation.