Biogen's ALS drug has failed phase 3. Will FDA approve anyway?

Biogen is “actively engaging with regulators” to determine the next steps. (Biogen)

Stop me if you think you've heard this one before. A Biogen neurodegenerative disease prospect has failed a pivotal study, but the Big Biotech has latched onto biomarker data and “trends favoring” the treatment as it heads into talks with the FDA. Will it be enough to get the candidate to market?

The drug this time around is tofersen, an antisense prospect licensed from Ionis Pharmaceuticals, and the indication is a subset of amyotrophic lateral sclerosis (ALS). With only a tiny fraction of ALS patients having the genetic mutations targeted by tofersen, the financial stakes for Biogen are much lower than with Aduhelm, with Jefferies analysts putting peak sales at up to $300 million. However, there are echoes of that saga in the tofersen readout.

Biogen ran the 108-subject clinical trial to show whether tofersen improves the functional status of ALS patients compared to placebo. Tofersen failed that test. In 60 patients with rapid disease progression, tofersen was no better than placebo, causing the study to miss its primary endpoint with a p-value of 0.97. 

While the study missed its primary endpoint, Biogen pointed to other measures to make the case for tofersen. The clinical trial linked the antisense prospect to changes in SOD1, suggesting it stops the production of the protein as intended. Biogen also highlighted changes in plasma neurofilament light chain, a potential marker of neuronal degeneration, as evidence of efficacy.

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Beyond those two secondary endpoints, Biogen presented trends favoring tofersen in patients with rapid disease progression, including on measures of respiratory function, muscle strength and a set of patient-reported outcomes. Biogen said integrated data from an ongoing open-label extension study reinforced the signs of efficacy in the pivotal clinical trial.

Armed with the data, Biogen is “actively engaging with regulators” to determine the next steps. In the interim, Biogen is also expanding its early access program to enable patients with SOD1-ALS to get tofersen free of charge. Biogen may revise or stop early access “if a clear path forward for tofersen is not established, or if another controlled trial is required by regulators,” pointing to a belief that the failed phase 3 may be enough to get tofersen to market. Some analysts are unconvinced. 

“Although we could point towards perhaps placebo not performing as badly as we expected, the data was difficult to interpret given the small magnitude of change over 28 weeks. Tofersen did seem to exhibit a "trend" where data were cut in various ways (i.e. early vs delayed tofersen start, baseline NFL) but this likely won't be enough to support a BLA,” Jefferies analysts wrote in a note to investors.

Safety will be a focal point if Biogen does try to seek approval on the grounds that signs of efficacy are enough given the unmet medical need. Almost 5% of patients on tofersen in the pivotal and extension trials suffered neurologic events, including two cases of inflammation of the spinal cord.