Biogen said today it will scrap development of Tysabri® (natalizumab) for a new indication of acute ischemic stroke (AIS) after the marketed drug failed a Phase IIb trial.

Tysabri missed its primary and secondary efficacy endpoints in the Phase IIb ACTION 2 study, Biogen said.

Biogen did not detail those results, saying that detailed findings from ACTION 2 would be presented at an unspecified “future scientific forum.”

“While we are disappointed with the ACTION 2 study results, we have furthered our knowledge of the disease and will continue to pursue innovative approaches in this area,” Michael Ehlers, M.D., Ph.D., evp, R&D at Biogen, said in a statement.

Later this year, Biogen plans to initiate a global Phase III study of BIIB093 (intravenous glibenclamide) in patients with a severe form of stroke, large hemispheric infarction (LHI).

In preclinical studies, BIIB093 was shown to block SUR1-TRPM4 (sulfonylurea receptor 1–transient receptor potential melastatin 4) channels that mediate stroke-related brain swelling. According to Biogen, clinical proof-of-concept studies demonstrated the potential of BIIB093 to reduce brain swelling, disability, and the risk of death in patients with LHI.

Biogen acquired BIIB093, formerly known as Cirara™ and glyburide, from Remedy Pharmaceuticals in May 2017, agreeing to pay $120 million upfront and undisclosed additional milestone payments and royalties.

“As pioneers in neuroscience, Biogen remains committed to developing treatments for people with acute neurological conditions, including stroke,” Ehlers added.

270 Participants, Two Dosages

Tysabri is an integrin receptor antagonist indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. The drug is also indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies and inhibitors of tumor necrosis factor-α (TNF-α).

ACTION 2 was a Phase IIb multicenter, double-blind, randomized, dose-ranging study with a 90-day follow up. The trial was intended to assess the safety and efficacy of Tysabri compared with placebo in approximately 270 individuals diagnosed with AIS, with last known normal (LKN) time ≤24 hours prior to treatment initiation.

The study evaluated a 300-mg dose and a 600-mg dose versus placebo, both either within 9 hours of LKN or between 9 and 24 hours after LKN.

ACTION 2’s primary aim was to assess the effects of Tysabri compared to placebo on clinical measures of independence and activities of daily living. The primary endpoint was a composite global measure of functional disability based on a score of 0 to 1 on a modified Rankin scale (mRS), and a score of ≥95 on the Barthel Index (BI) at day 90. The mRS measures independence with specific tasks pre- and post-stroke. BI consists of 10 items that measure activities of daily living and mobility.

Secondary outcome measures, all measured from day 5 to day 90, included: mRS score, BI score, Stroke Impact Scale-16 (SIS-16) score; Montreal Cognitive Assessment (MoCA) score, numbers of participants experiencing adverse events and serious adverse events; and NIH Stroke Scale (NIHSS) score.

In the Phase IIa ACTION study, Tysabri did not significantly decrease the primary endpoint of infarct volume at day 5, though Biogen continued clinical development after secondary and exploratory endpoints suggested the treatment improved clinical outcomes compared with placebo.

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