March 07, 2016

LOS ANGELES — An exploratory study of the use of the multiple sclerosis drug natalizumab (Tysabri, Biogen), in acute ischemic stroke showed no effect on the primary endpoint of infarct volume growth on imaging, but there was a suggestion of some possible clinical benefit.

"We are cautious about interpretation of these findings, keeping in mind there is potential for false-positive results," Jacob Elkins, MD, senior director of clinical development at Biogen, Cambridge, Massachusetts, said. "But we are encouraged by the consistent clinical findings, and believe these results support further studies of natalizumab in acute stroke."

The company is now planning a phase 2b study to investigate whether these findings can be confirmed.

He presented the findings of the ACTION trial, a phase 2 proof-of-concept study, here at the recent International Stroke Conference (ISC) 2016.

Dr Elkins explained that a well-documented inflammatory response after stroke leads to immune cells entering the brain, and an abundance of preclinical information suggests that this is detrimental.

Natalizumab is a monoclonal antibody directed against α4-integrin, a key molecule in this inflammatory process and thus an attractive target for new stroke therapies, Dr Elkins noted.

He added that natalizumab is highly effective in inhibiting inflammatory lesions in multiple sclerosis and has shown promising results in preclinical models of stroke, including reduction in stroke volumes and improvement in outcomes.

For the current study, 159 patients within 9 hours of onset of acute ischemic stroke were randomly assigned to a single intravenous dose of natalizumab, 300 mg, or placebo. The two groups were similar in baseline characteristics, with an average National Institutes of Health Stroke Scale (NIHSS) score of 13.

The primary endpoint of relative change in infarct volume from baseline to day 5 did not differ between the groups. However, secondary clinical outcomes appeared to favor treatment with natalizumab.

Dr Elkins reported that the natalizumb group were more than twice as likely to achieve an excellent score (0 - 1) on the modified Rankin Scale (mRS) at 30 days (odds ratio, 2.88), but by 90 days this had been attenuated somewhat (odds ratio, 1.48) and was no longer significant.

The natalizumab group also showed favorable outcomes on the Barthel Index, the Stroke Impact Scale-16, and the Montreal Cognitive Assessment, which persisted after adjustment for potential confounders. There was also a suggestion of less post-stroke depression in patients receiving natalizumab.

However, there was no difference in the NIHSS score, which Dr Elkins said was disappointing because this score is closely related to infarct volume.

He suggested that the results could be reflecting "a more diffuse process of inflammation rather than one focused on the infarct site alone."

Subgroup analysis suggested no effect of time to treatment and stronger evidence of benefit in patients with smaller infarcts.

Deaths and serious adverse events did not differ between the two groups.

Outside commentators on the study were measured in their response to the findings.

Bruce Ovbiagele, MD, vice chair of ISC 2016 and chief of neurology at Medical University of South Carolina, Charleston, commented to Medscape Medical News: "You have to consider the pathophysiology, and my concern is that natalizumab did not do what they thought it was going to in this regard.

"They set out to see an effect on infarct size but didn't find one," he said. "There was also no impact on NIHSS, which is the best surrogate for infarct size."

American Heart Association/American Stroke Association spokesperson Philip Gorelick, MD, Hauenstein Neuroscience Center, Grand Rapids, Michigan, added: "The ischemic cascade is an extremely complex process and this drug just targets one aspect of this."

Both commentators were also cautious about the suggested clinical benefits. "Yes they did show an effect on some mRS outcomes at 30 days, but this was greatly attenuated at 90 days, which is really what we look at as stroke recovery evolves quite a bit," Dr Ovbiagele said.

Dr Gorelick pointed out that regulators will be looking for a more homogenous response, with multiple endpoints going in the right direction, "because what they showed could have just been the play of chance."

The study was funded by Biogen, and Dr Elkins is an employee of the company. Dr Ovbiagele and Dr Gorelick have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2016. Abstract LB22. Presented February 19, 2016.

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