No Benefit for Natalizumab Within 9 Hours of Stroke

But is the difference in function vs MRI results because MRI doesn't show white matter damage and this drug lessened white matter damage?
http://www.medpagetoday.com/MeetingCoverage/ISC/56292?xid=nl_mpt_DHE_2016-02-20&eun=g424561d0r
Natalizumab (Tysabri), the biologic adhesion molecule blocker, didn't reduce infarct volume when it was given within 9 hours of stroke onset, an early trial showed.
In the phase II ACTION study, there were no differences in infarct volume on MRI whether patients had 300 mg natalizumab or placebo in that time frame, Jacob Elkins, MD, of Biogen, reported at a press briefing at the International Stroke Conference here.
Nor did it improve focal neurologic examination scores on the National Institutes of Health Stroke Scale (NIHSS) -- although it did produce some benefits on other secondary measures of function and cognition, Elkins said.
"We used MRI volume because we thought it would be a more sensitive measure of looking at the benefit than clinical outcomes, but what we ended up seeing was some evidence of benefit on clinical outcomes and not on MRI," Elkins said. "I think that our hypothesis now is that the inflammatory response, if it's happening after stroke and worsening the initial insult, we think it may play out as a more diffuse process rather than concentrated at the infarct site."
"That's what natalizumab may be blocking," he added.
But Bruce Ovbiagele, MD, of the Medical University of South Carolina in Charleston, who wasn't involved in the study, said that while it's an interesting concept, the results need careful interpretation.
"It's true that a host of secondary endpoints were positive, but infarct volume did not change," Ovbiagele told MedPage Today. "The NIHSS score, which was the next best thing, did not change, and then Rankin scores got worse. So one really has to be very careful about what one thinks about the medication."
He noted, however, that "conceptually it is compelling, and in terms of trying to add to what we have already to treat that more delayed time point, I think it's important."
Natalizumab is currently indicated for both Crohn's disease and multiple sclerosis (MS). While it's known to be a powerful and effective drug, it also carries a risk of progressive multifocal leukoencephalopathy (PML). It works by preventing leukocytes from moving across the blood-brain barrier.
Elkins said natalizumab was shown to reduce infarct volume in some experimental models of acute ischemic stroke. They conducted the ACTION trial to see if those results could be borne out in humans.
They randomized 161 patients to either placebo or to 300 mg intravenous natalizumab, and patients were grouped by whether it had been less than 6 hours since their stroke, or between 6 and 9 hours.
The primary endpoint was change in infarct volume from baseline to day 5, and key secondary endpoints included NIHSS scores, the Modified Rankin Scale (mRS), and the Barthel Index (BI). They also looked at Montreal Cognitive Assessment (MoCA) and Stroke Impact Scale-16 (SIS-16) scores. Patients who had hemorrhage or stroke isolated to the brainstem were excluded.
Overall, there was no difference in the primary endpoint of change in infarct volume at any time point: 24 hours, 5 days, or 30 days, Elkins said. Nor was there any benefit of natalizumab on NIHSS scores at 30 or 90 days.
He pointed out that there was a significant improvement for natalizumab-treated patients on mRS scores at 30 days, but it did not carry out to 90 days. And benefits on the BI, SIS-16, and MoCA scales were significant at 90 days only.
They also saw, in subgroup analyses, that outcomes were better for those with a smaller infarct size, but there were no significant benefits for treatment time window or tPA use.
Rates of serious adverse events were similar between groups, Elkins said, adding that there was less depression seen in those taking natalizumab.
The pattern of findings is "suggestive of a more diffuse process of post-ischemic inflammation rather than one focused at the infarct location," Elkins said, and Biogen is planning another phase IIb study to "confirm the initial signal seen in this trial."
Philip Gorelick, MD, MPH, of Michigan State University, who was not involved in the study, cautioned that the ischemic cascade is "extremely complex," raising the question of whether "we are fooling ourselves? Are we going high enough to make a difference with the attributable fraction of inflammation, or is there enough individual variation in inflammation or in the timing of inflammation that we're not going to be able to make a difference?"
Gorelick said the problem of inflammation may best be tackled with a combination of agents, such as natalizumab together with, say, an investigational intravenous glyburide drug that was presented at the same press briefing.