Natalizumab Misses Endpoint in Secondary Progressive MS

Pauline Anderson

April 26, 2016

VANCOUVER — Results of the randomized, placebo-controlled, phase 3 ASCEND trial showed that natalizumab (Tysabri, Biogen) did not delay disease progression in patients with secondary progressive multiple sclerosis (SPMS).

But while the primary endpoint was not significantly different between the groups, secondary analysis showed a significant effect of treatment on upper-extremity disability, the researchers report.

"There was a striking contrast between the lack of effect on ambulatory function" as measured by the Timed 25-Foot Walk (T25FW) test and the Expanded Disability Status Scale (EDSS), and the effect on upper-extremity function, said lead study author Deborah Steiner, MD, medical director, MS Clinical Development, Biogen, Cambridge, Massachusetts.

There was a significant benefit on that endpoint, with a 44% reduction in relative risk for progression as assessed by the 9-Hole Peg Test (9HPT) in patients treated with natalizumab, said Dr Steiner.

She reported the study results here at the American Academy of Neurology (AAN) 2016 Annual Meeting.

Blood-Brain Barrier

It's believed that natalizumab, a recombinant humanized monoclonal antibody, reduces inflammation by inhibiting the ability of inflammatory immune cells to pass through the blood-brain barrier, the authors explain. The drug is approved in the United States for the treatment of relapsing forms of MS.

Studies show that in relapsing MS, natalizumab significantly reduces intrathecal inflammatory responses, which results in fewer brain lesions and brain atrophy, as well as reduced frequency and severity of relapse and accumulation of disability. But while in SPMS, active brain-tissue injury is also associated with inflammation, the inflammatory response occurs at least partly behind the blood-brain barrier.

ASCEND was an international, multicenter trial in which adults with SPMS were randomly assigned to receive placebo or 300 mg intravenous natalizumab every 4 weeks for up to 96 weeks.

Study patients had advanced disability, particularly ambulatory disability. At baseline, 63% had a mean EDSS score of 6.0 to 6.5 (requiring a walking aid). Most patients had nonrelapsing SPMS, with 71% having been relapse-free for 2 or more years.

The primary outcome was a composite of disease progression measured with 3 tools: the EDSS and T25FW, both of which measure ambulatory disability, and the 9HPT, which measures upper-extremity disability.

For the 9-HPT, patients are instructed to pick up pegs from a container one at a time, put them into holes on a board in any order, and then remove the pegs one at a time and return them to the container. They are timed on the speed at which they can carry out this task.

The analysis included 448 patients receiving placebo and 439 taking the active drug.

The researchers found that at 2 years, the proportion of progressors on the primary endpoint was higher in the placebo group (48%) than in the treatment group (44%), but the difference was not statistically significant (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.66 - 1.13; P = .287).

Differences on the individual measurements of the T25FW and EDSS were also not statistically significant.

However, there was a significant difference in the 9HPT: 15% for the treatment vs 23% for placebo groups (OR, 0.56; 95% CI, 0.40 - 0.80; P = .001).

The "striking" contrast between the strong effect on the upper extremity and the lack of benefit for ambulatory function was "an unexpected finding," said Dr Steiner.

She noted that the 9HPT not only measures fine motor ability but also visual skills "because you need to be able to see where you're putting the peg."

The upper-extremity finding is notable, said Dr Steiner. "If you consider the fact that these are patients who are using either unilateral or bilateral assistance; and may be in wheelchairs, and the next step may be being confined to bed, being able to preserve upper-extremity function and still use one's hands is extremely important."

Natalizumab was generally well tolerated, and there were "no safety signals" observed, Dr Steiner reported. Adverse events, including urinary tract infection, headache, fatigue, and falls, were consistent with the known safety profile.

No Surprise

Invited to comment, Daniel Kantor, MD, a neurologist in private practice in Ponte Vedra Beach, Florida, president of the Medical Partnership 4 MS (MP4MS, an advocacy group for neurologists treating patients with MS), and chief medical correspondent for MSWorld, a patient support website, said the finding that natalizumab didn't improve ambulation in patients with SPMS was not unexpected.

"It didn't surprise me because, from a mechanism of action point of view, Tysabri is a very potent drug at the blood-brain barrier, and that's probably not the issue in most people with secondary progressive MS."

In SPMS, "you probably have ongoing inflammation that's occurring within the central nervous system itself," said Dr Kantor.

The primary endpoint probably failed because participants "were too far gone in terms of their walking ability," although their hand movement "might not be so bad," Dr Kantor surmised.

"What this trial shows is that the later you use the drug, the less it works, which is what we suspected before and this just confirms that," he said. "It never made scientific sense to me to go ahead with a secondary progressive MS trial."

When a study doesn't meet its primary endpoint, "you can't really interpret the rest of the results," added Dr Kantor. The positive finding for upper-extremity function "is compelling enough to design a new trial where you make the primary endpoint the 9-Hole Peg Test."

However, he said that he doubts such a trial would be approved. He is also "doubtful" that there will be further development of the drug in SPMS.

But in a way, said Dr Kantor, it might make more sense for patients with SPMS, but not relapsing MS, to be treated with natalizumab.

The drug has been linked to a rare, but potentially lethal, side effect: progressive multifocal leukoencephalopathy (PML). And since there are no biomarkers to determine which patients might do well on the medication, some patients with relapsing MS might not want to take the risk, according to Dr Kantor.

On the other hand, for those with secondary progressive MS, "you're accumulating disability, so perhaps it's worth it to take a medication with risks," he said.

The ASCEND trial was supported by Biogen. Dr Steiner is an employee of Biogen and may hold stock and/or stock options in the company. Dr Kantor has received speaking fees and research support from Biogen. He has received consulting fees from Genentech/Roche.

American Academy of Neurology (AAN) 2016 Annual Meeting. Emerging Science Session Poster 009. Presented April 19, 2016.

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