Eculizumab Greatly Reduces Neuromyelitis Optica Attacks

Daniel M. Keller, PhD

October 16, 2012

October 16, 2012 (Boston, Massachusetts) — Eculizumab, a humanized monoclonal antibody that inhibits cleavage of complement component C5 to active forms, significantly reduced the annual rate of attacks of neuromyelitis optica (NMO) in patients selected for aggressive disease activity.

Reporting trial results here at the American Neurological Association (ANA) 137th Annual Meeting, Sean Pittock, MB, MMedSci, MD, professor of neurology, director of the autoimmune neurology clinic, and co-director of the neuroimmunology laboratory at the Mayo Clinic in Rochester, Minnesota, said these findings support a central role for complement activation in the pathogenesis of NMO.

By inhibiting cleavage of C5, eculizumab prevents the generation of more downstream pro-inflammatory complement components C5a and C5b-9.

"It looks as if you can use a bullet drug to block complement and potentially significantly impact a very severe disease," Dr. Pittock told attendees. "We found that eculizumab significantly decreased annualized attack rate in NMO patients selected for aggressive disease activity."

Attacks recurred after stopping eculizumab, he added. "There was stability or improvement in the measures that we used, specifically the EDSS [Expanded Disability Status Scale], the Hauser Ambulation index, and the Visual Acuity [test]."

He concluded that "the drug was generally well tolerated and warrants further investigation in NMO."

Distinct Condition from MS

NMO is a central nervous system inflammatory demyelinating disease that causes severe attacks of optic neuritis and transverse myelitis but is distinct from classical multiple sclerosis. Attacks result in cumulative permanent disability, and only 25%-66% of patients remain free of relapses with current treatments.

This small open-label pilot study comprised 14 women (median age, 41.1 years) with NMO or NMO-spectrum disorder for a median of 4.25 years (range, 0.4 to 20.5 years) who had at least 2 attacks in the previous 6 months or at least 3 attacks in the previous 12 months.

Standard immunosuppressant therapy had failed for 6 of the patients. Failed therapies included rituximab, azathioprine, mycophenolate mofetil, and prednisone.

All patients were given tetravalent meningococcal vaccine. Eculizumab, 600 mg per week, was given for 4 weeks, then 900 mg at week 5, and then 900 mg every 2 weeks for 48 weeks.

Significant Reduction in Attacks

"In the year prior to screening visits...40 attacks occurred in 14 patients, [with] a median of 3 and a range of 2 to 4," Dr. Pittock reported. "Between screening and first infusion — that's a 2-week duration — 3 patients had each a single attack. During the 12 months on eculizumab, we had 2 possible attacks, and in the 12 months post-eculizumab we had 5 patients that had had 8 attacks."

During eculizumab therapy, 12 of the 14 patients were free of attacks. The median annual attack rate was 3 before treatment and 0 with eculizumab (P < .001).

Before treatment, the median EDSS score was 4.3 and declined to 3.5 with treatment (P < .01).

One case of meningococcal sepsis occurred while the patients were receiving eculizumab. Besides that case, all other adverse events were considered mild and included headache, nausea, dizziness, cough, diarrhea, abdominal pain, and rash. The 1 patient with meningococcal sepsis recovered completely and resumed eculizumab treatment.

Exciting Insights

Session moderator William Mobley, MD, PhD, professor and chair of the Department of Neurosciences at the University of California, San Diego, School of Medicine, who was not involved in the study, told Medscape Medical News that NMO and NMO-spectrum disorder have been "lumped" together with MS, "but now you've got some really interesting new insights about what the underlying mechanism might be. I just thought it was very, very exciting.

"You're now seeing evidence that you could pull that apart from maybe the bulk of MS, and you can actually treat it."

He took issue with the notion that eculizumab is a "bullet" drug. Because it targets the complement cascade, which has functions in many bodily systems, he likened it more to a shotgun.

"On the other's working, and it looks like the unintended effects are pretty small or maybe almost nonexistent. But you have to wonder what happens if you use an approach like that that impacts presumably many aspects of immune function," he said. "But on the other hand if I was one of those patients I'd be eager to have the treatment."

Dr. Mobley expressed surprise that there were not more infections during the trial because presumably a good amount of the complement system was prevented from being activated.

"We'll just have to see how it plays out, but if we really can have the results that he showed, which were impressive, and we don't have those infections or those other complications that you might imagine would come from blocking complement activation, then good for us," he concluded.

The study was supported by Alexion Pharmaceuticals. Disclosure information has been requested from Dr. Pittock. Dr. Mobley has disclosed no relevant financial relationships.

American Neurological Association (ANA) 137th Annual Meeting in partnership with the Association of British Neurologists. Abstract T1826. Presented October 9, 2012.