Pauline Anderson

May 04, 2017

BOSTON — The effectiveness of alemtuzumab (Lemtrada, Genzyme/Sanofi), a humanized anti-CD52 monoclonal antibody, extends to 6 years in some patients with active relapsing-remitting multiple sclerosis (MS), results of new research show.

The "exciting aspect" of the new data reflects the durability of alemtuzumab's effect, Barry Singer, MD, director, MS Center for Innovations in Care, Missouri Baptist Medical Center, St Louis, told Medscape Medical News.

"The data show that you can shut down the disease early," he said. "I call it rebooting the immune system."

However, the safety profile of alemtuzumab compared with other MS treatments is still a concern to some experts.

Here at the recent American Academy of Neurology 2017 Annual Meeting (AAN), Dr Singer and colleagues released results of two long-term extension studies — CARE-MS I in patients originally treatment-naive and CARE-MS II in patients with inadequate response to prior therapy — as well as other related research.

The intravenous (IV) alemtuzumab treatment protocol involves a course of 12 mg per day for 5 consecutive days, followed by a second course of three doses 12 months later.

The 2-year CARE-MS I core study included 376 patients receiving alemtuzumab. These patients had significantly greater improvement on clinical and MRI outcomes compared with those receiving subcutaneous interferon β-1a (SC IFNB-1a); for example, 59% of patients in the interferon group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (P < .0001).

A significantly greater proportion of patients receiving alemtuzumab achieved no evidence of disease activity (NEDA) than those receiving SC IFNB-1a.

About 95% of alemtuzumab recipients in the core study enrolled in the open-label, rater-blinded CARE-MS I extension trial (alemtuzumab as needed for relapse or on the basis of MRI activity). And 93% of these remained in the study to year 6. During this extension phase, researchers analyzed MRI lesions annually.

No Further Treatment

Of the initially treatment-naive patients, 63% received no further treatment with any disease-modifying therapy after the first two courses of alemtuzumab. Those who had two new lesions on the brain or spinal cord, either T2 or enhancing lesions, or a new relapse, had the option of re-treatment.

About 93% of the patients were free of gadolinium-enhancing T1 lesions at the end of the core study. This was reduced to 90% at year 3 and was maintained at 87% for the rest of the extension phase.

Most patients were also free of new or enlarging T2 hyperintense lesions in each year of the extension —  78% at the end of the core study, 72% at year 3, 70% at years 4 and 5, and 67% at year 6.

As well, most patients were free of MRI disease activity, defined as no new gadolinium-enhancing T1 lesions on current MRI or new/enlarging T2 hyperintense lesions since the last MRI: 77% at end of the core study, 72% at year 3, 70% at years 4 and 5, and 66% at year 6.

The results also showed that most patients were free of new T1 hypointense lesions in each year through to year 6.

CARE-MS II

Patients in the CARE-MS II study also did well in the extension phase. These patients had originally experienced at least one relapse after 6 or more months of a prior therapy.

In the CARE-MS II core study, 435 patients received alemtuzumab. About 93% of those completing this study enrolled in the extension phase, and 88% continued to year 6.

About half of the alemtuzumab recipients in this group received no further treatment after the initial two courses of the drug.

The proportion of patients with an improved (decrease of 1 point or greater) or stable (change of 0.5 point or less) on the Expanded Disability Status Scale score was 84.6% at the end of year 2, 80.4% at year 3, 76.7% at year 4, 76.4% at year 5, and 77.4% at year 6.

This extension study showed that through year 6, 72% of patients were free of 6-month confirmed disability worsening, 43% achieved 6-month confirmed disability improvement, and most patients achieved NEDA yearly.

"So you actually had a group of patients that got better, despite half of them not getting any more than those first two doses," said Dr Singer.

Alemtuzumab was approved for use in the United States in November 2014 for patients in whom two or more therapies failed.

"In clinical practice, the experience would be closer to the CARE-MS II results since the labeling is for patients who have failed prior treatments," Robert T. Naismith, MD, neurology/MS specialist, Washington University, St Louis, Missouri, told Medscape Medical News when asked to comment on alemtuzumab 6 years along.

Dr Singer noted that in several other countries, the drug is approved as a first-line therapy, and in his own experience, the drug is more effective in patients with milder disease.

"You have the ability to change the disease course for someone, so we shouldn't wait too long to use this product," he said.

Fewer Adverse Events

The overall incidence of adverse events (AEs) decreased from the end of the core study to the end of the CARE-MS II extension — from 92.6% to 76.5%. Meanwhile, the percentage of serious AEs was 9.9% at year 2 and was still 9.0% at year 6.

But the rate of infections fell from 61.8% to 43.4%. Dr Singer said he worries less about serious infections long term in patients taking alemtuzumab than other disease-modifying therapies.

And the percentage of thyroid-related adverse events including hyperthyroidism and hypothyroidism was cut in half —  from 8.8% at the end of the core study to 4.2%. The incidence of thyroid AEs appeared to peak in year 3.

Dr Naismith noted that most safety signals were seen in years 1 to 3 and that autoimmune events seemed to decline in years 4 to 6.

Patients with MS who had a relapse in the first year were more likely to require re-treatment, but their outcomes, too, were positive, commented Dr Singer. "Despite having to get an extra dose, they still did very, very well."

 
The brain volume loss went pretty much into the normal range… Dr Barry Singer
 

In other related research released at the AAN meeting, investigators reported that discontinuing SC IFNB-1a and initiating alemtuzumab also improved MRI outcomes and slowed brain volume loss over a 4-year follow-up.

"The brain volume loss went pretty much into the normal range — for the general population, not even in the MS range," commented Dr Singer.

"This is very important when I talk to individual patients."

Another study showed a very low proportion of patients treated with alemtuzumab from the CARE-MS studies (a pooled rate of 2.5%) progressed to secondary progressive MS.

As Dr Singer explained, the drug causes a rebalancing of the immune system with a "shift" in the cell population — the proportion of proinflammatory cells goes down while the proportion of T regulatory cells and natural killer cells goes up.

Still, MS is "a life-long disease," said Dr Singer. "It's almost impossible to know when it's over."

Convenience Factor

Asked to comment on this new research, John Corboy, MD, professor, Department of Neurology, University of Colorado, Aurora, said he was impressed with the "favorable" results.

It's important to do these extension trials, stressed Dr Corboy. "The team should be applauded for doing them."

An important advantage of alemtuzumab is the "convenience factor"; patients take the drug only infrequently and then may not need re-treatment, so they don't face interruptions in their daily life, said Dr Corboy.

"When patients have to take a medication multiple times a day, or multiple times a week, they're constantly reminded that they have MS."

However, said Dr Corboy, the drug's record of efficacy should be weighed against the risks for serious AEs, which are "extremely high" compared to other molecules with similar efficacy.

For example, he said, the serious AE rate over 2 years in a study of ocrelizumab, a humanized anti-CD20 monoclonal antibody recently approved to treat adults with relapsing forms of MS and primary progressive MS, was 7%. "That's dramatically lower than the serious adverse event rate in any of the alemtuzumab trials."

For his part, Dr Naismith described alemtuzumab as being "different" from other MS disease-modifying therapies and concluded that the new extension trial data verify its efficacy.

"The ongoing extension analysis confirms that the majority of patients do not require re-treatment through 6 years of treatment, with positive benefits on relapse rate reduction, disability reduction, MRI lesions, and brain volume loss," said Dr Naismith.

The research was sponsored by Sanofi and Bayer HealthCare Pharmaceuticals. Dr Singer reports speaking and/or consulting (Acorda, Bayer, Biogen, EMD Serono, Genentech, Novartis, Sanofi Genzyne, and Teva) and research (Acorda, Biogen, Medimmune, Novartis, Roche, and Sanofi Genzyme) support. Dr Corboy receives honoraria from Prime CME; is a board member of the National Multiple Sclerosis Society (Colorado/Wyoming chapter); receives research support from Med Day, Novartis, Biogen, Patient-Centered Outcomes Research Institute, and the National Multiple Sclerosis Society; and is Editor of Neurology Clinical Practice. Dr Naismith consults for Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Teva.

American Academy of Neurology 2017 Annual Meeting (AAN). CARE-MS I extension study: abstract S10.002, presented April 23, 2017. CARE-MS II extension study: abstract S24.006, presented April 24, 2017; abstracts S12.007 and S12.003, presented April 24, 2017; abstract P4.407, presented April 26, 2017.

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