Pauline Anderson

June 02, 2015

INDIANAPOLIS, Indiana — Longer-term data indicate that the effects of alemtuzumab (Lemtrada, Genzyme), a novel monoclonal antibody, are long-lasting in patients with relapsing-remitting multiple sclerosis (RRMS).

An extension study showed that patients treated with this drug remained free of new MRI disease activity for up to 4 years, even though most of them had not had a treatment for 3 years.

As well, the rate of brain atrophy remained low in these patients at the end of 4 years.

The results were released at a platform session during the Consortium of Multiple Sclerosis Centers (CMSC) 2015 Annual Meeting. Results of other alemtuzumab-related research were discussed during a poster session.

Active Disease

The drug, which targets the CD52 antigen found in abundance on B cells and T cells, received US Food and Drug Administration approval in November 2014 to treat patients with MS in whom two other therapies had failed. The drug depletes these B and T cells, which are thought to cause the damaging inflammatory process in MS, before these cells "come back and repopulate," said MS expert Ann Bass, MD, Neurology Center of San Antonio, Texas.

It's believed that this distinctive pattern of B and T cell repopulation may rebalance the immune system.

But the drug carries risks for significant adverse effects, which can include infusion-associated reactions such as itchiness, gastrointestinal adverse effects, kidney disease, infections, and thyroid disorders, that require "heavy" laboratory monitoring, said Dr Bass.

For this reason, alemtuzumab is typically used only in patients with highly active disease. "Candidates for this treatment include those who have already had a relapse on their current therapy, those who have MRI activity that's breaking through on the current therapy, and those who have disability progression that's worsening even on current therapy," said Dr Bass.

The 2-year multicenter, rater-blinded study, CARE-MS II, one of two pivotal trials for alemtuzumab, showed that compared with patients with RRMS taking subcutaneous interferon β-1a, 44 μg, those who had received a baseline alemtuzumab treatment (12 mg) and another treatment at 12 months had a 49% decreased annualized relapse rate and a 42% decrease in 6-month sustained accumulation of disability.

The drug seems to have "this nice control of the disease in the absence of ongoing treatment, which is quite novel," commented Anthony Traboulsee, MD, University of British Columbia, Canada, who addressed the platform session.

"One of the important questions is how long will this last before there is some breakthrough disease activity." That, he said, was the point of the open-label extension study.

At the end of the original 2-year trial, patients who were receiving interferon could opt to be begin taking alemtuzumab, and those who were already taking alemtuzumab could receive additional treatments — a third and fourth cycle — as needed.

For this analysis, MRI outcomes included gadolinium (Gd)-enhancing, new or enlarging T2 hyperintense and new T1 hypointense lesion activity; freedom from MRI activity (absence of Gd-enhancing and new or enlarging T2 lesions); and brain volume loss measured by change in brain parenchymal fraction (BPF).

Of the original study cohort, 393 (92.9%) alemtuzumab-treated patients entered the extension phase. At 4 years, 67.7% of these patients had received only the initial two courses of treatment, 24.2% had needed one additional course, and 7.4% had received two additional courses.

The proportions of patients free of Gd-enhancing lesions were 86.5% and 89.1% at years 3 and 4, respectively. The numbers of new or enlarging T2 (69.0% and 70.3%) or new T1 lesions (87.5% and 86.3%) remained stable.

Most patients were free of MRI activity at year 3 (68.4%) and year 4 (69.9%).

"What makes it novel is the fact that you can go for years and years after your treatment without having new MRI activity," commented Dr Traboulsee.

Brain Volume Loss

Alemtuzumab had slowed the reduction of BPF by 24% compared with interferon β-1a at the end of the initial CARE-MS II study. The extension study showed that the median rate of BPF loss was relatively low at years 3 and 4 (–0.10% and –0.19%, respectively).

Dr Traboulsee called this low rate "quite phenomenal."

"That's a really nice outcome in terms of seeing stabilization of brain volume change, and that's sustained, again, 36 months after their last treatment."

The durable effects of the drug may be due to the distinct pattern of lymphocyte depletion and repopulation following treatment, said Dr Traboulsee.

These 4-year results were previously presented at the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS), reported by Medscape Medical News at that time and at the 67th American Academy of Neurology Annual Meeting in April this year.

In an interview with Medscape Medical News during the AAN meeting, Alasdair J. Coles, PhD, University of Cambridge, United Kingdom (UK), who has been involved in the development of alemtuzumab for MS from the beginning, discussed data from both CARE-MS I, in treatment-naive patients with MS, and CARE-MS II in patients who had breakthrough disease activity while receiving another treatment.

"At 4 years, in both of these trials, 70% of patients are either stable or having improved disability compared to 4 years ago," Dr Coles said, "and 70% of patients have had no new MRI lesions over that time."

"This is the first drug to be used in MS that has consistently shown that patients improve, on average," he added. "So with this drug, we're moving the paradigm. A few years ago, the goal used to be reducing relapses, and then in the last 2 or 3 years, people have been talking about 'no evidence of disease activity' or NEDA. What we would say is we want a further goal, which is to improve disability."

Asked about what the mechanism for actual improvement may be, Dr Coles pointed out that in a separate study presented at the AAN meeting, also sponsored by Genzyme, Dr Traboulsee's group reported that MRI scans show that after alemtuzumab, there is some evidence of remyelination (S29.009).

"So I think, almost certainly, the mechanism for this is that we all have a capacity to repair — so that capacity is there. In people with MS, there's so much damage being done all the time that whatever their capacity is for repair is overwhelmed by tissue damage," he said. "But if you can stop tissue damage early on in the disease, then the capacity for repair results in a useful improvement in disability."

Peter Riskind, MD, PhD, University of Massachusetts Medical Center, MS Clinic, Worcester, asked whether any factors pointed to which patients would need additional alemtuzumab treatments. "There was no clear predictor as to who needed a third or fourth cycle," Dr Traboulsee reported.

Asked later by Medscape Medical News where alemtuzumab might fit into the RRMS drug landscape, Alan Thompson, MD, professor, University College London, UK, said it is "very effective" in patients with active MS, although it has a "challenging" adverse effect profile.

"It's the old adage that as the drugs become more effective, the side effect profile becomes more challenging," said Dr Thompson.

For people who won't consider natalizumab (Tysabri, Biogen Idec) because of the risk, albeit slim, for progressive multifocal leukoencephalopathy, alemtuzumab might be an appropriate alternative, he said.

Dr Thompson noted that it's sometimes the doctors who are more averse to taking such risks than patients. "There's a lot of discussion around who's tasking the risk here; is it the doctor or the patient?"

For that reason, he said, it's important "to have a conversation between the two and the decision should be a joint one."

Dr Coles added that since its approval, alemtuzumab has become an option for women with MS who hope to start a family in the near future but are anxious about having to withdraw from therapy, what he called, "a very real, every-day situation."

"Alemtuzumab can be given now, and in 12 months' time, and then 4 months after that, women can start and try to conceive safely, knowing that those two cycles of alemtuzumab will protect them from disease activity for 2 or 3 years or more," he said.

Robert Lisak, MD, Wayne State University Comprehensive Clinical & Research Center, Detroit, Michigan, and president of the CMSC, said that although alemtuzumab is "clearly an effective agent in relapsing forms of MS and an important part of the treatment armamentarium," he does not view it as a first-line therapy.

He stressed that neurologists who use this agent in any setting "should be experienced in evaluating and treating patients with MS and able to follow such patients very closely."

And should those patients, for whatever reason, not be able to be redosed with alemtuzumab, they can be safely switched to natalizumab, according to research led by Dr Bass that was presented in a poster.

"There seems to be no adverse events that are unexpected; there are no changes in the lymphocyte population that we don't already know about," she said. "So it seems to be safe to follow it up with Tysabri if needed."

CARE-MS I and CARE-MS II were funded by Genzyme. Dr Traboulsee receives consultant fees from Biogen, Chugai, Genzyme, MedImmune, Novartis, Roche, Serono, and Teva Innovation and is a principal investigator on clinical trials (Genzyme, Roche). Dr Bass receives compensation for consulting, serving on a scientific advisory board, and/or speaking from Ascend Therapeutics, Biogen Idec, Genzyme, Novartis, Quest, and Teva Neuroscience and research support from Biogen Idec, Genzyme, Novartis, Roche, and Teva Neuroscience. Dr Lisak receives research funding from Mallinckrodt, Teva, Sanofi, Novartis, Biogen Idec, Acorda; is on the advisory board of Mallinckrodt and Syntimmune; is expert witness for Teva and Acorda; and is on the speakers list for Teva (non–treatment/drug related). In the past year, Dr Thompson has received honoraria and support for travel for consultancy from Biogen Idec and MedDay; honorarium for consultancy from Eisai; and honoraria and support for travel for lecturing from Serono Symposia International Foundation, Novartis, Teva, and Remedica. He received support for travel from the MS International Federation as chair of their Medical and Scientific Advisory Board, from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and from the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief for the Multiple Sclerosis Journal.

Consortium of Multiple Sclerosis Centers (CMSC) 2015 Annual Meeting Platform session, poster DX11. Presented May 29, 2015.

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