LONDON — Data out to 6 years' follow-up of patients with multiple sclerosis (MS) in the two main phase 3 trials of alemtuzumab (Lemtrada, Genzyme Corp) continue to show encouraging results, with low rates of disease activity, a substantial number of patients showing improvement in disability, and brain atrophy slowing to near normal levels.

In addition, latest data on safety do not suggest any new serious adverse effects, suggesting that the recommended 4-year monitoring program (after last dose) is adequate, researchers say.

Both presenters of the 6-year results from the two studies — CARE MS 1 and CARE MS 2 — as well as outside experts said the latest results should lead to the drug being used more as neurologists gain confidence in its long-term safety and efficacy. But they stressed that, like most other MS therapies, alemtuzumab works best in earlier disease, and they warned against waiting too long to give it.

The new data were presented here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016.

Presenting the 6-year results from CARE MS 1, in which alemtuzumab was given to treatment-naive patients, was Alasdair J. Coles, MD, University of Cambridge, United Kingdom, who was one of the co-developers of the drug.

"We have shown a strong durable efficacy, with about a third of patients showing an improvement in disability, and nothing new in terms of the safety profile," Professor Coles concluded. "So I can recommend alemtuzumab as a useful addition to the armamentarium as first-line treatment for MS."

He reported that 57% of patients in CARE MS 1 were free of disease activity in year 6, with 86% free of clinical activity and 66% free of MRI activity.

Professor Coles emphasized the importance of using the drug earlier rather than later in the disease process. "Much of the benefit lies in the early use of alemtuzumab. These data do not apply to use later on in patients with advanced disease."

Noting that in the United Kingdom alemtuzumab has a first-line indication but in several other countries it is approved only for second- or third-line use, he suggested that as experience grows and longer follow-up continues to show both safety and efficacy this may change. "I would urge those countries where it is currently a second- or third-line agent to reconsider," he said.

Co-chair of the session at which Professor Coles presented the results, Sandra Vukusic, MD, Lyon University Hospital, France, agreed with this view.

"These are very impressive results. We have no other drug which can stop the disease for so long, but we have to use alemtuzumab early," she commented to Medscape Medical News. "Later on it doesn't work so well. And the safety may be worse as patients will have been exposed to many other drugs.

"In France, we can only use alemtuzumab when there are no other options — like a third-line therapy — and it doesn't work so well. I see that from my personal experience," she added. "I think we use it too late. I would like to see it available as first line for selected patients — those who have active disease."

Edward Fox, MD, Multiple Sclerosis Clinic of Central Texas, who presented the 6-year results from the CARE MS 2 study (in which alemtuzumab was given to patients who had had breakthrough activity while receiving one other treatment) was of a similar opinion.

"We're seeing very low annualized relapse rates maintained for 6 years and for the majority of patients this is 4 years since their last dose," Dr Fox said. "In CARE MS 2, the annualized relapse rate was 0.15 in year 6 and 43% of patients have shown improvement in disability compared to baseline. "This is unusual — especially for a medication which is not being given on a sustained basis."

Table. Disability Results at Year 6 in CARE MS 1 and CARE MS 2

Endpoint CARE MS-1 CARE MS-2
Free of 6-mo confirmed disability (%) 77 72
6-mo confirmed disability improvement (%) 34 43


Other impressive results from the 6-year data concern the slowing of brain atrophy. Median annual brain volume loss in both CARE MS 1 and CARE MS 2 was less than 0.2% in years 3, 4, 5, and 6, with 63% of CARE MS 1 and 50% of CARE MS 2 patients having received no additional treatment after the first year.

Aaron Boster, MD, OhioHealth, Columbus, an investigator in CARE MS 2, commented to Medscape Medical News that "this level of 0.2% annual brain volume loss is similar to what would be seen in normal aging. MS patients can lose brain volume 5 to 10 times faster than normal. Putting brain atrophy back to a normalized rate is just incredible."

In a presentation specifically on adverse events in the whole CARE MS program, Patrick Vermersh, MD, University Hospital Lille, France, gave the latest data on idiopathic thrombocytopenic purpura (ITP), the most serious side effect of alemtuzumab. The overall incidence in the whole CARE MS program has been 2.6% (21 patients). All these cases occurred within the 4-year monitoring period.

Of the patients who developed ITP, 1 had resolution with no treatment, 7 with first-line therapy, and 12 with second-line therapy, and 1 patient underwent splenectomy, he reported. There have been 2 cases of nephropathy (0.2%), both within in the 4-year monitoring period. Thyroid events peaked at 3 years and have subsequently declined.

Dr Fox pointed out that in its early development, alemtuzumab was tested in patients with more advanced disease, including those with secondary progressive MS and more advanced Extended Disability Status Scale (EDSS) ratings, and these patients did not have the same level of benefit. "We've seen this with all medications in MS. Early aggressive treatment gives better results down the road — not just with this medication," he commented to Medscape Medical News.

He reported that CARE MS 2 enrolled patients who were slightly older, with a longer duration of disease and higher EDSS score at baseline compared with CARE MS 1. "But they still had early active MS. They had less than 10 years' duration of disease and had a relapse or MRI activity within the past year. This is the type of patient who we will target this medication to — patients with any signs of breakthrough activity on their current medication."

Noting that in the United States, the US Food and Drug Administration indication is "generally recommended for patients who have tried two other medications," he said, "this is more restrictive than in some other countries, and so it is being used in a different group of patients as a result, but the word generally gives us some leeway. We know that patients with very active disease have a poor prognosis from the beginning and I believe they are candidates for alemtuzumab very early on."

"I believe that the question the patients have to consider is whether the 4 years of monitoring after the last dose is a responsibility they want to take and whether they feel it is justified. It certainly isn't for everyone."

He added: "In an ever-growing market of MS medicines, this is highly unique data — clinical stability over a long period of time with no new safety signals. This is getting attention, and the longer we see this stability the more confidence will grow in using this agent."

The CARE-MS I and II studies were funded by Genzyme.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Abstracts 168, 213, P1150, and P1181.

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