BOSTON — Data now out to 4 years on patients who received alemtuzumab in the original CARE-MS I and II studies show a low rate of relapse recurrence and disability progression and no unexpected adverse effects, even though most patients have not been treated with any disease-modifying therapies for 3 years, study investigators report.

The new 4-year data were presented in 2 posters at MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.

Other presentations at the meeting showed impressive results on disease-free outcomes and brain atrophy out to 3 years, with claims that brain atrophy appears to have slowed to almost that expected to be seen in healthy persons without MS.

One of the investigators, Alasdair J. Coles, PhD, University of Cambridge, United Kingdom (UK), who has been involved in the development of alemtuzumab for MS right from the start, told Medscape Medical News: "The news is that there is no news. Alemtuzumab remains highly effective at 4 years. There have always been concerns about its safety profile, but now we have data that shows there is nothing new to worry about at 4 years in terms of safety.

"Our 4-year data from the CARE-MS trials show that relapse remains low, on average disability is less than at baseline, there is no significant increase in lesions, and — this is the most exciting part in my opinion — by year 3 the rate of brain shrinkage comes into the normal range for a healthy adult," he added. "That is a very powerful message if you've got MS."

Alemtuzumab was approved for MS in its first markets last year, although it was turned down by the US Food and Drug Administration. Its efficacy certainly looks impressive, but concerns are focused on its adverse-effect profile: Around 35% of patients develop immune thyroid disease, and 1% to 2% of patients develop idiopathic thrombocytopenia (ITP). This has necessitated a strict monitoring program for patients taking the drug, which involves monthly blood and urine tests.

Benefit/Risk Profile Debated

Dr. Coles is adamant that the benefit is worth the risk. "For someone with MS what they want is choice. Alemtuzumab offers high efficacy. If you have aggressive MS or you're worried about the effect of the disease, alemtuzumab is a good option."

Because of the adverse-effect profile, some see alemtuzumab as a drug to be reserved for the most severe cases, but Dr. Coles thinks otherwise. "It is understandable that doctors want to reserve it for patients who have failed other treatments, but we know its efficacy is best when given early on. In the long run it is best for everyone if it is offered as first line or early second line for people [for whom] efficacy is the key determinant."

He says the patients most suitable are those thought to have an aggressive form of the disease — those who are having a high frequency of attacks or new MRI lesions.

Asked to comment on the latest data and how alemtuzumab will be used n practice, Waqar Rashid, MD, Brighton and Sussex University Hospitals, United Kingdom, who has not been involved in the trials with the drug, said in his view, "not too much has changed in this latest data.

"There are ongoing issues of thyroid disease and the numbers are slightly increasing over time as you would expect," he told Medscape Medical News. "My personal opinion is that it is clearly a very effective drug but there are significant safety issues."

Dr. Rashid believes the adverse-effect profile will put many patients off. "In my view there will only be a specific subset of patients who will be attracted to alemtuzumab. I would like more time to see if the autoimmune safety issues are going to plateau — I will certainly be watching this carefully. As more data become available on the risks, it will probably slowly gain favor."

Latest Data From CARE-MS I and II

CARE-MS I and II are the phase 3 studies of alemtuzumab in MS. In both trials the drug was given as 2 annual courses at the start of the study and 12 months later and compared with β-interferon. No further treatment is given unless patients have a new relapse or MRI lesions. Both studies recruited patients with relapsing-remitting MS who have active disease.

CARE-MS I was conducted in patients who were new to treatment, while CARE-MS II enrolled patients who had relapsed while receiving prior therapy. The active comparator part of the studies lasted 2 years, and patients are now being followed in an open-label extension phase. The current 4-year data are from the second year of the extension studies.

The extension study of CARE-MS I enrolled 349 eligible patients from the alemtuzumab group of the core study. Latest data show that over 4 years, 73% of these patients received only the initial 2 annual courses of the drug, while 21% of patients have received 1 additional course and 5% have received 2 additional courses, respectively. Fewer than 2% of patients received another disease-modifying treatment.

The CARE-MS II extension included 393 patients from the alemtuzumab group of the core study. Over 4 years, 68% of these patients received only the initial 2 annual courses, while 24% have received 1 additional course and 7% have received 2 additional courses. In addition, 5% of patients received another disease-modifying therapy during the extension phase.

In both studies, 4-year data show low rates of annual relapse rates similar to that in the core study.

Table 1. CARE-MS I: Annual Relapse Rates

Group Annual Relapse Rate
β-Interferon in core study (0 - 2 y) 0.39
Alemtuzumab in core study (0 - 2 y) 0.18
Alemtuzumab patients, 1-y extension 0.19
Alemtuzumab patients, 2-y extension 0.14


Table 2. CARE-MS II: Annual Relapse Rates

Group Annual Relapse Rate
β-Interferon in core study (0 - 2 y) 0.52
Alemtuzumab in core study (0 - 2 y) 0.26
Alemtuzumab patients, 1-y extension 0.22
Alemtuzumab patients, 2-y extension 0.23


Similar encouraging results were reported in terms of disability, with 73.5% of patients remaining stable or improving in terms of Expanded Disability Status Scale (EDSS) scores from baseline to year 4 in CARE-MS I and 66.2% in CARE-MS II.

Improvement in preexisting disability, as measured by sustained reduction in disability (SRD), was newly achieved by some patients in years 3 and 4 in both studies.

Table 3. CARE-MS I: Disability Results for Original Alemtuzumab Patients to 4 Years

Endpoint Years 0 - 2 Years 0 - 3 Years 0 - 4
Mean EDSS change from baseline –0.16 –0.10 –0.09
Proportion of patients achieving SRD (%)      
  3-mo SRD 30 33 36
  6-mo SRD 24 28 30
  12-mo SRD NA 24 26

NA = not available.


Table 4. CARE-MS II: Disability Results for Original Alemtuzumab Patients to 4 Years


Endpoint Years 0 - 2 Years 0 - 3 Years 0 - 4
Mean EDSS change from baseline –0.20 –0.06 0.00
Proportion of patients achieving SRD (%)      
  3-mo SRD 35 43 46
  6-mo SRD 29 35 41
  12-mo SRD NA 27 30

NA = not available.


Adverse Events

The incidence of most adverse effects, including infections, during the extension period was similar or reduced compared with that in the core study, with most adverse events being mild to moderate in severity, the investigators reported.

To date, 5 of 376 (1.3%) patients who received alemtuzumab in CARE-MS I and 18 of 435 (4.1%) in CARE-MS II have withdrawn from treatment because of adverse events.

Thyroid autoimmune reactions have had a cumulative incidence of 37.5% during the 4-year study period in CARE-MS I and 34.7% in CARE MS II. These peaked in year 3 and declined in year 4, consistent with the pattern observed in the phase 2 study, the investigators reported.

ITP has occurred in 1.1% of patients over 4 years in CARE-MS I (1 case in year 4) and 2.5% in CARE-MS II (6 cases in year 4). No cases of glomerulonephritis were reported in year 4 of either study.

Brain Atrophy Data

The latest brain atrophy data from CARE-MS II was presented in a poster by Elizabeth Fisher, MD, from the Cleveland Clinic in Ohio. These findings showed that the median yearly rate of brain volume loss with alemtuzumab decreased progressively over time.

Table 5. CARE MS II: Brain Atrophy by Treatment

Timepoint β-Interferon: Change in Brain Parenchymal Fraction (%) Alemtuzumab: Change in Brain Parenchymal Fraction (%)
Years 0 - 1 –0.54 –0.48
Years 1 - 2 –0.35 –0.22
Years 2 - 3 –0.10


Dr. Fisher commented to Medscape Medical News that the rate of brain loss at year 3 in the alemtuzumab patients is now approaching that seen in a longitudinal Cleveland Clinic study of healthy persons without MS in the same age group (0.07%). She pointed out that it was interesting that brain loss slowed progressively over several years.

"We haven't seen anything like this before," she said. "I would not have predicted that brain loss would slow even more in year 3."

Commenting on these data, Dr. Coles said: "Normally MS brain shrinkage is double that of non-MS patients. But by year 3 we are seeing similar values to non-MS patients. What this means is that by year 3 we are seeing virtually no brain atrophy that is attributable to MS. For me that is what patients will want to know."

Dr. Coles noted that the CARE-MS data on relapse and disability are in line with results from an open cohort of patients treated in the UK for much longer. "Our UK cohort of 87 patients have now been followed for 12 years, and on average they are still less disabled than they were at the start, and have had a very low relapse rate," he said.

Use in Clinical Practice

Dr. Coles noted that the drug has been given to around 1500 patients in clinical trials and several hundred more now in clinical practice. Although it has been approved in Europe and Canada for about a year, he pointed out that reimbursement is only now coming through, "so I think it's pretty impressive that we've treated any number."

On how the drug is being received by the clinical community, Dr. Coles said: "What I see is what I expected to see. Those who give it are pleased with the outcome and pleased with the monitoring. The hurdle is getting people to use it once. Once they have used it once they will use it again. The people who are most positive about it are those who've tried it."

Dr. Rashid says there are pockets of high use of alemtuzumab in the UK now, mainly in the centers that were involved in the trials. But other centers are slowly coming on board. He hasn't used alemtuzumab yet himself because it has only just been added to his hospital's formulary. "I do see it as an option for patients with aggressive disease who are not being controlled on standard treatment, but we have a plethora of drugs now and alemtuzumab will be competing with natalizumab and fingolimod for these patients," he noted.

He puts alemtuzumab and natalizumab at the top of the list in terms of efficacy but points out that both are hampered by safety issues.

"In the UK natalizumab has more stringent prescribing restrictions (2 or more relapses in the previous year) but personally I feel that if the patient is negative for JCV [JC virus] antibodies, it is a very safe option," he said. "There are data now on 120,000 patients on natalizumab compared with just a few hundred on alemtuzumab. That will be a factor that many will consider."

Dr. Coles receives consulting fees, lecture fees, and institutional grant support from Genzyme, Merck-Serono, and UCB-Celltech. Dr. Rashid has been reimbursed by Schering, Teva, and Biogen, for attending several conferences and academic meetings.

MS Boston 2014: The 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting. Abstracts P043, PO90, and P103. Presented September 11, 2014.


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