New data from 5-year follow-up of the pivotal phase 3 trials show that alemtuzumab (Lemtrada, Genzyme) continues to be associated with low rates of disease progression and brain atrophy in patients with relapsing-remitting multiple sclerosis (MS).

Presenting the brain atrophy data, Frederik Barkhof, MD, University Medical Centre Amsterdam, the Netherlands, reported that median annual brain volume loss was less than 0.2% in years 3, 4, and 5 in both the CARE-MS I and II studies.

"That is almost now down to the rate of normal aging in a non-MS population. This is a unique result considering it is achieved with just two infusions very early on," he said.

"Based on these findings alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continued treatment for relapsing-remitting MS patients," Dr Barkhof concluded.

Dr Frederik Barkhof

Several papers with new follow-up data on alemtuzumab were presented here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015.

CARE-MS

Presenting the clinical data from the CARE-MS I trial, Eva Havrdova, MD, Charles University, Prague, Czech Republic, noted that 40% of patients had no evidence of disease activity (NEDA) from years 3 to 5.

"In the patients who had no disease activity at year 2, 61% continue to show no disease activity at 5 years. These are the best responders — we need to try and define these patients better for future treatment guidance," she commented.

Dr Eva Havrdova

The CARE-MS I patients fared better than those in CARE-MS II, which was to be expected because CARE-MS II included patients who had already relapsed while receiving disease-modifying drug treatment before starting the study, whereas CARE-MS I included only treatment-naive patients.

Presenting the latest results from CARE-MS II, Edward J. Fox, MD, Central Texas Neurology Consultants, noted that 27% of patients in this study had no evidence of disease activity from years 3 to 5. And in patients who had no disease activity at year 2, 48% continued to show sustained NEDA at year 5.

"Patients who do well at 2 years continue to do well at 5 years," Dr Fox told Medscape Medical News.

Dr Edward J. Fox

Commenting on the data for Medscape Medical News, Jerry Wolinsky, MD, University of Texas, who has not been involved in the CARE-MS program, said, "It is very encouraging that the response is maintained for so long, even in the absence of continued treatment. This offsets some of the issues of safety. If you have to re-treat regularly I would think the autoimmune dysfunction would extend further."

Dr Jerry Wolinsky

He added: "What I would like to see is exactly what is happening to patients who have another round of treatment — whether they were dropping out of the longer-term data — and how selective the population is that is being reported at 5 years."

Both CARE-MS I and II compared alemtuzumab to interferon β-1a for the first 2 years of the studies. Alemtuzumab was given as two intravenous (IV) infusions at a dose of 12 g/d. This was given on 5 consecutive days at baseline and 3 consecutive days 1 year later. Ninety-five percent and 93% of patients completing this core study were enrolled into the extension study (years 3 to 5).

Patients showing disease activity could be given another alemtuzumab infusion, and latest data show that 68% of alemtuzumab recipients from CARE-MS I and 60% from CARE-MS II did not receive additional infusions during the following 4 years.

Table 1. Percentage of Patients Requiring Alemtuzumab Re-treatment After Core Study

Treatments CARE-MS I CARE-MS II
One re-treatment (%) 22.1 28.8
Two re-treatments (%) 8.0 9.9
Three re-treatments (%) 1.4 1.5

 

Dr Barkhof noted that the brain atrophy data showed the curves "flattening out" from year 3 onward, and this continued up to the 5-year mark, even though most patients had not received any additional treatment after the first year.

Table 2. Brain Atrophy Data: Median Yearly Change in Brain Parenchymal Fraction in Alemtuzumab Recipients

Time Point CARE-MS I CARE-MS II
Year 1 –0.59 (n = 367) –0.48 (n = 414)
Year 2 –0.25 (n = 351) –0.22 (n = 398)
Year 3 –0.19 (n = 320) –0.10 (n = 356)
Year 4 –0.15 (n = 314) –0.19 (n = 330)
Year 5 –0.20 (n = 312) –0.07 (n = 303)

 

Dr Barkhof suggested that the durable slowing of brain volume loss may be explained by distinct depletion and repopulation following acute treatment with alemtuzumab.

Other results suggested consistent effects on relapse rate and disability.

Table 3. Relapse and Disability Results at 5 Years

Endpoint CARE-MS I CARE-MS II
Relapse-free at 3 to 5 y (%) 70 58
Free from 6-mo disability progression from baseline to 5 y (%) 80 76
6-mo sustained reduction in disability (%) 33 43

 

Commenting for Medscape Medical News, Aaron Boster, MD, OhioHealth Physician Group, Columbus, an investigator in CARE-MS II, said, "I am overblown that we have such a profound and durable effect that extends out to 5 years. In addition, 33% to 43% of patients had improvement in 6 months confirmed disability at 5 years. That is unheard of. And these results occur despite the fact that 60% of patients have not received an additional infusion after the first two in the first year of the trial."

Safety

In terms of safety, 8.9% of patients withdrew from the CARE MS I extension study and 6.6% from the CARE-MS II extension study through year 5. No patient was said to have withdrawn because of safety.

Infection was highest after first treatment course (56.1% in CARE-MS and 63% in CARE-MS II) but declined to 40% and 44%, respectively, in year 5. Serious infections occurred in 0.6% of patients in CARE-MS I in year 5 vs <3% in CARE-MS II.

Thyroid adverse events peaked in year 3 in both studies and declined in years 4 and 5 (10.1% in year 5 in CARE-MS II).

The cumulative incidence of immune thrombocytopenia (ITP) through year 5 was 1.1% (n = 4) in CARE-MS I (one event in year 3 and one event in year 5) and 2.8% in CARE-MS II (n = 12).

One patient died during the CARE-MS I extension period (in year 3) and none died during the CARE-MS II extension.

Dr Boster said he thought the safety data were reassuring. "We are barely seeing any ITP when we get out to 5 years," he said.

Genzyme says there have been 34 cases of ITP in total and all cases have occurred within 48 months after last dose.

Alemtuzumab is subject to a risk evaluation and mitigation strategy program, which mandates that patients have monthly blood tests for autoimmune conditions such as ITP for 4 years after the last dose.

Dr Fox said that after this point patients would be encouraged to come back for regular checks but would no longer need monthly blood draws.

But Dr Wolinsky said he thought the blood tests should be continued for longer. "I wouldn't think 4 years would be enough," he told Medscape Medical News. "We can have some nasty surprises. It took us a while to understand the consequences of mitoxantrone. I would like to see longer-term registries to try and sort out what might happen late downstream."

Dr Fox noted that the extension phases of CARE-MS I and II are now finished but the patients from both studies will now be enrolled in a single database — known as TOPAZ — and will continue to be followed that way.

He commented to Medscape Medical News: "I am typically using alemtuzumab as per the US prescribing information — in patients who have tried two medicines beforehand and have either relapsed or are having side-effect issues. But I do think this long-term data does encourage us to think about expanding use of this drug. The durable effect will be of interest to many patients."

The CARE-MS I and II studies were funded by Genzyme. Dr Barkhof, Dr Havrdova, Dr Fox, and Dr Boster all receive consultancy fees/honoraria from Genzyme.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015. Abstracts 151, 152, and P1102. Presented October 9, 2015.

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