ARTICLE IN BRIEF
In an head-to-head comparison of several widely use multiple sclerosis (MS) drugs, alemtuzumab and natalizumab were found to be more effective than fingolimod and interferon beta in preventing relapse in patients with relapsing-remitting MS. But natalizumab was found to be more effective than alemtuzumab in enabling recovery from disability.
Alemtuzumab and natalizumab were found to be more effective than fingolimod and interferon beta in preventing relapse in patients with relapsing-remitting multiple sclerosis (MS), according to a head-to-head observational study. However, natalizumab was found to be more effective than alemtuzumab in enabling recovery from disability, according to the report published in the April issue of The Lancet Neurology.
“We have shown that alemtuzumab and natalizumab were equally effective in reducing relapse frequency and preventing confirmed disability accumulation over four years of follow-up,” the lead study author Tomas Kalincik, MD, PhD, a neurologist and senior research fellow at the University of Melbourne, told Neurology Today. “However, natalizumab was more likely to lead to disability improvement, particularly during the first year after commencing therapy.”
“Alemtuzumab seems better at controlling MS activity than fingolimod,” Dr. Kalincik said, adding that alemtuzumab and natalizumab were equally effective; there were no significant differences in their ability to modulate the risk of disability or improvements over three years of follow-up.
Based on these and other findings, treatment decisions regarding alemtuzumab and natalizumab should be primarily governed by their safety profiles, the study authors wrote.
For the study, the MS Study Group, comprising investigators from around the world, obtained longitudinal clinical data from 71 MS Base Centers — MS centers that were part of the MS Study Group consortium — in 21 countries, and from six non-MS Base Centers in the United Kingdom, Ireland, and Germany between November 1, 2015 and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting MS, exposure to one of the study therapies — alemtuzumab, interferon beta, fingolimod, or natalizumab — at age 65 years or younger, an Expanded Disability Status Scale (EDSS) score of 6.5 or lower, and no more than 10 years since the first MS symptom. The primary endpoint was annualized relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events.
Patients were treated between August 1, 1994 and June 30, 2016: 189 patients were given alemtuzumab (12-24 mg intravenous once per day for five days [cycle 1] or for three days [cycle 2]); 2,155 patients were given interferon beta-1a (44 μg subcutaneously) three times per week; 828 patients, fingolimod (0.5 mg oral) once per day; and 1,160 patients, natalizumab (300 μg intravenous) every four weeks.
Among findings, the patients given alemtuzumab had an annualized relapse rate of 20 percent versus 19 percent for those given natalizumab, and measures of disability were not significantly different between alemtuzumab and natalizumab.
However, the probability of disability improvement was 13 percent for alemtuzumab and 17 percent for natalizumab at two years, and 13 percent for alemtuzumab and 27 percent for natalizumab at four years.
Patients given alemtuzumab had an annual relapse rate of 19 percent compared to 53 percent for interferon beta, a statistically significant difference. The differences in relapse rates between the groups remained significant throughout the follow-up.
Similarly, patients given alemtuzumab had lower annualized relapse rates than those given fingolimod. However, on the measure of disability improvement, alemtuzumab was roughly similar to both interferon beta and fingolimod. The probability of disability improvement was 12 percent for alemtuzumab and 11 percent for interferon beta at two years, and 15 percent for alemtuzumab and 15 percent for interferon beta at five years. The probability of disability improvement was 11 percent for alemtuzumab and 19 percent for fingolimod at two years, and 11 percent for alemtuzumab and 26 percent for fingolimod at three years.
Dr. Kalincik and those who reviewed the report for Neurology Today agreed that a strength of the study was that it provided a naturalistic head-to-head comparison of the drugs that is not possible in randomized control trials that report averages for patients who must meet sometimes stringent inclusion criteria.
One of the study's weaknesses was that it lacked data on safety and MRI scans, wrote the authors of an editorial that accompanied the study. “Baseline MRI activity is a major determinant of treatment choice, which should be adjusted for,” wrote Maria Pia Sormani, MD, and Alice Laroni, MD, of the University of Genoa. “Moreover, MRI activity might drive treatment switch, introducing potential biases when censoring data as patients changed therapy.”
Emmanuelle Waubant, MD, PhD, FAAN, professor of neurology at the University of California, San Francisco, agreed. “This study is very much needed as it puts in perspective the impact of various medications in ‘real life,’” she told Neurology Today. “However, such observational studies are challenging to analyze as adjustments can be made for obvious available confounders, while some other important and relevant confounders may not be addressed.” In the case of this study, lesion load and disease activity on MRI were not available, she said, noting that these data can sway treatment decisions.
“The treatment choices could be different in 2000 versus 2010,” she added, “depending on drug availability.”
Dr. Waubant also noted that patients who received alemtuzumab were coming from different centers than those participating at MS Base Centers. “This is a big difference that may have impacted the findings as there are no doubts that clinical practice in these centers may have been overall quite different from the MS Base Centers,” she said. “Heterogeneity can impact results such as variability of timing of visits, and the definition of relapses/progression or ways to score EDSS may also have differed across sites.”
Fred D. Lublin, MD, FAAN, director of The Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Icahn School of Medicine at Mount Sinai, agreed the report provides useful real-world information for clinicians, but, he said, it raised other questions.
“Well-designed and implemented observational studies, such as that by Dr. Kalincik and colleagues, can include real world samples, but raise the question as to the adequacy of their statistical adjustments and a host of other variables that are not controlled for,” he said. “As we are unlikely to have well-designed head-to-head studies of our highly active agents, clinicians will need to integrate the data from all these sources in making decisions, hopefully with a clearer understanding of the strengths and limitations of each.”
Dr. Waubant said the best treatment for a given patient remains a decision that should be made after comprehensive discussion between the MS specialist and the patient and his/her family. “I would consider that alemtuzumab is a reasonable treatment alternative compared to natalizumab, although the overall respective treatment effectiveness should be studied in larger studies with more patients exposed to alemtuzumab,” she said. “Finally, short- and long-term safety differences between these drugs have not been addressed but are important to keep in mind when making treatment decisions.”
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•. Kalincik T, Brown JWL, Robertson N, et alfor the MSBase Study Group. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: A cohort study http://http://www.thelancet.com
/journals/laneur/article/PIIS1474-4422(17)30007-8/abstract. Lancet Neurol
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