Alemtuzumab in MS: Disability Reversal Possible

October 14, 2016

New data from the CARE-MS II trial showing that alemtuzumab (Lemtrada, Genzyme) appears to reverse some of the physical disability in multiple sclerosis (MS) have been published.

The paper, published online October 12 in Neurology, reports on the first 2 years of the trial, in which patients who had relapsed on a prior therapy were randomly assigned to alemtuzumab 12 mg or interferon β-1a. Main results from this trial have been published previously, including data showing a significantly greater improvement in mean Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores with alemtuzumab vs interferon.

The current analysis more fully characterizes the effect of alemtuzumab on disability in this population and shows a greater recovery of function across several disability measures with the drug compared with interferon, the authors, led by Gavin Giovannoni, MD, PhD, Queen Mary University, London, United Kingdom, report.

In addition to reporting EDSS-based scores, the usual measure of disability used in MS, they also give information on the more sensitive MSFC and Sloan Low Contrast Letter Acuity (SLCLA) scores.

For the EDSS scores, the current results not only confirm that alemtuzumab patients were more likely than interferon patients to show improvement in EDSS values but also show that the odds of improvement in all 7 EDSS functional systems were greater for alemtuzumab than interferon, reaching statistical significance in five domains (cerebral, cerebellar, sensory, pyramidal, and visual), the researchers state.

While the EDSS is the most commonly used neurologic disability index in MS trials, Giovannoni et al point out that it has been criticized for its emphasis on ambulation and insensitivity to other disability components, such as cognition, especially at lower scores.

They therefore also analyzed the results with the MSFC and SLCLA scores, which have greater sensitivity for cognition and visual acuity respectively, and found favorable results for alemtuzumab on both these scales.

Specifically, the likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than interferon (P = .03), an effect primarily driven by the upper limb coordination and dexterity domain.

In addition, alemtuzumab-treated patients had more favorable changes from baseline in SLCLA scores (P =.0014) and MSFC plus SLCLA composite scores (P = .0097) than interferon-treated patients.

The researchers conclude that: "The outcomes presented here not only support alemtuzumab's ability to slow disability accumulation, but also demonstrate superior benefit in improving preexisting disability in patients with RR [relapsing-remitting] MS with an inadequate response to prior DMT [disease-modifying therapy]."

They caution that the results should be considered in the context of the risks associated with the drug, including infusion-associated reactions, infections, and autoimmune adverse events, reminding that measures to manage these potentially serious risks are essential for the safe use of alemtuzumab.

Functional Repair?

In an accompanying editorial, Bibiana Bielekova, MD, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, speculates on the mechanism behind the sustained reduction in disability seen with alemtuzumab. She suggests it is more likely to be due to functional repair (ie, plasticity, such as formation of new synapses) than structural repair (ie, remyelination) given that early experience with the drug in more advanced patients did show any disability improvements.

She notes that if disability reduction is caused by plasticity, it should not be observed in patients with more advanced disability, where the extent of central nervous system tissue destruction precludes functional recovery because of the lack of neuronal reserves. But she adds that remyelination may also be less efficient in advanced disease.

She adds that even though alemtuzumab is one of the strongest MS-modifying treatments currently available, it is not curative, even when used relatively early in the disease process.

She points out that the 25-foot walk — a much more sensitive measure of disability than the EDSS — showed slow but sustained progression on this measure (which was equal for both drugs).

"This residual disease will need to be targeted by combination therapies if our goal is to arrest disability progression in all patients," she adds.

Dr Bielekova suggests that systemically administered treatments will not be able to tackle compartmentalized inflammation visualized on pathology outside of MS lesions and in the meninges, which may contribute to disability progression.

"Thus, despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients," she concludes.

The CARE-MS II study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. Dr Giovannoni reports receiving compensation for consulting and receiving grant/research support from AbbVie, Bayer HealthCare Pharmaceuticals, Biogen, Canbex, Five Prime, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB. Dr Bielekova has disclosed no relevant financial relationships.

Neurology. Published online October 12, 2016. Study full text, Editorial

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