The paper below came out yesterday. It demonstrates that active RRMSers treated with alemtuzumab are much more likely to have an improvement in disability compared to their contemporaries treated with interferon-beta (Rebif). Improvements were seen across all domains and were greater in upper limb than lower limb function. The latter is compatible with our length-dependent axonopathy hypothesis; there is more reserve capacity in the upper limbs than lower limbs, therefore there is greater chance of recovery of function in the former.
What is important that the improvement seems to be independent of relapses; i.e. MSers who have, or who don’t have relapses, in the 3-6 months before enrolment were as likely to improve. Not presented in this paper is the delayed improvements that occur in years 3, 4 and 5. When I was a trainee I was always told that most recovery from relapses occurs in the initial 6 months with some delayed recovery, from plasticity, occurring up to 2-years after a relapse. I espoused this dogma until I witnessed the effect of alemtuzumab on outcomes. The fact that so many MSers have delayed improvements is telling us something about the biology of recovery in MS. I have had one patient recently coming in to clinic and tell me that she has stopped self-catheterisation and has not needed a top-up of her bladder Botox injections; this was after completing her second course of alemtuzumab. I know another MSer who has run a half-marathon post-alemtuzumab, prior to treatment he was unable to walk much more than a mile. Behind this data are real-life stories that make such a difference to quality of life of individuals.
Are these observations unique to alemtuzumab? I suspect not, we are seeing this outcome with other high-efficacy therapies as well. The reason why they are so common with alemtuzumab is that the alemtuzumab trial programme was done in MSers very early in the course of their disease. Young age and reserve capacity (low disability) are what predicts outcome. Is there a lesson here? Yes, it is important to have alemtuzumab early in the course of your disease. If you wait until you become too disabled then your are unlikely to benefit as much, in terms of disability improvement, from alemtuzumab.
It is quite remarkable that we are moving from simply trying to delay, or slow, disability accumulation in MS to actually trying to improve disability. It is time to reflect on how far the field of MS treatments have come. Please note that despite the obvious benefits of alemtuzumab it comes with substantial risks; i.e. infusion reactions, infections and delayed secondary autoimmunity. Although uncommon all of these adverse events could be potentially be life-threatening. Alemtuzumab treatment is also irreversible hence the decision to be treated with alemtuzumab needs to be taken very seriously and after careful consideration.
I would like to take this opportunity to thank all the patients at Barts-MS who participated in the CARE-MS1 and CARE-MS2 trials, our staff who helped run the trials, Genzyme for sponsoring the studies, my co-investigators across the world and Professors Compston and Coles for daring to walk-the-talk, getting alemtuzumab to this point has been an ultra-marathon.
Although we have come so far, we still have many miles to go and questions to address. How do we de-risk alemtuzumab? Can we prevent secondary autoimmunity? Will alemtuzumab prevent the development of secondary progressive MS? Do we need an add-on a therapy to alemtuzumab to clear the brain and spinal cord of plasma cells and their pathogenic oligoclonal IgG bands? How do we stop the immune system from making anti-alemtuzumab antibodies? Can we make giving alemtuzumab easier and more convenient, for example via the subcutaneous route? If we give a booster VZV vaccination before alemtuzumab will we lower the risk of herpes zoster post-alemtuzumab? How does alemtuzumab really work; is it via B-cell depletion rather than T-cell depletion? If the B-cell is the key could we make immune depletion therapy much safer? How good is alemtuzumab compared to other DMTs and in particular compared to HSCT?
Giovannoni et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12. pii: 10.1212/WNL.0000000000003319.
METHODS: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.
RESULTS: Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.
CONCLUSIONS: In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
CoI: multiple, Prof. G is an author on the paper