MS Speaks

Lancet Neurol. 2017 Feb 10.

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

Kalincik T1, Brown JW2, Robertson N3, Willis M3, Scolding N4, Rice CM4, Wilkins A4, Pearson O5, Ziemssen T6, Hutchinson M7, McGuigan C7, Jokubaitis V8, Spelman T8, Horakova D9, Havrdova E9, Trojano M10, Izquierdo G11, Lugaresi A12, Prat A13, Girard M13, Duquette P13, Grammond P14, Alroughani R15, Pucci E16, Sola P17, Hupperts R18, Lechner-Scott J19, Terzi M20, Van Pesch V21, Rozsa C22, Grand'Maison F23, Boz C24, Granella F25, Slee M26, Spitaleri D27, Olascoaga J28, Bergamaschi R29, Verheul F30, Vucic S31, McCombe P32, Hodgkinson S33, Sanchez-Menoyo JL34, Ampapa R35, Simo M36, Csepany T37, Ramo C38, Cristiano E39, Barnett M40, Butzkueven H41, Coles A42; MSBase Study Group.

Author information

1Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia. Electronic address: tomas.kalincik@unimelb.edu.au.
2NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London Institute of Neurology, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
3Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, UK.
4Department of Neurology, Southmead Hospital, Westbury-on-Trym, Bristol, UK; School of Clinical Sciences, University of Bristol, Bristol, UK.
5Abertawe Bro Morgannwg University Local Health Board, Swansea, UK.
6Center of Clinical Neuroscience, Department of Neurology, MS Center Dresden, Dresden, Germany; Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
7School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland.
8Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.
9Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University, Prague, Czech Republic.
10Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
11Hospital Universitario Virgen Macarena, Sevilla, Spain.
12Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
13Hopital Notre Dame, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada; Université de Montreal, Montreal, QC, Canada.
14Centres intégrés de santé et de services sociaux de Chaudičre-Appalache, Levis, QC, Canada.
15Amiri Hospital, Qurtoba, Kuwait City, Kuwait.
16Azienda Sanitaria Unica Regionale Marche AV3, Macerata, Italy.
17Nuovo Ospedale Civile Sant'Agostino-Estense, Modena, Italy.
18Zuyderland Ziekenhuis, Sittard, Netherlands.
19University of Newcastle, Newcastle, NSW, Australia.
20Medical Faculty, 19 Mayis University, Kurupelit, Samsun, Turkey.
21Cliniques Universitaires Saint-Luc, Brussels, Belgium.
22Jahn Ferenc Teaching Hospital, Budapest, Hungary.
23Neuro Rive-Sud, Greenfield Park, QC, Canada.
24KTÜ Medical Faculty Farabi Hospital, Karadeniz Technical University, Trabzon, Turkey.
25University of Parma, Parma, Italy.
26Flinders University, Adelaide, SA, Australia.
27Azienda Ospedaliera San Giuseppe Moscati di Avellino, Avellino, Italy.
28Hospital Universitario Donostia, San Sebastián, Spain.
29C Mondino National Neurological Institute, Pavia, Italy.
30Groene Hart Ziekenhuis, Gouda, Netherlands.
31Westmead Hospital, Sydney, NSW, Australia.
32Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
33Liverpool Hospital, Sydney, NSW, Australia.
34Hospital de Galdakao-Usansolo, Galdakao, Spain.
35Nemocnice Jihlava, Jihlava, Czech Republic.
36Semmelweis University Budapest, Budapest, Hungary.
37University of Debrecen, Faculty of Medicine, Department of Neurology, Debrecen, Hungary.
38Hospital Germans Trias i Pujol, Badalona, Spain.
39Hospital Italiano, Buenos Aires, Argentina.
40Brain and Mind Centre, Camperdown, NSW, Australia.
41Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia; Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia.
42Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.


BACKGROUND:

Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years.

METHODS:

In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6ˇ5 or lower, and no more than 10 years since the first multiple sclerosis symptom.

The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models.

FINDINGS:

Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0ˇ19 [95% CI 0ˇ14-0ˇ23] vs 0ˇ53 [0ˇ46-0ˇ61], p<0ˇ0001) and fingolimod (0ˇ15 [0ˇ10-0ˇ20] vs 0ˇ34 [0ˇ26-0ˇ41], p<0ˇ0001), and was associated with a similar annualised relapse rate as natalizumab (0ˇ20 [0ˇ14-0ˇ26] vs 0ˇ19 [0ˇ15-0ˇ23], p=0ˇ78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio

---

0ˇ66 [95% CI 0ˇ36-1ˇ22], p=0ˇ37), fingolimod (1ˇ27 [0ˇ60-2ˇ70], p=0ˇ67), and natalizumab (0ˇ81 [0ˇ47-1ˇ39], p=0ˇ60). Alemtuzumab was associated with  probabilities of disability improvement [that were similar to] interferon beta (0ˇ98 [0ˇ65-1ˇ49], p=0ˇ93) and fingolimod (0ˇ50 [0ˇ25-1ˇ01], p=0ˇ18), and a lower probability of disability improvement than natalizumab (0ˇ35 [0ˇ20-0ˇ59], p=0ˇ0006).

INTERPRETATION:

Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.

________________
FUNDING:
National Health and Medical Research Council, and the University of Melbourne.