Comparative effectiveness of natalizumab and fingolimod in subgroups of patients with relapsing-remitting multiple sclerosis from three international cohorts
Sifat Sharmin1, Mathilde Lefort3, Johanna Balslev Andersen4, Emmanuelle Leray3, Dana Horakova5, Eva Havrdova5, Raed Alroughani6, Guillermo Izquierdo Ayuso7, Serkan Ozakbas8, Francesco Patti9, Marco Onofrj10, Alessandra Lugaresi11, Murat Terzi12, Pierre Grammond13, Francois Grand'Maison14, Bassem Yamout15, Alexandre Prat16, Marc Girard16, Pierre Duquette16, Cavit Boz17, Maria Trojano18, Pamela McCombe19, Mark Slee20, Jeannette Lechner-Scott21, Recai Turkoglu22, Patrizia Sola23, Diana Ferraro24, Franco Granella25, Julie Prevost26, Davide Maimone27, Olga Skibina28, Katherine Buzzard29, Anneke Van der Walt30, Bart Van Wijmeersch31, Tunde Csepany32, Daniele Litterio A. Spitaleri33, Ostoja (Steve) Vucic34, Romain Casey35, Marc Debouverie36, Gilles Edan37, Jonathan Ciron38, Aurélie Ruet39, Jérôme De Sèze40, Elisabeth Maillart41, Hélène Zephir42, Pierre Labauge43, Gilles Defer44, Christine Lebrun-Frénay45, Thibault Moreau46, Eric Berger47, Pierre Clavelou48, Jean Pelletier49, Bruno Stankoff50, Olivier Gout51, Eric Thouvenot52, Olivier Heinzlef53, Abullatif Al-Khedr54, Bertrand Bourre55, Olivier Casez56, Philippe Cabre57, Alexis Montcuquet58, Abir Wahab59, Jean-Philippe Camdessanché60, Aude Maurousset61, Ivania Patry62, Karolina Hankiewicz63, Corinne Pottier64, Nicolas Maubeuge65, Céline Labeyrie66, Chantal Nifle67, David Laplaud68, Nils Koch-Henriksen69, Finn Thorup Sellebjerg70, Per Soelberg Soerensen70, Claudia Christina Pfleger71, Peter Vestergaard Rasmussen72, Michael Broksgaard Jensen73, Jette Lautrup Frederiksen74, Stephan Bramow75, Henrik Kahr Mathiesen76, Karen Ingrid Schreiber70, Melinda Magyari70, Sandra Vukusic77, Helmut Butzkueven30, Tomas Kalincik2
1Clinical Outcomes Research Unit, University of Melbourne, 2University of Melbourne, 3Rennes University, 4University of Copenhagen, 5Charles University, 6Amiri Hospital, 7Servicio De Neurologia, 8DOKUZ EYLUL UNI. FACULTY OF MEDICINE, 9University of Catania, 10University G. d’Annunzio, 11Università di Bologna, 1219 Mayis Universitesi, 13CISSS Chaudière-Appalache, 14Neuro Rive-Sud, 15American University of Beirut, 16CHUM MS Center and Universite de Montreal, 17KTU Medical Faculty Farabi Hospital, 18Policlinico - Bari, 19University of Queensland, 20Flinders Medical Centre, Bedford Park, 21Hunter New England Health, 22Haydarpasa Numune Training and Research Hospital, 23Azienda Ospedaliera Universitaria, 24University of Modena and Reggio Emilia, 25Zeneca-UK, 26CSSS Saint-Jérôme, 27Ospedale Garibaldi - Catania, 28Neurosciences, Box Hill Hospital, 29Eastern Health, Dept Neuroscience, 30Monash University, 31Rehabilitation & MS-Centre Overpelt, 32University of Debrecen, 33A.O. "S. Giuseppe Moscati", 34Westmead Hospital, 35Université de Lyon, 36Hospital Central, 37CHU Pontchaillou, 38CHU de Toulouse, Hôpital Pierre-Paul Riquet, 39Univ. Bordeaux, 40CHU de Strasbourg, 41Hôpital Pitié-Salpêtrière, 42CHU Lille, 43CHU de Montpellier, 44Hopital Cote De Nacre, 45Université Nice Cote d'Azur, 46CHU de Dijon, 47CHU de Besançon, 48Hopital Gabriel Montpied, 49Aix Marseille Univ, 50Hopital De La Pitie Salpetriere, 51Fondation De Rothschild, 52Nimes University Hospital, 53Hôpital de Poissy, 54CHU d’Amiens, 55CHU de Rouen, 56CHU De Grenoble, 57CHU de la Martinique, 58CHU de Limoges, Hôpital Dupuytren, 59APHP, Hôpital Henri Mondor, 60CHU de Saint-Étienne, Hôpital Nord, 61CHU de Tours, Hôpital Bretonneau, 62Hôpital Sud Francilien, 63Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis, 64CH de Pontoise, Hôpital René Dubos, 65CHU La Milétrie, Hôpital Jean Bernard, 66CHU Bicêtre, 67Centre Hospitalier de Versailles, 68CHU de Nantes, 69Dept of Neurology, Aalborg Hospital, 70University of Copenhagen, Rigshospitalet, 71Aalborg University Hospital, 72Aarhus University Hospital, 73University Hospital of Northern Sealand, 74Rigshospitalet Glostrup and Institute of Clinical Medicine, University of Copenhagen, 75Copenhagen University Hospital, Rigshospitalet in Glostrup, 76Copenhagen University Hospital Herlev, 77Hopital Neurologique Pierre Wertheimer
Objective:

To compare the relative treatment effects of natalizumab and fingolimod in subgroups with relapsing-remitting multiple sclerosis (RRMS).

Background:

Natalizumab has proved to be more effective than fingolimod in reducing disease activity in RRMS. Whether this association is universal for all patient groups remains to be determined.

Design/Methods:

RRMS patients from three international registries who were given natalizumab or fingolimod were stratified based on sex, age, disease duration, expanded disability status scale (EDSS) score, presence of relapses or disability worsening, and MRI activity 12 months prior to treatment initiation. Study outcomes were number of relapses and cumulative hazards of first relapse, 6-month confirmed disability worsening and improvement events, recorded during study therapy.

Results:

A total of 5,148 patients (natalizumab: 1,989; fingolimod: 3,159) were included with mean age at baseline of 37.91 (SD 10.07) years and majority (71.83%) female. The median on-treatment follow-up was 25.05 (quartiles 14.92-40.89) months. Natalizumab was associated with fewer relapses compared to fingolimod (incidence rate ratio, IRR [95% CI]) in females (0.76 [0.65-0.88]); age group≤38 years (0.64 [0.54-0.76]); disease duration≤7 years (0.63 [0.53-0.76]); EDSS score˂4 (0.75 [0.64-0.88]); ˂6 (0.80 [0.70-0.91]); ≥6 (0.52 [0.31-0.86]); and patients with pre-baseline relapses (0.74 [0.64-0.86]). Natalizumab was also more efficacious regardless of absence (0.62 [0.49-0.77]) or presence (0.46 [0.35-0.61]) of new MRI lesion within the year before treatment initiation. Higher probability of confirmed disability improvement on natalizumab vs. fingolimod (hazard ratio, HR [95% CI]) was observed among females (1.36 [1.10-1.66]); age group>38 years (1.34 [1.04-1.73]); disease duration˃7 years (1.33 [1.01-1.74]); EDSS score˂6 (1.21 [1.01-1.46]) and ≥6 (1.93 [1.11-3.34]); and patients with no new MRI lesions (1.73 [1.19-2.51]).

Conclusions:

Natalizumab is associated with lower relapse frequency and higher chance of improvement in disability than fingolimod, which is most pronounced in females, patients with lower disability, and with pre-treatment relapses.