220 Safety of multiple sclerosis patients treated by natalizumab (Network EDMUS)

Background Natalizumab, a monoclonal antibody, has shown efficacy in reducing the relapse rate and delaying disability accumulation in relapsing remitting (RR) multiple sclerosis (MS) patients. However, severe opportunistic infections and infusion reactions have been observed in clinical trials. Therefore, a national risk management plan (RMP) has been launched in France by AFSSAPS with the participation of FFN. Evaluation of the benefit/risk ratio (BRR) of natalizumab in real life settings will give a measurement of the RMP impact. Objectives The main objective of the TYSEDMUS study is to establish the safety profile of natalizumab in real life settings. Secondary objectives are to describe the conditions for use of the treatment, the clinical evolution of the patients in terms of relapses and disability, and to compare the occurrence of malignancies and serious infections in this natalizumab-exposed population vs a non-exposed one. Methods TYSEDMUS is a multicentre observational cohort study promoted by AFSSAPS (Agence Francaise de Securite Sanitaire des Produits de Sante) involving French neurologists prescribing natalizumab. It aims at including all the patients exposed at least once to natalizumab. Patients9 characteristics under natalizumab (including clinical evolution), utilisation patterns of natalizumab and occurrence of adverse events are described and included in EDMUS databases. A group of non-exposed patients, never treated with natalizumab, either receiving or not other immuno-active therapies, will be later extracted from the EDMUS databases for comparison. Preliminary Results The study has been launched in November 2007. The follow-up duration is planned to be at least 5 years. By October 2009, a total of 1296 patients had been recruited. Study methods and descriptive results regarding the first 873 patients (76% female) are presented. The French neurologists mainly followed the requirements of the RMP recommendations. The overall tolerance of natalizumab was quite good. Less than 4% of the patients experienced a serious adverse event (SAE), and there had been no report of unexpected side effects. 31 serious adverse events had been reported in 29 patients, some of them not life-threatening. 16 led to treatment discontinuation; the other patients remained on TYSABRI®. Reported SAE were one cardiac arrest 3 weeks after the second infusion, 10 allergic or anaphylactic reactions, 5 suicide attempts, 7 non-opportunistic infections which fully and rapidly recovered, 1 liver enzyme increase (persisting after natalizumab discontinuation), 1 hypereosinophilia, 1 rectal carcinoma (discovered after 7 infusions), 1 severe MS relapse and 4 miscellaneous. No case of Progressive Multifocal Leucoencephalopathy had yet been reported by October 2009 in the data base. 47/873 patients discontinued treatment (5.4%). Among patients followed 1 year or more, the Annualized Relapse Rate (ARR) decreased from 2.0±1.2 to 0.2±0.4 (N=286, 90% reduction, p Conclusion The TYSEDMUS study should allow to evaluate the BRR and the good practice in the long term use of natalizumab in France. Etat des lieux Le natalizumab, anticorps monoclonal, reduit la frequence des poussees et retarde la progression du handicap des patients atteints de scleroses en plaques (SEP) remittentes. Toutefois des infections opportunistes graves et des reactions allergiques ont ete observees dans les essais therapeutiques. Un plan de gestion de risque a ete mis en place en France par l9AFSSAPS avec l9aide de la FFN. L9evaluation du rapport benefice risque en situation de vie reelle permettra de mesurer l9efficience de ce plan de gestion de risque. Objectifs L9objectif principal de l9etude Tysedmus consiste en l9analyse du profil de securite du natalizumab en situation d9utilisation reelle. Les objectifs secondaires sont la description des conditions d9utilisation en relation avec le plan de gestion de risque, l9evolution clinique des patients en terme de frequence des poussees et de progression du handicap, et de comparer la frequence de survenue d9affections malignes et/ou d9infections severes chez les patients exposes au natalizumab versus une groupe de SEP non exposes. Methodes TYSEDMUS est une etude observationnelle multicentrique de cohorte dont le promoteur est l9AFSSAPS soutenue par la FFN. Elle implique les neurologues francais qui prescrivent le natalizumab. Son objectif est d9inclure tous les patients exposes au moins une fois a une perfusion de natalizumab. Les caracteristiques cliniques et evolutives des patients, les strategies d9utilisation et le recensement des effets indesirables sont decrits et inclus dans la base de donnees EDMUS. Un groupe de patients atteints de SEP non exposes, recevant ou pas d9autres immunosuppresseurs, sera secondairement extrait de la base de donnees pour comparaison. Resultats preliminaires L9etude a debute en novembre 2007. La duree de suivi prevue est de 5 ans au moins. Au mois d9octobre 2009, un nombre total de 1296 patients avait ete recrute. Les resultats concernant les 873 premiers patients (76% de femmes) est presente. Les neurologues francais suivent en majorite les recommandations d9utilisation du plan de gestion de risques. La tolerance generale du produit est plutot bonne. Moins de 4% des patients ont presente un evenement indesirable grave (EIR) et aucun effet indesirable inattendu n9a ete rapporte (31 EIR pour 29 patients). 16 EIR ont conduit a une interruption de traitement ; les autres patients ont ete maintenus sous traitement. Les EIR rapportes sont les suivants : 1 arret cardiaque 3 semaines apres la 2eme perfusion, 10 reactions anaphylactiques ou allergiques, 5 tentatives de suicide, 7 infections non-opportunistes avec guerison complete rapide, 1 augmentation des enzymes hepatiques ayant persiste apres l9arret du natalizumab, 1 hypereosinophilie, 1 carcinome rectal (decouvert a la 7eme perfusion), 1 poussee severe de SEP et 4 EIR classes divers. A la date de l9analyse des donnees aucun cas de LEMP n9avait encore ete rapporte dans la base de donnees. Parmi les patients suivis au moins un an ou plus, la frequence annuelle des poussees a diminue de 2±1.2 a 0.2±0.4 (N=286, 90% reduction, p Conclusion L9etude Tysedmus permettra l9evaluation du plan de gestion de risques et des pratiques d9utilisation du natalizumab en France.