RESEARCH PAPER Ef cacy and safety of natalizumab in ...

1 Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as on 14 February 2014. Downloaded from on 29 November 2018 by guest. Protected by RESEARCH PAPER . ef cacy and safety of natalizumab in multiple sclerosis: interim observational programme results Helmut Butzkueven,1,2 Ludwig Kappos,3 Fabio Pellegrini,4 Maria Trojano,5. Heinz Wiendl,6 Radhika N Patel,7 Annie Zhang,7 Christophe Hotermans,7. Shibeshih Belachew,7 on behalf of the TYSABRI Observational Program (TOP). Investigators Additional material is ABSTRACT While the AFFIRM trial established the safety published online only. To view Background Clinical trials established the ef cacy and and ef cacy of natalizumab , data are needed to please visit the journal online ( safety of natalizumab . Data are needed over longer con rm the safety and ef cacy of natalizumab over jnnp-2013-306936).

2 Periods of time and in the clinical practice setting. treatment durations longer than 2 years and, Objective To evaluate long-term safety of natalizumab importantly, in a clinical practice setting. For numbered af liations see end of article. and its impact on annualised relapse rate and Expanded The Tysabri ( natalizumab ) Observational Disability Status Scale (EDSS) progression in patients with Program (TOP) was designed to evaluate the long- Correspondence to relapsing-remitting multiple sclerosis (RRMS). term safety of natalizumab monotherapy, as well as Dr H Butzkueven, Methods The Tysabri ( natalizumab ) Observational its impact on disease activity and disability progres- Department of Medicine, Royal Melbourne Hospital Brain Program (TOP) is an open-label, multinational, 10-year sion, in patients with RRMS in the clinical practice Centre, University of prospective study in clinical practice settings.

3 Setting. This PAPER presents ndings from an Melbourne, Level 4 East, Royal Results In this 5-year interim analysis, 4821 patients interim analysis of TOP data from study initiation Melbourne Hospital Campus, were enrolled. Follow-up for at least 4 years from in July 2007 to a data lock on 1 December 2012. Grattan Street, Parkville, natalizumab commencement in 468 patients and at least Melbourne, VIC 3050, Australia; 2 years in 2496 patients revealed no new safety signals. METHODS. There were 18 cases of progressive multifocal Patients copyright. leucoencephalopathy reported, following 11 44. Received 3 October 2013 Eligible RRMS patients met criteria for natalizumab natalizumab infusions. Mean annualised relapse rate Revised 20 December 2013 prescription in their respective countries and had Accepted 27 December 2013 decreased from in the 12 months prior to baseline three or fewer natalizumab infusions before enrol- Published Online First to on natalizumab therapy ( p< ), remaining ment in TOP.

4 Female participants were postmeno- 14 February 2014 low at 5 years. Lower annualised relapse rates were pausal, surgically sterile, or willing to practice observed in patients who used natalizumab as rst MS. effective contraception. therapy, in patients with lower baseline EDSS scores, and Patients were enrolled as soon as possible after in patients with lower prenatalizumab relapse rates. deciding to start natalizumab treatment. The latest Mean EDSS scores remained unchanged up to 5 years. permissible enrolment date was the day before Conclusions Interim TOP data con rm natalizumab 's patients' fourth natalizumab infusion (ie, 16 weeks overall safety pro le and the low relapse rate and after the start of natalizumab treatment). stabilised disability levels in natalizumab -treated patients The protocol was approved by each centre's with RRMS in clinical practice.

5 Independent ethics committee. The study was per- Trial registration number NCT00493298. formed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All Open Access patients provided written informed consent. Scan to access more free content INTRODUCTION. Study design natalizumab (Tysabri, Biogen Idec Inc, Cambridge, TOP is an ongoing, open-label, multinational, mul- Massachusetts, USA) is a selective adhesion mol- ticentre, prospective, observational study conducted ecule inhibitor that blocks 4 integrin, which is in clinical practice settings in Europe, Australia, expressed on the surface of lymphocytes and is Canada and Argentina. Patients receive natalizumab required for endothelial adhesion, facilitating jnnp-2013-307355 300 mg intravenously over approximately 1 h, migration of peripheral blood lymphocytes into the every 4 weeks.

6 Central nervous In the 2-year, phase 3 AFFIRM study2 of patients with relapsing-remitting multiple sclerosis (RRMS), Endpoints and assessments natalizumab monotherapy demonstrated consistent Data were collected at regular clinical visits every ef cacy in the overall study population and across 6 months. Data entry was Web based. Patients who To cite: Butzkueven H, multiple subgroups of patients prede ned on the discontinued natalizumab were encouraged to Kappos L, Pellegrini F, et al. basis of demographic and baseline disease remain in the study; if patients exited the study for J Neurol Neurosurg characteristics, including age, sex, number of brain any reason, physicians were asked to collect data Psychiatry 2014;85: MRI lesions, disability status and number of on serious adverse events for an additional 1190 1197.

7 Relapses in the prior 3 6 months where possible. 1190 Butzkueven H, et al. J Neurol Neurosurg Psychiatry 2014;85:1190 1197. Multiple sclerosis J Neurol Neurosurg Psychiatry: first published as on 14 February 2014. Downloaded from on 29 November 2018 by guest. Protected by The primary endpoint is long-term safety (incidence and type We also performed analyses comparable to those used in recent of serious adverse events). Secondary endpoints include mea- clinical trials, in which con rmed EDSS progression was de ned sures of MS disease activity (ie, the occurrence of clinical as an increase, sustained for 6 months, of points from a relapses) and change in Expanded Disability Status Scale (EDSS) baseline EDSS score , of point from a baseline EDSS. score. Multiple Sclerosis Severity Scale4 scores were recorded at score of to < or of points from a baseline EDSS.

8 Baseline. score of 5 Con rmed EDSS improvement was assessed in A clinical relapse was de ned as new or recurrent neurological the overall population and in patients with baseline EDSS scores symptoms, not associated with fever, lasting for 24 h and fol- and was de ned as a decrease of point in EDSS score lowed by a period of 30 days of stability or improvement. New sustained for 6 or recurrent neurological symptoms that occurred <30 days fol- Medical review of each case report was performed at the end lowing the onset of a protocol-de ned relapse were considered of data entry. Serious adverse events were evaluated for possible part of the same relapse. clinical signi cance or indication of a previously unknown risk. Con rmed EDSS progression was de ned per protocol as an The Drug safety Department at Biogen Idec evaluated serious increase of point in EDSS score sustained for 6 months.

9 Adverse event reports to ensure case validity and con rm Table 1 Baseline characteristics Characteristics TOP (N=4821) AFFIRM overall (N=942) AFFIRM natalizumab (n=627). A. Baseline characteristics of patients currently enrolled in TOP, compared with AFFIRM patients Mean age, years (SD) ( ) ( ) ( ). Female, n (%) 3466 (72) 660 (70) 449 (72). Mean number of relapses in prior year (SD) ( ) ( ) ( ). Number of relapses in prior year, n (%). 1 1713 (36) 560 (59) 374 (60). >1 3108 (64) 382 (41) 253 (40). EDSS score, mean (SD) ( ) ( ) ( ). EDSS score, n (%). 1297 (27) 510 (54) 339 (54). copyright. 2114 (44) 369 (39) 246 (39). 1386 (29) 63 (7) 42 (7). B. Additional baseline characteristics of patients currently enrolled in TOP. EDSS score, n (%)*. < 1773 (37). 3024 (63). MSSS score, mean (SD) ( ). Prior treatment Yes, n (%) 4384 ( ).

10 Prior number of DMTs used, n (%). 0 DMT 437 (9). 1 DMT 2213 (46). 2 DMTs 2171 (45). Treatment history, n (%). Therapy na ve 437 (10). IFN only 2131 (47). GA only 421 (9). Switched between GA and IFN 855 (19). Prior IS use** 697 (15). Disease duration . Median duration, years (range) ( ). Duration 8 years, n (%) 2203 (46). Treatment duration Median duration, years (range) ( ). Mean duration, years (SD) ( ). Duration 3 years, n (%) 2435 (51). *n=4797. n=4728. Ninety-three patients were not included because of missing baseline EDSS or disease duration information, and/or disease duration greater than 30 years (MSSS calculation does not include durations >30 years). n=4541. Two hundred eighty patients were not included because of use of other therapies, such as fingolimod, and combination with various steroid treatments.