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Natalizumab za liječenje relapsno‐remitirajuće multiple skleroze

Abstract

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Background

Natalizumab (NTZ) (Tysabri®) is a monoclonal antibody that inhibits leukocyte migration across the blood‐brain barrier, thus reducing inflammation in central nervous system, and has been approved worldwide for the treatment of relapsing‐remitting multiple sclerosis (RRMS).

Objectives

To evaluate the efficacy, tolerability and safety of NTZ in the treatment of patients with RRMS.

Search methods

We searched the Cochrane Multiple Sclerosis Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 1), MEDLINE (PubMed) and EMBASE, all up to 19 February 2010, and bibliographies of papers. Handsearching was carried out. Trialists and pharmaceutical companies were contacted. Furthermore, the websites of US Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMA) and the National Institute for health and Clinical Excellence (NICE) were also checked.

Selection criteria

All double‐blind, randomised, controlled trials analysing more than a single infusion of NTZ (dosage > 3 mg/kg intravenous infusion every 4 weeks), also including its use as add‐on treatment, versus placebo or other drugs in patients with RRMS. No restrictions on the basis of duration of treatment or length of follow up.

Data collection and analysis

Three reviewers independently selected articles which met the inclusion criteria. Disagreements were solved by discussion. Two reviewers independently extracted the data and assessed the methodological quality of each trial. Missing data was sought by contacting principal authors and Biogen Idec, through Biogen‐Dompé Italia.

Main results

Three studies met the inclusion criteria. These included one placebo‐controlled trial (942 patients) and two add‐on placebo‐controlled trials, i.e. one plus glatiramer acetate (110 patients) and the second plus interferon beta‐1a (1171 patients).

This review assessed the efficacy, tolerability and safety of NTZ in patients with RRMS. Data was conclusive with respect to efficacy and tolerability, but not safety. As far as efficacy is concerned, the results showed statistically significant evidence in favour of NTZ for all the primary outcomes and for the secondary ones where data was available. NTZ reduced the risk of experiencing at least one new exacerbation at 2 years by about 40% and of experiencing progression at 2 years by about 25% as compared to a control group. MRI parameters showed statistical evidence in favour of participants receiving NTZ. Infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis and menstrual disorders were reported as adverse events (AEs) more frequently after NTZ treatment. In this review NTZ was found to be well tolerated over a follow‐up period of two years: the number of patients experiencing at least one AE (including severe and serious AEs) during this period did not differ between NTZ‐treated patients and controls. Safety concerns have been raised about Progressive Multifocal Leukoencephalopathy (PML). In the trials included in this review, two cases of PML were encountered: one in a patient who had received 29 doses of NTZ and a second fatal case of PML in another patient after 37 doses of NTZ. Our protocol was insufficient to evaluate PML risk as well as other rare and long‐term adverse events such as cancers and other opportunistic infections, which are very important issues in considering the risk/benefit ratio of NTZ.

Authors' conclusions

Although one trial did not contribute to efficacy results due to its duration, we found robust evidence in favour of a reduction in relapses and disability at 2 years in RRMS patients treated with NTZ. The drug was well tolerated. There are current significant safety concerns due to reporting of an increasing number of PML cases in patients treated with NTZ. This review was unable to provide an up‐to‐date systematic assessment of the risk due to the maximum 2 year‐duration of the trials included. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs.

All the data in this review came from trials supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Plain language summary

Natalizumab za liječenje relapsno‐remitirajuće multiple skleroze

Vjeruje se da je kod multiple skleroze upala ključni proces koji uzrokuje nemogućnost provođenja impulsa kroz živce. Natalizumab (NTZ) je prvi od nove generacije protuupalnih terapija za multiplu sklerozu, a daje se intravenski svako 4 tjedna. Obično se propisuje nakon što su drugi lijekovi bili neuspješni ili ako se bolest brzo pogoršava.

Autori ovog Cochrane sustavnog pregleda procijenili su djelotvornost i sigurnost NTZ‐a u bolesnika s relapsno‐remitirajućom multiplom sklerozom (RRMS). U literaturi su pronađene 3 odgovarajuće studije koje su uključene, i u njima je sudjelovalo 2223 ispitanika. Rezultati pokazuju da terapije NTZ‐om smanjuje broj ispitanika koji su doživjeli relaps i broj ispitanika kojima je bolest napredovala nakon 2 godine. Koristan učinak NTZ‐a na aktivnost bolesti dokazan je i magnetskom rezonancom.

Iako su informacije o štetnim učincima terapije bile ograničene budući je većina bolesnika praćena 2 godine, među ispitanicima koji su primali NTZ uočene su sljedeće nuspojave: reakcije na infuziju, anksioznost, začepljenje sinusa, oticanje nogu, ukočenost, upala rodnice i menstrualni poremećaji. Međutim, broj ispitanika koji su doživjeli barem jednu štetnu reakciju (uključujući i teške i ozbiljne nuspojave) nije se razlikovao između osoba koje su uzimale NTZ i o osoba u kontrolnoj skupini. No, postoji ozbiljno upozorenje o mogućnosti razvoja progresivne multifokalne leukoencefalopatije, rijetke i često fatalne virusne bolesti koja je obilježena oštećenjem bijele tvari mozga. U studijama uključenima u ovaj sustavni pregled, PML je zabilježen u 2 pacijenta koja su liječena NTZ‐om dulje od 2 godine. Međutim, pronađeni podatci koji su predstavljeni u ovom sustavnom pregledu nisu bili dostatni da bi se procijenio rizik od PML‐a kao i potencijalne druge rijetke i dugoročne štetne reakcije (npr. karcinomi i druge upale) koje treba uzeti u razmatranje kad se razmatra o omjeru koristi i štete povezane s NTZ‐om. Nužan je neovisni sustavni pregled sigurnosnog profila NTZ‐a. NTZ bi trebali propisivati samo neurolozi koji su specijalizirani za MS, u kliničkim centrima i pacijente treba detaljno nadzirati.

Sve studije uključene u ovaj sustavni pregled financirala je farmaceutska industrija. U skladu s pravilima Cochranea, to se može smatrati potencijalnim izvorom pristranosti.