Neurological Sciences

, 30:155

Treatment of multiple sclerosis: role of natalizumab

Authors

    • Department of Neurology, Institute of Experimental NeurologyScientific Institute San Raffaele Vita-Salute University
MS Treatment

DOI: 10.1007/s10072-009-0147-2

Cite this article as:
Comi, G. Neurol Sci (2009) 30: 155. doi:10.1007/s10072-009-0147-2

Abstract

The results on relapse rate and disease progression of available drugs for multiple sclerosis are shown, as well as their most relevant side effects. Results from pivotal and long-term follw-up studies support the efficacy and safety of intererons and glatiramer acetate. The treatment with mitoxantrone is limited by the occurrence of infertility, cardiotoxicy and leukaemia. Efficacy and tolerability of natalizumab are undisputable, compared to other drugs. Risks related to its treatment are PML, opportunistic infections, hepatotoxicity, melanoma, and their occurrence needs to be more exactly assessed by post-marketing surveillance. The principles of induction versus escalating therapy are also discussed. The final therapeutic decision is based on the evaluation of the disease state and prognosis, based on clinical and instrumental measures, and on the safety/efficacy profile of each treatment.

Keywords

Interferon-betaGlatiramer acetateMitoxantroneNatalizumab

Introduction

The number of treatments for multiple sclerosis (MS) will increase in next 1–3 years, considering the number of new drugs in advanced phase III clinical trials. The availability of old and new treatments will require for a correct use, a deep knowledge of the potential benefits and risks of each treatment, how to use them, which first and which second, how to combine treatments, if utilise the escalating or the induction approach.

Interferons and glatiramer acetate

Five immunomodulatory treatments (interferon β 1a—Avonex, interferon β 1a—Rebif 22 and 44 mcg, interferon β-1b—Betaseron, glatiramer acetate (GA)—copaxone and natalizumab—Tysabri) and one immunosuppressive treatment (mitoxantrone) have been approved for MS patients with a relapsing course [18]. The effects of available treatment on disease activity and disability progression are reported in Table 1. The impact of IFNs and GA on disease activity is undisputable. On the contrary, the efficacy of these drugs on disability progression has been considered less convincing, incomplete and controversial [9]. A trend for an effect of IFNs and GA was detectable in all the clinical trials; however statistical significance of delayed progression to selected EDSS end points was demonstrated only in one clinical trial for RRMS [2]. Both methodological problems, such as short study period, limited study sample size, EDSS measurement limitations, study population selection bias, or a real modest impact of IFNs and GA on the mechanisms underlying the irreversible nervous damage in MS could explain the controversial results observed on disability. Both IFNs and GA have a quite safe profile, and modest tolerability problems. Long term follow up studies [8, 1012] concordantly support the efficacy and safety of interferons and GA in RRMS patients.
Table 1

Efficacy of IFNβ and glatiramer acetate versus placebo over 2 years in pivotal clinical studies of patients with MS

 

IM IFNβ-1a

SC IFNβ-1 (44 μg dose)

IFNβ-1b (8 MIU dose)

Glatiramer acetate

Relapse rate % reduction

32%; P = 0.002 [2]

32%; P < 0.005 [3]

34%; P = 0.0001 [1]

29%; P = 0.007 [39]

Relapse free % of patients

38 versus 26%; P = 0.03 [2]

32 versus 16%; P < 0.005 [3]

31 versus 16%; P = 0.007 [1]

34 versus 27%; P = 0.098 [39]

Disability progression % reduction

37%; P = 0.02 [2]

31%; P < 0.05 [35, 36]

29%; P = NS [1]

12%; P = NS [39]

Number of Gd+ lesions % reduction

52%; P = 0.05 [2]

84%a; P < 0.001 [35, 37]

NR

29%a; P = 0.003 [40]

Number of new or enlarging T2 lesions % reduction

33%; P = 0.002 [34]

78%; P < 0.0001 [37]

83%; P = 0.009 [38]

31%a; P < 0.003 [40]

Gd+ Gadolinium-enhancing, IFNβ interferon beta, MS multiple sclerosis, NS not statistically significant, NR not reported

aAssessed at 9 months

Mitoxantrone

Mitoxantrone is an anthracycline derivative, which achieves its cytotoxicity by arresting the cell cycle at the G2-M and S interphase. A series of controlled and uncontrolled studies demonstrated that the drug dramatically reduces the clinical and MRI activity in relapsing remitting and active secondary progressive MS with a significant impact on disability [1315]. Unfortunately with the progressive use of the drug in MS patients three major adverse effects emerged: infertility, cardiotoxicity [15] and acute myeloid leukaemia [16]. Left ventricular ejection fraction usually start to decrease when a cumulative dose of 120 mg/m2 is reached; however some exceptional cases have been reported after low doses of the drug [17, 18]. The risk of cariotoxicity is increased in older patients, perhaps relating to subclinical cardiac disease. The risk of acute myelogenous leukaemia has been for long time underestimated [16]. Two recent studies [19, 20] revealed a much higher risk of leukaemia. The first is a study on 5,472 patients combining together the results of searched literature for publications relating to mitoxantrone use in MS and a local data base. The overall risk was 1:333. The second study is a multicentre retrospective Italian survey of 2,854 cases with an even higher risk of 1:140 treated patients. In both studies the vast majority of AML occurred in patients exposed to >60 mg/m2.

Natalizumab

Natalizumab is a humanized monoclonal antibody targeting α4-integrin, a component of VLA-4 present on leukocytes. Binding of the antibody block the interaction with the ligand VCAM on the surface of endothelial cells at the level of blood brain barrier, reducing the transmigration of lymphocytes [21, 22] diminishing the inflammatory activity in EAE [23]. A phase II clinical trial [24] and two phase 3 clinical trials [5, 6] provided evidences on the magnitude of the efficacy of natalizumab in RRMS. Three months after the accelerated approval of the agent by FDI, two cases of progressive multifocal leukoencephalopathy (PML) was diagnosed in two patients from the SENTINEL trial who received a combination of interferon β 1a im and natalizumab and in another patient who received the treatment for a Crohn’s disease. Other opportunistic infections, probably due to a prolonged immunosuppression in peripheral organs [25] were also reported. On June 2009, approximately 50,000 patients were treated with natalizumab, 12,000 since at least 2 years. Seven new cases of PML in natalizumab treatment alone emerged in post marketing surveillance, none with an exposure inferior to 12 months. The exact risk of PML in patients in long term treatment is unknown. Other severe side effects of the drug include hepatotoxicity and melanoma [26, 27]. Compared to IFNs and GA, the absence of published systematic long term follow-up of pivotal clinical trials and of post marketing studies do not allow to conclude on the risk of this treatment. On the contrary, the efficacy is undisputable.

Indirect comparison of the results of clinical trials [16, 8] and of the head to head clinical trials [2830] indicate that: (a) interferon β-1b sc and interferon β-1a sc multi weekly injections are superior to interferon β-1a im once a week in the reduction of relapse rate; (b) GA compared to interferon β-1b sc and interferon β-1a sc has similar effects on relapse rate and lower effects on MRI activity; (c) natalizumab is superior to IFNs and GA on clinical measures.

The presently availability of multiple therapeutic options for MS and the probable further increase of disease modifying agents in the near future, as indicated by the large number of drugs in advanced phase III studies, provide the clinician the possibility to prescribe individualised treatments. The decision should be essentially based on the careful evaluation of the disease state and of the prognosis, based on clinical and instrumental measures and on the specific safety/efficacy profile of each treatment.

Induction versus escalating therapy

From the theoretical point of view, there are two opposite schemes of treatments: the escalating approach and the induction therapy. The rationale of escalating therapy is to start treatment with safe drugs and to move to more aggressive treatments only in case of failure of the ongoing treatment. The induction strategy is supported by the accumulating evidences that the disease prognosis is mostly defined in the early phase of the disease. Moreover because the target of all the approved treatments is inflammation, which predominates at the beginning of the disease course it is logical to concentrate all the therapeutic efforts in the early phases of the disease.

The escalating approach sees as first line treatment GA and beta interferons and as second line mitoxantrone and natalizumab. third line the combination therapy and forth line the very intensive immunosuppression (autologus bone marrow transplantation, high dose cyclophosphamide). The efficacy profile of mitoxantrone and natalizumab are very similar, having in mind all the methodological limitations of such indirect comparisons. On the contrary there are no doubts that natalizumab has a better safety profile, because fertility is not affected and the risk of PML is largerly lower than the risk of cardiotoxicity and acute leukaemia.

The induction approach is at present advisable in patients with breakthrough disease course only. About 15% of MS patients receive natalizumab as first line treatment because an aggressive course of the disease. The per cent of patient treated with mitoxantrone for the same indication is unknown, however the drug has been recommended by some guidelines [31]. Again the safety problems indicate a preference for the use of natalizumab, however the possibility of short courses of mitoxantrone can be considered, because both cardiomyopathy and leukaemia are rare for cumulative doses lower than 60 mg/m2 [20, 32, 33].

Conflict of interest statement

The authors declare that they have no conflict of interest related to the publication of this article.

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© Springer-Verlag 2009