Immunomodulatory drugs for multiple sclerosis

teaser

William A Sheremata
MD FRCPC FACP
Professor of Neurology
Director of the Multiple Sclerosis Center

Sylvia Delgado
MD
Assistant Professor of Neurology
University of Miami School of Medicine
Miami, FL
USA
E:[email protected]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), typically associated with relapsing signs and symptoms of neurological disease.

Relapses may appear to remit entirely, especially early in the course of illness, or may be followed by residual neurological impairment. In many patients, there is eventually a stepwise increase in disability, associated with recurrent exacerbations of illness or an insidious increase in disability seemingly unrelated to preceding attacks. Half of patients suffer gait impairment at the outset of their illness, but there are many different neurological problems that may occur singly or in combination with others, such as optic neuritis (or internuclear ophthalmoplegia), vertigo and impaired sensation, as well as pathological fatigue.(1–3)

The aetiology of MS is unknown, but insights into the mechanisms of the disease have been given by studying immunological perturbations in patients with MS and in the experimental model, experimental allergic encephalomyelitis (EAE).(4) EAE may be induced by sensitisation to whole nervous tissue, myelin or myelin proteins. Since the original experimental work several decades ago, EAE has been an important model for the study of cell-mediated immunity and hypersensitivity. More recently, EAE has become important in the preclinical evaluation of immunomodulatory therapies in MS.

Treatment of MS

Interferon-beta
To appreciate the breaking news on treatment advances in MS, a review of recent therapeutic achievements is necessary (see Table 1). Interest in the management of MS is currently centred on reducing exacerbations of disease and preventing disability. In 1993 a significant, but modest, 33% reduction in the risk of exacerbations was reported with interferon-beta (IFNbeta)-1b (Betaseron, 250mg) administered on alternate days over three years.(5) Remarkably, brain magnetic resonance imaging (MRI) revealed a 9.3% decrease in the volume of white matter lesions in treated patients, vs a 15.0% increase in placebo recipients.(6) Subsequently, in a natural history crossover study, a remarkable 90% decrease in gadolinium-enhancing lesions was shown one month after initiation of IFNbeta-1b, demonstrating a remarkable impact on the blood–brain barrier (BBB).(7) This result was somewhat overshadowed by an absence of data showing a reduced risk of disability and by prominent side-effects.

[[HPE16_table1_94]]

In 1996, IFNbeta-1a (Avonex; 30mg intramuscularly [IM] weekly) was reported to achieve similar reduction (30%) for exacerbations over the two years of the study, in addition to a 37% reduction in the risk of “sustained progression”, the primary outcome measure used in the study.(8) IFNbeta-1a has been used in higher (22mg and 44mg) doses (Rebif), with the clinical outcomes resembling those of IFNbeta-1b.(9,10) However, in a more recent direct-comparison 16-month study, IFNbeta-1a (Rebif, 44mg three times a week) demonstrated superiority over IFNb-1a (Avonex, 30mg once a week).(11)

From the pivotal studies, the treatment effects of the IFNs appear to become eventually similar, the exception being that, with weekly IM injections, skin reactions do not occur and there is a decrease in the side-effects observed.

However, the Prevention of Relapses and disability by Interferon beta–1a Subcutaneously in Multiple Sclerosis (PRISMS)-4 study showed the advantage of a 44mg dose over 22mg three times a week in patients with relapsing- remitting MS who had previously been on placebo in the two-year study.(11) IFNb-1beta also has a significant effect in secondary progressive MS, reducing relapse rates and the proportion of patients progressing.(12)

Glatiramer acetate
Glatiramer acetate (Copaxone), a synthetic co-polymer resembling myelin basic protein in size and charge, demonstrated a similar modest reduction in the risk of exacerbations in a three-year study reported in 1997.(13) The frequency and severity of local and systemic reactions to glatiramer acetate are not as prominent as those observed with IFNbeta-1a and -1b. The effects of the drug on MS appear to be sustained over six years.(14)

Mitoxantrone
The use of IFNbeta-1b offers very modest rewards in secondary progressive MS.(12) Approval of the cytotoxic drug mitoxantrone (Novantrone) for relapse reduction and stabilisation of secondary progressive and “worsening” MS has been received cautiously as a toxic, incomplete, interim solution to a difficult clinical problem.(15)

Future approaches
Study of the mechanisms that govern egress of cells across the blood–brain barrier has identified potential targets for therapeutic intervention in inflammatory central nervous disease.(16) The BBB is ordinarily impermeable to both proteins and cellular elements in the intravascular compartment. Activated T-cells and macrophages gain access to the CNS by expressing adhesion molecules on their surface following immune activation and by binding avidly to counter-receptors on the surface of the cerebral endothelium. When the very late activation antigen (VLA-4, or alpha4beta1 integrin) on the surface of a lymphocyte binds to the vascular cell adhesion molecule (VCAM)-1 on cerebral endothelium, a series of events is initiated in the endothelial cell that allows egress of the lymphocyte.(17,18) The primacy of this molecular interaction was demonstrated in blocking the induction of EAE in the guinea pig by the use of a murine monoclonal antibody (MAb) to VLA-4.(17)

Human studies demonstrated the safety of intravenous (IV) natalizumab, a humanised version of the MAb,(19,20) with brain MRI studies demonstrating a remarkable effect of natalizumab on preventing new lesion formation. No significant impact was seen on recovery when natalizumab was given within 72h of onset of an acute exacerbation.(21) Nevertheless, a study of placebo vs natalizumab (3mg/kg and 6mg/kg) administered once a month over six months resulted in a 91% decrease in new, enhancing brain lesions.(22) Although this study was not powered to show a clinical effect, exacerbations were significantly reduced (by approximately 50%).

To put the study results in perspective, IFNbeta products and glatiramer acetate do not reduce exacerbations in the first six months of use, whereas natalizumab does.

Ongoing pivotal studies of natalizumab have provided additional safety data, with more than 2,800 patients included in the studies, years of experience and a favourable therapeutic outcome. Currently, Biogen-Idec and Elan are seeking regulatory approval in the EU, Canada and the USA, based on relapse rate reduction after one year of study.

Conclusion
Despite an incomplete understanding of its aetiopathogenesis, the era of rational therapy has arrived for MS. The success of natalizumab in the management of this disease will stimulate the use of MAbs targeting other antigens in the immunological cascade. Indeed, clinical studies of anti-interleukin (IL)-12 MAbs are already underway. The anti-macrophage migration inhibitory factor MAb also has a remarkable impact on EAE.

Despite the safety of use of natalizumab, the consequences of long-term therapy with MAbs are unknown. An impact of natalizumab on the prevention of disability is anticipated, but no information is currently available on this issue.

References

1. Compston A, et al. McAlpine’s multiple sclerosis. 3rd ed. London: Churchill Livingstone;1988.
2. Neurol Clin 1995;13:57-73.
3. N Engl J Med 2000;343:938-52.
4. J Exp Med 1960;111:119-36.
5. Neurology 1993;43:655-61.
6. Neurology 1993;43:662-7.
7. Neurology 1997;49:862-9.
8. Ann Neurol 1996;39:285-94.
9. Lancet 1998;352: 1498-504.
10. Neurology 2001;56:1628-36.
11. Neurology 2002;59:1496-506.
12. Neurology 1995;45:1268-76.
13. Mult Scler 2000;6:255-66.
14. Lancet 1998;352:1491-7.
15. Lancet 2002;360:2018-25.
16. Mult Scler 2003;9:540-9.
17. Nature 1992;356:63-6.
18. N Engl J Med 2000;343:1020-34.
19. Neurology 1999;52:1072-4.
20. Neurology 1999;53:466-72.
21. Neurology 2004;62:2038-43.
22. N Engl J Med 2003;348:15-23.