2005 overview: Developments in clinical MS research

The past year has brought many important results in clinical Multiple Sclerosis (MS) research. This overview will bring you some key learning messages that I found significant in 2005.

Natalizumab

The promising 1-year results of the phase III natalizumab trials (the first drug in a new class of agents called selective adhesion molecule inhibitors) were recognized in the end of 2004. US Federal Drug Agency (FDA) granted Priority Review and Accelerated Approval, and the drug was approved in November 2004.

Three months later, in February 2005, natalizumab was withdrawn after two cases of progressive mulitfocal leucoencephalopathy (PML) (ref. 1; ref. 2). Both were trial patients on combined therapy with natalizumab and IFNb-1a (Avonex) and one case was fatal. A third case was disclosed retrospectively from a Crohn disease study who died from a presumed astrocytoma, later re-diagnosed as PML (ref. 3).

These tragic events naturally raise the question, whether new therapeutic agents interfering with basic immunological mechanisms, should be released without appropriate safety and efficacy data. The results of the two natalizumab trials (AFFIRM and SENTINEL) have still not been published in a peer-reviewed journal, although they have now been presented in their full range.

The clinical efficacy (AFFIRM) data look promising, with an annualized relapse rate reduction of 68% and a 42% reduction of risk of sustained disability progression. There is an obvious need for a detailed safety evaluation of the drug before it may be used again in clinical practice, although it seems clear that the last chapter has not been written in the natalizumab story.

Another lesson learned in the antibody story

Interferon-beta (IFNb) is the preferred first line treatment in MS, although another lesson was learned in the antibody story. Sorensen et al. (ref. 4 ) showed that neutralizing antibodies (NABs) against IFNb develops in a considerable proportion of treated patients after 12 months of therapy.

The authors found large differences between different commercial preparations, since IFNb-1a (Avonex) was much less immunogenic compared with IFNb-1b (Betaferon) and IFNb-1a (Rebif). These data may question results of previous head to head trials, showing an advantage of Rebif and Betaferon compared with Avonex. The duration of these studies was relatively short and the effect of NABs therefore presumably not reflected in the data.

Controversy still exists regarding patients that convert from definite NAB positive to NAB negative status, which the authors report to be 34%. Do these patients regain biological response to IFNb? There are still important questions that need to be answered regarding NABs and IFNb, although the recently published guidelines on the use of anti-IFNb antibody measurements in multiple sclerosis (ref. 5) pursue some of the basic problems in this regard.

Cognitive impairment

Cognitive impairment affect approximately 50% of all MS patients, but surprisingly few studies have looked at treatment options in this regard. Inspired by the positive results of cognitive enhancing treatment in Alzheimer disease, Krupp et al. used the new acetylcholineesterase inhibitor donepezil in 69 patients with MS, who had mild verbal memory impairment (ref. 6). The patients were randomized to donepezil or placebo and the authors found improvement of memory performance in the donepezil group.

It was later commented, that the use of anticholonergic bladder medication may have worsened the cognitive performance of the subjects and weakened the conclusions of the study (ref. 7). Hopefully the paper may inspire new studies in this field, which in turn could result in new treatment options for this disabling symptom.

Major pathophysiological contribution

A major contribution in the pathophysiological field was brought by Kutzelnigg et al. (ref. 8) presenting unique results from archival autopsies of 52 MS cases. The authors distinguished acute and relapsing from progressive MS, using a quantitative morphological technique. The essence of their hypothesis is that MS may start as a focal inflammatory disease, although it slowly becomes compartmentalized in the CNS in progressive disease. This will in turn lead to widespread neurodegeneration, characterized by axonal injury in the normal appearing white matter as well as cortical demyelination.

Looking at progressive MS as a diffuse low grade CNS inflammation with extensive neurodegenerative impact, may explain why this disease stage seem to be refractory to disease modifying treatments. It is of great interest to characterize the pathophysiological processes in progressive MS in order to explore future therapeutic options.

Activated microglia

In this regard, activation of microglia is considered to be one of the central pathophysiological events, and a study from Versijpt et al. (ref. 9) showed interesting data. Activated microglia express the peripheral benzodiazepine receptor that can be visualized in vivo using PET and the radiolabelled ligand PK11195.

In a study of 22 MS patients, the authors showed a correlation between PK11195 uptake and MRI measurements of cerebral atrophy in normal appearing white matter (NAWM). For the first time a relationship between subtle and diffuse inflammatory changes in normal appearing cerebral tissue and axonal/neural loss in MS is actually demonstrated.

With methodological refinement of tracer kinetics and quantification, PET could provide information of a central pathogenic process in MS, which may determine disease outcome. The effect of different treatment regimens on activated microglia is also of great interest in this context.

Cladribine

New interesting drugs are going into phase III trials in the end of 2005 and beginning of 2006. Cladribine is an antineoplastic agent, which has shown significant effectiveness and safety in the cure of hairy-cell leukemia, and the control of many other lymphoid malignancies.

Cladribine has a selective and sustained effect on CD4 T-cells, which makes it a possible candidate for a disease-modifying agent in MS. A previous randomized and controlled study have shown significant beneficial effect of cladribine, with regard to annualized relapse rate, MRI T1 enhancing lesions as well as T2 lesion volume, in patients with relapsing remitting MS. 

FTY720

FTY720 is a S1P receptor modulator, which selectively impair autoreactive T-cell homing, without significant effect on other components of the immune response. Results of a phase II study using two doses of FTY720 and placebo has been reported, showing more than 50% reduction of relapses and up to 80% reduction of MRI activity (Gd+ lesions).

Like cladribine, FTY720 is orally administered, which supposedly will optimize treatment compliance and thereby also efficacy.

Combination studies

Combination studies with interferon-beta are also increasing in numbers. Two well known drugs, Simvastatin and Minocycline, which both have significant immunomodulatory properties, are starting up as multicentre phase IV studies in combination with interferon-beta-1a.

Together with the numerous ongoing clinical trials, these studies will increase the effort to find better treatment options, and in the near future I believe we will have greater diversity of therapies and better treatment efficacy in MS.

References

1. Kleinschmidt-DeMasters BK and Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. New England Journal of Medicine 2005; 353 (4); 369-374

2. Langer-Gould A, Atlas SW, Green AJ, Bollen AW and Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. New England Journal of Medicine 2005; 353 (4); 375-381

3. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. New England Journal of Medicine 2005; 353 (4); 362-368

4. Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM and Bendtzen K. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 2005; 65 (1); 33-39

5. Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. European Journal of Neurology 2005; 12 (11); 817-827

6. Krupp LB, Christodoulou C, Melville P, Scherl WF, MacAllister WS and Elkins LE. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63 (9); 1579-1585

7. Tsao JW and Heilman KM. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2005; 64 (10); 1823; author reply 1823.

8. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128 (11); 2705-2712

9. Versijpt J, Debruyne JC, Van Laere KJ, De Vos F, Keppens J, Strijckmans K, et al. Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study. Multiple Sclerosis 2005; 11 (2); 127-134