2006 overview: Developments in clinical MS research

One of the most marked events in 2006 was the reintroduction of natalizumab. The drug was withdrawn since progressive multifocal leukoencephalopathy (PML) developed in three patients treated with natalizumab. A risk estimate for developing PML on natalizumab treatment, has now been calculated to approximately 1 in 1000 patients (ref. 1), based on a mean observation period of only 17.9 months.

We do not know if long-term use will increase this risk, and appropriate caution has to be taken while reintroducing the drug. The European Agency for the Evaluation of Medicinal Products (EMEA) recommend that Natalizumab treatment should be given as monotherapy, restricted to patients who are not responding to standard immunomodulatory treatment or patients with aggressive RRMS, until more substantial safety data are available.

Natalizumab is an α4 integrin antagonist that attenuates the inflammatory process in MS by inhibiting migration of lymphocytes to the CNS. The results of the large phase III trials AFFIRM (ref. 2) (Natalizumab vs. placebo) and SENTINEL (ref. 3) (Natalizumab and Interferon beta-1a vs. placebo and Interferon beta-1a) were eventually published this year. Both studies (AFFIRM/SENTINEL) showed reduction of sustained progression of disability (42%/24%) as well as reduction of relapse rate (68%/55%) during the first year, and reduction in accumulation of new or enlarging T2 hyperintense lesions (83%/83%) over two years.

There is no doubt that Natalizumab is an efficacious treatment and that MS patients need better disease modifying drugs, but the question is still to what limit these treatments can be maintained, without inducing potentially lethal conditions.

A number of new MS treatments are on the way and the results from two promising candidates were published in 2006.

Fingolimod (FTY-720) is an oral sphingosine-1 receptor modulator that indirectly inhibits neuro-inflammation by sequestering lymphocytes in lymphoid tissue. This mechanism of action is favorable, since the induced lymphopenia can be reversed by cessation of treatment. Furthermore, Fingolimod seem to have a direct immunomodulating effect on sphingosine-1 receptors in the CNS, although this effect is still poorly described.

A double blind, placebo-controlled, phase II study (ref. 4) of 281 relapsing-remitting MS (RRMS) patients receiving oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or placebo once daily, showed that annualized relapse rate was reduced 55% in the 1.25 mg group and there was no gain of the higher dose of 5.0 mg showing 53% reduction. Since serious adverse events were also increased in the high dose group, doses lower than 1.25 mg will be explored in future trials.

Interesting results were published by Warren et al. (ref. 5), using induction of immunotolerance in MS patients. This new treatment approach is desirable since it does not affect immunological activities unrelated to the disease, which is usually a problem for several MS immunomodulatory or immunosuppressive treatments. The central region of myelin basic protein (MBP) is an immunodominant epitope recognized by T-cells in HLA-DR2 positive MS patients, and is also a dominant target of MS autoantibodies.

The authors used the MBP residues 82-98 for tolerance induction in 32 patients with primary or secondary progressive MS in a double blind, placebo-controlled phase II clinical trial. MBP8298 was administered i.v. as a dose of 500 mg every 6 months for 24 months. The results showed a significant effect of treatment in HLA haplotypes DR2 and/or DR4 compared with placebo.

Long term follow up in this group showed a median time to progression of 78 months for the MBP8298 group, compared with 18 months for the placebo group. There were no significant adverse events and the safety profile was considered benign. MBP8298 seem to be a very promising treatment in HLA DR2 and/or DR4 primary or secondary progressive MS patients and results from an ongoing phase III study will be available in 2009.

Results of the CHAMPS (ref. 6) and ETOMS (ref. 7) study have shown that conversion from clinically isolated syndrome (CIS) to clinically definite MS (CDMS) is delayed by interferon beta-1a (IFNβ-1a) after 3 years. Long-term data were published in 2006 (ref. 8) showing that conversion to CDMS was delayed by 35% after 5 years compared to delayed initiation of therapy.

The statistical evaluation furthermore showed that adjusting for potential confounding effects might increase this delay to 43%. These results indicate that the effect of IFNβ-1a is sustained over time, and that immediate intervention has beneficial effect compared with delayed treatment initiation. Although the study design was open-label and therefore primarily providing information on drug safety, the results strengthens the incitement for early treatment with IFNβ-1a.

Effect of early intervention was also reported in a new randomized placebo controlled study on IFNβ-1b treatment of CIS (BENEFIT) (ref. 9). A dose of 250 mcgr IFNβ-1b was administered every second day for a period of 2 years. Results showed that conversion to CDMS was reduced by 47% (50% adjusted for confounding covariates) and prolonged by 363 days in the treatment group, which is in line with results obtained in the CHAMPS study of IFNβ-1a 30 mcgr weekly.

An interesting feature of the BENEFIT study was that robust treatment effect was found throughout all MRI subgroups, but the patients with monofocal clinical presentation and fewer T2 MRI lesions apparently had stronger treatment effect. This was not the case in the IFNβ-1a CHAMPS trial, and to some extent the ETOMS trial, where patients with more inflammatory disease activity on MRI had a higher relative effect of treatment.

The need for individualization of immunomodulatory treatment and prediction of disease course is evident in early MS and reliable prognostic markers have long been sought. The ideal situation would be if a simple blood test could provide the necessary information, which in fact have been hypothesized in a previous study (ref. 10).

Rauer et al. tested this hypothesis by investigating if the presence of serum MOG and MBP in patients with CIS, predict conversion to CDMS (ref. 11). The authors could not verify that anti-MOG/MBP predict the risk of a new relapse, and thereby conversion from CIS to CDMS, although median time to the next relapse was significantly shorter in the anti-MOG/MBP positive group. A number of methodological reasons may explain the diversity in results and more studies are warranted in this important field.

The final result of the neurodegenerative process in MS can be monitored by MRI atrophy measures, although this technique is time consuming and has high cost. Axonal loss in the optic nerve can be directly monitored by optic coherence tomography (OCT) which is a robust and quick method, that has low cost, and can be performed by nonphysician personnel.

Fisher et al. (ref. 12) studied the relation between visual function and nerve RNFL thickness as a surrogate measure of axonal loss in MS in 90 MS patients (180 eyes) and 36 normal controls (72 eyes). The results showed that low-contrast letter acuity and contrast sensitivity measurements are associated with RNFL thickness and that reductions in eyes with no history of optic neuritis reflect the general neurodegenerative process in MS.

In this way OCT may prove to be a highly relevant surrogate marker of disease progression and neurodegeneration in MS, although we still need to see how RNFL reductions is related to cerebral atrophy and other measures of neurodegeneration in different stages of the disease.

A rather controversial statement was presented by Confavreux et al. (ref. 13) looking at clinical similarities between the phenotypes of the four classical MS categories: Relapsing remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS) and progressive relapsing (PRMS). The authors retrospectively studied data from 1844 MS patients and found that the clinical phenotype and course of MS is age dependent.

They showed that disability milestones and the time, at which landmarks are reached in progressive types of MS, follow a predefined schedule that is not influenced by relapses. In this way the authors argue for a unifying disease concept regarding PPMS and SPMS, that is found to be "amnesic" to prior clinical history. The authors did not comment, whether this could imply, that disease-modifying treatment of RRMS is less relevant in a large perspective.

A recent study by Kappos et al. (ref. 14) speaks against this, since conversion to SPMS was delayed in patients receiving long term IFNβ-1a treatment compared to a natural history data-set. A higher class evidence (controlled, randomized data) for delay of SPMS due to well-documented disease modifying treatments, will probably never be obtained for obvious ethical reasons.

These some of the messages that I found of interest in 2006. I hope you have enjoyed reading this brief overview, even though it only represents just a fraction of the large and increasing number of publications in the exciting area of MS clinical research.

References

1. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. New England Journal of Medicine 2006; 354 (9); 924-933

2. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine 2006; 354 (9); 899-910

3. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. New England Journal of Medicine 2006; 354 (9); 911-923

4. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. New England Journal of Medicine 2006; 355 (11); 1124-1140

5. Warren KG, Catz I, Ferenczi LZ, Krantz MJ. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. European Journal of Neurology 2006; 13 (8); 887-895

6. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. New England Journal of Medicine 2000; 343 (13); 898-904

7. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357 (9268); 1576-1582

8. Kinkel RP, Kollman C, O'Connor P, Murray TJ, Simon J, Arnold D, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006; 66 (5); 678-684. [Epub 2006 Jan 25]

9. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67 (7); 1242-1249. [Epub 2006 Aug 16]

10. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. New England Journal of Medicine 2003; 349 (2); 139-145

11. Rauer S, Euler B, Reindl M, Berger T. Antimyelin antibodies and the risk of relapse in patients with a primary demyelinating event. Journal of Neurology, Neurosurgery and Psychiatry 2006; 77 (6); 739-742

12. Fisher JB, Jacobs DA, Markowitz CE, Galetta SL, Volpe NJ, Nano-Schiavi ML, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006; 113 (2); 324-332. [Epub 2006 Jan 10]

13. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006; 129 (3); 606-616. [Epub 2006 Jan 16]

14. Kappos L, Traboulsee A, Constantinescu C, Eralinna JP, Forrestal F, Jongen P, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 2006; 67 (6); 944-953