Introduction:

Multiple sclerosis (MS) is the most common neurological cause of disability in young adults with a lifetime risk of one in 400. MS is considered as an autoimmune inflammatory disorder of the central nervous system (CNS) which is influenced by environmental factors and susceptibility genes Reference Compston and Coles(1,Reference Kieseier, Hemmer and Hartung2). Both temporal and spatial dissemination of lesions in the CNS is needed to clinically diagnose MS. The risk for developing clinically definite MS (CDMS) is highest when asymptomatic white-matter lesions in the brain can be found by MRI Reference Brex, Ciccarelli, O'Riordan, Sailer, Thompson and Miller(3)). But also patients with an isolated clinical deficit as for example optic neuritis (clinically isolated syndrome; CIS) are at risk of developing MS in the course of time. In one follow-up study, the 10-year risk of developing CDMS was 39%, the 20-year risk was 49%, the 30-year risk was 54% and the 40-year risk was 60% Reference Rodriguez, Siva, Cross, O'Brien and Kurland(4)). The diagnostic criteria for MS (McDonald criteria) take these findings into consideration and allow diagnosing MS even before a second clinical event. Instead MRI evidence of dissemination of CNS lesions in time and space is sufficient for the diagnosis of MS Reference McDonald, Compston, Edan, Goodkin, Hartung, Lublin, McFarland, Paty, Polman, Reingold, Sandberg-Wollheim, Sibley, Thompson, van den Noort, Weinshenker and Wolinsky(5,Reference Polman, Reingold, Edan, Filippi, Hartung, Kappos, Lublin, Metz, McFarland, O'Connor, Sandberg-Wollheim, Thompson, Weinshenker and Wolinsky6). The presence of oligoclonal bands doubles the risk for having a second attack while not influencing the development of disability Reference Tintore, Rovira, Rio, Tur, Pelayo, Nos, Tellez, Perkal, Comabella, Sastre-Garriga and Montalban(7)).

In the course of years, the majority of MS patients develop progressive neurological disabilities. About 50% of MS patients will use a cane to support walking within 10 years and the disease course of most MS patients will develop into a secondary progressive form of the disease displaying substantial residual clinical deficits Reference Weinshenker, Bass, Rice, Noseworthy, Carriere, Baskerville and Ebers(8,Reference Weinshenker, Bass, Rice, Noseworthy, Carriere, Baskerville and Ebers9). The disease activity in early phases of the disease is apparently a strong predictor for the timing of disability as irreversible deficits may accumulate with each disease exacerbation. Therefore CIS and RRMS though not classified as progressive forms of MS strongly contribute to progressive persistent clinical impairment. This concept is the reason to initiate MS treatment at the earliest time point possible. The therapeutic approaches to the various forms of MS (CIS, RRMS, SPMS, PPMS) have been changed profoundly over the last decade and several novel disease-modifying therapies have been established Reference Kieseier and Wiendl(10-Reference Wiendl and Hohlfeld12). The current treatment strategies of the various subforms of MS will be discussed in the following paragraphs. Furthermore we describe a number of new, oral substances including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid currently tested in clinical trials. These substances are awaited to broaden our armament for MS therapy.

Treatment of clinically isolated syndromes: Interferon beta:

The effect of interferon beta (IFN) on the progression time from CIS to CDMS has been investigated in three multicenter, double-blind, placebo-controlled trials: The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial in 2000 Reference Jacobs, Beck, Simon, Kinkel, Brownscheidle, Murray, Simonian, Slasor and Sandrock(13)), the Early Treatment Of Multiple Sclerosis (ETOMS) trial in 2001 Reference Comi, Filippi, Barkhof, Durelli, Edan, Fernandez, Hartung, Seeldrayers, Sorensen, Rovaris, Martinelli and Hommes(14)) and the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis For Initial Treatment (BENEFIT) trial in 2006.

383 patients with a first demyelinating event were enrolled in the CHAMPS study. In addition, patients had to exhibit two ore more asymptomatic lesions on MRI to be included into the study Reference Jacobs, Beck, Simon, Kinkel, Brownscheidle, Murray, Simonian, Slasor and Sandrock(13)). The treatment group received intramuscular IFN beta-1a 30 μg once a week. The interim analysis showed a significant lower cumulative probability of the development of CDMS in the IFN beta than in the placebo group after 3 years (OR 0.56; 95% CI 0.38-0.81; P = 0.002). Therefore the trial was stopped and assessment of both outcome measures (development of CDMS and changes in findings on MRI of the brain) revealed that treatment benefit was also seen in patient subgroups based on age, gender and baseline brain MRI parameters. The beneficial effect of IFN beta-1a when initiated at the first clinical demyelinating event in patients with MRI evidence of subclinical demyelination in the brain was observed in patients with different manifestations (spinal cord syndromes, brainstem-cerebellar syndromes and optic neuritis) Reference Beck, Chandler, Cole, Simon, Jacobs, Kinkel, Selhorst, Rose, Cooper, Rice, Murray and Sandrock(15)). The CHAMPIONS study (Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance) was initiated as a 5-year open-label extension of the CHAMPS study in order to assess the long-term efficacy of early treatment with IFN beta. 53% of patients enrolled in CHAMPIONS (203/383; n= 100, initial treatment group; n= 103, delayed treatment group). The median time to start IFN beta-1 treatment in the delayed treatment group was 29 months. The cumulative probability of development of CDMS was significantly reduced in the initial treatment group (5 year incidence 36 ± 9%) in comparison to the delayed treatment group (49 ± 10%; P = 0.03) Reference Kinkel, Kollman, O'Connor, Murray, Simon, Arnold, Bakshi, Weinstock-Gutman, Brod, Cooper, Duquette, Eggenberger, Felton, Fox, Freedman, Galetta, Goodman, Guarnaccia, Hashimoto, Horowitz, Javerbaum, Kasper, Kaufman, Kerson, Mass, Rammohan, Reiss, Rolak, Rose, Scott, Selhorst, Shin, Smith, Stuart, Thurston and Wall(16)).

In the ETOMS study, 309 patients were recruited but four clinically silent white matter lesions (or only three if one of them was enhancing after administration of gadolinium) were required for this study Reference Comi, Filippi, Barkhof, Durelli, Edan, Fernandez, Hartung, Seeldrayers, Sorensen, Rovaris, Martinelli and Hommes(14)). Half of the patients received subcutaneous IFN beta-1a at 22 1g once a week and half placebo. Progression to CDMS was observed in fewer patients in the IFN group than in the placebo group (OR 0.61; 95% CI 0.37 – 0.99; P = 0.045), the time point at which 30% of patients had developed CDMS was significantly later in the treatment group and the number of relapse rates per year were significantly lower. MRI readout revealed fewer new lesion formations in the IFN group.

In the BENEFIT study 468 patients were recruited after their first demyelinating event and two clinically silent brain MRI lesions. Half received subcutaneous IFN beta-1b 250 μg e.o.d. and half placebo Reference Kappos, Polman, Freedman, Edan, Hartung, Miller, Montalban, Barkhof, Bauer, Jakobs, Pohl and Sandbrink(17)). 45% of the placebo patients progressed to CDMS and 85% fulfilled the McDonald criteria after 2 years. The treatment group showed significantly delayed conversion to CDMS (OR 0.50; 95% CI 0.36 – 0.70; P < 0.0001) and to b McDonald criteria MS (OR 0.54; 95% CI 0.43 – 0.67; P < 0.00001). A post-randomisation follow-up of all patients over an additional 3 years which was completed by 392 patients (84%) showed that the risk of progression of disability was reduced by 40% Reference Kappos, Freedman, Polman, Edan, Hartung, Miller, Montalban, Barkhof, Radu, Bauer, Dahms, Lanius, Pohl and Sandbrink(18)).

Any patient with a high risk for converting into CDMS may therefore be considered as suitable for IFN beta treatment. It is nevertheless still challenging to sort out those CIS patients who will develop CDMS and this question has been addressed by a number of studies. The majority of patients with CIS and additional asymptomatic white-matter lesions as assessed by MRI will convert into CDMS Reference Barkhof, Filippi, Miller, Scheltens, Campi, Polman, Comi, Ader, Losseff and Valk(19-Reference McFarland, Barkhof, Antel and Miller23). The Optic Neuritis Treatment Trial (ONTT) showed that the number of brain lesions in patients with monosymptomatic optic neuritis is a strong marker to identify patients with a high risk of developing CDMS (24)). Nearly 90% of patients with CIS and an abnormal MRI in the beginning were found to progress into CDMS in a 14-year prospective study Reference Brex, Ciccarelli, O'Riordan, Sailer, Thompson and Miller(3)) in contrast to only 21% of the patients with normal baseline MRI. The disease course after 20 years of follow-up was relapsing-remitting in 58% while 42% had further progressed into SPMS. A moderate correlation between T2 lesion volume at all time-points and 20-years EDSS was found (r(s) values 0.48 to 0.67; P < 0.001 and MSFC z-score (r(s) values (−0.50) to (−0.61); P < 0.001) Reference Fisniku, Brex, Altmann, Miszkiel, Benton, Lanyon, Thompson and Miller(25)). There are several reasons to initiate therapy with IFN beta without unnecessary retardation Reference Coyle and Hartung(26)). First, pathological events in the beginning of the disease are a strong predictor for the timing of disability and axonal damage caused by inflammation is an early feature of MS. Moreover, the inflammatory process in RRMS proceeds continuously and is not restricted to phases with clinical symptoms. Finally, the activity of the immune system may be influenced more easily in the beginning of the disease and it may be more difficult to deal with later on. Therefore, an early immuno-modulatory therapy is the most effective strategy at the moment to control and limit the progression of disease Reference Corboy, Goodin and Frohman(27)). Surrogate markers like MRI will help to identify those patients with CIS who will profit most from early treatment with IFN beta.

Glatiramer acetate:

The data of a randomized, placebo-controlled phase III study concerning the effect of glatiramer acetate have not been published so far. However, the study was recently completed and communications at a number of meetings suggest that the beneficial influence of GA on disease progression from CIS to CDMS might be comparable to the effect of the interferons. Approval of GA for CIS has been granted recently.

Treatment of relapsing-remitting MS:

Various agents are currently approved by the FDA (US Food and Drug Administration) for the treatment of RRMS: Three different IFN beta formulations (subcutaneous IFN beta-1b, Betaferon®/Betaseron®/Extavia®; intramuscular IFN beta-1a, Avonex®; subcutaneous IFN beta-1a, Rebif®), glatiramer acetate (Copaxone®), and mitoxantrone (Novantrone®). However, there is still an intent discussion about which disease-modifying drug should be chosen.

Interferon beta:

While clearly effective in MS in a number of clinical trials, the exact mode of action of the interferons is still a matter of debate and various biological activities have been described so far. Among others, interferons inhibit the proliferation of leukocytes, hamper antigen presentation, shift the cytokine production towards an anti-inflammatory Th2 phenotype and reduce the T cell migration capacity across the blood-brain barrier by down-regulation the expression of adhesion molecules and matrix metalloproteinases Reference Kieseier, Seifert, Giovannoni and Hartung(28-Reference Yong, Chabot, Stuve and Williams30).

The first class I trial (multicenter, randomized, double-blind, placebo-controlled) in RRMS demonstrated clinical efficacy of IFN beta-1b Reference Paty and Li(31-33). 372 patients with a maximal EDSS of 5.5 and at least two exacerbations in the previous 2 years were included into the study. One third received 1.6 million international units (MIU; 50 μg) of subcutaneous IFN beta-1b, one third 8 MIU (250 μg) IFN beta-1b and one third placebo. The annual exacerbation rate was investigated after 2 years and was significantly lowered in both treatment groups compared with the placebo group (annual exacerbation rate placebo: 1.27; 1.6 MIU: 1.17 and 8 MIU: 0.84. Statistical evaluation: 1.6 MIU vs. placebo, P= 0.0101; 8 MIU vs. placebo, P= 0.0001; 8 MIU vs. 1.6 MIU, P= 0.0086). These results might suggest a dose-dependent effect of IFN beta-1b treatment as well, but this was not a primary outcome measure in the design of the study. Evaluation of MRI (T2) revealed that IFN beta-1b patients had significantly lower lesion loads than patients treated with placebo. The 8-MIU treatment also reduced the confirmed 1-point EDSS progression rate but statistical significance was not reached for this parameter (29%, P = 0.016).

The effect of intramuscularly administered IFN beta-1a treatment was studied in a multicenter, randomized, placebo-controlled study Reference Jacobs, Cookfair, Rudick, Herndon, Richert, Salazar, Fischer, Goodkin, Granger, Simon, Alam, Bartoszak, Bourdette, Braiman, Brownscheidle, Coats, Cohan, Dougherty, Kinkel, Mass, Munschauer, Priore, Pullicino, Scherokman and Whitham(34-Reference Simon, Jacobs, Campion, Wende, Simonian, Cookfair, Rudick, Herndon, Richert, Salazar, Alam, Fischer, Goodkin, Granger, Lajaunie, Martens-Davidson, Meyer, Sheeder, Choi, Scherzinger, Bartoszak, Bourdette, Braiman, Brownscheidle and Whitham36). 301 patients with an EDSS of 1.0 to 3.5 were included who in addition suffered from at least two clinical events in the last 3 years. Dosage was 6 MIU (30 μg) of intramuscular IFN beta-1a once weekly vs. placebo. The primary outcome measure in this study was time to sustained progression of at least 1.0 point on the EDSS scale. The trial was stopped earlier than anticipated in the beginning and therefore only 57% of the patients enrolled (172 patients) completed 2 years of IFN beta-1a treatment. Study medication resulted in a significantly delayed time to sustained EDSS progression (−37%, P = 0.02). The Kaplan-Meier estimate of the percentage of patients with EDSS progression by the end of the 2 years was 34.9% in the placebo group vs. 21.9% in the treatment group. IFN beta-1a treated patients also had a significantly reduced number of disease exacerbations (P= 0.03) and a significantly lower number of gadolinium-enhanced lesions in the brain on MRI (−33%, P = 0.05) compared with the place group. The annual exacerbation rate over 2 years was reduced from 0.90 in the placebo-arm to 0.61 in the IFN beta-1a-arm. An interesting finding was that the reduction in the attack rate in the therapy group didn't reach statistical significance in the first year (−9.6%) but the reduction in patients after 2 years was significantly lower (32%, P = 0.002). This result suggests that the beneficial effect of IFN beta-1a might be delayed. However, patients who fully completed the 2 years already had a similar reduction in the attack rate in the first year (−29%) which on the other hand suggests that the 2-year completers do not represent the study cohort as a whole. Anyhow, IFN beta-1a clearly showed a significant effect in RRMS in this clinical trial as it reduced the accumulation of permanent physical disability, frequency of exacerbations and disease activity measured by gadloinium-enhanced lesions on brain MRI. The effect of IFN beta-1a administered subcutaneously was investigated in the Prevention of Relapses and Disability by IFN beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. PRISMS was a much larger multicenter, randomized, doubleblind, placebo-controlled trial (Class I) in 560 RRMS patients with a maximal EDSS score of 5.0 and additionally at least two relapses in the previous 2 years (37.38). Patients were divided into three groups: Subcutaneous IFN beta-1a at 22 μg (6 MIU) or 44 μg (12 MIU) three times a week or placebo. The relapse rate after 2 years was significantly reduced with both doses of IFN beta-1a than with placebo treatment (mean number per patient: 1.82 for 22 μg, 1.73 for 44 μg and 2.56 with placebo). Risk reduction was calculated as 27% (95% CI 14 – 39) for 22 μg and 33% (95% CI 21 – 44) for 44 μg. MRI assessment revealed significant improvement in the IFN beta-1a treatment group when compared to the placebo arm (median number of T2 active lesions −78%, P < 0.0001 and volume of T2 lesions −14.7%, P < 0.0001). Moreover, the confirmed 1-point EDSS progression rate was also significantly reduced (−30%, P < 0.05) by IFN beta-1a medication. Taken together this study further underlines the therapeutical value of IFN beta in RRMS patients. Additionally, this clinical trial demonstrates that IFN beta can significantly lower both the T2 disease burden as well as the confirmed 1 -point EDSS progression. This study was continued for another 2 years and named therefore PRISMS-4. The former placebo-treated patients were now re-randomized double-blindly to one of the two treatment groups receiving either a low or high dosage of IFN beta-1a (39)). This extensions study can be discussed because a bias can not be excluded based on previous dropouts and the re-randomization. Nevertheless, this extension phase showed both a clinical and a benefit on MRI level for IFN beta-1a. The PRISMS-4 study shows that patients still benefit from treatment in the third and fourth year although the first 2 years of therapy were associated with the greatest reduction in relapse rate and MRI burden. A dosedependent effect after 4 years was only seen for some clinical and MRI outcomes but not for others.

The OWIMS (Once Weekly Interferon for MS Study) trial IFN beta-1a was administered subcutaneously in a dosage of 22 igor 44 ig in comparison with placebo. After 48 weeks, a benefit on MRI level was confirmed for IFN beta-1a at 22 ig in RRMS but no significant clinical effect was observed (40)). IFN beta therapy often causes side effects. The most common are flu-like symptoms, elevation of liver enzymes and lymphopenia (32,Reference Jacobs, Cookfair, Rudick, Herndon, Richert, Salazar, Fischer, Goodkin, Granger, Simon, Alam, Bartoszak, Bourdette, Braiman, Brownscheidle, Coats, Cohan, Dougherty, Kinkel, Mass, Munschauer, Priore, Pullicino, Scherokman and Whitham34,38). These side effects, however, are generally mild and rarely last longer than some months after statement of treatment. Therapy can therefore be continued in most cases. Subcutaneous injection of IFN beta can also cause reactions at the injection site and side effects of IFN beta are observed more often at higher doses. The use of auto-injectors as well as training of patients to correctly inject IFN beta and concomitant anti-inflammatory medication can reduce these problems and therefore increase the compliance of patients.

In summary, IFN beta is effective in RRMS both on a clinical and on MRI level and IFN beta therapy may be considered in any patient with RRMS.

Glatiramer acetate:

Glatiramer acetate is a random polypeptide consisting of four different amino acids (glutamic acid, lysine, alanine and tyrosine) in a specific molar ratio. So far, its immunological mechanisms of action are still not fully unravelled but some of them seem to be distinct from those of the interferons. It is suspected that GA treatment leads to a shift from a Th1 to a Th2 phenotype, induces antigen specific T suppressor cells that may cross-react with putative autoantigens in the CNS and that it also directly inhibits antigen presentation Reference Yong(29,Reference Farina, Weber, Meinl, Wekerle and Hohlfeld41). In a large, multicenter, randomized, double-blind and placebo-controlled trial with 251 RRMS patients half of them received 20 mg subcutaneous glatriamer acetate daily and half placebo. To be enrolled patients had to have an EDSS score between 0 and 5.0 and they had to have suffered from at least two clinical attacks in the previous 2 years. The study was initiated for 2 years with an extension phase of another third year Reference Farina, Weber, Meinl, Wekerle and Hohlfeld(41)). The relapse rate over 2 years was significantly lower in GA treated patients (−29%, P = 0.007). MRI parameters were not investigated in this clinical trial. However, a second short duration trial specifically addressed MRI findings upon GA treatment Reference Compston and Coles(1)). 249 RRMS patients with a maximal EDSS score of 5.0 and at least one gadolinium-enhancing lesion on baseline MRI were enrolled and the treatment group showed a significant reduction in the total number of enhancing lesions (−35%, P = 0.001). Interestingly, the treatment effect only occurred after 6 months of treatment. This delay indicates that GA rather has a long-term immunomodulatory effect and rather no immediate immunosuppressive effect or effect on the blood-brain barrier. In an open-label extension trail all patients were assigned to GA for another 9 months. A reduction of 54% in the mean number of enhancing lesions for the previous placebo treated patients and an additional reduction of 25% for those always treated with GA was reported. These data suggest a sustained effect of glatiramer acetate over the period of one and a half years based on MRI parameters Reference Wolinsky, Comi, Filippi, Ladkani, Kadosh and Shifroni(43)).

A recent study concerning the long-term clinical efficacy as well as long-term safety profile of GA over 22 years was published in 2008. A lower relapse rate and a slower EDSS progression was found in this open-label observational study in RRMS patients Reference Miller, Spada, Beerkircher and Kreitman(44)). However, the study cohort is self-selected and therefore a bias of this study towards treatment effects can not be excluded. GA therapy generally causes only mild side effects and injection site reactions are usually minimal Reference Ziemssen, Neuhaus and Hohlfeld(45)). In summary, GA reduces clinical relapses in patients with RRMS and therefore can be recommended for treatment of these patients.

Treatment of secondary progressive MS:

Patients with SPMS are still a great challenge in terms of therapeutic treatment. It must be taken into account that the degree of disability and the inflammatory activity as determined by the annual relapse rate may vary widely in these patients. A successful therapeutic approach to patients with SPMS must therefore be personalized and especially weigh carefully between the expected clinical benefit and the adverse effects of the chosen therapy which might potentially occur.

Interferon beta:

Effect of IFN beta treatment in SPMS patients has been tested in several large, randomized, placebo-controlled trials. One trial in Europe and one in North America investigating IFN beta-1b in SPMS have been reported.

718 patients with and EDSS of 3.0 to 6.5 were enrolled in the European trail. Patients also had to have either two relapses or more than a 1.0 point increase in the EDSS score in the previous 2 years. Half were treated with the standard dose of IFN beta-1b and half received placebo (46)). IFN beta-1b treated patients had a significantly reduced 1-point EDSS progression rate (−33%, P = 0.0008) than placebo-treated patients and a significant improvement was also found concerning clinical and MRI attack rates and the volume of white-matter disease assessed by MRI. Subgroup analysis of patients with our without clinical attacks in the 2 years prior to study initiation or analysis of those patients who did or did not have attacks during the study all demonstrated similar therapeutical effects of IFN beta-1b. However, patients with an EDSS of at least 6.0 profited less and the North American trial failed to show any difference in time to confirmed progression of EDSS scores between both IFN beta-1b treatment groups and the placebo group Reference Panitch, Miller, Paty and Weinshenker(47)).

A retrospective analysis was conducted to unravel the reason for the discrepancy between the European and the North American trial Reference Kappos, Weinshenker, Pozzilli, Thompson, Dahlke, Beckmann, Polman and McFarland(48)) and it was found out that the European patients were situated in an earlier phase of SPMS and that their disease was more active both pre-study (number of relapses, MRI data) as well as during the study (EDSS score, number of relapses, MRI data). This indicates that IFN beta is more effective in the relapsing phase of the disease course.

The Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) trial which tested the effect of subcutaneous IFN beta-1a in SPMS similarly failed to find a statistically significant reduction in the confirmed 1-point EDSS progression rate (49)). Patients were post hoc separated into those with or without relapses and this analysis showed a beneficial therapeutic effect on the confirmed 1-point EDSS progression rate in the patient subgroup with attacks (P = 0.027). Such a re-analysis however gives raise to criticism about the validity of the results. The data would once more support the concept that IFN beta is most effective in patients with a residual inflammatory activity in early phases of SPMS.

The IMPACT trial investigated the effect of intramuscular IFN beta-1a in 436 patients with SPMS and an EDSS score of 3.5-6.5 Reference Cohen, Cutter, Fischer, Goodman, Heidenreich, Kooijmans, Sandrock, Rudick, Simon, Simonian, Tsao and Whitaker(50)). Patients either received 60 ig IFN beta-1a (twice the FDA-approved dose for RRMS) or placebo by intramuscular injection once a week over 2 years. The MS Functional Composite (MSFC) which includes quantitative tests of ambulation (timed 25-foot walk), arm function (nine-hole peg test) and cognition (paced auditory serial addition test) was chosen as a primary outcome measure. IFN beta-1a led to a significant amelioration of MSFC scale (P= 0.033) and this was mostly due to improvement in the nine-hole peg test. No difference was found in EDSS score. Patients treated with IFN beta-1a had significantly fewer relapses (P= 0.008) and it is therefore appropriate to consider IFN beta for treatment in SPMS patients who still experience relapses but not in those patients without clinical attacks. IFN beta-1b was approved for the treatment of SPMS patients in the US by the FDA and the European agency (EMEA) also approved IFN beta-1b and subcutaneous IFN beta-1a for SPMS with superimposed relapses. The efficacy of IFN-beta in patients with SPMS who do not experience relapses any more is unclear at the moment.

Treatment of primary progressive MS:

Primary progressive MS appears to be different from relapsing-remitting MS in terms of pathology and clinical appearance. So far, treatments for RRMS have failed in PPMS and neither the interferons nor glatiramer acetate have shown to be effective in this subform of MS and therefore can not be recommended Reference Miller and Leary(51,Reference Wolinsky, Narayana, O'Connor, Coyle, Ford, Johnson, Miller, Pardo, Kadosh and Ladkani52).

Oral disease modifying treatments for MS: Cladribine:

The adenosine deaminase-resistant nucleoside analogue cladribine accumulates – after phosphorylation into the active triphosphate deoxynucleotide – in lymphocytes and monocytes causing DNA damage and subsequent cell death Reference Beutler(53,Reference Sipe54). Since 1993 the substance is approved for the treatment of hairy cell leukemia.

Smaller placebo-controlled trials in chronic progressive MS Reference Beutler, Sipe, Romine, Koziol, McMillan and Zyroff(55,Reference Sipe, Romine, Koziol, McMillan, Zyroff and Beutler56) and RRMS patients Reference Romine, Sipe, Koziol, Zyroff and Beutler(57)) demonstrated that cladribine delays disease progression, nearly completely eliminates gadolinium-enhanced T1 lesions and stabilizes T2 lesion volume. Anyhow, a multicenter, double-blind, placebo controlled trial of cladribine in 159 patients with SPMS and PPMS showed no significant clinical benefit after 1 year (0.7 mg/kg, 2.1 mg/kg vs. placebo) Reference Filippi, Rovaris, Iannucci, Mennea, Sormani and Comi(58-Reference Rice, Filippi and Comi60). Side effects included upper respiratory tract infarctions, muscle weakness and injection site reactions. Since cladribine reduced the number and volume of gadolinium-enhanced T1-weighted brain lesions and overall T2 lesion load, there is a discrepancy between those MRI endpoints and the observed clinical effects Reference Rice, Filippi and Comi(60)). Meanwhile the substance is available as an oral formulation and a randomized, double-blind, placebo controlled phase III trial (1290 RRMS patients) has been initiated (CLARITY). The outcome parameters include relapse rate, EDSS progression and MRI activity and results from this trial are expected in 2009. Furthermore two other phase III trials investigate the substance in CIS patients (ORACLE) and pre-treated RRMS patients (ONWARD).

Teriflunomide:

Teriflunomide belongs to a group of malononitrilamide agents blocking the mitochondrial enzyme dihydroorotatedehydrogenase, is an analogue of leflonomide (known from the therapy of rheumatoid arthritis) and inhibits T and B cell proliferation by energy reduction Reference Korn, Magnus, Toyka and Jung(61,Reference Kaplan62). Teriflunomide has been found to display beneficial effects on the EAE model probably by suppression of TNFa and IL2 Reference Korn, Toyka, Hartung and Jung(63,Reference Smolen, Emery, Kalden, Van Riel, Dougados, Strand and Breedveld64). Results from a clinical phase II trial testing teriflunomide (7 or 14 mg/day vs. placebo over 36 weeks) in patients with RRMS and SPMS have recently been published Reference O'Connor, Li, Freedman, Bar-Or, Rice, Confavreux, Paty, Stewart and Scheyer(65)). The primary endpoint of the study was met since subjects receiving verum of either dose had significantly less active MS lesions and a reduced number of new lesions on MRI. Furthermore EDSS progression was delayed (high dose group) and a trend towards reduction in relapses was observed. Besides respiratory tract infections and headache the substance was well tolerated. Anyhow, serious side effects (e.g. toxic liver necrosis and pancytopenia) have been described in patients with rheumatoid arthritis. Therefore final appraisal of the substance has to wait for the results of an ongoing phase III trial investigating the safety and efficacy of the drug in MS.

Laquinimod:

Laquinimod (ABR-215062, SAIK-MS) is a novel orally active immunomodulator which is approximately 20 times more potent than its “ancestor” roquinimex (linomide), at least in EAE Reference Brunmark, Runstrom, Ohlsson, Sparre, Brodin, Astrom and Hedlund(66)). The synthetic compound is characterized by a convincing oral bioavailability and it mediates immunoregulatory properties without general immunosuppressive actions. In a number of different animal models mimicking autoimmune or inflammatory diseases the sustained inhibitory activity of the immune system could be shown Reference Jonsson, Andersson, Fex, Fristedt, Hedlund, Jansson, Abramo, Fritzson, Pekarski, Runstrom, Sandin, Thuvesson and Bjork(67-Reference Yang, Xu, Xiao, Hedlund and Link69). In clinical phase II studies of MS linomide significantly reduced active MRI lesions, but a phase II trial had to be halted due to unexpected severe side effects (e.g. serositis and myocardial infarction) Reference Andersen, Lycke, Tollesson, Svenningsson, Runmarker, Linde, Astrom, Gjorstrup and Ekholm(70,Reference Karussis, Meiner, Lehmann, Gomori, Schwarz, Linde and Abramsky71).

Two phase I studies indicated that laquinimod is well tolerated and results from a double-blind, randomized, multicenter proof-of principle study testing 0.1 mg/day and 0.3 mg/day vs. placebo in 180 patients with RRMS have recently been published Reference Polman, Barkhof, Sandberg-Wollheim, Linde, Nordle and Nederman(72)). A significant difference between laquinimod 0.3 mg/day and placebo was observed for the primary outcome measure, i.e. the mean cumulative number of active MRI lesions (5.24 vs. 9.44, respectively; 44% reduction). This effect was even more pronounced in those patients with at least one active lesion at baseline (52% reduction). Clinical outcome parameters (relapse rate, disability) were not different between the groups.

Based on these data laquinimod has a good potential to become a safe and effective oral treatment in MS. The substance is currently tested in a large phase III trial.

Fingolimod:

The orally available compound FTY720 (fingolimod, 2-amino-2-(2-(4-octylphenyl)ethyl)-propan-1,3-diole) is derived from the fungus Isaria sinclairii and exhibits profound and unique immunoregulatory effects by targeting sphingosine-1-phosphate (S1P) receptors Reference Hiestand, Rausch, Meier and Foster(73)). After in vivo phosphorylation FTY720 forms FTY720P which leads to internalization of the SIP1 receptor, resulting in a rapid and reversible inhibition of lymphocyte egress from peripheral lymph nodes, which prevents auto reactive T cells from sites of autoimmune inflammation Reference Linker, Kieseier and Gold(74)). Further effects were demonstrated on dendritic, endothelial and glia cells Reference Coelho, Payne, Bittman, Spiegel and Sato-Bigbee(75-Reference Mullershausen, Craveiro, Shin, Cortes-Cros, Bassilana, Osinde, Wishart, Guerini, Thallmair, Schwab, Sivasankaran, Seuwen and Dev77). The therapeutic potency of this agent has already been demonstrated in acute and chronic EAE models Reference Balatoni, Storch, Swoboda, Schonborn, Koziel, Lambrou, Hiestand, Weissert and Foster(78,Reference Fujino, Funeshima, Kitazawa, Kimura, Amemiya, Suzuki and Li79). The results of an international, double-blind, placebo-controlled phase II study involving 281 subjects with active RR-MS have recently been released Reference Kappos, Antel, Comi, Montalban, O'Connor, Polman, Haas, Korn, Karlsson and Radue(80)). The participants received one of two doses of oral FTY720 (1.25 mg/day or 5 mg/day, respectively) or placebo for 6 months. Both dosages of FTY720 significantly reduced the number of Gd-enhancing lesions and led to a 45% reduction in the annualized relapse rate. The 18-month extension phase of the trial included a switch of the placebo group to verum and demon stared sustained efficacy. Side effects included colds, sinusitis, mild headaches and gastrointestinal disorders. The underlying mechanism of drug action however warrants extensive safety analysis, especially with longer periods of administration. Two large phase III studies of FTY720 in MS are currently launched (2006). One study is testing the safety and efficacy of two doses (1.25 mg/day and 0.5 mg/day) against placebo (FREEDOMS I and II study), the other assesses the efficacy of FTY720 in a head-to-head design against an active comparator (IFNβ-1a i.m. once weekly; TRANSFORMS study). Results are expected in 2009.

In these trials, two fatal cases of viral encephalitis were recently reported (www.reuters.com/article/CHMMFG/idUSL0586762720080605).

Fumaric acid:

Oral application of fumaric acid esters (BG12, fumarate) represents an other strategy to induce beneficial immune modulation by enhancing Th2-driven responses in MS Reference Lee, Linker and Gold(81)).

An exploratory, prospective, open-label study of fumaric acid esters was conducted in patients with RR-MS. In this small trial including 10 subjects, a reduction of relapse rate and volume of gadolinium-enhancing lesions as assessed by MRI was observed after 12 weeks Reference Schimrigk, Brune, Hellwig, Lukas, Bellenberg, Rieks, Hoffmann, Pohlau and Przuntek(82)). However, 3 patients discontinued treatment during the first 3 weeks of the study and several patients experienced mild to moderate gastrointestinal discomfort.

A double-blind, placebo-controlled phase II study was performed to further test the safety and effectiveness in controlling disease course and development of MS brain lesions. In January 2006, the product sponsor announced that the study met its primary endpoint by reducing the number of active MRI lesions with 6 month of treatment (http://www.FDA.org). Details about the secondary outcome measures have not been released so far.

Conclusion: Both IFN beta and GA have proven efficacy in RRMS and represent first line treatment choices for those patients. Additionally, SPMS patients with superimposed relapses will profit from those treatments. IFN beta and GA still remain the most recognized therapeutic options for MS treatment but many novel treatment strategies are currently tested in clinical trials and some of them are expected to be approved in the following years, among them oral therapies. Various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. Results from these studies are awaited from both, clinicians and patients, and promising new candidates will help to further improve therapeutic possibilities in MS treatment.