ORAL AGENTS
All currently approved disease modifying treatments (DMT) for multiple sclerosis (MS) are parenteral. The disadvantages of these modes of administration are apparent and include local injection reactions with subcutaneous or intramuscular application, attendance at infusion centers (for intravenous application) as well as critical compliance and adherence issues [1]. Innovative new oral drugs for MS are expected not only to offer improved convenience but also provide agents with new mechanisms of action. These have shown promising results with regard to their efficacy. The results from recent phase II and III studies for oral compounds will be reviewed in the first part of this article.
Cladribine
Mechanism of action
Cladribine (2-chlorodeoxyadenosine) is an adenosine analogue. The administration of cladribine results in an accumulation of toxic deoxyribonucleotides, a disruption of cellular metabolism, DNA damage and subsequent apoptosis with equal effects on both dividing and quiescent cells [2]. Cladribine causes lymphopenia for several months.
Efficacy
Several phase II studies for parenteral cladribine were conducted, but no studies involving oral cladribine. In an intravenous cladribine phase II study, Beutler et al. demonstrated in patients with secondary progressive MS (SPMS, n=51) that 4-monthly dosages of cladribine (0.1 mg per kg body weight daily) for 7 days improved the EDSS score. Only 8.3% of patients taking cladribine had contrast enhancing lesions on brain MRI versus 50% on placebo after 12 months [3].
In the second cladribine phase II trial (n=52 with relapsing-remitting MS [RRMS]), each patient received either daily subcutaneous injections of cladribine 0.07 mg/kg or placebo for 5 consecutive days every 6 months. The results showed a favorable treatment effect of cladribine on relapse activity, and cladribine completely suppressed contrast enhancing lesions on brain MRI [4].
The largest cladribine trial (subcutaneously [SC]; n=159, 30% RRMS, 70% SPMS) thus far was published in 2000 [5]. Patients were treated with a total dose of 2.1 mg/kg, 0.7 mg/kg or placebo. After 12 months, both cladribine treatment groups experienced a reduction in number and volume of contrast enhancing lesions compared to placebo.
Adverse events
Adverse events were mainly dose-dependent and major side effects were related to bone marrow suppression. Two mild segmental herpes zoster infections occurred with cladribine (compared to one with placebo), one patient developed fatal autoimmune hepatic necrosis due to a newly transmitted hepatitis B infection. Other common side effects in the phase II trials were weakness, hypertension, ataxia and infections of the upper airways [5]. Long-term bone marrow toxicity and risks of malignancy in long-term therapy were discussed. Intravenous (IV) cladribine is approved by the US Food and Drug Administration (FDA) and other regulatory agencies for the treatment of hairy cell leukemia and other malignant lymphomas.
Phase III trial of oral cladribine
The efficacy of oral cladribine was investigated in a large phase III trial (CLARITY). CLARITY was a two-year, randomized, double-blind, placebo-controlled, multicenter trial. More than 1300 patients with RRMS were recruited. Oral cladribine was applied in either two or four treatment cycles in the first year (0.875 mg/kg/course) versus placebo. Each cycle consisted of once daily administration of one tablet for four to five consecutive days (participants took cladribine tablets for only 8-20 days per year). In the second year, two similar treatment cycles were administered. The primary endpoint was the relapse rate at 96 weeks.
In January 2009, Merck Serono reported preliminary data from CLARITY as a press release. Data were also presented at the American Academy of Neurology meeting in 2009. Oral cladribine met the two-year primary efficacy endpoint with a 55-58% relative risk reduction in the annualized relapse rates compared to placebo. Ninety per cent of patients treated with oral cladribine completed the study compared to 87% in the placebo group. As expected, lymphopenia was common with cladribine. The most frequently reported adverse events were headache and nasopharyngitis.
Fingolimod (FTY720)
Mechanism of action
Fingolimod (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydro-chloride; FTY720) is a spingosine-1-phosphate (S1P) receptor agonist. It is an analogue of myriocin, a metabolite of the fungus isaria sinclairii [6,7].
Fingolimod phosphate binds to S1P receptors and causes an internalization of these receptors. Lymphocytes require these receptors on the surface for migration from secondary lymphatic organs (such as lymph nodes, and lymphatic tissue associated with the spleen and mucosa) into the circulation [8]. In experimental autoimmune encephalomyelitis (EAE), fingolimod prevented disease onset and reduced neurological deficits [9-11]. In renal transplantation, fingolimod did not offer an advantage over the standard of care and further investigation was terminated.
Efficacy
Kappos et al. [12] investigated fingolimod in a double-blinded, randomized, placebo-controlled phase II trial in RRMS and SPMS (n=281, 1.25 mg or 5 mg fingolimod once daily versus placebo). At 6 months, the cumulative number of contrast enhancing lesions was lower with both fingolimod dosages (8.4 lesions per scan in the 1.25 mg fingolimod group (p <.01) and 5.7 lesions per scan in the 5 mg fingolimod group (p <.001) compared to placebo (14.8 lesions). Fingolimod reduced the annualized relapse rate by 53-55%. The therapeutic effects of fingolimod were maintained in an extension study (up to 2 years [13]).
In December 2008 Novartis issued a press release with preliminary results of one phase IIII head-to-head study (TRANSFORMS). TRANSFORMS (n=1292 with RRMS) was a randomized, double-blind, double-dummy study of fingolimod at two different dosages (1.25 mg and 0.5 mg) versus interferon beta (IFN-β)-1a intramuscular (IM) once weekly over 12 months. Patients who received 0.5 mg fingolimod per day had an annualized relapse rate of 0.16, representing a 52% reduction compared to a relapse rate of 0.33 with IFN-β-1a IM (p <.001). There was no significant difference between the two fingolimod dosages. Two other two-year phase III studies are ongoing.
Adverse events
The most common adverse events (mostly dose dependent) were cold, sinusitis, dyspnea, headache, nausea and diarrhea. During the extension phase of the study, two serious infections (herpes zoster and enterocolitis) occurred, and one patient developed reversible posterior encephalopathy. As expected, lymphocyte counts decreased by 20-30%. About 10 per cent of patients receiving fingolimod had an increase in liver enzymes.
Safety of fingolimod in TRANSFORMS (unpublished) was in line with earlier experiences. Severe adverse events included transient bradycardia at the beginning of treatment, mild hypertension, and elevation of liver enzymes. Bradycardia and hypertension are supposed to be due to the effects of S1P1-receptors in the heart and lung where the receptor can also be found. Macular edema [14] occurred in less than 1% of patients on fingolimod. Seven cases of skin cancer occurred in fingolimod treated patients. Also, two fatal cases of herpes zoster encephalitis occurred with the higher dose of fingolimod.
Teriflunomide
Mechanism of action
Teriflunomide is a dihydroorotate dehydrogenase inhibitor. Dihydroorotate dehydrogenase is the fourth enzyme in the biochemical cascade of the de novo pyrimidine synthesis. Inhibition of this key enzyme has a cytostatic effect on rapidly dividing cell populations such as T and B lymphocytes. It was suggested that reduced availability of pyrimidines will interfere with the metabolism of immune cells and reduce cell proliferation. Furthermore, teriflunomide is thought to possess several immunomodulatory properties (i.e., production of tumor necrosis factor alpha and interleukin-2).
Efficacy
O’Connor et al. investigated the safety, efficacy and optimal dose of teriflunomide in patients with RRMS and SPMS [15] in a randomized, double-blinded, placebo-controlled phase II trial. A total of 179 patients (157 RRMS, 22 SPMS, 36 weeks) were randomized to 7 mg/day or 14 mg/day of oral teriflunomide versus placebo. Teriflunomide (both dosages) reduced the mean number of combined unique active lesions per scan by 61% for both treatment arms versus placebo (p <.001). A lower proportion of patients in the high risk arm experienced progression (7.4% in the 14 mg/day group versus 23% with placebo; p <.04).
Adverse events
Commonly reported adverse events included nasopharyngitis, alopecia, nausea, paresthesia, diarrhea, back or limb pain and arthralgia. Serious adverse events were reported in 19 patients (10.6%) including hepatic dysfunction, neutropenia, rhabdomyolysis and trigeminal neuralgia. Clinically noteworthy laboratory values, mostly elevated liver enzymes, were reported in 7.8% of patients.
Teriflunomide is the active metabolite of leflunomide. Leflunomide has been licensed in the USA and other countries for the treatment of rheumatoid arthritis since 1998. Leflunomide is teratogenic in animal models and effective contraception for females is mandatory. “Wash-out” with cholestyramine leads to a rapid decrease in drug levels.
Phase III trial
In September 2004, the first teriflunomide phase III trial (TEMSO) started recruitment in 20 countries. Recruitment ended in December 2007 with 1080 participating patients. A head-to-head trial versus IFN-β-1a s.c. was recently initiated (TENERE).
Laquinimod
Laquinimod (N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-carboxamide) is a modified, oral formulation of linomide. Phase III trials of linomide in MS were promising but had to be stopped because of unforeseen serious cardiopulmonary toxicity [16].
Mechanism of action
The exact mechanism of action of laquinimod is incompletely understood. Its efficacy in previous experiments was ascribed to modulation of the T-helper-cell 1 and 2 balance, induction of transforming growth factor b, down-regulation of major histocompatibility complex II, and the Th17 response.
Efficacy
Polman et al. [17] investigated the efficacy of laquinimod (0.1 and 0.3 mg/d) in a randomized, multicenter, double-blinded, placebo-controlled trial in 209 patients with RRMS and SPMS. The mean cumulative number of active lesions was 5.24 in the 0.3 mg laquinimod group versus 9.44 in the placebo group after 24 weeks of treatment (44% reduction).
In a second randomized double-blind placebo-controlled multicenter phase II trial (n=306), patients with RRMS were randomized to receive oral laquinimod 0.3 mg or 0.6 mg or placebo [18]. Laquinimod 0.6 mg per day showed a significant reduction in the adjusted mean cumulative number of contrast enhancing lesions by 40% compared to placebo in the last four MRI scans of the study. The cumulative number of new T2 lesions was reduced by 44% in the high dose group versus placebo (p = .001).
Adverse events
The most common adverse events of laquinimod were cough, dyspnea, herpes infections, elevation of liver enzymes, hyperfibrinogenemia, etc. and breast cancer. There were no cases of myocardial infarction or serositis.
Phase III trial
ALLEGRO is a randomized, double-blind, placebo-controlled two-year study of laquinimod 0.6 mg in RRMS. Enrolment of more than 1000 patients at 152 sites worldwide was completed in November 2008.
Fumaric acid esters (BG00012)
Fumaric acid esters (FAE) are oral immunomodulators which are effective in psoriasis. BG00012 is a new formulation of FAE that contains dimethylfumarate as the active compound but no other esters.
Mechanism of action
In preclinical experiments, FAE influenced several aspects of immune functions that are thought to be involved in the pathogenesis of MS (i.e., induction of T helper cell 2 cytokines, chemokines and anti-oxidative factors, and apoptosis in activated T cells). In experimental autoimmune encephalomyelitis, FAE demonstrated therapeutic effects by reducing inflammation and preserving myelin and axons.
Efficacy
A small study (n=10) with FAE in MS was conducted with Fumaderm®. Fumaderm® consists of both dimethylfumarate and methylhydrogenfumarate and is licensed for the treatment of psoriasis in Germany. Fumaderm® significantly reduced the relapse rate and cumulative volume of contrast enhancing lesions over 18 weeks [19]. Subsequently, Kappos et al. investigated safety and effectiveness of BG00012 (“BG12”) (dimethylfumarate) in a double-blind, randomized, placebo-controlled phase II trial with 257 RRMS patients (placebo versus BG12 at 120, 360 or 720 mg/day for 24 weeks) [20]. Patients with the highest dose had 69% less contrast enhancing lesions and 48% less new or enlarging T2 lesions than patients in the placebo group. BG12 also reduced the number of new or enlarging T2 hyperintense lesions and new T1 hypointense lesions.
Adverse events
About 13% of patients with higher dose BG12 discontinued the phase II trial. The most common adverse events at all dosages were flushing, increased liver enzymes, gastrointestinal problems and infections.
Phase III trials
There are two ongoing phase III trials (DEFINE, CONFIRM) with more than 1000 patients per trial. Both are multicenter, parallel-group, randomized, placebo-controlled, dose-comparison trials. In DEFINE, patients are randomized to receive oral BG12 240 mg three times daily, BG12 240 mg twice daily, or placebo. DEFINE completed recruitment in January 2009. In CONFIRM, BG12 is compared to subcutaneous glatiramer acetate.
Oral alpha-4-beta-1-integrin antagonists
Natalizumab, the first licensed alpha-4-beta-1-integrin (very late antigen activation-4, VLA-4) and MS antagonist, achieves substantial reduction of MS disease activity. Currently, there are new small molecule compounds in development for the treatment of RRMS which also target VLA-4 including:
- CDP323 (UCB/Biogen Idec): a press release reported that the trial did not reach its endpoints and that development will be terminated
- SB683699 (firategrast, GSK)
- TBC4746 (Encysive/Schering Plough).
Blocking VLA-4 reduces leukocyte migration across the blood brain barrier which seems to be the main therapeutic effect.
Conclusions
Several oral agents for treatment of RRMS can be expected to successfully pass phase III trials in the next two years (Table 1). Due to regulatory requirements (at least in Europe), new compounds not only need to demonstrate efficacy versus placebo but will need to be superior versus a currently licensed agent. This approach may provide further guidance for positioning new agents in a future treatment algorithm. Although several agents led to a substantial reduction of disease activity in phase III (fingolimod, cladribine), safety concerns have already risen (opportunistic infections and risk of neoplasms). With more and more agents with different targets, the major challenge will be to define who receives which agent, at what time point and for how long.
 |
TABLE 1. Overview of phase II data for upcoming oral agents |
NEW MONOCLONAL ANTIBODIES
Since their introduction in the 1970s, monoclonal antibodies (mAbs) have provided the opportunity of blocking specific molecular targets in the pathology of numerous autoimmune disorders including MS. Natalizumab is currently the only licensed monoclonal antibody for MS treatment, but new monoclonal antibodies have already passed phase II studies. Rituximab, daclizumab and alemtuzumab will be reviewed here.
Although therapeutic targets of mAbs appear to be specific, use of these agents can carry the risk of hypersensitivity reactions, unexpected systemic inflammatory responses, unexpected adverse events (neoplasms, infections and opportunistic infections, and the development of unexpected autoimmune phenomena) and the formation of neutralizing antibodies.
Rituximab
Mode of action
Rituximab is a chimeric intravenous mAb directed against the CD20 antigen. CD20 is present on all B cells and pre-B cells. Thus, application of rituximab results in depletion of CD20 positive cells. There is longstanding experience with this agent for the treatment of Hodgkin´s lymphoma (HL) (>300,000 patients have been exposed). Also, rituximab is used for the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus and other autoimmune conditions. In RA, rituximab is often used with two subsequent infusions of 1000 mg two weeks apart every six months; this protocol was also applied in MS trials.
Efficacy
Rituximab has initially been investigated in neuromyelitis optica (NMO, Devic´s disease): treatment resulted in a reduction of relapses and improvement of neurological impairment [21]. In MS, early phase I and II studies also proved a reduction of MRI activity, and patients had fewer relapses (compared to baseline measurements) [22]. Hauser et al. (2008) [23] conducted a randomized, placebo-controlled trial (n=104) and found a profound reduction of contrast enhancing lesions from 3 months onwards. Furthermore, relapses were largely reduced compared to placebo. It was argued that the potent reduction of inflammatory activity with rituximab is more likely due to an interruption in the interplay between T cells and B cells than to an impact on humoral mechanisms [24].
Adverse events
The following adverse events can occur with rituximab treatment:
- Infusion reactions (occasionally severe): fever, chills, hypotonia, pain, fatigue
- Neutropenic fever (rare)
- Tumor-lysis syndrome (rare)
- Progressive multifocal leukoencephalopathy (PML)
Other anti-B cell approaches under investigation
- Atacicept (blocks later stages of B cell development, in phase II for RRMS)
- Ofatumumab (completely human antibody)
Daclizumab
Mode of action
The CD25 antigen (=alpha chain of IL-2 receptor) is the target of daclizumab. IL-2 is secreted by activated lymphocytes and stimulates secretion of other proinflammatory cytokines. In addition, IL-2 is involved in lymphocytic proliferation. Daclizumab is successfully used to prevent transplant rejection after kidney transplantation [25].
Efficacy
Bielekova et al. (2004) [26] demonstrated a substantial reduction in contrast enhancing lesions and also fewer relapses compared to pre-treatment measurements in IFN-β “treatment failures” (n=11, single-arm, open-label). Add-on treatment with daclizumab to IFN-β therapy was applied at a dose of 1 mg/kg body weight for seven infusions in this study. These results were corroborated by Rose et al. [27,28]. There was a correlation between natural killer (NK) cell expansion and treatment response while the reduction of T regulatory cells did not seem to be of importance.
The CHOICE study (daclizumab SC, phase II) [29] investigated daclizumab as an add-on to IFN-β. Daclizumab yielded a more than 70% reduction of Gd-enhancing lesions in comparison to placebo.
Adverse events
Special safety concerns include infections (although there were no infection-related safety signals in previous studies) and the early development of anti-daclizumab antibodies which may reduce the efficacy of the drug in mid- to long-term treatment of MS. Despite its previous use after kidney transplantation, there is no data on long-term efficacy and tolerability of daclizumab; further studies are about to be initiated.
Alemtuzumab
Mode of action
Alemtuzumab is directed against the CD52 antigen. CD52 is a membrane antigen expressed at high levels on T-lymphocytes and B-lymphocytes. CD52 is also expressed at lower levels on monocytes and eosinophils. The high density of CD52 expression on the cellular surface makes it a target for antibody-mediated lymphocyte depletion. Alemtuzumab depletes lymphocytes by antibody-dependent cytotoxicity and complement-mediated lysis, acting on mature lymphocytes (but not on hematological progenitor cells) (Figure 1).
 |
Figure 1. Hematological changes after alemtuzumab treatment with 20 mg IV on 5 consecutive days.
(Reprinted from The Lancet, 354(9191), Coles AJ, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. 1691-1695. Copyright © 1999, with permission from Elsevier) |
Efficacy
Previous experience with alemtuzumab is derived from treatment of hematological disorders like chronic lymphocytic leukemia (CLL). Earlier studies of alemtuzumab for MS demonstrated a potent reduction of contrast enhancing lesions [30,31]. Although markers of inflammatory activity were markedly reduced, patients seemed to suffer from ongoing disability progression and continuous cerebral atrophy. Coles et al. (1999) [32] treated patients with previous high disease activity with alemtuzumab in an open-label trial and found a reduction in the relapse rate from 2.2 to 0.14, as well as a reduction in disability in this relapsing remitting MS cohort. While RRMS patients had a substantial reduction of disease activity, patients with progressive MS experienced further disease progression (despite a low relapse frequency).
CAMMS223 [33] investigated alemtuzumab in early MS and demonstrated a significant treatment benefit. In comparison to SC treatment with IFN-β-1a, treatment with alemtuzumab resulted in a more than 70% reduction in the relapse rate and more than 60% reduction in the risk of progression after at least 2 years follow-up (n=334, maximum 3 years disease duration, EDSS 0-3). Alemtuzumab was administered at either 12 mg or 24 mg IV for 5 consecutive days, once per year (patients received 2 cycles one year apart during CAMMS223).
Adverse events
Dosing in CAMMS223 was stopped after a case of idiopathic thrombocytopenic purpura (ITP) with consecutive fatal cerebral hemorrhage. Already in earlier MS studies with alemtuzumab, infections including measles, herpes zoster, varicella zoster and spirochetal gingivitis occurred. An unexpected finding was autoimmune thyroiditis in 15 patients with SPMS. This adverse event had not been previously described in other cohorts. Also, glomerulonephritis occurred in one patient. Two new large phase III trials are ongoing (CARE I and II).
Conclusions
Monoclonal antibodies are especially interesting agents because of their relatively specific modes of action that offer the opportunity to more selectively target specific disease processes (Figure 2). Currently, however, reliable biomarkers are generally missing for stratification of such treatment approaches; thus we are unable to predict who may have a higher likelihood of responding to specific treatments. Also, (unforeseen) side effects which may even increase during long term treatment may hinder widespread, long term use of these potent agents. In addition to currently licensed agents and new oral compounds, mAbs need to be appropriately included in the treatment algorithm for MS. In the future, biomarkers may allow the development of more individualized treatment regimens for RRMS patients, thus improving long term treatment outcomes and maintaining a reasonable risk-benefit profile of such agents.
 |
Figure 2. Overview of therapeutic targets of upcoming oral agents and monoclonal antibodies for the treatment of MS (explanation in text). |
REFERENCES
1. WHO. Adherence to Long-term Therapies: Evidence for Action. World Health Organisation 2003.
2. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992;340:952-956. [Medline]
3. Beutler E, Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996;93:1716-1720. [Medline]
4. Romine JS, Sipe JC, Koziol JA, Zyroff J, Beutler E. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999;111:35-44. [Medline]
5. Rice GP, Filippi M, Comi G. Cladribine and progressive MS: Clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000;54:1145-1155. [Medline]
6. Fujita T, Inoue K, Yamamoto S, et al. Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyriocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives. J Antibiot (Tokyo) 1994;47:216-224. [Medline]
7. Billich A, Bornancin F, Devay P, Mechtcheriakova D, Urtz N, Baumruker T. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 2003;278:47408-47415. [Medline]
8. Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 2000;164:5761-5770. [Medline]
9. Webb M, Tham CS, Lin FF, et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004;153:108-121. [Medline]
10. Fujino M, Funeshima N, Kitazawa Y, et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003;305:70-77. [Medline]
11. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002;277:21453-21457. [Medline]
12. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355:1124-1140. [Medline]
13. O’Connor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009;72:73-79. [Medline]
14. Budde K, Schutz M, Glander P, et al. FTY720 (fingolimod) in renal transplantation. Clin Transplant 2006;20 Suppl 17:17-24. [Medline]
15. O’Connor PW, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006;66:894-900. [Medline]
16. Tan IL, Lycklama a Nijeholt GJ, Polman CH, Adèr HJ, Barkhof F. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult Scler 2000;6:99-104. [Medline]
17. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T; Laquinimod in Relapsing MS Study Group. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 2005;64:987-991. [Medline]
18. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomized, double-blind, placebo-controlled phase IIb study. Lancet 2008;371:2085-2092. [Medline]
19. Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006;13:604-610. [Medline]
20. Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomized, double-blind, placebo-controlled phase IIb study. Lancet 2008;372:1463-1472. [Medline]
21. Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 2005;64:1270-1272. [Medline]
22. Bar-Or A, Calabresi PA, Arnold D, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 2008;63:395-400. [Medline]
23. Hauser SL, Waubant E, Arnold D, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358:676-688. [Medline]
24. Yanaba K, Hamaguchi Y, Venturi G, Steeber DA, St Clair EW, Tedder TF. B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol 2007;179:1369-1380. [Medline]
25. Webster AC, Playford EG, Higgins G, Chapman JR, Craig J. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2004;(1):CD003897. [Medline]
26. Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U S A 2004;101:8705-8708. [Medline]
27. Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG. Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 2007;69:785-789. [Medline]
28. Rose JW, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 2004;56:864-867. [Medline]
29. Montalban X, Wynn M, Kaufmann M, Mang M, Fong A. Preliminary CHOICE results: a phase 2, randomized, double-blind, placebo controlled multicentre study of subcutaneous daclizumab in patients with active, relapsing forms of multiple sclerosis on interferon beta (abstract). 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Prague, Czech Republic, 2007.
30. Moreau T, Thorpe J, Miller D, et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994;344:298-301. [Medline]
31. Paolillo A, Coles AJ, Molyneux PD, et al. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology 1999;53:751-757. [Medline]
32. Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46:296-304. [Medline]
33. Coles AJ, Compston DA, Selmaj KW, et al; CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786-1801. [Medline]