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New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis

Fox, Edward J.a; Rhoades, Robert W.b

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Current Opinion in Neurology: February 2012 - Volume 25 - Issue - p S11-S19
doi: 10.1097/01.wco.0000413320.94715.e9
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Abstract

INTRODUCTION

Patients with relapsing-remitting multiple sclerosis (RRMS) most often receive disease-modifying therapy with interferon (IFN)-β or glatiramer acetate [1]. These agents are relatively safe and well tolerated and their efficacy is supported by results from large randomized controlled clinical trials [1]. Relapses and disability progression may still occur in patients receiving disease-modifying therapy, and there is an unmet need for new treatment alternatives with the potential to improve outcomes in patients with RRMS [1]. The need for new therapies is underscored by the need to ‘raise the bar’ for treatment success in patients with RRMS. Until recently, treatments for RRMS were considered effective if they partially decreased the annual relapse rate (ARR) and slowed the accumulation of physical disability on the Expanded Disability Status Scale (EDSS) score, and this is reflected in the indication for all currently available MS therapies [1]. Advances in MS therapies should not only delay progression but provide freedom from disease, which has been defined as freedom from gadolinium-enhancing T1 or new T2 lesions detected by MRI, freedom from relapses, and the absence of disability progression [2].

Recently approved or investigational agents in advanced development have the potential to significantly improve outcomes for patients with RRMS. This review summarizes results from clinical studies of these medications and considers their potential place in clinical practice.

NEW DISEASE MODIFYING AGENTS FOR MULTIPLE SCLEROSIS

Several agents for disease modification in MS are in advanced development and may soon be available. Additionally, agents previously approved for other indications are being evaluated for safety and efficacy in MS.

Box 1
Box 1:
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Fingolimod

Fingolimod is an oral sphingosine 1-phosphate (S1P) receptor modulator approved for the treatment of MS in 2010 in North America and 2011 in Europe. It is phosphorylated by sphingosine kinase to the active form, which binds with high affinity to S1P receptors (S1PR), of which five subtypes are present on various cells and tissues [3]. Binding of phosphorylated fingolimod results in internalization and degradation of the receptor and downregulation of S1PR mRNA. With the resulting decrease in S1PR on the cell surface, lymphocyte egress from lymphoid tissues into the periphery is inhibited [4]. This action is associated with decreased lymphocyte levels in the blood and cerebrospinal fluid (CSF) and reduced risk for inflammatory events characteristic of MS pathogenesis [5]. Fingolimod significantly reduces progression of experimental autoimmune encephalomyelitis (EAE) in experimental models, but effectiveness is lost in mice with S1PR defects in S1P1 and S1P5[6,7]. The pleiotropic influences of S1P receptors in the immune and central nervous systems may be attributable to a combination of anti-inflammatory and neuroprotective effects.

Efficacy

Phase 3 clinical trial results with fingolimod have demonstrated efficacy in patients with RRMS. The 12-month, double-blind TRANSFORMS study randomized 1292 patients with RRMS and a history of at least one relapse to oral fingolimod (0.5 or 1.25 mg/day) or intramuscular (i.m.) IFN-β-1a (30 μg/week). The ARR was 0.16 for 0.5 mg/day fingolimod, 0.20 for 1.25 mg/day fingolimod, and 0.33 for IFN-β-1a (P < 0.001 for each fingolimod dose vs. IFN-β-1a). Patients in the fingolimod groups had significantly fewer new or enlarged hyperintense T2 lesions and gadolinium-enhancing T1 lesions at 12 months compared with those who received IFN-β-1a (all P < 0.05). There were no significant differences among groups with respect to EDSS scores [8▪]. A 1-year extension of TRANSFORMS compared patients randomized to 0.5 or 1.25 mg daily fingolimod who remained on these regimens with those who received IFN-β-1a in the core study and were randomized to one of the two fingolimod doses in the extension phase. During this period, investigators knew that participants were receiving fingolimod but doses remained blinded. Results showed the sustained efficacy of fingolimod for the study outcome measures [9]. Patients switched from IFN-β-1a to 0.5 mg/day fingolimod had a reduction in ARR (from 0.31 to 0.22; P = 0.049) and those switched to fingolimod 1.25 mg/day also had a significant decrease in ARR (from 0.29 to 0.18; P = 0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium-enhancing T1 lesions were significantly decreased compared with the previous 12 months of IFN-β-1a therapy (P < 0.0001 for T2 lesions at both doses; P = 0.002 for T1 lesions for 0.5 mg/day fingolimod and P = 0.011 for T1 gadolinium-enhancing lesions with 1.25 mg/day fingolimod) [9].

The phase 3 FREEDOMS trial was a 24-month, double-blind, randomized study that included 1272 patients with EDSS scores of 0–5.5, and at least one relapse in the previous year or at least two relapses in the previous 2 years [10]. Patients were randomized to 0.5 mg/day fingolimod, 1.25 mg/day fingolimod, or placebo. The ARR was 0.18 for 0.5 mg/day fingolimod, 0.16 for 1.25 mg/day fingolimod, and 0.40 for placebo (P < 0.001 for each dose vs. placebo). Fingolimod also decreased the risk for disability progression [hazard ratio = 0.70; 95% confidence interval (CI) = 0.52–0.96) for 0.5 mg/day fingolimod and (hazard ratio = 0.68; 95% CI = 0.50–0.93) for 1.25 mg/day fingolimod vs. placebo, respectively. Both fingolimod doses were associated with a significant decrease in the number of new or enlarged T2 lesions, the number of gadolinium-enhancing lesions, change in volume of hypointense T1 lesions, and brain-volume loss (P < 0.001 for all comparisons at 24 months) [10].

Safety

In the placebo-controlled phase 3 trial, lower respiratory tract infections were more common with fingolimod than with placebo (9.6–11.4% for fingolimod compared with 6% for placebo) [10]. Seven patients receiving fingolimod 1.25 mg were diagnosed with macular edema. Increases in alanine aminotransferase occurred in 8.5–12.5% of patients in the fingolimod treatment group compared with 1.7% in the placebo group, but returned to the normal range [10]. In the TRANSFORMS trial, herpesvirus infections were diagnosed in 23 patients in the 1.25 mg/day group (5.5%), nine patients in the 0.5 mg/day group (2.1%), and 12 patients in the placebo group (2.8%). There were two deaths in patients treated with 1.25 mg/day fingolimod, one due to disseminated primary varicella zoster infection and the other from herpes simplex encephalitis [8▪].

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody against CD52, a glycoprotein antigen found on the surface of mature lymphocytes and monocytes. CD52 is absent from platelets, erythroid and myeloid cells, and hematopoietic stem cells. In transgenic mice expressing human CD52, alemtuzumab depletes peripheral blood lymphocytes with a lesser effect in lymphoid organs [11]. Alemtuzumab has also been shown to induce production of neurotrophic factors in reconstituted autoreactive T cells [12].

Efficacy

Alemtuzumab was studied in CAMMS223, a 3-year, phase 2, rater-blinded trial. CAMMS223 included 334 patients with RRMS, disease duration 3 years or less, and EDSS 3 or less, who were randomized to subcutaneous (SC) IFN-β-1a (44 μg three times per week) or annual intravenous (i.v.) cycles of alemtuzumab (12 or 24 mg/day) for 36 months [13]. Alemtuzumab was administered over 5 consecutive days at the onset and for 3 days at months 12 and 24. Only two courses of alemtuzumab were administered to most patients due to a hold on dosing detailed below. Alemtuzumab was associated with a significantly reduced rate of sustained disability accumulation vs. IFN-β-1a (9.0 vs. 26.2%, P < 0.001). The mean EDSS score improved by 0.39 point with alemtuzumab and worsened by 0.38 point with IFN-β-1a (P < 0.001). Alemtuzumab significantly decreased the ARR (0.10 vs. 0.36, P < 0.001), and significantly decreased T2 lesion burden vs. IFN-β-1a (P = 0.005) [13]. In a planned post-hoc analysis, significantly more patients randomized to alemtuzumab achieved sustained reduction in disability compared with those receiving IFN-β-1a (hazard ratio = 2.61, 95% CI = 1.5–4.4; P = 0.0004) [14]. Among patients with no clinical disease activity 3 months before treatment or any clinical or radiologic disease during the trial, disability improved after receiving alemtuzumab, but not IFN-β-1a. These results suggest that the improvement in disability seen in the trial was not entirely a result of inflammation suppression [12].

Two phase 3 trials of alemtuzumab are ongoing [CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405)]. CARE-MS I is a phase 3 comparison of i.v. alemtuzumab (12 mg/day for 5 days initially and for 3 days a year after) vs. subcutaneous IFN-β-1a (44 μg three times per week) in 581 patients with RRMS who had not received prior disease-modifying therapy. Results from this study showed that alemtuzumab treatment resulted in a 55% reduction in relapse rate vs. IFN-β-1a over 2 years (P < 0.0001). At 2 years, 8% of patients who received alemtuzumab and 11% of those treated with IFN-β-1a had a sustained increase in EDSS scores (P = 0.22) [15].

CARE-MS II is currently comparing alemtuzumab with IFN-β-1a subcutaneous in patients with RRMS who relapsed on prior therapy. The initial analysis of results in 840 patients showed a 49% reduction in relapse rate in patients receiving alemtuzumab 12 mg, compared with IFN-β-1a subcutaneous (P < 0.0001) [16]. The coprimary endpoint showed a 42% reduction in the risk of sustained disability measured by EDSS (P = 0.008).

Safety

In the CAMMS223 trial, adverse events in the alemtuzumab vs. IFN-β-1a subcutaneous groups included thyroid disorders (23 vs. 3%), immune thrombocytopenic purpura (ITP) (3 vs. 1%), and infections (66 vs. 47) [13]. In September 2005, the data and safety monitoring board (DSMB) recommended suspension of the alemtuzumab arm after three patients developed ITP, one of whom died. Safety and efficacy assessments proceeded during the suspension, and those randomized to IFN-β-1a subcutaneous continued treatment. A program was established for the effective identification and management of ITP, and the DSMB lifted the alemtuzumab dosing suspension in May 2007 [13].

In CARE MS-1, no patient receiving alemtuzumab withdrew from the trial due to an adverse event. Eighteen percent of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event and 0.8% developed ITP during the 2 year study [15]. Infections were reported more frequently in alemtuzumab-treated patients than in patients receiving IFN-β-1a subcutaneous-treated patients (67 vs. 46%). Infusion associated reactions were common in alemtuzumab-treated patients, but were typically controlled with concomitant medications.

There is evidence that the autoimmunity observed in MS patients receiving alemtuzumab may be driven by interleukin (IL)-21. Patients who developed secondary autoimmunity during treatment with alemtuzumab in the CAMMS223 study had more than two-fold greater levels of serum IL-21 at baseline than those who did not. Assessment of IL-21 may serve as a biomarker to help identify those at higher risk of developing autoimmunity [17].

BG-12 (Dimethyl Fumarate)

BG-12 is a fumaric acid ester with immunomodulatory properties. BG-12 has demonstrated benefits in animal models of EAE. Fumaric acid esters may decrease leukocyte passage through the blood–brain barrier and exert neuroprotective properties by the activation of antioxidative pathways [18].

Efficacy

DEFINE was a phase 3, randomized, double-blind, placebo-controlled, dose-comparison study of BG-12 in 1234 patients [19]. Patients with RRMS were randomized to BG-12 at a dose of either 240 mg twice a day or 240 mg three times a day, or to placebo. Both BG-12 doses were associated with a significant decrease in the proportion of patients who relapsed at 2 years compared with placebo (P < 0.0001). Both BG-12 doses were significantly superior to placebo in reducing ARR, the number of new or newly enlarging T2 hyperintense lesions, and the number of new gadolinium-enhancing lesions. BG-12 was also superior to placebo in slowing the rate of disability progression as measured by EDSS scores at 2 years [19]. The reduction in 12-week disability progression was 38 and 34% for the twice and three-times daily doses, respectively (P < 0.05 for both).

Safety

DEFINE results indicated that BG-12 had a safety profile comparable to that for placebo [19]. Results from a phase 2b study of BG-12 (120 or 240 mg three times per day) in 257 patients with RRMS indicated that adverse events occurring more often with BG-12 vs. placebo were abdominal pain, flushing, and hot flush [20]. Dosing interruptions were allowed for abnormal results of liver or renal function tests or lymphopenia, and treatment was discontinued in patients with abnormalities persisting for 4 weeks. Adverse events led to discontinuation in 8, 11, and 13% of those receiving BG-12 doses of 120 mg once daily, 120 mg three times daily, and 240 mg three times daily, respectively. Events leading to discontinuation included flushing, elevated alanine aminotransferase, nausea, diarrhea, and vomiting. There was no increased risk of infection associated with BG-12 use.

Laquinimod

Laquinimod is an immunomodulator with efficacy in MS. Although its mechanism of action is not fully understood, laquinimod has been shown to promote anti-inflammatory cytokine profiles in human peripheral blood mononuclear cells. In EAE models, laquinimod effectively reduced inflammation, demyelination, and axonal damage [21].

Efficacy

Laquinimod has been evaluated in the phase 3 ALLEGRO trial, a 2-year randomized, double-blind, placebo-controlled study that included 1106 patients with RRMS who were randomized to receive 0.6 mg laquinimod once daily or placebo. The primary outcome measure was the number of confirmed relapses. Laquinimod treatment resulted in a 23% reduction in ARR vs. placebo (P = 0.0024) and a 36% decrease in the risk for disability progression, as measured by EDSS (P = 0.0122). Treatment with laquinimod was also associated with a 33% reduction in progression of brain atrophy vs. placebo (P < 0.0001) [22].

A second phase 3 study of laquinimod, the BRAVO trial, is comparing 0.6 mg laquinimod once daily with placebo in patients with RRMS. The top-line results of BRAVO showed that the primary endpoint of reducing ARR was not reached (P = 0.075). Despite randomization, the laquinimod and placebo groups had dissimilar baseline MRI characteristics. After a preplanned sensitivity analysis adjusting for baseline MRI, laquinimod was associated with a statistically significant reduction of ARR (21.3%), of risk of disability progression on EDSS (33.5%), and of brain volume loss (27.5%) compared with placebo (all P < 0.05) [23].

Safety

In ALLEGRO, serious adverse events occurred in 22.2% of laquinimod patients and 16.2% of placebo patients. Herpesvirus infection occurred in 17 patients who received laquinimod vs. 20 patients on placebo, with cancers detected in eight vs. six patients, respectively. The most common adverse event that occurred more often with laquinimod vs. placebo was elevation in alanine transaminase (6.9% with laquinimod vs. 2.7% for placebo; elevations were more than three times the upper limit of normal in 4.9 and 2% of the laquinimod and placebo groups, respectively). Transaminase elevations, which were transitory, resulted in discontinuation in 13 patients receiving laquinimod and seven on placebo [22].

Teriflunomide

Teriflunomide is an oral reversible inhibitor of dihydroorotate dehydrogenase (DHODH), a mitochondrial membrane protein essential for pyrimidine synthesis [24]. DHODH blocks de-novo pyrimidine synthesis leading to an inhibition of the proliferation of autoreactive B and T cells. In the presence of teriflunomide, replication of hematopoietic and memory cells is preserved through metabolism of the existing pyrimidine pool. Teriflunomide has been shown to have additional activities, including modulation of immunoglobulin class switching, IL-2 production, and IL-2 receptor expression [25].

Efficacy

Teriflunomide (7 or 14 mg/day) was compared with placebo in a 36-week phase 2 trial in 157 patients with RRMS and 22 patients with secondary progressive MS still experiencing relapses. The mean values for the primary endpoint of combined unique active lesions per MRI scan were 0.5, 0.2, and 0.3, respectively, for placebo, 7 mg/day teriflunomide (P < 0.03 vs. placebo), and 14 mg/day teriflunomide (P < 0.01 vs. placebo). Patients who received teriflunomide also had significantly fewer T1-enhancing lesions or new or enlarging T2 lesions than those treated with placebo (P < 0.05 all comparisons). Patients receiving teriflunomide 14 mg/day had significantly reduced T2 disease burden. The proportion of patients with increased disability by EDSS at 36 weeks was significantly lower with teriflunomide compared with placebo (7.4 vs. 21.3%, P < 0.04), a relative reduction of 69% [26]. Two phase 2 studies evaluated teriflunomide as adjunctive therapy in persons with MS [27,28]. In these studies, patients receiving glatiramer acetate (n = 120) or a β-IFN (n = 116) were randomized to add placebo or teriflunomide 7 or 14 mg daily to their current therapy. In both studies, teriflunomide had good safety and tolerability and both doses were associated with improved disease control according to reduced number and volume of T1 gadolinium-enhancing lesions, compared with placebo.

Results from the phase 3 TEMSO study demonstrated significant reduction in ARR and disability progression with teriflunomide compared with placebo. TEMSO evaluated 1088 patients with relapsing forms of MS, EDSS scores at least 5.5, and at least one relapse in the previous year or at least two relapses in the preceding 2 years. Patients were randomized to teriflunomide 7 or 14 mg/day, or placebo. The adjusted ARRs with teriflunomide 7 and 14 mg/day were 0.370 and 0.369, respectively, compared with 0.539 for placebo (P < 0.001 for both comparisons) [29]. Time to first relapse was increased 24.4 and 28.1% for the 7 and 14-mg doses compared with placebo, respectively (P ≤ 0.01 for both comparisons). The 14-mg/day dose of teriflunomide was associated with a 29.8% reduction in the risk of sustained disability progression (P = 0.028).

A key prespecified endpoint of TEMSO was T2 burden of disease by MRI. Teriflunomide 7 mg/day resulted in a 39.4% reduction in T2 disease burden vs. placebo (P = 0.03); and teriflunomide 14 mg/day resulted in a 67.4% reduction (P < 0.001 vs. placebo). The numbers of gadolinium-enhancing T1 lesions and unique active lesions per scan were also reduced with both teriflunomide doses vs. placebo (P < 0.001 for all comparisons) [30].

Teriflunomide is also being evaluated as an adjunctive therapy in combination with IFN-β in the phase 3 TERACLES study, with estimated completion in 2014. Two additional studies are underway; TOWER and TENERE are monotherapy studies comparing teriflunomide with placebo and IFN-β-1a subcutaneous, respectively [31]. TOPIC is an ongoing phase 3 trial evaluating the efficacy and safety of once daily teriflunomide vs. placebo in patients with clinically isolated syndrome [32].

Safety

In the phase 2 study, serious adverse events were reported in 19 patients (seven placebo, five teriflunomide 7 mg/day, and seven teriflunomide 14 mg/day). These included elevated hepatic enzymes, hepatic dysfunction, neutropenia, rhabdomyolysis, and trigeminal neuralgia. Adverse events that appeared to occur more often with teriflunomide than placebo included nausea, paresthesia, limb pain, diarrhea, and arthralgia [26]. Teriflunomide was generally well tolerated in the TEMSO trial. Adverse events occurring at a higher rate in the teriflunomide groups vs. placebo were diarrhea, nausea, and alanine transferase increases. No serious opportunistic infections occurred in patients treated with teriflunomide [26].

B cell depletion

Several treatments are in development for the therapy of MS that target B cells. This therapeutic strategy is supported by observations that activated B cells and plasma cells accumulate in MS lesions and in the CSF of patients with MS. B cells may contribute to MS pathology by production of antimyelin autoantibodies and by regulating T cell responses via antigen presentation, cytokine release, and induction of regulatory T cells [33].

Rituximab

Rituximab is a chimeric monoclonal antibody that depletes CD20-positive B cells through cell-mediated and complement-dependent cytotoxic effects and promotion of apoptosis. In a phase II trial in patients with RRMS, rituximab treatment resulted in significantly decreased numbers of gadolinium-enhancing lesions vs. placebo (−91%; P < 0.001) as well as a significantly decreased risk for relapse (20.3 vs. 40.0%, P = 0.04) [34]. Rituximab was associated with infusion-related reactions and moderately increased risk of progressive multifocal leukoencephalopathy (PML) in patients receiving this agent for approved indications. Owing to an impending patent expiration and efficacy and safety concerns for use of rituximab in patients with MS, no phase 3 development of rituximab in MS is ongoing.

Ocrelizumab

Ocrelizumab is a humanized anti-CD20 monoclonal antibody that results in B cell depletion. It has been evaluated in a 48-week phase 2 study that included 220 patients with RRMS who were randomized to treatment with i.v. ocrelizumab (600 or 2000 mg for the first 24 weeks and 1000 mg for the second 24 weeks), i.m. IFN-β-1a (30 μg once weekly), or placebo. The mean number of gadolinium-enhancing lesions was reduced by 89% in the low-dose and 96% with high-dose group compared to placebo. At the end of 48 weeks of treatment, 80% of the patients who received the 600-mg dose and 72.7% of those who received the 2000/1000-mg dose were relapse-free. One patient on ocrelizumab died at 14 weeks due to brain edema after the occurrence of a systemic inflammatory response syndrome. No opportunistic infections were reported [35]. Phase 3 studies of ocrelizumab for rheumatoid arthritis and lupus were suspended when the respective DSMBs decided the risks outweighed the benefits in these patient populations [36].

Ocrelizumab is also being evaluated in ORATORIO, a 120-week, phase 3, double-blind, randomized, placebo-controlled trial in patients with primary progressive MS [37]. This trial consists of five treatment cycles of i.v. ocrelizumab 600 mg. The primary outcome measure is time to onset of sustained disability progression [34]. Two large global studies will compare ocrelizumab with IFN-β-1a subcutaneous (OPERA I and II) in patients with RRMS [38]. These phase 3, double-blind, double-dummy trials will assess efficacy and safety in patients randomized to ocrelizumab 600 mg i.v. every 24 weeks or IFN-β-1a subcutaneous three times weekly. Enrollment (N = 800) is projected to be completed in 2012, with data reported in 2014.

Ofatumumab

Ofatumumab is a third anti-CD20 antibody being developed for the treatment of MS. A 24-week, phase 2 safety and pharmacokinetics study in 38 patients with RRMS indicated no dose-limiting toxicities and no unexpected safety findings. Active treatment also resulted in significant reductions in the number of gadolinium-enhancing T1 lesions and new/enlarging T2 lesions in patients treated with ofatumumab vs. placebo [39]. This agent has not yet proceeded to phase 3 development.

Daclizumab

Daclizumab is a humanized monoclonal antibody directed against the high-affinity IL-2 receptor. This receptor is present on activated, but not resting, T cells. Binding of IL-2 to this receptor is necessary for clonal expansion and continued viability of activated T cells [40]. Although the anti-inflammatory effects of daclizumab were believed to result from decreased T cell activation, it is not associated with significant changes in T cell or B cell numbers or the ability of T cells to proliferate. It appears that the effects of daclizumab may be related to an increase in immunoregulatory CD56bright natural killer cells [41].

Efficacy

Daclizumab was evaluated for the treatment of RRMS in the phase 2 CHOICE trial. It was a double-blind placebo-controlled study in 230 patients with active disease despite IFN-β treatment. Patients were randomized to receive subcutaneous daclizumab 2 mg/kg every 2 weeks, subcutaneous daclizumab 1 mg/kg every 4 weeks, or placebo for 24 weeks, as an adjunct to their current IFN-β therapy (46% subcutaneous IFN-β-1a, 30% i.m. IFN-β-1a, and 24% subcutaneous IFN-β-1b). The primary endpoint was the total number of new or enlarged gadolinium-enhancing lesions detected between weeks 8 and 24. The mean number of new or enlarged gadolinium-enhancing lesions was 4.75 in the IFN-β–placebo group vs. 1.32 for patients who received IFN-β with high-dose daclizumab (P = 0.004), and 3.58 for those treated with IFN-β with low-dose daclizumab (P = 0.51) [42]. Daclizumab is also being compared with i.m. IFN-β-1a in a phase 3 study in patients with RRMS. The estimated date for completion is 2014 [43].

SELECT is a phase 2b clinical trial that evaluated two doses of daclizumab (150 or 300 mg every 4 weeks) in 600 patients with RRMS [44]. At 1 year, daclizumab was associated with 54 and 50% reductions in AAR for the 150 and 300-mg dose groups, respectively (P < 0.001 vs. placebo for both doses).

Safety

Safety data from the CHOICE trial indicated similar rates of infection across all treatment groups. The incidence of cutaneous adverse events was higher in the combined daclizumab groups (34%) vs. placebo (27%); grade 3 cutaneous events included rash (n = 1) and eczema (n = 2) in the daclizumab group. A higher incidence of grade-3 or grade-4 infections occurred in those who received daclizumab (4.6%) vs. placebo (1.3%). Grade 3 infections occurred in 10 patients in the high-dose daclizumab group, two in the low-dose daclizumab group, and two in the placebo groups. No opportunistic infections were observed and all infections resolved with therapy [42].

Cladribine

Cladribine is an immunosuppressant whose active metabolite disrupts cellular metabolism, inhibits DNA synthesis and repair, and leads to apoptosis of lymphocytes [45]. Cladribine has been shown to be effective for the treatment of RRMS in the CLARITY trial [45], but concerns about sustained immunosuppression and associated cancer risk resulted in withdrawal of applications for marketing authorization in the European Union [46] and discontinuation of development in the United States [47].

Benefits and limitations of emerging therapies for multiple sclerosis

The availability of new therapeutic options for disease modification has the potential to expand options for persons with MS. These new therapies have the potential to redefine the goals of therapies in the context of appropriate patient selection and management strategies.

Changing the course of disease

A goal for the treatment of MS not yet realized for many patients is freedom from disease activity, defined as a complete absence of relapses, MRI evidence of disease activity, and progression of disability [2]. Freedom from disease activity was demonstrated for 29.5% of patients treated with natalizumab in the AFFIRM trial [2], which is a reasonable benchmark for assessment of new MS therapies. Further, 3-year results from the CAMMS223 study indicated alemtuzumab often decreased EDSS scores rather than slowing increases [13].

Changing the course of disease in patients with MS is closely linked to the concept of neuroprotection. At present, the mechanisms underlying neurodegeneration in MS and how to promote neuroprotection are not completely understood [48▪▪]. Moreover, there is no consensus on biomarkers for neuroprotection that could be evaluated in studies of MS therapies [49]. A variety of measures have been suggested as potential candidates for assessment of neuroprotection in clinical trials [50]. It has been proposed that brain volume change on serial MRI may provide a sensitive overall measure of neuroprotection in MS trials [50]. However, the use of whole-brain atrophy to assess neuroprotection lacks specificity for tissue-related processes (e.g., loss of myelin or axons and increase in glial content). Inflammation can also confound atrophy measurements [51]. Prevention of white matter atrophy may be a practical MRI measure for assessment of neuroprotective effects of MS treatments. Loss of white matter reflects axonal damage and subsequent degeneration of neuronal cell bodies and gray matter atrophy [52].

Challenges in patient selection and monitoring

Although potentially providing improved efficacy, new treatments for MS also present challenges in patient selection and monitoring. For example, an electrocardiogram, ophthalmologic evaluation for macular edema, assessment of pulmonary function, and liver function tests are all recommended prior to initiation of treatment with fingolimod [53]. Patients receiving alemtuzumab will also require close monitoring for autoimmunity, and it is possible that pretreatment assessment of IL-21 levels may be useful for risk stratification with this treatment [17]. Rituximab requires monitoring of neurologic function due to risk for PML in patients receiving it for its current indications [54]. This requirement may extend to any anti-B-cell antibody approved for the treatment of MS. Increasing monitoring of patients for infection or malignancy will be important for many of the new MS treatments based on safety results from phase 2 and 3 clinical trials.

CONCLUSION

The emergence of a large number of new disease-modifying treatments for MS should prompt a re-evaluation of our approaches to the long-term management of these patients. First and most importantly, we need to set a higher standard for treatment success. Freedom from disease, as defined in preceding sections, should be our target. It is likely to be achievable in many patients using newer therapies, either alone or in combination with currently approved agents. Setting a higher standard for treatment success will result in less tolerance of relapses, clinical evidence of progression, or new lesions detected on MRI. Physicians are more likely to intensify treatment as necessary to recover more control over the disease.

Early initiation of disease-modifying therapy is also an important component of advancing treatment for MS. The Multiple Sclerosis Therapy Consensus Group recommends early initiation of treatment with the goal of terminating inflammation and reducing axonal damage [55]. Early intervention with the best available therapy and a high standard for treatment success has the potential to significantly improve long-term outcomes for MS patients.

Acknowledgements

None.

Conflicts of interest

E.F. has received consulting fees from Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Opexa, and Teva; fees for non-CME/CE services directly from a commercial interest or their agents (eg, speakers’ bureaus) from Bayer, Biogen Idec, EMD Serono, Pfizer, and Teva; and contracted research support from Biogen Idec, Genzyme, EMD Serono, Eli Lilly, Novartis, Ono, Roche, Sanofi-aventis, and Teva. R.R. has no conflict of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

alemtuzumab; BG-12; daclizumab; fingolimod; freedom from disease; laquinimod; multiple sclerosis; ocrelizumab; ofatumumab; teriflunomide

© 2012 Lippincott Williams & Wilkins, Inc.