Emerging Strategies for the Treatment of Multiple Sclerosis
Emerging Strategies for the Treatment of Multiple Sclerosis
An oral fumaric acid ester (Fumaderm®) was previously shown to be effective in patients with psoriasis and various formulations of fumaric acid esters have been in use for this disease in Germany for many years. The main component of Fumaderm, dimethylfumarate (BG-12), is rapidly metabolized to its main active metabolite, monomethylfumarate. The mechanism of action in MS is still under investigation, however, it seems that at least some of the drug's activity is related to monomethylfumarate's release of the transcription factor, Nrf-2, from its usual binding to Keap-1. Through inhibition of translocation of NF-κB into the nucleus this ultimately leads to a decrease in several inflammatory cytokines, chemokines and adhesion molecules. More recent work in animal models suggests BG-12 may have neuroprotective properties, with positive effects on the preservation of oligodendrocytes, myelin, axons and neurons through the reduction of oxidative stress.
A Phase IIb study randomized 257 patients to one of several dosing regimens of BG-12 or placebo for 24 weeks. The study met its primary end point, demonstrating a decrease in the number of gadolinium-enhancing lesions (GELs) on MRI scans and prompting the initiation of several Phase III trials.
Results from the DEFINE trial were reported in a platform presentation at the 2011 Joint European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). DEFINE was a multicenter, double-blind trial that randomized 1234 relapsing–remitting MS (RRMS) patients to BG-12 240 mg twice daily (b.i.d.), three-times daily (t.i.d.) or placebo for 2 years. The study met its primary end point with a 49 (b.i.d.) and 50% (t.i.d.) reduction in the proportion of patients who relapsed during the study period (p < 0.0001). Secondary clinical end points included the annualized relapse rate (ARR) and confirmed 12-week disability progression by the Expanded Disability Status Scale (EDSS). The ARR was 0.36 for placebo, 0.17 for BG-12 b.i.d. and 0.19 for BG-12 t.i.d. This corresponds to reductions of 53 and 48% for BG-12 b.i.d. and t.i.d., respectively, compared with placebo (p < 0.001). Disability progression was reduced by 38% with BG-12 b.i.d. (p < 0.01) and 34% with BG-12 t.i.d. (p < 0.05).
Biogen Idec (Weston, MA, USA) subsequently announced preliminary results of the CONFIRM trial in a press release. CONFIRM was also a multicenter, double-blind trial. The investigators randomized 1430 RRMS patients to BG-12 240 mg b.i.d., BG-12 240 mg t.i.d., placebo, or daily subcutaneous injection of glatiramer acetate for 2 years. The study met its primary end point with reduction in ARR of 44% for BG-12 b.i.d. (p < 0.0001) and 51% for BG-12 t.i.d. (p < 0.0001) compared with placebo, while glatiramer reduced ARR by 29% compared with placebo. One secondary clinical end point, the proportion of patients who relapsed, was decreased by 34% for b.i.d. (p < 0.003) and 45% for t.i.d. (p < 0.0001) while glatiramer decreased this by 29% (p < 0.01). All MRI end points, including a decrease in the number of new T2 and T1 lesions compared with placebo, were satisfied. There was no statistically significant difference in the remaining clinical end point, 12-week confirmed disability progression, possibly due to the unexpectedly low rate of progression in the placebo group.
The details regarding adverse events have not yet been published, however, according to what has been released the incidence of serious adverse events and events leading to drug discontinuation was similar in all groups in both trials. Flushing and gastrointestinal adverse effects were more common with BG-12 than with placebo, and there were no opportunistic infections nor treatment-related fatalities in either Phase III trial.
Teriflunomide, the active metabolite of the rheumatoid arthritis drug leflunomide, reversibly inhibits the mitochondrial enzyme DHODH. DHODH provides the rate-limiting step in de novo pyrimidine synthesis, a crucial pathway for proliferating lymphocytes. The salvage pathway provides a sufficient pyrimidine supply to resting lymphocytes; teriflunomide therefore selectively targets blasting rather than quiescent lymphocytes (Figure 1). This presumably allows it to limit inflammation without inducing a state of broad immunosuppression. Leflunomide has also been demonstrated to have DHODH-independent effects involving various other targets involved in inflammation such as the JAK/STAT pathway, COX-2, EGFR and iNOS, among others.
(Enlarge Image)
Figure 1.
The effect of teriflunomide on pyrimidine synthesis.
In the resting state, lymphocytes are able to replenish their pyrimidine pools by salvaging pyrimidines from catabolic processes. This is sufficient to synthesize phospholipids (membrane maintenance and second messengers) and glycoproteins (adhesion molecules). However, when lymphocytes begin proliferating, the need for pyrimidines increases, and de novo synthesis of pyrimidines becomes necessary to fuel the synthesis of new DNA molecules. Since teriflunomide is a high-affinity inhibitor of the key enzyme of de novo pyrimidine synthesis (DHODH), it targets proliferating (but not resting) lymphocytes in a semi-selective manner.
CTP: Cytidine triphosphate; DHODH: Dihydroorotate-dehydrogenase; TTP: Thymidine triphosphate; UTP: Uridine triphosphate.
Reproduced from [25] with permission from Elsevier.
A Phase II trial randomized 179 patients with relapsing forms of MS to placebo or daily teriflunomide, 7 or 14 mg, for 36 weeks. The study met its primary end point, demonstrating a decreased number of unique active MRI lesions for both doses of teriflunomide compared with placebo. On this basis several Phase III trials were initiated; most of these are ongoing, however, the TEMSO investigators have published results.
TEMSO was a multicenter double-blind trial that randomized 1088 patients with relapsing forms of MS to placebo or 7- or 14-mg doses of oral teriflunomide daily for 108 weeks. The study met its primary end point with significant reduction in ARR, from 0.54 in the placebo group to 0.37 in both teriflunomide groups, corresponding to relative risk reduction of 31.2 and 31.5% for the 7- and 14-mg doses of teriflunomide, respectively (p < 0.001). The key secondary end point, reduction in confirmed disability progression as defined by sustained increase in EDSS over 12 weeks, was met at the 14-mg dose (20.2 vs 27.3%; p = 0.03) although not at the 7-mg dose (21.7%; p = 0.08). The key MRI end point, change in total lesion volume, was also met by both doses, with the higher dose of teriflunomide demonstrating somewhat more robust efficacy than the lower.
There was no statistically significant difference in adverse events, serious adverse events, or adverse events requiring discontinuation of the study drug. Adverse events that were more common with teriflunomide included diarrhea, nausea and hair thinning, which only very rarely resulted in discontinuation of the study drug. Those receiving teriflunomide were more likely to have small elevations in alanine aminotransferase levels but these were not clinically relevant. Rare adverse effects included neutropenia, elevated blood pressure and dermatologic reactions. Importantly, there did not appear to be a difference in the rate of serious infection, opportunistic infection, or malignancy between teriflunomide and placebo.
There are several other Phase III trials of teriflunomide currently underway. TOWER (NCT00751881) is another randomized trial comparing teriflunomide (7 or 14 mg) to placebo in 1100 RRMS patients, which aims to provide confirmatory results to TEMSO. TENERE (NCT00883337), a randomized trial of approximately 300 RRMS patients comparing both doses of teriflunomide to subcutaneous IFN-β-1a, will provide data with an active comparator. TERACLES (NCT01252355) is a randomized trial of over 1400 relapsing patients looking at the combination of teriflunomide (7 or 14 mg) with IFN-β versus interferon alone. Teriflunomide is also being studied in clinically isolated syndrome in TOPIC (NCT00622700).
Alemtuzumab is a recombinant humanized IgG1 mAb currently available for the treatment of B-cell chronic lymphocytic leukemia. It targets CD52, a glycoprotein expressed mainly by B and T lymphocytes although also by various other components of the immune system, such as dendritic cells, monocytes/macrophages, natural killer (NK) cells and some granulocytes. The precise function of CD52 has not been fully elucidated; however, some studies have demonstrated effects on T-cell migration and costimulation.
Administration of alemtuzumab causes widespread and sustained depletion of CD52-positive cells, followed first by slow repopulation of B cells and eventually of T cells. Several studies have suggested a 'sparing' of T cells with a regulatory phenotype, thus inducing a durable regulatory 'resetting' of the immune system that may contribute to alemtuzumab's effect in MS.
CAMMS223, a Phase II trial that randomized 334 treatment-naive RRMS patients to alemtuzumab or interferon, met its coprimary outcomes of decreased ARR and decreased accumulation of disability. This led to the initiation of several Phase III trials.
CARE-MS I was a multicenter, rater-blind Phase III trial that randomized 581 treatment-naive RRMS patients to alemtuzumab (12 mg/day for 5 days by intravenous infusion followed by a second 3-day infusion 1 year later) or IFN-β-1a (44 µg subcutaneously three-times per week) and followed them over 2 years. The results of CARE-MS I were released to the press and presented at the ECTRIMS/ACTRIMS in 2011. Treatment with alemtuzumab resulted in a 55% reduction in relapse rate compared with interferon (ARR 0.18 vs 0.39; p < 0.0001), satisfying one of the study's primary end points. However, there was no significant difference in the other primary end point, 6-month confirmed disability progression measured by EDSS. It has been postulated this is likely at least partially explained by the unexpectedly low rate of disability progression in all arms; the study was not powered to detect a difference at the low rate that was observed. As for MRI end points, the number of new GELs, new T2 lesions, and new T1 lesions were all significantly reduced in the alemtuzumab group. In addition, patients who received alemtuzumab had significantly less change in brain parenchymal fraction, a measure of brain atrophy, compared with patients who received interferon (-0.87 vs -1.49; p < 0.0001).
Preliminary results from CARE-MS II (NCT00548405), a second Phase III, rater-blind, active-comparator trial, were recently made public in a press release. CARE-MS II randomized 840 RRMS patients who had experienced at least one relapse while on some disease-modifying therapy to either alemtuzumab or IFN-β-1a (both administered as in CARE-MS I). In this study, evaluating patients with more active and treatment-refractory MS, both coprimary outcomes were satisfied: alemtuzumab demonstrated a 49% reduction in relapse rate (p < 0.0001) and a 42% reduction in disability progression as measured by EDSS (p = 0.0084).
Several safety concerns have been raised by the above studies, particularly an increased risk of infection and emergent autoimmune diseases in patients treated with alemtuzumab. All three studies showed a modest increase in the incidence of infections although complete information regarding these events has not yet been published. There have been no treatment-related fatalities reported in the Phase III studies. In CAMMS223, 22.7% of patients had a thyroid-related adverse event, most commonly hyperthyroidism, and 2.8% developed immune thrombocytopenic purpura. The profile was slightly more favorable in the Phase III studies with approximately 18 and 16% developing an autoimmune thyroid disorder and 0.8 and 1% developing immune thrombocytopenic purpura in CARE-MS I and II, respectively. However, these patients were followed for only 2 years, as compared with the 3-year follow-up in CAMMS223. It is worth noting that in the two Phase III studies the adverse events were anticipated, detected by monitoring and appropriately managed. There is evidence linking emergent autoimmune diseases to high levels of IL-21, which could allow for risk stratification for these adverse events prior to alemtuzumab treatment.
It should be emphasized that alemtuzumab was compared directly to interferon in these trials in a head-to-head fashion, in contrast to the 'active comparator' method employed in other recent trials. Alemtuzumab has been granted fast track status by the US FDA and is slated to undergo priority expedited review in the first half of 2012.
Clinical and basic science evidence support the role of B lymphocytes in the immunopathogenesis of MS. Several plausible mechanisms include contribution to antibody-mediated myelin damage, upregulation of T-cell-mediated tissue destruction, and a role in neurodegeneration. As such, an agent that targets B cells, such as the anti-CD20 mAb rituximab, offers a logical approach to MS therapy. Rituximab demonstrated a rapid and sustained improvement in disease activity (both clinical and MRI outcomes) in an open-labeled Phase I trial of patients with RRMS, and a small double-blind Phase II trial, HERMES. Notably, in this trial rituximab decreased the mean number of new lesions by 91% compared with placebo. Rituximab unfortunately did not meet its primary disability end point in the subsequent Phase II/III Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS).
Although rituximab itself is not being further developed for MS, based on the encouraging proof-of-principle experience, newer anti-CD20 mAbs ocrelizumab and ofatumumab are currently being investigated. Theoretically, these humanized or fully human Abs might provide advantages over a chimeric antibody, possibly translating into decreased infusion reactions and improved tolerability. In addition, with respect to the mechanism of B-cell depletion, ocrelizumab shows increased antibody-dependent cell-mediated cytotoxicity and decreased complement-mediated cytotoxicity compared with rituximab, which could result in improved efficacy and better tolerability.
A multicenter, double-blind, placebo-controlled Phase II trial of ocrelizumab was recently completed. Two hundred and twenty patients were randomized to placebo, ocrelizumab 600 or 2000 mg (infused on days 1 and 15), or once-weekly intramuscular IFN-β-1a (30 µg) for 24 weeks. The primary end point, reduction in the number of GELs, was satisfied with relative reductions of 89 and 96% for the 600- and 2000-mg doses of ocrelizumab, respectively, compared with placebo (p < 0.0001). Key secondary end points included ARR, proportion of relapse-free patients and several additional MRI measures. ARR was reduced from 0.64 in the placebo group to 0.13 with ocrelizumab 600 mg and 0.17 with ocrelizumab 2000 mg (p < 0.0001). Comparison to interferon had been planned only as a tertiary analysis; however, there was a clear difference between ocrelizumab and interferon with respect to GELs (p < 0.0001) and even with respect to ARR with the 600-mg dose (p = 0.03), although not the 2000-mg dose (p = 0.09).
Infusion-related symptoms, which were generally mild-to-moderate, were seen in the ocrelizumab groups. The number of serious adverse events was small and similar among the groups. However, one patient in the ocrelizumab 2000-mg group died of a systemic inflammatory response of unknown etiology. Although Phase III trials in rheumatoid arthritis had significant rates of serious and opportunistic infections, none were identified in this trial. One potential explanation is that the patients in rheumatoid arthritis trials were universally being treated with an additional immunosuppressive agent concomitantly; patients being treated with immunosuppressants were excluded from this trial.
Several Phase III trials are now underway. OPERA I and II are comparing ocrelizumab (600 mg, as above) to interferon (44 µg subcutaneous injection three-times per week) in RRMS and plan to enroll approximately 800 patients each (NCT01412333, NCT01247324). In addition, because subgroup analysis of rituximab in OLYMPUS suggested a benefit to younger patients and those with GELs, ocrelizumab is also being studied in primary progressive MS. ORATORIO will compare ocrelizumab (600 mg, as above) to placebo in primary progressive MS and plans to enroll 630 patients (NCT01194570).
Also under investigation in MS is ofatumumab, a fully human mAb that targets a unique epitope on the CD20 molecule. Genmab announced positive interim results for a Phase II safety and pharmacokinetics study of ofatumumab in July 2010 (NCT00640328). A total of 38 patients were randomized to ofatumumab or placebo in a crossover design. Efficacy was assessed as a secondary end point; the number of GELs and new or enlarging T2 lesions was statistically significantly less in patients treated with ofatumumab compared with placebo. This study planned to enroll 324 patients in total with results anticipated in 2012. Another Phase II study, MIRROR, will compare several doses of ofatumumab administered subcutaneously to placebo in RRMS and plans to enroll approximately 200 patients (NCT01457924).
DAC is a humanized mAb to CD25, an accessory alpha subunit of the high-affinity IL-2 receptor. CD25 increases the affinity of this receptor for IL-2; DAC therefore inhibits high-affinity IL-2 receptor signaling and could theoretically inhibit T-cell activation. However, this does not seem to account for DAC's effects as T-cell activation and proliferation occur even in the absence of CD25, possibly due to cytokine redundancy. Rather, DAC's effects seem to be mediated by its influence on a subset of NK cells, CD56 NK cells. These cells express high levels of intermediate-affinity IL-2 receptor, which do not contain CD25; CD25 antagonism has been shown to increase IL-2 availability thus increasing intermediate-affinity IL-2 signaling and resulting in the expansion of CD56 NK cells. This is thought to increase CD56 NK cell-mediated lysis of autoreactive T cells. Corroborating the importance of CD56 NK cells, a substudy of the CHOICE Phase II trial found their proliferation to be an independent predictor of response to DAC.
CHOICE was a multicenter, double-blind, placebo-controlled Phase II trial. Two hundred and thirty relapsing MS patients who were already being treated with interferon were randomized to add on DAC (2 mg/kg every 2 weeks or 1 mg/kg every 4 weeks) or placebo for 24 weeks. The primary end point, the mean number of new or enlarged GELs, was satisfied with the high dose of DAC compared with placebo (1.32 vs 4.75; p = .004) but not the low dose (3.58 vs 4.75, p = 0.51). Various secondary clinical end points, such as ARR, time to relapse and change in EDSS, were not statistically significant.
Results of the SELECT trial, a multicenter, double-blind, Phase IIb trial that randomized 600 RRMS patients to DAC versus placebo, were presented at the 2011 ECTRIMS/ACTRIMS meetings. Patients received DAC 150 mg, DAC 300 mg, or placebo as a subcutaneous injection every 4 weeks for 52 weeks. The primary outcome measure was met, with DAC demonstrating significant reduction in ARR versus placebo (0.21 for 150 mg, 0.23 for 300 mg vs 0.46 for placebo, p < 0.001). The proportion of relapse-free patients was also higher in the DAC groups (81 and 80 vs 64%; p < 0.001). A tertiary clinical end point examined 3-month sustained disability; this was significant for DAC 150 mg (reduction by 57%, p = 0.02) though not for DAC 300 mg (reduction by 43%, p = 0.09). Several MRI end points, including mean number of new or newly enlarging T2 lesions at 1 year and mean number of GELs at 8–24 weeks were also significant in an MRI substudy. Serious adverse events included an increase in serious infections (2%), serious cutaneous events (1%), and transaminitis > five-times the upper limit of normal (4%). There was also one death in a DAC-treated patient due to complications of a psoas abscess.
DECIDE is a Phase III trial that will compare DAC (150 mg, as above) to IFN-β-1a (30 µg, intramuscular injection) as an active comparator for 96 weeks. DECIDE will enroll 1500 patients and is currently recruiting (NCT01064401).
Table 1 provides a summary of the current status of these agents.
Therapies in Phase III Clinical Trials
Dimethylfumarate
An oral fumaric acid ester (Fumaderm®) was previously shown to be effective in patients with psoriasis and various formulations of fumaric acid esters have been in use for this disease in Germany for many years. The main component of Fumaderm, dimethylfumarate (BG-12), is rapidly metabolized to its main active metabolite, monomethylfumarate. The mechanism of action in MS is still under investigation, however, it seems that at least some of the drug's activity is related to monomethylfumarate's release of the transcription factor, Nrf-2, from its usual binding to Keap-1. Through inhibition of translocation of NF-κB into the nucleus this ultimately leads to a decrease in several inflammatory cytokines, chemokines and adhesion molecules. More recent work in animal models suggests BG-12 may have neuroprotective properties, with positive effects on the preservation of oligodendrocytes, myelin, axons and neurons through the reduction of oxidative stress.
A Phase IIb study randomized 257 patients to one of several dosing regimens of BG-12 or placebo for 24 weeks. The study met its primary end point, demonstrating a decrease in the number of gadolinium-enhancing lesions (GELs) on MRI scans and prompting the initiation of several Phase III trials.
Results from the DEFINE trial were reported in a platform presentation at the 2011 Joint European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). DEFINE was a multicenter, double-blind trial that randomized 1234 relapsing–remitting MS (RRMS) patients to BG-12 240 mg twice daily (b.i.d.), three-times daily (t.i.d.) or placebo for 2 years. The study met its primary end point with a 49 (b.i.d.) and 50% (t.i.d.) reduction in the proportion of patients who relapsed during the study period (p < 0.0001). Secondary clinical end points included the annualized relapse rate (ARR) and confirmed 12-week disability progression by the Expanded Disability Status Scale (EDSS). The ARR was 0.36 for placebo, 0.17 for BG-12 b.i.d. and 0.19 for BG-12 t.i.d. This corresponds to reductions of 53 and 48% for BG-12 b.i.d. and t.i.d., respectively, compared with placebo (p < 0.001). Disability progression was reduced by 38% with BG-12 b.i.d. (p < 0.01) and 34% with BG-12 t.i.d. (p < 0.05).
Biogen Idec (Weston, MA, USA) subsequently announced preliminary results of the CONFIRM trial in a press release. CONFIRM was also a multicenter, double-blind trial. The investigators randomized 1430 RRMS patients to BG-12 240 mg b.i.d., BG-12 240 mg t.i.d., placebo, or daily subcutaneous injection of glatiramer acetate for 2 years. The study met its primary end point with reduction in ARR of 44% for BG-12 b.i.d. (p < 0.0001) and 51% for BG-12 t.i.d. (p < 0.0001) compared with placebo, while glatiramer reduced ARR by 29% compared with placebo. One secondary clinical end point, the proportion of patients who relapsed, was decreased by 34% for b.i.d. (p < 0.003) and 45% for t.i.d. (p < 0.0001) while glatiramer decreased this by 29% (p < 0.01). All MRI end points, including a decrease in the number of new T2 and T1 lesions compared with placebo, were satisfied. There was no statistically significant difference in the remaining clinical end point, 12-week confirmed disability progression, possibly due to the unexpectedly low rate of progression in the placebo group.
The details regarding adverse events have not yet been published, however, according to what has been released the incidence of serious adverse events and events leading to drug discontinuation was similar in all groups in both trials. Flushing and gastrointestinal adverse effects were more common with BG-12 than with placebo, and there were no opportunistic infections nor treatment-related fatalities in either Phase III trial.
Teriflunomide
Teriflunomide, the active metabolite of the rheumatoid arthritis drug leflunomide, reversibly inhibits the mitochondrial enzyme DHODH. DHODH provides the rate-limiting step in de novo pyrimidine synthesis, a crucial pathway for proliferating lymphocytes. The salvage pathway provides a sufficient pyrimidine supply to resting lymphocytes; teriflunomide therefore selectively targets blasting rather than quiescent lymphocytes (Figure 1). This presumably allows it to limit inflammation without inducing a state of broad immunosuppression. Leflunomide has also been demonstrated to have DHODH-independent effects involving various other targets involved in inflammation such as the JAK/STAT pathway, COX-2, EGFR and iNOS, among others.
(Enlarge Image)
Figure 1.
The effect of teriflunomide on pyrimidine synthesis.
In the resting state, lymphocytes are able to replenish their pyrimidine pools by salvaging pyrimidines from catabolic processes. This is sufficient to synthesize phospholipids (membrane maintenance and second messengers) and glycoproteins (adhesion molecules). However, when lymphocytes begin proliferating, the need for pyrimidines increases, and de novo synthesis of pyrimidines becomes necessary to fuel the synthesis of new DNA molecules. Since teriflunomide is a high-affinity inhibitor of the key enzyme of de novo pyrimidine synthesis (DHODH), it targets proliferating (but not resting) lymphocytes in a semi-selective manner.
CTP: Cytidine triphosphate; DHODH: Dihydroorotate-dehydrogenase; TTP: Thymidine triphosphate; UTP: Uridine triphosphate.
Reproduced from [25] with permission from Elsevier.
A Phase II trial randomized 179 patients with relapsing forms of MS to placebo or daily teriflunomide, 7 or 14 mg, for 36 weeks. The study met its primary end point, demonstrating a decreased number of unique active MRI lesions for both doses of teriflunomide compared with placebo. On this basis several Phase III trials were initiated; most of these are ongoing, however, the TEMSO investigators have published results.
TEMSO was a multicenter double-blind trial that randomized 1088 patients with relapsing forms of MS to placebo or 7- or 14-mg doses of oral teriflunomide daily for 108 weeks. The study met its primary end point with significant reduction in ARR, from 0.54 in the placebo group to 0.37 in both teriflunomide groups, corresponding to relative risk reduction of 31.2 and 31.5% for the 7- and 14-mg doses of teriflunomide, respectively (p < 0.001). The key secondary end point, reduction in confirmed disability progression as defined by sustained increase in EDSS over 12 weeks, was met at the 14-mg dose (20.2 vs 27.3%; p = 0.03) although not at the 7-mg dose (21.7%; p = 0.08). The key MRI end point, change in total lesion volume, was also met by both doses, with the higher dose of teriflunomide demonstrating somewhat more robust efficacy than the lower.
There was no statistically significant difference in adverse events, serious adverse events, or adverse events requiring discontinuation of the study drug. Adverse events that were more common with teriflunomide included diarrhea, nausea and hair thinning, which only very rarely resulted in discontinuation of the study drug. Those receiving teriflunomide were more likely to have small elevations in alanine aminotransferase levels but these were not clinically relevant. Rare adverse effects included neutropenia, elevated blood pressure and dermatologic reactions. Importantly, there did not appear to be a difference in the rate of serious infection, opportunistic infection, or malignancy between teriflunomide and placebo.
There are several other Phase III trials of teriflunomide currently underway. TOWER (NCT00751881) is another randomized trial comparing teriflunomide (7 or 14 mg) to placebo in 1100 RRMS patients, which aims to provide confirmatory results to TEMSO. TENERE (NCT00883337), a randomized trial of approximately 300 RRMS patients comparing both doses of teriflunomide to subcutaneous IFN-β-1a, will provide data with an active comparator. TERACLES (NCT01252355) is a randomized trial of over 1400 relapsing patients looking at the combination of teriflunomide (7 or 14 mg) with IFN-β versus interferon alone. Teriflunomide is also being studied in clinically isolated syndrome in TOPIC (NCT00622700).
Alemtuzumab
Alemtuzumab is a recombinant humanized IgG1 mAb currently available for the treatment of B-cell chronic lymphocytic leukemia. It targets CD52, a glycoprotein expressed mainly by B and T lymphocytes although also by various other components of the immune system, such as dendritic cells, monocytes/macrophages, natural killer (NK) cells and some granulocytes. The precise function of CD52 has not been fully elucidated; however, some studies have demonstrated effects on T-cell migration and costimulation.
Administration of alemtuzumab causes widespread and sustained depletion of CD52-positive cells, followed first by slow repopulation of B cells and eventually of T cells. Several studies have suggested a 'sparing' of T cells with a regulatory phenotype, thus inducing a durable regulatory 'resetting' of the immune system that may contribute to alemtuzumab's effect in MS.
CAMMS223, a Phase II trial that randomized 334 treatment-naive RRMS patients to alemtuzumab or interferon, met its coprimary outcomes of decreased ARR and decreased accumulation of disability. This led to the initiation of several Phase III trials.
CARE-MS I was a multicenter, rater-blind Phase III trial that randomized 581 treatment-naive RRMS patients to alemtuzumab (12 mg/day for 5 days by intravenous infusion followed by a second 3-day infusion 1 year later) or IFN-β-1a (44 µg subcutaneously three-times per week) and followed them over 2 years. The results of CARE-MS I were released to the press and presented at the ECTRIMS/ACTRIMS in 2011. Treatment with alemtuzumab resulted in a 55% reduction in relapse rate compared with interferon (ARR 0.18 vs 0.39; p < 0.0001), satisfying one of the study's primary end points. However, there was no significant difference in the other primary end point, 6-month confirmed disability progression measured by EDSS. It has been postulated this is likely at least partially explained by the unexpectedly low rate of disability progression in all arms; the study was not powered to detect a difference at the low rate that was observed. As for MRI end points, the number of new GELs, new T2 lesions, and new T1 lesions were all significantly reduced in the alemtuzumab group. In addition, patients who received alemtuzumab had significantly less change in brain parenchymal fraction, a measure of brain atrophy, compared with patients who received interferon (-0.87 vs -1.49; p < 0.0001).
Preliminary results from CARE-MS II (NCT00548405), a second Phase III, rater-blind, active-comparator trial, were recently made public in a press release. CARE-MS II randomized 840 RRMS patients who had experienced at least one relapse while on some disease-modifying therapy to either alemtuzumab or IFN-β-1a (both administered as in CARE-MS I). In this study, evaluating patients with more active and treatment-refractory MS, both coprimary outcomes were satisfied: alemtuzumab demonstrated a 49% reduction in relapse rate (p < 0.0001) and a 42% reduction in disability progression as measured by EDSS (p = 0.0084).
Several safety concerns have been raised by the above studies, particularly an increased risk of infection and emergent autoimmune diseases in patients treated with alemtuzumab. All three studies showed a modest increase in the incidence of infections although complete information regarding these events has not yet been published. There have been no treatment-related fatalities reported in the Phase III studies. In CAMMS223, 22.7% of patients had a thyroid-related adverse event, most commonly hyperthyroidism, and 2.8% developed immune thrombocytopenic purpura. The profile was slightly more favorable in the Phase III studies with approximately 18 and 16% developing an autoimmune thyroid disorder and 0.8 and 1% developing immune thrombocytopenic purpura in CARE-MS I and II, respectively. However, these patients were followed for only 2 years, as compared with the 3-year follow-up in CAMMS223. It is worth noting that in the two Phase III studies the adverse events were anticipated, detected by monitoring and appropriately managed. There is evidence linking emergent autoimmune diseases to high levels of IL-21, which could allow for risk stratification for these adverse events prior to alemtuzumab treatment.
It should be emphasized that alemtuzumab was compared directly to interferon in these trials in a head-to-head fashion, in contrast to the 'active comparator' method employed in other recent trials. Alemtuzumab has been granted fast track status by the US FDA and is slated to undergo priority expedited review in the first half of 2012.
Anti-CD20 Agents
Clinical and basic science evidence support the role of B lymphocytes in the immunopathogenesis of MS. Several plausible mechanisms include contribution to antibody-mediated myelin damage, upregulation of T-cell-mediated tissue destruction, and a role in neurodegeneration. As such, an agent that targets B cells, such as the anti-CD20 mAb rituximab, offers a logical approach to MS therapy. Rituximab demonstrated a rapid and sustained improvement in disease activity (both clinical and MRI outcomes) in an open-labeled Phase I trial of patients with RRMS, and a small double-blind Phase II trial, HERMES. Notably, in this trial rituximab decreased the mean number of new lesions by 91% compared with placebo. Rituximab unfortunately did not meet its primary disability end point in the subsequent Phase II/III Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS).
Although rituximab itself is not being further developed for MS, based on the encouraging proof-of-principle experience, newer anti-CD20 mAbs ocrelizumab and ofatumumab are currently being investigated. Theoretically, these humanized or fully human Abs might provide advantages over a chimeric antibody, possibly translating into decreased infusion reactions and improved tolerability. In addition, with respect to the mechanism of B-cell depletion, ocrelizumab shows increased antibody-dependent cell-mediated cytotoxicity and decreased complement-mediated cytotoxicity compared with rituximab, which could result in improved efficacy and better tolerability.
A multicenter, double-blind, placebo-controlled Phase II trial of ocrelizumab was recently completed. Two hundred and twenty patients were randomized to placebo, ocrelizumab 600 or 2000 mg (infused on days 1 and 15), or once-weekly intramuscular IFN-β-1a (30 µg) for 24 weeks. The primary end point, reduction in the number of GELs, was satisfied with relative reductions of 89 and 96% for the 600- and 2000-mg doses of ocrelizumab, respectively, compared with placebo (p < 0.0001). Key secondary end points included ARR, proportion of relapse-free patients and several additional MRI measures. ARR was reduced from 0.64 in the placebo group to 0.13 with ocrelizumab 600 mg and 0.17 with ocrelizumab 2000 mg (p < 0.0001). Comparison to interferon had been planned only as a tertiary analysis; however, there was a clear difference between ocrelizumab and interferon with respect to GELs (p < 0.0001) and even with respect to ARR with the 600-mg dose (p = 0.03), although not the 2000-mg dose (p = 0.09).
Infusion-related symptoms, which were generally mild-to-moderate, were seen in the ocrelizumab groups. The number of serious adverse events was small and similar among the groups. However, one patient in the ocrelizumab 2000-mg group died of a systemic inflammatory response of unknown etiology. Although Phase III trials in rheumatoid arthritis had significant rates of serious and opportunistic infections, none were identified in this trial. One potential explanation is that the patients in rheumatoid arthritis trials were universally being treated with an additional immunosuppressive agent concomitantly; patients being treated with immunosuppressants were excluded from this trial.
Several Phase III trials are now underway. OPERA I and II are comparing ocrelizumab (600 mg, as above) to interferon (44 µg subcutaneous injection three-times per week) in RRMS and plan to enroll approximately 800 patients each (NCT01412333, NCT01247324). In addition, because subgroup analysis of rituximab in OLYMPUS suggested a benefit to younger patients and those with GELs, ocrelizumab is also being studied in primary progressive MS. ORATORIO will compare ocrelizumab (600 mg, as above) to placebo in primary progressive MS and plans to enroll 630 patients (NCT01194570).
Also under investigation in MS is ofatumumab, a fully human mAb that targets a unique epitope on the CD20 molecule. Genmab announced positive interim results for a Phase II safety and pharmacokinetics study of ofatumumab in July 2010 (NCT00640328). A total of 38 patients were randomized to ofatumumab or placebo in a crossover design. Efficacy was assessed as a secondary end point; the number of GELs and new or enlarging T2 lesions was statistically significantly less in patients treated with ofatumumab compared with placebo. This study planned to enroll 324 patients in total with results anticipated in 2012. Another Phase II study, MIRROR, will compare several doses of ofatumumab administered subcutaneously to placebo in RRMS and plans to enroll approximately 200 patients (NCT01457924).
DAC
DAC is a humanized mAb to CD25, an accessory alpha subunit of the high-affinity IL-2 receptor. CD25 increases the affinity of this receptor for IL-2; DAC therefore inhibits high-affinity IL-2 receptor signaling and could theoretically inhibit T-cell activation. However, this does not seem to account for DAC's effects as T-cell activation and proliferation occur even in the absence of CD25, possibly due to cytokine redundancy. Rather, DAC's effects seem to be mediated by its influence on a subset of NK cells, CD56 NK cells. These cells express high levels of intermediate-affinity IL-2 receptor, which do not contain CD25; CD25 antagonism has been shown to increase IL-2 availability thus increasing intermediate-affinity IL-2 signaling and resulting in the expansion of CD56 NK cells. This is thought to increase CD56 NK cell-mediated lysis of autoreactive T cells. Corroborating the importance of CD56 NK cells, a substudy of the CHOICE Phase II trial found their proliferation to be an independent predictor of response to DAC.
CHOICE was a multicenter, double-blind, placebo-controlled Phase II trial. Two hundred and thirty relapsing MS patients who were already being treated with interferon were randomized to add on DAC (2 mg/kg every 2 weeks or 1 mg/kg every 4 weeks) or placebo for 24 weeks. The primary end point, the mean number of new or enlarged GELs, was satisfied with the high dose of DAC compared with placebo (1.32 vs 4.75; p = .004) but not the low dose (3.58 vs 4.75, p = 0.51). Various secondary clinical end points, such as ARR, time to relapse and change in EDSS, were not statistically significant.
Results of the SELECT trial, a multicenter, double-blind, Phase IIb trial that randomized 600 RRMS patients to DAC versus placebo, were presented at the 2011 ECTRIMS/ACTRIMS meetings. Patients received DAC 150 mg, DAC 300 mg, or placebo as a subcutaneous injection every 4 weeks for 52 weeks. The primary outcome measure was met, with DAC demonstrating significant reduction in ARR versus placebo (0.21 for 150 mg, 0.23 for 300 mg vs 0.46 for placebo, p < 0.001). The proportion of relapse-free patients was also higher in the DAC groups (81 and 80 vs 64%; p < 0.001). A tertiary clinical end point examined 3-month sustained disability; this was significant for DAC 150 mg (reduction by 57%, p = 0.02) though not for DAC 300 mg (reduction by 43%, p = 0.09). Several MRI end points, including mean number of new or newly enlarging T2 lesions at 1 year and mean number of GELs at 8–24 weeks were also significant in an MRI substudy. Serious adverse events included an increase in serious infections (2%), serious cutaneous events (1%), and transaminitis > five-times the upper limit of normal (4%). There was also one death in a DAC-treated patient due to complications of a psoas abscess.
DECIDE is a Phase III trial that will compare DAC (150 mg, as above) to IFN-β-1a (30 µg, intramuscular injection) as an active comparator for 96 weeks. DECIDE will enroll 1500 patients and is currently recruiting (NCT01064401).
Table 1 provides a summary of the current status of these agents.