We appear to be in the midst of a paradigm shift in the treatment of multiple sclerosis (MS). But is this really the case? Reports from the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), which took place October 13−16, 2010, in Gothenburg, Sweden, suggest that now is certainly an exciting time, with the promise of improved treatment outcomes and expanded therapeutic options for people with MS. Fingolimod, the first oral disease-modifying therapy (DMT) for MS, was recently approved by the FDA for the treatment of relapsing forms of the disease, and a number of new DMTs are in phase 2 and 3 trials. Clinical trials of several new molecules and monoclonal antibodies show promising results, including reductions in annualized relapse rate (ARR) and improvement in MRI measures of disease activity and progression. Although many of these new agents appear to have superior efficacy compared with the interferon betas and glatiramer acetate, like natalizumab, they carry the potential for serious adverse events. Only time and longer-term safety data will help determine where these new therapies will fit in the shifting therapeutic landscape of MS.

Oral Therapies in Phase 3 Trials

Teriflunomide is a selective inhibitor of de novo pyrimidine synthesis that reduces proliferating T- and B lymphocytes. In a double-blind, placebo-controlled, parallel-group study of 1088 relapsing MS patients randomized to receive placebo or teriflunomide 7 mg or 14 mg once daily for 108 weeks (EMSO),¹ both doses significantly reduced ARR compared with placebo. The risk of disability progression was reduced by 23.7% in the 7 mg group and 29.8% in the 14 mg group. In addition, patients treated with teriflunomide showed an improvement in MRI measures, including a reduced number of gadolinium-enhanced T1 lesions.² A significantly lower percentage change in T1 hypointense lesion volume was seen in the 14 mg group compared with baseline. Teriflunomide was well tolerated and had a manageable safety profile.

Cladribine (2-chlorodeoxyadenosine) is a synthetic adenosine analog that selectively depletes B and T cells by interfering with the mechanisms of DNA repair. The phase 3 CLARITY study found that treatment with oral cladribine significantly reduced ARR, risk of disability progression, and MRI measures of disease activity at 96 weeks.³ Two-thirds of the patients treated with cladibrine who were free of disease activity at 24 weeks after starting treatment were found to have sustained disease-activity free status at study end at 96 weeks.⁴ Cladribine was generally well-tolerated; however, serious adverse events included herpes zoster, three incidences of cancer, and four deaths.³

Laquinimod, an orally active drug being evaluated in two phase 3 multicenter, double-blind studies in MS patients, has been shown to reduce the percentage of the CD5+ B-cell subpopulation in stimulated B cells of healthy subjects and those with RRMS.⁵ In B cells from healthy subjects, laquinimod increased the percentage of CD86+ cells in stimulated B cells as well as in the CD25+ subpopulation in unstimulated cells. Similar results were found in B cells from RRMS patients, in whom laquinimod treatment increased the percentage of both CD86+ and IL10+ in CD25+ B cells. In a 36-week extension study of laquinimod, the most prominent safety signal was elevation of liver enzymes.⁶

BG-12, an oral formulation of dimethly fumarate that exhibits anti-inflammatory and potentially neuroprotective effects, is in phase 3 trials of patients with RRMS. In two open-label, randomized, crossover pharmacokinetic (PK) studies, healthy subjects were treated with BG-12 240 mg tid for 2 or 3 days alone or with a single intramuscular (IM) interferon beta-1a 30 mcg or subcutaneous glatiramer acetate 20 mg injection administered on the second day^.7 The PK profile of BG-12 remained unchanged by coadministration with IM interferon beta-1a or glatiramer acetate, and no new safety issues were uncovered. The most common adverse events were flushing, seen with BG-12 alone, or BG-12+ glatiramer acetate (50%–85%) and flu-like symptoms seen with BG-12+ IM interferon beta-1a (85%). There were no serious adverse events.

Oral Therapy in Phase 2 Trials

Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist that reduces trafficking of lymphocytes into the central nervous system.

The results of a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study performed in 343 patients with RRMS were presented at ECTRIMS.⁸ Subjects were randomized to receive placebo (n=99), firategrast 150 mg (n=48), 600 mg (n=95), or 900 mg (women)/1200mg (men) (n=100) bd. The primary outcome, or cumulative number of new Gd-enhancing brain lesions during the treatment phase, was statistically significant for the 900/1200mg firategrast group vs placebo (adjusted cumulative mean rate of Gd+ lesions 2.69 vs 5.31 [p=0.0026; 49% decrease]). In addition, a significant decrease in new T2 lesions was seen in the 900/1200mg group (p=0.009). A nonsignificant trend of fewer relapses with increasing dose was also observed. Firategrast was generally well tolerated at all dose levels.

Monoclonal Antibodies in Phase 2 Trials

Alemtuzumab, an anti-CD52 humanized monoclonal antibody that causes reversible lymphocyte depletion, significantly reduced the relapse rate and risk of sustained accumulation of disability compared with subcutaneous (SC) interferon beta-1a in a 3-year, phase 2 safety and efficacy trial with RRMS patients (CAMMS223).⁹ Adverse events included infusion reactions, immune thrombocytopenia, thyroid dysfunction, and infections, which were mostly mild to moderate. Alemtuzumab-treated subjects experienced sustained benefit at 60 months’ follow-up. In many patients, the efficacy of alemtuzumab appears to last as long as 4 years after the last dose.¹⁰ Ongoing phase 3 studies will evaluate the benefit–risk of alemtuzumab therapy in RRMS.

In a trial evaluating the efficacy and safety of the humanized anti-CD20 monoclonal antibody ocrelizumab in patients with RRMS treated for 24 weeks,¹¹ 220 RRMS patients were randomized to receive intravenous ocrelizumab at days 1 and 15 at total doses of 600 mg or 2000 mg, placebo, or weekly interferon beta-1a (as an open-label arm). Both ocrelizumab doses showed highly significant differences in the total number of Gd-enhancing T1 lesions at weeks 12, 16, 20, and 24 vs placebo; relative reductions were 89% for the 600 mg group and 96% for the 2000 mg group. ARR at week 24 was significantly reduced vs placebo. In addition, the total number of new and persisting Gd-enhancing T1 lesions was reduced in the groups treated with ocrelizumab. Infusion-related events such as swelling were mostly mild to moderate during the first infusion and decreased to rates similar to placebo with the second infusion. One patient in the 2000 mg group died from acute-onset thrombotic microangiopathy that occurred 12 weeks after treatment ended.

Ofatumumab is a fully human monoclonal antibody binding to CD20 antigen on B-lymphocytes; a multicenter, double-blind, randomized, placebo-controlled trial in patients with RRMS demonstrated efficacy in MRI parameters.¹² Twenty-six patients were randomized to ofatumumab 100 mg (N=8), 300 mg (N=11), 700 mg (N=7), and 12 to placebo (4 per cohort). Following treatment, the mean cumulative number of new gadolinium-enhanced lesions on monthly MRI from weeks 8 to 24 was 0.04 in the combined ofatumumab group compared with 9.69 in the combined placebo group—an estimated relative reduction of 99.8%. Reductions were also seen in the cumulative number of total active lesions and new or enlarging T2 lesions. No safety signals emerged from this trial.

References

1. O’Connor P, Wolinsky J, Confavreux G, et al. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: clinical efficacy and safety outcomes. Presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. P827.
2. Wolinsky J, O’Connor P, Confavreux G, et al. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: magnetic resonance imaging (MRI) outcomes. Presented at: ECTRIMS; October 13–16, 2010; Gothenburg, Sweden. 982.
3. Giovannoni G, Comi G, Cook S, et al; CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416-26.
4. Giovannoni G, Comi G, Cook S, et al. Analysis of sustained disease activity-free status in patients with relapsing–remitting multiple sclerosis treated with cladribine tablets, in the double-blind, 96-week CLARITY study. Presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. P825.
5. Nussbaum S, Snir A, Ram ES, et al. Immunomodulation by laquinimod of human B-cells from healthy individuals and patients with MS: targeting B-cell regulatory networks. Presented at: ECTRIMS: October 13­–16, 2010: Gothenburg, Sweden. P850.
6. Comi G, Abramsky O, Arbizu T, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler. 2010;16:1360-1366. Epub 2010 Sep 8.
7. Woodworth J, Zhao J, Stecher S, Yang L, Dawson K. Oral BG-12 in combination with interferon beta-1a or glatiramer acetate: pharmacokinetics, safety and tolerability. Presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. P478.
8. Miller D, Weber T, Montalban X, et al. Phase II trial of firategrast shows that oral anti-alpha4 therapy can suppress new MRI lesions in relapsing–remitting multiple sclerosis. Presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. P1139.
9. A phase II study comparing low- and high-dose alemtuzumab and high-dose Rebif^® in patients with early, active relapsing-remitting multiple sclerosis. Available at http://clinicaltrials.gov/ct2/show/NCT00050778?term=CAMMS223&rank=2. Accessed on November 4, 2010.
10. Coles A; on behalf of the CAMMS223 Study Group. Alemtuzumab long-term safety and efficacy: five years of the CAMMS223 trial. Presented at: ECTRIMS: October 13­–16, 2010; Gothenburg, Sweden. P410.
11. Kappos L, Calabresi P, O'Connor P, et al. Efficacy and safety of ocrelizumab in patients with relapsing–remitting multiple sclerosis: results of a phase II randomised placebo-controlled multicentre trial. Presented at: ECTRIMS, Gothenburg, Sweden. October 13­–16, 2010. P114.
12. Soelberg Sorensen P, Drulovic J, Havrdova E, Lisby S, Graff O, Shackelford S. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing-remitting multiple sclerosis (RRMS)—24-week results of a phase II study. Presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. P136.