Daclizumab, a humanized monoclonal antibody (Ab) targeting the CD25 subunit of the interleukin (IL)-2 receptor, is currently approved by the FDA for use in rheumatoid arthritis and other autoimmune diseases. Initially thought to decrease T-cell expansion via a reduction in IL-2 signaling, daclizumab was subsequently found to increase the levels of circulating CD56^bright natural killer (NK) cells. The contact dependent inhibitory effect of NK cells on T-cell survival is the proposed mechanism of action in relapsing MS [1]. It has been studied as a once-monthly subcutaneous injection.

After a successful Phase II study (SELECT) [2] and its 1 year extension (SELECTION) [3], the efficacy of daclizumab (monthly 150 mg subcutaneous injection) in RRMS was further assessed in a Phase III, randomized, multicenter, double-blind study, using the weekly intramuscular interferon (IFN) β-1a as an active comparator (DECIDE trial). The DECIDE trial enrolled over 1800 patients and successfully met its primary outcome by demonstrating a 45 % annualized relapse rate (ARR) reduction compared to weekly IFN β-1a (P < 0.0001). Secondary endpoints included the number of new or newly enlarging T2 lesions and the proportion of relapse-free patients. The majority of secondary endpoints were also met with statistically significant 54 % reduction in the number of new/enlarging T2 MRI lesions at week 96. The second-ordered secondary endpoint of disability progression confirmed at 12 weeks was not statistically different between the two groups. At 144 weeks, 16 % in the daclizumab high-yield process (HYP) group and 20 % in the IFN β-1a group had progressed. Although 67 % of patients were relapse-free in the daclizumab treatment arm (compared to 51 % in IFN arm) at 144 weeks, translating into relative reduction of 41 %, this was not considered significant on the basis of the prespecified hierarchical testing plan.

The adverse events and side effects reported in the DECIDE study included serious infections, which were reported in 4 % of patients (compared to 2 % in IFN arm). Patients in the daclizumab arm also had a higher incidence of cutaneous adverse events (37 % vs. 19 %) and serious cutaneous reactions (2 % vs. 1 %). Significant elevation of liver enzymes was observed in 6 % of daclizumab-treated patients (3 % in the IFN arm) [4]. It remains to be seen what type of monitoring, including liver function tests, will be recommended. The Biologics License Application requesting marketing approval of daclizumab for RRMS is currently in review process by the Food and Drug Administration (FDA) in the United States and has now been approved by the European Medicines Agency (EMA).

Ocrelizumab is a B-cell depleting monoclonal Ab with binding affinity towards a specific epitope of the common B-cell surface marker CD20. As a recombinant humanized Ab, ocrelizumab is less immunogenic than the human-mouse chimeric rituximab with repeated infusions, resulting in a potentially lower rate of infusion- associated adverse reactions. Compared to rituximab, in vitro studies also suggested that ocrelizumab had greater B-cell depleting capacity. This agent is given by intravenous infusion, with cycles given every 6 months.

The Phase II, multicenter, randomized, double-blind, dose-finding study assessed efficacy and safety of ocrelizumab in 220 patients with RRMS. Two ocrelizumab dosing regimens (600 mg and 2000 mg) were compared to placebo and the study also included an active, open label, rater-masked, control weekly IFN β-1a treatment arm. Both ocrelizumab doses had statistically significant impact on the total number of gadolinium-enhancing T1 lesions, the primary outcome of this study, showing relative reduction by 89 % at 600 mg and 96 % at 2000 mg dose. Compared to placebo and IFN treatment arms, a higher proportion of participants in both ocrelizumab treatment arms remained free of gadolinium-enhancing lesions (77 % and 88 %). The ARR at 24 weeks was 80 and 73 % lower in 600 and 2000 mg ocrelizumab arms vs. placebo.

With regard to adverse events, serious infection rates were similar across all four arms. Most infusion-associated reactions were mild to moderate and occurred with greater frequency in both ocrelizumab arms (35 % in 600 mg, 44 % at 2000 mg) than in placebo (9 %), but this difference was observed only during the first infusion [5]. One patient in the ocrelizumab 2000 mg group died of a systemic inflammatory response of unknown etiology.

The OPERA I and II Phase III trials, were multicenter, randomized double-blind, double-dummy studies comparing 600 mg dose of ocrelizumab, administered intravenously every 6 months to three-times weekly IFN β-1a in patients with RRMS. Both studies successfully met the primary outcome and showed 46 % and 47 % reduction of the ARR over a 2-year period when compared to IFN β-1a. The majority of the secondary outcomes were also met; specifically, the 43 % and 37 % reduction in confirmed disability progression at 24 months and reduction in total number of gadolinium T1-enhancing lesions (94 and 95 %), as well as reduction in total number of new and/or enlarging T2H lesions (77 and 83 %).

The incidence of serious adverse events including infections did not differ between the active and comparative treatment arms (6.9 % vs. 8.7 %) and the most frequent adverse events were mild-to-moderate infusion-associated reactions (34.3 % vs. 9.7 %). The data has been submitted for review to US and EU regulatory authorities and ocrelizumab has been designated a “breakthrough therapy” by the FDA [6].

Stem cell transplantation-based therapies in MS either seek to remove disease-causing immune cells and induce a reset of the immune system, or use multipotent stem cells with neuroprotective and restorative capabilities. After encouraging results from early studies, three main concepts of stem cell therapies are currently under investigation: hematopoietic stem cell transplantation (HSCT), mesenchymal stem cell transplantation, and glial progenitor cell transplantation (Table 5.2).