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Home arrow Environment arrow Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management

Future Directions in Treatment

Though traditionally B cells were not thought to be of central importance in the pathogenesis of MS, and therefore not initially a target for disease-modifying therapy, an anti-B-cell therapy a proof of concept (phase II) study indicated a potential role for rituximab (Rituxan®) in the treatment of RRMS [238]. While a clinical trial evaluating the use of rituximab in primary progressive MS (PPMS) patients did not show a statistically significant difference in time to confirmed disease progression compared to placebo, subgroup analysis revealed a significant difference in patients aged <51 years with gadolinium-enhancing lesions seen on MRI [239].

Data presented at the 2015 ECTRIMS meeting from recently completed pivotal studies of ocrelizumab, a humanized anti-CD20 monoclonal antibody given intravenously, have revealed a highly significant impact on both relapse reduction and reduction in the risk of progression in RRMS. Another anti-CD20 humanized monoclonal antibody under study, ofatumamab, has been successful in a proof of concept studies with either intravenous or subcutaneous preparations. The data of three large pivotal (phase III) clinical trials, two evaluating ocrelizumab in the RRMS population (OPERA I and II), and another in the progressive MS population (ORATORIO) were revealed at the 2015 ECTRIMS annual meeting in Barcelona, Spain. Ocrelizumab showed a significant effect for both relapsing-remitting and progressive MS. Ocrelizumab reduced the ARR at 96 weeks by 46% in OPERA I and 47% in OPERA II compared to IFN-p-1a [240]. In the ORATORIO PPMS study, ocrelizumab met the primary end point of a significant 24% reduction in 12-week confirmed disability progression (CDP) [241]. Key secondary end points including a 25% reduction in risk of CDP at 24 weeks, 17.5% reduction in brain volume loss, and 3.4% decrease in T2 lesion volume. The most common adverse events were mild-to-moderate infusion-related reactions [242]. Official publication of the results is newly released [243], [244].

Daclizumab is yet another humanized monoclonal antibody that binds to the a-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Its mechanism of action in MS is thought to be via blockage of the activation and expansion of autoreactive T cells. An important biological effect of daclizumab is the activation and expansion of immunoregulatory CD56 bright natural killer cells. Two phase III trials are recently completed and the drug has been submitted for approval by the Federal Drug Agency. The DECIDE study, which compared subcutaneous dacli- zumab high-yield process (HYP), administered at a dose of 150 mg every 4 weeks, with intramuscular IFN-p-1a. The annualized relapse rate was significantly lower with daclizumab HYP than with IFN-p-1a (0.22 vs. 0.39, 45% lower rate with dacli- zumab HYP). The number of new or newly enlarged hyperintense lesions on T2- weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with IFN-p-1a (4.3 vs. 9.4, 54% lower number of lesions with daclizumab HYP, P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with IFN-p-1a, but this finding was not statistically significant [245]. The results of the

OBSERVE single-arm study, which is evaluating the immunogenicity and pharmacokinetics of daclizumab HYP, have not been published at press time [246].

There is understandably substantial interest in the development of remyelinating agents in MS to repair damage myelin. The anti-LINGO-1 monoclonal antibody BIIB033 has undergone phase I randomized trials, and phase II results from the SYNERGY trial were reported in Barcelona in 2015 [247, 248]. Another monoclonal antibody under consideration for development is GSK1223249 which targets NOGO-A, an inhibitor of neurite outgrowth [249].

Laquinomod is a derivative of linomide, an agent studied in the 1980s for use in MS whose development was halted due to multiple adverse events including myocardial infarction. As with its parent molecule, serious adverse experience including cardiotoxicity has been recognized, and the pivotal study has been halted.

Other treatments in early clinical studies include secukinumab, an anti-IL-17A monoclonal antibody and firategrast, an oral agent acting against anti-a4-integrin (the target for natalizumab) [250, 251]. Second-generation, more specific sphingo- sine receptor agents being studied include siponimod and ONO-4641 [252, 253]. Ibudilast is a phosphodiesterase-4 inhibitor that reduces microglial inflammation and hopefully neurodegeneration in MS and is a promising option for treatment of progressive MS. The phase IIb trial Secondary and Primary Progressive Ibudilast NeuroNEXT trial in Multiple Sclerosis (SPRINT-MS) is currently under way.

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