Innovations In Clinical Neuroscience

MAY-JUN 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 5 – 6 , M A Y – J U N E 2 0 1 7 ] 30 BBB and CNS parenchyma. CYC has b een shown to decrease pro- inflammatory T-helper Th1 cytokine interferon-gamma and interleukin. 12 CYC might be useful in advanced cases of MS but has not been studied in a r andomized, clinical trial setting. Another example is laquinimod, an investigational CNS-active immunomodulator that can diffuse freely across the BBB without any active transport. Cardiotoxicity, however, at a dosage of 1.2mg/day halted its progress in clinical trials, which is clearly a limitation. 13 Whether laquinimod can be safely used at lower doses and have a beneficial effect on MS disability when combined with MAbs is yet to be determined. A third example of BBB-crossing drugs are sphingosine phosphate (SIP) receptors blockers. The SIP blocker fingolimod failed in the PPMS study; 14 however, a newly developed SIP blocker, siponimod, has shown a relatively short half-life compared to fingolimod, with fewer cardiac side-effects, and has BBB penetration capabilities. A phase III trial of siponimod in SPMS is ongoing (NCT01665144) and might contribute to the research and development of MS drugs that can cross the BBB. Combination therapy. Could drugs such as CYC, siponimod, and laquinimod be the future of MS therapies? Some other strategies that have been tried in oncology, for example, include the use of nanoparticles, immunoliposomes, peptide vectors, and influx transporters and could perhaps serve as model strategies for MS therapies moving forward. The idea of combination therapy in MS is not new. Many studies have explored safety, tolerability, and efficacy of several combination regimens, but these have been underpowered and/or poorly designed. The key to success is to combine agents that have been shown to A) penetrate the BBB with B) drugs such as MAbs that work effectively and show robust efficacy outside the CNS. For proof-of- concept studies, combination trials need t o identify patients with worsening EDSS, and selection of appropriate target populations is key. Enrollment of RRMS patients who fail disease- modifying therapies and whose EDSS c ontinues to worsen perhaps form the most eligible patient cohort in which to initiate combination therapy trials. CONCLUSION In summary, MS therapies that combine BBB-crossing molecules with peripherally acting MAbs should be a strategy of MS drug development. MS therapies that effectively limit or halt disease progression and improve overall treatment outcomes will need to address the disease mechanisms both inside and outside the CNS. It must also be recognized that the presence of lymphoid-follicle like structures are associated clinically with irreversible disability and, from a pathological perspective, show pronounced demyelination, microglial activation, and loss of neurites in the cerebral cortex. 14 Without addressing such fundamental pathological phenomena residing in a compartmentalized "zone" of the CNS, MS therapies will continue to have disappointing outcomes in treating worsening disability status in patients with MS. REFERENCES 1. Naismith RT, Trinkaus K, Cross AH. Phenotype and prognosis in African- Americans with multiple sclerosis: a retrospective chart review. Mult Scler. 2006;12:775–781. 2. Pardridge WM. The blood-brain barrier: bottleneck in the brain drug development. NeuroRx. 2005;2(1):3–14. 3. Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9:S3. 4. Cheng Z, Zhang J, Liu H. Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis and Alzheimer's disease-related animal models despite reported blood-brain barrier disruption. Drug Metab Dispos. 2010;38:1355–1361. 5. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376:221–234. 6. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 376:209–220. 7. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. NEJM. 1998;338:278–285. 8. Serafini B, Rosicarelli B, Magliozzi R, et al. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14:164–174. 9. Rubenstein JL, Combs D, Rosenberg J, et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood. 2003;101:466–468. 10. Cross AH, Stark JL, Lauber J, et al. Rituximab reduces B and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006;180:63–70. 11. Komori M, Lin YC, Cortese I, et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol. 2016;3:166–179. 12. Awad A, Stuve O. Review: Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. 2009;2:50–61. 13. Bruck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306:173–179. 14. Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomized, double-blind, placebo-controlled trial. The Lancet. 2016;387:1075–1084.

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