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 ] 29 transporters and metabolizing enzymes, c onstitute a barrier to the movement of both molecules and cells from the bloodstream into the CNS. The molar mass or the mass of one mole (6.02 x 10 23 molecules, Avogadro's number) of t he most commonly used MAbs in neuroimmunology, including those that are non-FDA approved, are as follows: natalizumab, 146kDa; rituximab, 143kDa; alemtuzumab,145kDa; ocrelizumab, 148kDa; and daclizumab, 142kDa. These molar masses are critical since BBB penetration is inversely related to the square root of the molecular weight (or molar mass) of a substance, 2 and typically, few molecules larger than 0.5kDa can cross the BBB. 3 There is no evidence that any of the MAbs impact neurodegeneration in a clinically significant manner over the long course of MS, and that is problematic— particularly in cases where MAbs are used as the sole therapeutic regimen for treatment of MS. Other molecular characteristics. The size and lipophilic or hydrophilic nature of molecules are not the only factors that limit a drug's ability to cross the BBB. 4 For example, a molecule's charge, tertiary structure, protein-binding properties, and saturable transport systems (e.g., L-dopa, caffeine) can also impact its ability to penetrate the BBB. Transmembrane diffusion can be used to transport lipid-soluble drugs across an intact BBB; however, approved MAbs drugs do not use this mechanism nor consider the above factors, and there is no evidence that MAbs cross either an intact or disrupted BBB. Because radiological stability in patients with MS—defined as having no new T1- gadolinium-enhanced lesions or expanding/new T2 lesions in the brain or spinal cord—is the cornerstone of the NEDA (no evidence of disease activity) concept, inablility of MAbs to penetrate the BBB is a therapeutic challenge, especially since MAbs are being considered for MS therapy in the face of worsening disability. Ocrelizumab. In two identical randomized, double-blind, double- dummy, parallel-group Phase III clinical trials—OPERA I and OPERA II 5 — investigators evaluated the efficacy and safety of ocrelizumab in comparison w ith interferon beta-1a in participants with RRMS. Participants were randomized to receive either ocrelizumab 600mg intravenously (IV) every 24 weeks plus interferon beta-1a placebo s ubcutaneously (SC) three times weekly (Group A) or interferon beta-1a 8.8mcg for Weeks 1 and 2, 22mcg for Weeks 3 and 4, and 44mcg for Week 5 and thereafter three times weekly SC plus ocrelizumab placebo IV every 24 weeks. Planned duration of double-blind treatment was 96 weeks. Participants who completed the 96- week, double-blind treatment had an option to enter a single-group, active treatment, open-label extension, provided they fulfilled the eligibility criteria. In another Phase III clinical trial, 6 investigators evaluated ocrelizumab versus placebo in participants with PPMS. All three studies reported impressive data, particularly the disability scores in the ORATORIO study. Investigators found a 24-percent reduced risk of clinical disability in the active treatment group compared to placebo. Ocrelizumab also reduced time required to walk 25 feet by 29 percent, the volume of chronic inflammatory brain lesions by 3.4 percent, and the rate of brain volume loss by 17.5 percent when compared to placebo. Magnetic resonance imaging (MRI) data, however, do not explain the beneficial effects ocrelizumab appeared to have on disability, given the molecular size of ocrelizumab and its poor penetration of the BBB. B-cells. MS is characterized by intrathecal compartmentalization of disease that cannot be reached by immunosuppressive agents, including MAbs. Although apparently restricted to late disease phases of MS, the development of lymphoid-tissue like structures in the brains of patients with MS suggests a pathophysiological role of B-cells in MS that is possibly perpetual, eventually being one of the many contributors leading to SPMS. The presence of lymphoid-follicle like structures in the meninges of some MS patients indicates that B-cells can mature and perpetuate a compartmentalized, humoral immune response. As patients transition into S PMS, factors that drive this process include autoreactive T-cells that cross the BBB and contribute to demyelination, axonal transection, gliosis, and subsequent axonal degeneration. 7 The c ascading neuroinflammation and neurodegeneration that follows continues unabated as the BBB forms an impenetrable barrier to drug molecules. Additionally, memory B-cells and plasma cells, central to humoral immunity, are found behind a "protected" BBB in lesions and cerebrospinal fluid (CSF) of patients with MS. Ectopic lymphoid follicles located in the meninges are hypothesized to drive the pathology of MS and have been shown to house B cells and plasma cells, 8 indicating that B cells migrate to the brain and can be sustained locally within the CNS. Plasma cells do not carry CD20 cell surface molecules and are not affected by anti- CD20 MAbs. Cerebrospinal fluid. If drugs are to effectively reach brain tissues, CSF concentrations must be at least as high as in serum. As an example, the poor BBB penetration of IV rituximab became apparent in a study in which the treatment of CNS lymphoma produced concentrations that were 1,000-fold less in CSF than seen in serum. 9 In another study that tracked immunoglobulin (IgG) levels and indices and oligoclonal band numbers in the CSF of 15 patients with MS, 10 poor BBB penetration of IV rituximab was revealed when investigators noted no consistent alterations in IgG or oligoclonal band numbers at Week 24 of treatment; however, B- and T-cells in the CSF compartment were reduced (although the mechanism is unclear.) The REVITALISE (rituximab by intravenous and intrathecal injection versus placebo in patients with low-inflammatory secondary-progressive MS) study 11 reported poor therapeutic efficacy of rituximab even when administered intrathecally—further evidence supporting the theory that MAbs do not penetrate an intact BBB. BBB-crossing drugs. An illustrative example of a drug that can cross an intact BBB is cyclophosphamide (CYC), an alkylating agent that penetrates the

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