Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study

Caryl J Schwartzbach,Debra Tompson,Robert Brown,Florian Then Bergh,Douglas L Arnold,Richard A Grove

doi:10.1007/s00415-016-8341-7

Caryl J Schwartzbach, Debra Tompson + Show 4 more

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https://doi.org/10.1007/s00415-016-8341-7

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Abstract

Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18–50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4–5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI −0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.

Highlights

Multiple sclerosis (MS) is a chronic progressive neurologic disorder, characterised by inflammatory-demyelinating lesions in the central nervous system (CNS) and associated axonal loss
oligodendrocyte precursor cell (OPC) differentiation is controlled by a range of molecules and their receptors, including constitutively active histamine H3 receptors expressed by neurons and OPCs [4]
The mean and median number of days since relapse was greater in the GSK239512 compared with the placebo group

Summary

Introduction

Multiple sclerosis (MS) is a chronic progressive neurologic disorder, characterised by inflammatory-demyelinating lesions in the central nervous system (CNS) and associated axonal loss. Relapsing-remitting MS (RRMS) accounts for 85% of all incident cases of MS and is associated with episodes of CNS dysfunction, reflecting acute inflammatory focal demyelination and subsequent spontaneous recovery, in turn reflecting resolution of focal inflammation and remyelination, with a variable contribution of CNS plasticity [1]. Decreased oligodendrocyte precursor cell (OPC) differentiation may play a role in remyelination failure [3]. The promotion of remyelination through increased OPC differentiation may provide functional recovery and prevent or reduce irreversible disability accumulation. OPC differentiation is controlled by a range of molecules and their receptors, including constitutively active histamine H3 receptors expressed by neurons and OPCs [4]. The importance of constitutive H3R activity in OPC differentiation is demonstrated by the ability of inverse agonists, which inhibit both ligand-independent and ligand-dependent receptor activation but not neutral antagonists of H3R, to promote OPC differentiation [4, 5]

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