Abstract
Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46–62, MBP124–139 and MBP147–170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0448-0) contains supplementary material, which is available to authorized users.
Highlights
Multiple sclerosis (MS) is a chronic neurodegenerative disease with an evident autoimmune background resulting in inflammatory demyelination and axonal and neuronal injury [1]
This study showed that subcutaneous administration of Xemys was safe and well tolerated in patients with MS who had previously failed to achieve sustained disease control following treatment with glatiramer acetate (GA) or β-interferons
The adverse events (AEs) related to Xemys were of mild or moderate severity and occurred mainly after treatment with submaximal and maximal doses of Xemys
Summary
Multiple sclerosis (MS) is a chronic neurodegenerative disease with an evident autoimmune background resulting in inflammatory demyelination and axonal and neuronal injury [1]. MS, which was first described in 1868 [2], is one of the most common diseases of the nervous system. It affects people aged 20–40 years worldwide, it has higher occurrence in women than in men and in those residing in northern than in southern latitudes. Natalizumab and alemtuzumab have been approved by the US Food and Drug Administration for the treatment of refractory MS, while daclizumab approval is very likely in the near future. Despite their effectiveness, these agents have been associated with serious adverse events (SAEs), significantly restricting their further application [4]. Convenient oral therapies, including fingolimod [11], teriflunomide [12], and dimethyl fumarate [13], have shown efficacy and tolerability and have been approved for the treatment of patients with MS
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