Safety, tolerability and pharmacodynamics of a novel immunomodulator, MIS416, in patients with chronic progressive multiple sclerosis

Alison M Luckey, Tim Anderson, Michael H Silverman, Gill Webster, Alison M Luckey, Tim Anderson, Michael H Silverman, Gill Webster

Abstract

Background: Preclinical studies have demonstrated that MIS416, a bacterially derived immune modulator, targets myeloid cells following systemic delivery. MIS416 stimulated myeloid cells have the capacity to regulate innate inflammation, a potential therapeutic target for progressive multiple sclerosis.

Objectives: To determine the safety, tolerability, pharmacodynamics and maximum tolerated dose and/or recommended Phase 2 dose of MIS416.

Methods: An open-label, non-randomized, phase II, dose-escalation study, in patients with progressive multiple sclerosis: dose-escalation phase, with MIS416 administered once weekly for four weeks to determine maximum tolerated dose; and dose-confirmation phase, administered once weekly for up to 12 weeks.

Results: The safety profile indicates the majority of adverse events were mild or moderate, tolerable, self-limiting and consistent with the known bioactivity of MIS416 (acute flu-like symptoms). Maximum tolerated dose was not reached. A dose of 500 µg/week was recommended for the Phase 2 dose.

Conclusion: MIS416 is well tolerated at a dose of 500 µg/week. The adverse event profile is consistent with the mechanism of action of MIS416, indicating bioactivity within the signal transduction pathways and supported by induction of a known MIS416 pharmacodynamic marker. It is recommended that safety and efficacy of MIS416 is investigated further in a larger randomized controlled trial. https://ichgcp.net/clinical-trials-registry/NCT01191996" title="See in ClinicalTrials.gov">NCT01191996.

Keywords: MIS416; Multiple sclerosis; NOD-2; PRR; TLR-9; immune modulator; myeloid cells; pattern recognition receptor; pharmacodynamic; safety.

Figures

Figure 1.
Figure 1.
Graphical representation of MIS416 which comprises 0.5 × 2.0 micron rod-shaped particles of bacterial cell wall skeleton containing muramyl dipeptide (L-alanine D-isoglutamine dipeptide), as part of the amino chain that crosslinks the peptidoglycan sugar backbone.
Figure 2.
Figure 2.
CONSORT 2010 flow diagram.
Figure 3.
Figure 3.
Plasma from blood samples collected at 24 hours and seven days post MIS416 dosing from each patient was assayed for neopterin using flow cytometry bead-based ELISA technology. The data shown are the mean values (pg/mL) + SD (n = 15). (DC Cohort; 500 µg/week.).

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Source: PubMed

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