Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis.Constantinescu CS, Asher A, Fryze W, Kozubski W, Wagner F, Aram J, Tanasescu R, Korolkiewicz RP, Dirnberger-Hertweck M, Steidl S, Libretto SE, Sprenger T, Radue EW. Neurol Neuroimmunol Neuroinflamm. 2015 May 21;2(4):e117. eCollection 2015 Aug.
OBJECTIVES:To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity.
METHODS:In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety.
RESULTS: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time.
CONCLUSIONS:MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, Natural Killer cells, endothelial cells and fibroblasts that functions as a cytokine. It is a white blood cell growth factor. GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. Thus, it is part of theimmune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection. GM-CSF also plays a role in embryonic development by functioning as an embryokine produced by reproductive tract. IT has also been suggested that GM-CSF is a cytokine that is important in the development of autoimmunity. In people with relapsing MS relapsing SPMS or RRMS an neutralising antibody was given to 25 pwMS and they got their dose response that 0.5mg/kg was not stopping relapse in 5/8 people but it was in 9/9 people in group treated with antibody but only in 5/8 people people on placebo, so no firm conclusions possible until phase II is done.