Background GM-CSF plays a central role in the inflammatory immune response cascade. GM-CSF is expressed at higher levels in the synovial fluid of patients with RA. Therefore, neutralization of GM-CSF activity by specific mAbs could be beneficial in treating RA (Cornish, et al., 2009). MORAb-022 is an investigational monoclonal antibody with high affinity for GM-CSF.
Objectives This Phase 1 study (NCT01357759) evaluated the safety and tolerability, pharmacokinetics/pharmacodynamics and preliminary evidence of activity of MORAb-022 in healthy subjects (HS) as well as in patients (Pts) with mild-to-moderate active RA.
Methods This was a double-blind, placebo-controlled, randomised, dose-escalating study in HS as well as in Pts with mild-to-moderate RA (according to ACR 2010 criteria) receiving stable MTX doses for ≥12 weeks prior to randomisation. HS received a single intravenous (IV) infusion of MORAb-022 0.0085, 0.042, 0.12, or 0.36 mg/kg or placebo and Pts received 0.36, 0.7, 1, 3, or 10 mg/kg or placebo on Day 1 with 85 days' follow-up. Clinical efficacy was an exploratory endpoint measured by DAS28 (CRP), ACR20 and ACRn.
Results 26 HS and 25 RA patients were enrolled (HS:77% male, mean age 41.1 years; Pts:56% females, mean age 55.4 years). Mean DAS28 (CRP) at baseline: placebo=4.1; MORAb-022, 0.36=3.6; MORAb-022, 0.7=4.5; MORAb-022, 1=3.8; MORAb-022, 3=3.8; MORAb-022, 10=4.8. MORAb-022 was generally well-tolerated. 14 treatment-emergent adverse events were observed in 25 Pts (56%). There was no evidence of immunogenicity. The mean Cmax and AUC0-inf for MORAb-022 increased approximately dose proportionally in both HS and Pts. The median half-life for MORAb-022 ranged from 9 to 13 days in both HS and Pts. All of the MORAb-022 dose cohorts demonstrated decreases in median DAS28 (CRP), however only the 10 mg/kg cohort showed a median decrease of more than 1.2 units by Day 2 (see Table). For Pts who received placebo, there was no discernable change in median DAS28 (CRP) results. 3/6 Pts who received placebo achieved an ACR20 response at any time as compared to 3/4 Pts in each of the 0.7 mg/kg, 3 mg/kg, and 10 mg/kg cohorts. 10 mg/kg dose cohort Pts demonstrated improvement in ACRn at Day 2, which was maintained through Day 29. The best mean (SD) ACRn for these Pts was 54.96 (40.52).
Conclusions MORAb-022 was generally well-tolerated in HS as well as in active RA Pts. Preliminary evidence of activity was observed but further evaluation is needed due to the small sample size in this study. PK was linear with a t1/2 =9–13 days.
Cornish AL, Campbell IK, McKenzie BS, Chatfield S, Wicks IP. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol. 2009; 5(10):554–559.
Disclosure of Interest A. Kivitz: None declared, L. Hazan: None declared, K. Hoffman Employee of: Morphotek, Inc, B. Wallin Employee of: Morphotek, Inc