Background Autoimmune diseases, including systemic lupus erythematosus (SLE), are associated with dysregulated T cell and B cell responses. AMG 570 is a bispecific molecule targeting T cell and B cell activity through inhibition of inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF). We hypothesize that targeting both ICOSL and BAFF will be more effective than single target inhibition in SLE and other autoimmune diseases. We investigated if targeting ICOSL and BAFF has superior efficacy to single target inhibition in mouse arthritis and lupus models. We also investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 570 in healthy subjects after single subcutaneous doses.
Methods A murine surrogate ICOSL/BAFF bispecific along with single or combination inhibition was evaluated in the mouse collagen-induced arthritis (CIA) and NZB/NZW lupus models. AMG 570 binding affinity to human and cyno ICOSL/BAFF was tested by Kinexa A. An ongoing, first-in-human study has enrolled healthy adult subjects into 6 escalating single-dose cohorts. Eight participants were enrolled into each cohort and randomized 3:1 to receive AMG 570 or placebo. The primary endpoint was treatment-emergent adverse events (AEs). Secondary endpoints included pharmacokinetics and pharmacodynamics.
Results ICOSL and BAFF dual inhibition was more effective than single inhibition in ameliorating arthritis incidence and severity in the mouse CIA model as well as reducing anti-dsDNA IgG, delaying proteinuria and improving survival in the NZB/NZW lupus model. Based on high affinity to ICOSL and BAFF, AMG 570 was selected for investigation in a single ascending dose study in healthy subjects. As of an ad hoc interim analysis following six cohorts, 48 healthy participants received one dose of investigational product (AMG 570 or placebo). Overall, 73 mild to moderate AEs were reported. The most common AEs were upper respiratory tract infection and injection site erythema. No drug-related serious AEs or fatal AEs were reported thus far. AMG 570 demonstrated nonlinear pharmacokinetics consistent with cell surface ICOSL binding. At the highest dose tested, AMG 570 achieved >90% mean ICOSL receptor occupancy on circulating B cells 8 days after dosing. AMG 570 led to a reduction in circulating naïve B cells and an increase in circulating memory B cells.
Conclusions Dual inhibition of ICOSL and BAFF is more efficacious than single target inhibition in mouse disease models. In healthy subjects to date, single doses of AMG 570 have been safe, well tolerated, and demonstrated pharmacodynamic activity consistent with inhibition of both ICOSL and BAFF.
Funding Source(s): Amgen Inc.
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