Background/Purpose:  B cell depletion therapy has provided evidence of the importance of B cells in the pathogenesis of rheumatoid arthritis and other inflammatory diseases. Consequently, targeted B-cell treatments are being investigated in autoimmune disorders. BTK is a crucial kinase in signaling cascades following B cell antigen receptor (BCR) activation in B cells, in Fc receptor binding of immune complexes in myeloid cells, and some toll-like receptor (TLR) signaling events in B cells, myeloid cells, and dendritic cells. GDC-0853 is a small molecule inhibitor of BTK that is highly selective, orally administered, non-covalent, and reversible. GDC-0853 has demonstrated efficacy in pre-clinical autoimmune disease models and is being developed for the treatment of rheumatoid arthritis and lupus, with future development for other autoimmune indications. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GDC-0853 in single ascending dose (SAD) and multiple ascending dose (MAD) studies in healthy adult volunteers.

Methods:  GDC-0853 was evaluated in two randomized, double-blind, placebo- controlled phase 1 trials with 53 active and 18 placebo subjects dosed in the SAD study, and 30 active and 10 placebo subjects dosed in the MAD study. The SAD study evaluated 9 cohorts at doses ranging from 0.5 mg to 600 mg; the MAD study evaluated 5 cohorts at doses of 20, 60, 150, and 250 mg BID, and 500 mg QD for 14 days. Safety and tolerability were assessed by clinical, laboratory, and ECG assessments. PK was characterized using a validated LC-MS/MS assay. PD was assessed using phospho-BTK (p-BTK), and cellular activation assays.

Results: GDC-0853 was well-tolerated in both the SAD and MAD studies and there were no dose-limiting adverse events (AEs) and no serious AEs. No subjects withdrew due to an AE, and a maximum tolerated dose was not reached. AEs were all mild and transient. In the SAD study, the most common event reported was headache in 4 subjects (7.5%). In the MAD study, AEs included skin reactions in 3 subjects (rash, contact dermatitis, and ECG site rash in 1 subject each), nausea in 2 subjects (6.7%), and fatigue, contusion, and asymptomatic bacteriuria in 1 subject each. Following oral administration to fasted subjects, rapid absorption was observed (median t_max of 1-3 hours). The steady-state t_1/2 ranged from 8.3-11 hours, and exposures increased approximately dose-proportionally. Three target engagement assays were used to demonstrate dose-dependent inhibition of p-BTK and BTK-dependent cellular activation. Basophil activation via FcεR, B cell activation via the B cell receptor, and constitutive p-BTK activity in whole blood lysates were inhibited in a dose-dependent manner by GDC-0853, with IC50’s ranging from 2-9 nM. Basophil and p-BTK activity in the MAD study were used to develop a PK/PD model to support dose selection for the phase II studies.

Conclusion:  GDC-0853 was well-tolerated in healthy subjects at doses that inhibit BTK activity. The safety, PK, and PD profiles support further investigation in phase II studies in rheumatoid arthritis, lupus, and other autoimmune indications.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-pharmacokinetics-and-biomarker-profile-from-phase-1-clinical-trials-of-healthy-volunteers-treated-with-gdc-0853-a-highly-selective-reversible-oral-brutons-tyrosine-kinase-btk-inhi/