Spebrutinib (CC-292) Affects Markers of B Cell Activation, Chemotaxis, and Osteoclasts in Patients with Rheumatoid Arthritis: Results from a Mechanistic Study

Abstract

Introduction: Spebrutinib (CC-292) is an orally administered, covalent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK), part of the B-cell and Fc receptor signaling pathways. This study evaluated spebrutinib pharmacology and mechanism of action over a 4-week treatment period in patients with active rheumatoid arthritis (RA).

Methods: Primary human B cells, T cells, natural killer cells, macrophages, dendritic cells, basophils, and osteoclasts were treated with spebrutinib in vitro. Clinical pharmacodynamics were studied in 47 patients with active RA on background methotrexate therapy randomized to oral spebrutinib 375 mg/day or placebo.

Results: In vitro, spebrutinib inhibited B-cell proliferation more potently than T-cell proliferation and reduced both lymphoid and myeloid cytokine production and degranulation, as well as osteoclastogenesis. Clinical efficacy trended higher in spebrutinib-treated RA patients, with 41.7% (10/24) achieving ≥ 20% improvement in ACR response criteria (ACR20) versus 21.7% (5/23) of placebo patients at week 4 (P = 0.25). Treatment-emergent adverse events were comparable between treatment groups. In spebrutinib-treated patients, median BTK occupancy in peripheral blood was 83%, and significant increases in total CD19+ and mature-naive CD27-CD38-IgD+ B cells and decreases in transitional CD27-CD38+ B cells were observed. Spebrutinib significantly reduced serum chemokines chemokine ligand 13 (CXCL13), macrophage inflammatory protein-1β (MIP-1β), and the bone resorption biomarker carboxy-terminal collagen cross-linking telopeptide (CTX-I) (P < 0.05). Clinical response to spebrutinib was associated with lower increases in CD19+ B cells and greater decreases in CXCL13 and MIP-1β from baseline to week 4. High CD19+ B cells and low CTX-I at baseline were associated with better spebrutinib clinical response.

Conclusions: Spebrutinib inhibited various leukocyte responses in vitro, including those of B cells and osteoclasts. In this small study in RA patients, spebrutinib was well tolerated, showed a downward trend for symptoms, significantly modulated B-cell populations, and reduced markers of chemotaxis and osteoclast activity.

Trial registration: NCT01975610.

Keywords: Background methotrexate therapy; Bruton’s tyrosine kinase inhibitor; CC-292; Rheumatoid arthritis; Spebrutinib.

Figures

Fig. 1

Patients achieving ACR20, ACR50, and ACR70 responses at week 4. ACR American College of Rheumatology response criteria

Fig. 2

Free BTK to total BTK in PBMC and spebrutinib’s effects on B-cell subsets. a Fraction of free BTK to total BTK in PBMC and b–d effects of spebrutinib on B-cell subsets in circulation. The binding of spebrutinib to BTK in PBMC is shown in a as the ratio of free (unbound) BTK to total BTK. Flow cytometry analysis of whole blood from patients at the indicated times post-treatment are shown as b percent change from baseline for CD19+ total B cells, c CD19+CD27−CD38−IgD+ mature naive B cells, and d CD19+CD27−CD38+ transitional B cells at weeks 1, 2, and 4. Data are represented as median values ± 95% confidence interval of placebo (open circles) and spebrutinib treatment (open triangles). *P < 0.05; **P < 0.01 versus collection date-matched placebo. BTK Bruton’s tyrosine kinase, PBMC peripheral blood mononuclear cells

Fig. 3

Changes in CTX-I expression and inflammation-associated proteins over time after administration of spebrutinib. Plasma levels from subjects at the indicated times post-treatment are shown as percent change from baseline for a CTX-I, b CXCL13, c MIP-1β, and d haptoglobin at weeks 1, 2, and 4. Data are represented as the median ± 95% confidence interval of placebo (open circles) and spebrutinib treatment (open triangles). *P < 0.05; **P < 0.01; ***P < 0.001 versus collection date-matched placebo. CTX-I carboxy-terminal collagen cross-linking telopeptide, CXCL13 chemokine ligand 13, MIP-1β macrophage inflammatory protein-1β

Fig. 4

Association between clinical response to spebrutinib and changes in biomarkers. Change in a CD19+ B cells, b CXCL13, and c MIP-1β in peripheral blood of spebrutinib-treated patients from baseline to week 4, by ACR20, ACR50, and ACR70 response status. Data are represented as the median, minimum, maximum, and interquartile range

Fig. 5

Association between clinical response to spebrutinib and baseline biomarkers. Baseline levels of a CD19+ B cells and b CTX-I in peripheral blood of spebrutinib-treated patients by ACR20, ACR50, and ACR70 response status. Data are represented as the median, minimum, maximum, and interquartile range