Bruton’s Tyrosine Kinase Inhibition for the Treatment of Rheumatoid Arthritis

Figures & data

Figure 1 Simplified schematic of the proposed mechanism of BTK inhibition in RA. (Figure modified and used with permission from American Laboratory Products Company. BTK Inhibitors as Cancer Drug Treatments. Available from: https://www.alpco.com/btk-inhibitors-as-cancer-drug-treatments).⁴⁴

Table 1 BTK Inhibitors Studied for Rheumatoid Arthritis

Trial Type	Mechanism	BTK Inhibitor	Study	Subjects Studied	Key Results
Preclinical	Second-generation Irreversible	Evobrutinib (M-2951)	Haselmayer et al 2019^Citation22	CIA mouse model	Significant dose-dependent inhibition of arthritis progression with evobrutinib versus disease control or methotrexate (MTX).
		Spebrutinib (CC-292, AVL-292)	Evans et al 2013^Citation8	CIA mouse model	Significant dose-dependent inhibition of arthritis progression with spebrutinib versus disease control; similar effect to dexamethasone.
		SOMCL-17-016	Liu et al 2021^25	CIA mouse model	Significant dose-dependent inhibition of arthritis progression with SOMCL-17-016 versus disease control; greater effect than ibrutinib or acalabrutinib.
	Reversible	CGI-1746	Di Paolo et al 2011^Citation31	CIA mouse model	Significant inhibition of arthritis development with prophylactic CGI-1746 versus dexamethasone. Significant inhibition of arthritis progression with CGI-1746 treatment versus disease control.
		Fenebrutinib (GDC-0853)	Crawford et al 2018^Citation16	CIA rat model	Significant dose-dependent inhibition of arthritis progression with fenebrutinib versus disease control; similar effect to dexamethasone.
		RN-486	Xu et al 2012^Citation27	CIA mouse model and AIA rat model	Significant inhibition of arthritis progression with RN-486 treatment versus disease control, as monotherapy and combined with MTX.
Phase I Clinical	Second-generation Irreversible	Evobrutinib (M-2951)	Becker et al 2019^Citation23	Healthy human participants: Part 1 (one dose) with 48 subjects and Part 2 (daily for 14 days) with 36 subjects, escalating doses, single-center	Sustained BTK occupancy by inhibitor (dose-dependent), well-tolerated safety profile, favorable pharmacokinetics.
		Spebrutinib (CC-292, AVL-292)	Evans et al 2013^Citation8	Healthy human participants (6 total), single dose, single-center	Sustained BTK occupancy by inhibitor in all subjects for 8–24 hours following drug administration, despite low/undetectable plasma levels of the drug.
		Tirabrutinib (ONO/GS-4059)	ClinicalTrials.gov Identifier: NCT02626026^Citation34	Part A with healthy human participants, Part B with RA patients (42 total); daily versus twice daily dosing, multicenter	The treatment arm given tirabrutinib 20mg daily for four weeks achieved ACR20 in 6% of participants at 2 weeks, 19% at 4 weeks, and 13% at 4 weeks post-treatment, compared to 20%, 0% and 0% respectively for the placebo cohort.
	Reversible	Fenebrutinib (GDC-0853)	Jones et al 2019^Citation2	Healthy human participants (18 total), male only, single dose, single-center	Fenebrutinib and MTX do not have significant interactions from a pharmacokinetic standpoint.
Phase II Clinical	Second-generation Irreversible	Evobrutinib (M-2951)	ClinicalTrials.gov Identifier: NCT02784106^Citation35	Phase IIa: Participants with RA on background MTX (65 total), single dose, single-center	ACR20 was achieved by 52% in the treatment group and 42% in the placebo group. However, the difference in responder proportion (0.10) did not reach statistical significance.
			ClinicalTrials.gov Identifier NCT03233230^Citation36	Phase IIb: Participants with RA with prior insufficient MTX response (390 total), three escalating doses, multicenter	None of the three treatment groups demonstrated statistically significant improvements in ACR20, ACR50, or ACR70. However, each treatment group demonstrated greater achievement of low DAS and remission DAS than the placebo group.
		Spebrutinib (CC-292, AVL-292)	Schafer et al 2020^Citation11	Phase IIa: Participants with RA on background MTX, female only (47 total), single dose, mulitcenter	The spebrutinib treatment group demonstrated a non-significant trend toward clinical improvement in arthritic symptoms, as well as statistically significant reductions in inflammatory markers, compared to placebo.
		Acalabrutinib (ACP-196)	ClinicalTrials.gov Identifier: NCT02387762^Citation32	Phase IIa: Participants with RA on background MTX, single dose (31 total), multicenter	Comparable disease activity score 28-C-reactive protein (DAS28-CRP) scores between acalabrutinib and placebo groups after 4 weeks of treatment.
	Reversible	Fenebrutinib (GDC-0853)	Cohen et al 2020 (ANDES)^Citation33	Phase II: Cohort 1: Participants with seropositive RA with prior suboptimal response to MTX (480 total). Cohort 2: Participants with seropositive RA on background MTX, with prior suboptimal response to TNF inhibitor (98 total). Escalating doses, international multicenter	Cohort 1: Significant improvement in ACR50 with higher dose fenebrutinib (150 mg daily or 200 mg twice daily) versus placebo. ACR50 was similar with fenebrutinib 200 mg twice daily versus adalimumab, and fenebrutinib 50 mg daily versus placebo. Cohort 2: Non-significant trend toward improved ACR50 with fenebrutinib 200 mg twice daily versus placebo.
Clinically suspended	Experimental Irreversible	Poseltinib (LY3337641/HM71224)	Genovese et al 2020^Citation24	Phase II: Part A, RA patients with mild disease (36 total). Part B, RA patients with moderate-to-severe disease (250 total). Escalating doses, multicenter	Study terminated after an interim analysis that showed minimal likelihood of achieving adequate clinical response.
	Reversible	GDC-0834	Liu et al 2011^Citation6	CIA rat model	Marked decrease in arthritis severity versus disease control; similar effect to MTX.

Abbreviations: CIA, collagen-induced arthritis; AIA, adjuvant-induced arthritis; RA, rheumatoid arthritis; MTX, methotrexate; ACR20, American College of Rheumatology 20% response; ACR50, American College of Rheumatology 50% response; ACR70, American College of Rheumatology 70% response; DAS, Disease Activity Score.

Table 2 Mechanisms of BTK Inhibitors Studied for Rheumatoid Arthritis

BTK Inhibitor	Mechanism
Ibrutinib	First-generation Irreversible
Acalabrutinib (ACP-196)	Second-generation Irreversible
Evobrutinib (M-2951)	Second-generation Irreversible
Spebrutinib (CC-292, AVL-292)	Second-generation Irreversible
SOMCL-17-016	Second-generation Irreversible
Tirabrutinib (ONO/GS-4059)	Second-generation Irreversible
Poseltinib (LY3337641/HM71224)	Second-generation Irreversible
CGI-1746	Reversible
Fenebrutinib (GDC-0853)	Reversible
GDC-0834	Reversible
RN-486	Reversible

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Di Paolo JA, Huang T, Balazs M, et al. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 2011;7(1):41–50. doi:10.1038/nchembio.481

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Crawford JJ, Johnson AR, Misner DL, et al. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development. J Med Chem. 2018;61(6):2227–2245. doi:10.1021/acs.jmedchem.7b01712

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Xu D, Kim Y, Postelnek J, et al. RN486, a selective Bruton’s tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. J Pharmacol Exp Ther. 2012;341(1):90–103. doi:10.1124/jpet.111.187740

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Study to evaluate safety and pharmacokinetics of GS-4059 (tirabrutinib) in healthy volunteers and participants with Rheumatoid Arthritis (RA). Available from: https://ClinicalTrials.gov/show/NCT02626026. Accessed August 4, 2021.

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Jones NS, Winter H, Katsumoto TR, et al. Absence of pharmacokinetic interactions between the Bruton’s tyrosine kinase inhibitor fenebrutinib and methotrexate. J Pharmacol Exp Ther. 2019;371(1):202–207. doi:10.1124/jpet.119.257089

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Safety and Efficacy Study of M2951 in participants with rheumatoid arthritis. Available from: https://ClinicalTrials.gov/show/NCT02784106. Accessed August 4, 2021.

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Phase IIb Study of evobrutinib in subjects with rheumatoid arthritis. Available from: https://ClinicalTrials.gov/show/NCT03233230. Accessed August 4, 2021.

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Schafer PH, Kivitz AJ, Ma J, et al. Spebrutinib (CC-292) affects markers of B cell activation, chemotaxis, and osteoclasts in patients with rheumatoid arthritis: Results from a Mechanistic Study. Rheumatol Ther. 2020;7(1):101–119. doi:10.1007/s40744-019-00182-7

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ACP-196 versus placebo in subjects with rheumatoid arthritis on background methotrexate. Available from: https://ClinicalTrials.gov/show/NCT02387762. Accessed August 4, 2021.

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Cohen S, Tuckwell K, Katsumoto TR, et al. Fenebrutinib versus placebo or adalimumab in rheumatoid arthritis: a randomized, double-blind, Phase II trial. Arthritis Rheumatol. 2020;72(9):1435–1446. doi:10.1002/art.41275

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Genovese M, Spindler A, Sagawa A, et al. Safety and efficacy of poseltinib, Bruton’s tyrosine kinase inhibitor, in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled, 2-part Phase II Study. J Rheumatol. 2021;48(7):969–976. doi:10.3899/jrheum.200893

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