. 2021 Oct 5;81(14):1605–1626. doi: 10.1007/s40265-021-01592-0

Table 3.

Ongoing and completed clinical trials (phase II or III) with Bruton’s tyrosine kinase (BTK) inhibitors in systemic autoimmune diseases

Trial no. and type	Disease	Treatment arms	Treatment duration	Primary outcome	Results
Acalabrutinib
NCT02387762 phase IIa, R, DB, PC	Active RA background MTX	• Placebo daily + stable MTX (7.5–25 mg) weekly	4 weeks	DAS28-CRP at 4 weeks	No results reported
NCT02387762 phase IIa, R, DB, PC	Active RA background MTX	• ACA 15mg daily + stable MTX (7.5–25 mg) weekly	4 weeks	DAS28-CRP at 4 weeks	No results reported
BMS-986142
NCT02638948 phase II, R, DB, PC	Active RA with inadequate response to MTX	• Placebo daily + MTX	12 weeks	% ACR20/ACR70 response at 12 weeks	No significant difference in % ACR20 or ACR70 response at 12 weeks in both treatment arms compared to placebo^#
		• BMS 100 mg daily + MTX
		• BMS 200 mg daily + MTX
NCT02843659 phase II, R, DB, PC	Moderate to severe primary SjS	• Placebo daily	12 weeks	Mean change ESSDAI from baseline at 12 weeks	Terminated due to inability to meet protocol objectives
NCT02843659 phase II, R, DB, PC	Moderate to severe primary SjS	• BMS 350 mg daily	12 weeks	Mean change ESSDAI from baseline at 12 weeks	Terminated due to inability to meet protocol objectives
Branebrutinib
NCT04186871 phase II, R, DB, PC	Active SLE, primary SjS or RA	SLE/SjS:	*	SLE: % ≥ 50% reduction mCLASI from baseline at 24 weeks SjS: % changes in composite score from baseline at 24 weeks RA: % ACR50 response at 12 weeks	Currently recruiting
		• Placebo daily^¥
		• BRA daily
		RA:
		• Placebo daily, followed by abatacept
		• BRA daily followed by abatacept
Elsubrutinib
NCT03682705 phase II, R, DB, PC	Active RA with inadequate response/ intolerance to DMARD	• Placebo + placebo daily	12 weeks	Change in DAS28-CRP from baseline At 12 weeks	Significant effect of combined ELS + UPA treatment compared to placebo, but no difference compared to UPA monotherapy^#
		• ELS 60mg + upadacitinib 15 mg daily
		• ELS 60 mg + placebo daily
		• ELS 20 mg + placebo daily
		• ELS 5 mg + placebo daily
		• Placebo + 15 mg upadacitinib daily
NCT03978520 phase II, R, DB, PC	Moderate to severely active SLE	• Placebo + placebo daily^¥	*	Achievement of SRI-4 and steroid dose ≥ 10 mg prednisone equivalent at 24 weeks	Currently recruiting
		• ELS + upadacitinib daily
		• ELS + placebo daily
		• Placebo + upadacitinib daily
NCT04451772 LTE of NCT03978520	Moderate to severely active SLE	• Placebo + placebo daily^¥	Up to 56 weeks	Number of participants with adverse events through week 104	Currently recruiting
		• ELS + upadacitinib A daily
		• ELS + upadacitinib B daily
		• ELS + placebo daily
Evobrutinib
NCT02784106 phase IIa, R, DB, PC	RA with stable MTX treatment	• Placebo daily + MTX	12 weeks (extension through 26 weeks)	% ACR20 response at 12 weeks	No significant difference in ACR20 % between placebo and treatment^#
		• EVO 2 × 50 mg daily + MTX
		Extension period from 12–26 weeks both arms with EVO 2 × 50 mg daily
NCT03233230 phase IIb, R, DB, PC	RA with inadequate response to MTX	• Placebo daily	12 weeks	% ACR20 response using hsCRP at 12 weeks	No significant difference in ACR20 % between placebo and treatment arms^#
		• EVO 25 mg daily
		• EVO 75 mg daily
		• EVO 2 × 50 mg
NCT02975336 phase II, R, DB, PC	Active SLE	• Placebo daily	52 weeks (extension through 104 weeks)	SRI-4 response at 52 weeks	No significant difference in SRI-4 response between placebo and treatment arms^#
		• EVO 25 mg
		• EVO 75 mg daily
		• EVO 2 × 50 mg daily
		Extension period from 52–104 weeks both arms with EVO 2 × 50 mg daily
Fenebrutinib
NCT02833350 phase II, R, DB, PC	Active RA with inadequate response to MTX (cohort 1) or TNF inhibition (cohort 2)	Cohort 1:	12 weeks	% ACR50 response at 12 weeks	Cohort 1: ACR50 response rate was significantly higher in 150 mg (28%), 2 × 200 mg (35%) and ADA (36%)-treated patients compared to placebo (15%). [128] Cohort 2: ACR50 response rate was increased in 2 × 200 mg treated patients (25%) compared to placebo (15%), although not significantly (p = 0.07) [128]
		• Placebo daily
		• FEN 50 mg daily
		• FEN 150 mg daily
		• FEN 2 × 200 mg daily
		• Adalimumab 40 mg/2 weeks all arms + MTX and folic acid
		Cohort 2:
		• Placebo daily
		• FEN 2 × 200 mg daily
		Both arms: + MTX and folic acid
NCT02983227 LTE of NCT02833350	RA with inadequate response to MTX (cohort 1) or TNF inhibitors (cohort 2)	• 2 × 200 mg FEN daily	52 weeks	% adverse events by week 60 % ACR50 response at 52 weeks	Cohort 1: 60.2% reported AE, 57.1% ACR50 response^# Cohort 2: 57% reported AE, 50% ACR50 response
NCT02908100 phase II, R, DB, PC	Moderate to severe SLE	• Placebo daily	48 weeks	SRI-4 response at week 48	No significant difference in SRI-4 response between placebo and treatment arms^#
		• FEN 150 mg daily
		• FEN 2 × 200 mg daily
		All arms + standard care
NCT03407482 LTE of NCT02908100	SLE	• FEN 2 × 200 mg daily	*	% adverse events by week 8	Terminated due to lack of efficacy in parent study
Poseltinib
NCT02628028 phase II, R, DB, PC	RA with mildly active (part A) or moderately to severely (part B) disease	Part A:	Part A: 4 weeks Part B: 12 weeks + 52 weeks extension	Part A: Number of treatment emergent/serious adverse events or adverse event of special interest Part B: % patients with ACR20 response at 12 weeks	Part A: No safety signals precluded start of part B. [131] Part B: Interim analysis indicated no statistical difference in ACR20 rate, trial was discontinued [131]
		• Placebo daily
		• POS 5 mg daily
		• POS 10 mg daily
		• POS 30 mg daily
		Part B:
		• Placebo daily
		• POS 5 mg daily
		• POS 10 mg daily
		• POS 30 mg daily
Orelabrutinib
NCT04305197 phase Ib/IIa, R, DB, PC	Mild to moderate SLE	• Placebo daily	12 weeks	% patients with (serious) adverse events	Currently recruiting
		• ORE 50 mg daily
		• ORE 80 mg daily
		• ORE 100 mg daily
Remibrutinib
NCT04035668 phase II, R, DB, PC	Active primary SjS	• Placebo^¥	*	Changes in ESSDAI from baseline at 24 weeks	Currently recruiting
		• REM low dose
		• REM intermediate dose
		• REM high dose
		• REM high dose 2
Rilzabrutinib
NCT02704429 phase II, open label	Newly diagnosed or relapsed pemphigus vulgaris with moderate-severe disease	Part A:	Part A: 12 weeks + 12 weeks follow-up Part B: 24 weeks + 4 weeks follow-up	Part A: Incidence of adverse events at 4 weeks; % control of disease activity (CDA) at week 4	Part A: 74% treatment emergence adverse events 52% CDA at 4 weeks [133]
		• RIL 2 × 400–600 mg daily
		Part B:
		• 24 weeks RIL + 4 weeks follow-up
NCT03762265 phase III, R, DB, PC	Newly diagnosed or relapsing moderate to severe pemphigus vulgaris or foliaceus	• Placebo + ≤ 5 mg prednisone daily	68 weeks + 48 weeks extension	% complete remission at week 37	Active, not recruiting
NCT03762265 phase III, R, DB, PC		• RIL + ≤ 5 mg prednisone daily	68 weeks + 48 weeks extension	% complete remission at week 37	Active, not recruiting
Spebrutinib
NCT01975610 phase IIa, R, DB, PC	RA (female) with stable MTX treatment	• Placebo daily	4 weeks	% ACR20 response at 4 weeks	10/24 treated patients reached ACR20 by 4 weeks, compared to 5/23 placebo-treated patients (p = 0.25) [134]
NCT01975610 phase IIa, R, DB, PC	RA (female) with stable MTX treatment	• SPE 375 mg daily	4 weeks	% ACR20 response at 4 weeks
TAS5315
NCT03605251 phase II, R, DB, PC	RA with inadequate response to MTX	• Placebo^¥	12 or 36 weeks	% ACR20 response at 12 weeks	Completed, no data reported
		• TAS low dose
		• TAS high dose
		All arms + MTX; after 12 weeks, placebo group is randomized into low or high dose
Tirabrutinib
NCT03100942 phase II, R, DB, PC	Active SjS	• Placebo daily	TIR: 49.4 weeks LAN: 50.4 weeks FIL: 50.3 weeks	% patients fulfilling protocol-specified response at 12 weeks	No significant difference in improvement of clinical symptoms at 12 weeks was found for any treatment arm compared to placebo^#
		• TIR 40 mg daily
		• Lanraplenib 30 mg daily
		• Filgotinib 200 mg daily
		After 24 weeks, placebo group is randomized into other groups through 48 weeks
NCT02626026 # phase I, R, DB, PC	Healthy individuals (cohort 1) and active RA (cohort 2)	Cohort 1, part A:	Part A: 1 week Part B: 4 weeks	% treatment-emergent adverse events and % treatment-emergent laboratory abnormalities at 7 days (part A) or 59 days (part B)	Part A: No apparent differences in adverse events or laboratory abnormalities^# Part B: No apparent differences in adverse events, but more laboratory abnormalities in treated patients
		• Placebo daily
		• TIR 2 × 10 mg TIR daily
		Cohort 1, part B:
		• Placebo daily
		• TIR 20 mg daily
		Cohort 2, part B:
		• Placebo daily
		• TIR 20 mg daily

ACA acalabrutinib, ACR20 American College of Rheumatology 20, BMS BMS-986142, BRA branebrutinib, CDA control of disease activity, DAS28-CRP disease activity score 28-C-reactive protein, DB double blind, DMARD disease-modifying anti-rheumatic drug, ELS elsubrutinib, ESSDAI EULAR Sjögren’s syndrome disease activity index, EVO evobrutinib FEN fenebrutinib, FIL filgotinib, hsCRP high sensitive CRP, LAN lanraplenib, mCLASI modified Cutaneous Lupus Erythematosus Disease Area and Severity Index, MTX methotrexate, ORE orelabrutinib, PC placebo-controlled, POS poseltinib, R randomized, RA rheumatoid arthritis, REM remibrutinib, RIL rilzabrutinib, SjS Sjögren’s syndrome, SLE systemic lupus erythematosus, SPE spebrutinib, SRI-4 SLE responder index-4, TAS TAS5315, TIR tirabrutinib, TNF tumor necrosis factor, UPA upadacitinib

^#Unpublished data obtained from clinicaltrials.gov

*Information on treatment duration not available

^¥Information on dose not available