Table 1 A summary of approved BTK inhibitors and those under clinical trials

Approved

Ibrutinib

First-generation, irreversible, covalent binding to Cys481

0.5

Moderate

420/560/840 mg, QD

Approved for: CLL, MCL, GVHD, WM, and MZL

Phase 3: AML

Phase 2: DLBCL, HCL, CNSL, MM, wAIHA, COVID-19, FL, RS, and ALL

Phase 1: R/R T cell lymphoma

[28, 57]

Acalabrutinib

Second-generation, irreversible, covalent binding to Cys481

3.0–5.1

High

100 mg BID

Approved for: CLL and R/R MCL

Phase 3: DLBCL and COVID-19

Phase 2: WM, CNSL, wAIHA, FL, RS, and RA

Phase 1: MZL, MM, and AML

[28, 57]

Zanubrutinib

0.3

High

160 mg BID, or 320 mg QD

Approved for: R/R MCL; WM, and R/R MZL

Phase 3: hemophagocytic lymphohistiocytosis, CLL, and DLBCL

Phase 2: NMOSD, ITP, RS, SLE, COVID-19, and CNSL

Phase 1: AML

[65]

Orelabrutinib

1.6

High

150 mg QD

Conditionally approved for R/R MCL and R/R CLL in China

Phase 3: PCNSL, DLBCL, and SLE

Phase 2: ITP, RMS, and FL

[66]

Tirabrutinib

6.8

High

480 mg QD

Approved for R/R PCNSL in Japan

Phase 2: Pemphigus, CLL, SS, WM, MCL, and MZL

Phase 1: RA

[67]

Under clinical trials

Spebrutinib

(CC-292)

Second-generation, irreversible, covalent binding to Cys481

 < 0.5

High

1000 mg QD, or 500 mg BID

Phase 2: acute RA

Phase 1: DLBCL and FL

[68, 69]

Branebrutinib (BMS-986195)

0.1

High

1–10 mg QD

Phase 2: atopic dermatitis, RA, SLE, and SS

[55, 70]

SHR-1459

3

High

300 mg QD

Phase 2: R/R B cell NHL and PMN

[71]

DTRMWXHS-12

0.7

High

200 mg QD

Phase 2: R/R CLL and R/R NHL

Phase 1: MCL

[72]

Tolebrutinib (SAR 442,168)

0.7

High

60 mg QD

Phase 3: MS and Myasthenia Gravis

[73, 74]

Evobrutinib (M2951)

38–58

Moderate

75 mg QD, or 75 mg BID

Phase 3: RMS

Phase 2: SLE and RA

[74, 75]

Elsubrutinib (ABBV-105)

0.18

High

Phase 2: SLE and RA

[76]

AC0058TA

–

High

50/100/200 mg QD, or 100 mg BID

Phase 1: SLE

[77]

TG-1701

6.7

High

–

Phase 1: CLL and NHL

[78]

M7583

1.48

High

900 mg QD, or 300 mg BID

Phase 2: B cell malignancies

[79, 80]

Nemtabrutinib (ARQ 531, MK-1026)

Third-generation, reversible, non-covalent, binding to both WT BTK and

BTK^Cys481S mutant

MT: 0.85

Mut: 0.39

Moderate

65 mg QD

Phase 2: CLL/SLL, RS, MZL, MCL, FL, and WM

[57, 81, 82]

Pirtobrutinib (LOXO-305)

0.85

High

200 mg

Phase 3: CLL/SLL and MCL

Phase 2: NHL

[83]

Fenebrutinib (GDC-0853)

WT: 0.9

Mut: 1.6

High

50/150 mg QD, or 200 mg BID

Phase 3: RMS

Phase 2: CSU, SLE, RA

Phase 1: CLL and DLBCL

[84, 85]

Vecabrutinib (SNS-062)

WT: 4.6

Mut 1.1

High

25 mg escalated to 500 mg

Phase 2: B lymphoid cancers

[86, 87]

HMPL-760

–

High

–

Phase 1: CLL/SLL and NHL

BMS-986142

Non-covalent, reversible binding to BTK

0.5

High

Phase 2: RA and SS

[88]

BIIB091

0.071

High

–

Phase 1: healthy volunteers

[89, 90]

Rilzabrutinib (PRN1008)

Third-generation, reversible, transient covalent binding to Cys481

1.3

High

400 mg BID

Phase 3: ITP

Phase 2: wAIHA, asthma, atopic dermatitis, CSU, IgG4-related disease, and Pemphigus

[54, 91]

PRN473

1.8

High

Multiple topical doses

Phase 2: atopic dermatitis

[54]

SN-1011

–

High

–

Phase 1: healthy volunteers

Remibrutinib (LOU064)

Covalent binding to an inactive conformation of BTK

1.3

High

100 mg QD

Phase 3: RMS, CSU

Phase 2: asthma, SS, hidradenitis suppurativa

[92, 93]

NX-2127

Catalyze ubiquitylation and proteasomal degradation of BTK and BTK^Cys481S mutant

 < 5

–

100–300 mg QD

Phase 1: B cell malignancies

[94]