Introduction
Extracellular target in RA
Granulocyte macrophage-colony stimulating factor
Intracellular targets in RA
Janus kinase-signal transducer and activator of transcription pathway
JAK1 | JAK2 | JAK3 |
---|---|---|
Common γ chain receptor family
IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 |
Common γ chain receptor family
IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 | |
Gp130 receptor family
IL-6, IL-11, IL-27, IL-31 |
Gp130 receptor family
IL-6, IL-11, IL-27, IL-31 | |
Interferon
IFNα/β/γ |
Interferon
IFNα/β/γ | |
Hormones
Erythropoietin Thrombopoietin Prolactin Growth hormone | ||
GM-CSF receptor family
IL-3R, IL-5R, GM-CSF-R |
Study name | Number of subjects | Subject characteristics | Intervention | Primary endpoints | Results |
---|---|---|---|---|---|
ORAL start [59] | 958 | MTX naive | Tofacitinib (5 or 10 mg) vs. MTX 20 mg per week | ACR70 response Mean change in modified total Sharp score | 25.5, 37.7 vs. 12.0% 0.2, <0.1 vs. 0.8 |
ORAL scan [60] | 797 | MTX-IR | Tofacitinib (5 or 10 mg) vs. placebo | ACR20 response Mean change in modified total Sharp score Mean change in HAQ-DI DAS remission | 51.5, 61.8 vs. 25.3% 0.12, 0.06 vs. 0.47a
−0.40, −0.54 vs. −0.15 7.2, 16 vs. 1.6% |
ORAL solo [63] | 611 | DMARD-IR* | Tofacitinib (5 or 10 mg) vs. placebo | ACR20 response Mean change in HAQ-DI DAS remission | 59.8, 65.7 vs. 26.7% −0.50, −0.57 vs. −0.19 5.6, 8.7 vs. 4.4% (NS) |
ORAL sync [64] | 792 | DMARD-IR* | Tofacitinib (5 or 10 mg) vs. placebo | ACR20 response Mean change in HAQ-DI DAS remission | 52.1, 56.6 vs. 30.8% -0.44, -0.53 vs. -0.16 8.5, 12.5 vs. 2.6% |
ORAL standard [62] | 717 | MTX-IR | Tofacitinib (5 or 10 mg) vs. adalimumab 40 mg q2w vs. placebo | ACR20 response Mean change in HAQ-DI DAS remission | 51.5, 52.6, 47.2 vs. 28.3% 0.55, −0.61, 0.49 vs. −0.24 6.2, 12.5, 6.7 vs. 1.1% |
ORAL step [61] | 399 | TNFi-IR | Tofacitinib (5 or 10 mg) vs. placebo | ACR20 response Mean change in HAQ-DI DAS remission | 41.7, 48.1 vs. 24.4% −0.43, −0.46 vs. −0.18 6.7, 8.8 vs. 1.7% |
Study name | Number of subjects | Subject characteristics | Intervention | Primary endpoints | Results |
---|---|---|---|---|---|
RA-BEGIN [68] | 588 | DMARD naive | Baricitinib 4 mg + MTX 10-20 mg per week vs. baricitinib 4 mg vs. MTX 10–20 mg per week | ACR20 response | 77 vs. 62%a
|
RA-BEAM [69] | 1307 | MTX-IR | Baricitinib 4 mg vs. adalimumab 40 mg q2w vs. placebo | ACR20 response | 70 vs. 61 vs. 40%b
|
RA-BUILD [66] | 684 | DMARD-IR | Baricitinib (2 or 4 mg) vs. placebo | ACR20 response | 62 vs. 39%c
|
RA-BEACON [67] | 527 | TNFi-IR | Baricitinib (2 or 4 mg) vs. placebo | ACR20 response | 55 vs. 27%c
|
RA-BEYOND | Estimated 3073 | Baricitinib (2 or 4 mg) | 1 drug-related adverse event or any serious adverse events | Ongoing |
Study drug | Estimated enrolment | Subject characteristics | Intervention | Primary endpoints |
ClinivalTrials.gov identifier |
---|---|---|---|---|---|
Filgotinib | 1200 | MTX naive | Filgotinib + MTX vs. filgotinib vs. MTX | ACR20 response | NCT02886728 |
1650 | MTX-IR | Filgotinib vs. adalimumab vs. placebo | ACR20 response | NCT02889796 | |
423 | bDMARD-IR | Filgotinib vs. placebo | ACR20 response | NCT02873936 | |
ABT-494 | 975 | MTX naive | ABT-494 vs. MTX | ACR50 response; DAS28-CRP remission | NCT02706873 |
1500 | MTX-IR | ABT-494 vs. adalimumab vs. placebo | ACR20 response | NCT02629159 | |
600 | MTX-IR | ABT-494 vs. MTX | ACR20 response; DAS28-CRP LDA | NCT02706951 | |
600 | csDMARD-IR | ABT-494 vs. placebo | ACR20 response; DAS28-CRP LDA | NCT02675426 |
Bruton’s tyrosine kinase pathway
Phosphoinositide-3-kinase pathway
PI3K isoform | Catalytic subunit | Regulatory subunits | Substrate | Product | |
---|---|---|---|---|---|
Class IA | PI3Kα PI3Kβ PI3Kδ | p110α p110β p110δ | p85α, p85β, p55α, p55γ, p50α | PI-4,5-P2 | PIP3 |
Class IB | PI3Kγ | p110γ | p101, p84 | PI-4,5-P2 | PIP3 |
Class II | PIK3-C2 PIK3-C3 PIK3-C2 | PI-4-P PI | PI-3,4P2 PI-3-P | ||
Class III | VPS34 | P150 | PI | PI-3-P |