Publications

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate

Ann Rheum Dis. 2015;74(2):333–340

Keystone EC,

Taylor PC,

Drescher E,

Schlichting DE,

Beattie SD,

Berclaz PY,

Lee CH,

Fidelus-Gort RK,

Luchi ME,

Rooney TP,

Macias WL,

Genovese MC.

Recent innovations in the treatment of RA have focused on the use of small molecules to inhibit intracellular kinases such as the JAK family. Baricitinib (LY3009104, formerly INCB028050) is an orally administered, potent, selective and reversible inhibitor of JAK1 and JAK2, which has shown anti-inflammatory effects, as well as preservation of cartilage and bone, in preclinical rodent studies.

This phase IIb study was designed to investigate multiple doses and dosing regimens of baricitin...

Keywords:

• JAK,
• Baricitinib,
• Phase 2

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels

Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]

Isomäki P,

Junttila I,

Vidqvist KL,

Korpela M,

Silvennoinen O.

Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...

Keywords:

• Preclinical,
• MOA

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]

Boyle DL,

Soma K,

Hodge J,

Kavanaugh A,

Mandel D,

Mease P,

Shurmur R,

Singhal AK,

Wei N,

Rosengren S,

Kaplan I,

Krishnaswami S,

Luo Z,

Bradley J,

Firestein GS

Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology.

Keywords:

• JAK,
• Tofacitinib,
• Phase 1,
• MOA

Lipid profile changes in patients with chronic inflammatory arthritis treated with biologics and tofacitinib in randomized clinical trials: A systematic review and meta-analysis

Arthritis Rheumatol. 2015;67(1):117–127

Souto A,

Salgado E,

Maneiro JR,

Mera A,

Carmona L,

Gómez-Reino JJ

Systemic inflammation, reflected by high levels of C-reactive protein and the erythrocyte sedimentation rate, has been identified as an independent risk factor for cardiovascular disease, the most important cause of death in RA and SpA. Studies with TNF antagonists have given contradictory results on cardiovascular risk. As such, this systemic literature search aimed to analyse lipid changes in RA and SpA subjects treated with biologics or tofacitinib in randomized clinical trials.

The s...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Cardiovascular

Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: Patient-reported outcomes from a Phase 3 trial

Arthritis Care Res (Hoboken). 2014 Sep 3. doi: 10.1002/acr.22453. [Epub ahead of print]

Strand V,

Burmester GR,

Zerbini CA,

Mebus CA,

Zwillich SH,

Gruben D,

Wallenstein GV

For many patients with rheumatoid arthritis, improvements in pain, physical function, fatigue, and health-related quality of life (HRQoL) are more important and meaningful than improvements in joint swelling, tenderness, or inhibition of structural damage. These patient-perceived benefits of RA therapy contribute importantly to overall clinical efficacy.

This paper presents patient-reported outcomes (PROs) form the ORAL Step trail, which assessed tofacitinib 5 mg or 10 mg twice daily, or ...

Keywords:

• JAK,
• Tofacitinib,
• Phase 3

Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials

Arthritis Res Ther. 2014;16(4):R158

Isaacs JD,

Zuckerman A,

Krishnaswami S,

et al.

Despite preclinical and healthy volunteer studies of tofacitinib showing no evidence of nephrotoxicity, increases in mean serum creatinine levels have been observed in patients treated with the drug during the RA clinical development programme. This report explores the clinical significance of this change.

Serum creatinine values and renal adverse event data were pooled from patients who received =1 dose of tofacitinib either with background DMARDs or as monotherapy in five Phase 3 studie...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Renal

Analysis of Infections and All-Cause Mortality in Phase II, III and Long-Term Extension Studies of Tofacitinib in Patients with Rheumatoid Arthritis

Arthritis Rheumatol. 2014;66(11):2924–2937

Cohen S,

Radominski SC,

Gomez-Reino JJ,

et al.

This study pools data from the global tofacitinib RA development programme (phase II, phase III and long-term extension studies) to determine the rate of infections and all-cause mortality with tofacitinib treatment. In total, 4,789 patients within these studies received tofacitinib, at varying doses and with varying duration.

The overall incidence rate of serious infections was 3.09 events/100 patient-years (95% CI 2.73–3.49), which was stable over time, with pneumonia and skin and soft...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Phase 3,
• LTE,
• Mortality,
• Infections

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

Arthritis Rheumatol. 2014 Jun 18. [Epub ahead of print]

Winthrop KL,

Yamanaka H,

Valdez H,

et al.

It is well established that patients with RA are at an increased risk of herpes zoster (HZ). What is less well known is whether some of the newer therapies available for treatment of RA increase this risk. Tofacitinib has been reported to be associated with an increased risk of HZ and this study quantifies that risk and reviews potential factors that represent an increased risk. Using data from the tofacitinib RA development programme; phase 2, 3, and long-term extension clinical trials, over 20...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Infections

Tofacitinib Versus Methotrexate In Rheumatoid Arthritis

N Engl J Med. 2014;370(25):2377–2386.

Lee EB,

Fleischmann R,

Hall S,

et al.

ORAL Start is the latest trial to be reported in the tofacitinib clinical development programme. It compares the use of tofacitinib monotherapy to MTX monotherapy, in RA patients who have had either no or a sub-therapeutic dose of MTX in the past. Nine hundred and fifty eight patients received either tofacitinib (5 mg or 10 mg) twice daily, or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks. The co primary efficacy endpoints were ACR 70 response, and mean c...

Keywords:

• JAK,
• Tofacitinib,
• Phase 3

Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor

Science 344, 2014; doi: 10.1126/science.1249783

Brooks AJ,

Dai W,

O’Mara ML et al

Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive. Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor i...

Keywords:

• JAK,
• Preclinical,
• MOA