170 Forecasting Phase 3 Dose-Response for Abrocitinib, an Oral Janus Kinase 1 Selective Inhibitor, Using Investigator’s Global Assessment and Eczema Area and Severity Index

Abstract Background Anaemia, thrombocytopenia and leukopenia in rheumatoid arthritis (RA) patients treated with non-Janus Kinase 1 (JAK1) selective inhibitors may be due to inhibition of haematopoietic growth factors signalling through JAK2. Therefore, we investigated anaemia, thrombocytopenia and leukopenia in patients with active RA with prior inadequate response/intolerance to biologic disease-modifying anti-rheumatic drugs (bDMARDs) treated with filgotinib (FIL), a selective JAK1 inhibitor (FINCH-2; NCT02873936). Methods In the randomised, double-blind, placebo-controlled Phase 3 FINCH-2 trial, patients were randomised 1:1:1 to oral FIL 200 mg, 100 mg, or placebo (PBO) once daily plus conventional synthetic DMARDs for 24 weeks. In this subgroup analysis, we assessed shifts from baseline (BL) in haemoglobin (hgb), platelets (plt), neutrophils and lymphocytes. Results A total of 448 patients were treated; FIL 200 mg, n = 147; FIL 100 mg, n = 153; PBO, n = 148. Hgb, plt, lymphocyte and neutrophil counts remained consistent throughout the study. At BL, 28.8%, 0.9%, 2.2% and 5.8% patients had mild–moderate low hgb, plt, neutrophil and lymphocyte, respectively, and 1.1% had severely low lymphocyte levels. Of patients with mild–moderate hgb levels at BL, 13.1% with FIL 200 mg, 9.5% FIL 100 mg, and 7.6% PBO achieved normal hgb at Week 24, respectively (Table). Of those with normal BL hgb, only 6–9.8% had mild low levels at Week 24. Patients with BL mild-moderate low plts and neutrophils had normal levels at Week 24, except one with mild neutropenia on FIL 100 mg. Of patients with normal plt and neutrophil levels at BL, >94% maintained these at Week 24 in all treatment groups. By Week 24, 3.2%, 5.2% and 2.2% of patients treated with FIL 200 mg, FIL 100 mg and PBO, respectively, in the mild–moderate subgroup and 1.7% in the severe subgroup treated with FIL 100 mg had normal lymphocyte counts. Conclusion In this subgroup analysis, most patients with normal hgb, plt, lymphocyte and neutrophil at BL maintained them over 24 weeks of FIL treatment. Of the patients with mild–moderately low hgb at BL, >9% shifted towards normalisation. Similar patterns of improvement were observed for plt, lymphocyte and neutrophil counts. These results suggest that FIL does not increase the incidence of anaemia, thrombocytopenia or leukopenia in patients who entered the study with active RA despite prior bDMARDs.

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The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.7b01135 ◽

2017 ◽

Vol 60 (23) ◽

pp. 9676-9690 ◽

Cited By ~ 8

Author(s):

Tony Siu ◽

Jason Brubaker ◽

Peter Fuller ◽

Luis Torres ◽

Hongbo Zeng ◽

...

Keyword(s):

Selective Inhibitor ◽

Janus Kinase ◽

Janus Kinase 1 ◽

Pharmacokinetic Properties

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15059 Baricitinib, an oral reversible Janus kinase 1 and 2 inhibitor, for atopic dermatitis: Head and neck response across two phase 3 studies

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2020.06.200 ◽

2020 ◽

Vol 83 (6) ◽

pp. AB28

Author(s):

Eric Simpson ◽

Robert Bissonnette ◽

Fabio P. Nunes ◽

Maria Jose Rueda ◽

Carle Paul

Keyword(s):

Atopic Dermatitis ◽

Head And Neck ◽

Janus Kinase ◽

Phase 3 ◽

Two Phase ◽

Janus Kinase 1

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Crisaborol-Salbe verbessert die Krankheitsschwere gemessen am Atopischen Dermatitis Severity Index (ADSI): Gepoolte Ergebnisse zweier Phase-3 Studien

10.26226/morressier.5b50aeb5b1b87b0009beb4f9 ◽

2018 ◽

Author(s):

Jonathan I. Silverberg

Keyword(s):

Severity Index ◽

Phase 3

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Faculty Opinions recommendation of Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718010200.793476613 ◽

2013 ◽

Author(s):

Victoria Werth

Keyword(s):

Randomized Controlled Trials ◽

Plaque Psoriasis ◽

Global Assessment ◽

Severity Index ◽

Biologic Agents ◽

Controlled Trials ◽

Physician Global Assessment ◽

Systematic Analysis ◽

Severe Plaque Psoriasis ◽

Randomized Controlled

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Kinetic‐Pharmacodynamic Model of Platelet Time Course in Patients With Moderate‐to‐Severe Atopic Dermatitis Treated With Oral Janus Kinase 1 Inhibitor Abrocitinib

CPT Pharmacometrics & Systems Pharmacology ◽

10.1002/psp4.12548 ◽

2020 ◽

Vol 9 (10) ◽

pp. 553-560

Author(s):

Elena Soto ◽

Christopher Banfield ◽

Pankaj Gupta ◽

Mark C. Peterson

Keyword(s):

Atopic Dermatitis ◽

Time Course ◽

Pharmacodynamic Model ◽

Janus Kinase ◽

Severe Atopic Dermatitis ◽

Janus Kinase 1

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FRI0136 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH PRIOR INADEQUATE RESPONSE TO METHOTREXATE (FINCH1)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4704 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 650.2-651

Author(s):

P. C. Taylor ◽

E. Elboudwarej ◽

B. Downie ◽

J. Liu ◽

R. E. Hawtin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Migration ◽

Active Rheumatoid Arthritis ◽

Immune Cell ◽

Janus Kinase ◽

Inadequate Response ◽

Bone Biology ◽

Janus Kinase 1 ◽

Immune Cell Migration ◽

Dose Dependent

Background:Filgotinib (FIL), an oral selective Janus kinase 1 (JAK1) inhibitor has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those with prior inadequate response to methotrexate (MTX) therapy (FINCH1;NCT02889796).Objectives:A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2was conducted to identify RA-associated markers altered by FIL vs MTX or adalimumab (ADA).Methods:FINCH1 RA patients (pts) were randomized to receive either a stable dose of MTX with placebo (PBO+MTX), ADA+MTX, and either FIL100mg+MTX or FIL200mg+MTX, once daily. Plasma, serum, and urine samples were taken from a subset of pts (~548) at baseline (BL) and weeks (wks) 4 and 12. Twenty-six pre-defined cytokines (biomarkers) were evaluated using ELISA. BL correlation between biomarkers and clinical response measures (DAS28CRP, SJC28, TJC28, CDAI, Patient Assessment and FACIT), were analyzed by Spearman Rank. Multiscale bootstrap resampling evaluated significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4 and 12 were compared between arms using PBO-adjusted estimates from a linear mixed effects model. A 5% false-discovery rate was applied for all analyses.Results:At BL, distinct biomarker-based pt clusters (CL) were identified. The strongest intra-group correlations were in bone-cartilage resorption/inflammation (CL1; Rho range 0.37–0.88) and JAK activity (CL2; Rho range 0.41–0.71). Individual BL cytokine levels were significantly associated with DAS28CRP, with unique biomarkers specific to various subcomponents of the score. Eleven biomarkers were associated with DAS28CRP, while 5, 3, and 2 were associated with CDAI, SJC28, and TJC28, respectively. The magnitude of FIL-associated treatment effects was time- and dose-dependent. Significant biomarker changes from BL were observed in FIL pts, relative to PBO+MTX pts. FIL100mg+MTX led to a significant change in 8 biomarkers by either 4 or 12 wks of treatment; FIL200mg+MTX significantly changed these and an additional 4 biomarkers by either time point. The greatest effect of FIL200mg+MTX was at 12 wks for CXCL13 (-38.4%) and IL6 (-53.7%). All treatment arms led to significant reductions in TNFα relative to PBO+MTX. FIL200mg+MTX treatment led to larger reductions of TNFα than ADA+MTX treatment at both wk4 (-24.7% vs -17.9%) and wk12 (-20.5% vs -12.2%), although the differences were not statistically significant.FIL and ADA caused differential patterns of cytokine response at either wks 4 or 12. Of 12 biomarkers with a significant FIL200mg+MTX treatment effect, there was a significantly larger reduction in TNFSF13B and CTX1 relative to ADA+MTX at 12 wks. Of 8 biomarkers with FIL100mg+MTX effects, only 2 (CXCL10 at wk 4; CXCL13 at wks 4 and 12) had significant differences from ADA+MTX. Relative either to FIL200mg+MTX or FIL100mg+MTX, and despite the same direction of effect, ADA+MTX led to a significantly larger reduction in CCL2, CXCL10, CCL4, and CXCL13.Conclusion:Compared with PBO, 12 wks of FIL treatment significantly reduced cytokines associated with JAK activity1, bone biology2, inflammation2, and immune cell migration2in MTX-IR pts. The effects were largely FIL dose-dependent; most cytokines exhibited similar effects regardless of treatment arms, but differential changes between FIL+MTX and ADA+MTX were observed, supportive of the different mechanisms of action of these therapies.References:[1]Majoros A, et al. Front Immunol. 2017;8:29[2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

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