Toreforant, an orally active histamine H4-receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate: mechanism of action results from a phase 2, multicenter, randomized, double-blind, placebo-controlled synovial biopsy study
| Autor: | Gary S. Firestein, David L. Boyle, Dion Chen, Cesar Calderon, Samuel E. DePrimo, Paul J. Dunford, Robin L. Thurmond, William Barchuk |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pharmacology medicine.medical_specialty medicine.drug_class business.industry Immunology Antagonist Receptor antagonist Placebo medicine.disease Gastroenterology Rheumatology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Internal medicine Pharmacodynamics Rheumatoid arthritis medicine Biomarker (medicine) Methotrexate business 030215 immunology medicine.drug |
| Zdroj: | Inflammation Research. 68:261-274 |
| ISSN: | 1420-908X 1023-3830 |
| Popis: | In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant. Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0–52) or placebo (weeks 0–12) followed by toreforant 30 mg/day (weeks 12–52). Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics. Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected. While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation. |
| Databáze: | OpenAIRE |
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