Toreforant Pharmacology Unclear for Rheumatoid Arthritis

synovial joint human finger
synovial joint human finger
Investigators found that while in vivo and in vitro preclinical trials of toreforant reduced IL-17 production and arthritis disease severity, phase 2 study data showed low levels of efficacy in patients with RA.

In patients with rheumatoid arthritis (RA), biomarker signals associated with toreforant pharmacology remain unclear, according to study results published in Inflammation Research. However, data indicated some modest associations between biomarkers and clinical response.

The study included participants who had active RA despite methotrexate treatment. They were randomly assigned 3:1 to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52). The first 12 weeks were a double-blind period and the following 40 weeks were an open-label extension period.

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The researchers performed primary biomarker analyses of 39 different proteins/mRNA transcripts measured in synovial biopsy (n=39) and/or time-match serum (n=15) samples collected at baseline and week 6. They assessed clinical response using C-reactive protein-based 28-joint disease activity scores.

Of 21 participants (16 toreforant, 5 placebo), 18 (13 toreforant, 5 placebo) completed the 12-week double-blind period, with no participants completing open-label treatment due to early study determination. The study was terminated when results from a phase 2b efficacy study of toreforant did not show a treatment effect in RA.

Using biomarker profiling, the researchers found potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-α, and interleukin (IL)-8 in the synovium. They also observed potential trends between biomarkers and clinical response, including synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3.

The researchers detected only minimal synovial gene expressions of IL-17A and IL-17F.

“The biomarker findings do not reveal robust pharmacodynamics effects associated with toreforant treatment either in synovial or serum samples, although some trends are apparent,” the researchers wrote.

This phase 2 study was sponsored by Janssen Research & Development, LLC.


Boyle DL, DePrimo SE, Calderon C, et al. Toreforant, an orally active histamine H4-receptor agonist, 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 [published online February 9, 2019]. Inflamm Res. doi: 10.1007/s00011-019-01218-y