SAN DIEGO -- Bruton's tyrosine kinase (BTK) continues to be on industry's radar as a drug target in rheumatology, with multiple studies of candidate agents being presented at the American College of Rheumatology's annual meeting here.
BTK is a key factor in B cell development and thus is involved both in immunology and in malignancies arising from abnormal B cell proliferation. Not long after BTK was discovered some 25 years ago, it was including rheumatoid arthritis, prompting an .
However, early animal experiments drew industry's attention away from rheumatologic disease and toward the more lucrative field of hematologic malignancies. Ibrutinib was the first BTK inhibitor to reach the market, approved in 2013 for mantle cell lymphoma and later for a including chronic lymphocytic leukemia, graft-versus-host disease, and Waldenstrom's macroglobulinemia. Another BTK inhibitor was approved just last week: acalabrutinib (Calquence) for mantle cell lymphoma, and dozens of trials in various hematologic malignancies are underway.
But the effectiveness of drugs targeting B cells in inflammatory diseases -- such as rituximab, which simply inactivates them -- has had researchers looking at BTK as perhaps a sharper tool for modulating B cell activity in rheumatologic conditions.
And it's not just small university spinoffs who've been interested. Companies reporting data on BTK inhibitors over the past few years include , , , , , , , , and .
Most of these reports involved preclinical data. Genentech's GDC-0853 and Gilead's GS-4059 have completed phase I trials, and at last year's meeting, a was reported: a 47-patient, randomized, placebo-controlled trial testing this agent as an add-on to methotrexate in rheumatoid arthritis over 4 weeks.
Those results were a bit disappointing: although there were trends toward greater achievement of ACR20 responses (20% reduction in symptoms according to ACR criteria) with the BTK inhibitor, the difference from placebo was not statistically significant at week 4. No significant differences in ACR50 or ACR70 responses were seen either.
Although the trial may have been too small and too short to expect significant differences on these measures, and no safety issues were identified, Celgene dropped the BTK program.
Nevertheless, studies this year at ACR reported encouraging data for BTK inhibitors in models of lupus complications and rheumatoid arthritis. No new clinical data were on the agenda here, but a is listed on Clinicaltrials.gov as ongoing.