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ATLANTA -- An orally available inhibitor of Bruton's tyrosine kinase (BTK), an important regulator of B cell proliferation and myeloid cell activity, was modestly effective for treating rheumatoid arthritis (RA) and apparently safe in a phase II trial reported here.

At the highest dose (200 mg twice daily), 34.5% of patients not responding adequately to methotrexate (MTX-IR) achieved the primary endpoint of ACR50 response (50% reduction in symptoms by the American College of Rheumatology [ACR] criteria) with the investigational drug fenebrutinib, compared with 14.5% of a placebo group, reported Stanley Cohen, MD, of Metroplex Clinical Research Center in Dallas.

Speaking at ACR's annual meeting, Cohen said fenebrutinib showed clear signs of efficacy and adequate safety in this early study. The drug also was superior to placebo in patients with inadequate responses to tumor necrosis factor inhibitors (TNF-IR), at 25.0% versus 12.0% (P<0.2, prespecified as the threshold for meeting this endpoint).

One disappointment, however, was fenebrutinib didn't outperform adalimumab in the MTX-IR group, in which the latter drug produced ACR50 responses in 36.0%. This was specified as a key secondary endpoint. Of course, adalimumab was not given to the TNF-IR group.

BTK as a target in RA has an interesting history. On paper it sounds like a reasonable point of attack in the disease. As Cohen explained, it's part of the B-cell signalling pathway that leads to antibody production as well as cytokine release, plus it mediates signalling in myeloid cells in response to binding of antibody molecules' Fc proteins. The latter, too, stimulates cytokine as well as chemokine release.

All of that adds up to an apparent role in promoting autoimmune inflammation. And yet, the first BTK inhibitor to reach the market, ibrutinib (Imbruvica), did so not for inflammatory disease, but for hematologic malignancies. Early in its development, there was , but if clinical studies were ever done they were never listed on Clinicaltrials.gov nor published.

And one bit of clinical information that did see print was a case report of .

Nevertheless, BTK inhibition in general has gotten considerable attention from drug developers in the rheumatology space. At the ACR's 2017 meeting, several groups reported early results (preclinical and phase I) with non-ibrutinib BTK inhibitors, which have the advantage of oral activity. The only other class of oral targeted RA therapy are the JAK inhibitors, which come with an array of restrictions and side effects that make the idea of a different mechanism more attractive.

So now comes fenebrutinib, apparently the first such agent to complete a phase II trial in RA. (Results in multiple sclerosis for another, evobrutinib, were reported earlier this year. And fenebrutinib has also been tested in systemic lupus erythematosus, in another phase II trial . Those results were negative, which neither the investigators nor other rheumatologists could explain.)

In the study Cohen presented, three doses of fenebrutinib were tested in the MTX-IR group, ranging from 50 mg once daily to 200 mg twice daily, as well as placebo and 40 mg adalimumab by injection every other week. Forty patients got the lowest fenebrutinib dose, while all the other arms each had 110 patients. The TNF-IR group, which totaled 120 patients, was randomized 1:1 to placebo or 200 mg fenebrutinib twice daily. Most patients were recruited in Eastern Europe; approximately one-third were from Latin America, and a handful were in North America.

The treatment period was 12 weeks. Completion rates ranged from 92% to 97% in the MTX-IR portion of the study, and 90%-98% in the TNF-IR groups.

Cohen also reported rates of ACR20 and ACR70 responses (20% and 70% reductions in symptoms, respectively). In both MTX-IR and TNF-IR groups at the 200-mg twice daily dose, rates were comparable to those seen with other biologic and quasi-biologic RA drugs: roughly 60% for ACR20 and 15% for ACR70, which might be expected to be higher with treatment continuing beyond 12 weeks. Adalimumab in the MTX-IR group achieved slightly higher response rates, but the difference from fenebrutinib at 200 mg twice daily was not significant.

Other outcomes, such as DAS28-CRP scores and erythrocyte sedimentation rate, also demonstrated that fenebrutinib was more effective than placebo. Few patients achieved clinical remission but Cohen said that was expected given the short treatment period.

For safety, Cohen said fenebrutinib showed nothing of great concern. Infections were infrequent and no more common than with placebo. Grade 3-4 adverse events were somewhat more frequent with the highest dose of fenebrutinib relative to adalimumab (eight vs four out of 110 patients in each group) but Cohen was not bothered, especially since infections with adalimumab were considerably more frequent than with placebo or any dose of the BTK inhibitor.

One death occurred in the study, a myocardial infarction in a patient taking the high dose of fenebrutinib.

Cohen did note that fenebrutinib at the higher doses was occasionally associated with increased liver enzymes -- affecting three patients at the 200-mg BID dose -- but these resolved quickly, he said. No significant hematological or renal effects were seen.

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