medwireNews: Evobrutinib does not improve treatment response in patients with rheumatoid arthritis (RA) who do not respond adequately to methotrexate, phase IIb study data indicate.
In the trial, presented at the ACR Convergence 2020 virtual meeting, the primary endpoint of ACR20 response rate at 12 weeks was not significantly different across the three evobrutinib doses tested versus placebo.
The response rates among the RA patients were 59.2% for the 98 patients randomly assigned to receive evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, at a dose of 25 mg once daily, 59.6% for the 99 given evobrutinib 50 mg twice daily, and 51.0% for the 96 patients given evobrutinib 75 mg once daily. This was comparable to the 49.5% rate seen among the 97 patients receiving placebo.
Presenter Maya Buch (University of Manchester, UK) described the findings as “unexpected,” given that evobrutinib is a highly selective molecule and there have been positive findings reported with the BTK inhibitor fenebrutinib.
She commented on the high placebo response, which they looked into “in quite a bit of detail,” but “we couldn’t find any specific reason why the placebo response was so high.”
The patients had previously received methotrexate 7.5–25.0 mg/week for at least 16 weeks or a stable dose for at least 8 weeks but had not received biologic DMARDs. Despite methotrexate therapy, the patients had active disease at the start of the trial with at least six tender and swollen joints.
Although the study did not meet the primary endpoint, there was “nominally significant” improvement with evobrutinib at all doses versus placebo for low disease activity (LDA) rates and remission rates.
Rates of DAS28-hsCRP of 3.2 or below ranged from 20% to 24% among evobrutinib-treated patients, compared with 7.2% among placebo-treated patients, while a DAS28-hsCRP below 2.6 was achieved by 10% in each evobrutinib treatment group versus 1%, respectively.
Buch noted that there was no dose effect on these response rates and there was no significant difference between evobrutinib and placebo on magnetic resonance imaging (MRI) outcomes, such as synovitis and osteitis, in a subset of patients assessed.
She commented, however, that “placebo scores in the MRI patient subset were not consistent with other studies, showing greater improvements in synovitis and osteitis, and less progression of erosions than typically reported.”
Evobrutinib was generally well tolerated at all doses, with no significant difference in treatment-emergent adverse events, and adverse events of grade 3 were infrequent, being reported in seven patients taking evobrutinib versus two of those taking placebo. There was one grade 4 hypersensitivity adverse event but this was unrelated to treatment.
“Whilst targeting BTK seems safe and well tolerated, this did not appear to be a significantly effective approach in improving the signs and symptoms of patients with rheumatoid arthritis,” Buch commented.
She added: “We were seeing a biological effect, we were seeing some clinical effect but why it wasn’t to the degree that was expected and the absence of dose response, I think is somewhat […] still inexplicable.”
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