A new oral drug – B-cell inhibitor, fenebrutinib – has a similar effect to the market-leading TNF inhibitor adalimumab in patients with rheumatoid arthritis who haven’t responded to other RA medications, a clinical trial shows.
Fenebrutinib is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor that targets B-cells, preventing their activation through the B-cell antigen receptor signalling pathway. Fenebrutinib is not currently TGA-listed for any indication in Australia.
BTK inhibitors have demonstrated utility for the treatment of multiple sclerosis, but clinical evidence of their efficacy for rheumatoid arthritis patients is currently limited.
In a phase II clinical trial sponsored by Roche, the BTK inhibitor therapy was tested in two patient populations with rheumatoid arthritis: those who had had an inadequate response to methotrexate, and those who had failed prior TNF inhibitor therapy.
Around 580 patients with seropositive active RA were randomised into the study to receive either fenebrutinib, adalimumab (in the first patient group) or placebo. Doses of fenebrutinib ranged from 50 mg to 150 mg once daily, or 200 mg twice a day.
At 12 weeks, based on ACR50 response rates, fenebrutinib was comparable in efficacy (and had a similar safety profile) to adalimumab with a 200 mg twice daily dose for patients with an inadequate response to methotrexate.
However, fenebrutinib had a relatively slower onset of response than adalimumab, the study showed.
Professor Stephen Hall, a rheumatologist at the Cabrini Medical Centre in Melbourne, said fenebrutinib provided reasonable benefit to refractory RA patients, although it was not a dramatic response.
He said fenebrutinib may well have a role to play in the treatment of rheumatoid arthritis, but where exactly it fits in to clinical practice would depend on larger phase III studies. Based on its mechanism of action, he said it could be useful for patients who have failed other treatments.
“This is the first substantial study of fenebrutinib,” said Professor Hall. “The observed response gives enough encouragement to test the drug in bigger trials.”
Professor Hall said subsequent studies should also include seronegative patients, as well as MRI imaging to look at the trajectory of response.
Professor Peter Youssef, a rheumatologist at Royal Prince Alfred Hospital in Sydney, agreed, adding that some biological agents – including the other B-cell inhibitor, Rituximab – tended to work better in seropositive patients.
“This trial selected a group of seropositive patients, so we don’t know if [fenebrutinib] will work in seronegative patients,” he said.
Professor Youssef said a phase III study longer than 12 weeks was needed to see whether fenebrutinib remained effective over time and if other side effects were reported, such as low immunoglobulin levels that would predispose patients to bacterial infections.