Prof Peter Nash

Evidence is lining up for the likely fourth JAK inhibitor – with filgotinib shown to help treatment-refractory patients with moderate to severe active rheumatoid arthritis achieve a clinical response.

A randomised controlled trial, published in JAMA, compared filgotinib at 100mg or 200mg once daily to placebo in 448 adult patients from 114 sites internationally, including Australia.

Patients in the three groups had previously had an inadequate response or intolerance to at least one biologic and 23% had failed three bDMARDs.

Patients were able to continue on stable doses of conventional dMARDs, glucocorticoids or NSAIDs during the study period.

The study found ACR20 response rates were higher at 12 weeks with the JAK1 inhibitor (66% for 200 mg, 57.5% for 100 mg) than placebo (31.1%).

The benefit of filgotinib was seen in all patients regardless of treatment history including those who had previously been treated with three or more biologics.

Patients receiving filgotinib also had improved scores on secondary outcomes including the HAQ-Disability Index, Clinical Disease Activity Index and Simplified Disease Activity Index.

Infections were reported in just over a third of patients (34.0 – 36.1%) on filgotinib compared to 25.7% of the control group, but serious infections were rare (<2.0%).

There were also some elevations of laboratory measures including creatine kinase and hepatic transaminases.

Associate Professor Peter Nash, a triallist in filgotinib studies, told the limbic that the drug, similar to the other JAK inhibitors, appeared to have good efficacy in a difficult-to-treat patient population.

He said the number needed to treat to achieve one DAS-28 CRP remission was just over three and the number needed to harm (cause a serious adverse event) was about 25.

“The JAKs are clearly here to stay because they have now had two studies where a JAK inhibitor plus methotrexate has beaten the gold standard which is adalimumab plus methotrexate in rheumatoid arthritis.”

“The data shows they have now got something like 15-20% of the Australia RA market – within two years. They are getting 30% plus of patients who are failing methotrexate go direct to a JAK and 30% of people failing a biologic go directly to a JAK.”

Widespread use across indications

He said the JAK inhibitors were now also being used for ulcerative colitis, psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata and there was data in ankylosing spondylitis.

Safety issues were manageable, for example, by taking care in patients with known risk factors including a past history of VTE or those on COX-2 inhibitors.

“Zoster is an issue and if we could get the new killed vaccine Shingrix out of America, we could put an end to that risk as well.”

He said that any infection risk attributed to RA treatments was much higher with corticosteroids.

“So if you control the disease you get people off corticosteroids and reduce their infection risk, osteoporosis risk, and cardiovascular risk, etcetera.”

He said the JAK inhibitor upadacitinib was due to launch in the US in the next few weeks.

“I think that people have to realise that JAKs are not the same. Each one has its own individual fingerprint and because efficacy has been similar amongst the group that it’s really going to boil down to any safety advantages one over the other.”

“In the most recent published study, upadacitinib might have the best rates of remission, tofacitinib has been around the longest with a 10-year safety update and baricitinib has this VTE issue that needs to be resolved.”

An editorial in JAMA said postmarketing surveillance studies will clarify the potential harms of filgotinib and whether its safety profile differs from tofacitinib or baricitinib.

“Having more viable treatment options for refractory RA is highly desirable. RA is a heterogeneous disease, and a significant proportion of patients with RA are either nonresponders or are intolerant to all current therapies,” the editorial said.

“However, to help promote use, these oral JAK inhibitor therapies will need to be priced at levels comparable with the conventional synthetic DMARDs rather than the biologics.”