Conference Coverage

Analysis provides key questions – and answers – regarding future of JAK inhibitors for RA




MAUI, HAWAII – Now is a good time to assess the future of the Janus kinase inhibitor class of oral small-molecule medications for rheumatoid arthritis based on new evidence that addresses many of the key questions rheumatologists have about these agents, Dr. Roy Fleischmann said at the 2016 Rheumatology Winter Clinical Symposium.

Baricitinib is likely to win Food and Drug Administration approval within a year, and would join tofacitinib (Xeljanz) as the second Janus kinase (JAK) inhibitor. A once-daily formulation of tofacitinib also was recently approved. Additional investigational agents, filgotinib and ABT-494, are headed for phase III testing, noted Dr. Fleischmann of the University of Texas Southwestern Medical Center and co–medical director of the Metroplex Clinical Research Center, Dallas.

Dr. Roy Fleischmann Bruce Jancin/Frontline Medical News

Dr. Roy Fleischmann

Here’s what rheumatologists want to know about the Janus associated kinase inhibitors, or Jakinibs:

Does Jakinib monotherapy look like a viable strategy?

Yes, according to Dr. Fleischmann, who pointed to the RA-BEGIN baricitinib trial and the DARWIN2 filgotinib trial, both presented at last fall’s American College of Rheumatology annual meeting in San Francisco.

Dr. Fleischmann presented the RA-BEGIN results at the American College of Rheumatology meeting. In this randomized trial conducted in methotrexate-naive rheumatoid arthritis patients, baricitinib 4 mg/day monotherapy outperformed methotrexate in terms of ACR response and demonstrated efficacy similar to baricitinib plus methotrexate, but with fewer side effects. Radiographic disease progression was significantly greater over 52 weeks with methotrexate than with baricitinib monotherapy, and significantly greater with baricitinib monotherapy than with combination therapy. However, baricitinib monotherapy was as effective as baricitinib in combination with methotrexate in slowing disease progression among patients who had elevated high-sensitivity C-reactive protein before treatment that normalized in response to therapy.

“So if baricitinib is approved and is available, I would use it as monotherapy initially and watch the C-reactive protein. If it drops to normal I’m fine, and if it doesn’t I’d add methotrexate for combination therapy,” according to the rheumatologist.

The randomized DARWIN2 trial included 283 methotrexate inadequate responders and showed that filgotinib is also effective as monotherapy.

“Tofacitinib, baricitinib, and filgotinib all work as monotherapy, and why shouldn’t they? There are no antibodies because these are small molecules,” Dr. Fleischmann commented.

A key safety finding in RA-BEAM, in his view, was that herpes zoster occurred in 1.4% of baricitinib-treated patients as well as in 1.2% of the adalimumab (Humira) arm.

“The message here, I think, is that we should be thinking about zoster in all patients with rheumatoid arthritis,” he said.

Is there a clinically meaningful efficacy difference between the Jakinibs?

Not so far, but as yet there have been no head-to-head trials.

How about in terms of safety?

“Safety may be the difference between these drugs. Efficacy doesn’t seem that different,” he said.

Based upon the clinical trials data to date, which involves hundreds of patients per Jakinib, it appears there is a hint of a difference, with less lymphopenia and anemia being seen with filgotinib, the most JAK 1–selective of the Jakinibs. Baricitinib is a JAK 1/2 inhibitor, tofacitinib a JAK 3/1/2 inhibitor, and ABT-494 is relatively JAK 1–selective. But definitive answers regarding comparative safety must await the creation of multi-thousand-patient postmarketing registries, in Dr. Fleischmann’s opinion.

Which is more effective: a Jakinib or a tumor necrosis factor inhibitor?

Only one clinical trial has addressed this question with sufficient power to yield a statistically significant answer. This was the RA-BEAM trial presented at the 2015 ACR meeting. RA-BEAM was a randomized head-to-head study of baricitinib plus methotrexate versus adalimumab plus methotrexate in 1,305 methotrexate inadequate responders. Baricitinib was the clear winner, with week 24 ACR 20 and ACR 50 responses of 70% and 45%, respectively, compared with 61% and 35% for adalimumab. Particularly impressive was baricitinib’s outperformance of adalimumab on the pain component of the ACR score.

“This is the first study to show a Jakinib plus methotrexate is actually superior to a TNF inhibitor plus methotrexate. And adalimumab is a really, really good drug. Is it a big difference? It’s not tremendous, but it’s a difference. Is it clinically significant? In that extra 9%-10% of patients, it obviously is; in most it’s probably not,” Dr. Fleischmann said.

Will an oral Jakinib be the first drug physicians prescribe in rheumatoid arthritis patients, or the last?

“The data so far shows that Jakinib monotherapy is very viable, as opposed to biologic monotherapy, which is viable but less so. RA-BEAM showed baricitinib was superior to a TNF inhibitor, and there are studies to suggest but don’t prove that tofacitinib is, too,” he said.

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