JAK Inhibitors 2013 – A Progress Report

November 11, 2013

ACR 2013: Latest results from continuing trials of the tofacitinib show the most effective dosages for RA, good news about safety, but a warning about an age difference.

New results are coming in from continuing effectiveness and safety trials of the first janus kinase (JAK) Inhibitor – tofacitinib (Xeljanz) -- approved in 2012 to treat moderate to severe rheumatoid arthritis (RA). These provided a bevy of presentations at the 2013 annual meeting of the American College of Rheumatology.

Among them:

•    A 10-mg dose appears most effective, and may work as monotherapy.  The news from a special session on JAK inhibitors in RA was that high (10 mg), medium (8 mg), and low (5 mg) doses of tofacitinib are all effective in RA patients who have had an inadequate response (or intolerance) to methotrexate.

“However, in phase 3 studies the highest dose, 10 mg, had the most effects on disease activity and quality of life, and outperformed methotrexate as monotherapy,” said Iain B. McInnes MD in a wrap-up of the latest clinical data JAK inhibitors in RA. McInnis is chair of medicine and head of the Institute of Infection, Immunity and Inflammation at the University of Glasgow.

•    The higher dose levels are not more dangerous. A poster showing pooled data from two open-label, long-term extension studies (LTEs) in almost 5,000 patients revealed no extra risks among those who stay on either 5 mg or 10 mg of tofacitinib BID for up to five years -- either in monotherapy or in combination therapy with conventional disease modifying antirheumatic drugs (DMARDs).

“If you stay on the drug long-term, whatever dose, you get no additional side effects, no increase in lab abnormalities, they stay stable over time” according to lead author Jrgen Wollenhaupt MD professor of medicine and director of Rheumatology at the University of Hamburg, and colleagues. “We also found that the number of adverse events, serious adverse events, or malignancies remain stable, so from year to year there is no additional risk,” said Wollenhaupt, the lead author, in an interview at the conference.

The study among 4,827 patients randomized in previous phase 2 and phase 3 clinical trials, using 10-mg and the 5-mg regimens approved in the US, also found the two dosage levels comparable in safety and efficacy.

A total of 1,246 patients (25.8%) discontinued tofacitinib, due to adverse events (AEs) (n=616, 12.8%), most commonly infections (55.8%) or to lack of efficacy (2.3%).

“Even if you treat for a longer period with the double dose, there are no additional safety signals in terms of lab abnormalities or infections, and no signals when the two doses are used in mono or combination therapy,” Wollenhaupt added. “Also, the rates of adverse events per 100 patient years, such as malignancies and herpes zoster rates, are comparable. But we could not determine if the higher dose was more effective.”

•    However, age is a risk factor. Safety data from a post-hoc, pooled analysis of five phase 3 studies and two ongoing LTEs compared the two doses in 3,439 older and younger patients. Those over age 65 had an increased risk of discontinuation due to AEs. The analysis concluded that the benefit-risk profile of tofacitinib must be taken into account when considering treatment of older RA patients.

Other JAK-related news from ACR:

•    Another poster revealed data showing improvements in physical function and health-related quality of life among 1.165 patients in three randomized controlled phase 3 clinical trials of tofacitinib mono- or combination therapy (including TNF inhibitors). In particular, patients reported improvements in the physical, pain, and vitality domains after three and six months, reported the team from Stanford University and elsewhere, led by rheumatologist Vibeke Strand. All patients had previously had an inadequate response to DMARDs or non-biologics.

•    A late-breaking abstract of a proof-of-concept study from the Netherlands among 91 patients taking varying doses of a new JAK molecule, GPLG6034 found it are well-tolerated compared with a placebo. The data also suggest maximum efficacy was achieved with a dose of 200 mg/day. Larger 24-week studies in RA patients are evaluating optimal doses of GPLG6034 for efficacy and safety.

•    Another new selective JAK inhibitor, baracitinib, is currently in clinical trials for RA. A 12-week dose-ranging study crried out in Japan appeared to find clinical efficacy. Retrospective analysis of Phase 2b data by Edward Keystone MD of the University of Toronto and coworkers found that early non-response to the drug may be a useful predictor of prognosis.