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Progress in Oral Biologics for Rheumatoid Arthritis

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 2012 Annual European Congress of Rheumatology (EULAR)

Berlin, Germany / June 6-9, 2012

Berlin - Oral therapies for rheumatoid arthritis that target very specific molecular steps in the inflammatory pathway have reached phase III trials. The data generated from these trials indicate that the anti-inflammatory activity of targeted oral agents may approach that of the targeted injectable monoclonal antibodies currently in use. Unlike the injectable agents, which typically act extracellularly to inhibit such pro-inflammatory proteins as tumour necrosis factor, the oral agents block intracellular pathways of inflammation. Like the injectable agents, the oral targeted agents may also have broad applications against other inflammatory processes, such as Crohn’s disease. Based on efficacy data so far, the most significant hurdle to regulatory approval will be the ability to show that the intracellular targets can be safely inhibited in chronic regimens.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Studies presented here at EULAR continue to generate encouraging data regarding the efficacy and safety of oral targeted therapies. New data were presented on the Janus kinase (JAK) inhibitors tofacitinib and GLPG0634 as well as on fostamatinib, a spleen tyrosine kinase (Syk) pathway inhibitor. All of these have reached or are nearing phase III trials. There are no controlled data with which to judge whether the oral agents are as effective or as safe as the injectable targeted therapies such as the tumour necrosis factor (TNF) inhibitors—which have become a mainstay in control of moderate to severe rheumatoid arthritis (RA)—but the studies are sufficiently advanced to lead many investigators to conclude that oral agents will soon be made available for routine use.

Summarizing progress, including new data presented here at EULAR, “the new orally bioavailable kinase inhibitors will impact shortly on the strategies that we employ in the treatment of RA,” predicted Prof. Iain B. McInnes, University of Glasgow, UK. If the oral agents approach the level of safety and efficacy of the injectable biologics as the current data suggest, the convenience of an oral agent is expected to provide a large clinical advantage.

Efficacy Data

Although there are as yet no direct comparisons between oral and injectable agents, the indirect data suggest that targeted oral therapies can suppress RA inflammatory activity to a degree similar of that associated with TNF inhibitors. In one double-blind trial presented at EULAR, the 513 participants were randomized to oral tofacitinib 5 mg b.i.d., 10 mg b.i.d. or placebo. However, a parallel arm in which 204 additional patients were treated with adalimumab 40 mg injected every 2 weeks provided a benchmark.

“Improvements from baseline in all 8 Short-Form 36 [quality of life (QOL)] domains were statistically significantly better with tofacitinib 10 mg b.i.d. than placebo and numerically higher than adalimumab at 3 months before rescue of non-responders,” reported Prof. Ronald F. van Vollenhoven, Karolinska Institute, Stockholm, Sweden. After 3 months, when poor responders were switched to tofacitinib according to the prespecified design of the trial, the differences quickly diminished, although there was still a significant advantage at 6 months (P<0.05) for those initially randomized to tofacitinib.

Although tofacitinib has now been evaluated in 5 phase III multicentre studies in RA, this was the first to provide a side-by-side, although non-randomized comparison to a TNF inhibitor. At month 3, the proportions of patients reporting symptom improvement was 36% in the placebo group, 64% in the group receiving adalimumab, 68% of those receiving tofacitinib 10 mg and 70% of those receiving the 5-mg dose. At 12 months, despite a switch of placebo non-responders to active therapy, those initiated on either dose of tofacitinib still did numerically better on several QOL scales, including physical functioning, than those initially randomized to placebo or adalimumab.

JAK Inhibition

Additional support for the premise that oral JAK inhibition can yield an anti-inflammatory effect commensurate with TNF inhibitors was derived from a meta-analysis of 32 placebo-controlled trials. The meta-analysis included studies with tofacitinib, adalimumab, certolizumab and etanercept, as well as non-TNF inhibitor biologics such as abatacept and rituximab. Compared by odds ratio for achieving ACR20, ACR50 and ACR70 responses at 3 or 6 months, the efficacy of the therapies was similar.

 “Both as a monotherapy and in combination with methotrexate (MTX), tofacitinib in active doses was associated with ACR20/50/70 responses that were comparable to currently available TNF inhibitors,” concluded senior author Dr. Maria Cecilia Vieira, MAPI Consultancy, Boston, Massachusetts, who presented these data during the 2012 EULAR.

The accumulating efficacy data with JAK inhibitors in RA which, in addition to tofacitinib, include ruxolitinib, baricitinib and GLPG0634, have provided compelling evidence that JAK is an appropriate target for the control of RA, but the safety data will be critical for moving these agents forward.

In a systematic review presented at EULAR on the safety of protein kinase inhibitors in RA, which included JAK inhibitors, Syk inhibitors and inhibitors of other targets, such as MAP kinase, 28 studies with >3000 participants were identified. While a broad range of adverse events were associated with the various agents, the 2 drugs with the highest rate of withdrawal for serious adverse events were masitinib (20%), a c-KIT inhibitor, and imatinib (44%), an ABL inhibitor. The lowest number of withdrawals was associated with VX-702 (3%), a MAP inhibitor, tofacitinb (7%) and the Syk inhibitor fostamatinib (6%), according to lead author Dr. Eva Salgado, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.

There were no new clinical data presented on the JAK inhibitors ruxolitinib or baricitinib at EULAR, but results of a double-blind phase II study of GLPG0634 were presented by researcher Dr. Frédéric Vanhoutte, Galapagos NV, Mechelen, Belgium. The study randomized 36 RA patients who had an inadequate response to MTX to GLPG0634 100 mg b.i.d., 200 mg q.d. or placebo. The primary end point was the ACR20 response.

“This is the first JAK inhibitor selective for the JAK1 subtype,” Dr. Vanhoutte reported. “Overall, 83% of patients on active therapy vs. 33% of placebo patients [P<0.01] achieved the ACR20 response by 4 weeks. This remarkable result includes the absence of effects on LDL.” A dose-ranging study is now underway to advance clinical trials of this agent.

Double-blind data on a JAK1/JAK2 inhibitor, currently known as LY3009104, were also presented during the 2012 EULAR. In this phase IIb trial, 301 patients with active RA on stable doses of MTX were randomized to receive placebo or one of 4 once-daily doses ranging from 1 mg to 8 mg. The study was conducted over 12 weeks.

“Onset of efficacy was rapid with statistically significant differences seen in the study end points from week 2 onwards,” reported Dr. Edward Keystone, Mount Sinai Hospital, Toronto, Ontario. The end points included ACR20, ACR50, ACR70 and the Disease Activity Score 28 (DAS28). At the 2 highest doses, 4 mg and 8 mg, 75% and 78% of the 2 groups, respectively, achieved ACR20 vs. 41% of those randomized to placebo. ACR70 was reached by 23% and 20% of those receiving the 4-mg and 8-mg dose, respectively, and 2% of those receiving placebo.

Other Targets for Inhibition

The same principle of blocking enzymatic pathways important to cytokine release is being pursued for other targets, most notably Syk. There were limited new efficacy data presented on these agents at the 2012 EULAR meeting, but the safety of fostamatinib, one of the best studied representatives of this class, was assessed. In 2 trials conducted by a team of authors from the company developing this agent, hepatic and renal function were independently evaluated for their potential to alter fostamatinib pharmacokinetics. While both studies indicated that even substantial functional impairment of these organs would not adversely affect the activity of fostamatinib, the consistency of drug levels in patients with hepatic dysfunction was the more reassuring because of the importance of this organ to fostamatinib metabolism.

Oral anti-inflammatory agents have obvious advantages for clinical application over injectable drugs if efficacy and safety are similar, as about 30% of RA patients have little or no response to TNF inhibitors. The addition of new drug classes may expand the number of patients who can be rescued with targeted therapies when the response to non-biologic DMARDs such as MTX is inadequate. Biomarkers predicting response to these agents are being pursued.


Oral targeted therapies for the control of RA appear to be approaching regulatory approval, judging from data presented here at the 2012 EULAR. Of oral agents, inhibitors of JAK and Syk pathways have reached the most advanced stages of development. Phase III trials with tofacitinib, the best studied of these drugs, continue to support the principle that intracellular mechanisms of the inflammatory cascade can be inhibited with acceptable tolerability. If follow-up data continue to support the safety of these agents, an important expansion of therapeutic options for RA can be expected.


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