Novel Oral Inhibitors of Select Enzymatic Pathways in Rheumatoid Arthritis Inflammation

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 - 75th Annual Meeting of the American College of Rheumatology

Chicago, Illinois / November 5-9, 2011

Chicago - Small-molecule inhibitors of enzymatic pathways that control inflammation in rheumatoid arthritis (RA) are advancing rapidly in clinical trials and are expected to generate the next major evolution in targeted therapy. The most advanced of these inhibitors, all of which are being developed as oral agents, are in late-stage phase III studies. Not the least important aspect of these agents is that they promise to provide a wider array of therapeutic targets, increasing options for those individuals who do not respond or who are intolerant to the current biologics. The development of a growing array of oral therapies is also expected to be well accepted by many of those patients who are now dependent on intravenous drug infusions for disease control. Although the introduction of TNF inhibitors was a critical advance for the levels of sustained disease control they made possible in patients with moderate-to-severe disease, small-molecule inhibitors are poised to greatly simplify highly effective targeted therapy.

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

New data presented here at the 2011 ACR meeting have documented substantial progress toward the development of a wide array of new oral biologic therapies that are highly targeted against very specific pathways of inflammation in rheumatoid arthritis (RA). In addition to efficacy, the safety data, which are critical for immunomodulating therapies, have been encouraging for several agents now entering late-phase trials. Here at the ACR, interim 1-year results from a 2-year phase III study were presented on the most advanced of these agents.

SCAN Study: JAK Mode of Action

The excitement generated by these drugs also stems from their ability to halt activity of key mediators of the autoimmune inflammatory response such as lymphocytes, monocytes and neutrophils. The promise of the oral agents may be best represented by the 1-year phase III data generated by the SCAN study with tofacitinib, an oral Janus kinase (JAK) inhibitor. The JAK signalling pathway is important to signal transduction of a variety of pro-inflammatory cytokines, including interleukins (IL) 2, 7, 15 and 21, and its inhibition has provided potent modification of the autoimmune-related inflammatory activity in experimental RA studies. In the SCAN study, 797 patients on a stable dose of methotrexate (MTX) were randomized to tofacitinib 5 mg b.i.d., 10 mg b.i.d. or placebo. However, 2 placebo groups were created: in 1 of these, patients were switched to the 5-mg regimen at 6 months; in the other, patients were switched to the 10-mg regimen. Rescue in either placebo group at 3 months was permitted if there was less than a 20% reduction from baseline in swollen or tender joint counts.

“At the 1-year interim evaluation, there was a significant reduction in RA efficacy measures for every outcome measured for the 10-mg dose vs. those in the placebo groups,” reported Prof. Désirée van der Heijde, Leiden University Medical Center, The Netherlands. This included protection against structural damage as measured with the modified Total Sharp Score, the primary objective. While the 5-mg dose was not superior to placebo (all groups continued to receive MTX), it was superior for ACR20, another measure of efficacy used in this study. The other measures that favoured the 10-mg dose over placebo included the HAQ-DI and DAS28-4(ESR) scores.

Protection Against Structural Damage

While the symptomatic benefits of the oral JAK inhibitor over a stable dose of MTX validates the activity of this agent, the more impressive result was the protection against structural damage, which is increasingly being recognized as the most important measure of efficacy in a progressive disease. In fact, the most important advantage of biologics, including the older TNF inhibitors, over traditional disease-modifying antirheumatic drugs (DMARDs) is their potential to halt disease progression, not just control symptoms. The ability of an oral biologic to demonstrate this protection against disease progression is highly encouraging, particularly because these agents may be better tolerated as well as more convenient than injectable agents.

“The adverse events (AEs), including the serious AEs and serious infection events, were well distributed across the 4 arms of the study,” Prof. van der Heijde told delegates. Although previous studies have also associated tofacitinib with an encouraging safety profile, she observed that there were no new safety concerns with 1-year follow-up in a relatively large trial.

Complete safety analyses will not be available until the ongoing 2-year study is completed, but long-term data collated from several extension studies with tofacitinib provided similar reassurance. In the pooled data of 3227 patients with a total treatment duration of 3118 patient-years, the most frequent AEs were nasopharyngitis (10%), upper respiratory infection (7.3%) and urinary tract infection (4.6%). Senior investigator Prof. Jürgen Wollenhaupt, University of Hamburg, Germany, reported that serious infection events were only recorded in 2.9% of patients.

Results from a comparative study of tofacitinib and adalimumab in patients who also received MTX were presented here at the ACR. They demonstrated comparable efficacy for ACR20, ACR50 and HAQ-DI. Presented by Dr. Ronald F. van Vollenhoven, Karolinska Institute, Stockholm, Sweden, the data indicated safety profiles similar to those associated with each agent in previous studies. This study did not compare the agents for structural damage, which will be a critical end point for definitive studies.

Other Promising Oral Agents on the Horizon

Other promising oral small-molecule agents are also moving forward. They include new safety data on fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, which is reaching phase III studies, and LX2931, an inhibitor of sphingosine-1-phosphate lyase (S1PL) now in phase II studies. Like JAK, Syk mediates function of cell receptors important to immune activation. S1PL also mediates signal transduction important to inflammation, particularly in regard to lymphocyte trafficking. Both targets have long been pursued in experimental models and inhibitors of these enzymes are now showing substantial promise as clinical trials advance.

The new data with fostamatinib were restricted to long-term safety, a critical factor before advancing to phase III trials. Encouraging efficacy data from phase II trials such as TASKiL 1, 2 and 3 have previously been reported. Dr. Arthur Kavanaugh, University of California, San Diego, summarized the pooled extension safety data from 803 patients with a cumulative 1083 patient-years of exposure. The most common AEs were diarrhea (27.4%), hypertension (22.5%) and urinary tract infections (12.7%). The rates of serious infection events (3.4%) and gastrointestinal events (1.8%) were both low. A concern was raised that the highest rates of treatment discontinuations and dose reductions were in a study that enrolled patients refractory to TNF inhibitors. However, based on both the efficacy and safety observed so far, Dr. Kavanaugh indicated that phase III studies are warranted. “There were no significant new safety signals in the long-term exposure to fostamatinib, which is an encouraging result as this molecule enters the registration trials,” Dr. Kavanaugh confirmed.

In the multicentre phase II study of LX2931, 208 patients with active RA on a stable dose of MTX were randomized to receive 70 mg, 110 mg or 150 mg of the S1PL inhibitor or placebo. The patients were compared for ACR20, ACR50 and ACR70 as well as DAS28-4 response at 12 weeks. In addition to safety analyses, a variety of biomarkers of inflammatory activity, including blood lymphocyte count, were measured.

“LX2931 did demonstrate activity relative to placebo, particularly at the higher doses,” reported Dr. Roy M. Fleischman, University of Texas Southwestern Medical School, Dallas. Specifically, the advantage of the 150-mg dose over placebo for ACR20 was statistically significant (60% vs. 44.3%; P=0.038). However, even though Dr. Fleischman characterized the safety profile as “favourable,” he expressed some caution about the future of this agent, which appeared to be less robust than other biologics that have reached this stage of clinical testing. Nevertheless, he did conclude that the activity of a S1PL inhibitor is representative of an ever increasing range of targets for anti-inflammatory effects.


Oral small-molecule inhibitors of pro-inflammatory mediators have demonstrated activity and safety in RA control. If approved, these agents have the potential to provide a major advance in the treatment of autoimmune diseases. While there is a potential for these agents to be both more effective and better tolerated than TNF inhibitors, even a comparable efficacy and safety profile would confer a substantial advantage over injectable drugs. Importantly, the data so far validate the premise that enzymatic pathways of inflammation are targetable, providing the potential for a large expansion in options for the control of RA and other inflammatory diseases.

Note: At press time, tofacitinib, fostamatinib and LX2931 are not approved in Canada.

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