JAK Inhibitors and Other Biologics Are the Future of RA Treatment

VBCR - February 2014, Volume 3, No 1 - Rheumatoid Arthritis
Wayne Kuznar

By Wayne Kuznar

San Diego, CA—Developments in therapeutics for rheumatoid arthritis (RA) have been taking place at breathtaking speed. Biologic agents have greatly increased the ability to improve the lives of patients with RA, and integrating their use with conventional agents will lead to optimal patient outcomes, said Ronald van Vollenhoven, MD, PhD, at the Rational Approach to Treating RA symposium presented during the 2013 American College of Rheumatology (ACR) meeting. Expect additional biologic agents, biosimilars, and oral agents with efficacies comparable to biologics, he said.

Nine biologic agents, acting at various receptor sites and with different targets, are currently approved for the treatment of patients with RA. Targets include tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, T-cells, and B-cells. “By using the biologics, we are very specifically interfering with immune inflammatory mechanisms, and we’re doing that at several different levels,” said Dr van Vollenhoven, Professor and Chief of the Unit for Clinical Therapy Research, Inflammatory Diseases, Karolinska Institute, Stockholm, Sweden.

In the treatment of patients with RA, dual goals are symptom relief and, in the long run, prevention of structural damage, he said. The combination of methotrexate with an anti-TNF drug or other biologic agent in early RA is superior to monotherapy in achieving an ACR 20% symptom improvement (ACR20) response (approximately 70% vs 50%, respectively). Furthermore, ACR70 responses are more frequent and remission is achieved about twice as often with combination therapy compared with single-agent strategy.

Radiographic joint damage is also less progressive with combination strategy. Significantly fewer patients in a TNF-only arm have new erosions compared with methotrexate monotherapy, and the best radiographic result is achieved with the combination strategy, which is evidence of prevention of structural damage.

Methotrexate acts as the cornerstone of RA therapy, said Dr van Vollenhoven. Adding injections of a corticosteroid every 2 weeks to methotrexate has shown to be an effective, although inconvenient, strategy to improve response rates. This observation led to the design of a study known as OPERA, in which 180 patients at 14 Danish hospitals were treated with adalimumab (Humira) plus methotrexate and intra-articular triamcinolone or methotrexate and triamcinolone as first-line therapy (Hrslev-Petersen K, et al. Ann Rheum Dis. 2013 Mar 7. Epub ahead of print). The addition of adalimumab significantly improved the Disease Activity Score in 28 joints (DAS28) C-reactive protein (CRP), the remission rate, function, and quality of life (Table 1).

table_1_OPERA_p9

The 2001 Swefot (Swedish Pharmacotherapy) trial included patients with early RA, who were given methotrexate up to 20 mg weekly (van Vollenhoven RF, et al. Lancet. 2009;374:459-466). At 3 to 4 months, patients who did not achieve a DAS28 <3.2 were randomized to receive either sulfasalazine (Azulfidine) and hydroxychloroquine (Plaquenil) or the anti-TNF agent infliximab (Remicade).

Compared with the conventional therapy, infliximab added to methotrexate improved the rate of a good response based on the European League Against Rheumatism (EULAR) criteria at 12 months, from 25% to 39% (P = .016). At 2 years, anti-TNF therapy combined with methotrexate was still superior to conventional therapy on this measure, but the difference was no longer significant (P = .26). The difference between the 2 groups narrowed because the rate of good response in patients receiving conventional therapy increased to 31%; the response to infliximab also improved to 43%, noted Dr van Vollenhoven.
On an intent-to-treat basis, 2-year radiographic data of patients in the Swefot trial showed significantly less disease progression in patients taking infliximab compared with patients taking conventional therapy (P <.02).

“In the direct comparison of an anti- TNF therapy against a very well-established and good combination of disease-modifying antirheumatic drugs, we see a clinical benefit that is proven after 1 year, and a radiological benefit that is proven after 2 years,” said Dr van Vollenhoven.

Predicting which patients require aggressive therapy versus moderate therapy would enable individuali­zation of treatment. Baseline serum samples of 235 patients enrolled in the Swefot trial were tested with the 12 biomarker disease-activity assay called Vectra DA. None of the 5 patients with a low baseline multibiomarker disease activity (MBDA) score and only 1 of 29 with a moderate MBDA score at baseline had radiographic disease progression compared with 42 of 201 with a high baseline MBDA score. CRP did not predict disease progression.

Future Developments
“In the coming 2 or 3 years, we’re going to learn a lot about IL-17 as a target,” said Dr van Vollenhoven. IL 17 is intricately involved in the regulatory mechanism for T lymphocytes. Clinical and experimental evidence with IL-17 blockade indicates improved ACR responses, DAS28 and DAS28-erythrocyte sedimentation rate (ESR) scores, and CRP levels compared with placebo in patients with active RA. Promising results have also been achieved in patients with psoriatic arthritis treated with IL-17–targeted therapy.

Janus kinase (JAK) is a family of intracellular non–receptor tyrosine kinases that transduce cytokine-mediated signals. “If you block the JAK enzymes, you downregulate the inflammation pathways, because it ends up not being able to stimulate the inflammatory gene expression,” he said.

Oral JAK inhibitors being developed for the treatment of patients with RA are tofacitinib (Xeljanz)—approved in the United States—VX-509, baricitinib, and GLPG0634 (Table 2). Each blocks a different JAK enzyme, which could potentially result in differential efficacy and safety.

table_2_oral_jak_inhibitors_p10

In a phase 2b study, the percentage of patients achieving ACR20, ACR50, and ACR70 responses, a DAS28-CRP <2.6, and a CDAI ≤2.8 were superior with baricitinib in a dose-dependent manner, compared with placebo at 12 and 24 weeks. Baricitinib, which has JAK1 and JAK2 as its main targets, has since progressed to a phase 3 study.

Tofacitinib’s targets are JAK1 and JAK3. In the ORAL Standard trial, 717 patients with RA who did not respond to methotrexate were randomized to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of ada­limumab once every 2 weeks, or placebo with continuation of methotrexate (van Vollenhoven R, et al. N Engl J Med. 2012;367:508-519).

At 6 months, the ACR20 response rates were superior with 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and with adalimumab (47.2%) compared with placebo (28.3%; P <.001 for all). The active-treatment groups also had greater reductions in the Health Assessment Questionnaire Disability Index score at month 3 and higher percentages with a DAS28-4(ESR) <2.6 at month 6 compared with placebo.

“It was not a head-to-head trial, but side-by-side, it looks like we’re getting the same kind of efficacy with [the JAK inhibitor] tofacitinib versus adalimu­mab, the anti-TNF agent,” said Dr van Vollenhoven.

In terms of safety, there were more treatment-emergent adverse events, especially gastrointestinal events and infections, with tofacitinib and adalimumab compared with placebo. Tofacitinib was also associated with a reduction in neutrophil counts. “What is different with tofacitinib, and probably other JAK inhibitors, is that we will probably have to monitor them, by taking blood counts,” he said. “They can cause elevations in liver enzymes and they can also cause cytopenias.”

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