Arthritis Clinical Trial Results RevealedArthritis Clinical Trial Results Revealed

Washington, DC—Late-breaking research presented at the recent annual conference of the American College of Rheumatology and the Association of Rheumatology Health Professionals highlighted results from phase 2 and 3 clinical trials testing experimental agents to treat arthritis. Candidates ranged from the nonspecific anti-inflammatory chondroitin sulfate to biologic agents that target specific immune response modifiers.

For rheumatoid arthritis, a disease characterized by immune and/or inflammatory responses gone awry, researchers are testing the potential of a number of therapies that target immune response modifiers, such as cytokines and their cell receptors. An international team of investigators reported results from a randomized, double-blind, placebo-controlled phase 2a trial of a drug called CP-690,550, which inhibits a receptor for several interleukins and had shown efficacy in targeting this receptor (Janus kinase 3) in rodent models of arthritis and in humans with psoriasis.

This study compared the efficacy, safety, tolerability, and effects on health and functional status of 3 different doses of oral CP-690 550 (5 mg, 15 mg, or 30 mg, given twice daily) with placebo, in individuals with moderate to severe active rheumatoid arthritis. The 264 study participants—all of whom were intolerant or unresponsive to methotrexate or drugs that block the actions of the tumor necrosis factor (TNF) alpha cytokine and who also had at least 9 painful or tender joints, 6 swollen joints, and evidence of systemic inflammation—were randomly assigned to receive the drug or placebo for 6 weeks with 6 weeks of post-dosing follow-up.

The investigators measured patient outcomes using the American College of Rheumatology (ACR) criteria, the current gold standard for evaluating the effectiveness of new agents in rheumatoid arthritis trials. Improvement is denoted as ACR 20, ACR 50, or ACR 70, reflecting a 20%, 50%, or 70% improvement, respectively, in measured parameters (http://www.rheumatology.org/publications/response/205070.asp). For example, a patient reaching an ACR 20 response would experience a 20% improvement in tender and swollen joint counts and a 20% improvement in 3 of 5 ACR measures (patient and physician assessments, pain, disability, and erythrocyte sedimentation rate, a measure of inflammation).

At week 6, an ACR 20 response was achieved in 29% of the placebo group vs 70% to 81% of patients receiving the drug. An ACR 50 response occurred in 6% of the placebo group vs 33% to 54% of patients receiving the drug; ACR 70 responses occurred in 3% of the placebo group vs 13% to 28% of patients receiving the drug. Adverse events, most commonly headache and nausea, increased in a dose-dependent manner.

“All 3 doses of CP-690,550 were efficacious and all 3 separated from placebo starting at week 1,” said first author Joel Kremer, MD, of the Albany Medical College, in Albany, NY. “Further studies, including alternative dose regimens and longer duration of therapy, are warranted.”

Targeting the A3 adenosine receptor (A3AR) may also have potential for the treatment of rheumatoid arthritis. A3AR is overexpressed in the synovial tissue and peripheral blood mononuclear cells of patients with this disease and stimulation of this receptor decreases production of TNF-α. A drug targeting the receptor, CF101, ameliorated symptoms of rheumatoid arthritis in animal models (Baharav E et al. J Rheumatol. 2005;32:469-476).

In a phase 2a multicenter, randomized, double-blind trial with no placebo group, 74 patients with active rheumatoid arthritis were randomly assigned to receive 1 of 3 doses of oral CF101, twice daily for 12 weeks. All participants were unresponsive to antirheumatic drugs that suppress the immune and/or inflammatory systems, including methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and cyclosporine. Participants receiving an intermediate dose of CF101 had a maximal response; 60%, 36%, and 12% of the patients taking this dose achieved ACR 20, ACR 50, and ACR 70 responses, respectively. CF101 was well tolerated with no dose-limiting toxic effects.

“A significant correlation between baseline A3AR expression [in peripheral blood mononuclear cells] and ACR responses was noted, suggesting the receptor can be developed as a marker to predict response to the drug,” said study investigator Pnina Fishman, PhD, of Can-Fite BioPharma, in Petach Tikva, Israel.

Another trial assessed the potential of combination therapy of methotrexate and infliximab or abatacept for patients with rheumatoid arthritis. Infliximab, first approved in 1998 by the US Food and Drug Administration for the treatment of Crohn disease, is an antibody directed against TNF-α and is often prescribed to treat inflammation associated with that disorder, as well as rheumatoid or psoriatic arthritis. Abatacept, approved in 2005 for rheumatoid arthritis, binds to and inhibits T-cell activity and provides benefit to some patients with rheumatoid arthritis who are unresponsive to treatments that inhibit TNF-α (Genovese MC et al. N Engl J Med. 2005;353:1114-1123).

This 1-year, double-blind, randomized, placebo-controlled phase 3 trial included 431 patients with rheumatoid arthritis who had an inadequate response to methotrexate and no prior anti-TNF therapy. Patients were randomly assigned to receive methotrexate plus either abatacept every 4 weeks, infliximab every 8 weeks, or placebo every 4 weeks. Patients randomized to placebo were switched to abatacept after 6 months but were not included in the 1-year analysis.

At the 6-month analysis, symptom improvement was measured through disease activity scores that include 28 joint counts for tenderness and swollenness (a score <2.6 corresponds to clinical remission). The mean score for study patients at baseline was 6.8, and the mean change from baseline was −2.5, −2.3, and −1.5 for the abatacept, infliximab, and placebo groups, respectively. At 1 year, the mean change was −2.9 for abatacept and −2.3 for infliximab.

An ACR 20 response at 6 months was achieved at a rate of 66.7%, 59.4%, and 41.8% in the abatacept, infliximab, and placebo groups, respectively. An ACR 50 response was found in 40.4%, 37.0%, and 20.0% of patients in these groups, and an ACR 70 response occurred in 20.5%, 24.2%, and 9.1% of patients, respectively. At the 1-year analysis of the abatacept and infliximab groups, an ACR 20 response was found in 72.4% of individuals in the abatacept group and 55.8% of those in the infliximab group. ACR 50 responses were achieved in 45.5% and 36.4% of patients, and ACR 70 responses in 26.3% and 20.6% in abatacept and infliximab groups, respectively.

At 6 months, patients in both drug groups had a reduction in disease activity compared with those in the placebo group; those receiving abatacept had a durable response through 1 year, said lead author Michael Schiff, MD, of the Denver Arthritis Clinic. While both drugs were well tolerated, abatacept exhibited a more favorable safety profile, he added.

Other clinical trials are examining whether such agents as the anti-inflammatory supplement chondroitin sulfate or licofelone, a drug with dual inhibitory activity against the inflammation-stimulating molecules 5-lipoxygenase and cyclooxygenase, can prevent cartilage loss due to osteoarthritis. Researchers from universities in France and Belgium conducting a 2-year phase 3 trial, the STudy on Osteoarthritis Progression Prevention (STOPP) found that chondroitin 4,6-sulfate significantly reduced the progression of joint-space narrowing in patients with knee osteoarthritis compared with placebo.

In this prospective, double-blind, placebo-controlled study, 622 patients with knee osteoarthritis were randomly assigned to receive 800 mg daily of oral chondroitin 4,6-sulfate or placebo for 24 months. The primary efficacy outcome was the minimal joint space narrowing measured over 2 years, on digitalized x-rays.

Patients from the placebo group had a mean joint-space narrowing of about 0.24 mm after 2 years, while those receiving chondroitin 4,6-sulfate had a mean joint space narrowing of 0.10 mm—a significant difference. “There was significant reduction in pain, and tolerance was excellent [in the chondroitin 4,6-sulfate group],” said first author Jean-Yves Reginster, MD, PhD, of the University of Liège, in Belgium. “We conclude that chondroitin 4,6-sulfate given continuously for 2 years slows down the progression of osteoarthritis.”

A second randomized phase 3 clinical trial tested the therapeutic effectiveness of licofelone in patients with osteoarthritis. In this 2-year double-blind study, 301 patients received either 200 mg of licofelone twice daily or 500 mg of naproxen twice daily. Cartilage volume loss was assessed with quantitative magnetic resonance imaging and x-rays. All clinical symptoms significantly improved at 24 months compared with baseline, with no significant difference between the 2 treatment groups. However, there was significantly less cartilage loss in the licofelone group at 24 months compared with the naproxen group (−3.11 mm vs −4.21 mm).

“Treatment with licofelone significantly reduced the loss of cartilage volume thickness when compared to naproxen in patients,” said lead author Jean-Pierre Pelletier, MD, of the Notre-Dame Hospital at the University of Montreal Hospital Centre, in Quebec. “The chondroprotective effect of licofelone was found . . . more so in patients with miniscule extrusion, meaning patients who are at high risk for progressive disease.”

Further studies of these and other drugs for the treatment of osteoarthritis and rheumatoid arthritis may help tailor treatments to patients with varying stages of these diseases. Many scientists and clinicians at the conference predicted that novel targeted therapies will be the focus of rheumatology research and clinical trials over the next several years.