WASHINGTON, D.C.—Several studies were presented during a late-breaking abstract session here at the 2012 ACR/ARHP Annual Meeting, held November 9–14. Turn to page 37 for some highlights from the session.
Reducing Dose of Etanercept Effective in Reducing RA Flares in Select Patients
Ronald F. van Vollenhoven, MD, PhD, professor and chief of the unit for clinical therapy research, inflammatory diseases and chief of the clinical trials unit in the department of rheumatology at the Karolinska Institute in Stockholm, Sweden, presented results of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Subjects Who Have Achieved a Stable Low Disease Activity-state (DOSERA) trial. The randomized, double-blind, multicenter study was undertaken to assess the effect of discontinuing or reducing the dose of etanercept (ETN) in patients with rheumatoid arthritis (RA) being treated with combination ETN and methotrexate (MTX)
The study included 73 patients with RA treated with ETN (50 mg weekly) plus MTX (stable dose, 7.5–25 mg/week) and who had maintained low disease activity/remission as measured by Disease Activity Score (DAS) 28 <3.2 for at least 11 months. To be eligible for the study, patients also had to be at least 18 years old with no prior treatment with non–antitumor necrosis factor (TNF) biologic agents or no prior attempt to discontinue ETN due to stable disease. Patients were randomly assigned to continued therapy with the same dose of ETN (50 mg weekly; n=23), a reduced dose of ETN (25 mg/weekly; n=27), or placebo (n=23) while continuing with MTX.
The primary endpoint of the study was the proportion of nonfailures at 48 weeks between patients treated with ETN (50 mg/week) versus placebo. Failure was defined as DAS28 >3.2 and an increase in DAS28 >0.6 or disease progression. A comparison of nonfailure and DAS28 outcomes for all three groups was also made.
Overall, the results showed that patients who maintained the full ETN dose (50 mg) and the reduced dose (25 mg) had response better than the placebo group. The study found that the proportion of nonfailures at 48 weeks was 52% for patients who continued on ETN (50 mg/week) versus 13% for those on placebo, with an odds ratio (OR) of 7.2 (95% CI, 1.7–29.8; P=0.007). The proportion of nonfailures for patients who continued on the reduced ETN (25 mg/week) dose was 44% versus 13% for placebo, with an OR of 4.2 (95% CI, 1.0–17.0) (P=0.044).
Although ETN at 25 mg/week is not yet an approved dose of ETN, Dr. van Vollenhoven said that the findings of the study suggest that it may be worthwhile for rheumatologists to try the reduced 25 mg/week dose of ETN in their patients to maintain low disease activity. He said the risk of doing this seems small given that the study also showed that patients who had a flare at the reduced dose and were treated again at the higher dose were able to regain low disease activity.
Potential New Drug for Psoriatic Arthritis
Arthur Kavanaugh, MD, professor of clinical medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego, reported on the results of a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety study of two doses of apremilast (CC-10004) in subjects with active psoriatic arthritis (PALACE 1) study.
The study included 504 patients with a diagnosis of psoriatic arthritis (PsA) for six months or more treated currently or previously with disease-modifying antirheumatic drugs (DMARDs) or biologics randomized to apremilast (20 mg twice daily; n=168), apremilast (30 mg twice daily; n=168), or placebo (n=168). Patients were excluded from the study if they failed previous treatment with more than three DMARDs or biologic agents or more than one biological TNF inhibitor, or if they had active tuberculosis. Patients were allowed concurrent treatment with stable doses of methotrexate, sulfasalazine, and/or leflunomide.
Overall, 23.6% of patients had received prior biologic treatment, of which 9.3% failed treatment with a biologic agent. Of the 64.9% of patients receiving DMARDs at baseline, most were taking methotrexate (54.2%).
Based on the primary endpoint of achieving ACR20 at Week 16, the study found that significantly more patients treated with apremilast achieved ACR20 than those taking placebo. Compared with 19.4% of patients in the placebo group, 31.3% of patients treated with apremilast (20 mg; P=0.0140) and 41.0% of those treated with apremilast (30 mg; P<0.0001) achieved ACR20 at 16 weeks.
Similar results were seen at 24 weeks, with significantly more patients treated with apremilast achieving ACR50 and ACR70 compared with placebo. Overall, ACR50 was achieved in 4.2% of patients receiving placebo versus 15.3% of patients treated with apremilast (20 mg; P<0.05) and 19.9% of those treated with apremilast (30 mg; P<0.0001), and ACR70 was achieved in 0.6% of the placebo group versus 5.5% in the apremilast (20 mg) group (P<0.05) and 11.2% in the apremilast (30 mg) group (P<0.0001).
The study also found that apremilast was well tolerated, with most adverse events reported across all treatment groups as mild to moderate. The adverse events included diarrhea, nausea, headache, and upper respiratory tract infection. One or more serious adverse events occurred in eight patients on 20 mg apremilast and nine on 30 mg apremilast compared with seven on placebo. According to Dr. Kavanaugh, one patient receiving 20 mg apremilast died, but her death was not thought to be drug related.
One early measure of efficacy of the trial, he said, was the high number of patients who continued in this study. Across the three treatment arms, only 5–7% of patients discontinued treatment due to adverse events.
Novel Agent Shows Promise for Treatment of Active RA
In the first presentation of results of a new biologic with a different mode of action from established treatment options for RA, Harald Burkhardt, MD, of the CIRI/division of rheumatology at Johann Wolfgang Goethe-University in Frankfurt am Main, Germany, reported on the results of a multinational trial, double-blind, placebo-controlled phase Ib/IIa study on the safety and clinical activity of MOR103, a human monoclonal antibody targeting granulocyte-macrophage colony-stimulating factor, to treat patients with active moderate RA.
Pooling data from three European patient cohorts, the study included 96 patients (69 undergoing treatment with MOR103 and 27 in a placebo group) with active adult onset of RA of at least six months duration despite ongoing treatment, and moderate disease as indicated by >3 swollen and tender joints, elevated C-reactive protein, and a DAS28-erythrocyte sedimentation rate <5.1. The study used a sequential ascending dose design to randomize the patients treated with MOR103 to three different doses administered intravenously. Of the 69 patients who received MOR103, 24 received 0.3 mg/kg, 22 received 1.0 mg/kg, and 23 received 1.5 mg/kg. Most of these patients, along with the 27 in the placebo group, also received concurrent treatment with MTX. Other drugs used concurrently in all cohorts included other DMARDs, glucocorticosteroids, and nonsteroidal antiinflammatory drugs.
Based on an intent-to-treat analysis, the study found no statistically significant differences in adverse events between the active treatment cohorts and placebo groups, with the majority of adverse events reported as mild to moderate in all of the cohorts. Among the patients treated with MOR103, the most frequent adverse events were nasopharyngitis (n=9) and worsening of RA (n=9). Of the nine patients in whom RA worsened, all but one had worsening of the disease four weeks after the last treatment, according to Dr. Burkhardt. One serious adverse event (paronychia) was reported in the placebo group and one (pleurisy) in a patient treated with 0.3 mg/kg of MOR103 that required hospitalization.
Using ACR20, DAS28 changes, and European League Against Rheumatism (EULAR) responses at Days 29 and 57 to assess clinical activity, the study found the most significant therapeutic effect of MOR103 in patients treated with 1 mg/kg with 68.2% of patients in this cohort achieving the ACR20 endpoint at Week 4 compared to 7.4% in the placebo group (P=0.0001). Patients treated with MOR103 1.5 mg/kg also showed a therapeutic effect, although it did not significantly differ from placebo (30.4% versus 7.4%, respectively).
Patients in the MOR103 1.0 mg/kg and 1.5 mg/kg had significant decreases of DAS28 at Week 4, with a mean difference of 1.12 and 0.61, respectively, while patients in the placebo group had a slight increase (0.17) in DAS28. The percentage of patients who achieved EULAR response was significantly greater in the MOR103 1.0 mg/kg (68.2%) and 1.5 mg/kg (69.5%) groups compared to placebo (7.4%) (P=0.0002 and P=0.0001, respectively).
Overall, the results of the study showed a favorable safety of MOR103 at all dose levels and promising clinical activity with 1.0 mg/kg as the dose that demonstrates the efficacy potential of MOR103.
“Provided that MOR103 will confirm the promising initial study results in further clinical development, it has the potential to become a valuable means in the therapeutic armentarium of future RA treatment,” said Dr. Burkhardt.
Pooled Analysis of Short- and Long-Term Efficacy of Tofacitinib
Gerd R. Burmester, MD, of the department of rheumatology and clinical immunology at Charité-University Medicine Berlin, reported on short- and long-term efficacy of tofacitinib in patients with RA who fail to achieve adequate response to prior treatment with TNF inhibitors. Using data from multiple randomized clinical trials that pooled 614 patients to access short-term efficacy at three months, the study found that patients treated with tofacitinib at 5 or 10 mg twice daily achieved significant reductions in the signs and symptoms of RA (as measured by ACR20/50/70 response and DAS28-defined remission) and improvement in physical function (as measured by the Health Assessment Questionnaire-Disability Index [HAQ-DI]) and other patient-reported outcomes, such as pain and fatigue, compared with placebo.
This efficacy was maintained over 24 months as shown by the sustained improvement in signs and symptoms of RA (measured by ACR20/50/70 and DAS) as well as physical function (HAQ-DI), pain, and fatigue in 510 patients pooled from the long-term extension studies. For the short-term analysis, the efficacy of tofacitinib was demonstrated regardless of inadequate response to one or two prior TNF inhibitors.
According to Dr. Burmester, these results show consistent improvement in signs and symptoms of RA and physical function with tofacitinib in patients who are difficult to treat (i.e., those with an inadequate response to previous treatment with TNF inhibitors). Based on these large patient numbers, including long-term observations, he said that tofacitinib may also be a therapeutic option in those patients who have failed biologics.
Mary Beth Nierengarten is a freelance medical journalist based in St. Paul, Minn.
