Apremilast, an oral investigational drug, significantly improved the signs and symptoms of psoriatic arthritis (PsA) in patients whose disease failed to respond to previous disease-modifying antirheumatic drugs (DMARDs), including biologic agents, according to the results of the phase 3 clinical trial, PALACE-1.
“This large, first phase 3 study of apremilast in PsA showed that the drug was effective in DMARD- and/or biologic-experienced patients with PsA, and was well tolerated with acceptable safety,” stated lead investigator Arthur F. Kavanaugh, MD, Professor of Clinical Medicine and Director of the Center for Innovative Therapy at the University of California, San Diego. “These results are encouraging for both physicians and patients, with a potentially effective and safe oral therapy for patients with PsA,” including those who do not respond to other antirheumatic agents, he said.
Apremilast was effective in combination with other DMARDs, but was even more effective as a monotherapy and in biologic-naïve patients. No unexpected safety concerns were reported. Apremilast inhibits phosphodiesterase 4 and acts by decreasing proinflammatory mediators while increasing anti-inflammatory mediators, Dr Kavanaugh noted. Approximately 3000 patients have been treated with the drug to date.
The multicenter, double-blind, placebo-controlled, parallel-group PALACE-1 trial randomized 168 patients (median age, 60 years) with moderate-to-severe PsA to receive apremilast 30 mg twice daily, apremilast 20 mg twice daily, or placebo. The study enrolled patients with active PsA (defined as at least 3 tender and 3 swollen joints) who had failed 1 to 3 previous DMARDs or biologics. During the trial, 66% of the patients received concurrent DMARDs.
At baseline, the patients’ median duration of PsA was approximately 7 years. The median number of tender joints was approximately 22, and the median number of swollen joints was approximately 21. The patients who did not improve by week 16 were switched to one or the other of the active treatments. At week 24, all of the patients received active treatment for the extension phase of the study.
For overall study results, the primary end point of reaching the ACR 20% criteria for improvement (ACR20) in the signs and symptoms of PsA at week 16 was significant for both doses of apremilast versus placebo: 40% for the 30-mg dose and 31% for the 20-mg dose versus 19% for placebo (P = .001 for both comparisons with placebo).
Higher responses were seen in the patients receiving apremilast monotherapy compared with the overall population. In the monotherapy group, ACR20 at week 16 was achieved by 50.8% of the patients taking the 30-mg dose and by 31.5% of the patients taking the 20-mg dose, versus by 10.5% of the patients in the placebo group (P = .001 for both comparisons with placebo).
Among the biologic-naïve patients treated with apremilast plus a DMARD, ACR20 at week 16 was achieved in 37% of the 30-mg group and in 33% of the 20-mg group versus in 27% of the placebo group. Among the biologic-naïve patients receiving apremilast monotherapy, ACR20 was achieved in 58%, 24%, and 12% of patients, respectively.
Significant responses favoring apremilast were observed across all of the arthritis-related secondary end points, including ACR50, ACR70, and the 28-joint Disease Activity Score.
The safety of apremilast was acceptable, with no new signals of concern observed in this study. Any serious adverse events (AEs) were reported in 5.2% of the group receiving apremilast 30 mg twice daily, in 4.8% of those receiving the 20-mg dose, and in 4.2% of the placebo group. AEs leading to drug discontinuation occurred in 7.1%, 6%, and 4.8% of the patients, respectively. One death was reported in a patient using apremilast 20 mg twice daily. No opportunistic infections, lymphoma, or cardiovascular events were reported.
PALACE-1 is 1 of 3 pivotal phase 3 clinical studies in the apremilast development program. Results of the PALACE-2 and PALACE-3 trials were reported in September 2012. Representatives of the drug manufacturer said that the company will submit a New Drug Application to the US Food and Drug Administration in the first half of 2013.
Scott J. Zashin, MD, a Clinical Assistant Professor of Internal Medicine, Division of Rheumatology, University of Texas Southwestern Medical School, Dallas, suggested that apremilast may find a role as a first-line therapy for patients with moderate-to-severe rheumatoid arthritis who do not want to self-inject or receive an infusion. But until longer-term safety data are available, “apremilast should be reserved for those patients who have failed DMARDs and biologics because of a lack of efficacy or toxicity,” Dr Zashin commented.