WASHINGTON — In the phase 3 PALACE-1 trial, the investigational agent apremilast led to significant improvement in the signs and symptoms of psoriatic arthritis (PsA) in patients who failed to respond to recommended drugs, including disease-modifying antirheumatic agents (DMARDs) and biologics.
Apremilast monotherapy demonstrated robust improvement in primary and secondary end points, with no unexpected safety issues. The drug had the most robust effect as monotherapy and in biologic-naïve patients.
The results were presented here at the ACR 2012 by lead author Arthur Kavanaugh, director of the Center for Innovative Therapy at the University of California, San Diego.
"PALACE-1 is the first phase 3 study of apremilast in patients with psoriatic arthritis. This large study showed that the drug is effective in DMARD- and/or biologic-experienced psoriatic arthritis patients, is well tolerated, and has a good side-effect profile," Dr. Kavanaugh explained. These results show that apremilast is "a potentially effective and safe oral therapy for psoriatic arthritis patients," he added.
Results from 2 other pivotal phase 3 trials — PALACE-2 and PALACE-3 — were released in September. The maker of apremilast, Celgene, expects to submit a New Drug Application to the US Food and Drug Administration (FDA) in the first half of 2013, according to a press release from the company.
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), decreases pro-inflammatory mediators and increases anti-inflammatory mediators. About 3000 patients have been treated with the drug to date, Dr. Kavanaugh noted.
PALACE-1 was a multicenter, double-blind, placebo-controlled, parallel-group study with 2 active treatment groups. Study participants had active PsA (at least 3 tender and 3 swollen joints) and had failed 1 to 3 previous DMARD or biologic agents. Two thirds of patients received concurrent DMARDs during the trial.
The 504 patients with moderate to severe PsA were randomized to receive apremilast 30 mg twice daily, apremilast 20 mg twice daily, or placebo. If no improvement was observed by week 16, patients were rerandomized to 1 of the 2 apremilast groups. At week 24, all patients were put on active treatment for the extension phase of the study.
At baseline, median age was about 60 years, median body mass index was slightly above 30 kg/m², and median duration of PsA was about 7 years. The median number of tender joints was about 22 and the median number of swollen joints was about 21.
Significant Improvement Seen
At week 16, more patients in the 30 mg group (40%; P = .0001 vs placebo) and in the 20 mg group (31%; P = .0001 vs placebo) met the primary end point — an improvement in the signs and symptoms of PsA of at least 20% (ACR20) — than in the placebo group (19%).
The same was true for patients receiving apremilast monotherapy (no DMARDs or biologics); more patients in the 30 mg group (50.8%; P = .0001 vs placebo) and in the 20 mg group (31.5%; P = .0001 vs placebo) met the ACR20 end point at week 16 than in the placebo group (10.5%).
Among biologic-naive patients treated with apremilast plus a DMARD, ACR20 at week 16 was achieved by 37% of the 30 mg group, 33% of the 20 mg group, and 27% of placebo patients. Among biologic-naive patients treated with apremilast monotherapy, ACR20 was achieved by 58%, 24%, and 12%, respectively.
Significant responses favoring apremilast were observed across all arthritis-related secondary end points, including ACR50, ACR70, and disease activity score (DAS)-28.
"Patients who received apremilast monotherapy and those who were biologic-naive had higher ACR20 responses. Overall, there appeared to be some attenuation of response in the groups treated with combination therapy. We are trying to understand these data," Dr. Kavanaugh said.
No new safety concerns about apremilast were raised in PALACE-1. Any serious adverse event was seen in 5.2% of the 30 mg group, 4.8% of the 20 mg group, and 4.2% of the placebo group.
In the 30 mg group, 7.1% discontinued the drug because of an adverse event, as did 6.0% of the 20 mg group and 4.8% of the placebo group. One death was reported in the 20 mg group. No opportunistic infections, lymphoma, or cardiovascular events were reported. Few changes were seen in laboratory tests.
Scott J. Zashin, MD, clinical professor of medicine in the division of rheumatology at the University of Texas Southwestern Medical School in Dallas, said that "TNF blockers are the biologics that are most commonly used to treat RA and psoriatic arthritis when patients fail to respond to or are not candidates for DMARDs."
"Apremilast performed better in patients who had never received a biologic, compared with the overall population studied," he said.
When asked how apremilast is likely to be used if approved by the FDA, Dr. Zashin said that "apremilast may be useful as a first-line therapy in the small number of patients who require the efficacy of a biologic but are reluctant to self-inject or take an infusion. For the majority of patients, until longer-term safety data are available, apremilast should be reserved for patients who have failed DMARDs and biologics due to lack of efficacy or toxicity."
Dr. Kavanaugh reports receiving financial support from Celgene. Dr. Zashin reports receiving financial support from URL Pharma, Amgen, and Abbott Labs.
ACR 2012: Abstract L13. Presented November 13, 2012.
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