SAN DIEGO – The novel oral phosphodiesterase-4 inhibitor apremilast cut an impressively wide swath through the annual meeting of the American College of Rheumatology on the strength of positive results in three separate pivotal phase III trials for psoriatic arthritis and a favorable phase II study in Behçet’s syndrome.
Dr. Alvin F. Wells reported that apremilast resulted in clinically meaningful improvement in psoriatic arthritis symptoms, physical function, and associated skin psoriasis at 16 weeks in the PALACE 4 trial. Moreover, the improvement remained durable through 52 weeks in the phase III clinical trial.
PALACE 4 compared apremilast against placebo as a first-line treatment in 527 patients with psoriatic arthritis not previously treated with a disease-modifying antirheumatic drug. This was a population with active disease: a mean baseline 11 swollen and 20 tender joints; a Health Assessment Questionnaire Disability Index score averaging 1.07; and a 50% prevalence of dactylitis, with a mean severity score of 2.0. Sixty-five percent of patients had enthesitis, with a median Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) of 3.0. Participants had a mean 16-year history of psoriasis and a 3.4-year duration of psoriatic arthritis.
The primary study endpoint was attainment of an American College of Rheumatology 20% improvement (ACR20) response at 16 weeks. This was achieved in 29.2% of patients randomized to apremilast at 20 mg twice daily, 32.3% on 30 mg twice daily, and 16.9% on placebo. At week 16, patients on placebo were re-randomized to apremilast at 20 mg or 30 mg twice weekly. By week 52, an ACR20 response was achieved by 53% of patients in the apremilast 20 mg twice-daily group and 59% of those on the higher dose, according to Dr. Wells, director of the Rheumatology and Immunotherapy Center in Franklin, Wisc.
Apremilast also scored well on numerous secondary endpoints (see chart). For example, the swollen joint count decreased by a median of 89% over the course of 52 weeks in patients on apremilast at 20 mg twice daily.
"The way I like to think of that result is at least 50% of patients had an 89% improvement in their swollen joint count," he explained.
During the first 16 weeks of PALACE 4, there were fewer serious adverse events in apremilast-treated patients than with placebo-treated patients. The most frequent side effects of apremilast were nausea, diarrhea, and headache, affecting 16%, 12%, and 8%, respectively, of patients in the higher-dose arm. These adverse events were almost exclusively mild or moderate, they began within the first 2 weeks of treatment, and they resolved in 4 weeks despite continued treatment. Less than 2% of apremilast-treated patients dropped out of the study due to nausea or diarrhea through week 52.
PALACE 4 differed from the PALACE 2 and 3 trials, also presented at the ACR meeting, in that PALACE 2 and 3 involved only patients with psoriatic arthritis previously treated with biologic agents or other disease-modifying antirheumatic drugs. All three studies had the same design, and the results in terms of both efficacy and safety were consistent across the full clinical trial program. No clinically meaningful changes in laboratory values were seen in any of the PALACE trials, suggesting ongoing lab monitoring may not be necessary.
Also at the ACR annual meeting, Dr. Gülen Hatemi of Istanbul University, Turkey, in a reprise of her report several weeks earlier at the annual congress of the European Academy of Dermatology and Venereology, presented a phase II study showing apremilast to be highly effective in treating the oral ulcers that are the cardinal feature of Behçet’s syndrome.
Celgene filed for approval of apremilast for psoriatic arthritis with the Food and Drug Administration earlier this year and anticipates a decision in March 2014. The company also plans to apply to the European regulatory agency for the same indication before year’s end, and to petition the FDA for approval in psoriasis within the same time frame. A 500-patient phase III study of apremilast in ankylosing spondylitis, known as POSTURE, is well underway.
PALACE 4 was sponsored by Celgene. Dr. Wells reported receiving a research grant from the company.