PALACE 4 is the first large randomized controlled study to examine the efficacy and safety of a novel agent in patients naïve to previous DMARD therapy
Long-term, clinically meaningful improvements seen in manifestations of psoriatic arthritis such as physical function (HAQ-DI), skin (PASI-75/50), swollen and tender joints, enthesitis and dactylitis
“These encouraging results suggest that apremilast may have the potential to be used alone and as a first-line therapy.”
PALACE 4 is the first large, randomized, controlled study to examine the efficacy and safety of a novel agent exclusively in systemic or biologic DMARD-naïve psoriatic arthritis patients. Apremilast monotherapy demonstrated clinical benefits over 52 weeks in this treatment-naïve patient population, including clinically meaningful improvements in signs and symptoms of psoriatic arthritis, as well as manifestations of psoriatic arthritis such as physical function (HAQ-DI), skin (PASI-75/50), swollen and tender joints, enthesitis and dactylitis.
At week 16, a statistically significantly greater proportion of patients treated with apremilast monotherapy achieved a modified ACR20 (the study’s primary endpoint) versus placebo: 29.2% (apremilast 20 mg; P=0.0076) and 32.3% (apremilast 30 mg; P=0.0011) versus 16.9% (placebo). For those patients randomized to apremilast and completing 52 weeks of the study, an ACR20 response of 53.4% (apremilast 20 mg) and 58.7% (apremilast 30 mg) at week 52 was observed. ACR 50 and 70 was reached by 31.9% and 18.1% of patients, respectively, for apremilast 30 mg.
“In addition to maintaining its long-term safety and tolerability profile consistent with the previously reported data, apremilast monotherapy showed significant clinical benefit in systemic or biologic DMARD-naïve psoriatic arthritis patients,” said Alvin Wells, M.D., Ph.D., Director, Rheumatology and Immunotherapy Center, Franklin, WI, US. “These encouraging results suggest that apremilast may have the potential to be used alone and as a first-line therapy.”
Durable improvements in multiple endpoints—including enthesitis (inflammation at sites where tendons, ligaments or joint capsule fibers insert into bone), dactylitis (swelling of a finger or toe), impaired physical function as assessed by HAQ-DI, swollen and tender joint counts and associated skin psoriasis—were maintained or increased in patients completing 52 weeks of treatment.
Apremilast monotherapy demonstrated an acceptable safety profile and was generally well-tolerated up to 52 weeks. No new safety concerns were identified with longer treatment duration, and the profile was consistent with previously reported safety data on apremilast. The most common adverse events (AEs) reported through 52 weeks were nausea, diarrhea and headache. Discontinuation rates for diarrhea and nausea in the combined apremilast treatment groups were less than 2% over 52 weeks. No serious AEs of diarrhea or nausea were reported in any treatment group up to 52 weeks. No systemic opportunistic infections, including no cases of tuberculosis (new or reactivations), were reported.
These results are from investigational studies. Apremilast is not an approved product for any indication.
The New Drug Application (NDA) and the New Drug Submission (NDS), based on the combined data from PALACE 1, 2 and 3 for psoriatic arthritis, were submitted to health authorities in the U.S. and Canada in Q1 2013 and Q2 2013, respectively. An NDA to the U.S. Food and Drug Administration for psoriasis, in addition to a combined psoriatic arthritis/psoriasis Marketing Authorization Application (MAA) in Europe, are on-track for the fourth quarter of 2013.
About PALACE Program
PALACE 1, 2, 3 and 4 are the pivotal phase III multi-center, double-blind, placebo-controlled, parallel-group studies with two active-treatment groups. In PALACE 1, 2 and 3, approximately 1,500 subjects were randomized 1:1:1 to receive either apremilast 20 mg BID, 30 mg BID or identically appearing placebo for 24 weeks, with a subsequent active treatment phase up to 52 weeks followed by a long-term safety phase in which all patients are treated with apremilast. The PALACE 1, 2 and 3 studies included a wide spectrum of patients with active psoriatic arthritis, including those who had been previously treated with oral DMARDs, and/or biologic DMARDs, including patients who had previously failed a tumor necrosis factor (TNF) blocker. PALACE 3 includes a large subset of patients with significant skin involvement with psoriasis.
In PALACE 4, more than 500 DMARD-naïve patients were randomized 1:1:1 to receive either apremilast 20 mg BID, 30 mg BID, or identically appearing placebo, for 24 weeks, with a subsequent active treatment phase up to 52 weeks, followed by a long-term safety phase in which all patients are treated with apremilast.
The primary endpoint of the PALACE 1, 2, 3 and 4 studies is the modified American College of Rheumatology criteria for 20 percent improvement (ACR20) at week 16. Secondary endpoints include other measures of signs and symptoms, physical function and patient-reported outcomes at weeks 16 and 24.
Taken together, the PALACE program includes the most comprehensive psoriatic arthritis program to date intended for regulatory submission.
Apremilast, an oral, targeted inhibitor of phosphodiesterase 4 (PDE4), intracellularly modulates the expression of a network of pro-inflammatory and anti-inflammatory cytokines. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Elevation of cAMP also increases anti-inflammatory cytokines such as IL-10.
About Psoriatic Arthritis
Psoriatic arthritis is a painful, chronic inflammatory disease associated with the skin condition psoriasis. An estimated 125 million people worldwide have psoriasis, approximately 30 percent of whom may also develop psoriatic arthritis. Psoriatic arthritis is a chronic disorder with progressive and additive joint inflammation that can lead to deleterious effects on quality of life and increases work disability. In addition to psoriatic skin lesions, common signs and symptoms of psoriatic arthritis include pain, stiffness and swelling in several to many joints, as well as inflammation of the spine. Patients often experience psoriasis on average for 10 years before the onset of joint symptoms, and many psoriatic arthritis patients go undiagnosed. To learn more about psoriatic arthritis, go to www.discoverpsa.com. To learn more about the role of PDE4 in inflammatory diseases, go to www.discoverpde4.com.
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