Apremilast Is Effective and Well Tolerated in Patients with Psoriatic Arthritis

With up to 30-40% of patients with psoriasis also having psoriatic arthritis, there is a need for new treatments that are more effective with fewer side effects than current options. One such option may be the oral phosphodiesterase 4 inhibitor apremilast, which has been shown to regulate inflammatory mediators.

In “Treatment of Psoriatic Arthritis in a Phase 3 Randomised, Placebo-Controlled Trial with Apremilast, an Oral Phosphodiesterase 4 Inhibitor,” published in Annals of the Rheumatic Diseases, the authors discussed results from the first trial of the four-part phase 3 Psoriatic Arthritis Long-term Assessment of Clinical Efficacy clinical trial (PALACE 1). This trial assessed the efficacy, tolerability and safety of apremilast in a cohort of patients with treatment-resistant active psoriatic arthritis.

Researchers recruited adult patients with active psoriatic arthritis who met the Classification Criteria for Psoriatic Arthritis (CASPAR) at screening. To participate, patients also had to have a have a minimum of three swollen and three tender joints, despite previous treatment with disease-modifying antirheumatic drugs (DMARDs) and/or biologic treatment, or current treatment with DMARDs.

Exclusion criteria included:

• Failure to respond to prior treatment with more than three DMARDs or biologics or more than one tumor necrosis factor blocker
• Non-psoriatic arthritis inflammatory rheumatic or autoimmune joint diseases
• Other forms of psoriasis
• ACR functional class IV
• Use of phototherapy or DMARDs other than methotrexate, leflunomide, or sulfasalazine within 4 weeks of randomization
• Use of adalimumab, etanercept, golimumab, infliximab, certolizumab pegol or tocilizumab within 12 weeks of randomization or alefacept or ustekinumab within 24 weeks of randomization
• Prior treatment with apremilast
• Topical treatment for psoriasis within 2 weeks of randomization

For the study, eligible patients were randomized on a 1:1:1 ratio to receive twice-daily placebo, apremilast 20 mg, or apremilast 30 mg for 16 weeks. Patients who failed to achieve a 20% or greater reduction in swollen and tender joint counts by week 16 were either continued on their current dose of apremilast or, if on placebo, randomized to receive either apremilast dose. Patients were started on 10 mg apremilast and dose-titrated over the first week of treatment at 10 mg/day until target dose was reached. Treatment continued through week 24, at which point all remaining patients on placebo were randomized to receive apremilast.

Five-hundred four (504) patients were randomized and received at least one dose of study medication; 444 patients completed week 24 of the study.

Patients were assessed for safety at weeks 4, 16, and 24, and for efficacy at weeks 16 and 24. The primary efficacy endpoint for the study was the proportion of patients achieving 20% improvement in modified ACR response criteria (ACR20). Secondary efficacy endpoint was change from baseline in Health Assessment Questionnaire—Disability Index (HAQ-DI) at week 16.

The authors reported that at baseline, “327 (64.9%) patients were taking DMARDs, of whom 273 (83.5%) were taking methotrexate; 119 (23.6%) had prior biologic exposure, and 47 (9.3%) were considered biologic therapeutic failures.”

Analysis of the data showed that at week 16, significantly more patients receiving apremilast 20 mg (31.3%, p=0.0140) and 30 mg (39.8%, p=0.0001) achieved an ACR20 response versus placebo (19.4%), with efficacy “demonstrated across patients with varying treatment experience.”

Biologic-naïve patients “generally experienced higher absolute ACR20 response rates compared with biologic-experienced patients and patients with a history of biologic failure.” The authors also reported higher ACR20 response rates in patients on the higher apremilast dose.

Treatment with apremilast was also associated with “significantly greater reductions (improvements) in HAQ-DI compared with placebo,” at week 16. At week 24, “a significantly greater proportion” of patients receiving apremilast 20 mg and 30 mg achieved ACR20 versus placebo.

In patients with baseline enthesitis, mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was “significantly higher” for apremilast 30 mg versus placebo. Likewise, in patients with psoriasis affecting 3% or greater of their body surface area, “significantly greater proportions” of patients treated with either dose of apremilast “achieved at least 50% reduction from baseline Psoriasis Area and Severity Index.”

The most common adverse events up to week 24 of treatment were diarrhea, nausea, headache, and upper respiratory tract infection. Most adverse events were mild to moderate in severity and self-limiting, with discontinuation rates due to adverse events similar across treatment groups.

In their discussion of these results, the authors noted that currently available DMARDs have demonstrated “variable efficacy in treating all of the rheumatologic and dermatologic manifestations” of psoriatic arthritis. Although tumor necrosis factor blockers and other biologic agents have demonstrated substantial responses for many patients, they are not effective in all patients and are associated with several safety concerns.

Against this “unmet medical need for novel therapeutic agents that address the varied clinical manifestations of psoriatic arthritis,” this study showed that treatment with apremilast leads to improvements in the signs and symptoms of psoriatic arthritis. This efficacy was observed “regardless of prior biologic experience or concomitant DMARD use, with a higher absolute rate of ACR20 response in biologic-naïve patients.”

Symptoms and physical function continued to improve through week 24 in patients treated with apremilast compared with placebo, with greater response rates and improvement in patients who received twice-daily apremilast 30 mg. Treatment with apremilast was well tolerated, with most adverse events gastroenterological in nature. The authors reported no imbalance between placebo and apremilast in terms of major adverse cardiac events or serious infections.

Based on these results, the authors concluded that apremilast is effective for the treatment of active psoriatic arthritis “across a diverse group of patients with prior treatment experience, alone or in combination with traditional DMARDs.” By showing that apremilast was well tolerated in the majority of patients and demonstrated an acceptable safety profile, these results confirm the therapeutic potential of twice-daily apremilast for treatment of patients with psoriatic arthritis.