New Drug on the Block: Apremilast for Moderate-to-Severe Plaque Psoriasis

Andrea G. Scott, PharmD, MPH

Disclosures

February 27, 2015

Question:

What is significant about apremilast for moderate-to-severe plaque psoriasis?

Response from Andrea G. Scott, PharmD, MPH
Medical writer, Atlanta, Georgia

In September 2014, the US Food and Drug Administration (FDA) approved apremilast (Otezla®), a phosphodiesterase-4 (PDE-4) inhibitor, for the treatment of moderate-to-severe plaque psoriasis.[1] Apremilast is also approved for the treatment of active psoriatic arthritis, but this article will focus on its use in plaque psoriasis.

Psoriasis is an inflammatory disease in which epidermal keratinocytes proliferate at a much higher rate, resulting in itchy, scaly plaques anywhere on the body but particularly on the scalp, elbows, and knees. Treatments include topical medications such as steroids and synthetic vitamin D3 analogs, systemic medications such as methotrexate and cyclosporine, and biologics. The type of treatment used depends on the type and severity of psoriasis as well as patient preferences and characteristics.[2]

The mechanism of action of apremilast relates to the inflammatory response. PDE-4 inhibitors prevent the breakdown of cyclic adenosine monophosphate (cAMP), an important part of many cellular processes (including inflammation), and prevent production of proinflammatory cytokines. Specifically, apremilast inhibits tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and interleukins (IL)-12 and -23, among others. Apremilast also decreases dermal thickness and the keratinocyte proliferation index, similar to cyclosporine.[3]

Safety and efficacy of apremilast were assessed in two phase 2 studies[4,5] and are currently being evaluated in two phase 3 studies.[6,7]

Papp and colleagues[4] randomly assigned patients to receive apremilast 20 mg daily, apremilast 20 mg twice daily, or placebo for 12 weeks. At week 12, 24.4% of patients receiving apremilast 20 mg twice daily had ≥ 75% decrease in Psoriasis Area and Severity Index (PASI) score compared with 10.3% receiving placebo (P = .023). Achievement of ≥ 75% decrease in PASI score was similar in patients receiving placebo or apremilast daily. The mean percent difference decrease in PASI score was significantly higher for both doses of apremilast compared with placebo (20 mg twice daily, 52.1%; 20 mg daily, 30.3%; placebo, 17.4%). The most common adverse effects reported with apremilast included headache, diarrhea, nasopharyngitis, and nausea.[4]

The second phase 2 trial[5] compared various doses of apremilast with placebo. Patients were randomly assigned to receive apremilast 10 mg, 20 mg, or 30 mg twice a day or placebo for 16 weeks. Patients in the placebo group were then switched over to one of the active treatment groups for 8 weeks. At week 16, significantly more patients using apremilast 20 mg twice a day (29%, P < .0001) and 30 mg twice a day (41%, P < .0001) achieved ≥ 75% decrease in PASI score compared with placebo (6%). Dermatology Life Quality Index scores increased significantly from baseline for patients on apremilast 20 mg and 30 mg twice daily compared with placebo. Nausea, upper respiratory tract infection, and diarrhea were among the most common adverse effects.[5]

Apremilast is being studied head-to-head with other treatments. According to ClinicalTrials.gov, apremilast 30 mg twice daily is being compared with etanercept 50 mg once-weekly injection in a randomized, double-blinded, double-dummy study. Treatment will last for 16 weeks, with an apremilast extension phase for 88 weeks. Study completion is expected in August 2015.[8]

The safety profile for apremilast is fairly mild. The most common adverse effects in the studies were nausea and diarrhea, particularly with 30 mg twice daily. To decrease gastrointestinal adverse effects, apremilast is titrated from 10 mg daily to 30 mg twice daily over 5 days. In patients with a creatinine clearance < 30 mL/min, the dose should be reduced to 30 mg daily.[9] As a substrate of cytochrome (CYP) 450, apremilast should not be administered with CYP450 inducers such as rifampin or carbamazepine. Apremilast is not an inhibitor or inducer of any of the CYP enzymes, P-glycoprotein, or the organic anion transporters.[9]

Depression, which may be a comorbid condition of psoriasis,[10] was observed in 1.3% of patients treated with apremilast and in 0.4% receiving placebo.[9] Weight loss of 5%-10% was seen in 12% of patients treated with apremilast compared with 5% of patients treated with placebo. Two percent of patients using apremilast had ≥ 10% weight loss.[9]

Apremilast appears to be a safe and effective medication for plaque psoriasis. The phase 3 studies will be important for determining long-term safety as well as its comparative effectiveness with a biologic. As some injectables have biosimilar counterparts coming to market over the next several years, it may be difficult for apremilast, currently priced at about $2000 per month,[11] to compete with pricing. Apremilast will be available only through specialty pharmacies, although this applies to biologics as well.

Few oral medications are available for plaque psoriasis, and apremilast is the only approved PDE-4 inhibitor; it may potentially offer an alternative for patients who have not had success with TNF-alpha inhibitors or other systemic therapy. Health providers and patients should be aware of the precautions and adverse effects when starting apremilast.

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