Efficacy, Tolerability, and Pharmacodynamics of Apremilast in Recalcitrant Plaque Psoriasis: A Phase II Open-Label Study
August 2013 | Volume 12 | Issue 8 | Original Article | 888 | Copyright © 2013
Alice B. Gottlieb MD PhD,a Robert T. Matheson MD,b Alan Menter MD,c Craig L. Leonardi MD,d Robert M. Day PhD,e ChiaChi Hu EdM,e Peter H. Schafer PhD,e and James G. Krueger MD PhDf
aDepartment of Dermatology, Tufts Medical Center, Boston, MA
bOregon Medical Research Center, PC, Portland, OR
cDermatology Research Center, Baylor University Medical Center, Dallas, TX
dDepartment of Dermatology, Saint Louis University School of Medicine, St. Louis, MO
eCelgene Corporation, Summit, NJ
fLaboratory for Investigative Dermatology, Rockefeller University, New York, NY
BACKGROUND: Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediators. This phase II, multicenter, open-label study evaluated the efficacy, tolerability, and pharmacodynamics of apremilast in patients with recalcitrant plaque psoriasis.
METHODS: This multicenter, open-label study comprised four phases: pre-treatment (≤35 days), treatment (12 weeks), extension (12 weeks), and observational follow-up (4 weeks). Patients with recalcitrant plaque psoriasis received apremilast 20 mg BID for 12 weeks. Responders (≥75% improvement in Psoriasis Area and Severity Index [PASI-75]) continued treatment and non-responders (< PASI-75) were titrated to apremilast 30 mg BID through week 24. Efficacy assessments included change in static Physician's Global Assessment, PASI, and body surface area, and proportion of patients achieving PASI-50, PASI-75, and PASI-90. Other assessments included adverse events, lesional skin biopsies to assess changes in epidermal thickness, and immunohistochemistry to assess changes in peripheral blood subsets.
RESULTS: A total of 30 patients were enrolled. At week 12, 67% of patients had a ≥1-point improvement in static Physician’s Global Assessment, meeting treatment effect criterion. Mean percent decreases (improvements) from baseline were –59% for PASI score and –53% for body surface area. Most adverse events were mild. Median reduction in epidermal thickness was 34% at week 12 (P=0.083); five patients showed absence of keratin 16. Significant reductions in CD11c, CD3, and CD56 indicate that apremilast reduced myeloid dendritic cell, T-cell, and NK-cell or NK–T-cell infiltration into the epidermis and dermis. Reduced inflammatory leukocytes, with a pattern of broad, partial inhibition, suggested reduced IL-23/Th17 and Th22 response pathways.
CONCLUSIONS: These results confirm apremilast's biological and clinical activity and support ongoing studies in psoriasis. Clinicaltrials.gov Identifier: NCT00521339.
J Drugs Dermatol. 2013;12(8):888-897.
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Psoriasis treatment with traditional systemic or biologic therapies may be compromised by safety and tolerability concerns, administration (injection versus oral), and lack/loss of response.1-5 Efficacious, safe, well-tolerated, and easy-to-use treatment options remain a goal for psoriasis patients.
Cyclic adenosine monophosphate (cAMP) is a naturally occurring intracellular secondary messenger that functions as a modulator of inflammatory responses.6,7 Phosphodiesterase 4 (PDE4) is the predominant PDE in inflammatory cells and present in keratinocytes.8 Apremilast (Celgene Corporation, Summit, NJ), a small molecule specific inhibitor of PDE4, works intracellularly to elevate cAMP levels, modulating a network of inflammatory mediators implicated in psoriasis and psoriatic arthritis (PsA).9-11 In preclinical studies, apremilast reduced production of pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α, IL-23, and interferon-γ, and increased production of anti-inflammatory mediators, such as IL-10.8 Apremilast has shown efficacy in moderate to severe plaque psoriasis and active PsA12-14 and is in phase III studies for psoriasis, PsA, and ankylosing spondylitis. This phase II, open-label study assessed the efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis.
This phase II, multicenter, open-label study evaluated the efficacy, tolerability, safety, and pharmacodynamics of apremilast in patients with recalcitrant plaque psoriasis from August 2007 to May 2009 at four US centers. The study comprised four phases: pre-treatment (≤35 days), treatment (12 weeks), extension (12 weeks), and observational follow-up (4 weeks). Patients received oral apremilast 20 mg BID for 12 weeks. A one-time apremilast dose reduction to 20 mg QD was allowed for patients unable to