Emerging Oral Immunomodulators for the Treatment of Psoriasis: A Review of Phase III Clinical Trials for Apremilast and Tofacitinib

August 2015 | Volume 14 | Issue 8 | Original Article | 786 | Copyright © August 2015

Rachel McAndrew MD,a,b Ethan Levin MD,b and John Koo MDb

aMichigan State University, College of Human Medicine, East Lansing, MI
bUniversity of California San Francisco, Department of Dermatology, San Francisco, CA

BACKGROUND: Increased knowledge of the molecular regulatory mechanisms that contribute to the pathogenesis of psoriasis and other inflammatory diseases has created new opportunities for the development of targeted drug therapy for inflammatory conditions. Two new oral medications, apremilast and tofacitinib, have been developed for their immunomodulatory properties, and their potential efficacy in treating psoriasis is being evaluated.
METHODS: We reviewed phase III randomized, placebo-controlled clinical trial results for apremilast and tofacitinib for efficacy and safety in psoriasis.
RESULTS: Psoriasis Area and Severity Index (PASI) 75 after 16 weeks for apremilast was between 28.8% and 33.1%. PASI 75 was 39.5% after 12 weeks on tofacitinib 5 mg, and 63.6% after 12 weeks on tofacitinib 10 mg. Common side effects for both drugs included nasopharyngitis and upper respiratory tract infections. Gastrointestinal disturbance was common for apremilast. Dyslipidemia and infections were more common with tofacitinib than placebo.
CONCLUSION: Both new oral medications, apremilast and tofacitinib, appear to be effective in treating psoriasis.

J Drugs Dermatol. 2015;14(8):786-792.


Psoriasis is a chronic immune-mediated inflammatory condition that affects approximately 2.6% of the population of the United States.1 Psoriasis affects men and women alike, and although the prevalence is much higher in Caucasians, it afflicts people from all different ethnic backgrounds.1 For some, psoriasis may only be a mild nuisance, while for others it can be a widespread, debilitating problem. The negative psychological impact of untreated psoriasis was shown to be similar to the impact of major medical conditions such as breast cancer, coronary artery disease, congestive heart failure, and diabetes.2 Not only do psoriasis patients experience similar psychological effects to those with major systemic medical problems, but they are also at a higher risk of developing co-morbidities such as cardiovascular disease, metabolic syndrome, and diabetes.3
The development of new oral immunomodulatory medications has shown promising results in the treatment of psoriasis. This paper reviews current concepts regarding the pathogenic mechanisms in psoriasis, and specifically the targets for the new small molecule oral medications, apremilast (Otezla®), and tofacitinib (Xeljanz®). This paper also presents the most up-to-date phase III clinical trial data for these medications in the treatment of moderate-to-severe psoriasis.

Pathogenesis of Psoriasis

The understanding of the pathogenesis of psoriasis has been evolving in science for years. The Th1 pathway (including interleukin (IL)-2, IL-12, tumor necrosis factor-α, and interferon-γ) has traditionally been implicated in the pathogenesis.4,5 More recently, the involvement of the Th17 pathway (including IL-17, IL-22, and IL-23) has been elucidated as the major pathogenic pathway in psoriasis.6-8 Both apremilast and tofacitinib have demonstrated effects on the Th1 and Th17 pathways implicated in the pathogenesis of psoriasis (Figure 1).

Role of Phosphodiesterase 4 in Psoriasis

Apremilast is a small molecule inhibitor of phosphodiesterase (PDE)-4. The PDEs are a family of intracellular enzymes found in many cell types, and the PDE4 isotype is especially abundant in immune cells.9,10 The PDEs are the sole means of cyclic adenosine monophosphate (cAMP) degradation.11 cAMP is a secondary messenger whose activity modulates cellular inflammation. The inhibition of PDE4 allows cAMP to remain active in immune cells. The increased activity of cAMP enhances the activity of the transcription factor CREB (cAMP response element-binding protein), while inhibiting another transcription factor, nuclear factor (NF)-κβ.12 NF-κβ is responsible for the