Upcoming Psoriasis Treatments
Total Page：16
File Type：pdf, Size：1020Kb
RPesidentediatric C doermatologyRneR In the Pipeline for Psoriasis: Upcoming Psoriasis Treatments George Han, MD, PhD Psoriasis is a chronic debilitating disease in several decades according to one population-based which dermatologists take a frontline role in study.2 Currently, psoriasis affects 1% to 8% of the improving the quality of life of affected patients. worldwide population depending on the country3 and Although recent years have seen the advent of certainly represents one of the bread-and-butter skin numerous new medications for the treatment of conditions that fall under the care of dermatologists. psoriasis, there still is considerable room for Improvements in psoriasis therapies over the last improvement in our treatment of this condition. decade have revolutionized the treatment of this Novel insights into the underlying mechanisms debilitating condition, including increased use of bio- of psoriasis have yielded excitingCUTIS new potential logics as well as refinements in both administration medications, many with promising preliminary (dose timing) and mechanism of action. Meanwhile, efficacy data. The upcoming systemic agents for many novel and exciting therapies currently are in the treatment of psoriasis are presented in this the pipeline, ranging from developmental stages article, encompassing novel biologics and small- to clinical trials, that target various cytokines and molecule medicines (eg, IL-17 receptor blockers, regulatory molecules involved in the pathogenesis Janus kinase [Jak] inhibitors). The underlying of psoriasis. This article will provide an overview of mechanismsDo and currently availableNot data for each new andCopy upcoming systemic agents for the treatment drug will be discussed to impart a working knowl- of psoriasis as well as the currently available data for edge of these new treatment options to dermatol- each drug. It is important for dermatology residents ogy residents, as these drugs may soon be added to become familiar with these therapies, as they may to our armamentarium for treating psoriasis. soon become widely available. Cutis. 2014;93:E12-E16. Novel Biologics Biologic agents, which are protein-based drugs made soriasis is an extremely important disease entity from living cells, constitute several currently available for dermatologists, affecting patients’ quality therapies for psoriasis. The earliest and most widely Pof life to a similar degree as other chronic available drugs in this family include etanercept, medical conditions such as diabetes mellitus and adalimumab, and infliximab. Central to this class of congestive heart failure.1 The incidence of psoriasis drugs is the concept that psoriasis is a helper T cell in the United States is rising, doubling within the last (TH1) disease that involves the interaction between T cells and antigen-presenting cells in psoriatic plaques. These agents target proinflammatory cyto- kines, such as tumor necrosis factor a (TNF-a). Although several TNF-a agents are already in use, From Albert Einstein College of Medicine/Montefiore Medical new products are coming to market and gaining Center, New York, New York. The author reports no conflict of interest. approval for psoriasis and/or psoriatic arthritis. For Correspondence: George Han, MD, PhD instance, certolizumab has shown not only a sig- ([email protected]). nificantly increased achievement of psoriasis area E12 CUTIS® WWW.CUTIS.COM Copyright Cutis 2014. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Resident Corner and severity index (PASI) 75 response (ie, PASI regulators of psoriasis may have increased efficacy and ≥75% decrease from baseline) but also a significantly created a more favorable safety profile, several drugs improved PASI 90 response as compared to control targeting IL-17 are under development, with some (P.001)4; to put this finding in context, the rates extremely promising early-stage results. of PASI 90 for the higher dose (400 mg) of certoli- Perhaps no class of drugs is as anxiously awaited zumab approached 50%, while the PASI 90 for etan- as the IL-17 receptor blockers.11 The IL-17 family of ercept was approximately 23% in numerous studies.5,6 cytokines encompasses 6 different molecules: IL-17A Golimumab, another TNF-a agent, also has been to IL-17F.12 Of these molecules, at least IL-17A and approved for the treatment of psoriatic arthritis. IL-17F have been implicated in a wide variety of The arrival of ustekinumab, which targets the inflammatory diseases, including psoriasis, multiple p40 protein subunit of IL-12 and IL-23, was accom- sclerosis, systemic lupus erythematosus, inflammatory panied by some degree of fanfare, as it went head- bowel disease, and chronic mucocutaneous candi- to-head against etanercept in a well-publicized trial diasis.13-17 Overall, development of specific IL-17 that showed increased efficacy in treating psoriasis treatment reflects the paradigm that targeting more as measured by PASI scores.6 Development of novel specific key regulators in the pathway of keratinocyte therapeutics in this class has been centered on identi- activation may lead to improved clinical efficacy fying new molecules in the proinflammatory cascade while mitigating side effects, such as having less sup- or more specific targets (Figure). For some time, it pressive effects on overall immune defense. Indeed, was thought that IL-12 played a more important role the preliminary data from trials of agents targeting than IL-23 (both targeted by ustekinumab) due to IL-17 are very promising. Brodalumab is a human the effects of IL-12 on IFN-; however, further stud- monoclonal antibody targeting the IL-17 receptor ies ultimately revealed that IL-23 is the more critical that inhibits binding of most of the IL-17 subtypes cytokine, as it is intimately involved in regulating to the receptor. In phase 2 trials (N198), the mean TH17 cells and is a potent activator of keratinocyte PASI scores were greater than 85% for the higher proliferation.7,8 Thus, although IL-12 does play a role doses tested (40, 210, and 280 mg), which were in driving keratinocyte activation through IFN- significantly greater compared to placebo (P.001), production, IL-23 has provenCUTIS to be the more impor- with a large proportion of patients achieving tant molecule. Several new drugs that specifically tar- PASI 90 or PASI 100.18 These results were remarkable, get IL-23 such as guselkumab and tildrakizumab also as such high rates of clearance had not been previ- are under development. Meanwhile, further research ously observed with any other biologics. At the same has clarified that downstream of IL-23, TH17 cells time, results of a phase 2 trial of ixekizumab (N142), further secrete IL-17 and IL-22, which act as critical a humanized IgG4 monoclonal antibody against regulators of keratinocyte development, angiogenesis, IL-17A, were released.19 Psoriasis area and sever- and Dofurther cytokine release Notin psoriatic plaques.9 ity indexCopy scores were significantly improved versus Although fezakinumab was being studied to target placebo (P.001). In the high-dose group (150 mg), IL-22, development was discontinued as of August more than 80% of patients achieved PASI 75, 2011.10 Following the general idea that more specific more than 70% of patients achieved PASI 90, and nearly 40% of patients achieved PASI 100 with complete clearance of psoriatic lesions.19 A third agent, secukinumab was developed as a human IgG1 monoclonal antibody to IL-17A. Phase 2 tri- als encompassing 404 patients also were conducted showing PASI 75 rates of more than 50% and more Tofacitinib TH1 IFN-␥ Ruxolitinib than 40% in the early and monthly dosing regimens, IL-12 Baricitinib respectively, both significantly improved from pla- Ustekinumab Jak/STAT pathway cebo (P.001).20,21 Myeloid IL-23 TH17 Dendritic IL-17 Keratinocyte Cell Activation Tildrakizumab Brodalumab Guselkumab Ixekizumab Small Molecules Secukinumab TNF-␣ Although the field of biologic therapy is experi- TH22 Etanercept encing rapid growth with many new agents under Adalimumab IL-22 Iniximab development, the manufacture of biologic agents remains expensive and complex. An advantage of small molecules is that they are easier to manufac- ture and may be administered orally, a characteristic Psoriasis pathway and targets of selected agents. that would certainly be preferable over injections WWW.CUTIS.COM VOLUME 93, MARCH 2014 E13 Copyright Cutis 2014. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Resident Corner for many patients. Although older medications formulation of phosphodiesterase-4 also is under (eg, methotrexate) have long been a part of the development, with phase 2 trials of AN2728 revealing dermatologist’s armamentarium for treatment of pso- significantly improved overall target plaque severity riasis, there also are newer targeted therapies on score of areas treated with the higher concentration the horizon. 2% ointment as compared to control (P.004)(dis- Janus kinases (Jak) are intracellular tyrosine crete untreated plaques on the same individual served kinases that respond to cytokine signaling to medi- as self-controls in this trial).29 Another novel target is ate the STAT pathway. Overall, these kinases are sphingosine-1-phosphate receptor 1, or S1P1, which involved in responding to signals from proinflamma- is a G protein–coupled receptor on endothelial cells tory