Michael Abrouk, MD1; Jessica Gandy, MD1; Mio Nakamura, MD2; Kristina Lee, MS2; Merrick Brodsky, MD1; Rasnik Singh, MD3; Henry Zhu, MD4; Benjamin Farahnik, MD5; Tina Bhutani, MD2; John Koo, MD2 

1Irvine School of Medicine, University of California, CA, USA
2Department of Dermatology, Psoriasis and Skin Treatment Center, University of California – San Francisco, San Francisco, CA, USA
3David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA, USA
4Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
5The Larner College of Medicine, University of Vermont, Burlington, VT, USA 

Conflicts of Interest:
JK is a speaker for AbbVie, Leo, and Celgene. JK conducts research for Amgen, Janssen, Novartis, Photomedex, Galderma, Pfizer and Merck. BF is an advisor for Cutanea. BF conducts research for Abbvie, Janssen, and Merck. JK and BF have no stocks, employment or board memberships with any pharmaceutical company. The other authors report no conflicts of interest.

ABSTRACT
While there are several commercially available treatment options for psoriasis and psoriatic arthritis, there remains a large number of individuals who are refractory to current modalities. In the recent past, there has been increasing evidence that interleukin (IL)-17 plays a vital role in the pathophysiology of psoriasis. Preclinical, phase II, and phase III studies of secukinumab (Cosentyx®) targeting IL-17 and its receptor have thus far proved to be promising. We reviewed the results of phase II and phase III clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only published studies were considered in the present review. We also performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumab OR AIN457) AND (psoriasis OR psoriatic arthritis). In our review of the literature, seven phase III and five phase II clinical trials, as well as open-label extension studies with unpublished findings were found. Results from phase III clinical trials indicated secukinumab to be efficacious and safe for the treatment of psoriasis and psoriatic arthritis according to Psoriasis Area and Severity Index (PASI) and American College of Rheumatology (ACR) scores. The safety profile of this agent was similar across all studies, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. Secukinumab demonstrates rapid and robust clinical improvement accompanied by a favorable short- term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis and psoriatic arthritis treatment. Additional extension studies of lower level evidence are needed to further understand the safety profile of the drug.

Key Words:
anti-interleukin-17, biologics, IL-17A, psoriasis, psoriatic arthritis, secukinumab, therapy

Introduction

Psoriasis is a common, multifaceted chronic inflammatory disease of the skin that affects 3-4% of the adult population in the United States, with 5-30% suffering from concurrent psoriatic arthritis.1,2 The pathogenesis is largely multifactorial with a combination of immune dysregulation, genetic susceptibility, and environmental factors; thus, there is a wide range of disease severity and areas of involvement. While there are a number of available treatment options currently on the market, there are still many individuals who remain refractory to these modalities.

Since there still remains a large population of individuals who are resistant to current treatment methods, the need for further research to develop novel therapeutic modalities is great.3,4The interleukin (IL)-17 pathway has demonstrated significant potential as a new target for treatment. As a proinflammatory cytokine, IL-17 is produced by type 17 helper (Th-17) T cells and is a downstream product of IL-23.5-8 The IL-17 pathway mediates a diverse set of biological responses that contribute to the eventual in ammation, activation and recruitment of neutrophils, cessation of neutrophil apoptosis, and angiogenesis.9-12 There has also been increasing research of IL-17, including the the IL-17 receptor, and its expression in synovial tissues, as well as its importance in the pathogenesis of psoriatic arthritis.13-15 To futher support the role of IL-17 in psoriatic disease, studies have demonstrated elevated levels of IL-17 in both the serum and lesions of patients with active psoriasis.16-21

One of the newest biologic agents approved by the US FDA for the treatment of psoriasis is secukinumab (Cosentyx®), a fully human monoclonal antibody. Secukinumab acts by inhibiting the effector function of IL-17A and has been shown in previous studies to be better than placebo and etanercept.22 Herein, we review the data regarding the efficacy and safety of secukinumab in patients with moderate-to-severe plaque psoriasis.

Mechanism of Action and Pharmacokinetics

Secukinumab is a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds and neutralizes IL-17A. IL-23 activates Th-17 cells, which release IL-17.23 IL-17 release increases expression of proinflammatory cytokines leading to recruitment of immune cells, activation of keratinocytes, and enhancement of angiogenesis. This can eventually lead to synovial inflammation and psoriatic plaque development.23 Secukinumab has been administered either subcutaneously (SC) at a low, medium or high dose (75 mg, 150 mg, 300 mg) or intravenously (IV) at a dose of 10 mg/kg.24 Secukinumab is available in 150 mg pre-filled syringes or injection pens. The FDA approved dosing for the treatment of psoriasis with secukinumab consists of SC injections with a loading dose of once weekly 300 mg injections for the first 4 weeks for induction, followed by 300 mg every 4 weeks thereafter for maintenance. A dose of 150 mg was acceptable for some patients.23 For patients being treated for psoriatic arthritis, the dosing schedule is as follows: secukinumab is administered with a SC injection of 150 mg every week for the first 4 weeks as a loading dose, followed by 150 mg every 4 weeks thereafter. For patients with both psoriasis and psoriatic arthritis, the psoriasis dosing is recommended. Maximal plasma concentration is reached in approximately 6 days and the mean half-life is 27 days with an average bioavailability of 73%. Typically, secukinumab takes the form of a lyophilized formulation that can be reconstituted.23 However, two clinical trials, FIXTURE and JUNCTURE, have detailed the various preparations and dosing forms of secukinumab, which includes a liquid formulation delivered either via pre- lled syringe or an auto-injector pen, respectively.22,25

Methods

We reviewed the results of clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only completed studies were considered in the present review; recruiting, not yet recruiting, withdrawn and terminated trials were eliminated (Table 1). In order to identify any other studies that may have assessed secukinumab, we performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumabWe reviewed the results of clinical trials for secukinumab in the treatment of psoriasis OR AIN457) AND (psoriasis OR psoriatic arthritis). We also reviewed citations within articles to identify relevant resources. Overall measures of efficacy and incidence of adverse events for each medication were calculated by tabulating values from independently conducted studies (Table 2). To the best of our knowledge there was only one open label extension study and no studies of lower level of evidence (3, 4, or 5), such as case series or case reports, commenting on the efficacy or side effects of secukinumab on a smaller scale.26

TrialFirst AuthorComparatorNDosing
JUNCTUREPaulPlacebo404Secukinumab 150 mg SC single administration at week 0, or 150 mg SC at weeks 0, 1, 2, 4, or 150 mg SC at weeks 0, 4, 8, or placebo
FEATUREBlauveltPlacebo177Secukinumab 150 mg or 300 mg SC once weekly between weeks 0 and 4, and once again at week 8, or placebo
ERASURELangleyPlacebo738Secukinumab 150 mg or 300 mg SC once weekly for 5 weeks then every 4 weeks, or placebo
FIXTURELangleyEtanercept1306Secukinumab 150 mg or 300 mg SC once weekly for 5 weeks then every 4 weeks, or etanercept SC twice weekly for 12 weeks then once weekly, or placebo
ERASURE subanalysisOhtsukiPlacebo87Secukinumab 150 mg or 300 mg SC once weekly for 5 weeks then every 4 weeks, or placebo
SCULPTUREMrowietzPlacebo966Secukinumab 150 mg or 300 mg SC weekly for 5 weeks then once at week 8, then at week 12 patients achieving PASI75 were re-randomized to either 150 mg or 300 mg SC given at fixed interval or retreatment as-needed regimen
STATUREThaciPlacebo43Secukinumab 10 mg/kg IV at baseline, weeks 2 and 4, or 300 mg SC at baseline and week 4
CLEARThaciUstekinumab676Secukinumab 300 mg SC at weeks 0, 1, 2, 3, and every 4 weeks starting at week 4, or ustekinumab 45 mg or 90 mg SC (depending on subject body weight at baseline) at weeks 0 and 4 and then every 12 weeks
FUTURE 1MeasePlacebo606All patients assigned to receive an IV loading dose of secukinumab at a dose of 10 mg/kg at 0, 2, and 4 weeks followed by secukinumab SC at a dose of either 150 mg or 75 mg every 4 weeks or placebo. Placebo group was switched to secukinumab SC at a dose of 150 mg or 75 mg at week 16 or 24 depending on the clinical response.
FUTURE 2McInnesPlacebo397Secukinumab 300 mg or 150 mg or 75 mg SC to receive once a week from baseline and then every 4 weeks from week 4
Table 1. Phase III clinical trial data for secukinumab

 

EndpointStudySecukinumab 300 mgSecukinumab 150 mgSecukinumab 75 mgPlaceboEtanercept 50 mgUstekinumab 45 mg or 90 mg
PASI75ERASURE81.6%†71.6%†—4.5%——
FIXTURE77.1%†*67%†*—4.9%44%—
FEATURE75.9%‡69.5%‡—0%——
JUNCTURE86.7%‡71.7%‡—3.3%——
CLEAR91%¢————79.1%
FUTURE 1—61.1%*64.8%*8.3%——
FUTURE 263%‡48%‡28%‡16%——
SCULPTUREBy week 12: 90.1%By week 12: 84.4%————
Fixed interval: 84.4% week 52: 59.7%Fixed interval: 62.1% week 52: 45.8%————
Retreatment as needed: 67.6% week 52: 13.8%Retreatment as needed: 52.4% week 52: 11.2%————
PASI90ERASURE59.2%†39.1%†—1.2%——
FIXTURE54.2%†*41.9%†*—1.5%20.7%—
FEATURE60.3%‡45.8%‡—0%——
JUNCTURE55%‡40%‡—0%——
CLEAR72.8%¢————53.4%
FUTURE 1—45.3%*49%*3.6%——
FUTURE 249%**33%**12%**9%——
PASI100ERASURE28.6%†12.8%†—0.8%——
FIXTURE24.1%|*14.4%|*—0%4.3%—
FEATURE43.1%‡8.5%¤—0%——
JUNCTURE26.7%‡16.7%¶—0%——
CLEAR8.9%¥————25.7%
IGA 0/1ERASURE65.3%†51.2%†—2.4%——
FIXTURE62.5%†*51.1%†*—2.8%27.2%—
FEATURE69%‡52.5%‡—0%——
JUNCTURE73.3%‡53.3%‡—0%——
CLEAR80.8%¢————65.1%
ACR50FUTURE 1—34.6%*30.6%*7.4%——
FUTURE 235%‡35%‡18%‡7%——
ACR20FUTURE 1—50%*50.4%*17.3%——
FUTURE 254%‡51%‡29%‡15%‡——
Table 2. Primary and secondary endpoints at week 12 for secukinumab compared to placebo, etanercept, and ustekinumab
Disclaimer: These data were tabulated from independent studies that were not conducted in a head-to-head manner.PASI: Psoriasis Area and Severity Index; values indicate percentage improvement of cutaneous symptomsIGA: Investigator’s global assessment†P<0.001 for the comparison with placebo| No comparison with placebo was performed because there were no patients with a response in the placebo group*P<0.001 for the comparison with etanercept**P<0.0005 for the comparison with placebo‡P<0.0001 for the comparison with placebo¤P=0.057 for the comparison with placebo‡‡P=0.057 for the comparison with placebo¶P=0.0006 for the comparison with placebo¢P<0.0001 for the comparison with ustekinumab¥P=0.0003 for the comparison with ustekinumab

Clinical Trials

Phase I/II Trials

Sun protection should also be recommended to acne patients.8 A systemic review found no convincing evidence that natural sunlight improves acne, although such studies are inherently difficult to conduct.9 Several oral acne treatments, including doxycycline and isotretinoin, are potentially photosensitizing.10 The US Food and Drug Administration official labelling for medications containing benzoyl peroxide and topical retinoids advises sun avoidance,11,12 although no effect on ultraviolet Binduced erythema was shown with use of either benzoyl peroxide or adapalene in one study13. In addition to providing sun protection, the emollient component of the sunscreen may improve epidermal barrier function. Finally, sun protective measures may prevent or minimize postinflammatory hyperpigmentation, particularly in patients with higher skin types.14

Phase III Trials

Seven phase III clinical trials have been completed to determine the efficacy and safety of different doses of secukinumab for plaque psoriasis and psoriatic arthritis.24,28,31-35 The most recent trials, FUTURE 1 and FUTURE 2, essentially validated IL-17A as a therapeutic target for the treatment of psoriasis and psoriatic arthritis. In the FUTURE 2 phase III, double-blind, placebocontrolled study, patients receiving the 300 mg, 150 mg and 75 mg doses were found to achieve a significantly higher American College of Rheumatology (ACR20) score at week 24 compared with placebo. The most common adverse events reported were urinary tract infections and nasopharyngitis.31 FUTURE 2 is the first large phase III trial for secukinumab. Data from week 52 suggests that the efficacy of the drug at higher dosages (300 mg and 150 mg) can be sustained over long periods of time.28 In FUTURE 1, another randomized, double-blind phase III trial, the efficacy of IV secukinumab (10 mg/kg) followed by SC dosing vs. placebo was evaluated. In this study, patients with psoriatic arthritis received IV secukinumab at weeks 0, 2, and 4 followed by either placebo or a SC dose of either 150 mg or 75 mg every 4 weeks. The primary endpoint was a 20% improvement from baseline in the ACR20 by week 24. ACR20 scores at week 24 were significantly higher in the group receiving the SC secukinumab vs. the IV dosing paired with placebo. The most common adverse events were nasopharyngitis, headache, upper respiratory tract infection, and diarrhea. Serious adverse events included stroke (4), myocardial infarction (2) vs. no serious adverse events (AEs) in the placebo group.24

ERASURE, a two-phase III double-blind, 52-week trial used the PASI75 to compare secukinumab to placebo. Langley et al. demonstrated that secukinumab at 300 mg and 150 mg SC was significantly superior in treating psoriasis compared to placebo. This trial showed that the 300 mg and 150 mg SC doses of secukinumab were markedly more effective in treating psoriasis than etanercept. In an ERASURE 52-week subanalysis published by Ohtsuki et al., secukinumab was found to be efficacious in the long-term treatment of plaque psoriasis in Japanese patients.22,36

In a different study with a similar design by Langley et al., the FIXTURE trial compared secukinumab to placebo and etanercept. This trial showed that secukinumab 300 mg was superior to etanercept 50 mg twice weekly in terms of proportion of patients reaching PASI75 (77.1% vs. 44%, respectively) and PASI90 (54.2% vs. 20.7%, respectively) (P<0.001 for all groups compared to placebo).22

FEATURE and JUNCTURE each compared the efficacy of secukinumab to placebo when administered by pre-filled syringe (FEATURE) and auto-injector pen (JUNCTURE). Both studies by Blauvelt et al. and Paul et al., respectively, demonstrated that secukinumab administration via either syringe or injector pen was effective with acceptable safety profiles.25,33,34

The CLEAR trial compared secukinumab to ustekinumab, demonstrating secukinumab 300 mg was more efficacious than ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg) in terms of proportion of patients achieving PASI75 (91% vs. 79.1%, respectively) and investigator’s global assessment (IGA) of 0 or 1 (80.8% vs. 65.1%, respectively). The SCULPTURE trial investigated the retreatment as-needed protocol vs. fixed interval regimen of secukinumab dosing. At week 12, patient outcomes were assessed with the PASI75, at which point participants were re-randomized to two new groups: retreatment as-needed or fixed interval dosings. The primary endpoint was maintaining PASI75 results until week 52. Mroweitz et al. demonstrated that secukinumab at fixed interval dosing (every 4 weeks after the initial loading dose) conferred clear benefit vs. the retreatment as-needed model. Both protocols showed that AEs were comparable to other trials with no serious AEs noted. Although both protocols require further study.25,33,34

By week 12, the five studies comparing secukinumab to placebo each demonstrated statistically significant superiority of secukinumab over placebo at all SC dosings. Within these studies, the proportion of patients reaching PASI75 was statistically significant for all dosing levels of secukinumab (300 mg, 150 mg, and 75 mg) vs. comparators and placebo. Secukinumab was similarly superior to placebo in terms of IGA 0/1, ACR20, ACR50, PASI90, PASI100, and the Dermatology Life Quality Index (DLQI) (Table 2). The most common AEs among the studies were nasopharyngitis, headache, upper respiratory tract infection, and diarrhea. Mild and transient neutropenia, without associated infections, was noted in a minority of patients in each trial. Some serious adverse effects observed in the FUTURE 1 trials were stroke and myocardial infarction (Table 1).

Cost-Utility of Secukinumab

Currently, there have been only a few studies detailing the costbenefit analysis of secukinumab for moderate-to-severe plaque psoriasis. Lee et al. evaluated the cost utility of secukinumab, as well as other systemic biologic agents, compared with the standard of care, which was arbitrarily defined as methotrexate, cyclosporine, topical corticosteroids, or phototherapy.37 The investigators demonstrated that secukinumab was associated with the second highest total cost ($70,313 Canadian dollars). The lowest cost was the standard of care. However, the highest quality of life (QoL) gains were found with secukinumab 300 mg. Thus, while the standard of care with non-biologics remains the most appropriate option in terms of cost analysis, Lee et al. posits that biologic agents, especially secukinumab, yield substantial QoL gains. Since psoriasis and psoriatic arthritis can be debilitating conditions in terms of their impact on QoL, productivity loss, psychosocial issues and individual burden of disease, biological agents such as secukinumab have the potential to replace the standard of care due to marked improvements in QoL.15,18-20,23,29,32-34,38-44

Discussion

Secukinumab has the potential to address the unmet needs of patients with psoriasis refractory to current treatment modalities. The results of phase III clinical trials reinforce IL-17 as an essential therapeutic target and demonstrate the overall efficacy of secukinumab in the treatment of psoriasis and psoriatic arthritis. In the treatment of psoriasis, secukinumab was found to perform significantly better than several contemporary biologic agents currently in use, such as etanercept and ustekinumab. Within the context of these studies, there were no substantial differences noted in the safety profiles of secukinumab compared with other biologic agents; the most common AEs included nasopharyngitis, upper respiratory infection, and headache. However, there were several other AEs that were unique to secukinumab and not observed with etanercept, adalimumab, or ustekinumab. Some of the AEs unique to secukinumab were neutropenia, diarrhea and candidiasis, but was thought to be IL-17 specific. A small portion of patients experienced low-grade neutropenia with each of the agents, though these episodeswere self-controlled and transient. Mild or moderate Candida infections were more frequent with secukinumab compared with etanercept, ustekinumab, and placebo. No patients discontinued the study drug due to Candida infections and no serious or invasive fungal infections were reported in any of the studies.

Recent epidemiologic studies suggest that treating psoriasis with systemic immunosuppressant therapies leads to a reduction of cardiovascular events such as myocardial infarction and stroke. Interestingly, IL-17 has been measured in atherosclerotic plaques and thought to play an important role in overall plaque formation. Past studies have reported elevated levels of IL-17 in patients suffering from unstable angina and acute myocardial infarction. In tandem, these findings suggest that blocking the IL-17 pathway through biologic agents, such as secukinumab, has the potential to reduce the overall risk of cardiovascular events in patients with psoriasis. However, we do not yet have any long-term data for this medication, unlike the long-term safety and efficacy data available for other biologics like etanercept and adalimumab. While the initial clinical results reviewed here look promising, more long-term data is needed for secukinumab.15,18-20,23,29,32-34,38-44

Conclusion

Secukinumab has the potential to address the unmet needs of patients with psoriasis and psoriatic arthritis recalcitrant to current treatment modalities. The phase III clinical trials suggest that anti-IL-17 inhibitors have improved efficacy compared to available biologic agents and placebo. Relative to the standard of care with non-biologic therapies, secukinumab is superior in terms of overall QoL scores. Further long-term studies are necessary to confirm the favorable efficacy and safety profiles of this biologic agent demonstrated in phase III trials.

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