¹SKiN Centre for Dermatology, Peterborough, ON, Canada
²Queen’s University, Kingston, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada
⁴K Papp Clinical Research, Waterloo, ON, Canada

Conflict of interest:
Fabian Rodriguez-Bolanos has no conflicts of interest. Melinda Gooderham and Kim Papp have been an investigator, speaker, advisory board member and consultant for Valeant Pharmaceuticals.

Abstract
The ili (IL)-17 inhibitors have proven to be highly effective in the treatment of psoriasis. The most recently approved agent, brodalumab, had few cases of suicidal behavior, including completed suicide, in the phase 3 clinical program leading both the US FDA and Health Canada to add a boxed warning to its label. This raises the importance of identifying the psychiatric comorbidities associated with psoriasis. It is also necessary to critically examine the data from the brodalumab clinical trial program to determine whether there is enough information to establish causality and whether other factors, other than the drug, could be playing a role.

Key Words:
biologics, brodalumab, IL-17, plaque psoriasis, Siliq, suicidal ideation and behavior

Introduction

Psoriasis is a prevalent skin condition.¹ Plaque psoriasis is the most common type of psoriasis in all populations.² The impact of psoriasis is magnified by its nature and chronicity, which can lead to important psychological morbidity. It can significantly affect quality of life, even when the disease is not extensive.³

We are starting to understand the complexity of this disease, in which different genetic, immunologic and environmental factors all play a part.⁴ Psoriasis is considered a multisystem, immunemediated inflammatory disease.⁵ It has been observed epidemiologically that the frequency of some noncutaneous disorders and conditions is significantly higher in the psoriatic population, including rheumatologic, inflammatory bowel, cardiovascular, metabolic, and psychiatric/psychological diseases.⁶

By further elucidating the immune mechanisms involved, research has allowed for the development of targeted therapies. Brodalumab, a human monoclonal immunoglobulin G2 (IgG2) antibody directed at the interleukin (IL)-17 receptor A, is one of the latest medications to be approved for the treatment of moderate to severe plaque psoriasis. With data from research trials demonstrating impressive efficacy in clinical score improvement in psoriatic patients, brodalumab is proving to be a useful addition to our therapeutic arsenal.^7-8

There have been some concerns regarding suicidal ideation and behavior (SIB) in patients treated with brodalumab, as four cases of suicide were documented during clinical trials. Because of these reports, a boxed warning was added to the monograph of the drug. The importance of this issue has prompted the authors to take a careful look through these cases in order to gain better insight into patient-specific contributing factors. The authors examined salient features of each incident, compared reports of SIB with other biologics and explored the complex relationship between inflammatory diseases, such as psoriasis, depression and suicidal ideation.

Mental Health and Psoriasis

It is not an understatement to say that the disease carries a burden which is not only physical but also psychological. Although the mechanisms of the relationship are not well understood and underestimated in its affects, psoriasis has long been recognized to be associated with adverse impacts on mental health. In the 1960s a popular ad campaign labeled the emotional burden of this skin disease as the “heartbreak of psoriasis”.⁹ Studies have reported that up to half of patients with psoriasis experience, at some point during their disease, helplessness and isolation that can lead to functional limitations, impacting them socially and psychologically.^10-11

In general, SIB is not uncommon. According to the World Health Organization (WHO), about 804,000 suicide deaths occurred in 2012 worldwide.¹² It is an important public health problem with complex and multiple risk factors, including a combination of demographic, social and cultural influences. A study by Vilhjalmsson et al. found that adults are more likely to contemplate suicide under certain conditions, such as highly stressful domestic, financial, and particularly legal circumstances; SIB is also more pervasive in individuals who experience extensive physical health problems and perceive their lives as stressful.¹³ A cross-national study reported an estimated lifetime prevalence of suicidal ideati on, plan, and attempt in the overall sample of 9.2%, 3.1%, and 2.7%, respectively.¹⁴

Suicidal behavior includes both attempted suicide and completed suicide. A systematic review with meta-analysis by Singh et al. reported that psoriasis patients were more than twice as likely to have suicidal ideation than those without psoriasis (odds ratio [OR], 2.05; 95% confidence interval [CI], 1.54–2.74).¹⁵ This same study also documented that patients with psoriasis have a higher likelihood of suicide attempts (OR, 1.32; 95% CI,1.14–1.54) and completed suicide (OR, 1.20; 95% CI, 1.04–1.39) compared to patients without psoriasis.¹⁵ Furthermore, younger patients and those with severe disease seem more likely to contemplate and attempt suicide.¹⁵ These results should be interpreted in the context of limited available studies and possible sources of heterogeneity and bias.

Interestingly, another recent systematic review with metaanalysis by Chi et al. did not support an association between psoriasis and suicide.¹⁶ No increase in the risk of suicide (relative risk [RR] 1.13; 95% CI 0.87–1.46), suicide attempt (RR 1.25; 95% CI 0.89–1.75), or suicidality (RR 1.26; 95% CI 0.97–1.64) among people with psoriasis was found,¹⁶ therefore not substantiating the results reported by Singh. They also comment on the limited and very low-quality of the available evidence.

There has been interest in trying to elucidate possible neurophysiological impacts, such as mood and depression, from psoriasis linked to proinflammatory cytokines. Different studies have reported an association between IL-1, IL-6, IL-17, tumor necrosis factor-alpha (TNF-α), and depression;^17-22 however, it has yet to be determined how these immunomodulatory changes could alter neurotransmitters and other neurological mechanisms. According to these observations, the implication could be made that reducing disease severity could potentially improve the proinflammatory state, including depression.

Brodalumab: Mechanism of Action

Brodalumab is one of the available therapies that target the IL-17A pathway of psoriasis. This pathway is also targeted by secukinumab and ixekizumab which specifically bind to IL-17A, and bimekizumab which targets both IL-17A and IL-17F. Brodalumab differs from these by its mechanism of action, because instead of blocking IL-17A or IL-17F directly, it blocks the IL-17 receptor A (IL-17RA). More specifically, brodalumab is a monoclonal antibody that selectively binds to the IL-17RA, thereby inhibiting its interactions with cytokines IL-17A, IL-17C, IL-17F, IL17A/F heterodimer, and IL-25. Significant gene expression changes and almost complete reversal of the psoriatic phenotype have occurred as a result of IL-17RA antagonism.²³ It was approved by the US FDA in 2017 and by Health Canada in 2018 for the treatment of moderate to severe plaque psoriasis.^24-25 Three different phase 3 studies have confirmed the efficacy of this medication in psoriasis: AMAGINE-1, AMAGINE-2, and AMAGINE-3.^7-8 Data suggests that prior use of biologics does not affect the efficacy of brodalumab.²⁶

Brodalumab and Reported SIB

During phase 3 clinical studies, concerns about brodalumab possibly causing suicidal ideation emerged with 4 completed suicides, which led to the early termination of all studies at that time.²⁷ Most of these events occurred during the long-term, open-label phase. One case of completed suicide was later adjudicated as indeterminate according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Even when there was lack of definitive causation, concerns regarding the association of brodalumab with SIB events remained.

Table 1 summarizes completed suicides and the clinical characteristics of these patients who received brodalumab for plaque psoriasis. The details of these deaths revealed pre-existing psychiatric and vulnerable social circumstances. One death, an overdose, was considered an indeterminate suicide.

Following the initial concern regarding SIB reports, the electronic Columbia Suicide Severity Rating Scale (eC-SSRS) and Patient Health Questionnaire-8 (PHQ-8) were implemented for prospective evaluation of most patients in the long-term extension phase studies (after the double-blind phase had been completed). According to the FDA analysis, brodalumab users with a history of suicidality had approximately 12-18 fold increase in SIB incidence than users without a history.²⁷ However, more detailed information regarding this analysis, including confidence intervals, are not provided in the FDA review. As the psychologic and psychiatric aspects of many skin disorders, including psoriasis, are known to coexist, it is not unreasonable to expect that individuals with a prior history of suicidality are prone to exhibit SIB in the future. The cross-national study referenced earlier in this paper,¹⁴ reported that among individuals with a lifetime history of suicidal ideation, the probability of ever planning a suicide is approximately 33% and the probability of ever making a suicide attempt is approximately 30%.

If we consider the clinical information from all of the patients who completed suicide, each case could be explained by exogenous factors. As reported by Hashim et al., there are several factors that may have created an exaggerated suicidality signal in the brodalumab trials. Unlike the clinical trials for other recently approved biologics, there was not a specific exclusion of subjects with a history of psychiatric events or prior suicide attempts.²⁸

Lebwohl et al.²⁹ published a study in which psychiatric adverse effect data was gathered from five psoriasis clinical trials in the brodalumab development program: a phase 2, randomized, double-blinded, placebo-controlled, dose-ranging study; an open-label, long-term extension of the phase 2 study; and three phase 3, randomized, double-blind, controlled trials (AMAGINE-1, AMAGINE-2, AMAGINE-3 and their open-label long-term extensions). According to the investigators’ analysis, SIB events among psoriatic patients in the brodalumab program did not demonstrate evidence of causality when compared with controls and timing of those events,²⁹ given that the incidence of suicides in the study population did not differ significantly from that seen in a general background population. Danesh and Kimball commented that the timing of the clinical trial during an economic crisis in the United States, in combination with demographics of the patients recruited in the study, could have contributed to the increased incidence of SIB.³⁰

SIB with Other Biologics

Depression and suicidal ideation have been reported with other psoriasis treatments including monoclonal therapies. A review of the literature focusing on SIB events linked with biologic agents and small molecules used to treat psoriasis has previously been published.²⁹ More specifically, clinical trials, case reports and post-marketing data covering SIB with monoclonal antibodies, including anti-TNF-α (infliximab, adalimumab), anti-IL12/23 (ustekinumab) and anti-IL-17A (ixekizumab) medications.^31-33 Although the quality of the case reports is weak, rates reported in the clinical trials are not different than rates in the general population and, therefore, no clear association can be established.

A study by Minnema et al. also explored the association with monoclonal antibodies, depression and SIB. The investigators collected data reported in VigiBase (the WHO’s global Individual Case Safety Report [ICSR] database) of adverse effects related to depression and SIB. The findings showed that monoclonal antibodies used to treat autoimmune diseases for immune system suppression had a higher reporting odds ratio (ROR), 1.9 (95% CI 1.8–2.0) for depression and 3.6 (95% CI 3.0–4.4) for SIB.³⁴ Methodologically, however, the study suffers from many limitations, including the source of the data and the fact that there is no control population.

Conclusion

Psychiatric pathology and SIB may be more common in psoriasis patients. Medical professionals should be aware of this association and be poised to provide the necessary interventions when faced with a patient reporting significant depression or SIB. There is no clear evidence that monoclonal antibodies influence neurological function and modulate behavior in humans. More research in this area is necessary in order to begin to understand the potential effects of proinflammatory cytokines on inducing changes in the nervous system and mood. In the specific case of brodalumab, there is not enough evidence to establish causation of SIB in patients treated, as prevalence is comparable to the background population. Additionally, based on existing evidence, brodalumab exhibits a similar safety profile with other IL-17 cytokine inhibitors used to treat moderate to severe plaque psoriasis. We should take into consideration that the clinical trials for brodalumab did not exclude patients according to their psychiatric history, something that has become standard in the research of newer drugs. Nevertheless, it is yet to be determined whether the screening tools currently in use will translate into plausible changes. Based on observed risk of SIB attributable to the completed suicides, the FDA included a boxed label warning for this medication. When prescribing brodalumab, or any other biologic agent, physicians should screen patients for psychiatric comorbidities. Assessment of risk versus benefit and having ongoing honest conversations with patients are crucial and extend beyond the label warning in order to mitigate SIB risk. Thus, the optimal therapeutic approach in the psoriatic population addresses both the obvious physical symptoms as well as complex emotional aspects of psoriasis.

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¹SKiN Centre for Dermatology, Peterborough, ON, Canada
²Queen’s University, Kingston, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada
⁴K Papp Clinical Research, Waterloo, ON, Canada

Conflict of interest:
Fabian Rodriguez-Bolanos has no conflicts of interest. Melinda Gooderham and Kim Papp have been an investigator, speaker, advisory board member and consultant for Leo Pharma, Kyowa Hakko Kirin, Valeant Pharmaceuticals and Bausch Health.

Introduction

Psoriasis is a prevalent skin condition.¹ Plaque psoriasis is the most common type of psoriasis in all populations.² The impact of psoriasis is magnified by its nature and chronicity, thus leading to important psychological morbidity. It can significantly affect quality of life, even when the disease is not extensive.³

We are starting to understand the complexity of this disease, in which different genetic, immunologic and environmental factors play a part.⁴ Psoriasis is considered a multisystem, immune-mediated inflammatory disease.⁵  It has been observed epidemiologically that the frequency of some noncutaneous diseases and conditions are significantly increased in psoriasis; including rheumatologic conditions, inflammatory bowel disease, cardiovascular disease, metabolic disease, and psychological disorders.⁶

Brodalumab, a human monoclonal IgG2 antibody directed at the IL-17 receptor A, is one of the latest medications to be approved for the treatment of moderate to severe plaque psoriasis. Data from clinical trials show brodalumab to be highly effective and is a useful tool to add to our therapeutic arsenal.^7-8 Attention to suicidal ideation and behaviour (SIB) in patients treated with brodalumab developed following four cases of suicide documented during the psoriasis clinical trial program. We consider it necessary to critically examine these cases in order to gain insight into why they might have happened and possible causal relationships.

Mental Health and Psoriasis

• Psoriasis has long been associated with an impact on mental health.⁹
• Studies have reported that up to half of patients with psoriasis experience helplessness and isolation that translate into functional limitations consequently impacting psoriasis patients socially and psychologically.^10-11
• According to the WHO, about 804 000 suicide deaths occurred in 2012 across the world.¹²
• SIB is an important public health problem that has been associated with an interaction between multiple factors, including: demographic, social, and cultural.
• Vilhjalmsson et al.¹³ found that adults are more likely to contemplate suicide under certain conditions, such as highly stressful domestic, financial, and particularly legal, circumstances.  As well, those who experience extensive physical health problems and who perceive their lives as stressful are also susceptible.¹³
• A cross-national study reported an estimated lifetime prevalence of suicidal ideation, plan, and attempt in the overall sample of 9.2%, 3.1%, and 2.7%, respectively.¹⁴
• Suicidal behaviour includes both attempted suicide and completed suicide.
• Singh et al.¹⁵ reported that psoriasis patients were more than twice as likely to have suicidal ideation than patients without psoriasis (odds ratio [OR], 2.05; 95% CI, 1.54-2.74).¹⁵  That same study also documented that patients with psoriasis have a higher likelihood of suicide attempts (OR, 1.32; 95% CI,1.14-1.54) and completed suicide (OR, 1.20; 95% CI, 1.04-1.39) compared to patients without psoriasis.¹⁵
• Also, younger patients and patients with severe disease seemed more prone to suicidal ideation and attempted suicide.¹⁵ It was discussed that these results should be interpreted in the light of limited available studies and possible sources of heterogeneity and bias.
• Another recent systematic review with meta-analysis by Chi et al.¹⁶ did not support an association between psoriasis and suicide.¹⁶
• No increase in the risk of suicide (relative risk [RR] 1.13; 95% CI 0.87–1.46), suicide attempt (RR 1.25; 95% CI 0.89–1.75), or suicidality (RR 1.26; 95% CI 0.97–1.64) among people with psoriasis was found,¹⁶ which does not support the results reported by Singh. They also comment on the limited and very low-quality of the available evidence.
• There are ongoing investigations into the possible neurophysiological impact of psoriasis in mood and depression with special emphasis on the relationship between proinflammatory cytokines and mood disorders.
• Different studies have reported an association between IL-1, IL-6, IL-17, TNF-α, and depression;^17-20 however, it is yet to be determined how these changes could alter neurotransmitters and other neurological mechanisms.

Brodalumab as Effective Therapeutic Option

• Brodalumab is one of the available therapies that target the interleukin-17A (IL-17A) pathway of psoriasis.
• Other antibody therapies, secukinumab and ixekizumab, specifically bind to IL-17A while bimekizumab binds to a common epitope of IL-17A and F.
• Brodalumab blocks the interleukin-17 receptor A (IL-17RA).  It is a monoclonal antibody that selectively binds to the IL-17RA, thereby inhibiting its interactions with the array of IL-17 homologues: IL-17A, IL-17C, IL-17F, IL17A/F heterodimer, and IL-25.
• Significant gene expression changes and near complete reversal of the psoriatic phenotype have occurred as a result of IL-17RA antagonism.²¹
• Brodalumab was approved by the FDA in 2017 and by Health Canada in 2018 for the treatment of moderate to severe plaque psoriasis.^22-23
• Three phase III studies have confirmed the efficacy of this medication in psoriasis: AMAGINE-1, AMAGINE-2, and AMAGINE-3.^7-8 Data suggests that prior use biologics does not affect the efficacy of brodalumab.²⁴

Brodalumab and Reported SIB

• Late in the clinical studies, a suicide signal emerged with 4 completed suicides occurring during the Phase 3 clinical trials. This led Amgen to terminate all, then current, clinical studies.²⁵
• Most of the suicides occurred during the long-term, open-label phase. One case of completed suicide was later adjudicated as indeterminate according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Despite the lack of definitive causal association between SIB and brodalumab, concerns regarding a possible association remained. See Table 1.
• According to their analysis, brodalumab users with a history of suicidality had an approximate of 12 – 18 fold increase in SIB incidence rate than users without a history.²⁵ However, more detailed information regarding this analysis, including confidence intervals, are not provided in the document.
• It is logical to expect those with a prior history of suicidality are prone to develop SIB in the future. The cross-national study referenced earlier in this paper,¹⁴ reported that among individuals with a lifetime history of suicidal ideation, the probability of ever planning a suicide is approximately 33%, and the probability of ever making a suicide attempt is approximately 30%.
• If we consider the clinical information from all of the patients who completed suicide, all cases could be explained by exogenous factors.
• As mentioned by Hashim et al, there are several factors that may have created an exaggerated suicidality signal in the brodalumab trials. Unlike the clinical trials for other recently approved biologics, there was not a specific exclusion of subjects with a history of psychiatric events or prior suicide attempts.²⁶
• Lebwohl et al.,²⁷ published a study in which psychiatric adverse effect data was gathered from 5 psoriasis clinical trials in the brodalumab development program.  According to their analysis, SIB events among patients with psoriasis in the brodalumab program did not demonstrate evidence of causality when compared with controls and timing of those events,²⁷ given that the incidence of suicides in the study population does not differ significantly from that seen in a general background population.
• Danesh and Kimball commented that the timing of the clinical trial during an economic crisis in the United States, in combination with demographics of the patients recruited in the study, could have caused increased observations of SIB.²⁸

Table 1: Completed suicides during clinical trial in patients treated with brodalumab for plaque psoriasis.

SIB Observed During Treatment with Other Biologics

• Depression and suicidal ideation have been reported with other psoriasis therapies including monoclonal therapies.
• A review of the literature regarding SIB events with biologic agents and small molecules used to treat psoriasis has previously been published.²⁹Reports of SIB with monoclonal antibodies in clinical trials, case reports and post-marketing data include: anti TNF-α (infliximab, adalimumab), anti-IL12/23 (ustekinumab) and anti-IL-17A (ixekizumab) medications.^29-31 However, the quality of the case reports is weak, rates in the clinical trials are not different than rates in the general population and, therefore, no clear association can be established.
• A study by Minnema et al.³² also explored the association between monoclonal antibodies and depression and SIB. They reported that those monoclonal antibodies that suppress the immune system showed higher reporting odds ratio (ROR), 1.9 (95% CI 1.8–2.0) for depression and 3.6 (95% CI 3.0–4.4) for SIB.³² Methodologically, however, the study has limitations including the source of data and lack of a control population.

Conclusions

Psychiatric pathology and SIB may be more common in psoriasis patients. Medical professionals should be aware of this association and also provide the necessary interventions when faced with a patient reporting significant depression or SIB. There is no clear evidence that monoclonal antibodies can influence neurological function and modulate behaviour in humans. More research in this area is necessary to begin to understand the effects of proinflammatory cytokines may have on the nervous system and mood. In the specific case of brodalumab, there is not enough evidence to establish causation of SIB in patients treated as rates correspond to the prevalence in the background population. We should take into consideration that the clinical trials for brodalumab did not exclude patients according to their psychiatric history, something that has become standard in research of newer drugs. Nevertheless, it is yet to be determined whether the screening tools used will translate into plausible changes. The regulatory agencies were concerned about the completed suicides that occurred with this medication and, therefore, the FDA included a black box warning. When prescribing brodalumab, or any other biologic agent, physicians should screen patients for psychiatric comorbidities. Assessment of risk versus benefit, and having an honest conversation with patients regarding the label, will help provide better patient care for both physical and mental health.

¹McMaster University, Faculty of Health Sciences, Hamilton, ON, Canada
²University of Toronto, Faculty of Medicine, Toronto, ON, Canada
³Skin Centre for Dermatology, Peterborough, ON, Canada
⁴Probity Medical Research, Waterloo, ON Canada
⁵Queen’s University, Kingston, ON Canada
⁶K Papp Clinical Research, Waterloo, ON Canada

Conflict of interest:
MG and KP have been investigators, consultants, advisory board members and speakers for Amgen, Kyowa Kirin, Leo, MedImmune and Valeant.
KP has been a consultant for Astra Zeneca. SRS has no conflicts to disclose.

ABSTRACT
Interleukin (IL)-17 is important in the pathophysiology of psoriasis and has proven to be an effective therapeutic target. Brodalumab, the third commercially available IL-17 antagonist, was approved by the US FDA in February 2017 for the treatment of moderate-to severe plaque psoriasis. As brodalumab enters the marketplace, it is imperative to investigate its safety profile. We conducted a safety assessment of brodalumab using publicly available adverse event data from phase II and III clinical trials. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and candidiasis. The FDA issued a black box warning after six patients treated with brodalumab across four clinical trials committed suicide, but no causal relationship was identified. Current evidence suggests a similar safety profile for brodalumab compared to other IL-17 antagonists used to treat moderate-to-severe plaque psoriasis.

Key Words:
biologics, chronic plaque, psoriasis, IL-17, interleukin-17, interleukin-17A, monoclonal antibody, safety

Introduction

Interleukin (IL)-17 is important in the pathophysiology of psoriasis and has proven to be an effective therapeutic target. Brodalumab is an IL-17R inhibitor¹ evaluated in rheumatoid arthritis², Crohn’s disease³, and psoriatic arthritis⁴, and is approved for the treatment of moderate-to-severe, chronic plaque psoriasis in Japan, US, and Europe. Development in rheumatoid arthritis was stopped for futility.² The Crohn’s disease program was terminated as a trend to worsening of disease was observed in a phase II study.³ Amgen terminated the psoriasis and psoriatic arthritis programs for commercial reasons,⁵ however, sufficient data had been collected for submission to regulatory agencies for approval. Brodalumab was approved by the Japanese Pharmaceuticals and Medical Devices Agency in July 2016 (Lumicef®), the US FDA in February 2017 (Siliq™), and the European Medicines Agency in July 2017 (Kyntheum®) for treatment of moderate-to-severe plaque psoriasis.

Given the mechanism of action, the anticipated safety profile of brodalumab should reflect that of other IL-17 blockers. More controversial is the posited reason for abandoning the psoriasis and psoriatic arthritis program. A numerical imbalance in the number of suicides occurring in patients receiving brodalumab compared to placebo was observed, which would affect the labelling requirements.⁶,⁷ Herein, we review the publicly available safety data for brodalumab across the entire development program.

Methods

To identify all available brodalumab randomized clinical trials (RCTs), a search of the ClinicalTrials.gov database was conducted with key words “brodalumab”, “KHK 4827”, OR “AMG 827”. Of the 30 studies retrieved, only those with available data that were completed or terminated early were included in the analysis. Studies with data unavailable, currently or not yet recruiting patients, or withdrawn studies were excluded. We also searched the PubMed database with the terms “brodalumab”, “KHK 4827”, OR “AMG 827”. After reviewing available studies, adverse event data was compiled from journal publications and appendices of 10 RCTs (six with open-label extensions) and one prospective case series (Table 1).

Safety Assessment

As brodalumab has entered the marketplace, it is imperative to continually assess its safety. A safety assessment is an ongoing process evaluating events occurring in a specific population exposed to a medical compound compared to an appropriate general population. The highest quality data is acquired from adverse event reporting in placebo-controlled RCTs. These adverse events have standardized definitions of severity based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. To date, there have been six phase II and four phase III RCTs evaluating the efficacy and safety of brodalumab in treating psoriasis, psoriatic arthritis, Crohn’s disease, asthma and rheumatoid arthritis (Table 1).^1-4,8-12 All studies had a 12-week induction period where patients received brodalumab on day 1, week 1, week 2, and subsequently every other week until week 10, and were assessed on week 12. Six of the studies continued with an open-label extension offering brodalumab to all patients. Adverse event data is currently available for open-label extensions until week 52, however, the phase II psoriasis study by Papp et al.¹⁴ has data available until week 120. A 52-week prospective case-series conducted by Yamasaki et al.¹⁰ investigating brodalumab’s efficacy in 30 patients with either generalized pustular psoriasis or psoriatic erythroderma was also included in our safety analysis. Targan et al.³ terminated their study prematurely as brodalumab was found to worsen Crohn’s disease activity. During the 12-week induction period within these studies, 4118 patients were treated with at least one dose of brodalumab. During the induction, the most common adverse events reported with brodalumab use were nasopharyngitis (7.4%), upper respiratory tract infection (5.6%), headaches (4.3%), arthralgias (3.0%), and injection site reaction (2.1%). Due to the immunosuppressive nature of brodalumab, serious infections, candidiasis, and neutropenia are considered adverse events of interest. Only 1.7% of brodalumab patients reported serious infections, similar to the placebo group (1.5%). Candidiasis was reported in 1.1% of patients, typically oropharyngeal, and 0.5% were found to have clinically insignificant neutropenia. Major adverse cardiovascular events, headache, fatigue, diarrhea, nausea, and vomiting were reported by less than 1% of participants. Targan et al.,³ similar to another IL-17 antagonist, secukinumab, discovered worsening of Crohn’s disease activity with IL-17 inhibition in 24 (18%) of 130 patients, and thus, this study was terminated early. Subsequent RCTs in other disease states excluded subjects with a history of Crohn’s disease.A total of 4340 patients received brodalumab for an extended duration of 52 to 120 weeks. The adverse event data was compiled from six open-label extensions and a 52-week study by Yamasaki and colleagues.¹⁰ The most common adverse events reported with longer duration of brodalumab therapy were injection site reaction (4.5%), Candida infections (4.1%), and nasopharyngitis (3%). Other side effects included upper respiratory tract infection (1.8%), serious infection (1.4%), arthralgias (1.1%), and neutropenia (1.1%). Headache, fatigue, major adverse cardiovascular events, and gastrointestinal adverse events (e.g., nausea, vomiting and diarrhea) were reported by less than 1% of patients. Depressed mood was described by only 1.5% of brodalumab patients, similar to the 1.3% of participants receiving ustekinumab during the AMAGINE-2 and AMAGINE-3 trials.¹² All brodalumab clinical trials were stopped on May 22, 2015, as six participants treated with brodalumab, across all programs, committed suicide. Of these six, four were enrolled in psoriasis studies, one in the rheumatoid arthritis trial, and one in a psoriatic arthritis study.¹⁵ Of the four psoriasis patients, two completed suicide during the open-label extension of AMAGINE-2 and the remaining two occurred during the open-label extension of AMAGINE-1, one of which was deemed to be an unintentional heroin overdose on autopsy. One suicide was completed during the induction period of the rheumatoid arthritis study by Pavelka et al.², and one during the AMVISION-1 open-label extension¹⁵. Our analysis showed that only 1.5% of patients who received brodalumab reported depressed mood. The FDA conducted a thorough analysis of the data available in 2015 and determined that there was no established drug-related risk of suicide or suicidal ideation.¹⁵ To date, there has been no additional data correlating brodalumab use and suicide.

Discussion

The spectrum of adverse events seen with brodalumab is consistent with other drugs blocking IL-17. Nasopharyngitis and upper respiratory tract infections were the most commonly reported infections. Candida infections, seen in 4% of patients, is consistent with other agents blocking IL-17.^16,17 Though stopped for futility, patients in a study evaluating secukinumab for the treatment of Crohn’s disease showed a trend to worsening of disease compared to patients receiving placebo.¹⁸ The foregoing somewhat mirrors the results seen with brodalumab.³ Incidental and self-correcting neutropenia, seen with brodalumab, was also observed in programs with secukinumab and ixekizumab.^16,17Suicidal ideation was reported at low rates across most clinical trial programs evaluating interventions for moderate-to-severe plaque psoriasis.⁷ The numerical imbalance of completed suicides seen in the brodalumab psoriasis studies warranted a boxed warning on the US FDA approved label, though the same label states there is no causal association between brodalumab exposure and suicide.¹⁹ Depression and suicidal ideation are common in the psoriasis population²⁰, as they are in many chronic diseases²¹. Challenges in ascertaining differential rates in suicide include rates that vary of time²², rates that vary country to country²³, and rates displaying significant differences in rates within the same country⁶.Overall, the safety profile of brodalumab is consistent with other drugs blocking IL-17 and broadly consistent with the spectrum of adverse events seen with biologic agents used to treat moderate-to-severe plaque psoriasis.

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Introduction

Phosphodiesterase 4 (PDE4) is a key enzyme in the regulation of immune responses of inflammatory diseases through degradation of the second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP). Apremilast (APR), a selective PDE4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines by increasing intracellular levels of cAMP and promoting the production of anti-inflammatory cytokines. The efficacy and safety of APR in the treatment of psoriasis and psoriatic arthritis has been demonstrated in phase 2/3 studies and is reviewed here. Across all studies, treatment was generally well-tolerated with some mild gastrointestinal complaints that occurred early and resolved over time. Meaningful improvement of psoriasis and psoriatic arthritis including dactylitis and enthesitis were observed. Routine monitoring is not required given the absence of drug associated physiologic, biochemical, and haematological changes. APR proves to be a new promising systemic therapy for treating psoriatic disease.

Background

• Psoriasis is an immune mediated disease involving skin, joints, and possibly the bowel.^1-4
• Recent clinical studies have shown precise blockade of phosphodiesterase 4 (PDE4) to be effective in the treatment of psoriasis⁵ and PsA.^6,7
• PDE4 belongs to the phosphodiesterase family of enzymes involved in the breakdown of cyclic adenosine 3′,5′-monophosphate (cAMP).^8,9
• Increase in cAMP leads to a cascade of cellular events resulting in a reduction of inflammatory mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-23, and IL-17, as well as increase in anti-inflammatory cytokines such as IL-10.^8,9,10
• Inhibition of PDE4 leads to an increase in the intracellular cAMP concentration, thereby reducing the production of inflammatory mediators and increasing anti-inflammatory mediators.^8,11

PDE4 Inhibitor in the Treatment of Psoriasis

• Apremilast (APR, CC-10004, Otezla™), a PDE4 inhibitor, has been shown to block the production of pro-inflammatory cytokines that play a major role in the pathogenesis of psoriasis.
• APR demonstrated a range of anti-inflammatory effects on a variety of cell lines in vitro,¹¹ and biologic activity in a pilot study in humans.¹²
• APR has been evaluated in a number of phase 2^5,13,14 and phase 3 clinical trials (Efficacy and Safety Trial Evaluating the Effects of APR in Psoriasis [ESTEEM] 1 and 2 and LIBERATE), demonstrating efficacy in psoriasis^15-17 and psoriatic arthritis (PsA).^6,7,19-21

Apremilast Use in Psoriasis

Results from Phase 3 Studies in Plaque Psoriasis

• Efficacy and safety of APR 30 mg BID was evaluated in two phase 3 randomized, placebo-controlled studies ESTEEM 1¹⁵ and ESTEEM 2¹⁶ and compared with etanercept and placebo (PBO) in a phase 3b study (LIBERATE)¹⁷, the results of which are not described here.
• In ESTEEM1, 844 patients with plaque psoriasis (Psoriasis Area Severity Index (PASI) ≥12, Body Surface Area [BSA] ≥10%, static Physician’s Global Assessment [sPGA] ≥3) were randomized 2:1 to APR 30 mg BID (n=562) or PBO (n=282) for the first 16 weeks. See Figure 1 for study design after week 16.¹⁵
• In ESTEEM 2, 413 similar patients with psoriasis were randomized to PBO (n=138) or APR 30 mg BID (n=275) through Week 16. See Figure 1 for study design after Week 16.¹⁶

Figure 1.ESTEEM 1 and 2 study design^15,16

^aDoses of APR were titrated during the first week of administration.

^bA responder was defined as a patient achieving ≥PASI-75 (ESTEEM 1) or ≥PASI-50 (ESTEEM 2) at Week 32.

^cIn ESTEEM 1, patients were switched to APR at the time of loss of PASI-75, but no later than Week 52

In ESTEEM 2, patients were switched to APR at time of loss of effect, defined as time of loss of 50% of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52.

^dAt Week 32, patients will have the option of adding topical and/or UVB therapy. The decision may be made at Week 32 only, but does not need to be initiated at this visit. T = topicals; P = UVB phototherapy.

• Significant improvements with APR 30 mg BID were observed at Week 16 for PASI-75 (a reduction of ≥75% in PASI scores) and sPGA scores.
• In ESTEEM 1, significantly more patients in the APR group achieved PASI-75 (33.1%), PASI-50 (58.7%) and sPGA 0-1 (21.7%) vs. PBO (*P<0.0001, all),¹⁵ (Figure 2A)
• In ESTEEM 2, patients treated with APR achieved PASI-75 (28.8%), PASI-50 (55.5%) and sPGA 0-1 (20.4%) vs. PBO (*P<0.0001, all).¹⁶ (Figure 2B)

Figure 2A and 2B.PASI-75 (primary endpoint), PASI-50, and sPGA response at Week 16^15,16

Patients achieving PASI-75, PASI-50, and sPGA response with APR 30 mg BID vs. PBO. A. Response at Week 16 in ESTEEM 1. B. Response at Week 16 in ESTEEM 2. sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline. *P

• For the subgroup of patients who received APR 30 mg BID from Day 0 and continued on therapy, with PASI-75 responders at Week 32, there was a mean percent change from baseline in PASI score of -80% at Week 52.¹⁵
• Improvements with APR 30 mg BID were also seen in nail, scalp and palmoplantar psoriasis as well as quality of life and pruritus.^15,16,18
• Patients treated with APR 30 mg BID achieved a 50% improvement in the Nail Psoriasis Severity Index (NAPSI-50) response at Week 16 vs. PBO. In ESTEEM 1, 33.3% of APR patients achieved NAPSI-50 response vs. 14.9% PBO (P<0.0001),¹⁵ and in ESTEEM 2, 44.6% of APR patients achieved NAPSI-50 vs. 18.7% PBO (P<0.0001).¹⁶
• Patients in the APR 30 mg BID group achieved significant scalp improvement, with ScPGA 0-1 (Clear-Minimal) at Week 16 vs. those in the PBO group. In ESTEEM 1, 46.5% APR vs. 17.5% PBO (P<0.0001),¹⁵ and in ESTEEM 2, 40.9% APR vs. 17.2% PBO (P<0.0001)¹⁶.
• Palmoplantar psoriasis also improved. In ESTEEM 2, 65.4% of patients treated with APR 30 mg BID achieved PPPGA 0-1 (Clear-Minimal) vs. 31.3% of patients treated with PBO.¹⁶
• APR 30 mg BID was associated with an improvement in quality of life with significantly higher proportion of patients who achieved clinically important differences in the Dermatology Life Quality Index (DLQI) and pruritus VAS from baseline at Week 16.
• In ESTEEM 1, 70.2% of patients in the APR group achieved a clinically significant improvement in DLQI response vs. 33.5% with PBO (P<0.0001),^15,22 and in ESTEEM 2, 70.8% of patients treated with APR achieved a significant DLQI response vs. 42.9% with PBO (P<0.0001).²³
• For pruritus VAS, 70.6% of patients in ESTEEM 1 treated with APR achieved significant improvement vs. 33.7% with PBO (P<0.0001) in ESTEEM 1.²²

Safety and Tolerability Profile

• APR demonstrated an acceptable safety profile and was generally well-tolerated for up to 52 weeks as most adverse events (AEs) were mild or moderate in severity.
• Discontinuation rates for diarrhea and nausea were each <2% in the APR 30 mg BID group through Week 52.^15,16
• The most frequently reported AEs during the PBO-controlled period and APR-exposure period were diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis, tension headache, and headache.^15,16
• Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes were not significantly affected.
• AEs in ≥5% reported during Weeks 0-16 and Weeks 0-52 in ESTEEM 1 are shown in Table 1.¹⁵ AEs reported during Weeks 0-16 in ESTEEM 2 are shown in Table 2.¹⁶

The apremilast-exposure period (Weeks 0-52) included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated.
Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times the number (n) of patients reporting the event divided by patientyears
within the phase (up to the first event start date for patients reporting the event).¹⁷

APR Use in Psoriatic Arthritis

Results from Phase 3 Studies in Psoriatic Arthritis

• Efficacy and safety of APR were evaluated in four phase 3 trials in the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical program in patients with PsA.^6,7,9,19-21
• Key inclusion criteria in PALACE 1,2 were adults with a documented diagnosis of PsA at baseline (duration ≥6 months; met the Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), ≥3 swollen and ≥3 tender joints despite past or current disease-modifying antirheumatic drugs (DMARDs) and/or biologics.^6,7,19 In PALACE 3, patients also had at least one psoriatic lesion ≥2 cm, and in PALACE 4, DMARD and/or biologics naïve patients were included.^20,21 Study design for the PALACE clinical trial program is shown in Figure 3.²⁰
• The results of a 24-week PBO-controlled phase of PALACE 1 have been published, as well as the 52-week period results.^6,7
• In PALACE 1, patients with active PsA (n=504) were randomized (1:1:1) to PBO, APR 20 mg BID or APR 30 mg BID. See Figure 3 for details.

Figure 3.PALACE Study Design^6,7,19-21

p class=”p-sm”>Note: Plasma samples for the biomarker assay were obtained at baseline and Weeks 4, 16, 24, and 40.
*All doses were titrated over the first week of treatment.
§Patients whose swollen and tender joint counts had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized
(1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo. Apremilast-treated patients continued on their initial apremilast dose.
‡At Week 24, all remaining placebo patients were re-randomized to apremilast 20 mg BID or 30 mg BID.

• At Week 16, significantly more patients receiving APR 20 mg BID (30.4%; P=0.0166) and 30 mg BID (38.1%; P=0.0001) achieved an ACR20 response vs. PBO (19.0%).⁶
• At Week 24, an ACR20 response of 45.3% was observed in patients treated with APR 30 mg BID independent of their response at Week 16.⁶
• At Week 52, ACR20 response was observed among patients receiving APR continuously for 52 weeks (n=254) in 63.0% (20 mg BID) and 54.6% (30 mg BID) of patients.⁷ ACR50 and ACR70 responses were observed in 24.8% and 15.4% of patients receiving APR 20 mg BID and 24.6% and 13.8% of patients receiving APR 30 mg BID, respectively.⁷
• Patients treated with APR had a statistically significant improvement in physical function, as measured by changes from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score (P=0.0004 vs. PBO) and the 36-Item ShortForm Health Survey v2 Physical Functioning domain score (P=0.0001 vs. PBO).
• Significant improvements were also seen in most ACR component scores, particularly swollen and tender joint counts and patient assessment of pain (P6
• In patients with enthesitis, the mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was significantly higher for APR 30 mg BID vs. PBO (P=0.0334), and significantly greater proportions of patients receiving APR 20 mg BID (32.0%; P=0.0037) and 30 mg BID (33.6%; P=0.0013) achieved a MASES score of 0 at Week 24 vs. PBO (14.4%).⁶
• In patients with dactylitis, mean change from baseline in dactylitis severity score was higher with APR vs. PBO. Greater proportions of patients with dactylitis achieved scores of 0 at Week 24 with APR 20 mg BID (50.9%), APR 30 mg BID (47.7%) vs. PBO (40.9%); these differences did not reach statistical significance at Week 24.⁶
• At Week 52, in patients who received APR continuously from baseline, the median change in MASES was 100% with APR 20 mg BID and 66.7% with APR 30 mg BID, and a MASES score of 0 was observed in 50.7% (35/69) of patients receiving APR 20 mg BID and 38.2% (34/89) receiving APR 30 mg BID.⁷
• AEs in the PALACE 1 trial were similar to the psoriasis studies with gastrointestinal, mild or moderate in severity, occurred early, self-limited, did not recur, and infrequently led to discontinuation (<2.5%) through Week 24.⁷
• No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.
• For an overview of AEs occurring in ≥5% of PALACE 1 see Table 3.

Warning and Precautions: Data from Studies in Psoriasis and PsA

Weight Decrease

• During the controlled period of the trials, weight decrease between 5%-10% of baseline body weight was reported in 12% of psoriasis and 10% of PsA patients treated with APR 30 mg BID vs. 3-5% treated with PBO. Weight decrease of ≥10% of body weight occurred in 2% of patients treated with APR 30 mg BID vs. 1% in the PBO group.
• It is recommended that patients treated with APR should have their weight monitored regularly.²⁴

Depression

• While treatment with APR was associated with a risk of depression, data from the clinical trials do not suggest an increase in depression nor suicidal ideation in subjects treated with APR vs. PBO.²⁴

Drug Interactions

• Co-administration with cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) resulted in a reduction of systemic exposure of APR, which may result in a loss of its efficacy and is not recommended.²⁴

Approval and Indications

Apremilast was approved by Health Canada in November, 2014. It is indicated for the treatment of plaque psoriasis in adult patients with moderate to severe disease who are candidates for phototherapy or systemic therapy. It is also indicated for psoriatic arthritis either alone or in combination with methotrexate, for the treatment of active arthritis in adult patients who have had an inadequate response, intolerance, or contraindication to a prior disease-modifying anti-rheumatic drug (DMARD).²⁴ The recommended daily dosing is 30 mg PO BID. However, an initial titrated dose from 10 mg to 30 mg over the first week is recommended and is available in a convenient dosing pack.

Conclusion

Treatment with APR demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis^15-17 and improving signs, symptoms and physical function in PsA.^6,7,19-21 APR demonstrated an acceptable safety profile and was well-tolerated with generally mild GI complaints occurring early in the course of the treatment and resolving with time, and there was no requirement for laboratory monitoring.^5-7,15-21 Based on these results, APR should be considered as a therapeutic option in the treatment of plaque psoriasis and PsA.

Acknowledgement

The authors gratefully acknowledge the medical editorial support from Flora Krasnoshtein in preparing the original manuscript.

References

1. Najarian DJ, Gottlieb AB. J Am Acad Dermatol. 2003 Jun;48(6):805-21; quiz 22-4.
2. Nestle FO, et al. N Engl J Med. 2009 Jul 30; 361(5):496-509.
3. Ritchlin CT. Curr Opin Rheumatol. 2005 Jul;17(4):406-12.
4. Salari-Sharif P, et al. Curr Pharm Des. 2010 16(33):3661-7.
5. Papp K, et al. Lancet. 2012 Aug 25;380(9843):738-46.
6. Kavanaugh A, et al. Ann Rheum Dis. 2014 Jun;73(6):1020-6.
7. Kavanaugh A, et al. J Rheumatol. 2015 Mar;42(3):479-88.
8. Schafer P. Biochem Pharmacol. 2012 Jun 15;83(12):1583-90.
9. Schafer PH, et al. Cell Signal. 2014 Sep;26(9):2016-29.
10. Baumer W, et al. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
11. Serezani CH, et al. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
12. Gottlieb AB, et al. Curr Med Res Opin. 2008 May;24(5): 1529-38.
13. Papp KA, et al. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e376-83.
14. Strand V, et al. J Am Acad Dermatol 2011:64(2): AB154. [Poster abstract P3337]. Presented at the American Academy of Dermatology 2011 69th Annual meeting; February 4-8, 2011; New Orleans, LA.
15. Papp K, Reich C, Leonardi C, et al. J Am Acad Dermatol 2015;73:37-49.
16. Paul C, Cather J, Gooderham M, et al. Br J Dermatol. 2015. doi:10.1111/bjd.14164.
17. Reich K, Soung J, Gooderham M, et al.: Presented at the 73rd Annual Meeting of the American Academy of Dermatology; San Francisco; March 20-24, 2015.
18. Rich P, Gooderham M, Bachelez H, et al. J Am Acad Dermatol http://dx.doi.org/ 10.1016/j.jaad.2015.09.001
19. Cutolo M, et al. [Presentation number 815]. Presented at ACR 2013. American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
20. Edwards CJ, et al. [Poster 311]. Presented at ACR 2013 American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
21. Armstrong AW, et al. [Poster P1691]. Presented at: the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
22. Gooderham M, et al. [Poster P1688]. Presented at the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
23. Otezla® (APR) [Full Prescribing information]. Summit, NJ: Celgene Corporation; revised June 2015.

Conflict of interest:
Dr. Gooderham and Dr. Papp have both attended advisory board meetings and been involved in clinical research on dupilumab for Sanofi and Regeneron.

ABSTRACT
Atopic dermatitis results when aberrant barrier function and immune activation occur within the skin. Standard therapies for atopic dermatitis have fallen short, prompting efforts to discover novel therapeutics for this disease. Of these, dupilumab, a fully human monoclonal antibody that inhibits the actions of both IL-4 and IL-13, has shown the greatest promise. Clinical trials of systemic dupilumab in moderate-to-severe atopic dermatitis have demonstrated marked improvement in patient symptoms, including pruritus and clinically visible disease. Importantly, dupilumab treatment has been correlated with changes in the molecular signature of diseased skin, with reduction of both inflammatory and proliferative markers. Dupilumab recently received US FDA breakthrough therapy designation for atopic dermatitis, with ongoing trials in both adult and pediatric populations. Altogether, dupilumab has shed new light on the pathomechanisms driving atopic dermatitis and is making unprecedented advances towards highly effective control of this debilitating disease.

Key Words:
atopic dermatitis, dupilumab, eczema, IL-4Rα, IL-4, IL-13, monoclonal antibody, EASI-50, EASI-75, SCORAD

Introduction

Atopic dermatitis (AD) is the most common chronic in ammatory skin disease, resulting from defects in skin barrier function and innate and adaptive immune responses.^1,2 In its acute stages, AD presents with highly pruritic, inflamed lesions. Histologically, the epidermis of acute lesions is characterized by intracellular edema (spongiosis), and a sparse infiltrate consisting primarily of T lymphocytes. Marked perivascular inflammatory cell infiltrates with large numbers of T lymphocytes and macrophages are seen in the dermis. In its chronic stages, lesions are lichenified and plaque-like. Histologically, chronic lesions are distinguished by epidermal hyperplasia with prominent hyperkeratosis and minimal spongiosis.^3-7

It is estimated that up to 30% of children and 10% of adults are affected by AD, with approximately 85% of all cases beginning within the first 5 years of life (early-onset AD).^3,4,8 Although many children experience remission of their disease by adolescence, a portion will continue to be affected into adulthood.⁹ As well, a number of patients will have their first episode of AD diagnosed in adult life (late-onset AD), a presentation that often results in a more treatment-refractory form of the disease.⁴ Of those affected by AD, up to 20% have a moderate-to-severe presentation, which often manifests as a recurrent disease with remitting and relapsing phases.¹⁰ Importantly, AD impacts all aspects of patients’ lives, from their physical wellbeing to their psychological and economical quality of life by disrupting sleep, daily functioning, and requiring patients to attend frequent medical appointments.^11-14

Genetics play a large role in the development of AD. Affected individuals often have a strong family history of atopy, including AD, asthma and allergic rhinitis: the atopic triad.¹⁵ Genome-wide association studies have implicated a number of genetic loci in the development of AD, including the 1q21, 3p26, 3q21, 5q31-33, 16q, 17q25, and 20p regions. These genetic loci are primarily involved in skin barrier and immune function.^16-21 Importantly, interventions aimed at repairing these defects in skin barrier function and immune dysregulation hold promise for treatment, prevention and, potentially, a cure for AD.

Recent advances in our understanding of the underlying pathogenesis and risk factors for AD has resulted in two opposing theories that attempt to explain the onset and natural history of the disease: the outside-in and the inside-out hypotheses.^22,23 The outside-in hypothesis proposes that genetic variations within the population result in a subpopulation of individuals that harbor defects in skin barrier function. A disrupted barrier permits allergens and microbes to cross the epithelium, which in turn triggers an in ammatory reaction. Alternatively, the inside-out hypothesis proposes that the underlying defects occur at the level of the immune system. A polarized immune response in AD patients results in immunoglobulin E (IgE) sensitization to skin pathogens and contaminants. The resultant immune response induces local inflammation and skin barrier breakdown.^22,23 While debate around these theories remains, it is evident that a number of genetic and environmental factors contribute to skin barrier dysfunction and immune dysregulation in AD. The polyfactorial nature of AD accounts for the heterogeneity in severity and natural history of this disease. It is nonetheless apparent that optimal treatment of AD requires a comprehensive approach aimed at repairing defects in skin barrier function and addressing the characteristic immune abnormalities.

No currently available therapy provides complete remission or cure for affected patients. Management of AD includes patient education, optimal skin care practices, antihistamines (preferably first generation – sedating antihistamines), topical corticosteroids or topical calcineurin inhibitors (TCIs), systemic corticosteroids, systemic calcineurin inhibitors, phototherapy, and other oral immune-suppressants.^7,24 These treatments work to restore skin barrier function and suppress the in ammatory response.

The availability of safe and effective treatment for moderate-to- severe AD remains a significant unmet need. Research focused on the pathophysiology of AD has identified promising targets for the treatment of this disease. One targeted therapy that has shown promise in early clinical development and is the focus of this review is dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist.

Immune Dysfunction in AD

Recent research has demonstrated that immune system dysfunction plays a central role in the development and persistence of AD. These cellular and cytokine targets provide potential therapeutic opportunities. AD skin has been shown to harbor increased levels of the TH2 cytokines IL-4, IL-5, IL-10, and IL-13, with a corresponding decrease in the TH1 cytokines interferon-γ and IL-2.^25-30 IL-4 and IL-13 have established roles in B-cell differentiation and class switching, thus providing a plausible link to characteristic elevations of serum IgE levels in AD patients.^4,31 Importantly, these TH2 cytokines have been shown to contribute to AD pathogenesis, as mice genetically engineered to over-express these cytokines develop skin barrier defects and an AD-like disease.^32-35 High levels of the TH2 cytokines IL-4 and IL-13 in AD skin have been shown to act as inhibitors of both epidermal differentiation and production of antimicrobial peptides.^36-38 IL-4 and IL-13 signal through a common receptor, IL-4Rα, to activate the Signal Transducer and Activator of Transcription 6 (STAT6)/Janus kinase 1 (JAK1) signalling cascade, and genetic polymorphisms in IL-4, IL-13 and IL-4Rα have all been associated with the development of AD in speci c populations.^39-44 Mice that have been genetically engineered to over-express a constitutively active STAT6 display decreased expression of epidermal differentiation complex genes, including laggrin, loricrin, and involucrin, and develop an AD- like disease by allowing for enhanced penetration of allergens and pathogens across the skin barrier.⁴⁵ Importantly, IL-4 deficiency was shown to be protective against the development of allergic skin inflammation in these mice, as was treatment with immune- modulators targeting either IL-4 or IL-13.⁴⁵ Additionally, IL-4 and IL-13 have also been demonstrated to regulate expression of genes, such as β-defensins and cathelicidin, involved in susceptibility to skin pathogens including Staphylococcus aureus and herpes simplex virus, potentially accounting for the fact that AD patients have an increased propensity for infection by these pathogens.^36-38 Together, this evidence suggests that targeting TH2 polarization in AD, including antagonism of IL-4 and IL-13, could be ef cacious in the treatment of AD.

Dupilumab Clinical Trials in AD

Given the importance of the TH2 in ammatory pathway in AD, it is not surprising that researchers have explored if the inhibition of IL-4 and IL-13 could provide a potential new treatment approach for this chronic, difficult-to-manage disease. Dupilumab is a fully human monoclonal antibody that binds the IL-4α receptor subunit, effectively blocking signalling from both IL-4 and IL-13. First tested for therapeutic value in asthma,⁴⁶ dupilumab has shown impressive results in trials for AD, and looks to change the management landscape for this debilitating disease. To date, several phase I and II trials have been completed, with other phase II and III trials currently underway in both adult and pediatric populations (Table 1).

Recently, a collection of phase I/II trials were published, which looked at the effects of dupilumab on moderate-to-severe AD refractory to topical glucocorticoids and calcineurin inhibitors.⁴⁷ Four trials in this publication include two phase I, 4 week monotherapy trials looking at safety as a primary endpoint (NCT01259323/study M4A and NCT01385657/study M4B) and two phase II trials, one 12 week monotherapy trial (NCT01548404/study M12) and one trial of dupilumab plus mid- high potency topical glucocorticoids with 4 weeks active treatment and 8 weeks follow-up period (NCT01639040/study C4). In the program, patients aged 18 years or older with moderate-to-severe AD and an Investigator Global Assessment (IGA) of ≥3 and a Scoring Atopic Dermatitis (SCORAD) score of ≥20 (study C4), or an Eczema Area and Severity Index (EASI) score ≥12 (studies M4A and M4B) or ≥16 (study M12), were included. Remarkably, in these phase I/II trials, patients treated with dupilumab experienced rapid improvement in AD disease activity. In study M12, the 12 week monotherapy trial, significantly more patients in the dupilumab arm experienced a ≥50% reduction in EASI score (EASI-50) as compared to the placebo arm (85% vs. 35%, respectively; p<0.001), near-to-complete clearance of skin lesions with an IGA of 0 or 1 (40% vs. 7%, respectively; p<0.001), and decreased pruritus with improvement on the pruritus Numerical Rating Scale (NRS) (56% vs. 15%, respectively; p<0.05).⁴⁷ When combined with topical glucocorticoids in the C4 study, all patients treated with dupilumab reached EASI-50, compared with only half of those receiving topical glucocorticoids plus placebo (p=0.002). Importantly, patients receiving dual therapy with dupilumab used less than half the glucocorticoid therapy required by those patients receiving glucocorticoid plus placebo (p=0.16).⁴⁷

The adverse event (AE) profiles were similar between the groups receiving either dupilumab or placebo in all of the studies. Most AEs were considered mild-to-moderate in severity, transient, and more likely to result in study discontinuation in the placebo group. The most common treatment-emergent adverse events (TEAEs) were nasopharyngitis and headache, which were more frequently reported in those subjects receiving dupilumab. Serious AEs were more frequently reported in the placebo groups (9/80) compared with the dupilumab groups (2/127). Interestingly, there were four times as many skin infections reported in the placebo groups (17/80) compared to the dupilumab groups (6/127), suggesting that dupilumab might improve skin barrier function. There were more injection site reactions in the dupilumab group but these were generally mild. There were no opportunistic infections or deaths in any of these studies.⁴⁷

When evaluating the molecular signature of genes expressed in non-lesional and lesional skin from the patients included in these trials, dupilumab-treated skin showed marked improvements with downregulation of markers of both epidermal proliferation and upregulation of genes involved in skin barrier function.²⁶ Dupilumab treatment also suppressed the expression of genes related to the activation of T cells and related inflammatory pathways, a major driver in AD clinical disease. After only 4 weeks of dupilumab treatment, the transcriptome of skin harvested from AD patients resembled that of non-lesional skin.²⁶

Another phase II international 16 week dose-ranging study (NCT01859988) including 380 patients has been completed and recently published.⁴⁸ Patients were 18 years or older and had an EASI score of ≥12 at screening (≥16 at baseline) with an inadequate response to topical therapy. This was a dose ranging study and patients were randomized to receive dupilumab 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks or placebo once a week for 16 weeks. When compared to placebo, all dupilumab dosing regimens showed a significant improvement in EASI score from baseline. The least-square means improvement of EASI score was -73.7% (300 mg every week), -68.2% (300 mg every 2 weeks), -65.4% (200 mg every 2 weeks), -63.5% (300 mg every 4 weeks), -44.8% (100 mg every 4 weeks) compared to -18.1% (placebo) (p48 The AE profile was similar to previously published studies with the most commonly reported AEs of nasopharyngitis, exacerbation of AD, headache and upper respiratory tract infection. There were more reports of herpes infections in the dupilumab group (8%) when compared to placebo (2%) as well as conjunctival inflammation (7% vs. 3%, respectively). The rate of injection site reactions was 7% in the dupilumab group vs. 3% in the placebo group.⁴⁸

A summary of the burden of disease in this patient group has also been published, which showed a significant burden of disease including that on quality of life as based on a number of patient reported measures: Dermatology Life Quality Index (DLQI), EuroQoL (EQ-5D) Health Status Questionnaire, Hospital and Anxiety Depression Scale (HADS), 5-D Pruritus and Patient Oriented Eczema Measure (POEM).⁴⁹

The pooled results of the 300 mg dupilumab group from this 16 week phase II study and the 300 mg group of the M12 study compared to placebo were presented recently.⁵⁰ Dupilumab was administered weekly as monotherapy and no additional topical steroids were allowed; the analysis included a total population of patients given placebo (n=115) or dupilumab 300 mg (n=118) with a loading dose at week 1. The improvement in SCORAD from baseline was 37 points for dupilumab (baseline score 66) and 11 for placebo (baseline score 68), respectively (p50 The safety profile was similar to previous studies and between the two groups. The TEAEs occurring in ≥5% of trial participants during the 12 week placebo-controlled period for placebo vs. 300 mg dupilumab included upper respiratory tract infection (33.9% vs. 42.4%), skin infections (29.7% vs. 16.4%), conjunctival inflammation/ infection (3.5% vs. 15.3%), headache (7.8% vs. 14.4%), and dermatitis (14.8% vs. 11.0%), respectively. There were more injection site reactions in the dupilumab group (13.6%) vs. placebo (6.1%). There were no deaths in either study.^48,50

Results from these studies have been extremely encouraging and prompted the quick expansion to clinical trials to evaluate the efficacy of dupilumab in pediatric patients, as well as the longterm safety of the drug. Currently, a phase II pharmacokinetic study in pediatric patients ≥6 and <18 years is ongoing (NCT02407756) as well as a long-term extension study for patients who participated in any trial from the phase I-III program (NCT01949311). Both members of the dermatologic community and patients affected by AD eagerly await the final results of these clinical trials.

Conclusion

Over the last several years, a number of important scientific and clinical discoveries have been made regarding the pathogenesis of AD. We now understand better than ever that AD results from defects in skin barrier function and innate and adaptive immune responses, both of which have important therapeutic implications. These discoveries not only explain the limitations of currently used treatments for AD, but also provide a map forward in our discovery of novel therapeutics for this difficult-to-treat skin disorder. Dupilumab is helping to shed new light on the pathomechanisms driving atopic dermatitis, and leading the way towards highly effective control of this debilitating disease.

References

1. Schmitt J, Langan S, Deckert S, et al. Assessment of clinical signs of atopic dermatitis: a systematic review and recommendation. J Allergy Clin Immunol. 2013 Dec;132(6):1337-47.
2. Shaw TE, Currie GP, Koudelka CW, et al. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011 Jan;131(1):67-73.
3. Kay J, Gawkrodger DJ, Mortimer MJ, et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994 Jan;30(1):35-9.
4. Bieber T. Atopic dermatitis. N Engl J Med. 2008 Apr 3;358(14):1483-94.
5. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part II: immune cell subsets and therapeutic concepts. J Allergy Clin Immunol. 2011 Jun;127(6):1420-32.
6. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part I: clinical and pathologic concepts. J Allergy Clin Immunol. 2011 May;127(5):1110-8.
7. Lio PA, Lee M, LeBovidge J, et al. Clinical management of atopic dermatitis: practical highlights and updates from the atopic dermatitis practice parameter 2012. J Allergy Clin Immunol Pract. 2014 Jul-Aug;2(4):361-9; quiz 70.
8. Williams H, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):209-13.
9. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010 Aug;105(2):99-106; quiz 7-9, 17.
10. DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. 2012 May-Jun;33(3):227-34.
11. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006 Jul;155(1):145-51.
12. Boguniewicz M, Abramovits W, Paller A, et al. A multiple-domain framework of clinical, economic, and patient-reported outcomes for evaluating benefits of intervention in atopic dermatitis. J Drugs Dermatol. 2007 Apr;6(4):416-23.
13. Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. Pediatr Dermatol. 2008 Jan-Feb;25(1):1-6.
14. McKenna SP, Doward LC. Quality of life of children with atopic dermatitis and their families. Curr Opin Allergy Clin Immunol. 2008 Jun;8(3):228-31.
15. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003 Dec;112(6 Suppl):S118-27.
16. Cookson WO. The genetics of atopic dermatitis: strategies, candidate genes, and genome screens. J Am Acad Dermatol. 2001 Jul;45(1 Suppl):S7-9.
17. Cookson WO, Moffatt MF. The genetics of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2002 Oct;2(5):383-7.
18. Haagerup A, Bjerke T, Schiotz PO, et al. Atopic dermatitis — a total genome-scan for susceptibility genes. Acta Derm Venereol. 2004 84(5):346-52.
19. Hoffjan S, Epplen JT. The genetics of atopic dermatitis: recent findings and future options. J Mol Med (Berl). 2005 Sep;83(9):682-92.
20. Lee YA, Wahn U, Kehrt R, et al. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet. 2000 Dec;26(4):470-3.
21. Morar N, Willis-Owen SA, Moffatt MF, et al. The genetics of atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):24-34; quiz 5-6.
22. Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011 Jul;242(1):233-46.
23. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol. 2008 Jun;121(6):1337-43.
24. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013 Feb;131(2):295-9 e1-27.
25. Esnault S, Benbernou N, Lavaud F, et al. Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) from atopic patients. Clin Exp Immunol. 1996 Jan;103(1):111-8.
26. Hamilton JD, Suarez-Farinas M, Dhingra N, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014 Dec;134(6):1293-300.
27. Jujo K,Renz H,Abe J,et al.Decreased interferon gamma and increased interleukin-4 production in atopic dermatitis promotes IgE synthesis. J Allergy Clin Immunol. 1992 Sep;90(3 Pt 1):323-31.
28. Kaminishi K, Soma Y, Kawa Y, et al. Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci. 2002 May;29(1): 19-25.
29. Renz H, Jujo K, Bradley KL, et al. Enhanced IL-4 production and IL-4 receptor expression in atopic dermatitis and their modulation by interferon-gamma. J Invest Dermatol. 1992 Oct;99(4):403-8.
30. Tang M, Kemp A, Varigos G. IL-4 and interferon-gamma production in children with atopic disease. Clin Exp Immunol. 1993 Apr;92(1):120-4.
31. Lebman DA, Coffman RL. Interleukin 4 causes isotype switching to IgE in T cell- stimulated clonal B cell cultures. J Exp Med. 1988 Sep 1;168(3):853-62.
32. Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001 Oct;117(4): 977-83.
33. Jin H, He R, Oyoshi M, et al. Animal models of atopic dermatitis. J Invest Dermatol. 2009 Jan;129(1):31-40.
34. Lee GR, Flavell RA. Transgenic mice which overproduce Th2 cytokines develop spontaneous atopic dermatitis and asthma. Int Immunol. 2004 Aug;16(8):1155-60.
35. Zheng T, Oh MH, Oh SY, et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009 Mar;129(3):742-51.
36. Howell MD, Fairchild HR, Kim BE, et al. Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation. J Invest Dermatol. 2008 Sep;128(9): 2248-58.
37. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007 Jul;120(1):150-5.
38. Kim BE, Leung DY, Boguniewicz M, et al. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008 Mar;126(3):332-7.
39. Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013 Jul 1; 2(3): e24137.
40. Hackstein H, Hecker M, Kruse S, et al. A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics. 2001 May-Jun;53(4):264-9.
41. Hershey GK, Friedrich MF, Esswein LA, et al. The association of atopy with a gain- of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med. 1997 Dec 11;337(24):1720-5.
42. Howell MD, Gao P, Kim BE, et al. The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. J Allergy Clin Immunol. 2011 Nov;128(5):1006-14.
43. Tamura K, Suzuki M, Arakawa H, et al. Linkage and association studies of STAT6 gene polymorphisms and allergic diseases. Int Arch Allergy Immunol. 2003 May;131(1):33-8.
44. Tanaka T, Hitomi Y, Kambayashi Y, et al. The differences in the involvements of loci of promoter region and Ile50Val in interleukin-4 receptor alpha chain gene between atopic dermatitis and Japanese cedar pollinosis. Allergol Int. 2012 Mar;61(1):57-63.
45. Sehra S, Yao Y, Howell MD, et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J Immunol. 2010 Mar 15; 184(6):3186-90.
46. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66.
47. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014 Jul 10;371(2):130-9.
48. Thaci D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016 Jan 2;387(10013):40-52.
49. Simpson EL, Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): Insights from a phase 2b clinical trial of dupilumab in adults. J Am Acad Dermatol. 2016 Jan 14. [Epub ahead of print]
50. Papp K, Simpson E, Beck L, et al. Efficacy and safety of dupilumab for moderate- to-severe atopic dermatitis in adults: a pooled analysis of two phase 2 randomized clinical trials. Oral and poster presentations. Presented at the 23rd World Congress of Dermatology; June 8-13, 2015; Vancouver, BC.

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²K. Papp Clinical Research, Waterloo, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada

ABSTRACT
Phosphodiesterase 4 (PDE4) is a key enzyme in the regulation of immune responses of inflammatory diseases through degradation of the second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP). Apremilast, a selective PDE4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines by increasing intracellular levels of cAMP and promoting the production of anti-inflammatory cytokines. The efficacy and safety of apremilast in the treatment of psoriasis and psoriatic arthritis has been
demonstrated in phase 2 and 3 studies and will be reviewed here. Across all studies, treatment was generally well-tolerated with some mild gastrointestinal complaints that occurred early and resolved over time, resulting in few drop-outs. Meaningful changes in dactylitis and enthesitis were also observed. Routine monitoring is not required given the absence of drug associated physiologic,
biochemical, and haematological changes. Apremilast proves to be a new promising systemic therapy for treating psoriatic disease.

Key Words:
psoriasis, chronic plaque psoriasis, apremilast, PDE4 inhibitors, psoriatic arthritis, immunology, inflammation

Introduction

Psoriasis is a disease complex involving skin, joints, and possibly the bowel.¹ Each manifestation of the psoriasis disease complex is expressed through an inflammatory, immune-mediated process. This has been described in the skin,² joints³ and bowel⁴. Therefore, interference in the immunological pathways common to psoriasis and psoriatic arthritis (PsA) could demonstrate clinical improvement of both. Recent clinical studies have shown precise blockade of phosphodiesterase 4 (PDE4) to be effective in the treatment of psoriasis⁵ and PsA^6,7.

PDE4 belongs to the phosphodiesterase family of
enzymes involved in the breakdown of cyclic adenosine
3′,5′-monophosphate (cAMP).^8,9 cAMP is a secondary messenger central for immune response regulation, and the inhibition of its breakdown leads to a cascade of cellular events resulting in a reduction of inflammatory mediators such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-23, as well as production of anti- inflammatory cytokines such as IL-10.^8,9

PDE4, found in cells of the immune system and keratinocytes, is the key enzyme responsible for cAMP breakdown. Through their cAMP-blocking actions, PDE4 inhibitors can prolong or enhance the effects of cAMP resulting in the reduction of both T-helper 1 (Th1) and Th2 immune responses.¹⁰ PDE4 is
expressed selectively in immune cells and plays a central role in the activation of these cells, which are upregulated in chronic plaque psoriasis and other inflammatory conditions such as PsA.⁹ Inhibition of PDE4 leads to an increase in the intracellular cAMP concentration, thereby reducing the production of inflammatory mediators and increasing anti-inflammatory mediators.^8,11 PDE4
inhibitors and their immune-modulating effects are currently under investigation in a variety of inflammatory conditions such as asthma, chronic obstructive pulmonary disease (COPD), atopic
dermatitis, psoriasis and PsA.^8-10

PDE4 Inhibitor in the Treatment of Psoriasis

The PDE4 inhibitor, apremilast (CC-10004, Otezla™), has been shown to block the production of interferon (IFN)-gamma, TNFalpha, IL-12 and IL-23 – the pro-inflammatory cytokines that play a major role in the pathogenesis of psoriasis. Apremilast, through its action to increase intracellular cAMP concentration,
demonstrated a range of anti-inflammatory effects on a variety of cell lines in vitro, ¹² reduction in the psoriasiform response in a preclinical model of psoriasis in vivo, as well as biologic activity
in a pilot study in humans¹³.

To date, apremilast has been evaluated in a number of phase 2^14-16 and phase 3 clinical trials (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1 and 2), demonstrating efficacy in psoriasis^17,18 and PsA^6,7,19-21. Another phase 3b study evaluating the efficacy and safety of apremilast, compared with etanercept and placebo in patients with moderate to severe plaque psoriasis, is ongoing (ClinicalTrials.gov Identifier: NCT01690299).

Apremilast Use in Psoriasis

Results from Phase 2 Studies in Plaque Psoriasis

Apremilast demonstrated efficacy in phase 2 clinical trials.^14-16 In a 12-week, phase 2, randomized, placebo-controlled trial in 259 patients, apremilast 20 mg twice daily (BID) achieved a Psoriasis
Area and Severity Index (PASI)-75 in 24.4% of patients vs. 10.3% in the placebo group. A dose-response was observed with a mean percent reduction in PASI from baseline of 17.4%, 30.3% and 52.1% for placebo, apremilast 20 mg once daily (OD) and apremilast 20 mg BID, respectively.¹⁴

Efficacy of apremilast was also shown in the phase 2b doubleblind, randomized, placebo-controlled crossover trial in 352 patients, which compared apremilast 10 mg, 20 mg, 30 mg or placebo BID for 16 weeks, at which point patients receiving placebo were then randomized to 20 mg or 30 mg BID up to 24 weeks. Primary endpoint of PASI-75 at 16 weeks was 11% for 10 mg, 29% for 20 mg, and 41% for 30 mg BID vs. 6% of patients on placebo.¹⁵

Treatment with apremilast also resulted in significant
improvement on patient-reported quality of life outcomes, with particular benefit noted at the 30 mg BID dose.¹⁶ Adverse effects were mild to moderate, and included headache, nausea, urinary tract infection (UTI) and diarrhea. No significant changes in laboratory values were observed in any of the trials.

Results from Phase 3 Studies in Plaque Psoriasis

The efficacy and safety of apremilast 30 mg BID was evaluated in two phase 3 randomized, placebo-controlled studies ESTEEM 1¹⁷ and ESTEEM 2¹⁸. The efficacy and safety of apremilast compared with etanercept and placebo in patients with moderate to severe plaque psoriasis is being evaluated in a phase 3b study (NCT01690299).

In ESTEEM1, 844 patients with moderate to severe plaque
psoriasis (PASI ≥12, Body Surface Area [BSA] ≥10%, static Physician’s Global Assessment [sPGA] ≥3) were randomized 2:1 to apremilast 30 mg BID (n=562) or placebo (n=282). At Week 16, all patients in the placebo group were switched to apremilast 30 mg BID through Week 32. At Week 32, all patients in the apremilast 30 mg BID group who achieved PASI-75 were
randomized (1:1, blinded) to continue apremilast 30 mg BID or receive placebo. Upon loss of PASI-75, patients who were rerandomized to placebo resumed apremilast 30 mg BID.¹⁷

In ESTEEM 2, 413 patients with moderate to severe psoriasis (PASI ≥12, BSA ≥10%, and sPGA ≥3) were randomized to placebo (n=138) or apremilast 30 mg BID (n=275) through Week 16. As in ESTEEM 1, at Week 16, all patients receiving placebo were switched to apremilast 30 mg BID through Week 32, followed by a randomized withdrawal phase through Week 52. At Week 32, all patients in the apremilast 30 mg BID group who achieved PASI-50 were randomized (1:1, blinded) to
continue apremilast 30 mg BID or receive placebo. Upon loss of PASI-50, patients who were re-randomized to placebo resumed apremilast 30 mg BID.¹⁸

Patients re-started apremilast at the time of loss of effect, defined as time of loss of 75% (ESTEEM 1) and 50% (ESTEEM 2) of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52. Patients initially on placebo or randomized to apremilast 30 mg BID who did not attain a PASI-75 or PASI-50, in ESTEEM 1 and ESTEEM 2, respectively, were
able to add topicals and/or ultraviolet B (UVB) phototherapy at Week 32 at the discretion of the investigator.^17,18 Study design of ESTEEM clinical trial program is shown in Figure 1.

Figure 1. ESTEEM 1 and 2 study design^{17, 18}

^aDoses of apremilast were titrated during the first week of administration.
^bA responder was defined as a patient achieving ≥PASI-75 (ESTEEM 1) or ≥PASI-50 (ESTEEM 2) at Week 32.
^cIn ESTEEM 1, patients were switched to apremilast at the time of loss of PASI-75, but no later than Week 52. In ESTEEM 2, patients were switched to apremilast at
time of loss of effect, defined as time of loss of 50% of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52.
^dAt Week 32, patients will have the option of adding topical and/or UVB therapy. The decision may be made at Week 32 only, but does not need to be initiated at
this visit. T = topicals; P = UVB phototherapy.

Figure 2A and 2B. PASI-75 (primary endpoint), PASI-50, and sPGA response at Week 16^17,18

Patients achieving PASI-75, PASI-50, and sPGA response with apremilast 30 mg BID vs. placebo. A. Response at Week 16 in ESTEEM 1. B. Response at Week 16 in
ESTEEM 2. sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline. *P

Significant improvements with apremilast 30 mg BID were
observed at Week 16 for PASI-75 (a reduction of ≥75% in PASI scores) and sPGA scores. In ESTEEM 1, significantly more patients in the apremilast group achieved PASI-75 (33.1%), PASI-50 (58.7%) and sPGA 0-1 (21.7%) vs. placebo (*P<0.0001, all),17 and in ESTEEM 2, patients treated with apremilast achieved PASI-75 (28.8%), PASI-50 (55.5%) and sPGA 0-1 (20.4%) vs. placebo (*P<0.0001, all)18. (Figure 2)

Improvements with apremilast 30 mg BID were also seen in the Nail Psoriasis Severity Index (NAPSI-50), scalp PGA (ScPGA 0-1), Palmoplantar Psoriasis Physician’s Global Assessment (PPPGA), Dermatology Life Quality Index (DLQI), and pruritus scores on the Visual Analogue Scale (VAS).^17,18

More patients treated with apremilast 30 mg BID achieved NAPSI-50 response at Week 16 vs. placebo. In ESTEEM 1, 33.3% of patients in the apremilast group achieved NAPSI-50 response vs. 14.9% with placebo (P<0.0001),¹⁷ and in ESTEEM 2, 44.6% of patients in the apremilast 30 mg BID group achieved NAPSI-50
vs. 18.7% with placebo (P<0.0001)¹⁸.

As well, a higher proportion of patients in the apremilast 30 mg BID group achieved ScPGA 0-1 (Clear-Minimal) at Week 16 vs. those in the placebo group. In ESTEEM 1, 46.5% in the apremilast group vs. 17.5% with placebo (P<0.0001),¹⁷ and in ESTEEM 2, 40.9% of patients in the apremilast group achieved ScPGA 0-1 vs. 17.2% with placebo (P<0.0001)¹⁸. In ESTEEM 2, 65.4% of patients treated with apremilast 30 mg BID achieved PPPGA 0-1 (Clear-Minimal) vs. 31.3% of patients treated with placebo.¹⁸ PPPGA 0-1 was not reported in ESTEEM 1.¹⁷

Apremilast 30 mg BID was associated with a significantly higher proportion of patients who achieved minimum clinically important difference (MCID) in DLQI and pruritus VAS from baseline at Week 16. Over 90% of patients receiving apremilast 30 mg BID, who were PASI-75 responders at Week 16, achieved MCID in DLQI and pruritus VAS. In ESTEEM 1, 70.2% of patients in the apremilast group achieved a MCID DLQI response vs. 33.5% with placebo (P<0.0001),^17,22 and in ESTEEM 2, 70.8% of patients treated with apremilast achieved a MCID DLQI response vs. 42.9% with placebo (P<0.0001)²³. For pruritus VAS, 70.6% of patients in ESTEEM 1 treated with apremilast achieved MCID vs. 33.7% with placebo (P<0.0001) in ESTEEM 1.²²

Time to loss of PASI improvement and PASI-75 response
were also evaluated at 52 weeks in ESTEEM 1. Of the patients re-randomized to placebo, 70.3% regained PASI-75 response after re-initiation of treatment with apremilast 30 mg BID. The duration of re-treatment ranged from 3.4-22.1 weeks.¹⁷ The median time to loss of PASI-75 response was 5.2 and 15.7 weeks for patients re-randomized to placebo and apremilast 30 mg BID, respectively. For the subgroup of patients who received apremilast 30 mg BID from Day 0 and continued on therapy, with PASI-75 responders at Week 32, there was a mean percent change from baseline in PASI score of -80% at Week 52.¹⁷

Safety and Tolerability Profile

Apremilast demonstrated an acceptable safety profile and was generally well-tolerated for up to 52 weeks in the treatment of plaque psoriasis. Most adverse events (AEs) were mild or moderate in severity. Discontinuation rates for diarrhea and nausea were each <2% in the apremilast 30 mg BID group through Week 52. The most frequently reported AEs during the
placebo-controlled period and apremilast-exposure period were diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis, tension headache, and headache.²⁴

In ESTEEM 1, apremilast 30 mg BID was generally welltolerated for up to 52 weeks with no increase in the incidence of AEs over time. Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes were not significantly affected, which is consistent with prior apremilast trials. AEs in ≥5% reported during Weeks 0-16 and over the entire apremilastexposure period (Weeks 0-52) of either placebo or apremilasta 30 mg BID group are shown in Table 1.¹⁷

In ESTEEM 2, the majority of AEs were mild or moderate in severity and discontinuation rates due to AEs during Weeks 0-16 were low (placebo: 5.1%; apremilast: 5.5%). In patients receiving apremilast, diarrhea and nausea were mostly mild in severity, with the highest incidence during the first week of dosing, generally resolving within 1 month, with few patients reporting use of concomitant medications. Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes again were consistent with prior apremilast studies; laboratory values were not significantly changed and serious AEs were low across treatment groups. AEs
reported during Weeks 0-16 in ≥5% are presented in Table 2.¹⁸

Apremilast Use in Psoriatic Arthritis

Results from Phase 3 Studies in Psoriatic Arthritis

The efficacy and safety of apremilast were evaluated in the phase 3 Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial program studies in patients with PsA.^6,7,9,19-21

The key inclusion criteria in PALACE 1 and 2 were adults with a documented diagnosis of PsA at baseline (duration ≥6 months; met the Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), ≥3 swollen and ≥3 tender joints despite past or current disease-modifying antirheumatic drugs (DMARDs) and/or biologics.^6,7,9,19 In PALACE 3, in addition to the above inclusion criteria for PALACE 1 and 2, patients also had to have at least one psoriatic lesion ≥2 cm, and PALACE 4 was in DMARD and/or biologics naïve patients.^20,21 Study design for the PALACE clinical trial program is shown in Figure 3.²⁰

Figure 3. PALACE Study Design^6,7,19-21

Note: Plasma samples for the biomarker assay were obtained at baseline and Weeks 4, 16, 24, and 40.
*All doses were titrated over the first week of treatment.
§Patients whose swollen and tender joint counts had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized
(1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo. Apremilast-treated patients continued on their initial apremilast dose.
‡At Week 24, all remaining placebo patients were re-randomized to apremilast 20 mg BID or 30 mg BID.

The results of a 24-week placebo-controlled phase of PALACE 1 have been published, as well as the 52-week period results, and will be presented here.^6,7 Patients with active PsA (n=504) were randomized (1:1:1) to placebo, apremilast 20 mg BID or apremilast 30 mg BID. At Week 16, patients without ≥20% reduction in swollen and tender joint counts were required to
be re-randomized equally to either apremilast dose if initially randomized to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses. Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology 20% improvement criteria (ACR20) at Week 16. ^6,7

At Week 16, significantly more patients receiving apremilast 20 mg BID (30.4%; P=0.0166) and 30 mg BID (38.1%; P=0.0001) achieved an ACR20 response vs. placebo (19.0%).⁷ At Week 24, a significantly greater proportion of patients receiving apremilast 20 mg BID and 30 mg BID achieved ACR20, ACR50 and ACR70 vs. placebo, and these response rates were maintained in the active treatment groups (P≤0.0001 vs. placebo, all). An ACR20 response of 45.3% was observed at Week 24 in patients treated with apremilast 30 mg BID independent of their response at Week 16.⁷ At Week 52, ACR20 response was observed among patients receiving apremilast continuously for 52 weeks (n=254) in 63.0% (20 mg BID) and 54.6% (30 mg BID) of patients.⁷

Patients who continued receiving apremilast through Week 52 demonstrated sustained rates of ACR20 response over 52 weeks. At Week 52, 63.0% of patients who received apremilast 20 mg BID from baseline and 54.6% who received 30 mg BID achieved an ACR20. ACR50 and ACR70 responses were observed in 24.8% and 15.4% of patients receiving apremilast 20 mg BID and 24.6% and
13.8% of patients receiving apremilast 30 mg BID, respectively.⁷

Patients treated with apremilast had a statistically significant improvement in physical function, as measured by changes from baseline in Health Assessment Questionnaire–Disability Index
(HAQ-DI) score (P=0.0004 vs. placebo) and the 36-Item ShortForm Health Survey v2 Physical Functioning domain score (P=0.0001 vs. placebo). Significant improvements were also seen in most ACR component scores, particularly swollen and tender joint counts and patient assessment of pain (P placebo).⁶

Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses compared to placebo (P6 Among patients receiving apremilast continuously for 52 weeks, response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function.⁶

In patients with baseline enthesitis, the mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was significantly higher for apremilast 30 mg BID vs. placebo (P=0.0334), and significantly greater proportions of patients receiving apremilast 20 mg BID (32.0%; P=0.0037) and
30 mg BID (33.6%; P=0.0013) achieved a MASES score of 0 at Week 24 vs. placebo (14.4%). In patients with baseline dactylitis, mean change from baseline in dactylitis severity score was higher with apremilast vs. placebo. Greater proportions of patients with dactylitis achieved scores of 0 at Week 24 with apremilast 20 mg BID (50.9%), apremilast 30 mg BID (47.7%) vs. placebo (40.9%); these differences did not reach statistical significance at Week 24.⁶ At Week 52, in patients with enthesitis and dactylitis at baseline who received apremilast continuously through Week 52, the median change from baseline in MASES at Week 52 was 100% with apremilast 20 mg BID and 66.7% with apremilast 30 mg BID, and a MASES score of 0 was observed in 50.7% (35/69) of patients receiving apremilast 20 mg BID and 38.2% (34/89) receiving apremilast 30 mg BID.⁷

At Week 16, treatment with apremilast was associated with significantly greater reductions (improvements) in HAQ-DI vs. placebo (key secondary endpoint, SE). The mean SE changes from baseline were -0.09 (0.04) (placebo), -0.20 (0.04) (apremilast 20 mg BID; P=0.0252 vs. placebo), and -0.25 (0.04) (apremilast 30 mg BID; P=0.0015 vs. placebo).⁶

As well, HAQ-DI scores were maintained in both apremilast groups over 52 weeks with continued treatment. At Week 52, mean reductions in HAQ-DI score were –0.37 (0.48) with apremilast 20 mg BID and –0.32 (0.55) with apremilast 30 mg BID, with improvements of ≥0.13 observed in 60.0% and 59.8%, respectively, and improvements of ≥0.30 observed in 45.8% and 44.7%, respectively.⁷

The most common AEs in the PALACE 1 trial were gastrointestinal (GI), mild or moderate in severity, occurred early, self-limited, did not recur, and infrequently led to discontinuation (<2.5%) in the apremilast 20 mg BID and 30 mg BID groups through
Week 24. No imbalance in major adverse cardiac events,
serious or opportunistic infections, malignancies or laboratory abnormalities was observed. For an overview of AEs occurring in ≥5% in any treatment group during the placebo-controlled phase (Weeks 0-24) and apremilast exposure period (Weeks 0-52) of PALACE 1 see Table 3. There were no new emergent AEs over the
52-week period.⁷

Warnings and Precautions: Data from Studies in
Psoriasis and PsA

Weight Decrease

Psoriasis: During the controlled period of the trials, weight decrease between 5%-10% of body weight was reported in 12% of psoriasis patients treated with apremilast 30 mg BID vs. 5% treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% of patients treated with apremilast 30 mg BID vs.
1% in the placebo group. It is recommended that patients treated with apremilast should have their weight monitored.

PsA: During the controlled period of the trials, weight decrease between 5%-10% of body weight was reported in 10% of patients with PsA treated with apremilast 30 mg BID vs. 3.3% of placebo. It is recommended that patients treated with apremilast should have their weight monitored regularly.²⁵

Depression

Psoriasis and PsA: While treatment with apremilast was associated with a risk of depression, data from the clinical trials do not suggest an increase in depression nor suicidal ideation in subjects treated with apremilast vs. placebo.²⁵

Drug Interactions

Psoriasis and PsA: The use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with apremilast is not recommended. It has been shown that the coadministration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of its efficacy.²⁵

Conclusion

Treatment with apremilast demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis^17,18 and improving signs, symptoms and physical function in PsA.^6,7,19-21 Apremilast demonstrated an acceptable safety profile and was well-tolerated with generally mild GI complaints occurring early in the course of the treatment and resolving with time, and there was no requirement for laboratory monitoring.^6,7,19-21,24 Based on these results, apremilast should be considered as a therapeutic option in the treatment of plaque psoriasis and PsA.

Acknowledgement

The authors gratefully acknowledge the medical editorial support from Flora Krasnoshtein in preparing this manuscript.

References

1. Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol. 2003 Jun;48(6):805-21; quiz 22-4.
2. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009 Jul 30; 361(5):496-509.
3. Ritchlin CT. Pathogenesis of psoriatic arthritis. Curr Opin Rheumatol. 2005 Jul;17(4):406-12.
4. Salari-Sharif P, Abdollahi M. Phosphodiesterase 4 inhibitors in inflammatory bowel disease: a comprehensive review. Curr Pharm Des. 2010 16(33):3661-7.
5. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012 Aug 25;380(9843):738-46.
6. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014 Jun;73(6):1020-6.
7. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015 Mar;42(3):479-88.
8. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012 Jun 15;83(12):1583-90.
9. Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014 Sep;26(9):2016-29.
10. Baumer W, Hoppmann J, Rundfeldt C, et al. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
11. Serezani CH, Ballinger MN, Aronoff DM, et al. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
12. Serezani CH, Ballinger MN, Aronoff DM, et al. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
13. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008 May;24(5): 1529-38.
14. Papp KA, Kaufmann R, ThaÁi D, et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind,placebo-controlled, parallel-group, dose-comparison study. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e376-83.
15. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet. 2012 Aug 25;380(9843):738-46.
16. Strand V, Hu A, Day R, Sloan V. P3337: Improved quality of life with apremilast (APR) in the treatment of psoriasis: results from a phase IIb randomized controlled study J Am Acad Dermatol 2011:64(2): AB154. [Poster abstract P3337]. Presented at the American Academy of Dermatology 2011 69th Annual meeting; February 4-8, 2011; New Orleans, LA.
17. Papp K, Reich K, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from the randomized treatment withdrawal phase of a phase 3, randomized, controlled trial (ESTEEM 1). [Poster 8359]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
18. Paul C, Cather J, Gooderham M, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). [Poster 8412]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
19. Cutolo M, Myerson GE, Fleischmann RM, et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2). [Presentation number 815]. Presented at ACR 2013. American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
20. Edwards CJ, Blanco FJ, Crowley J, et al. Long-term (52-Week) Results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement (PALACE 3). [Poster 311]. Presented at ACR 2013 American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
21. Edwards CJ, Wells AF, Adebajo AO, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, is associated with long-term (52-Week) improvements in enthesitis or dactylitis in patients with psoriatic arthritis: results from the PALACE 4 phase 3, randomized, controlled trial. Presented at European League Against Rheumatism Congress; June 1-14, 2014; Paris, France.
22. Armstrong AW, Griffiths CEM, Tencer T, et al. Effect of apremilast on patientreported outcomes in patients with moderate to severe plaque psoriasis in the ESTEEM 1 trial. [Poster P1691]. Presented at: the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
23. Gooderham M, Cather J, Crowley J, et al. Effects of apremilast on healthrelated quality of life in patients with moderate to severe plaque psoriasis: 16-week results from the ESTEEM 2 trial. [Poster P1688]. Presented at the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
24. Reich K, Papp K, Leonardi C, et al. Long-term safety and tolerability of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from a phase III, randomized, controlled trial (ESTEEM 1). [Poster 8296]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
25. Otezla^® (apremilast) [Full Prescribing information]. Summit, NJ: Celgene Corporation; revised December 2014. Available at: http://www.otezla.com/ otezla-prescribing-information.pdf. Accessed August 2, 2015.

Key Words:
IL-17, interleukin-17, interleukin-17A, interleukin-17R, monoclonal antibody, chronic plaque psoriasis, psoriatic arthritis

Pathogenesis of Plaque Psoriasis

Psoriasis vulgaris (plaque psoriasis) is a chronic, inflammatory, immune-mediated disease.¹ Genetically-susceptible individuals subjected to various environmental factors develop inflammation and subsequent keratinocyte proliferation.²

In psoriasis both the innate and adaptive immune system are dysregulated.³ The current pathogenic model in psoriasis highlights the role of T helper 17 (Th 17)/interleukin 17 (IL-17) axis dysfunction as an important source of inflammation.^3,4 Initially, activated dendritic cells may drive the activation of a subgroup of T cells (Th 17 cells) through IL-23, producing IL-17, interferon-γ (IFN-γ) and other proinflammatory cytokines. This array of cytokines results in keratinocyte and vascular response changes.^3-5 A consequence of keratinocyte response to the proinflammatory cytokines is production of chemokines and cytokines, which enhance cell recruitment. Specifically, neutrophil recruitment creates a positive feedback loop.^4,6 Because of its potential action on keratinocytes, IL-17 has been considered a “driver” cytokine in psoriasis.^3,7 Treatments targeting the IL-17 pathway using monoclonal antibodies have shown significant clinical efficacy in reducing the inflammation in this condition.^3,4,8-14

Psoriasis affects 2-3% of the population worldwide¹⁵, and it is associated with significant impairment of quality of life and work productivity¹⁶. Multiple efforts are being made to better understand its pathogenesis and to develop treatments with specific targets.

The purpose of this manuscript is to review the current literature regarding the efficacy and safety of IL-17 inhibitors in the treatment of moderate-to-severe plaque psoriasis.

T cell Differentiation and Impact of Th 17 Cells

Although T-helper 1(Th1) subset of activated T cells is the predominant cell type in plaque psoriasis, Th17 plays an integral role in the pathogenesis of plaque psoriasis.^17,18

In a bridging of the innate and adaptive immune system, undifferentiated T cells bind antigen presenting cells (APCs) and through T cell receptor (TCR)-binding, co-stimulation and the cytokine milieu, T cells differentiate into an effector phenotype.¹⁹

APC-derived cytokine, interleukin-12 (IL-12), causes differentiation of Th1 cells, and IL-1β, IL-6 and transforming growth factor-β (TGFβ) cause differentiation of Th17 cells. IL-23 is necessary for stabilization, survival and proliferation of the Th17 cell type.¹⁹

IL-17: A Driver of Plaque Psoriasis

IL-23-activated Th17 cells were discovered to produce IL-17, IL-6 and tumor necrosis factor (TNF) through antigen-specific stimulation.^18,20 IL-17 acts on epithelial cells such as keratinocytes to produce antimicrobial peptides and chemokines, which attract neutrophils and other inflammatory cells.¹⁷

The IL-17 family is a group of molecules involved in host defense against pathogens and inflammatory processes.^21-26 There are six known subtypes (A, B, C, D, E and F) and increased expression of three of them (A, C and F) has been implicated in the pathogenesis of inflammation in psoriasis. However, their functions are not fully elucidated.^23,24,27,28 These molecules interact with a group of transmembrane receptor subunits known as IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE.^27,29-32

IL-17A, composed of 155 amino acids and with a molecular weight of 15 kDa, is the best studied member of this family. It has been related to important roles in different disorders including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and psoriasis;^23,27,33-36 IL-17A forms homodimers or heterodimers with molecules of IL-17F, which interact with heteromeric receptors (two IL-17RA subunits and one IL- 17RC subunit). This interaction triggers downstream gene activation.^21,23,30 IL-17 isoforms have been identified as products of Th17 cells. However, other cells involved in the immune response, such as CD8+ T cells, eosinophils, mast cells, natural killer cells, neutrophils, Tc17 cells and a subset of gamma delta (γδ) T cells (Vγ9Vδ2) related to the activation of keratinocytes in psoriasis, are able to produce these molecules as well.^{21,22,30,37,38}

IL-17A induces recruitment of cells to psoriatic lesions through stimulation of keratinocyte production of chemokines. For example, CCL20 recruits myeloid dendritic cells and Th17 cells that perpetuate the inflammatory process.^3,21,39-41 IL-17A also stimulates keratinocytes to produce other chemokines such as CXCL1, CXCL3, CXCL5, CXCL6, CXCL8 and B-defensin that act as neutrophil chemoattractants.^{20,21,39,40,42,43} IL-17A-mediated stimulation of macrophages, fibroblasts and endothelial cells contributes to the amplification of the inflammatory response in psoriatic lesions. This amplification is the result of increased production of molecules such as CXCL8 (IL-8), IL-1, IL-6 and TNF-α.^21,25,44 Additionally, IL-17A potentiates skin barrier disruption through downregulation of the expression of filaggrin.⁴⁵ IL-17C, which interacts with receptor subunits IL-17RA and IL-17RE, is also present in psoriatic lesions and has been reported as the most abundant isoform. IL-17C localizes to keratinocytes, endothelial cells and leukocytes. Its effect on the production of TNF-α and synergistic actions are similar to those produced by IL-17A.^27,46

Therapeutic Implications of IL-17 Inhibition

The molecular features of IL-17 made it an attractive therapeutic target and specifically as targeted therapy in plaque psoriasis. Currently, three monoclonal antibodies targeting IL-17 are in clinical development – brodalumab, ixekizumab and secukinumab.^8-13

Brodalumab is a human, anti-IL-17-receptor (anti–IL-17RA) monoclonal antibody that binds with high affinity to human interleukin-17RA. IL-17RA blockade inhibits the biologic activity of interleukins 17A, 17F, 17A/F heterodimer and 17E (IL-25).⁸ Ixekizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody⁹ and secukinumab is a fully human IgG1κ monoclonal antibody^10-13 that selectively bind and neutralize IL-17A.

Clinical Efficacy of IL-17 Inhibitors

At the time of this review, Phase 3 trial results for brodalumab and ixekizumab have been reported in press releases (presented later in the manuscript), while results of the Phase 3 program for secukinumab were recently published.^8-13 Inclusion criteria for all Phase 2 and 3 programs required chronic plaque psoriasis having severity measures of psoriasis area and severity index (PASI) ≥12, body surface area (BSA) ≥10% and static physician global assessment (sPGA) of ≥3.^8-13

Demonstrated Efficacy in Phase 2 Trials

Four Phase 2 studies on three IL-17 inhibitors for plaque psoriasis have been published to date.^8-11

Brodalumab

In a Phase 2 randomized, double-blind, placebo-controlled, doseranging study of brodalumab included 198 patients, who received either placebo or 70 mg, 140 mg, or 210 mg subcutaneous (SC) brodalumab at weeks 0, 1, 2, 4, 6, 8, and 10 or 280 mg at weeks 0, 4, 8. The PASI 75 at week 12 was 33%, 77%, 82% and 67%, for the 70 mg, 140 mg, 210 mg and 280 mg dosing regimens, respectively. The PASI 75 response at week 12 in all active treatment arms was statistically significant compared to placebo (p<0.001, for all). The PASI 90 of the three highest dose groups was 72% for 140 mg, 75% for 210 mg, and 57% for 280 mg vs. placebo (p<0.001, for all).⁸

Ixekizumab

The Phase 2, double-blind, placebo-controlled trial of ixekizumab included 142 patients with chronic moderate-to-severe plaque psoriasis who were treated with either placebo or 10 mg, 25 mg, 75 mg or 150 mg SC ixekizumab at weeks 0, 2, 4, 8, 12, and 16. The PASI 75 responses at week 12 were 29% (10 mg), 77% (25 mg), 83% (75 mg) and 82% (150 mg) vs. placebo (p<0.001, for all). The PASI 90 scores of the 50 mg, 75 mg and 150 mg were notable, at 50%, 59% and 71%, respectively, vs. placebo (p<0.001, for all).⁹

Secukinumab

There were two Phase 2 programs for secukinumab, a doseranging study¹⁰ and a regimen-finding study¹¹.

The dose-ranging study examined 125 patients who received placebo, 25 mg, 75 mg or 150 mg SC secukinumab at weeks 0, 4, 8 vs. a single dose of 25 mg. Primary endpoint of PASI 75 at week 12 was met by 57% of patients receiving 75 mg and 82% of patients receiving 150 mg vs. placebo (p=0.002 and p<0.001, respectively). PASI 90 was reached by 52% of patients on the 150 mg dose vs. placebo (p<0.001). This was the only group that reached statistically-significant PASI 90 response vs. placebo.¹⁰

The regimen-finding study included 404 patients who were randomized to placebo or one of three SC secukinumab 150 mg dosing regimens: single (week 0), early (weeks 0, 1, 2, 4) and monthly (weeks 0, 4, 8). At week 12, PASI 75 was 54.5% for early and 42% for monthly dosing regimen vs. placebo (1.5%) (p<0.001 for both), and only 10.6% for the single regimen (p=0.0225 vs. placebo). Noteworthy is the somewhat lower PASI 75 response observed in the 150 mg monthly regimen (42%) compared to that in the dose-ranging study (82%). PASI 90 responses were 31.8% and 17.4%, for the early and monthly regimens, respectively, vs. placebo (p<0.001 for both), and 30% for the single regimen (p=0.556 vs. placebo).¹¹

Demonstrated Efficacy in Phase 3 Trials

Secukinumab

Secukinumab was further evaluated in four Phase 3 randomized, double-blind, placebo-controlled trials – two 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis)¹², one 12-week trial, FEATURE, a bridging study assessing response of self-administration by pre-filled syringe¹³, and SCULPTURE, a 52-week trial comparing fixed-dose vs. retreatment-as-needed maintenance regimen with 150 mg or 300 mg secukinumab. The SCULPTURE trial is ongoing and results have not yet been published.¹⁴

In the ERASURE study, 738 patients were randomly assigned to SC secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks) or placebo.¹²

In the FIXTURE study, 1,306 patients were randomly assigned to SC secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly) or placebo.¹²

Co-primary endpoints at week 12 of PASI 75 and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator’s global assessment were met by a higher proportion of patients treated with secukinumab vs. those treated with etanercept or placebo.¹²

The proportion of patients meeting PASI 75 at week 12 was higher with both secukinumab doses than with placebo or etanercept. In the ERASURE study, the rates were 81.6% with secukinumab 300 mg, 71.6% with secukinumab 150 mg, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with secukinumab 300 mg, 67.0% with secukinumab 150 mg, 44.0% with etanercept, and 4.9% with placebo (p<0.001 for each secukinumab dose vs. comparators).¹²

The proportion of patients with a response of 0 or 1 on the modified investigator’s global assessment (IGA mod 2011) at week 12 was also higher with each secukinumab dose than with either placebo or etanercept. In the ERASURE study, the rates were 65.3% with secukinumab 300 mg, 51.2% with secukinumab 150 mg, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with secukinumab 300 mg, 51.1% with secukinumab 150 mg, 27.2% with etanercept, and 2.8% with placebo (p<0.001 for each secukinumab dose vs. comparators).¹²

In the FEATURE trial, 177 patients were randomized to SC secukinumab 300 mg or 150 mg, or placebo. Each treatment was delivered using a pre-filled syringe once a week for 4 weeks, and again at week 8. Co-primary endpoints at week 12 of PASI 75 were met by 75.9% in 300 mg group, 69.5% in 150 mg group, and 0% in placebo group; IGA mod 2011 0/1 were 69.0% in 300 mg group, 52.5% in 150 mg group, and 0% in placebo group (p<0.0001 for all comparisons vs. placebo). The usability of pre-filled syringe reached 100%; all patients successfully self-administered treatment at week 1, and reported high Self-Injection Assessment Questionnaire-assessed acceptability of the pre-filled syringe throughout the trial.¹³

Ixekizumab

Ixekizumab was studied in the largest Phase 3 program to date in 3,866 patients with moderate-to-severe plaque psoriasis. It was evaluated against placebo and etanercept. In the three UNCOVER studies, patients were randomized to either placebo or SC ixekizumab 80 mg every 2 or 4 weeks for 12 weeks, following a 160 mg induction dose. In the two active comparator studies (UNCOVER-2 and 3) patients were randomized to receive etanercept 50 mg twice weekly for 12 weeks. In UNCOVER-1, respondents to treatment either continued to receive placebo or ixekizumab 80 mg every 4 or 12 weeks for up to 60 weeks. Both dosing regimens of ixekizumab resulted in significantly greater levels of skin clearance vs. placebo and etanercept. At week 12, PASI 75 was achieved by 78-90% of patients treated with ixekizumab either every 2 or 4 weeks. PASI 100 was achieved by 31-41% of patients treated with ixekizumab vs. 5-7% of patients treated with etanercept. While the results have been reported in a press release by the sponsor Eli Lilly, they have not been formally published at the time of this review. The reader should interpret this data with caution as it has not been peer reviewed and it does not discuss trial design or statistical methodology used. (Source: press release August 21, 2014; www.lilly.com)

Brodalumab

In the Phase 3, placebo-controlled, randomized trial, AMAGINE-1, 661 patients with moderate-to-severe plaque psoriasis were treated with placebo, 140 mg or 210 mg SC brodalumab every 2 weeks. At week 12, PASI 75 was achieved by 60.3% of patients in the 140 mg group and 83.3% in the 210 mg group vs. placebo (2.7%, p<0.001). PASI 90 was achieved by 42.5% of patients in the 140 mg group, and 70.3% in the 210 mg group vs. placebo (0.9%, p<0.001). While the results have been reported, they have not been formally published at the time of this review. (Source: Papp KA, Reich K, Leonardi C, et al. Gene to Clinic, London, UK, 2014)

Phase 3 trials evaluating brodalumab are currently underway (ClinicalTrials.gov numbers: NCT01708590, NCT01708603, NCT01708629). As well, clinical trials evaluating secukinumab (NCT01544595, NCT01806597, NCT01365455, NCT01358578, NCT01406938, NCT01636687, NCT01412944, NCT01555125) and ixekizumab (NCT01777191, NCT01597245, NCT01646177, NCT01107457, NCT01624233) are also ongoing.

IL-17 Inhibitors: Safety and Tolerability in Phase 2 and Phase 3 Trials

Phase 2 Trials

The adverse event profiles from each of the anti-IL-17 Phase 2 trials were similar. The most commonly reported events were nasopharyngitis, upper respiratory tract infection, and headache.^8-11

Injection site reactions were observed with brodalumab and ixekizumab, but none were reported in either of the secukinumab trials.^8-11

Laboratory parameter changes of interest were similar in all trials. Each had cases of neutropenia with the higher doses. There were two cases of grade 3 neutropenia in the brodalumab 210 mg group⁸, two cases of grade 2 neutropenia in the ixekizumab 75 mg and 150 mg groups⁹, and two cases of grade 1-2 neutropenia in the secukinumab dose-finding study in the 3 X 150 mg cohort¹⁰. There were also cases of grade 1-2 neutropenia in the regimenfinding study in both the induction and maintenance phase, but resolved during the course of the study in all cases.¹¹

Phase 3 Trials

The adverse event profiles from each of the anti-IL-17 Phase 3 trials were also similar. The most common reported events were nasopharyngitis, upper respiratory tract infection, and headache.^12,13 (Sources: press release August 21, 2014; www.lilly.com; Papp KA, Reich K, Leonardi C, et al. Gene to Clinic, London, UK, 2014)

The rates of infection were higher with secukinumab than with placebo in all trials, and were similar to those with etanercept.^12,13 In the FEATURE study, the incidence of Candida infection in the secukinumab 300 mg group was twice that of the 150 mg group (one oral and one vulvovaginal candidiasis vs. one vulvovaginal candidiasis, respectively). All infections were mild-to-moderate and resolved without treatment.¹³ Overall, secukinumab had a comparable safety profile to that reported in previous Phase 2 trials, and while mild-moderate neutropenia was observed, it was reversible without the need for treatment interruption.10-13

Injection site reactions were reported with ixekizumab, but most were mild and did not result in treatment discontinuation. The overall rates and severity of adverse events were similar with ixekizumab and etanercept. (Source: press release August 21, 2014; www.lilly.com)

Conclusion

The results from Phase 2 and 3 trials targeting IL-17 with brodalumab, ixekizumab and secukinumab help validate IL-17 as an effective therapeutic target in the treatment of plaque psoriasis.^8-13

References

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10. Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind,placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013 Feb;168(2):412-21.
11. Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized,double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2013 Feb;168(2):402-11.
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13. Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety, and usability results from a randomized controlled trial in Psoriasis (FEATURE). Br J Dermatol. 2014 Aug 16.[Epub ahead of print]
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16. Armstrong AW, Schupp C, Wu J, et al. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 2012;7(12):e52935.
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