Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

A review of emerging IL-17 inhibitors in the treatment of psoriasis focusing on preclinical through phase II studies

Introduction: Interleukin-17 has recently been identified as a key player in the pathogenesis of psoriasis. As such, several drugs targeting IL-17 are in various stages of clinical development.

Areas covered: In this review, the authors describe several emerging therapies and drug candidates targeting IL-17. The authors detail many biologic injectable drug candidates as well as numerous potential oral and topical small molecule drug candidates.

Expert opinion: Approval of IL-17 inhibitors has significantly improved the treatment options for psoriasis patients. Secukinumab and ixekizumab are approved in both Europe and the USA, and brodalumab is likely facing approval by the end of 2016. Numerous additional biologic and small molecule drug candidates are in the pipeline, and once deemed safe and effective will likely offer significant benefit to our psoriasis population.     

CCR6 as a possible therapeutic target in psoriasis

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T_H17 subset of CD4⁺ T cells, which produces IL-17A/F, IL-22, TNF-α and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3α, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation.

Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/T_H17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease.

What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis.

Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.     

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

Introduction: There is strong pharmaceutical development of agents targeting the IL-17–TH17 pathway for the treatment of psoriasis (Ps) and psoriatic arthritis (PsA). Lung cancer accounts for 28% of all cancer-related deaths worldwide, and roughly 80% of patients with newly-diagnosed non-small cell lung cancer (NSCLC) present with metastatic disease, with a poor prognosis of around 12 months. Therefore, there is a high unmet medical need for the development of new and potent systemic treatments in this deadly disease. The emergence of immunotherapies such as anti-PD-1 or anti-PDL1 as candidate therapies in non-small cell lung cancer (NSCLC) indicates that targeting critical immuno-modulatory cytokines including those within the IL-17-Th1/Th17 axis may have proven benefit in the treatment of lung cancer.

Areas covered: In this review we describe the current evidence for aberrant IL-17-Th1/Th17 settings in cancer, particularly with regard to targeting this axis in NSCLC. We further discuss the current agents under pharmaceutical development which could potentially target this axis, and discuss the current limitations and areas of concern regarding the use of these in lung cancer.

Expert opinion: Current evidence suggests that moving forward agents targeting the IL-17-Th1/Th17 pathway may have novel new oncoimmunology indications in the treatment paradigm for NSCLC.     

Novel systemic therapies for the treatment of psoriasis

Introduction: The immunopathogenesis of psoriasis has led to the discovery and development of several promising treatment options for psoriasis, including those that target the IL-17 and IL-23 pathways as well as small molecules that act on intracellular signaling pathways including the Janus kinase inhibitor and phosphodiesterase-4 inhibitor. Studies have demonstrated efficacy although long-term risks are not fully known. This review looks at novel systemic therapies for psoriasis that have emerged recently.

Areas covered: Systemic treatments for psoriasis that are in the late phase of development were reviewed, with the main focus on the efficacy and adverse effects of individual treatments.

Expert opinion: The future of psoriasis treatment is likely to be based on clinical, genetic and immune biomarkers that will individualize treatment and may potentially optimize disease outcome.     

Guselkumab for the treatment of moderate-to-severe plaque psoriasis

Introduction: Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis.

Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis.

Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.     

The safety of ixekizumab in psoriasis drug therapy

ABSTRACT

Introduction: Ixekizumab, a humanized IgG4 monoclonal antibody that selectively binds and neutralizes interleukin IL-17A, has been approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of moderate to severe plaque psoriasis (2016), active psoriatic arthritis (FDA 2017, EMA 2018), and active ankylosing spondylitis (FDA 2019).

Areas covered: This review evaluates the safety profile of ixekizumab for the treatment of moderate-to-severe psoriasis. A literature search was performed for articles published through November 2019.

Expert opinion: These studies show that ixekizumab demonstrates a favorable safety profile. Antidrug antibodies can be detected in up to 17% of patients but they do not significantly affect clinical response or safety of the treatment. Injection site reactions, erythema or pain, develop in up to 10% of the patients during the first 12 weeks of treatment, an incidence similar to that of etanercept. Infections overall do not cause a safety problem; mucocutaneous Candida infections, occur at a rate of in 1.9/100 patient-years, but are easily managed and usually do not determine treatment discontinuation. The occasional de novo appearance or exacerbation of preexistent inflammatory bowel disease remains a cause of concern, and requires close monitoring of patients at risk.     

The safety of brodalumab for the treatment of psoriasis

ABSTRACT

Introduction: Brodalumab is a newly developed targeted biologic agent for the treatment of psoriasis that blocks IL-17 receptor A.

Areas covered: This review sought to provide a detailed overview on safety of brodalumab for the treatment of psoriasis. A PubMed search was conducted for relevant literature. Here we review the efficacy and safety data from key phase II, phase III and open-label extension clinical trials, as well as systematic reviews and meta-analyses.

Expert opinion: The unique mechanism of action of brodalumab offers advantages on efficacy over other targeted treatments, with a quick onset of action and long-term maintenance of treatment response. Brodalumab has a favorable safety profile, similar to other IL-17 inhibitors. Infections, especially mucocutaneous candidiasis, must be monitored. Suicidal ideation was detected in brodalumab trials, although a causal relationship has not been revealed. Brodalumab is a highly efficacious and comparably safe therapeutic choice in patients with moderate to severe psoriasis, especially when rapid control of the disease is desired.     

Real-world incidence of inflammatory bowel disease among patients with other chronic inflammatory diseases treated with interleukin-17a or phosphodiesterase 4 inhibitors

Objectives: (1) To assess the real-world incidence of inflammatory bowel disease (IBD) in patients with or without other chronic inflammatory diseases (CIDs), and (2) to understand whether IBD incidence differs in CID patients receiving interleukin-17a signaling antagonists (anti-IL-17a) or phosphodiesterase 4 inhibitors (PDE4i) versus patients using a biologic not indicated for IBD or biologic-naïve patients.

Methods: The MarketScan Research Databases (January 2010–July 2017) were used. A CID population was created from patients with ankylosing spondylitis, psoriatic arthritis, psoriasis or rheumatoid arthritis (RA). The CID population was stratified into different cohorts based on the baseline treatments received: (1) anti-IL-17a, (2) PDE4i, (3) biologic-naïve, and (4) non-IBD-indicated biologic (i.e. biologics not indicated for the treatment of IBD and excluding anti-IL-17a and PDE4i); a non-CID cohort was also created. The 1?year incidence rate (IR) of IBD was compared between cohorts using a logistic regression model adjusting for baseline characteristics.

Results: CID cohorts included older patients than the non-CID cohort (mean age range: 48.4–54.4 versus 46.3?years). The 1?year IR of IBD was 1.41% in the anti-IL-17a cohort (N?=?355), 0.68% in the PDE4i cohort (N?=?2195), 0.47% in the biologic-naïve cohort (N?=?424,767), 0.51% in the non-IBD-indicated biologic cohort (N?=?56,317) cohort and 0.25% in the non-CID cohort (N?=?1,008,436). After 1?year of follow-up, the odds of having IBD were 2.85 (p?=?.0213) and 1.42 (p?=?.1891) times higher in the anti-IL-17a and PDE4i cohorts, respectively, compared to the biologic-naïve cohort, and 2.86 (p?=?.0253) and 1.21 (p?=?.4978) times higher compared to the non-IBD-indicated biologic cohort. Similar results were observed in sensitivity analyses where patients with RA only were excluded (since anti-IL-17a and PDE4i agents are not indicated for RA).

Conclusions: Anti-IL-17a treatment was associated with a nearly three-fold higher risk of IBD in CID patients. Treatment decisions for patients with CIDs should take into account the risk of developing of IBD.     

Targeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs

Introduction: IL-6 is a key cytokine in the pathogenesis of rheumatoid arthritis (RA). The clinical efficacy of tocilizumab (TCZ), a humanized anti-IL6-receptor mAb, confirmed the value of IL-6 blockade in this disease. A number of new anti-IL-6 biologics are currently in Phase I – III of clinical development for RA.

Areas covered: This article reviews the available results from Phase II trials of investigational anti-IL-6 agents in RA. The authors discuss the potential relevance of alternative IL-6-blocking agents, with regard to their specific molecular targets in IL-6 signaling pathways and to the main open questions in the clinical research agenda for anti-IL-6 biologics.

Expert opinion: The results of Phase II trials of new anti-IL-6 biologics show promising results in terms of efficacy. The most frequently reported adverse events were not unexpected based on previous experience with TCZ. Further evidence is needed to appraise whether the difference in molecular structure or in the specific target of new anti-IL-6 biologics might result in added therapeutic value over TCZ. New data from Phase III trials that provides a head-to-head comparison against TCZ and anti-TNF agents with or without methotrexate background treatment are expected in the future.     

Safety of secukinumab in the treatment of psoriasis

ABSTRACT

Introduction: Secukinumab is a human monoclonal antibody that selectively targets and neutralizes interleukin (IL)-17A, a cytokine that is normally involved in mucocutaneous defense against extracellular organisms and is abnormally expressed in psoriasis. In 2015, secukinumab was the first IL-17A inhibitor approved for the treatment of moderate-to-severe psoriasis.

Areas covered: This review evaluates the safety profile of secukinumab for the treatment of moderate-to-severe psoriasis and its role in the clinical landscape. A literature search was performed for articles published through February 2016; additional data from a pooled safety analysis of 10 Phase II and III secukinumab studies were reviewed.

Expert opinion: Collectively, these studies show that secukinumab demonstrates a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer. Mucocutaneous candidiasis is a common side effect and occurs at a rate of 3.55/100 subject-years with secukinumab 300 mg, yet these infections usually do not interfere with maintenance of secukinumab therapy. The combination of proven efficacy and safety make secukinumab an excellent new treatment choice for individuals with moderate-to-severe psoriasis.     

Targeting IL-23 in human diseases

Importance of the field: IL-23 is one of the most intriguing cytokine for its many immunological functions, which are the basis of its important role in host defense but also of its possible contribution to the pathogenesis of several diseases.

Areas covered in this review: The literature and patents about IL-23 pathway and their targeting in therapeutic potential applications. Findings published within the last 5 years receive particular attention.

What the reader will gain: An overview of the emerging role of IL-23 in physiological and pathological conditions and a review of the different approaches (IL-23 pathway-based) currently used for autoimmune diseases and cancer therapies and the results obtained both in preclinical models and in clinical trials.

Take home message: Inhibition/targeting of IL-23 may be a good and novel therapeutic strategy, especially in the treatment of diseases like psoriasis, for which current treatments show more pronounced side effects than those of IL-23-blocking and employed as part of specific patient-tailored therapies in inflammatory bowel diseases.     

A safety evaluation of guselkumab for the treatment of psoriasis

Introduction: Guselkumab is a fully human monoclonal IgG1λ antibody for the treatment of plaque psoriasis that inhibits interleukin (IL)-23p19 subunit, reducing the proliferation of type 17 helper T (Th-17) cells and thus production of Th-17-derived pro-inflammatory cytokines, especially IL-17 and IL-22.

Areas covered: In the following article, the mechanism of action and mainly the efficacy and safety profile of guselkumab available from results of trials will be discussed. We summarized these data after a literature review including PubMed search, relating proceedings and abstracts from relevant international conferences, assessment reports from European and United States regulatory agencies and treatment guidelines up to April 2018.

Expert opinion: The central role of IL-23 in psoriasis pathogenesis is supported by genetic links of IL-23 and IL-23R alleles to psoriasis susceptibility; early clinical trials have demonstrated that sufficient inhibition of IL-23p19 results in rapid resolution of the disease. Targeting IL-23, may be responsible for the high efficacy and durable responses of guselkumab, avoiding some adverse effects of IL-17A blockade, like mucocutaneous candida infections or triggering/worsening of inflammatory bowel disease, experienced with agents acting selectively against this molecule and that seem to be class related.     

Ixekizumab for treatment of adults with moderate-to-severe plaque psoriasis and psoriatic arthritis

Introduction: The interleukin (IL)-17 family of cytokines has emerged as an important pro-inflammatory mediator of psoriasis and psoriatic arthritis (PsA). Ixekizumab is an IL17A inhibitor that has been approved for the treatment of chronic plaque psoriasis. Phase III studies of ixekizumab in treating of PsA demonstrated promise by minimizing disease severity and progression.

Areas covered: This review focuses on the biologic properties, pharmacokinetics and key clinical trial results that demonstrated the safety and efficacy of ixekizumab in treating psoriatic disease.

Expert commentary: Ixekizumab is a biologic that has been approved for the treatment of chronic plaque psoriasis. With respect to safety, ixekizumab is generally well tolerated with injection-site reactions, nasopharyngitis, and upper respiratory tract infections being the most common adverse events. Most patients with anti-drug antibodies have low antibody titer levels resulting in no meaningful interference in clinical response to ixekizumab.     

Novel investigational vascular endothelial growth factor (VEGF) receptor antagonists for psoriasis

Introduction: Affecting 1 million people in the UK, psoriasis is a commonly diagnosed inflammatory disease arising from autoimmune processes that are triggered by environmental factors in genetically susceptible individuals. The pathophysiology of psoriasis has been widely studied and there is evidence that angiogenesis is a key component.

Areas covered: In this review the role of vascular endothelial growth factor-A (VEGF), as a key angiogenic mediator in psoriasis pathogenesis is discussed. VEGF is found in higher levels in plaques, normal skin and plasma of patients with psoriasis. The level of VEGF also fluctuates in accordance with disease activity and in response to conventional treatments. There are several VEGF inhibitors currently licenced for use; primarily in the fields of oncology and there are case reports of patients being treated with these therapies for metastatic cancer who have demonstrated significant improvement in their psoriasis. VEGF inhibitory agents have suggested promising utility for the treatment of psoriasis following animal studies.

Expert opinion: VEGF may represent a novel treatment target in psoriasis. However, VEGF inhibitors can cause significant side effects such as hypertension and left ventricular dysfunction. The risks of treatment must be carefully evaluated before VEGF inhibitors are trialled or advocated for psoriasis.     

Emerging anti-inflammatory drugs for atherosclerosis

Introduction: Cardiovascular disease is the most common cause of morbidity and mortality worldwide. Inflammation is responsible for initiation and progression of atherosclerosis, and leads to plaque vulnerability. Evidence-based therapies reduce the risk of initial and recurrent cardiovascular events but many patients experience recurrent events due to the failure of conventional therapies to adequately address inflammation.

Areas covered: Statins were originally developed for their LDL cholesterol-lowering effects, but are now thought to improve cardiovascular morbidity and mortality through anti-inflammatory effects as well. Drugs that inhibit the various inflammatory pathways responsible for atherosclerosis are the subject of current research. These include antioxidants, phospholipase A₂ inhibitors, leukotriene pathway inhibitors, CCL2-CCR2 pathway inhibitors, non-specific anti-inflammatory drugs (i.e., methotrexate), IL-1 inhibitors and p-selectin inhibitors.

Expert opinion: Currently, only three anti-inflammatory drugs (methotrexate, darapladib and canakinumab) are being investigated in Phase III clinical trials of atherosclerosis. The development of cardiovascular drugs requires long, expensive Phase III trials to demonstrate incremental improvement in cardiovascular events. Imaging end points and soluble biomarkers accelerate Phase II development, but further validation is needed before these can be used as surrogate end points in the large trials leading to drug approval. Improved access to currently available therapies like statins would decrease the burden of cardiovascular disease worldwide.     

Pharmacological management of axial spondyloarthritis in adults

ABSTRACT

Introduction: Spondyloarthritis (SpA) refers to a group of disorders sharing common clinical, genetic and imaging characteristics. Axial (ax) SpA corresponds to a subgroup that mainly affects the axial skeleton, leading to inflammatory back pain and progressive radiographic changes of the sacroiliac joints and the spine. axSpA are currently subdivided into two forms, namely the radiographic and nonradiographic form, and are associated with musculoskeletal pain, restriction of spinal mobility, specific extra-articular features and overall, altered quality of life. The therapeutic management of axSpA has considerably progressed and is now well standardized.

Areas covered: Herein, the author reviews the pharmacological treatments that may be used in axSpA, including radiographic and nonradiographic forms in addition to the role of nonsteroidal anti-inflammatory drugs (NSAIDs), TNF alpha (TNFi), and IL-17A (IL-17Ai) inhibitors.

Expert opinion: NSAIDs remain the mainstay of initial therapy and biological agents may be then envisaged. TNFi and IL-17Ai may be used in axSpA, but physicians have more experience with TNFi. Only TNFi are licensed for the treatment of nonradiographic axSpA. IL-17Ai may be used as first or second line biologic disease modifying antirheumatic drugs (bDMARDs) and further results are needed to better define their position in the therapeutic management of axSpA.     

No meaningful association between suicidal behavior and the use of IL-17A-neutralizing or IL-17RA-blocking agents

ABSTRACT

Introduction: An emerging class of agents blocking IL-17 signaling represents a very promising therapeutic approach. One of these agents, brodalumab, has been associated with an increased risk of suicide behavior.

Areas covered: This review sought to provide an overview strictly focused on suicide behavior signals related to the use of IL-17 agents. Data collection regarding this peculiar safety aspect was primarily based on: (i) a revision of safety outcomes belonging to phase II and phase III trials; (ii) a systematic search using the Pubmed Medline database; and (iii) collecting recent data issued as posters or communications in eminent international meetings.

Expert opinion: Whilst secukinumab and ixekizumab were not associated with increased signal of suicidal behavior, being recently approved for the treatment of psoriasis by EMA and FDA, brodalumab raised concern because of suicide behavior cases that led to pause momentarily its development program during pre-marketing stage before obtaining the positive recommendation by an FDA advisory panel for its approval. Indeed, a careful re-evaluation of brodalumab safety profile is being performed and no evidence clarified a significant association or a pathogenic mechanism linking brodalumab treatment to the risk of suicidal behavior, suggesting that cases of suicidal behavior accidentally occurred during brodalumab trials.     

Inflammatory bowel disease therapies discontinued between 2009 and 2014

Introduction: New therapeutic approaches are currently under development, which consider the fundamental mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). The disease is associated with inflamed intestinal and colonic mucosa in response to the dysregulated immune system.

Areas covered: The aim of this article is to review drugs that have been designed for the treatment of IBD and discontinued between 2009 and 2014. Herein, nine molecules with different mechanisms of action are under review. Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from the Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. Finally, NU-206 and alkaline phosphatase also ceased in development during Phase I and II tests.

Expert opinion: The development in our knowledge and understanding of the pathophysiology of IBD and the identification of key objectives for the future play significant roles in IBD therapeutic development. Furthermore, well-planned clinical trials with concise measures of efficacy and safety are required to better decide whether to extend or terminate the development process. Some anti-inflammatory cytokines such as IL-2, IL-12, IL-17, IL-18, IL-23 and INF-γ could garner more attention in the future.