Ixekizumab for treatment of psoriasis

Psoriasis is a prevalent chronic inflammatory skin disease of unknown etiology. Recent advances in understanding the pathogenesis of psoriasis suggest that IL-17 is a key proinflammatory mediator present in the skin. Several agents targeting IL-17 or its receptor are in clinical trials for the treatment of psoriasis. This review focuses on the biological rationale and the results of clinical trials with ixekizumab, a humanized IgG4 monoclonal antibody. Ixekizumab binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. The currently available Phase I–III data indicate that ixekizumab is a promising drug, although long-term data of efficacy and safety are needed before ixekizumab and other IL-17 targeting therapeutics can find their place in clinical practice.     

Ixekizumab for the treatment of ankylosing spondylitis

ABSTRACT

Introduction

Ixekizumab (IXE) is a high affinity IgG4 approved for the treatment of ankylosing spondylitis (AS). Recently, two phase III randomized clinical trials (COAST-V, COAST-W) showed significant and sustained improvements in signs and symptoms of AS as evaluated by ASAS40 response. Areas covered: The authors performed a comprehensive literature search on this topic, by a review of published articles to date. The authors introduced the structure and the mechanism of action of IXE, and critically reviewed data from clinical trials, concerning its efficacy and safety in AS.Expert opinion: IXE proved dramatic efficacy and tolerable safety in patients with AS, in particular, patients with intolerance or insufficient response to TNFi, which provides an alternative and breakthrough for the treatment options of AS. IXE might not work in AS with IBD and uveitis involvement. Patients treated with IXE should be aware of candida infection in long term application.     

Targeted therapies: what they teach us about the pathogenesis of psoriasis and psoriatic arthritis

Introduction: Biologic therapy has revolutionized treatment pathways in psoriatic joint and skin disease. It has also provided a useful tool with which pathological pathways of this condition may be explored.

Areas covered: This review presents data on the clinical and biological effects of targeted therapy in psoriatic arthritis and psoriasis. Therapeutic agents covered include inhibitors of TNFα, inhibitors of the IL-23/IL-17 axis and inhibitors of intracellular small molecules involved in the transduction of the inflammatory signal. Trial data on clinical and imaging efficacy is reviewed in parallel with studies on biological effects at tissue level. Pathological insights gained from the use of these treatments are explored.

Expert commentary: A close relationship exists between specific pathological types and clinical manifestations of psoriatic disease, including responses to treatment. Studying these relationships is likely to improve understanding of disease and enable rational selection of specific treatments for patients with specific pathotypes.     

The role of IL-17 in the treatment of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory articular disease characterized by psoriasis, synovitis and enthesitis. Current treatment of PsA is mainly based on the use of classical and biological DMARDs; however, 30–40% of patients could not respond to these or have a loss of response.

Areas covered: Recently, the discovery of new pathogenic mechanisms have made possible the development of new drugs that target the IL-17 with the possibility to interfere with the Th17 cells that are considered the cell type mainly involved in the development of the inflammation in PsA. New molecules have shown efficacy and safety over the various components of the disease in randomized clinical trials. These drugs have been recently approved for the treatment of PsA and included in the newest treatment recommendations. Other molecules are currently being tested in phase III clinical trials and are potential new treatment options for PsA.

Expert Commentary: The aim of this paper is to review the role of IL-17 in the pathogenesis and treatment of PsA, with a discussion on the emerging anti-IL-17 drugs for PsA.     

Tofacitinib for the treatment of psoriasis and psoriatic arthritis

Introduction: Psoriasis and psoriatic arthritis (PsA) are inflammatory immune-mediated conditions which can cause considerable disability and reduced quality of life. Management can be complex as clinical heterogeneity may lead to different treatment pathways. Tofacitinib is a novel, oral Janus Kinase (JAK) inhibitor with proven efficacy in rheumatoid arthritis.

Areas covered: This review analyzes recent studies of tofacitinib in psoriatic disease treatment. The relevant literature was identified using clinicaltrials.gov, PubMed, and Google Scholar. Tofacitinib efficacy was demonstrated in PsA by the OPAL Broaden and OPAL Beyond phase-III studies, and received FDA and EMA approval. Tofacitinib was superior to placebo for the treatment of moderate-to-severe plaque psoriasis in the OPT Pivotal 1 and 2, OPT Retreatment studies, but FDA approval was declined for this indication based on issues of clinical efficacy and long-term safety.

Expert commentary: Tofacitinib is an important oral drug for the treatment of PsA. However, the long-term safety data require further evaluation. Tofacitinib and other JAK inhibitors show potential to broaden the treatment options in PsA and other inflammatory conditions.     

Interleukin‐17A: a unique pathway in immune‐mediated diseases: psoriasis,psoriatic arthritis and rheumatoid arthritis

Experimental evidence points to the importance of the cytokine interleukin‐17A (IL‐17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL‐17A is produced by many other cell types including CD8⁺ T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL‐17A up‐regulates expression of numerous inflammation‐related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL‐17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro‐inflammatory cytokines, including tumour necrosis factor. Several direct IL‐17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL‐17A in disease pathogenesis, although levels of response are not predicted by pre‐clinical findings. IL‐17A inhibitors produced rapid down‐regulation of the psoriasis gene signature and high clinical response rates in patients with moderate‐to‐severe plaque psoriasis, consistent with an important role for IL‐17A in psoriasis pathogenesis. Clinical response rates with IL‐17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL‐17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL‐17A in these diseases.     

Secukinumab for the treatment of psoriatic arthritis

Introduction: Secukinumab (Cosentyx) is an interleukin-17A (IL-17A) inhibitor administered subcutaneously. Through 2016, it had received approval in a number of countries, including the USA, Japan and in the EU for the treatment of plaque psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS).

Areas covered: This review addresses the mechanism of action, efficacy and safety of secukinumab observed in clinical studies of patients with PsA. Data from recent studies of secukinumab in psoriasis, PsA and AS are included.

Expert commentary: Secukinumab appears to be effective in improving various aspects of PsA, including improvements in psoriatic skin, enthesitis and dactylitis, as well as inhibition of the radiographic progression of peripheral arthritis. Secukinumab was in general well tolerated; the most common adverse events were nasopharyngitis, headache, and upper respiratory tract infection.     

Certolizumab pegol for the treatment of psoriatic arthritis and plaque psoriasis

ABSTRACT

Introduction: Certolizumab pegol (CZP) is an Fc-free PEGylated TNF-α inhibitor approved for the treatment of psoriatic arthritis (PsA) and plaque psoriasis in many countries. It demonstrated favorable results in PsA in terms of improvement in peripheral arthritis, dactylitis, and enthesitis in a phase III trial (RAPID-PSA) and in real-life experiences. Recently, three phase III randomized clinical trials (CIMPASI-1, CIMPASI-2, CIMPACT) showed significant and sustained improvements in signs and symptoms of moderate-to-severe plaque psoriasis as well as in quality of life parameters as compared to placebo and etanercept.

Areas covered: We reviewed the structure and the mechanism of action of CZP, and critically analyzed data from clinical trials and real-life, concerning its efficacy and safety in all aspects of the psoriatic disease. We designed a comprehensive literature search on this topic, by a review of published articles in indexed international journals up until 31 July 2019.

Expert opinion: CZP demonstrated positive results in several domains of psoriatic disease, also in patients previously exposed to other TNF-α inhibitors and in patients receiving re-treatment after treatment interruption. The peculiar chemical structure, along with its well-established efficacy and safety, support CZP as the drug of choice in specific subgroups of patients with psoriatic disease, in particular patients with comorbidities and pregnant or breastfeeding female patients.     

A review of ixekizumab in the treatment of psoriatic arthritis

ABSTRACT

Introduction: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disorder with articular, peri-articular, and extra-articular features along with selected co-morbidities as a sequela to chronic inflammation. There is accumulating evidence that the Th-17 signaling pathway is of critical importance in PsA pathogenesis.

Areas covered: Ixekizumab (IXE) is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody directed against IL-17A. Two phase III randomized clinical trials, SPIRIT-P1 and SPIRIT-P2, unequivocally demonstrated superiority of IXE (80 mg every two or 4 weeks) dosing over placebo in moderate-to-severe PsA patients that failed either NSAIDs, conventional disease-modifying anti-rheumatic drugs (csDMARDs), or tumor necrosis factor-α inhibitors (TNFi) for numerous articular and cutaneous parameters. IXE also delayed structural progression of PsA. No new safety signals were identified as compared with chronic plaque psoriasis studies which included many more patients.

Expert opinion: IXE is a highly effective treatment for moderate to severe PsA patients, including those that have been previously exposed to csDMARD and TNFi. Most domains of PsA significantly improved with IXE treatment and disease modification was achieved.     

Secukinumab (AIN457) for the treatment of psoriasis

Psoriasis is a chronic inflammatory disease with a multifactorial origin that appears in patients with genetic predisposition and is induced by environmental factors, and characterized by alterations in the innate and adaptive immunity. IL-17A is one of the specific cytokines involved in the pathogenesis of psoriasis and its inhibition is highly effective in the treatment of patients with moderate and severe psoriasis. Secukinumab is a monoclonal antibody that specifically binds to IL-17A and inhibits the interaction to its receptor, and it has demonstrated its efficacy and safety in the treatment of psoriasis. Phase II and III clinical trials indicate that > 80% of the patients receiving secukinumab achieve Psoriasis Area Severity Index (PASI) 75 at week 12. In the Phase III efficacy of response and safety of two fixed secukinumab regimens in psoriasis trial, PASI 75 rates were 81.6% with 300 mg secukinumab, 71.6% with 150 mg secukinumab and 4.5% with placebo, and responses were maintained up to 52 weeks in the majority of patients. In the Phase III Full Year Investigative Examination Of Secukinumab versus Etanercept Using Two Dosing Regimens To Determine Efficacy in Psoriasis study, the efficacy of secukinumab was compared to etanercept. The results indicate that both doses of secukinumab (150 and 300 mg) showed superior efficacy compared with etanercept throughout the study; PASI 75 rates at week 12 were 77.1% with 300 mg secukinumab, 67% with 150 mg of secukinumab, 44% with etanercept and 4.9% with placebo. PASI 90 and PASI 100 were 54 and 24% with secukinumab 300 mg and 21 and 4% with etanercept at week 12. At week 52, PASI 90 continued to be higher in the secukinumab group (65%) compared with the etanercept group (33%). Regarding safety, the most common side effects were nasopharyngitis and headache. The rate of infections was higher with secukinumab than placebo. This was especially the case for Candida infections, which were more common in the secukinumab group (4.7% with secukinumab 300 mg and 2.3% with secukinumab 150 mg), but all cases were resolved with conventional treatment. Secukinumab is a well-tolerated treatment that has demonstrated efficacy in treating moderate-to-severe plaque psoriasis. Nevertheless, long-term studies are necessary to confirm Phase II and Phase III data.     

Tofacitinib for the treatment of moderate-to-severe psoriasis

Because of the increased knowledge about the underlying cytokine network in psoriasis, selective systemic agents for the treatment of moderate-to-severe psoriasis have been developed during the past decade. The marked upregulation of JAK/STAT pathways in psoriasis and the identification of multiple key mediators in psoriasis pathogenesis that signal through JAK/STAT pathways led to investigation of JAK proteins as potential therapeutic targets for psoriasis treatment. A novel JAK-STAT inhibitor, tofacitinib, has been tested in preclinical studies for the treatment of psoriasis. Considering the satisfactory safety profile and the encouraging efficacy observed in the Phase II and Phase III trials, tofacitinib may represent an important therapeutic to be included into the psoriasis paradigm.     

The role of IL 23 in the treatment of psoriasis

Introduction: The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis. Human IL-23 is primarily produced by antigen-presenting cells and induces and maintains differentiation of Th17 cells and Th22 cells, a primary cellular source of proinflammatory cytokines such as IL-17 and IL-22, which mediate the epidermal hyperplasia, keratinocyte immune activation and tissue inflammation inherent in psoriasis. Agents that target the p40 subunit common to both IL-12 and IL-23 have shown robust clinical activity, but selectivity for IL-23p19 could offer advantages in efficacy and safety with respect to anti-p40 blockade.

Areas covered: Relevant references regarding the role of the IL-23/IL-17 pathway in the pathogenesis of psoriasis/psoriatic arthritis and clinical trials with IL-23p40 and IL-23p19 blocking agents were obtained through a literature search in MEDLINE/Pubmed for articles published until November 2016. Moreover, ongoing registered clinical trials (RCTs) of moderate-to-severe psoriasis and psoriatic arthritis were searched through clinicaltrials.gov website, and a manual search was made for pertinent communications at the 2016 American Academy of Dermatology and European Academy of Dermatology and Venereology meetings.

Expert commentary: There are potential advantages in selective blockade of the IL23-specific p19 subunit with respect to distal blockade of IL-17A or its receptor. Acting upstream in the IL-23/IL-17 cytokine pathway is likely to reduce the expression of multiple pro-inflammatory cytokines acting on keratinocytes -including IL-17F, IL-21 and IL-22-, in addition to IL-17A. On the other hand, safety data thus far suggest that these drugs might be devoid of some adverse effects of IL-17A blockade that seem to be class related, such as mucocutaneous Candida infections or triggering or worsening of inflammatory bowel disease.

Specific IL-23p19 blockade with high-affinity monoclonal antibodies seems to be able to induce long-term remissions of the activity in psoriasis and might eventually represent a paradigm change in the treatment of psoriasis. The results of phase III and comparative head-to-head trials with these agents are eagerly awaited.     

Abatacept for the treatment of psoriatic arthritis

ABSTRACT

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by the presence of psoriasis, arthritis, and enthesitis, with the association of other musculoskeletal and extra-articular manifestations. Current treatment of PsA is based on the use of conventional, biological and targeted synthetic disease modifying anti-rheumatic drugs; however, patients may not respond or have a loss of response to these agents. Recently, a deeper understanding of the pathogenetic mechanisms has made possible the development of new drugs that actively interact with the activation of immune system, inhibiting the co-stimulation between antigen-presenting cells and lymphocytes.

Areas covered: The aim of this paper is to review the role of the activation of the immune system in the pathogenesis and treatment of PsA, with a discussion on the emerging CTLA4Ig drugs (abatacept) for PsA. A search in PubMed and EMBASE was performed with the keywords: ‘abatacept’, ‘CTLA4,’ and ‘Psoriatic Arthritis.’ We considered preclinical studies, phase I, II and III clinical trials.

Expert commentary: The inhibitors of co-stimulation may represent an effective treatment strategy by acting on the very early phase of the immunological process that brought about the development of inflammation and activation of the immune system, mainly for patients with peripheral joint involvement and mild psoriasis.     

Guselkumab for the treatment of adults with moderate to severe plaque psoriasis

Introduction: Guselkumab is a subcutaneously administered monoclonal antibody that targets the IL-23p19 cytokine subunit and has been approved by the US FDA and the EMA for the treatment of moderate-to-severe psoriasis in adult patients.

Areas covered: This review outlines the pharmacologic properties, efficacy and safety of guselkumab for the treatment of moderate-to-severe plaque psoriasis in adults.

Expert opinion: In clinical trials, guselkumab markedly improved disease, regardless of topographical locations and patient subpopulations, with corresponding improvements in quality of life measures, and was generally well tolerated. Guselkumab has been shown to be more effective than adalimumab in phase III pivotal trials (VOYAGE 1 and VOYAGE 2) at both week 16 and week 24 for PASI75, PASI90, PASI100 and IGA(0/1); the corresponding PASI 90 response rates at week 16 were 73.3% vs 49.7% in VOYAGE 1 and 70.0% vs 46.8% in VOYAGE 2 (P < 0.001 in both). Guselkumab has been shown to be superior to secukinumab in PASI90 response rate at week 48 in a head-to-head trial (ECLIPSE); it is also successful in treating patients with incomplete responses to adalimumab (VOYAGE 2) and ustekinumab (NAVIGATE). Guselkumab may be effective in treating psoriatic arthritis, with several phase III trials ongoing.     

Brodalumab for the treatment of psoriasis

Introduction: Psoriasis is a complex disease in which the alteration of the IL-23/Th17 axis appears to be crucial for its pathogenic mechanisms, and anti-IL17 agents are rapidly becoming important therapeutic tools. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab.

Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association.

Expert commentary: By blocking the IL-17 receptor A, brodalumab antagonizes signaling from IL-17A, IL-17F, IL-17A/F and IL-25, and this probably contributes to the high efficacy observed in clinical trials. Considering the different therapeutic target and the potential biological implications that blocking IL-17RA instead of IL-17A might have, brodalumab may not necessarily belong to the same class that includes secukinumab and ixekizumab, but it may be classified in a distinct group.     

Tildrakizumab for the treatment of psoriasis

Introduction: Psoriasis is an immune-mediated skin disease amenable to targeted immunotherapy. Tildrakizumab is a humanized IgG1 monoclonal antibody targeting interleukin-23 p19 and is approved for use in moderate to severe psoriasis.

Areas covered: This article reviews the mechanism of action, pharmacokinetics, safety, tolerability, and clinical efficacy of tildrakizumab, administered subcutaneously every 12 weeks, in treatment of moderate to severe psoriasis.

Expert commentary: In two phase 3 clinical trials, tildrakizumab showed a consistent low occurrence of adverse events, underlining safety and tolerance. The long half-life permits subcutaneous injections every 12 weeks. Seventy eight percent of patients achieved PASI 75 (a > 75% improvement from baseline PASI) at 28 weeks, 58% achieved PASI 90, 29% achieved PASI 100 and 70% achieved a Physician’s Global Assessment score of clear or almost clear. A high proportion of patients maintained PASI response after 2 years of treatment. Tildrakizumab improved Dermatology Life Quality Index, psoriasis-related personal relationship problems and sexual difficulties. Baseline PASI score, PGA, and BMI were not predictive of PASI 90 response at week 12, however achievement of PASI 50 by week 8 was predictive of a PASI 90 response at week 12.     

Recombinantly engineered human proteins: transforming the treatment of psoriasis

Psoriasis is a chronic, inflammatory disease with lesions that produce considerable physical discomfort and often lead to substantial disruption in patients' daily activities. The use of currently available, nonspecific, systemic immunosuppressive therapies for patients with moderate to severe psoriasis is limited by an inability to maintain disease remission safely. Advances in recombinant DNA technology paralleled with increased understanding of the immunopathology of psoriasis have led to the development of numerous biologic agents for the treatment of this disease. These new biologic therapies target specific steps in psoriasis pathology, including direct effects on T cells, T cell activation, T cell migration, and cellular production and secretion of cytokines. By selectively targeting the activities of T cells that are directly involved in psoriasis pathogenesis, these novel agents offer improved safety profiles and enhanced efficacy. In this article, the mechanisms of T cell pathogenicity that guided the development of these new biologic therapies are reviewed along with clinical data on the progress of these agents.     

New therapies versus first-generation biologic drugs in psoriasis: a review of adverse events and their management

Introduction: Biologic drugs have revolutionized the treatment of moderate to severe psoriasis in recent years because of their high efficacy and low risk of toxicity. However, even within the group of biologic therapies, there are differences related to the different mechanisms of action.

Areas covered: We review the main adverse events associated with the biologic agents currently available for the treatment of psoriasis and the new inhibitors targeting the p19 subunit of interleukin (IL) 23 and the IL-17A receptor. This review covers injection site reactions, infections, cardiovascular events, demyelinating disorders, tumours, class effects secondary adverse events, immunogenicity, safety in pregnancy and vaccines efficacy.

Expert commentary: More than a decade after the first approval of biologic drugs for use in psoriasis, the good safety profile of these drugs is one of the main justifications and incentives for their long-term use. The emergence of new pharmacological groups has made it possible to avoid some of the class effects of first-generation biologic agents and the new therapies appear to pose less risk of reactivation of latent infections, such as hepatitis B virus and tuberculosis. However, they are associated with new adverse effects related to their mechanism of action, including candidiasis and the risk of exacerbation or onset of inflammatory bowel disease.