Dupilumab for the treatment of asthma

Introduction: Dupilumab is a fully human IgG4 monoclonal antibody directed against the α subunit of the interleukin (IL)-4 receptor (IL-4Rα). Since the activation of IL-4Rα is utilized by both IL-4 and IL-13 to mediate their pathophysiological effects, dupilumab behaves as a dual antagonist of these two sister cytokines, which blocks IL-4/IL-13-dependent signal transduction.

Areas covered: Herein, the authors review the cellular and molecular pathways activated by IL-4 and IL-13, which are relevant to asthma pathobiology. They also review: the mechanism of action of dupilumab, the phase I, II and III studies evaluating the pharmacokinetics as well as the safety, tolerability and clinical efficacy of dupilumab in asthma therapy.

Expert opinion: Supported by a strategic mechanism of action, as well as by convincing preliminary clinical results, dupilumab currently appears to be a very promising biological drug for the treatment of severe uncontrolled asthma. It also may have benefits to comorbidities of asthma including atopic dermatitis, chronic sinusitis and nasal polyposis.     

Tralokinumab for uncontrolled asthma

Introduction: Asthma is a chronic inflammatory disease of the airways mainly related to allergen exposure, in which various cytokine-specific pathways interact among themselves to promote IgE hyperproduction, bronchial hyperresponsiveness, eosinophil local recruitment and airways remodeling. IL-13 is known for its prominent pathogenic role in this disease and therapeutic blocking approaches are underway.

Areas covered: Anti-IL-13 antibodies are currently investigated in clinical studies in uncontrolled asthma. Tralokinumab is a human IgG4 anti IL-13 antibody which was recently evaluated in a Phase II study demonstrating the maximal efficacy in a subset of asthma patients characterized by the highest sputum IL-13 levels. The results of this study are discussed in this paper.

Expert opinion: The IL-13 blockade with various therapeutic approaches such as tralokinumab has the potential to improve the asthma control in patients subsets in whom the blocked cytokine is demonstrated to be overexpressed.     

Biological therapies for eosinophilic asthma

Introduction: Severe uncontrolled asthma is by definition refractory to traditional therapies or can be controlled only with therapies that have intolerable side effects. Monoclonal antibodies that target interleukin (IL)-5/IL-5Rα, IgE, and IL-4Rα have shown favorable results in clinical trials, including reductions in asthma exacerbations and other important clinical outcomes. These biological agents offer treatment alternatives to patients with uncontrolled severe eosinophilic asthma.

Areas covered: This article reviews how the shifting emphasis toward identifying distinct asthma phenotypes has led to the approval of biological therapies that preferentially benefit patients with severe eosinophilic asthma. The clinical trials that led to the approval of these biologic treatments are discussed in detail.

Expert opinion: Biologic therapies targeting the IL-5, IgE, IL-4/IL-13 signaling pathways have been successful in clinical trials in subjects with severe eosinophilic asthma. Some of these agents have also been successful regardless of peripheral blood eosinophil counts. These treatments have shown a relatively favorable safety profile in clinical trials, although long-term safety data for some of these agents are limited. Due to the high costs associated with these medications, they should be reserved for select patients where they yield a therapeutic and pharmacoeconomic advantage.     

Lebrikizumab in the treatment of asthma

ABSTRACT

Introduction: Severe asthma continues to be a major clinical problem despite the availability of effective asthma medications such as inhaled corticosteroids. Several targeted biologic therapies are emerging to treat patients with severe asthma.

Areas covered: This review provides an update of information on lebrikizumab, a novel monoclonal antibody that targets IL-13 and is currently in advanced stages of development. It describes the role of IL-13, a key effector cytokine in Type 2 (T2) airway inflammation in asthma and discusses the results of recent phase 2 trials investigating lebrikizumab’s efficacy and safety in patients with severe asthma. Furthermore, it provides insight into the current ongoing trials with lebrikizumab and outlines future research needs.

Expert opinion: Several emerging therapeutic targets have been identified for patients with severe asthma. By specifically targeting IL-13, lebrikizumab has the potential to block several downstream signals that play a role in disease progression including airway inflammation, mucus hypersecretion and airway remodeling. The effects of lebrikizumab have been more marked in individuals with high serum periostin levels which reflect underlying IL-13 activity and T2 airway inflammation. Ongoing trials with lebrikizumab aim to further examine its long-term safety and efficacy in a larger population and explore its effects on airway inflammation and function.     

Omalizumab is effective in treating severe asthma in patients with severe cardiovascular complications and its effects on sCD200, d-dimer,CXCL8, 25-hydroxyvitamin D and IL-1β levels

Background: There have been concerns about the cardiovascular safety of omalizumab.

Objectives: In this study, the clinical status of the omalizumab receiving severe asthma patients and the cytokine expressions patterns were investigated.

Materials and methods: In a pilot study described below we examined the levels of serum eosinophil cationic peptid (ECP), CD200, d-dimer, 25-hydroxyvitamin D (25(OH)D), CXCL8 and IL-1β in asthma patients treated with anti-IgE therapy, to explore their relationship with disease activity, and the impact of anti-IgE therapy impact on those levels. Exercise stress testing and blood samples were taken at all follow up visits from the time of first diagnosis and after 20 months of treatment during the disease remission.

Results: Fractional exhaled nitric oxide concentrations and serum levels of sTRAIL, sCD200, D-dimer, ECP, total IgE, IL-1β and Hs-CRP were decreased while CXCL8, 25(OH)D were increased after starting the treatment of anti-IgE. Our first case of a patient, who had both protein C and S deficiency and hence a high risk for thromboembolism, documents for the first time the safety of omalizumab for asthmatic patients with concurrent risk factors contributing to arteriothrombotic events.

Conclusion: Omalizumab might be used carefully in patients with cardiovascular diseases.     

Treatment of severe asthma: entering the era of targeted therapy

Introduction: It is estimated that 5 – 10% of asthma patients suffer from severe asthma. Severe asthma is associated with increased morbidity and mortality. These patients are not controlled with currently available treatments and therefore additional treatment options are needed. Asthma is a heterogeneous disease, and different asthma patient groups probably have different underlying pathophysiology. Novel therapies with, for example, monoclonal antibodies that target certain immunological pathways have become available. These novel treatments are not effective in all patients but only in certain phenotypes.

Areas covered: This review covers the current evidence and novel developments in treatment with monoclonal antibodies in different asthma phenotypes. This includes monoclonal antibodies against IgE, against interleukin (IL)-5 and antibodies targeting IL-13 pathways. Although there is a certain overlap between patient groups benefiting from these treatments, a more detailed identification of responder profiles for these therapies is needed for personalized therapy.

Expert opinion: In recent years, novel monoclonal antibodies have been developed, which are a promising addition to existing therapy in the treatment of severe asthma with eosinophilic inflammation and Th2-driven disease. We expect that several of the new antibodies will become available for clinical practice. In addition, it must be acknowledged that so far no effective strategies are available for patients with non-eosinophilic asthma and further research and development is necessary for this patient group.     

Targeting the IL-23/IL-17 axis for the treatment of psoriasis and psoriatic arthritis

Introduction: A growing amount of data supporting the pathogenic role of the IL-23/IL-17 axis in inflammatory/autoimmune disorders has provided the rationale to target the system for therapeutic purpose. Several compounds have been and are currently under intense investigation in psoriasis and psoriatic arthritis (PsA) yielding impressive results.

Areas covered: In this review article, we provide an overview of currently available data on the IL-23/IL-17 system as a target for treatment for psoriasis and PsA. We searched MEDLINE for articles on drug therapy for psoriasis and PsA published between 1 January 2010 and 31 May 2015. One of these agents, ustekinumab, has been recently approved for the treatment of psoriasis and PsA, and a number of IL-23/IL-17-targeted compounds under investigation in these diseases.

Expert opinion: As our knowledge of the role of the IL-23/IL-17 axis in the pathogenesis of psoriasis and PsA deepens, it enables the development of more targeted therapies in the management of these conditions. Early data on IL-23/IL-17 targeting drugs appear promising, although incomplete. Given the key role IL-23/IL-17 in host defence, the safety profile of targeted drugs should be thoroughly assessed in future studies.     

哮喘患者诱导痰中嗜酸细胞IL-4和IL-5mRNA表达

目的 :探讨IL - 4、IL - 5在哮喘诱导中痰嗜酸细胞 (EOS)炎症的作用。方法 :斑点分子杂交检测哮喘患者诱导痰中嗜酸细胞IL - 4、IL - 5mRNA表达。结果 :哮喘患者痰液中EOS细胞浸润密度增加 ,IL - 4、IL - 5mRNA表达比正常人明显升高 (p<0 .0 1) ,而正常对照组无明显变化 (p >0 .0 5 )。结论 :IL - 4、IL - 5mRNA表达增加可能在导致哮喘EOS气道炎症的过程中起信号途径作用。     

Mepolizumab for eosinophilic severe asthma: recent studies

Introduction: In September 2014 two large clinical studies of the anti-IL-5 monoclonal antibody mepolizumab in severe asthma were published in the New England Journal of Medicine (MENSA and SIRIUS).

Areas covered: Eosinophilic inflammation has long been recognised as a feature of asthma. Identification of IL-5 as a key cytokine specific for eosinophil development and survival lead to development of monoclonal antibody therapy targeting this pathway. These two important new studies suggested that this treatment could reduce exacerbation rates by 50% in asthmatic patients with persistent peripheral blood eosinophilia and persistent symptoms despite high-dose-inhaled corticosteroids and additional controller therapy, and frequent exacerbations. In the second study, mepolizumab was shown to reduce oral steroid requirement by a median of 50% in similar patients who additionally required oral prednisone to control disease.

Expert opinion: This represents an important new treatment option in an area of unmet need, and together with a large dose ranging study (DREAM) published in 2012 form the basis for filing for registration in the USA and Europe.     

Brodalumab-an IL-17RA monoclonal antibody for psoriasis and psoriatic arthritis

Introduction: IL-17 is a growing target for autoimmune and inflammatory diseases. Brodalumab is a fully human anti-IL-17RA monoclonal antibody that has been investigated in a range of disease including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and asthma.

Areas covered: This review aims to summarize up-to-date pharmacological properties of brodalumab and the clinical efficacy and safety data presented in clinical trials. The focus of this review will be on psoriasis, psoriatic arthritis and rheumatoid arthritis although we will briefly touch on the other indications in which the drug has been studied as we feel it adds to our understanding of the IL-17 pathway and highlights areas where research is still needed.

Expert opinion: Brodalumab has shown good efficacy in psoriasis in small but extended studies with a moderate effect on psoriatic arthritis. Brodalumab studies are clearly negative in rheumatoid arthritis and inflammatory bowel disease. The data are equivocal in asthma; however, further studies in this disease are justifiable. The safety profile of this drug thus far is not worrisome although longer studies in more patients are needed.     

Interleukin-2 receptor blockade with humanized monoclonal antibody for solid organ transplantation

Importance of the field: Induction therapy has reduced the incidence of acute rejection compared with historical standards. The potency of currently available induction immunosuppression is not without risk and should be carefully considered. Induction with daclizumab, an IL-2 receptor antagonist, has been used safely and effectively for over 10 years across different transplant types. As a result of daclizumab use, transplant centers are able to implement steroid-sparing or calcineurin minimization protocols. Unfortunately, the manufacturing costs have resulted in withdrawal of this agent from the market reducing the options for patients undergoing transplantation.

Areas covered in this review: This review will update the reader on recently published daclizumab studies in adult solid organ transplant recipients, focusing on comparative studies with other induction agents.

What the reader will gain: This paper will provide a summary of comparative studies between daclizumab and other induction therapies focusing on their efficacy and safety.

Take home message: Novel applications, such as long-term use in combination with calcineurin-inhibitor dose reduction and its value in the treatment of acute or chronic rejection have yet to be explored. Since daclizumab has been withdrawn from the market, future IL-2 receptor blockade will have to be achieved with basiliximab, which is a chimeric, monoclonal antibody directed against the same epitope.     

Monoclonal antibodies for asthma and chronic obstructive pulmonary disease

Introduction: In asthma and chronic obstructive pulmonary disease (COPD), the inflammation in the airways cannot always be controlled with conventional therapies, such as inhaled corticosteroids. Addition of more specific anti-inflammatory therapies, such as monoclonal antibodies, against inflammation pathways might improve the disease outcome.

Areas covered: This review individually discusses the major inflammation pathways and their potential blocking monoclonal antibodies in asthma and COPD.

Expert opinion: The current use of omalizumab in asthma provides a good example on the potential therapeutic role of monoclonal antibodies in both asthma and COPD. There are many other monoclonal antibodies which are currently investigated as possible therapies in these diseases. The identification of the disease subsets in which such antibodies might exert the maximum benefit opens the door for personalized medicine and for targeted biological therapy in asthma and COPD.     

Bimekizumab for the treatment of psoriatic disease

ABSTRACT

Introduction: Psoriasis and psoriatic arthritis are common diseases with significant physical and emotional burden. Several biologics are FDA-approved to treat psoriasis and psoriatic arthritis, though some patients remain refractory to, or have lost response to, therapy and/or cannot tolerate the associated risks and side effects. Bimekizumab is a new biologic that inhibits both IL-17A and IL-17F. It is currently in phase III clinical trials. To date, phase II studies show promise in its ability to rapidly resolve symptoms while remaining safe and well-tolerated.

Areas covered: This review serves to summarize the literature regarding the use of bimekizumab for psoriasis and psoriatic arthritis. Bimekizumab has undergone phase I and phase II clinical trials with results showing significant disease improvement or resolution, as well as safety and tolerability. Phase III studies are now actively enrolling.

Expert opinion: Bimekizumab is a burgeoning biologic offering significant promise through its unique bispecific targeting of both IL-17A and IL-17F. Clinical trials have shown the potential of rapid symptom improvement after treatment with bimekizumab, with some patients seeing improvement after only two weeks. To date, bimekizumab has been shown to be safe and well-tolerated by patients, without any associated significant adverse events.     

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma,metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma

Importance to the field: In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies.

Areas covered in this review: This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website.

What the reader will gain: Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21.

Take home message: rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.     

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Canakinumab for treatment of cryopyrin-associated periodic syndrome

Importance of the field: Autoinflammatory syndromes such as cryopyrin-associated periodic syndromes (CAPS) place a heavy burden on affected individuals as well as on their families due to significant morbidity and increased mortality. The inflammatory response in CAPS is caused by an overwhelming activation of the pro-inflammatory cytokine IL-1, which was identified as a promising treatment target.

Areas covered in this review: This article focuses on the pathogenic background and different clinical manifestations in CAPS. Furthermore, the development program and characteristics of canakinumab, a recently approved fully human anti-IL-1β mAb for the treatment of CAPS, are described and compared to other available IL-1 blocking agents.

What the reader will gain: Canakinumab targets selectively human IL-1ß with high affinity and prevents the cytokine from interaction to its receptor and, thus, effectively blocks the inflammatory response in CAPS. In all studies performed, canakinumab showed a rapid improvement of symptoms of CAPS and a complete clinical response was achieved in most patients. Inflammatory markers such as C-reactive protein and serum amyloid-A protein were reduced to normal levels within few days. In comparison to other IL-1 blockers, canakinumab provides a longer plasma half-life and less injection site reactions.

Take home message: Canakinumab offers the possibility of permanent disease control, almost symptom-free life, and hopefully less long-term morbidity and mortality in patients with CAPS.     

Anti-interleukin-23 agents for the treatment of ulcerative colitis

ABSTRACT

Introduction: Treatment of ulcerative colitis (UC) aims to control symptoms and to suppress intestinal inflammation. Despite considerable advances, a proportion of patients do not respond to currently available drugs. The interleukin (IL)-23 axis plays a significant role in the pathogenesis of UC and has thus become an important target for drug development.

Areas covered: The review briefly summarizes the pathophysiology of the IL-12/23 axis and provides a synopsis of the available evidence for efficacy and safety of ustekinumab, mirikizumab (LY3074828), risankizumab (BI655066/ABBV066), brazikumab (MEDI2070; formerly AMG139) and guselkumab (CNTO1959) in UC. We also provide an overview of ongoing and anticipated trials in this field.

Expert opinion: A Phase 2 trial with mirikizumab and a Phase 3 trial with ustekinumab have demonstrated the efficacy of anti-IL-23 agents in achieving clinical and endoscopic outcomes in UC with a favorable safety profile. Trials of other anti-IL-23 agents in UC are under way and designed to explore head-to-head efficacy with existing biologics, as well as the prospect of combination biological therapy. Apart from data on longer term efficacy and safety, future trials should also explore strategies to inform the positioning of IL-23 antagonists in therapeutic algorithms.     

An evaluation of mepolizumab for the treatment of severe asthma

Introduction: Asthma is considered one of the most common chronic conditions globally, characterized by variable airflow obstruction and symptoms. Severe asthma is diagnosed when asthma control requires high-intensity therapy or continues to remain uncontrolled despite treatment. Eosinophilic inflammation is known to be perpetuated by the activity of IL-5 in a proportion of severe asthma subjects, and targeting IL-5 may offer a therapeutic option.

Areas covered: In this review, we discuss the role and pathogenesis of IL-5 and eosinophils in asthma and rationale of antagonizing IL-5 in severe eosinophilic asthma. Mepolizumab is the first of three anti-IL-5 biologics licensed in 2015 for use in this subgroup of patients. We discuss clinical and real-life studies leading up to its approval and post-marketing outcomes in terms of efficacy and safety to-date, as well as its pros and cons.

Expert opinion: IL-5 antagonism has paved the way for an additional personalized therapeutic opportunity for use in severe asthma with eosinophilic inflammation, though there is limited evidence on the long-term implications of suppressing/depleting eosinophils and the duration for which they should be administered.     

5T4-modified vaccinia Ankara: progress in tumor-associated antigen-based immunotherapy

Importance of the field: The expression and biology of the tumor-associated antigen (TAA) 5T4 suggest it is an effective target for cancer immunotherapy.

Areas covered in this review: Development of a vaccine comprising highly attenuated modified vaccinia Ankara virus encoding 5T4 (MVA-5T4, a.k.a. TroVax^®).

What the reader will gain: Preclinical studies demonstrated that MVA-5T4 is safe and effective in prophylactic and active treatment of syngeneic murine tumor models. Over 700 doses of MVA-5T4 have been administered to over 200 patients to date. Results from clinical trials on metastatic colorectal, metastatic renal and hormone-refractory prostate cancer patients demonstrate that MVA-5T4 is safe and immunogenic as a monotherapy and in combination with standard-of-care therapies. MVA-5T4 induced potent and sustained immune responses in approximately 95% of tested patients. Post hoc analyses have noted a correlation between anti-5T4 immune responses and indicators of clinical benefit. A Phase III randomized, placebo controlled study, which investigated MVA-5T4 added to first line standard of care to evaluate whether vaccination prolonged survival of patients with metastatic clear cell renal cell cancer did not meet the primary endpoint (overall survival).

Take home message: With its minimal side effects and ability to produce immune responses MVA-5T4 is a promising addition to the cancer therapy arsenal.