Biologic targeted therapy in allergic asthma

ObjectiveTo review the structure, function, clinical utility, and safety of current biologic targeted therapies being used for the treatment of asthma.Data SourcesMedical literature obtained from PubMed and OVID searches from June to November 2013.Study SelectionsStudies were selected based on article impact, relevance, and clinical significance. Particular emphasis was placed on articles discussing therapies targeted at IgE, interleukin (IL)-4, IL-4 receptor, IL-5, IL-13, tumor necrosis factor-α, CRTh2, and toll-like receptors 7 and 9.ResultsSince the approval of omalizumab in 2003, the development of biologic asthma therapies has grown at a remarkable pace. With approximately 30 drugs currently in clinical trials and dozens more in development, the future of asthma biologic therapies is promising. Despite several well-publicized setbacks, researchers remain focused on elucidating the complex pathophysiology of asthma. The hope is that asthma biologic therapies will eventually be tailored to an individual's asthma phenotype. With more than 300 million people worldwide affected by asthma and with roughly 5% to 10% of this population living with severe, uncontrolled asthma, the need for new biologic therapies is great.ConclusionThe introduction of each new biologic therapy into clinical trials has been associated with great anticipation, but the outcome of these trials, in many cases, has led to disappointment. Given the lack of overwhelming positive responses, these results have emphasized that asthma is a complex clinical syndrome with multiple underlying genotypes and clinical phenotypes. It has become abundantly clear that it is very unlikely that there is one “magic bullet” to cure all patients with asthma.     

Real-life studies of biologics used in asthma patients: key differences and similarities to trials

ABSTRACT

Introduction: The precision medicine approach that is now mandatory for severe asthma management includes the use of novel biologic agents blocking specific immunological mechanisms that are responsible for disease phenotypes and endotypes: monoclonal antibodies blocking IgE, IL-5 and IL-4/IL-13 immunological pathways are so far available.

Areas covered: Clinical trials involving a large number of patients proved their efficacy in reducing asthma exacerbations, improving lung function and quality of life, and reducing the need for systemic corticosteroid treatment. Since biologics have been available for routine use, a series of real-life experiences on severe asthmatics treated with them have been published: these studies confirmed the beneficial effects in a real-world setting (effectiveness) of these drugs and showed novel aspects that were not covered by clinical trials, such as their effect on particular subgroup of patients, unexpected adverse events, and potential novel indications.

Expert opinion: Both clinical trials and real-life experiences are needed to establish robust data on biologic agents for severe asthma, with real-life studies giving more broader insights on different aspects related to the biologics themselves and to the disease.     

Benralizumab for the treatment of asthma

Introduction: The classification of asthma into phenotypes and endotoypes allows for the use of targeted therapies, including three biologics which target interleukin 5 (IL-5) signaling in eosinophilic asthma.

Areas covered: As of December 2016, two monoclonal antibodies, mepolizumab and reslizumab, are approved by U.S. Food and Drug Administration and one, benralizumab, is in clinical development. Two phase 3 trials for benralizumab, SIROCCO and CALIMA, were published in September 2016. Although there are no direct comparisons among these three anti-IL-5 therapies, the goal of this review is to summarize the current data and discuss their potential similarities and differences, with a focus on benralizumab.

Expert commentary: Compared to mepolizumab and reslizumab, the possible advantages of benralizumab are less frequent dosing and a potential to reduce exacerbations irrespective of the blood eosinophil count. Some improvements in asthma symptom scores and quality of life occur with all three biologics, but the clinical meaningfulness of these improvements is less clear. A more defined reference range for eosinophil levels is necessary to determine which subjects will best benefit from these medications. Until quality randomized controlled trials directly compare the three, choosing among them for the treatment of eosinophilic asthma remains difficult.     

Cost-effectiveness and comparative effectiveness of biologic therapy for asthma: To biologic or not to biologic?

Objective

To evaluate relevant studies and documents that address the cost-effectiveness and comparative effectiveness of biologics current approved by the US Food and Drug Administration for the treatment of asthma.

A prediction model for asthma exacerbations after stopping asthma biologics

BackgroundLittle is known regarding the prediction of the risks of asthma exacerbation after stopping asthma biologics.ObjectiveTo develop and validate a predictive model for the risk of asthma exacerbations after stopping asthma biologics using machine learning models.MethodsWe identified 3057 people with asthma who stopped asthma biologics in the OptumLabs Database Warehouse and considered a wide range of demographic and clinical risk factors to predict subsequent outcomes. The primary outcome used to assess success after stopping was having no exacerbations in the 6 months after stopping the biologic. Elastic-net logistic regression (GLMnet), random forest, and gradient boosting machine models were used with 10-fold cross-validation within a development (80%) cohort and validation cohort (20%).ResultsThe mean age of the total cohort was 47.1 (SD, 17.1) years, 1859 (60.8%) were women, 2261 (74.0%) were White, and 1475 (48.3%) were in the Southern region of the United States. The elastic-net logistic regression model yielded an area under the curve (AUC) of 0.75 (95% confidence interval [CI], 0.71-0.78) in the development and an AUC of 0.72 in the validation cohort. The random forest model yielded an AUC of 0.75 (95% CI, 0.68-0.79) in the development cohort and an AUC of 0.72 in the validation cohort. The gradient boosting machine model yielded an AUC of 0.76 (95% CI, 0.72-0.80) in the development cohort and an AUC of 0.74 in the validation cohort.ConclusionOutcomes after stopping asthma biologics can be predicted with moderate accuracy using machine learning methods.     

Determinants of Participation in HIV Clinical Trials: The Importance of Patients’ Trust in Their Provider

Abstract

Purpose: To investigate the factors that contribute to willingness to participate in HIV clinical trials and to determine the impact of a brief intervention on willingness to participate. Methods: 115 consecutive outpatients receiving HIV primary care participated in this prospective study. Each patient completed a questionnaire about clinical trials and met with a research assistant who discussed the purpose of clinical trials. After the educational intervention, participants completed a second questionnaire and responses from the two surveys were compared. Results: 115 patients were enrolled (56% had previously enrolled in a clinical trial; 50% of whom were currently enrolled in a trial); 92% would consider participating in a future clinical trial. Increased patient trust in the provider was associated with increased willingness to participate in a trial. After the intervention, 94% indicated that they would be willing to be contacted about a clinical trial for which they may be eligible and 85% preferred to be contacted by their primary physician. Conclusions: Patients’ trust in their provider may predict willingness to participate in clinical trial. Providing HIV-infected patients and their providers with information about HIV clinical trials at the site where they receive care may increase participation rates in HIV clinical trials.     

Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma – an update

Introduction: The development of monoclonal antibody-based biologics targeted at inhibition of the Th2 cytokines IL-4, IL-5 and IL-13 represent potentially effective treatments for patients with the glucocorticoid refractory eosinophilic asthma phenotype.

Areas covered: Asthma exhibits marked heterogeneity both clinically and at the molecular phenotypic level, requiring specifically targeted treatments to block the key pathways of the disease. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of reproducible and straightforward discriminatory biomarkers may aid identification of those patients most likely to benefit from treatment with these expensive interventions. This narrative review is based on English-language original articles in PubMed or Med-Line that reported significant clinical findings published in the last two years on the evidence demonstrating the effectiveness or otherwise of the targeting of IL-4, IL-5, or IL-13 in carefully selected patients with severe refractory asthma.

Expert commentary: The use of a baseline peripheral blood eosinophilia as a simple reproducible biomarker to identify patients with particular sub-phenotypes of asthma to guide the effective use of biologic therapy represents a significant step forward.     

Translational research and efficacy of biologics in Crohn's disease: a cautionary tale

In the last several years many biologic agents for Crohn's disease have been developed. Due to their unique molecular specificity biologics are de facto indicators of the ultimate significance of the molecule targeted by the biologic itself. Here, we have reviewed many clinical studies that have used biologics for Crohn's disease. Their results show that despite potentially sound theoretical mechanisms of action and some initially promising data, most biologics – with few notable exceptions - have failed. Pharmacologic, study design or patient-related issues might explain these findings in some studies. However in many cases clinical failure of biologics might highlight the complexity of in vivo events and the potential deficiencies of current experimental settings. Hence, these observations call for new and efficient ways of predicting drug efficacy in clinical trials based on bench research. Conceivably, computer-based pathogenetic models could be used to simulate and predict clinical studies results in vivo.     

Therapeutic Potential of Targeting Interleukin 5 in Asthma

It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of interleukin (IL)-4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were, for the most part, disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review summarises the current evidence, demonstrating the effectiveness or otherwise of the targeting of IL-5 in patients with asthma.     

Current status and future prospects for biologic treatments of psoriasis

Introduction: Biological agents have transformed psoriasis treatment by selectively targeting immune signaling molecules involved in psoriasis pathogenesis. While biologics offer the most effective treatment of moderate to severe psoriasis, they are not without complications. Some patients treated with biologics have poor clinical responses, form anti-drug antibodies, or develop adverse events. Additionally, there is growing need for head-to-head studies comparing biologic treatment regimens, efficacy, and safety.

Areas covered: Here we review the literature surrounding biologics already in clinical use and those undergoing development and clinical trials. We also investigate the development and approval of small molecules inhibitors and biosimilars used to treat psoriasis.

Expert commentary: As the psoriasis treatment armamentarium continues to expand, it is important to follow the safety profile of these drugs both in clinical trials and in post-marketing registries to ensure their long-term safety. Physicians must be aware of the limitations of existing safety data of a drug and the potential risk for rare adverse events when selecting appropriate treatments and monitoring patient outcomes.     

Design of telehealth trials – Introducing adaptive approaches

BackgroundThe field of telehealth and telemedicine is expanding as the need to improve efficiency of health care becomes more pressing. The decision to implement a telehealth system is generally an expensive undertaking that impacts a large number of patients and other stakeholders. It is therefore extremely important that the decision is fully supported by accurate evaluation of telehealth interventions.ObjectiveNumerous reviews of telehealth have described the evidence base as inconsistent. In response they call for larger, more rigorously controlled trials, and trials which go beyond evaluation of clinical effectiveness alone. The aim of this paper is to discuss various ways in which evaluation of telehealth could be improved by the use of adaptive trial designs.ResultsWe discuss various adaptive design options, such as sample size reviews and changing the study hypothesis to address uncertain parameters, group sequential trials and multi-arm multi-stage trials to improve efficiency, and enrichment designs to maximise the chances of obtaining clear evidence about the telehealth intervention.ConclusionThere is potential to address the flaws discussed in the telehealth literature through the adoption of adaptive approaches to trial design. Such designs could lead to improvements in efficiency, allow the evaluation of multiple telehealth interventions in a cost-effective way, or accurately assess a range of endpoints that are important in the overall success of a telehealth programme.     

Chronic rhinosinusitis with nasal polyps: insights into mechanisms of disease from emerging biological therapies

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease of the upper airway, with long-term morbidity. With detailed mechanistic studies currently lacking, understanding of the immunopathogenesis is still limited. However, outcomes from CRSwNP clinical studies using biologics that block key mediators or cells may provide some insights into how immune signaling pathways potentially integrate and modulate each other and contribute to disease. Current treatments are often ineffective and there is an urgent unmet clinical need for effective therapeutic strategies. Emerging biologics hold promise.

Areas covered: This review covers the biology of CRSwNP in terms of the clinical outcomes reported from blocking immune cascades with available biologics. Immune amplification mechanisms and how biologics can potentially modulate such ‘master’ cytokines and signaling proteins that drive inflammation and contribute to tissue remodeling in CRSwNP are discussed.

Expert commentary: Biologics have the potential to transform CRSwNP treatment. The ability to predict clinical response in a complex disease as CRSwNP to a biologic cannot necessarily be predicted by measuring a single protein or cell as a biomarker of disease. Further studies with biologics must be carefully undertaken to fully evaluate wider biomarker associated pheno-endotype responses along with any associated asthma outcome measures.     

Immunogenicity of biologic therapies: causes and consequences

Introduction: Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional therapies, and subsequently revolutionized the management of numerous chronic diseases. Repetitive administration of these protein-based therapeutics to immunocompetent patients elicit immune responses in the form of Anti Drug Antibodies (ADAs), which in turn impact their pharmacological properties and may trigger adverse events.

Areas covered: Structural characteristics determining the immunogenicity of biologics are reviewed along with strategies to minimize it. Next, the different types of treatment-emerging ADAs, their potential clinical implications, and assays to detect them are addressed. Emphasis is put on the review of data on the immunogenicity of different types of biologics across numerous indications. Finally, practical considerations are discussed on how to manage patients with issues around the immunogenicity of their biologic treatment.

Expert commentary: Immunogenicity is a clinically relevant criterion when selecting a biologic. Besides intrinsic properties of the agent (namely its structure), its respective mode of action, dosing regimen, comedication, and the indication treated must be considered. ADA detection assays need to be standardized to improve comparability of available data and to allow clinical decision-making.     

Certolizumab pegol: a new biologic targeting rheumatoid arthritis

The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia^®, UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn’s disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.     

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.     

Patient and family member perspectives on searching for cancer clinical trials: A qualitative interview study

ObjectiveClinical trials are vital in the context of ovarian cancer and may offer further treatment options during disease recurrence, yet enrollment remains low. Understanding patient and family member experiences with identifying trials can inform engagement and education efforts.MethodsInterviews were conducted with 33 patients who had experience with clinical trial conversations and 39 nominated family members. Thematic analysis examined experiences and generated findings for clinical practice.ResultsTrial conversations with providers at diagnosis were uncommon and often overwhelming. Most participants delayed engagement until later in the disease course. With hindsight, though, some wished they considered trials earlier. Difficulty identifying appropriate trials led some to defer searching to providers, but then they worried about missed opportunities. Most family members felt unqualified to search.ConclusionTrial conversations during clinical encounters should start early and include specifying search responsibilities of providers, patients, and family. Patients and family members can be engaged in searches but need guidance.Practice implicationsTrials should be discussed throughout the disease course, even if patients are not ready to participate or are not making a treatment decision. Education should focus on identifying trials that meet search criteria. Transparency regarding each individual’s role in identifying trials is critical.     

Overall and comparative safety of biologic and immunosuppressive therapy in inflammatory bowel diseases

ABSTRACT

Introduction: Efficacy and safety are key aspects when choosing therapies for patients with inflammatory bowel diseases (IBD). While several randomized trials and indirect comparisons have informed the comparative efficacy of medications, there has been a limited synthesis of safety of different agents.

Areas covered: We focus on the overall and comparative risk of serious and opportunistic infections and malignancy of biologic and immunosuppressive therapy in IBD, based on randomized trials, open-label extension and registry studies, and real-world comparative observational studies.

Expert opinion: TNFα antagonists may be more immunosuppressive than non-TNF-targeted biologic agents and increase the risk of systemic infections. Most consistent risk factors for serious infections include use of combination therapy with immunosuppressive agents and/or corticosteroids, moderate to severe disease activity, and older age. TNFα antagonists may also be associated with an increased risk of lymphoma, especially when combined with thiopurines. Real-world comparative safety studies, especially with newer biologic agents, are warranted to inform decision-making. Comparative safety of pharmacotherapy for IBD should be viewed in conjunction with efficacy and in the context of treatment strategies/approach, rather than in the context of specific agents used.