Matteo Ferrando

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma

Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma. IL-13 and IL-4 partly share the same receptor and signaling pathways and both are deeply involved in immunoglobulin E (IgE) synthesis, eosinophil activation, mucus secretion and airways remodeling. Several anti-IL-13 strategies have been proposed (anrukinzumab, lebrikizunab and tralokinumab), with relevant clinical results reported with lebrikizumab. Such studies facilitate better definition of the possible predictive markers of response to a specific treatment (e.g. eosinophils, total IgE, fraction of exhaled nitric oxide and periostin). In parallel, anti-IL-4 strategies have been attempted (pascolizumab, pitakinra and dupilumab). So far, dupilumab was reported capable of reducing the severity of asthma and the rate of exacerbations. IL-13 and IL-4 are crucial in TH2-mediated inflammation in asthma, but it remains clear that only specific endotypes respond to these treatments. Although the use of anti-IL-14 and anti-IL-13 strategies is promising, the search for appropriate predictive biomarkers is urgently needed to better apply biological treatments.

Personalized Medicine in Allergy

Allergic disease is among the most common pathologies worldwide and its prevalence has constantly increased up to the present days, even if according to the most recent data it seems to be slightly slowing down. Allergic disease has not only a high rate of misdiagnosis and therapeutic inefficacy, but represents an enormous, resource-absorbing black hole in respiratory and general medicine. The aim of this paper is to summarize principal therapeutic innovations in atopic disease management befallen in the recent years in terms of personalized/precision medicine.

Reslizumab and Eosinophilic Asthma: One Step Closer to Precision Medicine?

Human eosinophils represent approximately 1% of peripheral blood leukocytes. However, these cells have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophilic inflammation is present in a significant proportion of patients with severe asthma. Asthma is a chronic inflammatory disorder that affects more than 315 million people worldwide, with 10% having severe uncontrolled disease. Although the majority of patients can be efficiently treated, severe asthmatics continue to be uncontrolled and are at risk of exacerbations and even death. Interleukin-5 (IL-5) plays a fundamental role in eosinophil differentiation, maturation, activation and inhibition of apoptosis. Therefore, targeting IL-5 is an appealing approach to the treatment of patients with severe eosinophilic asthma. Reslizumab, a humanized anti-IL-5 monoclonal antibody, binds with high affinity to amino acids 89–92 of IL-5 that are critical for binding to IL-5 receptor α. Two phase III studies have demonstrated that reslizumab administration in adult patients with severe asthma and eosinophilia (≥400 cells/μL) improved lung function, asthma control, and symptoms. Thus, the use of blood eosinophils as a baseline biomarker could help to select patients with severe uncontrolled asthma who are likely to achieve benefits in asthma control with reslizumab. In conclusion, targeted therapy with reslizumab represents one step closer to precision medicine in patients with severe eosinophilic asthma.

Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma

The definition of asthma has changed considerably in recent years, to the extent that asthma is no longer considered a single disease but a heterogeneous disorder that includes several phenotypes and, possibly, endotypes. A more detailed analysis of the immunological mechanisms underlying the pathogenesis of asthma shows interleukin 5 (IL-5) to be a crucial cytokine in several asthma phenotypes. In fact, IL-5 exerts selective action on eosinophils, which, in turn, sustain airway inflammation and worsen asthma symptoms and control. Clinical trials have shown drugs targeting IL-5 or its receptor alpha subunit (IL-5Ra) to be a promising therapeutic approach to severe asthma, whose characteristics render standard therapy of little use: systemic corticosteroids only partially control the disease and have well-known adverse effects, and omalizumab is used for allergic subtypes. Analysis of the design process of clinical trials reveals the importance of patient selection, taking into account both clinical data (e.g., exacerbations, lung function, and quality of life) and biomarkers (e.g., eosinophils, which are predictive of therapeutic response).

Update on immunotherapy for the treatment of asthma.

Purpose of review Despite that specific immunotherapy can boast being more than a century old, there is still skepticism about its real effectiveness, and therefore it is still used too little in clinical practice. The purpose of this review was to analyze the most recent articles in the literature to highlight scientific evidence for the proper use of allergen immunotherapy (AIT). Recent findings In the near future, the concept of medicine for trials will have to be revised and in certain cases abandoned in favor of a personalized medicine, able to use a drug more targeted for the individual patient and not for the disease. Summary For AIT, it will become increasingly important to use products designed properly, standardized and with a well documented effectiveness in clinical studies. We must overcome the disputes of subcutaneous immunotherapy versus sublingual immunotherapy, arrive at the concept of personalized medicine regarding AIT, framing in different phenotypes of asthma patients to use the optimal preparation for each particular patient.

Targeting Interleukin-5 or Interleukin-5Rα: Safety Considerations

Asthma is a highly prevalent chronic disease of the airways; approximately 10% of patients with asthma will experience a severe form of the disease. New understanding of the pathogenesis of asthma has enabled the development of novel drugs and provided hope for patients with asthma. Interleukin (IL)-5 and IL-5 receptor subunit α (IL-5-Rα) plays a crucial role in the development, maturation, and operation of eosinophils so were the first important therapeutic target of these new drugs. While the results of early clinical trials of these drugs were not promising, results improved once researchers discovered the drugs worked best in patients with high eosinophil levels. Patients treated with both anti-IL-5 and IL-5-Rα experienced significant decreases in exacerbations. Trials have also demonstrated promising safety profiles; adverse events have been few and frequently only observed with placebo or considered unrelated to the study drug. The positive efficacy and safety profiles of these drugs has led to trials with interesting results in other diseases that are also secondary to the action of eosinophils: Churg–Strauss syndrome, hypereosinophilic syndrome, nasal polyposis, chronic obstructive pulmonary disease, atopic dermatitis, and esophagitis. In this review, we explore the main clinical trials of anti-IL-5 and IL-5-Rα, both in asthma and in other pathologies, with particular reference to the interesting safety and efficacy results.

Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience.

Eosinophils represent approximately 1% of peripheral blood leukocytes in normal donors and their maturation and differentiation in the bone marrow are mainly regulated by interleukin (IL)-5 [Broughton et al. 2015]. IL-5, a cytokine that belongs to the β common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils and, to some extent, of basophils. IL-5 binds to a heterodimer receptor composed of the specific subunit IL-5Rα and a common subunit βc shared with IL-3 and GM-CSF. Human eosinophils express approximately a three-fold higher level of IL-5Rα compared with basophils. Major sources of IL-5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5.

Asthma:: personalized and precision medicine

Purpose of review In this review, we herein describe the progress in management of severe asthma, evolving from a ‘blockbuster approach’ to a more personalized approach targeted to the utilization of endotype-driven therapies. Recent findings Severe asthma characterization in phenotypes and endotypes, by means of specific biomarkers, have led to the dichotomization of the concepts of ‘personalized medicine’ and ‘precision medicine’, which are often used as synonyms, but actually have conceptual differences in meaning. The recent contribute of the omic sciences (i.e. proteomics, transcriptomics, metabolomics, genomics, …) has brought this initially theoretic evolution into a more concrete level. Summary This step-by-step transition would bring to a better approach to severe asthmatic patients as the personalization of their therapeutic strategy would bring to a better patient selection, a more precise endotype-driven treatment, and hopefully to better results in terms of reduction of exacerbation rates, symptoms, pulmonary function and quality of life.

The path to personalized medicine in asthma

ABSTRACT Introduction: Asthma is a common respiratory disorder, since about 10% of the population suffer from this disease, and up to 10% have a severe form. Recent findings have allowed a greater and deeper understanding of the pathophysiological mechanisms, distinguishing two groups of patients according to the prevalent cellular population that drives the inflammatory process, and consequentially, to intervene on different cellular targets. Areas covered: Currently, several biological drugs directly interfering with these pathophysiological mechanisms (namely IgE, IL-4, IL-5, IL-13, and IL-17) are under investigation. Expert commentary: With the elucidation of mechanisms, new-targeted drugs have been developed. Asthma therapy is changing from a ‘one size fits all’ therapy to a ‘precision medicine’ model, where we may prescribe the most appropriate treatment for each patient. Moreover, in the near future, the possibility to act a ‘sequential bio-combination therapy’ can be envisaged, using different biological drugs in the same patient to act on different pathophysiological mechanisms.

Biosimilars in allergic diseases.

Purpose of review This article realizes an overview on the world of biological and biosimilar drugs in allergic and immunologic diseases’ treatment strategies. We started talking about the history of asthma treatments progresses, continuing to daily biological therapies, concluding with the economic point of view. Recent findings Nowadays, the only pharmacological–biological approach approved for allergic diseases is omalizumab. Several other monoclonal antibodies are currently running premarketing studies but the costs of these therapies are difficult to be sustained by healthcare systems. Summary Several biological treatments have gone or are going off-patent, opening the drug market to biosimilars. In this way, in future, it will be possible to reduce health costs and increase accessibility to therapies that currently are not affordable to all patients.