Pitrakinra for asthma

Importance of the field: In asthma IL-4 and IL-13 have been demonstrated to play major pathogenic roles and therefore their blockade would potentially represent a plausible therapeutic approach.

Areas covered in this review: Pitrakinra is a dual IL-4/IL-13 inhibitor currently under development for asthma and the existing preclinical and clinical data are discussed.

What the reader will gain: Inhaled pitrakinra demonstrated a good anti-inflammatory potential and a good safety profile on a short-term basis but its place in asthma therapy is still to be found.

Take home message: Specific anticytokine therapies might in the near future reshape asthma therapy.     

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.     

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.     

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.     

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.     

Disabling inflammatory pathways with biologics and resulting clinical outcomes in severe asthma

Introduction: Patients with severe asthma have a significant unmet need with persistent symptoms and/or frequent exacerbations despite high intensity treatment. These severe unrelenting symptoms have a huge impact on heathcare resources due to frequent hospital admissions and requirement for intensive and expensive medications. There is a compelling need for more effective and safer therapies to help severe asthma sufferers to achieve adequate control of their disease.

Areas covered: Expanding knowledge of innate and adaptive immune responses has led to development of new biologic approaches for severe asthma. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. Their specific role in distinctively targeted subpopulations of severe asthmatics will be also discussed.

Expert opinion: Defining and phenotyping severe asthma patients will become increasingly important as some patients who were previously classified as having severe asthma may become well-controlled with a targeted phenotype-specific treatment. However, pharmacoeconomic concerns should also be taken into account given the elevated acquisition costs of recombinant human monoclonals and of the diagnostic screening procedures for the identification of potential responders.     

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.     

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.     

Gene therapy to restore electrophysiological function in heart failure

Introduction: Heart failure (HF) is a major public health epidemic and a leading cause of morbidity and mortality in the industrialized world. Existing treatments for patients with HF are often associated with pro-arrhythmic activity and risk of sudden cardiac death. Therefore, development of novel, effective and safe therapeutic options for HF patients is a critical area of unmet need.

Areas covered: In this article, we review recent advances in the emerging field of cardiac gene therapy for the treatment of tachy- and bradyarrhythmias in HF. We provide an overview of gene-based approaches that modulate myocardial conduction, repolarization, calcium cycling and adrenergic signaling to restore heart rate and rhythm.

Expert opinion: We highlight major advantages of gene therapy for arrhythmias, including the ability to selectively target specific cell populations and to limit the therapeutic effect to the region that requires modification. We illustrate how advances in our fundamental understanding of the molecular origins of arrhythmogenic disorders are allowing investigators to use targeted gene-based approaches to successfully correct abnormal excitability in the atria, ventricles and conduction system. Translation of various gene therapy approaches to humans may revolutionize our ability to combat lethal arrhythmias in HF patients.     

Biological therapies for psoriasis

Introduction: Biological therapies have revolutionized moderate-to-severe psoriasis treatment. Increased understanding of disease pathogenesis has yielded multiple therapeutic targets involving the IL-23/Th17 pathway, while current therapies continue to be monitored for long-term efficacy and safety.

Areas covered: This review details current understanding of psoriasis immunopathogenesis specifically related to therapeutic targets. Approved and emerging biological psoriasis therapies targeting TNF-α, IL-12/23p40, IL-17 and IL-23p19 are covered. Biological agent uses in special circumstances are reviewed together with the emerging debate on biosimilar therapies and their potential future role in psoriasis and other inflammatory diseases.

Expert opinion: Psoriasis treatment has expanded and has become more effective due to increased understanding of disease pathogenesis. However, lack of efficacy in select psoriasis patients, safety concerns and limited treatment efficacy in psoriasis variants (e.g., pustular) are areas which still need improvement. As such, pharmacogenomics will be of vital importance in future for individualized psoriasis care. Further, a better understanding of the multiple psoriasis comorbidities, especially cardiovascular disease, continues to be of significant interest in the psoriasis community. Last, the emergence of biosimilar agents has the potential to change psoriasis treatment, especially as it relates to better access for the psoriasis community worldwide.     

Immunotherapy of chronic inflammatory demyelinating polyradiculoneuropathy

Introduction: There are now two chemotherapy agents, one tyrosine kinase inhibitor and three immunotherapy products approved for the treatment of metastatic melanoma, but an unmet need persists because these options are toxic and of limited therapeutic benefit. Active specific immunotherapy with therapeutic vaccines could be a useful addition to the therapeutic armamentarium, especially in patients whose tumor burden has been reduced by other treatment modalities.

Areas covered: This article reviews various sources of melanoma antigens, such as peptides, gangliosides, autologous tumor and cancer stem cells including allogeneic and autologous cell lines. The advantages and disadvantages of various antigen sources and allogeneic and autologous approaches are discussed with an emphasis on the theoretical benefits of immunizing against cancer stem cells. The results from published randomized trials testing the benefit of various vaccine approaches are summarized, as well as promising results from three Phase II trials (one randomized) of patient-specific stem cell antigen-based products.

Expert opinion: Immune responses directed toward the unique neoantigens and stem cell antigens expressed on continuously proliferating, self-renewing, autologous tumor cells could potentially overcome the limitations inherent in these other antigen-based approaches, that to date, have yielded disappointing results in randomized trials.     

Psychosocial issues need more attention in COPD self-management education

Abstract

Objective: To find out how regularly the contents of patient education regarded as essential for COPD patients’ self-management are provided by healthcare professionals in specialised healthcare (SHC) and primary healthcare (PHC) in Finland.

Design: A cross-sectional study based on an e-questionnaire with 42 items on the content of self-management education of COPD patients.

Setting: The study sample included all public SHC units with pulmonary outpatient clinics (n?=?29) and nine out of 160 health centres in Finland.

Subjects: 83 doctors and 162 nurses.

Main outcome measures: The respondents’ answers on how regularly they included the contents regarded as essential for COPD patients’ self-management in their education of COPD patients.

Results: COPD patients were educated regularly on medical issues regarding COPD treatment, such as smoking cessation, exercise and pharmacological treatment. However, issues vital for coping with the disease, such as psychological well-being, stress management or fatigue, were often ignored. Patient education in SHC seemed to be more systematic than education in PHC. The education provided by the asthma/COPD nurses (n?=?70) was more systematic than the education provided by the other nurses (n?=?84).

Conclusion: Healthcare professionals’ continuous education should cover not only the medical but also the psychosocial aspects of coping with COPD. The role of doctors and nurses should be considered to ensure that there is no gap in COPD patients’ education. Training asthma/COPD nurses and promoting specialised nurse-led asthma/COPD clinics in primary care could be beneficial while improving practices of patient education that enhance patients’ ability to cope with the disease.

• KEY POINTS

• Issues vital for coping with chronic obstructive pulmonary disease (COPD), such as psychological well-being, stress and fatigue, are irregularly included in self-management education both in primary and specialised healthcare.

• Patient education provided by asthma/COPD nurses is more regular than patient education provided by other nurses.

• The distribution of work between doctors and nurses should be considered to ensure that there is no gap in COPD patients’ education.

     

Zalutumumab in head and neck cancer

Introduction: Plaque psoriasis is a chronic inflammatory disease that can result in significant physical, psychological and quality of life impairments. Until recently, biologic treatment for psoriasis was limited to tumor necrosis factor-α inhibitors and an interleukin (IL)-12/23 p40 subunit inhibitor. Newly developed biologics targeting the pro-inflammatory IL-17A cytokine have shown success in providing higher levels of clinical efficacy in patients with psoriasis. Secukinumab, a member of this novel class of IL-17 inhibitors, is the latest biologic to receive US FDA approval for the treatment of moderate-to-severe plaque psoriasis.

Areas covered: This comprehensive review will cover the pharmacology, efficacy, safety and future role of secukinumab and other IL-17 blockers in the treatment of plaque psoriasis.

Expert opinion: While biologics have revolutionized patient care for chronic plaque psoriasis, they are associated with loss of response over time. When treatment failure occurs with existing biologics, physicians are left with few alternative treatment options to offer patients. The introduction of secukinumab has provided an additional therapeutic agent that offers improved skin clearance, better health related quality of life and a favorable side-effect profile.     

Benralizumab as a potential treatment of asthma

Introduction: Current anti-inflammatory asthma therapies including inhaled corticosteroids and leukotriene modifiers, are not always able to appropriately control the disease and other approaches are needed. These therapies specific target IgE (omalizumab) or IL-5 (mepolizumab). However, there is research underway investigating interleukin-based monoclonal antibodies such as benralizumab, an anti-IL-5R monoclonal antibody which is currently in phase III clinical development.

Areas covered: This review summarizes the existing preclinical and clinical data of benralizumab. Data reviewed includes benralizumab’s efficacy and safety data. The author also provides their expert opinion on this potential therapeutic and provide their perspectives for its future development.

Expert opinion: Benralizumab was able to interfere significantly with disease-related morbidity and in particular with hospitalizations due to asthma exacerbation rates in a subset of patients with higher systemic eosinophil burden and higher doses of inhaled corticosteroids. The sustained inhibitory effect on eosinophilic inflammation might be an advantage which can be translated in less frequent dosing. Further attempts should be made to better define the asthma endotype in which such an antibody would be the most efficacious.     

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.     

Biologics for the treatment of adult-onset still’s disease

ABSTRACT

Introduction: Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown etiology, and approximately 60–70% of patients develop a chronic form. Up to 20–30% of patients who are refractory to conventional therapy need biologic agents. Recently, anti-cytokine biologic agents according to pathophysiology have resulted in significant progress in the treatment of AOSD.

Area Covered: Due to rarity and heterogeneous features of the disease, treatment of AOSD is not based on the controlled study but on case-based retrospective data. Here, we review the current status of the pathogenesis, limitations of therapeutic guidelines and outcome measures, utility of biologic agents, and future perspectives for treatment.

Expert opinion: IL-1 inhibitors are more effective for systemic manifestations and IL-6 inhibitors for both joint disease and systemic features. Anti-TNF agents would be useful for patients with the pure rheumatoid subgroup. Systemic manifestations respond rapidly, but arthritis shows rather slow response. Clinical response must be obtained within 2 to 3 months, and biologics with different mechanisms of action are required for non-responders. For patients in prolonged remission, we need to try tapering of biologics. Randomized controlled studies, new therapeutic agents, and composite biomarkers are required to improve the outcome of patients with AOSD.     

Ixekizumab for the treatment of psoriasis: up-to-date

ABSTRACT

Introduction: Ixekizumab (an IL-17A antagonist) is a biologic therapeutic licensed for use in moderate-to-severe plaque psoriasis and psoriatic arthritis. IL-17 antagonists (also including Secukinumab and Brodalumab) represent a new generation of biologic therapy with rapid and high response rates, quickly becoming a crucial part of the psoriasis treatment armamentarium.

Areas covered: In this review, we describe how IL-17A antagonists disrupt inflammatory cascades in psoriasis and summarize results from clinical trials examining the safety and efficacy of ixekizumab against placebo and comparators.

Expert opinion: Ixekizumab induces a 75% reduction in psoriasis area severity index (PASI 75) in 89% of patients after 12 weeks and after 1 year, PASI 75 is maintained in 80% of patients. Ixekizumab is superior to both etanercept and ustekinumab, however, further comparator trials are needed to determine superiority between newer agents. Network meta-analysis suggests that ixekizumab is one of the most rapid and efficacious agents for treating psoriasis, but ideally more long-term real-world data are needed to determine the persistence of response. Candida may be commonly encountered during treatment and IL-17 agents should be avoided in patients with inflammatory bowel disease. Overall, ixekizumab represents an efficacious and well-studied therapeutic that can offer biologic-naïve and bio-failure patients durable disease control.     

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.     

Novel approaches to biological therapy for psoriatic arthritis

ABSTRACT

Introduction: Improved understanding of the immunopathogenic mechanisms in psoriatic arthritis (PsA) has led to the development of targeted biological therapies, which demonstrate superior clinical efficacy to traditional disease-modifying antirheumatic drugs (DMARDs). There are currently 3 classes of biological agents that are approved for the treatment of psoriatic disease: tumor necrosis factor alpha inhibitors (TNFi), including etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol; ustekinumab, a monoclonal antibody (mAb) directed against interleukin (IL)-12 and IL-23; and secukinumab, a human anti-IL-17A mAb. Other agents are in development. Our growing experience with these medications has revolutionized the approach to disease management in PsA.

Areas covered: This article discusses the rationale for using biological therapies in PsA, highlighting clinical trial evidence that supports the use of these agents. We summarize novel treatment approaches using biological therapies in the management of PsA, including early intervention, targeted therapy, TNFi switching, combination therapy, and tapering or discontinuation of biological therapy. We conclude with a discussion of the importance comorbidities have on selection of therapy.

Expert opinion: The advent of highly effective biological therapies has revolutionized the management of patients with PsA. Growing experience with these agents has led to novel treatment approaches that may improve clinical outcomes for PsA patients.     

Predictors of response to therapy with omalizumab in patients with severe allergic asthma – a real life study

Objectives: Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody, used for the treatment of severe refractory allergic asthma. However, not all patients with IgE levels within the limits of administration, respond to treatment. The aim of the present study, was to determine clinical and inflammatory characteristics that could predict response to omalizumab.

Methods: We studied retrospectively patients treated with omalizumab as per GINA guidelines in one asthma tertiary referral center. Demographic and functional characteristics, level of asthma control, fractional exhaled nitric oxide, blood and eosinophils and IgE level, induced sputum cell count, eosinophil cationic protein and Interleukin-13 in sputum supernatant were recorded. All measurements were performed before starting treatment with omalizumab. Response to treatment was evaluated according to the physician’s global evaluation of treatment effectiveness. Patients were characterized as early responders when improvement was achieved within 16 weeks and as late responders when improvement was achieved between 16 and 32 weeks. Patients who did not show any improvement after 32 weeks of therapy were considered as non-responders.

Results: Forty-one patients treated with omalizumab were included in the study. 28 (68.3%) patients were characterized as responders while 13 patients (31.7%) were considered as non-responders. Among responders, 25 (89%) were early responders and 3 (n = 11%) were late responders. Responders were characterized by lower baseline FEV₁ and FEV₁/FVC and higher IL-13 levels in induced sputum supernatant compared to non-responders. Late responders had higher serum IgE levels, shorter disease duration and higher number of blood eosinophils. Finally, using ROC curve analysis, the best predictors of response to omalizumab were FEV₁ (AUC = 0.718) and IL-13 in sputum supernatant (AUC = 0.709).

Conclusion: Lower baseline FEV₁ and higher IL-13 levels in induced sputum supernatant were predictors of response to omalizumab. Patients with higher baseline serum IgE levels, shorter disease duration and higher blood eosinophils may experience a late response and might benefit from a more prolonged treatment before being characterized as non-responders.