Expert review of respiratory medicine
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Expert Rev Respir Med · Jun 2015
Alectinib: a selective, next-generation ALK inhibitor for treatment of ALK-rearranged non-small-cell lung cancer.
Crizotinib was the first clinically available anaplastic lymphoma kinase (ALK) inhibitor, showing remarkable activity against ALK-rearranged non-small-cell lung cancer (NSCLC). Despite initial responses, acquired resistance to crizotinib inevitably develops, with the brain being a common site of relapse. Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity also against ALK mutations conferring resistance to crizotinib, including the gatekeeper L1196M substitution. ⋯ Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with CNS metastases. Based on these data, the drug received Breakthrough Therapy Designation by the US FDA and has been recently approved in Japan for the treatment of ALK-positive, advanced NSCLC patients. However, patients may eventually develop resistance to alectinib, highlighting the need for novel therapeutic strategies to further improve the management of ALK-rearranged NSCLC.
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Expert Rev Respir Med · Jun 2015
ReviewDefining exacerbations in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease is a very common disease often punctuated by intermittent episodes of exacerbation. These exacerbations affect the natural history of the disease, accelerating a decline in lung function. They affect the individual in many ways and affect the health service caring for these patients. ⋯ The definitions used most are either symptom based, for example, breathlessness, sputum production and sputum purulence, or event driven, for example, an event causing a patient to seek healthcare input or change to medications. In this article, we discuss the importance of exacerbations, the clinical definitions, clinical trial definitions, physiological and biomarker evidence of exacerbations and the challenges associated with each of these. Application of a practical definition would aid in our clinical management of patients with chronic obstructive pulmonary disease and facilitate developments in future therapeutic advances through clinical trials.
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Expert Rev Respir Med · Apr 2015
ReviewEfficacy and safety of reslizumab in patients with moderate to severe eosinophilic asthma.
Reslizumab, a neutralizing anti-IL-5 monoclonal antibody, is a promising adjunctive treatment for severe eosinophilic asthma. Monthly intravenous 3.0 mg/kg reslizumab had resulted in improvements in lung function and asthma control. ⋯ Stringent selection of patients with a high eosinophil burden, who are poorly controlled despite moderate to high doses of inhaled corticosteroid, confers the most significant treatment response. Future trials should compare the dose, delivery platform, frequency of dosing and study combinations with other biologics, which will affect its maximal clinical efficacy.
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Expert Rev Respir Med · Apr 2015
ReviewImmunology, genetics and microbiota in the COPD pathophysiology: potential scope for patient stratification.
Chronic obstructive pulmonary disease (COPD) is characterized by sustained inflammation of the airways, leading to destruction of lung tissue and declining pulmonary function. Although smoking is the most obvious risk factor for COPD, only about 20% of smokers develop COPD and smoking cessation does not reverse progression of COPD, indicating that while smoking is an important cause or initiating factor, it is not the only driver of ongoing chronic inflammation and disease progression in COPD patients. We hypothesize that smoking-induced changes in lung microbiota, epithelial integrity and epigenetic control of gene expression result in autoantigen induction and perturbed immune regulation in genetically vunerable individuals. In our view, COPD patients may be stratified according to their immunological and inflammatory status related to specific changes in the lung microbiota (innate and adaptive immunity), presence of autoantigens (adaptive immunity: Th1-B-cell axis) and epigenetic modifications (inflammation and structural changes).
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Expert Rev Respir Med · Apr 2015
ReviewThe efficacy and safety of inhaled human α-1 antitrypsin in people with α-1 antitrypsin deficiency-related emphysema.
α-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition characterized by low circulating levels of α-1 antitrypsin (AAT), a serine protease inhibitor. Significant work has been carried out in the development of AAT augmentation therapy for AATD. ⋯ Inhalation therapy offers the opportunity for easier and more efficient delivery of AAT directly to the lungs with some evidence of a reduction in local inflammatory and proteolytic activity, potentially offering an alternative therapeutic option to the iv. route. There are, however, theoretical obstacles to the potential efficacy of aerosol-delivered AAT and although there have been a number of short-term studies examining inhaled AAT and its effect on lung inflammation, there has only been one long-term study to date in AATD looking at clinical outcomes, which is as yet unpublished.