The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting ß2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.

Treating moderate-to-severe allergic asthma with anti-IgE monoclonal antibody (omalizumab). An update.

Increased asthma severity is not only associated with enhanced recurrent hospitalisation and mortality but also with higher social costs. Most cases of asthma are atopic in nature, with the trigger for acute asthma attacks and chronic worsening of inflammation being allergens inducing an immune response through immunoglobulins of IgE class. Currently antiinflammatory treatments are effective for most of asthma patients, but there are subjects whose disease is incompletely controlled by inhaled or systemic corticosteroids and these patients account for about 50% of the healthcare costs of asthma. Omalizumab is a humanized recombinant monoclonal anti-IgE antibody developed for the treatment of allergic diseases and with clear efficacy in adolescent and adult patients with moderate-to-severe allergic asthma.. The anti-IgE antibody inhibits IgE functions blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade, omalizumab represents a really new approach to the treatment of atopic asthma. Omalizumab improves quality of life of patients with severe persistent allergic asthma that is inadequately controlled by currently available asthma medications. This therapy is well tolerated and significantly improves symptoms, disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids. In other words, omalizumab may fulfil an important need in patients with moderate-to-severe asthma.

Italian real-life experience of omalizumab.

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.

Adenosine 5'-monophosphate increases levels of leukotrienes in breath condensate in asthma.

Hyperresponsiveness (AHR) is a key physiological abnormality in asthma. In clinical and research studies AHR is measured bronchial challenge, with methacholine (MCh), but more recently with adenosine-5'-monophosphate (AMP). In the search for markers of airway inflammation in asthmatic patients, we measured the concentrations of histamine and cysteinyl-leukotrienes (cys-LTs) before and after MCh and AMP challenges in the exhaled breath condensate of 13 patients with mild asthma (FEV1 78.5%pred) and nine healthy non-smokers, using specific enzyme immunoassays. With methacholine challenge we did not find any differences between asthmatics and normal subjects in the pre- and post-challenge concentrations of cys-LTs: 27.2+/-1.4 vs. 29.2+/-1.2 pg/ml and 26.3+/-2.2 vs. 27.5+/-4.2 pg/ml, respectively or histamine: 5.1+/-0.4 vs. 5.1+/-0.6 nM and 4.5+/-0.4 vs. 4.4+/-0.3 nM; P>0.05). In asthmatic patients cys-LT levels were significantly higher after AMP challenge (56.2+/-9.7 vs. 31.7+/-6.9 pg/ml; P<0.05); but there was no difference in healthy subjects (27.2+/-4.6 vs. 30.3+/-4.7 pg/ml). There was no difference in histamine concentrations in asthmatic (5.9+/-1.8 vs. 4.5+/-0.5 nM), or healthy subjects (5.5+/-0.4 vs.5.7+/-0.9 nM) after AMP challenge. In conclusion, our results show that the cys-LTs are increased in exhaled breath condensate after AMP challenge, which may indicate that the AMP acts indirectly by releasing cys-LTs from primed mast cells. The detection of LTs and histamine in exhaled breath condensate may be useful in monitoring asthma.

Increased frequency dependence of specific airway resistance in patients with laryngeal hemiplegia.

The aim of this study was to investigate whether patients with laryngeal hemiplegia (LH) show a frequency-dependent increase in specific airway resistance (sRaw), measured by body plethysmography. In addition to the flow-volume loop, usually considered in the functional evaluation of upper airway obstructions, variations in sRaw at respiratory frequencies of 30+/-5 (=0.5 Hz), 60+/-5 (=1 Hz) and 90+5 breaths x min(-1) (=1.5 Hz) in 21 never-smoking patients (LH group, mean age+/-SD 55+/-12.09 yrs; 17 females) whose unilateral vocal-cord paralysis was documented by laryngoscopy and who had no signs or symptoms of other respiratory diseases studied. They were compared to 21 healthy control subjects (C group: 50.1+/-15.44 yrs; 10 females). The sRaw values at 30+/-5 breaths min(-1) were similar in the two groups (5.54+/-1.88 versus 5.68+/-1.06 cmH2O x s(-1); p=NS), but at increasing frequencies (30+/-5, 60+/-5 and 90+/-5 breaths min(-1)), they progressively and significantly increased in the LH patients (from 5.54+/-1.88 to 6.63+/-1.96 and 8.05+/-2.6 mH2O x s(-1); p<0.0005), and not significantly in controls (5.68+/-1.06, 5.85+/-0.95 and 5.9+/-1.12 cmH2O x s(-1); p=NS). Linear discriminant analysis using AsRaw (sRaw at 1.5 Hz-sRaw at 0.5 Hz) and forced inspiratory flow at 50% of the vital capacity made it possible to correctly classify all of the controls and 19 of the 21 patients. In conclusion, the multiple, rapid and noninvasive plethysmographical testing of frequency-dependent increase in specific airway resistance with the flow-volume loop, allows the sufficiently satisfactory discrimination of laryngeal hemiplegia patients from controls.