Publications by authors named "Pablo Altman"

19 Publications

  • Page 1 of 1

The pharmacology of the prostaglandin D receptor 2 (DP) receptor antagonist, fevipiprant.

Pulm Pharmacol Ther 2021 Apr 4;68:102030. Epub 2021 Apr 4.

Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ, 07936, USA.

Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the prostaglandin D (DP) receptor. The DP receptor is a mediator of inflammation expressed on the membrane of key inflammatory cells, including eosinophils, Th2 cells, type 2 innate lymphoid cells, CD8 cytotoxic T cells, basophils and monocytes, as well as airway smooth muscle and epithelial cells. The DP receptor pathway regulates the allergic and non-allergic asthma inflammatory cascade and is activated by the binding of prostaglandin D. Fevipiprant is metabolised by several uridine 5'-diphospho glucuronosyltransferase enzymes to an inactive acyl-glucuronide (AG) metabolite, the only major human metabolite. Both fevipiprant and its AG metabolite are eliminated by urinary excretion; fevipiprant is also possibly cleared by biliary excretion. These parallel elimination pathways suggested a low risk of major drug-drug interactions (DDI), pharmacogenetic or ethnic variability for fevipiprant, which was supported by DDI and clinical studies of fevipiprant. Phase II clinical trials of fevipiprant showed reduction in sputum eosinophilia, as well as improvement in lung function, symptoms and quality of life in patients with asthma. While fevipiprant reached the most advanced state of development to date of an oral DP receptor antagonist in a worldwide Phase III clinical trial programme, the demonstrated efficacy did not support further clinical development in asthma.
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http://dx.doi.org/10.1016/j.pupt.2021.102030DOI Listing
April 2021

Uncontrolled asthma across GINA treatment steps 2 - 5 in a large US patient cohort.

J Asthma 2021 Mar 31:1-13. Epub 2021 Mar 31.

Novartis Pharmaceuticals Corporation, Global Medical Affairs, East Hanover, NJ, USA.

Objective: Despite advances in treatment, asthma remains uncontrolled in many patients, with increased risk of exacerbation and associated healthcare resource utilization (HCRU). We describe patient characteristics, exacerbations, asthma control, and HCRU using GINA treatment step (GS) as a proxy for asthma severity. .

Methods: Using a large, US, health-claims database, 4 longitudinal cohorts of 517,738 patients in GS2-5, including a subgroup of patients with baseline eosinophil (EOS) counts, were analyzed retrospectively (study period 2010 - 2016). Index for each cohort was patients' first time entering the GS, determined by first claim of first regimen. Uncontrolled asthma was defined according to published criteria as a multi-dimensional measure that includes number of exacerbations. Key variables including, baseline characteristics, post-index exacerbations, and HCRU (all-cause and asthma-specific events) are summarized by descriptive statistics.

Results: Uncontrolled asthma was reported in 19.8% patients in GS2, 44.8% in GS3, 49.3% in GS4, and 58.6% in GS5. Annualized mean (SD) rates of exacerbation 12 months post-index generally increased across GS2-5 (0.26 [0.86], 0.32 [0.79], 0.36 [0.83], 0.29 [0.86], respectively). HCRU also increased with increasing GS, with higher HCRU among the uncontrolled cohort within each GS. In patients with EOS ≥300 cells/µL, uncontrolled asthma also increased with increasing GS (21.8%, 43.9%, 50.5%, 67.2% for GS2-5, respectively).

Conclusions: This large database study provides real-world evidence of the substantial degree of uncontrolled asthma in US clinical practice across GS, supporting calls for better asthma management. Healthcare burden tends to increase with lack of control in all groups, highlighting the need for improved patient education, adherence, access, and treatment optimization.

Supplemental data for this article can be accessed at publisher's website.
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http://dx.doi.org/10.1080/02770903.2021.1897834DOI Listing
March 2021

Short-course systemic corticosteroids in asthma: striking the balance between efficacy and safety.

Eur Respir Rev 2020 Mar 3;29(155). Epub 2020 Apr 3.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Short courses of systemic corticosteroids (SCS), both oral and injectable, are very effective for the resolution of acute asthma symptoms, including exacerbations. However, the benefits of SCS, even short courses, must be balanced against the impact of their side-effects. While the adverse consequences of long-term use are widely recognised, there appears to be a perception in the medical community that short courses of SCS are safe. Limited but growing evidence in the literature suggests that even very brief dosing periods (3-7 days) of SCS are enough to cause significantly negative outcomes for patients. Short courses of SCS are associated with increased risk of adverse events including loss of bone density, hypertension and gastrointestinal ulcers/bleeds, in addition to serious impacts on mental health. Strategies to improve asthma control are recommended, including: 1) as-needed combination therapies in mild asthma; 2) risk factor reduction; 3) improving adherence/inhaler technique; 4) earlier initiation of add-on therapies; 5) use of biologics in appropriate patients; 6) development of new therapies to better control the disease; and 7) widespread education of the medical community. We propose that patients and primary care physicians should consider a cumulative SCS dose of 1 g per year as a highly relevant and easy-to-recall threshold.
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http://dx.doi.org/10.1183/16000617.0151-2019DOI Listing
March 2020

The impact of the prostaglandin D receptor 2 and its downstream effects on the pathophysiology of asthma.

Allergy 2020 04 20;75(4):761-768. Epub 2019 Aug 20.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Current research suggests that the prostaglandin D (PGD ) receptor 2 (DP ) is a principal regulator in the pathophysiology of asthma, because it stimulates and amplifies the inflammatory response in this condition. The DP receptor can be activated by both allergic and nonallergic stimuli, leading to several pro-inflammatory events, including eosinophil activation and migration, release of the type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 from T helper 2 (Th2) cells and innate lymphoid cells type 2 (ILCs), and increased airway smooth muscle mass via recruitment of mesenchymal progenitors to the airway smooth muscle bundle. Activation of the DP receptor pathway has potential downstream effects on asthma pathophysiology, including on airway epithelial cells, mucus hypersecretion, and airway remodelling, and consequently might impact asthma symptoms and exacerbations. Given the broad distribution of DP receptors on immune and structural cells involved in asthma, this receptor is being explored as a novel therapeutic target.
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http://dx.doi.org/10.1111/all.14001DOI Listing
April 2020

The prostaglandin D receptor 2 pathway in asthma: a key player in airway inflammation.

Respir Res 2018 Sep 29;19(1):189. Epub 2018 Sep 29.

Novartis Pharmaceuticals Corporation, One Health Plaza East Hanover, East Hanover, NJ, 07936-1080, USA.

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D (PGD) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as T2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD mainly exerts its biological functions via two G-protein-coupled receptors, the PGD receptor 1 (DP) and 2 (DP). The DP receptor is mainly expressed by the key cells involved in type 2 immune responses, including T2 cells, type 2 innate lymphoid cells and eosinophils. The DP receptor pathway is a novel and important therapeutic target for asthma, because increased PGD production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP receptor pathway and the current understanding of its role in asthma.
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http://dx.doi.org/10.1186/s12931-018-0893-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162887PMC
September 2018

Comparison of peak inspiratory flow rate via the Breezhaler®, Ellipta® and HandiHaler® dry powder inhalers in patients with moderate to very severe COPD: a randomized cross-over trial.

BMC Pulm Med 2018 Jun 14;18(1):100. Epub 2018 Jun 14.

Novartis Pharma AG, Basel, Switzerland.

Background: The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated.

Methods: This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices.

Results: In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders.

Conclusions: Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients' COPD severity, age or gender.

Trial Registration: The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.
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http://dx.doi.org/10.1186/s12890-018-0662-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001060PMC
June 2018

Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials.

NPJ Prim Care Respir Med 2018 05 24;28(1):18. Epub 2018 May 24.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV), ≥4 point increase in St George's Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV was approximately 55% predicted, and mean FEV reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p < 0.001). No statistically significant differences were found between the glycopyrronium and tiotropium treatment groups in time to CID or sustained CID. Glycopyrronium is effective in delaying time to clinically important deteriorations, with similar efficacy to tiotropium.
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http://dx.doi.org/10.1038/s41533-018-0084-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967309PMC
May 2018

Gender-specific estimates of COPD prevalence: a systematic review and meta-analysis.

Int J Chron Obstruct Pulmon Dis 2018 10;13:1507-1514. Epub 2018 May 10.

Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.

Rationale: COPD has been perceived as being a disease of older men. However, >7 million women are estimated to live with COPD in the USA alone. Despite a growing body of literature suggesting an increasing burden of COPD in women, the evidence is limited.

Objectives: To assess and synthesize the available evidence among population-based epidemiologic studies and calculate the global prevalence of COPD in men and women.

Materials And Methods: A systematic review and meta-analysis reporting gender-specific prevalence of COPD was undertaken. Gender-specific prevalence estimates were abstracted from relevant studies. Associated patient characteristics as well as custom variables pertaining to the diagnostic method and other important epidemiologic covariates were also collected. A Bayesian random-effects meta-analysis was performed investigating gender-specific prevalence of COPD stratified by age, geography, calendar time, study setting, diagnostic method, and disease severity.

Measurements And Main Results: Among 194 eligible studies, summary prevalence was 9.23% (95% credible interval [CrI]: 8.16%-10.36%) in men and 6.16% (95% CrI: 5.41%-6.95%) in women. Gender prevalences varied widely by the World Health Organization Global Burden of Disease subregions, with the highest female prevalence found in North America (8.07% vs 7.30%) and in participants in urban settings (13.03% vs 8.34%). Meta-regression indicated that age ≥40 and bronchodilator testing contributed most significantly to heterogeneity of prevalence estimates across studies.

Conclusion: We conducted the largest ever systematic review and meta-analysis of global prevalence of COPD and the first large gender-specific review. These results will increase awareness of COPD as a critical woman's health issue.
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http://dx.doi.org/10.2147/COPD.S146390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953270PMC
October 2018

Patient perception of Breezhaler and Ellipta device feedback mechanisms in COPD: The ADVANTAGE Study.

Curr Med Res Opin 2019 02 15;35(2):221-227. Epub 2018 May 15.

d Novartis Product Lifecycle Services, Novartis Pharmaceuticals & Novartis Global Services Center , Dublin , Ireland.

Objectives: The primary objective of the ADVANTAGE study was to compare device-naïve chronic obstructive pulmonary disease (COPD) patients' perception of the Breezhaler and Ellipta devices' feedback mechanisms of dose delivery confirmation. The secondary objective was to assess comfort with the inhalers' mouthpiece in terms of ease to form a tight seal around the mouthpiece. These objectives were achieved by using a novel, patient perception of inhaler questionnaire developed and tested during cognitive interviews of patients by Evidera, London, United Kingdom.

Methods: Ten COPD patients were interviewed to collect feedback on the interpretation, relevance and language of the questionnaire. This questionnaire was then used in ADVANTAGE to compare patients' perception (n = 100) of both devices. Patients completed the questionnaire after a single inhalation of placebo through each inhaler.

Results: Using the final questionnaire, patients reported being more confident of the feedback mechanism of Breezhaler than that of the Ellipta device (mean score 4.3 versus 3.6 respectively, estimated difference [95% CI]: 0.75 [0.51, 0.99], p < .0001). Patients also reported better comfort (ease to form a tight seal with the lips) with the Breezhaler mouthpiece than the Ellipta mouthpiece (mean score 4.3 versus 3.9 respectively, estimated difference [95% CI]: 0.41 [0.21, 0.61], p < .0001). There were no safety concerns associated with either device.

Conclusion: COPD patients showed greater preference for the Breezhaler over the Ellipta inhaler for confidence of dose delivery and comfort of the mouthpiece.

Trial Registration: The trial is registered at ClinicalTrials.gov (ClinicalTrials.gov number NCT02551224).
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http://dx.doi.org/10.1080/03007995.2018.1464437DOI Listing
February 2019

LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis.

Int J Chron Obstruct Pulmon Dis 2017 17;12:907-922. Epub 2017 Mar 17.

Novartis Pharma AG, Basel, Switzerland.

Background: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD.

Methods: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.

Results: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, <0.0001), with patients more likely to achieve clinically important improvements in FEV of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both <0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (<0.0001 and =0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]).

Conclusion: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.
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http://dx.doi.org/10.2147/COPD.S130482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364009PMC
August 2017

Comparative efficacy of long-acting β2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis.

Int J Chron Obstruct Pulmon Dis 2017 19;12:367-381. Epub 2017 Jan 19.

Analysis Group, Inc., Boston, MA, USA.

Purpose: Long-acting β2-agonists (LABAs) have demonstrated efficacy in patients with COPD in clinical trials. The purpose of this study was to assess the comparative efficacy of all available dosages of all LABA monotherapies using a network meta-analysis.

Methods: A systematic literature review identified 33 randomized controlled trials of LABA monotherapies (salmeterol 50 μg twice daily [BID]; formoterol 12 μg BID; indacaterol 75, 150, and 300 μg once daily [OD]; olodaterol 5 and 10 μg OD, and vilanterol 25 μg OD). Clinical efficacy was evaluated at 12 and 24 weeks in terms of trough forced expiratory volume in 1 second (FEV), transition dyspnea index focal score, St George's Respiratory Questionnaire total score, and rate of COPD exacerbations. The relative effectiveness of all LABA monotherapies was estimated by Bayesian network meta-analysis.

Results: At 12 and 24 weeks, indacaterol 300 and 150 μg OD were associated with statistically significant improvement in trough FEV compared to all other LABA monotherapies; vilanterol 25 μg OD was superior to formoterol 12 μg BID. At 12 weeks, indacaterol 75 μg OD was associated with significant improvement in trough FEV compared to formoterol 12 μg BID and olodaterol (5 and 10 μg OD); salmeterol 50 μg BID was superior to formoterol 12 μg BID and olodaterol 5 μg OD. Indacaterol 300 μg OD was also associated with significant improvement in transition dyspnea index focal score compared to all other LABAs at 12 or 24 weeks. Indacaterol 150 μg OD had significantly better results in exacerbation rates than olodaterol 5 μg and olodaterol 10 μg OD.

Conclusion: Indacaterol 300 μg, followed by 150 and 75 μg, were the most effective LABA monotherapies for moderate to severe COPD.
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http://dx.doi.org/10.2147/COPD.S119908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5261557PMC
October 2017

Optimizing identification and management of COPD patients - reviewing the role of the community pharmacist.

Br J Clin Pharmacol 2017 01 2;83(1):192-201. Epub 2016 Nov 2.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

The aim of this paper was to propose key steps for community pharmacist integration into a patient care pathway for chronic obstructive pulmonary disease (COPD) management. A literature search was conducted to identify publications focusing on the role of the community pharmacist in identification and management of COPD. The literature search highlighted evidence supporting an important role for pharmacists at each of the four key steps in the patient care pathway for COPD management. Step 1 (primary prevention): pharmacists are ideally placed to provide information on disease awareness and risk prevention campaigns, and to encourage lifestyle interventions, including smoking cessation. Step 2 (early detection/case finding): pharmacists are often the first point of contact between the patient and the healthcare system and can therefore play an important role in the early identification of patients with COPD. Step 3 (management and ongoing support): pharmacists can assist patients by providing advice and education on dosage, inhaler technique, treatment expectations and the importance of adherence, and by supporting self-management, including recognition and treatment of COPD exacerbations. Step 4 (review and follow-up): pharmacists can play an important role in monitoring adherence and ongoing inhaler technique in patients with COPD. In summary, pharmacists are ideally positioned to play a vital role in all key stages of an integrated COPD patient care pathway from early disease detection to the support of management plans, including advice and counselling regarding medications, inhaler technique and treatment adherence. Areas requiring additional consideration include pharmacist training, increasing awareness of the pharmacist role, administration and reimbursement, and increasing physician-pharmacist collaboration.
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http://dx.doi.org/10.1111/bcp.13087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225927PMC
January 2017

Safety of inhaled glycopyrronium in patients with COPD: a comprehensive analysis of clinical studies and post-marketing data.

Int J Chron Obstruct Pulmon Dis 2015 11;10:1599-612. Epub 2015 Aug 11.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Background: Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents.

Methods: We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 μg, placebo (both delivered via the Breezhaler device), or tiotropium 18 μg (delivered via the HandiHaler device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated.

Results: The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data.

Conclusion: The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points.
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http://dx.doi.org/10.2147/COPD.S81266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541545PMC
April 2016

Indacaterol vs tiotropium in COPD patients classified as GOLD A and B.

Respir Med 2015 Aug 22;109(8):1031-9. Epub 2015 May 22.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address:

Introduction: According to current GOLD strategy, patients with COPD classified as groups A and B may be treated with inhaled bronchodilators, either long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). However, there is little guidance on which class of agent is preferred and a lack of prospective data to differentiate the two.

Methods: In this study, we performed post-hoc analyses of pooled data from two prospective, controlled clinical trials comparing the LABA indacaterol and LAMA tiotropium in 1422 patients with moderate airflow limitation and no history of exacerbations in the previous year. This population fits the definitions of GOLD A and B groups and could be further stratified by symptom severity using Baseline Dyspnea Index (i.e. modeling GOLD A or B) and inhaled corticosteroid (ICS) use at baseline. Outcomes measured after 12 weeks of treatment were lung function (forced expiratory volume in 1 s; FEV1), health status (St George's Respiratory Questionnaire; SGRQ), symptoms (Transition Dyspnea Index; TDI) and rescue medication use.

Results: In 'GOLD A' patients not receiving ICS, differences favored indacaterol versus tiotropium (trough FEV1 0.05 L; rescue medication use -0.41 puffs/day; TDI total score 0.94 points; SGRQ total score -3.13 units, all p < 0.01). In 'GOLD B, no ICS' patients, compared with tiotropium, indacaterol treatment increased trough FEV1 (0.055 L, p < 0.05) and permitted a larger reduction in rescue medication use (-0.81 puffs/day, p = 0.004). In all patients, and in patients not using ICS, differences favored indacaterol for all variables.

Conclusions: Our findings suggest that patients in GOLD groups A and B may experience greater benefits with indacaterol than with tiotropium.
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http://dx.doi.org/10.1016/j.rmed.2015.05.012DOI Listing
August 2015

INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD.

Eur Respir J 2014 Dec 30;44(6):1548-56. Epub 2014 Oct 30.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol (INSTEAD) study investigated the effect of switching patients at low risk of chronic obstructive pulmonary disease (COPD) exacerbations from salmeterol/fluticasone (SFC; inhaled corticosteroid (ICS) regimen) to indacaterol monotherapy (non-ICS regimen). This 26-week, double-blind, double-dummy, parallel-group, phase IV study, randomised 581 patients with moderate COPD to indacaterol 150 μg once daily or SFC 50/500 μg twice daily. Patients had been receiving SFC 50/500 μg for ≥3 months, with no COPD exacerbations for more than a year before the study (patients for whom ICS is not recommended). The primary objective was to demonstrate non-inferiority of indacaterol to SFC, measured by trough forced expiratory volume in 1 second (FEV₁) after 12 weeks (non-inferiority margin of 0.06 L). The primary objective was met, with a mean treatment difference of 9 mL (95% CI -45-26 mL). There were no significant differences between treatments in terms of breathlessness (transition dyspnoea index) or health status (Saint George's Respiratory Questionnaire) at weeks 12 or 26, or rescue medication use or COPD exacerbation rates over 26 weeks. Safety profiles of both treatments were as expected. This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 μg with no efficacy loss.
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http://dx.doi.org/10.1183/09031936.00126814DOI Listing
December 2014

Addressing unmet needs in the treatment of COPD.

Eur Respir Rev 2014 Sep;23(133):333-44

Novartis Pharma AG, Basel, Switzerland. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

The burden of chronic obstructive pulmonary disease (COPD) is considerable, both socially and economically. Central to COPD management is the use of long-acting bronchodilators, which provide patients with optimal bronchodilation and improvements in symptoms. The once-daily, long-acting β2-agonist indacaterol, the long-acting muscarinic antagonist glycopyrronium, and the indacaterol/glycopyrronium fixed-dose combination QVA149 have all been shown to significantly improve lung function and patient-reported outcomes. The ability to take medication appropriately is important. Easy to use, low resistance devices may help patients take their medication and achieve good drug deposition. There is a need to optimise COPD management by treating the right patients with the right therapy at the right time during the course of their disease. Herein, we present a view on the current COPD management landscape and current unmet needs, and look to the future of COPD treatment and how patient care can be optimised.
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http://dx.doi.org/10.1183/09059180.00004014DOI Listing
September 2014

A simple rule to identify patients with chronic obstructive pulmonary disease who may need treatment reevaluation.

Respir Med 2014 Sep 14;108(9):1310-20. Epub 2014 Jul 14.

Mylan Specialty, L.P., 110 Allen Road, 4th Floor, Basking Ridge, NJ 07920, USA. Electronic address:

Background: A simple rule based on short-acting inhaled β2-agonist (SABA) use could identify patients with chronic obstructive pulmonary disease (COPD) at increased risk of exacerbations and signal the need for maintenance therapy change, similar to asthma "Rules of Two(®)".

Methods: Associations between SABA use, COPD exacerbations, and health care costs over 1 year were examined retrospectively using de-identified patient data from the Optum Research Database (ORD; N = 56,581) and the Impact National Benchmark Database (IMPACT™; N = 9423). Nebulized and metered-dose inhaler (MDI) SABA doses were normalized to 2.5 mg and 90 mcg albuterol equivalents, respectively.

Results: The GOLD initiative establishes ≥2 exacerbations/year as indicative of increased risk in COPD. We identified a correlation (p < 0.0001) between 1.5 SABA doses/day and this frequency of exacerbations. In ORD, patients using ≥1.5 versus <1.5 SABA doses/day experienced significantly more exacerbations: 1.92 (95% confidence interval [CI], 1.89-1.96) versus 1.36 (95% CI, 1.34-1.38) per patient year (PPY). Above-threshold use was associated with higher average annual COPD-related costs (2010 $US): $21,868 (standard deviation [SD], $53,910) versus $11,686 (SD, $32,707) for nebulized SABA only, $9216 (SD, $30,710) versus $7334 (SD, $24,853) for MDI SABA only, and $15,806 (SD, $35,260) versus $11,233 (SD, $27,006) for both nebulized and MDI SABA. IMPACT™ validated these findings.

Conclusion: Patients with COPD using ≥1.5 SABA doses/day were at increased risk of exacerbations. Our results suggest a "Rule of 3-2": SABA use ≥3 times in 2 days should be considered a clinical marker for needing treatment reevaluation.
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http://dx.doi.org/10.1016/j.rmed.2014.07.002DOI Listing
September 2014

Rising Costs of COPD and the Potential for Maintenance Therapy to Slow the Trend.

Am Health Drug Benefits 2014 Apr;7(2):98-106

Medical Director, Medical Affairs, Mylan Specialty LP, Basking Ridge, NJ, at the time of writing.

Background: Chronic obstructive pulmonary disease (COPD) affects an estimated 14% of adults in the United States between the ages of 40 and 79 years. This progressive disease is characterized by persistent airflow limitation. The management of patients with COPD is focused on reducing risk factors, relieving symptoms, and preventing exacerbations.

Objective: To examine the peer-reviewed literature on the impact of maintenance therapy on the direct treatment costs of patients with COPD in the United States.

Methods: PubMed was searched for articles written in English that were published between 2000 and 2013, using the search terms "COPD," "economics," "exacerbation," "maintenance," and related terms. Articles reporting the results of longitudinal studies of the costs associated with the management of patients with COPD, the costs associated with hospitalizations for acute exacerbations of COPD, and randomized clinical trials evaluating the effects of maintenance therapy on the incidence of COPD exacerbations were included in this review.

Results: The search identified a total of 277 articles, and 11 of these articles were deemed appropriate for inclusion in this review. The direct healthcare costs for patients with COPD increased by 38% between 1987 and 2007, and continued to increase by approximately 5% annually between 2006 and 2009. The costs associated with hospital admissions for patients with COPD accounted for the largest absolute increase ($2289 per admission in constant 2007 US dollars). Recent estimates suggest that the aggregate costs associated with the treatment of acute exacerbations are between $3.2 billion and $3.8 billion, and that annual healthcare costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations. The results of 2 large clinical trials of maintenance therapy, including a long-acting cholinergic antagonist or a long-acting beta-2 agonist, showed a 16% to 17% reduction in the incidence of exacerbations compared with placebo. Nevertheless, maintenance therapy remains underutilized, with only 30% to 35% of patients with COPD in private and public health insurance plans receiving prescriptions for maintenance therapy.

Conclusions: The treatment of acute exacerbations of COPD remains the major driver of increasing healthcare costs associated with this condition. The appropriate use of maintenance therapy has been shown to reduce the incidence of exacerbations and has the potential to reduce overall costs associated with the management of patients with COPD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049119PMC
April 2014

Considerations for managing chronic obstructive pulmonary disease in the elderly.

Clin Interv Aging 2014 13;9:23-30. Epub 2013 Dec 13.

Medical Affairs, Mylan Specialty L.P., Basking Ridge, NJ, USA.

Chronic obstructive pulmonary disease (COPD) is common in older people, with an estimated prevalence of 10% in the US population aged ≥75 years. Inhaled medications are the cornerstone of treatment for COPD and are typically administered by one of three types of devices, ie, pressurized metered dose inhalers, dry powder inhalers, and nebulizers. However, age-related pulmonary changes may negatively influence the delivery of inhaled medications to the small airways. In addition, physical and cognitive impairment, which are common in elderly patients with COPD, pose special challenges to the use of handheld inhalers in the elderly. Health care providers must take time to train patients to use handheld inhalers and must also check that patients are using them correctly on a regular basis. Nebulizers should be considered for patients unable to use handheld inhalers properly. What follows is a review of issues associated with COPD and its treatment in the elderly patient.
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http://dx.doi.org/10.2147/CIA.S52999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864989PMC
September 2014