Triple Therapy with Mometasone/Indacaterol/Glycopyrronium or Doubling the ICS/LABA Dose in GINA Step 4: IRIDIUM Analyses.

INTRODUCTION: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. METHODS: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25-75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. RESULTS: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. CONCLUSION: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02571777.

Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV1, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV1; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Living with sarcoidosis: Virtual roundtable dialogue with patients and healthcare professionals.

BACKGROUND: Sarcoidosis is a multisystem disease, characterised by the infiltration of various organs by non-necrotising granulomas. The disease's heterogeneity complicates the study of patients' experiences. OBJECTIVE: To gather insight into life experiences, unmet needs and views on hypothetically emerging treatment options among patients living with sarcoidosis. METHODS: Multinational, virtual, interactive, moderated discussion of specific questions between people with sarcoidosis, with experienced clinicians participating. RESULTS: Nine patients with sarcoidosis from Australia, Denmark, Germany, Italy, Japan and the US, and three clinicians took part. All patients had pulmonary sarcoidosis, self-assessed as mild by five patients. The path to diagnosis was convoluted, with up to four physicians and a large number of tests involved. There was agreement that the process would be improved by earlier referral to specialists. The patients made a clear distinction between 'living with a condition' (adapting to the disease) and 'being ill'. The concept of remission was viewed sceptically as disease might develop in multiple organs. Panellists had a pragmatic attitude to therapies: side effects during a treatment course were accepted if overall symptoms improved. When considering hypothetical new therapies, improved quality of life (QoL) was the most important need; improved tolerability had lower priority. New therapies should be targeted on reducing disease progression and improving symptoms and QoL rather than corticosteroid withdrawal. CONCLUSIONS: The interactive exchange provided insights into the need for earlier specialist referrals, distrust of the concept of remission in sarcoidosis, and the need for therapies targeted on reducing disease progression and improving symptoms and QoL.

Towards high-throughput screening (HTS) of polyhydroxyalkanoate (PHA) production via Fourier transform infrared (FTIR) spectroscopy of Halomonas sp. R5-57 and Pseudomonas sp. MR4-99.

High-throughput screening (HTS) methods for characterization of microbial production of polyhydroxyalkanoates (PHA) are currently under investigated, despite the advent of such systems in related fields. In this study, phenotypic microarray by Biolog PM1 screening of Halomonas sp. R5-57 and Pseudomonas sp. MR4-99 identified 49 and 54 carbon substrates to be metabolized by these bacteria, respectively. Growth on 15 (Halomonas sp. R5-57) and 14 (Pseudomonas sp. MR4-99) carbon substrates was subsequently characterized in 96-well plates using medium with low nitrogen concentration. Bacterial cells were then harvested and analyzed for putative PHA production using two different Fourier transform infrared spectroscopy (FTIR) systems. The FTIR spectra obtained from both strains contained carbonyl-ester peaks indicative of PHA production. Strain specific differences in the carbonyl-ester peak wavenumber indicated that the PHA side chain configuration differed between the two strains. Confirmation of short chain length PHA (scl-PHA) accumulation in Halomonas sp. R5-57 and medium chain length PHA (mcl-PHA) in Pseudomonas sp. MR4-99 was done using Gas Chromatography-Flame Ionization Detector (GC-FID) analysis after upscaling to 50 mL cultures supplemented with glycerol and gluconate. The strain specific PHA side chain configurations were also found in FTIR spectra of the 50 mL cultures. This supports the hypothesis that PHA was also produced in the cells cultivated in 96-well plates, and that the HTS approach is suitable for analysis of PHA production in bacteria. However, the carbonyl-ester peaks detected by FTIR are only indicative of PHA production in the small-scale cultures, and appropriate calibration and prediction models based on combining FTIR and GC-FID data needs to be developed and optimized by performing more extensive screenings and multivariate analyses.

Efficacy of once-daily, single-inhaler, fixed-dose combination of mometasone/indacaterol/glycopyrronium in patients with asthma with or without persistent airflow limitation: Post hoc analysis from the IRIDIUM study.

BACKGROUND: A novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ2-agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL. METHODS: Patients with post-bronchodilator FEV1 ≤80% of predicted and FEV1/FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV1, PEF, and FEF25%-75%) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 µg), high-dose MF/IND (320/150 µg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 µg). RESULTS: Of the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV1, FEF25%-75%, PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively. CONCLUSIONS: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

Mometasone/Indacaterol/Glycopyrronium (MF/IND/GLY) and MF/IND at Different MF Strengths versus Fluticasone Propionate/Salmeterol Xinafoate (FLU/SAL) and FLU/SAL+ Tiotropium in Patients with Asthma.

Background: Once-daily, single-inhaler mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY, an ICS/LABA/LAMA) and MF/IND (an ICS/LABA) via Breezhaler® have been approved for the maintenance treatment of patients with asthma inadequately controlled with medium-or high-dose ICS or medium-or high-dose ICS/LABA treatment. Objective: Once-daily (o.d.) formulations of MF/IND/GLY and MF/IND at different MF dose strengths have been compared with twice-daily (b.i.d.) fluticasone propionate/salmeterol xinafoate (FLU/SAL), and b.i.d. FLU/SAL+ o.d. tiotropium (TIO) in the PALLADIUM, IRIDIUM and ARGON studies. Methods: The similarity in study design and consistent outcomes in these studies prompted the pooling of data in this review to better characterise these novel once-daily controller formulations. Results: Pooled data from PALLADIUM and IRIDIUM studies showed comparable or greater efficacy with o.d. MF/IND formulations versus b.i.d. FLU/SAL. The o.d. MF/IND/GLY was superior to b.i.d. FLU/SAL in the IRIDIUM study, and similar to, if not more efficacious than b.i.d. FLU/SAL + o.d. TIO in the ARGON study. Conclusion: These formulations therefore provide novel once-daily treatment options for patients across asthma severity and flexibility for clinicians to step-up or step-down the treatment using the same device and formulations.

Long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate high-dose, and indacaterol acetate/mometasone furoate high-dose, in Japanese patients with inadequately controlled asthma: Results from two open-label, 52-week studies.

INTRODUCTION: The 52-week long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) high-dose (150/50/160 µg) and IND/MF high-dose (150/320 µg) was evaluated in two studies enrolling Japanese patients with inadequately controlled asthma. METHODS: Study 1 (IND/GLY/MF) and Study 2 (IND/MF) were 52-week, phase III, open-label, single-arm, multicenter studies conducted in Japanese adult patients with inadequately controlled asthma. The primary endpoint was incidence and severity of treatment-emergent adverse events (AEs) over 52-weeks. RESULTS: In Study 1, 94 patients received IND/GLY/MF high-dose and 84 (89.4%) patients completed the 52-week study treatment; in Study 2, 51 patients received IND/MF high-dose and 48 (94.1%) patients completed the 52-week study treatment. In Study 1, 68.1% and 6.4% of 94 patients reported ≥1 AE and ≥1 serious AE (SAE) respectively. In Study 2, 78.4% of 51 patients reported ≥1 AE; no patients reported SAEs. The most commonly reported AEs were asthma (exacerbation; 30.9% and 54.9%) and nasopharyngitis (18.1% and 29.4%) in Study 1 and Study 2, respectively. Severe AEs including asthma (exacerbation) were reported in 13.8% and 13.7% of patients in Study 1 and Study 2, respectively. In Study 1, 10 patients (10.6%) reported treatment-related AEs, of which dysphonia (9 patients [9.6%]) was the most commonly reported; no treatment-related AEs were reported in Study 2. In Study 1, one death (not study drug-related) was reported after study discontinuation (92 days after last dose of study medication). CONCLUSIONS: Once-daily IND/GLY/MF and IND/MF high-dose were well-tolerated in Japanese patients with inadequately controlled asthma. No unexpected safety findings were observed.Supplemental data for this article is available online at.

Revealing the Phenotypic and Genomic Background for PHA Production from Rapeseed-Biodiesel Crude Glycerol Using Photobacterium ganghwense C2.2.

Polyhydroxyalkanoates (PHA) are promising biodegradable and biocompatible bioplastics, and extensive knowledge of the employed bacterial strain's metabolic capabilities is necessary in choosing economically feasible production conditions. This study aimed to create an in-depth view of the utilization of Photobacterium ganghwense C2.2 for PHA production by linking a wide array of characterization methods: metabolic pathway annotation from the strain's complete genome, high-throughput phenotypic tests, and biomass analyses through plate-based assays and flask and bioreactor cultivations. We confirmed, in PHA production conditions, urea catabolization, fatty acid degradation and synthesis, and high pH variation and osmotic stress tolerance. With urea as a nitrogen source, pure and rapeseed-biodiesel crude glycerol were analyzed comparatively as carbon sources for fermentation at 20 °C. Flask cultivations yielded 2.2 g/L and 2 g/L PHA at 120 h, respectively, with molecular weights of 428,629 g/mol and 81,515 g/mol. Bioreactor batch cultivation doubled biomass accumulation (10 g/L and 13.2 g/L) in 48 h, with a PHA productivity of 0.133 g/(L·h) and 0.05 g/(L·h). Thus, phenotypic and genomic analyses determined the successful use of Photobacterium ganghwense C2.2 for PHA production using urea and crude glycerol and 20 g/L NaCl, without pH adjustment, providing the basis for a viable fermentation process.

Polyaniline-Derived Nitrogen-Containing Carbon Nanostructures with Different Morphologies as Anode Modifier in Microbial Fuel Cells.

Anode modification with carbon nanomaterials is an important strategy for the improvement of microbial fuel cell (MFC) performance. The presence of nitrogen in the carbon network, introduced as active nitrogen functional groups, is considered beneficial for anode modification. In this aim, nitrogen-containing carbon nanostructures (NCNs) with different morphologies were obtained via carbonization of polyaniline and were further investigated as anode modifiers in MFCs. The present study investigates the influence of NCN morphology on the changes in the anodic microbial community and MFC performance. Results show that the nanofibrillar morphology of NCNs is beneficial for the improvement of MFC performance, with a maximum power density of 40.4 mW/m2, 1.25 times higher than the anode modified with carbonized polyaniline with granular morphology and 2.15 times higher than MFC using the carbon cloth-anode. The nanofibrillar morphology, due to the well-defined individual nanofibers separated by microgaps and micropores and a better organization of the carbon network, leads to a larger specific surface area and higher conductivity, which can allow more efficient substrate transport and better bacterial colonization with greater relative abundances of Geobacter and Thermoanaerobacter, justifying the improvement of MFC performance.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

One time a day mometasone/indacaterol fixed-dose combination versus two times a day fluticasone/salmeterol in patients with inadequately controlled asthma: pooled analysis from PALLADIUM and IRIDIUM studies.

BACKGROUND: Despite currently available standard-of-care inhaled corticosteroid (ICS)/long-acting ß2-agonist therapies, a substantial proportion of patients with asthma remain inadequately controlled. This pooled analysis evaluated efficacy and safety of mometasone furoate/indacaterol acetate (MF/IND) versus fluticasone propionate/salmeterol xinafoate (FLU/SAL) in patients with inadequately controlled asthma. METHODS: This analysis included patients from PALLADIUM (NCT02554786) and IRIDIUM (NCT02571777) studies who received high-dose MF/IND (320/150 µg) or medium-dose MF/IND (160/150 µg) one time a day or high-dose FLU/SAL (500/50 µg) two times a day for 52 weeks. Reduction in asthma exacerbations, improvement in lung function, asthma control, and safety were evaluated for 52 weeks. RESULTS: In total, 3154 patients (high-dose MF/IND, n=1054; medium-dose MF/IND, n=1044; high-dose FLU/SAL, n=1056) were included. High-dose MF/IND showed 26%, 22% and 19% reductions in rate of severe, moderate or severe, and all (mild, moderate and severe) exacerbations versus high-dose FLU/SAL, respectively, over 52 weeks (all, p<0.05). High-dose MF/IND improved trough FEV1 versus high-dose FLU/SAL at weeks 26 (Δ, 43 mL, p=0.001) and 52 (Δ, 51 mL, p<0.001). Reductions in asthma exacerbation rate and improvement in trough FEV1 with medium-dose MF/IND were comparable with high-dose FLU/SAL over 52 weeks. All treatments improved Asthma Control Questionnaire-7 score from baseline to 52 weeks with no difference between treatments. Safety was comparable between high-dose MF/IND and high-dose FLU/SAL. CONCLUSIONS: One time a day, single-inhaler, high-dose MF/IND reduced asthma exacerbations and improved lung function versus two times a day, high-dose FLU/SAL in patients with inadequately controlled asthma. Similarly, improved outcomes were seen with one time a day, medium-dose MF/IND and two times a day, high-dose FLU/SAL, but at a lower ICS dose.

Complete genome sequence of Photobacterium ganghwense C2.2: A new polyhydroxyalkanoate production candidate.

Polyhydroxyalkanoates (PHAs) are biodegradable bioplastics that can be manufactured sustainably and represent a promising green alternative to petrochemical-based plastics. Here, we describe the complete genome of a new marine PHA-producing bacterium-Photobacterium ganghwense (strain C2.2), which we have isolated from the Black Sea seashore. This new isolate is psychrotolerant and accumulates PHA when glycerol is provided as the main carbon source. Transmission electron microscopy, specific staining with Nile Red visualized via epifluorescence microscopy and gas chromatography analysis confirmed the accumulation of PHA. This is the only PHA-producing Photobacterium for which we now have a complete genome sequence, allowing us to investigate the pathways for PHA production and other secondary metabolite synthesis pathways. The de novo assembly genome, obtained using open-source tools, comprises two chromosomes (3.5, 2 Mbp) and a megaplasmid (202 kbp). We identify the entire PHA synthesis gene cluster that encodes a class I PHA synthase, a phasin, a 3-ketothiolase, and an acetoacetyl-CoA reductase. No conventional PHA depolymerase was identified in strain C2.2, but a putative lipase with extracellular amorphous PHA depolymerase activity was annotated, suggesting that C2.2 is unable to degrade intracellular PHA. A complete pathway for the conversion of glycerol to acetyl-CoA was annotated, in accordance with its ability to convert glycerol to PHA. Several secondary metabolite biosynthetic gene clusters and a low number of genes involved in antibiotic resistance and virulence were also identified, indicating the strain's suitability for biotechnological applications.

Pharmacokinetics of mometasone furoate delivered via two dry powder inhalers.

BACKGROUND: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients. OBJECTIVES: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 µg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 µg (2 inhalations of 200 µg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks. METHODS: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 µg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 µg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 µg (low-dose ICS) or 320 µg (high-dose ICS) via Breezhaler®, or 200 µg (low-dose ICS) or 800 µg (2 inhalations of 400 µg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose. RESULTS: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUClast of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and Cmax of MF increased in a dose-proportional manner over the range of 50-400 µg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUClast and Cmax) for MF 80 and 320 µg via Breezhaler® was comparable with MF 200 and 800 µg via Twisthaler®, respectively, on Day 28. CONCLUSION: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 µg (low), 160 µg (medium), and 320 µg (high) delivered via Breezhaler® as MF doses comparable to the 200 µg, 400 µg and 800 µg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.

Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study.

BACKGROUND: Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting ß2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. METHODS: This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 µg, 150 µg) or medium-dose MF-IND (160 µg, 150 µg) once daily via Breezhaler; high-dose MF (800 µg [400 µg twice daily]) or medium-dose MF (400 µg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed. FINDINGS: Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. INTERPRETATION: Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control. FUNDING: Novartis Pharmaceuticals.

Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study.

BACKGROUND: Patients with asthma who are inadequately controlled on inhaled corticosteroid-long-acting ß2-adrenoceptor agonist (ICS-LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF-IND-GLY) versus ICS-LABA in patients with inadequately controlled asthma. METHODS: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS-LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF-IND-GLY (80 µg, 150 µg, 50 µg; 160 µg, 150 µg, 50 µg) or MF-IND (160 µg, 150 µg; 320 µg, 150 µg) once daily via Breezhaler, or high-dose fluticasone-salmeterol (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV1 with MF-IND-GLY versus MF-IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed. FINDINGS: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF-IND-GLY, n=620; high-dose MF-IND-GLY, n=619; medium-dose MF-IND, n=617; high-dose MF-IND, n=618; high-dose FLU-SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF-IND-GLY (treatment difference [Δ] 76 mL [95% CI 41-111]; p<0·001) and high-dose MF-IND-GLY (Δ 65 mL [31-99]; p<0·001) showed superior improvement in trough FEV1 versus corresponding doses of MF-IND at week 26. Improvements in trough FEV1 were greater for both medium-dose MF-IND-GLY (99 mL [64-133]; p<0·001) and high-dose MF-IND-GLY (119 mL [85-154]; p<0·001) than for high-dose FLU-SAL at week 26. Overall, the incidence of adverse events was balanced across the treatment groups. Seven deaths were reported (one with medium-dose MF-IND-GLY, two with high-dose MF-IND-GLY, and four with high-dose MF-IND) during the study; none of these deaths was considered by the investigators to be caused by study drugs or other study-related factors. INTERPRETATION: Once-daily, single-inhaler MF-IND-GLY improved lung function versus ICS-LABA combinations (MF-IND and FLU-SAL) in patients with inadequately controlled asthma. The safety profile was similar across treatment groups. MF-IND-GLY therefore constitutes a good treatment option in these patients. FUNDING: Novartis Pharmaceuticals.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 µg) and high (320 µg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 µg) and high (800 µg) doses respectively, delivered via Twisthaler®. METHODS: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 µg) and high (320 µg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 µg) and high (800 µg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 µg and 320 µg delivered via Breezhaler®, and MF 200 µg and 800 µg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. RESULTS: The LS mean difference in trough FEV1 after four weeks of treatment between MF low dose 80 µg (Breezhaler®) and MF low dose 200 µg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 µg (Breezhaler®) and MF high dose 800 µg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. CONCLUSION: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 µg) and high (320 µg) doses delivered with Breezhaler® with MF at low (200 µg) and high (800 µg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses.

Indacaterol acetate/mometasone furoate provides sustained improvements in lung function compared with salmeterol xinafoate/fluticasone propionate in patients with moderate-to-very-severe COPD: results from a Phase II randomized, double-blind 12-week study.

BACKGROUND AND PURPOSE: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use. MATERIALS AND METHODS: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313). RESULTS: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL (P<0.001). In addition, IND/MF (QMF149) treatment significantly improved COPD exacerbation-related parameters during the 12-week period. Other significant improvements with IND/MF (QMF 149) vs Sal/Flu were noted for dyspnea at week 12 and other COPD symptoms and COPD rescue medication use over the 12 weeks. The safety and tolerability profiles of both the treatments were similar. CONCLUSION: IND/MF (QMF149) (150/160 µg once daily) offered superior lung function and symptom efficacy and a favorable safety profile compared with Sal/Flu (50/500 µg twice daily) in patients with moderate-to-very severe COPD.

Complete genome sequence of Tsukamurella sp. MH1: A wide-chain length alkane-degrading actinomycete.

Tsukamurella sp. strain MH1, capable to use a wide range of n-alkanes as the only carbon source, was isolated from petroleum-contaminated soil (Pitești, Romania) and its complete genome was sequenced. The 4,922,396 bp genome contains only one circular chromosome with a G + C content of 71.12%, much higher than the type strains of this genus (68.4%). Based on the 16S rRNA genes sequence similarity, strain MH1 was taxonomically identified as Tsukamurella carboxydivorans. Genome analyses revealed that strain MH1 is harboring only one gene encoding for the alkB-like hydroxylase, arranged in a complete alkane monooxygenase operon. This is the first complete genome of the specie T. carboxydivorans, which will provide insights into the potential of Tsukamurella sp. MH1 and related strains for bioremediation of petroleum hydrocarbons-contaminated sites and into the environmental role of these bacteria.

Newly isolated alkalophilic Advenella species bioaugmented in activated sludge for high p-cresol removal.

In this work, an alkalophilic bacterium (LVX-4) capable of using p-cresol as sole source of carbon and energy was screened and isolated from soil polluted by used oil. Phylogenetic (16S rRNA) and phenotypic characterization using Biolog GN microplates and API 20NE strips indicated that LVX-4 strain is a new Advenella species. It showed both the capability to degrade of p-cresol at high concentrations (750 mg/L) and to use p-cresol for growth in a pH from 7 to 10, although the optimum pH was 9. Moreover bioaugmentation of activated sludge with this strain lead to the complete removal of p-cresol in less than 100 h. This is the first study that shows the potential of Advenella sp. to be bioaugmented in activated sludge system for p-cresol biodegradation.

[The concept of bacterial species]. / Conceptul de specie bacteriana.

Prokaryotes are the most abundant living organisms and also most diverse from genetically and metabolically point of view, being responsible for the majority of biogeochemical processes playing the most important role in life cycle on the planet. Considering this, there is a general agreement among taxonomists, that there is a very small number of bacterial species recognized and described today, mostly because of controversial issues concerning bacterial species concept. One of the most accepted approaches, even today, is the polyphasic taxonomy because it is based on diverse information, obtained from classic taxonomy but also from molecular level. The development of new molecular techniques, especially sequencing rRNA genes conducted to an improved concept, that we intended to evaluate in this review, and even more, to reconstruction of group specific phylogenetic tree.