Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD.

BACKGROUND: While current therapies reduce symptoms in chronic obstructive pulmonary disease (COPD) patients, substantial unmet need remains and novel treatments are highly desired. Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase specifically expressed in leucocytes and involved in their recruitment and activation. This study evaluated the safety, pharmacokinetics (PK) and dose-response characteristics of inhaled GSK2269557, a PI3Kδ inhibitor, in moderate-to-severe COPD patients with stable disease. METHODS: In this randomised, double-blind, placebo controlled, parallel group study, patients received once daily inhaled treatment with GSK2269557 1000 µg or placebo for 14 days (Part A, primary aim safety, N = 28 patients). In part B of the study (primary aim pharmacodynamic dose-response, N = 36 patients), GSK2269557 100, 200, 500, 700, 1000, 2000 µg or placebo was given for 14 days. In both Part A and B, GSK2269557 was added to the usual maintenance therapy. Safety, PK assessments and induced sputum collection for cytokine analysis were conducted at baseline and after 7 and 14 days of treatment. Adverse events (AEs) were monitored throughout. RESULTS: In Part A, mean age was 61.7 years (SD 6.7), 29% were females, and mean FEV1% predicted was 59.7% (SD 11.4)2. In Part B, mean age was 63.3 years (SD 6.3), 44% were females, and mean FEV1% predicted was 56.5% (SD 11.5)2. GSK2269557 was well tolerated in both parts of the study; the most commonly reported AEs were cough and headache, with cough being reported with a greater incidence in the GSK2269557 groups vs. placebo (Part A: 19% vs. 14% and Part B: range of 0-80% for different doses vs. 0% on placebo). No drug-related serious AEs or clinically significant changes in any other safety parameters were reported. GSK2269557 was rapidly absorbed into plasma following all doses with a maximum peak at approximately 2 h. Following repeat administration, accumulation in plasma was approximately 2-3 fold from Day 1 to Day 7. At Day 14, relative to placebo, sputum interleukin (IL)-8 and IL-6 levels were reduced on average by 32% and 29% respectively after inhalation of GSK2269557 1000 µg in Part A. In Part B, although inhibition of both IL-8 and IL-6 levels was observed, the levels were variable and there was insufficient evidence to support a monotonic dose-response. CONCLUSIONS: In this study, inhaled GSK2269557 had an acceptable safety profile for progression into larger studies in COPD patients. Moreover, inhalation of GSK2269557 resulted in suppression of sputum IL-8 and IL-6 levels, consistent with the known anti-inflammatory activity of a PI3Kδ inhibitor. Inhibition of inflammatory cytokines in the airway compartment may contribute to the potential therapeutic benefit of a PI3Kδ inhibitor in chronically inflamed COPD patients.

A randomized phase I comparative pharmacokinetic study comparing SB5 with reference adalimumab in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: SB5 is a biosimilar to the reference adalimumab (ADL) currently in development. The primary study objective was to demonstrate pharmacokinetic (PK) equivalence of SB5 to European Union-sourced adalimumab (EU-ADL), and United States-sourced adalimumab (US-ADL) in healthy subjects. Safety, tolerability and immunogenicity were also assessed as secondary objectives. METHODS: In this phase I, single-blind trial, 189 healthy volunteers were randomized to a single 40 mg dose of SB5, EU-ADL or US-ADL and PK was evaluated for 71 days afterwards. Serum adalimumab concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) test. PK parameters were calculated based on actual sampling times relative to dosing and non-compartmental analysis methods, and equivalence was determined using predefined margins of 0.8-1.25. RESULTS AND DISCUSSION: Baseline characteristics and demographics were comparable between the three groups. Mean values of area under the concentration-time curve from time zero to infinity (AUCinf ), maximum serum concentration (Cmax ) and AUC from time zero to the last quantifiable concentration (AUClast ) were similar between groups, and 90% confidence interval for these parameters were within the predefined equivalence margins for all pairwise comparisons. No discontinuations due to treatment-emergent adverse events (TEAEs) or deaths were reported. Number and kind of TEAEs were comparable between the three groups and considered mild to moderate. The incidence of subjects with antidrug antibodies (ADA) and the overall incidence of neutralizing antibody (NAb) were comparable across the three groups. WHAT IS NEW AND CONCLUSION: The PK of SB5 was equivalent to that of EU-ADL and US-ADL. SB5 was well tolerated with similar safety and immunogenicity profile to EU-ADL and US-ADL.

Abediterol (LAS100977), a novel long-acting ß2-agonist: efficacy, safety and tolerability in persistent asthma.

BACKGROUND: Abediterol (LAS100977) is a novel, long-acting ß2-agonist, in development for the once-daily treatment of asthma in combination with mometasone. Here we report the results of a Phase IIa trial of single doses of abediterol added to ongoing maintenance therapy (inhaled corticosteroids) in patients with persistent mild-to-moderate asthma. METHODS: This was a randomised, double-blind, placebo- and active-comparator-controlled, five-way crossover study. Male patients (18-70 years) with a clinical diagnosis of persistent asthma received abediterol (5, 10 and 25 µg), salmeterol and placebo, on top of ongoing maintenance therapy. Lung function was determined using spirometry and whole body plethysmography. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) after a single dose. RESULTS: All three abediterol doses induced statistically significant increases in trough FEV1 vs placebo and salmeterol. Improvements in other lung function parameters were also statistically significantly greater with all abediterol doses vs both placebo (p < 0.0001) and salmeterol (p < 0.05) than the first assessment at 5 min post-dose. These improvements were sustained to 36 h post-dose. The profile of treatment-emergent adverse events judged as related to abediterol was consistent with that seen after adrenergic stimulation and occurred exclusively in patients who received abediterol 10 µg or 25 µg. CONCLUSIONS: This first-in-patient study revealed the potent, rapid and long-acting bronchodilatory effect of abediterol in patients with persistent mild-to-moderate asthma together with an overall good safety and tolerability profile. Further studies are now underway to establish the optimal efficacy-safety-tolerability profile for this compound.

Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma.

UNLABELLED: Leukotriene B4 (LTB4) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model. In this double-blind, 3-period crossover study, 22 patients with mild, atopic asthma were randomized to one of three treatments per period: 100 mg/day JNJ-40929837 for 6 days followed by 50 mg/day on day 7; 10 mg/day montelukast for 6 days; and matched placebo. The BAC was performed on day 6 of each treatment period. Primary outcome was BAC-induced late asthmatic response (LAR) measured by maximal percent reduction in forced expiratory volume (FEV1) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV1, EAR and LAR evaluated by area under the FEV1/time curve (AUC0-2, AUC3-10, respectively), change in baseline FEV1 after 5-day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB4 levels and sputum basal LTB4 levels. No significant differences were observed in the primary or secondary FEV1 endpoints with JNJ-40929837 versus placebo. Compared with placebo (n = 17, LS mean = 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV1 with JNJ-40929837 (n = 16, LS mean = 28.6, P = 0.63) but montelukast (n = 17, LS mean = 22.6, P = 0.01) significantly attenuated the LAR. JNJ-40929837 substantially inhibited LTB4 production in whole blood, decreased sputum LTB4 levels and was well-tolerated. The number of adverse events leading to study withdrawal was the same in JNJ-40929837 and placebo groups. In conclusion, JNJ-40929837 demonstrated target engagement in blood and sputum. No significant impact in response to allergen inhalation was observed with JNJ-40929837 versus placebo. REGISTRATION: This study is registered at ClinicalTrials.gov: NCT01241422.

[Results of autologous blood donation in orthopedic hip and knee joint replacement]. / Ergebnisse der Eigenblutspende bei orthopädischem Hüft- und Kniegelenkersatz.

OBJECTIVE: This study was undertaken to investigate the efficiency of autologous blood donation (ABD) with regard to saving of homologous transfusion, to determine the reasons for exclusion from donations and the rate of incidents during the procedure, and to investigate the quality of autologous fresh frozen plasma (AFFP). METHODS: During an observation period of 4.5 years, all patients scheduled for elective orthopaedic hip and knee replacement were included. A period of 4 years was evaluated retrospectively, and the last half year was evaluated prospectively. RESULTS: Among a collective of 710 patients, 55 (8%) non-donors and 655 (92%) donors with a total number of 1592 ABD were found. Mean age of non-donors with hip surgery was significantly higher than that of donors (72 vs. 64 years), the same was observed in patients with knee surgery (71 vs. 68 years). In the hip surgery group, 11 of 338 patients were non-donors (3%), compared with 44 of 372 patients with knee surgery (12%). In the prospective part of the study, 7% of 121 patients were non-donors. Reasons for exclusion from donation were 5 times of medical and 4 times of organisational nature. In donors for hip surgery, a mean of 3.0 units was collected, compared with 1.9 units in donors for knee surgery. On the day before operation, mean haemoglobin concentrations were similar in donors and non-donors. During ABD, 11 incidents were observed, representing 0.69% of all ABD, 83.5% of 327 donors with hip surgery left the hospital without any transfusion of homologous blood, 16.5 of donors with hip surgery received one or more homologous transfusions, compared with 100% of non-donors (p < 0.001). In knee surgery, 93.3% of donors and 63.6% of non-donors required no homologous blood, whereas 6.7% of donors and 36.4% of non-donors received one or more homologous transfusions (p < 0.001). 529 of 2850 autologous blood units (19%) were not transfused, and 19 of these units were rejected due to technical or organisational problems. In 97 patients with 240 ABD and 240 AFFP, prothrombine time, fibrinogen concentration and AT III in defrosted AFFP exceeded 70% of the values determined before ABD. CONCLUSION: ABD is a safe procedure in almost all, even elderly, patients scheduled for elective orthopaedic hip or knee replacement in both types of operations, ABD reduces the risk of homologous transfusion significantly. A number of 3-4 units is necessary for total hip replacement, whereas 2 units are sufficient for partial or total knee replacement. Haemostatic quality of AFFP meets the requirements of fresh frozen homologous plasma.

[Compatibility and efficacy of Meditonsin]. / Verträglichkeit und Wirksamkeit von Meditonsin.

Heavy metals, including mercury, have recently been in discussion in connection with ecology and therapy. As Meditonsin represents a 0,004% solution of mercury cyanide the following were investigated: absorption, excretion, effect on the kidneys and the chemical behaviour of mercury cyanide and other mercury salts as well as the antimicrobial effectivity in in vitro tests. With the dose recommended for adults neither an increase of mercury ions nor an increased excretion of these could be detected in the blood or the urine respectively. Even in minimal inhibitory concentrations Meditonsin is characterised in the in vitro tests by an excellent antimicrobial effect.