BACKGROUND Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibro... more BACKGROUND Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor. METHODS A Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker. RESULTS Absolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies. CONCLUSIONS AZD5634 showed favorable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential.
Background:Oral corticosteroids such as prednisolone are potent anti-inflammatory drugs but their... more Background:Oral corticosteroids such as prednisolone are potent anti-inflammatory drugs but their use is limited by side effects caused by unwanted actions on the glucocorticoid receptor (GR), such as increased insulin resistance, and off-target actions on the mineralocorticoid receptor (MR) that disrupt electrolyte balance and increase water retention. AZD9567 is an oral, selective, non-steroidal glucocorticoid receptor modulator being developed to treat inflammatory diseases. Pre-clinical and phase 1 clinical data indicate that AZD9567 is the first GR modulator with an improved efficacy–dysglycaemic side effect profile versus prednisolone.Objectives:To compare the efficacy, safety and tolerability of AZD9567 with prednisolone in patients with active rheumatoid arthritis (RA), at doses with predicted equivalent anti-inflammatory activity.Methods:In this phase 2a, randomised, double-blind, parallel-group, multicentre study in RA patients with DAS28-CRP ≥ 3.2 despite stable treatment...
AimsThis 3‐part, randomised, phase 1 first‐in‐human study (NCT03436316) investigated the safety, ... more AimsThis 3‐part, randomised, phase 1 first‐in‐human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3‐kinase (PI3K) γδ inhibitor developed as a novel inhaled anti‐inflammatory treatment for respiratory disease.MethodsHealthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1–7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once‐daily doses on Days 4–12.ResultsIn total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A ...
Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose stu... more Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose study after inhalation of AZD8154 or placebo in healthy participants at baseline (DLCOBaseline) and follow-up (DLCOFollow-up) 6 days after dosing. Initially, DLCOFollow-up timepoint was 2 h earlier than the DLCOBaseline timepoint and clinically significant decreases in DLCOFollow-up (absolute change up to 19% from baseline and DLCO%predicted values less than 70) were observed then. The observed reduction in DLCOFollow-up was confirmed as a false positive finding after alignment of DLCO timings. As a consequence, when DLCO is used in clinical studies, measurements should be strictly standardized in relation to time of the day.
BackgroundThe Respiratory Symptoms Questionnaire (RSQ) is a novel, four-item patient-reported dia... more BackgroundThe Respiratory Symptoms Questionnaire (RSQ) is a novel, four-item patient-reported diagnosis-agnostic tool designed to assess the frequency of respiratory symptoms and their impact on activity, without specifying a particular diagnosis. Our objective was to examine its validity in patients with asthma and/or chronic obstructive pulmonary disease (COPD).MethodsBaseline data were randomly sampled from patients who completed the RSQ in the NOVELTY study (ClinicalTrials.gov: NCT02760329). The total sample (n=1530) comprised three randomly selected samples (n=510 each) from each physician-assigned diagnostic group (asthma, asthma+COPD and COPD). The internal consistency and structural validity of the RSQ were evaluated using exploratory and confirmatory factor analyses; psychometric performance was observed using Classical Test Theory and Item Response Theory analyses.ResultsFor the total sample, the mean±sd RSQ score was 5.6±4.3 (range 0–16). Irrespective of diagnosis, the in...
Identification of pathological changes in early and mild obstructive lung disease has revealed th... more Identification of pathological changes in early and mild obstructive lung disease has revealed the importance of the small airways and their contribution to symptoms. Indeed, significant small airways dysfunction has been found before any overt airway obstruction is detectable by conventional spirometry techniques. However, most therapies for the treatment of obstructive lung disease target the physiological changes and associated symptoms that result from chronic lung disease, rather than directly targeting the specific underlying causes of airflow disruption or the drivers of disease progression. In addition, while spirometry is the current standard for diagnosis and monitoring of response to therapy, the most widely used measure, forced expiratory volume in 1 second, does not align with the pathological changes in early or mild disease and may not align with symptoms or exacerbation frequency in individual patient. Newer functional and imaging techniques allow more effective assessment of small airways dysfunction; however, significant gaps in our understanding remain. Improving our knowledge of the role of small airways dysfunction in early disease in the airways, along with the identification of novel endpoints to measure sub-clinical changes in this region, i.e. those not captured as symptoms or identified through standard FEV1, may lead to the development of novel therapies that directly combat early airways disease processes with a view to slowing disease progression and reversing damage. This expert opinion paper will discuss small airways disease in the context of asthma and COPD and highlight gaps in current knowledge that impede earlier identification of obstructive lung disease and the development and standardization of novel small airways-specific endpoints for use in clinical trials.
AZD8154 is an inhaled PI3Kgd inhibitor developed for treatment of asthma. This first in human stu... more AZD8154 is an inhaled PI3Kgd inhibitor developed for treatment of asthma. This first in human study evaluate the safety, tolerability and PK of AZD8154 in healthy volunteers after inhalation of single ascending doses (Part 1) and characterized the systemic PK after an intravenous (IV) dose (Part 2). This was a randomized, single-blind, placebo-controlled and sequential group design study. In Part 1, subjects received AZD8154 target delivered doses of 0.1, 0.3, 0.9, 2.7, 5.4 and 7.7 mg via nebulisation respectively in six cohorts (6:2 active:placebo). In Part 2, 0.15 mg AZD8154 was administered IV to six subjects, after a wash-out period they were given 2.7 mg inhaled target delivered dose. Overall, single inhaled doses of AZD8154 up to target delivered dose 7.7 mg were well tolerated and no safety concerns were raised. A population PK model, using non-linear mixed effect modelling, was developed to describe the PK of AZD8154. The final PK model successfully described the trends and variability in the data. The PK of AZD8154 was characterized by an early rapid absorption phase with tmax occurring at 0.17 to 0.75 h, followed by a flat period of about 12 - 24 h, before declining in a typically mono-phasic manner. The systemic exposure of AZD8154 increased in a dose proportional manner. The terminal mean half-life was 18 to 29 h and the pulmonary bioavailability was on average 94%. In summary, AZD8154 displayed dose proportional PK characteristics in the dose range studied (0.1 to 7.7 mg) with a half-life potentially suitable for once-daily dosing and the data supports further evaluation in a multiple ascending dose study.
Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and sh... more Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma–COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329).NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY aims to recruit real-world patients, unlike clinical studies with restrictive inclusion/exclusion criteria.Data collected at yearly intervals include clinical assessments, spirometry, biospecimens, patient-reported out...
Rationale: In mild asthma, as-needed budesonide/formoterol (BUD/FORM) reduces long-term severe ex... more Rationale: In mild asthma, as-needed budesonide/formoterol (BUD/FORM) reduces long-term severe exacerbation risk vs terbutaline as-needed, with similar reduction as maintenance BUD + terbutaline as-needed. In a post-hoc analysis of SYGMA 1 (NCT02149199) we examined the short-term risk of a severe exacerbation after a single day at various levels of reliever use, comparing BUD/FORM as-needed vs terbutaline as-needed ± maintenance BUD. Methods: 3836 patients with mild asthma were randomised to placebo twice-daily (bid) + terbutaline 0.5mg as-needed, placebo bid + BUD/FORM 200/6µg as-needed or maintenance BUD 200µg bid + terbutaline as-needed. The proportion of patients with >2, >4, >6 or >8 reliever inhalations on any day, with an exacerbation during the next 21 days were compared. Results: The proportion of patients with >4, >6 or >8 as-needed inhalation use days was lower with BUD/FORM as-needed vs terbutaline as-needed ± maintenance budesonide, with reduced risk of severe exacerbation during the next 21 days vs terbutaline as-needed (Fig). The safety of BUD/FORM as-needed was consistent across all inhalation groups, with no new safety findings. Conclusions: In mild asthma, anti-inflammatory reliever therapy with BUD/FORM as-needed reduces higher (>4 inhalations) reliever use days and reduces exacerbations within the next 21 days vs terbutaline as-needed.
BACKGROUND Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibro... more BACKGROUND Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor. METHODS A Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker. RESULTS Absolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies. CONCLUSIONS AZD5634 showed favorable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential.
Background:Oral corticosteroids such as prednisolone are potent anti-inflammatory drugs but their... more Background:Oral corticosteroids such as prednisolone are potent anti-inflammatory drugs but their use is limited by side effects caused by unwanted actions on the glucocorticoid receptor (GR), such as increased insulin resistance, and off-target actions on the mineralocorticoid receptor (MR) that disrupt electrolyte balance and increase water retention. AZD9567 is an oral, selective, non-steroidal glucocorticoid receptor modulator being developed to treat inflammatory diseases. Pre-clinical and phase 1 clinical data indicate that AZD9567 is the first GR modulator with an improved efficacy–dysglycaemic side effect profile versus prednisolone.Objectives:To compare the efficacy, safety and tolerability of AZD9567 with prednisolone in patients with active rheumatoid arthritis (RA), at doses with predicted equivalent anti-inflammatory activity.Methods:In this phase 2a, randomised, double-blind, parallel-group, multicentre study in RA patients with DAS28-CRP ≥ 3.2 despite stable treatment...
AimsThis 3‐part, randomised, phase 1 first‐in‐human study (NCT03436316) investigated the safety, ... more AimsThis 3‐part, randomised, phase 1 first‐in‐human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3‐kinase (PI3K) γδ inhibitor developed as a novel inhaled anti‐inflammatory treatment for respiratory disease.MethodsHealthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1–7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once‐daily doses on Days 4–12.ResultsIn total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A ...
Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose stu... more Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose study after inhalation of AZD8154 or placebo in healthy participants at baseline (DLCOBaseline) and follow-up (DLCOFollow-up) 6 days after dosing. Initially, DLCOFollow-up timepoint was 2 h earlier than the DLCOBaseline timepoint and clinically significant decreases in DLCOFollow-up (absolute change up to 19% from baseline and DLCO%predicted values less than 70) were observed then. The observed reduction in DLCOFollow-up was confirmed as a false positive finding after alignment of DLCO timings. As a consequence, when DLCO is used in clinical studies, measurements should be strictly standardized in relation to time of the day.
BackgroundThe Respiratory Symptoms Questionnaire (RSQ) is a novel, four-item patient-reported dia... more BackgroundThe Respiratory Symptoms Questionnaire (RSQ) is a novel, four-item patient-reported diagnosis-agnostic tool designed to assess the frequency of respiratory symptoms and their impact on activity, without specifying a particular diagnosis. Our objective was to examine its validity in patients with asthma and/or chronic obstructive pulmonary disease (COPD).MethodsBaseline data were randomly sampled from patients who completed the RSQ in the NOVELTY study (ClinicalTrials.gov: NCT02760329). The total sample (n=1530) comprised three randomly selected samples (n=510 each) from each physician-assigned diagnostic group (asthma, asthma+COPD and COPD). The internal consistency and structural validity of the RSQ were evaluated using exploratory and confirmatory factor analyses; psychometric performance was observed using Classical Test Theory and Item Response Theory analyses.ResultsFor the total sample, the mean±sd RSQ score was 5.6±4.3 (range 0–16). Irrespective of diagnosis, the in...
Identification of pathological changes in early and mild obstructive lung disease has revealed th... more Identification of pathological changes in early and mild obstructive lung disease has revealed the importance of the small airways and their contribution to symptoms. Indeed, significant small airways dysfunction has been found before any overt airway obstruction is detectable by conventional spirometry techniques. However, most therapies for the treatment of obstructive lung disease target the physiological changes and associated symptoms that result from chronic lung disease, rather than directly targeting the specific underlying causes of airflow disruption or the drivers of disease progression. In addition, while spirometry is the current standard for diagnosis and monitoring of response to therapy, the most widely used measure, forced expiratory volume in 1 second, does not align with the pathological changes in early or mild disease and may not align with symptoms or exacerbation frequency in individual patient. Newer functional and imaging techniques allow more effective assessment of small airways dysfunction; however, significant gaps in our understanding remain. Improving our knowledge of the role of small airways dysfunction in early disease in the airways, along with the identification of novel endpoints to measure sub-clinical changes in this region, i.e. those not captured as symptoms or identified through standard FEV1, may lead to the development of novel therapies that directly combat early airways disease processes with a view to slowing disease progression and reversing damage. This expert opinion paper will discuss small airways disease in the context of asthma and COPD and highlight gaps in current knowledge that impede earlier identification of obstructive lung disease and the development and standardization of novel small airways-specific endpoints for use in clinical trials.
AZD8154 is an inhaled PI3Kgd inhibitor developed for treatment of asthma. This first in human stu... more AZD8154 is an inhaled PI3Kgd inhibitor developed for treatment of asthma. This first in human study evaluate the safety, tolerability and PK of AZD8154 in healthy volunteers after inhalation of single ascending doses (Part 1) and characterized the systemic PK after an intravenous (IV) dose (Part 2). This was a randomized, single-blind, placebo-controlled and sequential group design study. In Part 1, subjects received AZD8154 target delivered doses of 0.1, 0.3, 0.9, 2.7, 5.4 and 7.7 mg via nebulisation respectively in six cohorts (6:2 active:placebo). In Part 2, 0.15 mg AZD8154 was administered IV to six subjects, after a wash-out period they were given 2.7 mg inhaled target delivered dose. Overall, single inhaled doses of AZD8154 up to target delivered dose 7.7 mg were well tolerated and no safety concerns were raised. A population PK model, using non-linear mixed effect modelling, was developed to describe the PK of AZD8154. The final PK model successfully described the trends and variability in the data. The PK of AZD8154 was characterized by an early rapid absorption phase with tmax occurring at 0.17 to 0.75 h, followed by a flat period of about 12 - 24 h, before declining in a typically mono-phasic manner. The systemic exposure of AZD8154 increased in a dose proportional manner. The terminal mean half-life was 18 to 29 h and the pulmonary bioavailability was on average 94%. In summary, AZD8154 displayed dose proportional PK characteristics in the dose range studied (0.1 to 7.7 mg) with a half-life potentially suitable for once-daily dosing and the data supports further evaluation in a multiple ascending dose study.
Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and sh... more Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma–COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329).NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY aims to recruit real-world patients, unlike clinical studies with restrictive inclusion/exclusion criteria.Data collected at yearly intervals include clinical assessments, spirometry, biospecimens, patient-reported out...
Rationale: In mild asthma, as-needed budesonide/formoterol (BUD/FORM) reduces long-term severe ex... more Rationale: In mild asthma, as-needed budesonide/formoterol (BUD/FORM) reduces long-term severe exacerbation risk vs terbutaline as-needed, with similar reduction as maintenance BUD + terbutaline as-needed. In a post-hoc analysis of SYGMA 1 (NCT02149199) we examined the short-term risk of a severe exacerbation after a single day at various levels of reliever use, comparing BUD/FORM as-needed vs terbutaline as-needed ± maintenance BUD. Methods: 3836 patients with mild asthma were randomised to placebo twice-daily (bid) + terbutaline 0.5mg as-needed, placebo bid + BUD/FORM 200/6µg as-needed or maintenance BUD 200µg bid + terbutaline as-needed. The proportion of patients with >2, >4, >6 or >8 reliever inhalations on any day, with an exacerbation during the next 21 days were compared. Results: The proportion of patients with >4, >6 or >8 as-needed inhalation use days was lower with BUD/FORM as-needed vs terbutaline as-needed ± maintenance budesonide, with reduced risk of severe exacerbation during the next 21 days vs terbutaline as-needed (Fig). The safety of BUD/FORM as-needed was consistent across all inhalation groups, with no new safety findings. Conclusions: In mild asthma, anti-inflammatory reliever therapy with BUD/FORM as-needed reduces higher (>4 inhalations) reliever use days and reduces exacerbations within the next 21 days vs terbutaline as-needed.
Uploads
Papers by christina keen