Shuying Yang

Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF

Rationale Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose. Methods We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung. Results We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF. Conclusions Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-of-mechanism trial of this agent is currently underway. Trial registration number NCT01725139, pre-clinical.

A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with ≤2% and >2% blood eosinophils.

BACKGROUND A six month study of the p38 MAPK inhibitor, losmapimod, suggested a trend in reducing COPD exacerbations with the 15 mg twice daily dose. OBJECTIVE AND METHODS Using data from this study which evaluated the efficacy of twice daily losmapimod, 2.5 mg, 7.5 mg, and 15 mg, versus placebo in patients with moderate-to-severe COPD, we analysed the effect of losmapimod in reducing the rate of moderate/severe exacerbations in patient subgroups with ≤2% and >2% blood eosinophils at baseline. Lung function, fibrinogen and hsCRP were also evaluated. RESULTS In the ≤2% eosinophil subgroup, there was an exposure-related reduction in the rate of moderate/severe exacerbations with losmapimod relative to placebo (losmapimod 15 mg: 55% reduction; losmapimod 7.5 mg: 29%; losmapimod 2.5 mg: 10%); with the 15 mg dose reaching statistical significance (15 mg/placebo mean rate ratio [95% CI]: 0.45 [0.22; 0.90]). There was also an improvement in lung function with 15 mg losmapimod over Weeks 1-12. No improvement in the rate of moderate/severe exacerbations or post-bronchodilator FEV1 was observed for subjects treated with Losmapimod compared to placebo in the patient subgroup with blood eosinophils >2% at baseline. Transient reductions in fibrinogen and hsCRP were observed with losmapimod 7.5 mg and 15 mg in both eosinophil subgroups. CONCLUSIONS These findings indicate eosinophil-related heterogeneity within COPD and suggest that losmapimod could be a potential therapy to reduce exacerbations in COPD patients with eosinophil levels ≤2%. This needs to be explored further in a prospectively designed study with pre-specified criteria for blood eosinophil subgroups in COPD patients.

Generating Virtual Patients by Multivariate and Discrete Re-Sampling Techniques

PurposeClinical Trial Simulations (CTS) are a valuable tool for decision-making during drug development. However, to obtain realistic simulation scenarios, the patients included in the CTS must be representative of the target population. This is particularly important when covariate effects exist that may affect the outcome of a trial. The objective of our investigation was to evaluate and compare CTS results using re-sampling from a population pool and multivariate distributions to simulate patient covariates.MethodsCOPD was selected as paradigm disease for the purposes of our analysis, FEV1 was used as response measure and the effects of a hypothetical intervention were evaluated in different populations in order to assess the predictive performance of the two methods.ResultsOur results show that the multivariate distribution method produces realistic covariate correlations, comparable to the real population. Moreover, it allows simulation of patient characteristics beyond the limits of inclusion and exclusion criteria in historical protocols.ConclusionBoth methods, discrete resampling and multivariate distribution generate realistic pools of virtual patients. However the use of a multivariate distribution enable more flexible simulation scenarios since it is not necessarily bound to the existing covariate combinations in the available clinical data sets.

Does short-term placebo response predict the long-term observation? Meta-analysis on forced expiratory volume in 1 second from asthma trials

The objectives of this work were: (1) to characterize the placebo FEV1 response in asthma; (2) to identify the potential factors with strong influence on FEV1; (3) to determine the predictability of the early (week 2) placebo FEV1 response to the longer term (week 12) FEV1 response. Placebo FEV1 data of about 800 subjects from 11 randomized 12‐week clinical trials in mild‐to‐moderate asthmatics were collected. Stepwise logistic regression methods using SAS were used to model the week 12 trough FEV1 change from baseline greater than a clinically relevant value (150 mL) and to select the predictive covariates. The study effect was assessed using hierarchical logistic regression models implemented in WinBUGS. The results indicated that the early (week 2) placebo response was significantly predictive of the FEV1 response at week 12. Age, baseline predicted FEV1, and season showed statistical significance in the model. The final model showed satisfactory predictability with the area under the receiver operating characteristic curve (ROC) of 80%. The late (week 12) FEV1 response with placebo was positively related to the early (week 2) FEV1 change. The use of the predictive modeling approach proposed in this article presents a valuable method to increase the efficiency of clinical trial design in asthma population.