Application of structured statistical analyses to identify a biomarker predictive of enhanced tralokinumab efficacy in phase III clinical trials for severe, uncontrolled asthma.

BACKGROUND: Tralokinumab is an anti-interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2. METHODS: The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data. RESULTS: FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting tralokinumab efficacy. DISCUSSION: A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population. TRIAL REGISTRATION: STRATOS 1 and 2 are registered on ClinicalTrials.gov ( NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo.

The reflex response to distension of the small intestine in vivo is complex and not well understood. The aim of this study was to characterize the neural mechanisms contributing to the complex time course of the intestinal secretory response to distension. Transmucosal potential difference (PD) was used as a marker for mucosal chloride secretion, which reflects the activity of the secretomotor neurons. Graded distensions (5, 10, and 20 mmHg) of distal rat duodenum with saline for 5 min induced a biphasic PD response with an initial peak (rapid response) followed by a plateau (sustained response). The rapid response was significantly reduced by the neural blockers tetrodotoxin and lidocaine (given serosally) and by intravenous (iv) administration of the ganglionic blocker hexamethonium and the NK(1) receptor antagonist SR-140333. Serosal TTX and iv SR-140333 significantly reduced the sustained response, which was also reduced by the NK(3) receptor antagonist talnetant and by the vasoactive intestinal polypeptide (VPAC) receptor antagonist [4Cl-d-Phe(6), Leu(17)]-VIP. Serosal lidocaine and iv hexamethonium had no significant effect on this component. Inhibition of nitric oxide synthase had no effect on any of the components of the PD response to distension. The PD response to distension thus seems to consist of two components, a rapidly activating and adapting component operating via nicotinic transmission and NK(1) receptors, and a slow component operating via VIP-ergic transmission and involving both NK(1) and NK(3) receptors.