Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data.

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

Pharmacokinetic Modeling of Intrathecally Administered Recombinant Human Arylsulfatase A (TAK-611) in Children With Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by deficient arylsulfatase A (ASA) activity, which leads to neuronal sulfatide accumulation and motor and cognitive deterioration. Intrathecal delivery of a recombinant human ASA (TAK-611, formerly SHP611) is under development as a potential therapy for MLD. We used serum and cerebrospinal fluid (CSF) TAK-611 concentrations measured during the phase I/II trial of intrathecal TAK-611 to develop a pharmacokinetic (PK) model describing drug disposition. CSF data were well characterized by a two-compartment model in the central nervous system (CNS); a single central compartment described the serum data. Estimated parameters suggested rapid distribution of TAK-611 from CSF into the putative brain tissue compartment, with persistence in the brain between doses (median distributive and terminal half-lives in the CNS: 1.02 and 477 hours, respectively). This model provides a valuable basis for understanding the PK distribution of TAK-611 and for PK/pharmacodynamic analyses of functional outcomes.

Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor.

Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor. The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials. For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV1 were not correlated for individual patients. However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV1 changes was observed (p<0.0001). Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals.