CPTR was a cross-sector initiative that was launched in 2010, in partnership with the Bill & Melinda Gates Foundation and TB Alliance, to expedite the development of safer and shorter duration anti-tuberculosis (TB) drug regimens. Over its nearly 10-year history, CPTR achieved a significant number of accomplishments by maintaining its focus on critical gaps in tools and knowledge that previously impeded the acceleration of drug development strategies in this complex arena. Through collaboration with multiple organizations, including pharmaceutical and diagnostic industries, academic institutions, non-government organizations and global government bodies, CPTR delivered actionable solutions to bridge these critical knowledge gaps and provided the foundation for an efficient and effective TB drug development process.
CPTR spearheaded several important advances to innovate TB regimen and rapid DST development.
- CPTR’s combination development model established the gold standard for TB drug development programs and clinical trials. Traditional drug development models substituted or added one drug at a time to an existing regimen, meaning the path to a completely novel regimen would take decades. Since the launch of CPTR, several trials testing multiple novel drugs together have been conducted, unlocking the potential to introduce more broadly effective TB cures much more quickly. These advances have been made possible in part by the development of clinical pharmacology models to support such innovative research.
- CPTR created the Relational Sequencing TB Data Platform (ReSeqTB) to integrate and standardize global TB patient data dispersed among multiple private and public databases, providing a tool to help identify correlations between Mycobacterium tuberculosis (M.tb) mutations and clinically relevant resistance. This aided the development of new rapid drug susceptibility tests, facilitated international research and collaboration, and ultimately, directly enabled interpretation of sequencing data for personalized patient care. CPTR partnered with the Translational Genomics Research Institute’s (TGen’s) Pathogen Genomics Division to sequence isolates with critical patient-outcome data to help bridge knowledge gaps in identifying TB drug-resistance patterns across the globe.
- Collaborations between the Critical Path Institute and the Special Programme for Research and Training in Tropical Diseases (hosted at the World Health Organization), enabled by CPTR, led to the implementation of the Platform for Aggregation of Clinical TB Studies (TB-PACTS) which integrated data from numerous Phase III TB drug trials. Still in use today, this platform is now funded by the ERA4TB program under the IMI’s AMR Accelerator Initiative and provides a robust and comprehensive set of data which drug developers use for analysis and help evolve concepts such as biomarkers, predictability of earlier stage clinical data, and clinical trial design.
- In partnership with Critical Path Institute and CDISC, CPTR finalized version 2.0 of the CDISC TB Therapeutic Area User guide, which includes all necessary terminology required to support Rapid Drug Susceptibility testing and pediatric information.
- CPTR’s work led to the regulatory endorsement of the in vitro hollow fiber system of tuberculosis (HFS-TB) – a preclinical model to evaluate TB drugs individually or in combination – by leading regulatory authorities, including the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA).
- CPTR, in partnership with SIMCYP, developed a Physiologically-Based Pharmacokinetic (PBPK) TB-specific set of models and compound files to inform the design of first-in-human studies that simultaneously evaluate the exposure and efficacy of novel anti-TB combination regimens of up to 4 drugs. This collection of models was comprised of 1) a comprehensive PBPK model of the TB-infected lung, which includes relevant aspects of drug distribution into granulomatous lesions; 2) a compound library for standard-of-care and recently approved drugs (with metabolites); and 3) a virtual South-African population, which captures relevant genetic variants and TB-related physiologic changes that affect drug distribution in this population. With these components integrated into SIMCYP version 16 (an already recognized modeling and simulation platform), development teams and regulators evaluating novel TB regimens have a robust tool to optimize clinical trial design for first-in-human studies.
- CPTR, in partnership with SIMCYP scientists, developed a model-based cardiovascular risk-stratification algorithm to optimize predictions of clinically-observed electrophysiological effects of existing and novel TB drugs. This platform integrated preclinical ion channel activity data with drug exposure information to predict the potential risk of drug-induced Torsade de pointes (TdP). With a user-friendly interface, all members of preclinical and clinical development teams can use this tool to create a common, quantitative-based set of estimates to inform the drug and regimen development process for TB.
- CPTR and the WHO partnered to sponsor a model-based meta-analysis of the Phase III quinolone-containing trials in order to further critical learnings from the REMox,TB Rifaquin and OFLOTUB trials through the aggregated data set provided through TB-PACTS. This analysis, termed as TB Reanalysis of Fluoroquinolone Executed Clinical Trials (TB-ReFLECT), was led by University of California San Francisco, and helped the research community understand the drivers for study outcomes as well as influence future TB trial design.