Hollow fiber model system of non tuberculosis mycobacterium

Hollow Fiber System Model of Non-Tuberculosis Mycobacterium

Pre-clinical hollow fiber system model of non-tuberculosis mycobacterium (HFS-NTM), PK/PD and translation for NTM combination regimens to patients program

Pre-clinical hollow fiber system model of non-tuberculosis mycobacterium (HFS-NTM),PK/PD and translation for NTM combination regimens to patients program

Hollow Fiber Systems Models

HFS: Biofilm, intracellular and extracellular

Mycobacterium avium complex

Mycobacterium abscessus complex

Mycobacterium kansasii

Mycobacterium fortuitum

Mycobacterium chelonae

Monotherapy PK/PD

Microbial kill, resistance suppression, toxicity, whole genome sequencing (resistant mutants)

Combination Therapy Factorial Design

Microbial kill, resistance suppression, y-slopes, time-to-extinction

Combination Therapy Regimen Ranking

Microbial kill, resistance suppression, y-slopes, time-to-extinction

Combination Therapy Morphism Maps and Translation To Patients

Patient predicted y-slopes, time-to-extinction, time-to-cure, biomarkers for relapse

Hollow Fiber System Models of NTMs (HFS-NTM) are several models, each for the following organisms:

Mycobacterium avium complex (MAC)

Mycobacterium abscessus complex (MABC)

Mycobacterium kansasii

Mycobacterium fortuitum

Mycobacterium chelonae

For each of these bacteria, we have the following hollow fiber models:

Extracellular log-phase growth / plaktonic

Intracellular in human macrophage cell lines

Biofilm

All of our HFS-NTM models havestandardized SOPs and QCprocedures, run in replicates and wecan perform > 100 hollow fibers inparallel.

The HFS-NTM models have been used for:

Regulatory submission packages for PK/PD, dose findings, combination regimen design and phase II/III studies for several drugs in development.

Identifying compounds that are not efficacious against specific NTMs

HFS-NTM models provide platform where combination regimens of different chemical entities with different concentration-time profiles in lung lesions can be combined in factorial design to rank regimens.

VIEW HFS-NTM CASE STUDIES

Novel ceftazidime / avibactim, rifabutin, tedizolid, and moxifloxacin (CARTM) regimen

New regimen for pulmonary Mycobacterium avium disease

Comparison of a Novel Regimen of Rifapentine, Tedizolid and Minocycline with SOC for Pulmonary Mycobacterium kansasii

Comparison between new regimen and standard of care for pulmonary Mycobacterium kansasii

Mapping Patient Responses toHFS-NTM Microbial Responses

Kill Slopes and Time-to-Cure Derived in HFS-NTM is Translated to Patients

Bypasses problem of one-to-one translation observed with other preclinical models (e.g. 0% relapse in preclinical model has been equated to 0% relapse in patients given the same duration of therapy) – failed paradigm.

Ranking of regimens is based on combined kill slopes and time-to-extinction which is predicted to identify ultra-short therapy duration.

We have developed re-infection HFS-NTM models that combine kill slopes and time-to-cure output with design for second prophylaxis

PREDICTING PATIENT RESPONSES CASE STUDIES

Morphism mapping for clinical pulmonary Mycobacterium kansasii

Nouveau short-course therapy and morphism mapping for clinical pulmonary Mycobacterium kansasii

Praedicare has developed clinical endpoints and biomarkers of response for patients treated for NTMs for use in clinical trials and patient care

Our mathematical modeling and patented approaches that utilize patient sputum bacillary changes to identify kill slopes thresholds in the first 8 weeks that predict time-to-cure months to years later are biomarkers that can be used for clinical trial endpoints

Our models and biomarker can be used to rank combination regimens, design clinical trials (sample size, minimal sputum sampling schedule and narrowing 95% confidence intervals for the desired patient responses.

We have developed SOPs and QCs for the models and their implementation.