Savic Lab, UCSFImplications for ongoing research and the design of future clinical trials
Rada Savic, PhD Dept. Bioengineering and Therapeutic Sciences Schools of Medicine and Pharmacy, UC San Francisco
Goal: Identify the right regimen for the right patient at the right time
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Adverse
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Introduction
3
Introduction
TB Drug Development Research Gaps/Opportunities
4
Introduction
Clinical Study Design
Safety Data Repositories
Drug Regimen Optimization
Data Science
• Relapse
Future TB regimens: is the fight lost already?
Sputum culture conversion rate
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Adapted from Gillespie et. al NEJM October 23rd 2014
Boeree et. al CROI February 25th 2015 Hazard ratios differ between 8 and 12 weeks
Courtesy of Michael Hoelscher, 2015
Are we using the right endpoints and at the right time ? 1. Study Design and Endpoints
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http://tools.insight-rx.com:3838/power/
Proposals for New Study Designs
If keep using current approach, large uncertainty in outcomes needs to be addressed – increase in sample size
Phase 2C – longitudinal liquid cultures + up to 1 year follow up
Rolling Phase 2A-towards 3
Studies in subpopulations
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1. Study Design and Endpoints
Optimization Combinatorics
Drugs Doses Frequencies Duration
2. Optimizing Multidrug TB Regimen
Dose Ranging Rifampin: Time to stable culture conversion on MGIT liquid and solid media preliminary results
Courtesy of Michael Hoelscher and Martin Boeree, 2015
35mg/kg of rifampicin resulted in an increased likelihood of, and shorter time to culture conversion in liquid
media, not in solid
Dose Ranging Rifapentine: TBTC 29/29X – TBTC 31
2/23/2016 Future TB regimens: is the fight lost already?
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Rifapentine
Optimal Dose of Pyrazinamide
C C
Caseum diffusion
Accumulation in cellular layers
Single dose Steady state
2. Optimizing Multidrug TB Regimen
Future TB regimens: is the fight lost already? 13
Dynamic Evolution of Lesions in TB Dr. JoAnne Flynn
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• Lesions in infection
are dynamical structures
Towards Patient Stratification
• 4 month regimen worked well in 80% patients
• Hard/Easy to treat and all in between
Stratification based on
HIV))
• Demographics (Nuttrion, Age, Weight, etc)
• More refined biomarker (Scans + Immunological)
Goal: Identify the right regimen for the right patient at the
right time
Algorithms
MGIT Outcome predictors: X-ray extent/class, cough, race & drug exposure
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Networking Analytics Compute
Storage & Content Delivery
Application Services
Elastic
Lambda EC2 Container
Service
Elastic
Beanstalk EC2 VPC Direct Connect Route 53 EMR Data Pipeline Kinesis
Machine
Learning
Formation CloudTrail Config OpsWorks
Future TB regimens: is the fight lost already? 17
Main messages
Consider Learning Type of Study Design (e.g. Phase 2C)
Major gaps in understanding PKPD relationship for even old TB drugs
• PKPD, Modeling and Clinical Trial Simulations are critical
Large variability in drug response between patients
Dynamic Complexity of lung granulomas and ability of drug to reach site of action
Images, novel biomarkers
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5. Conclusions
Future TB regimens: is the fight lost already?
Is the Flight Lost Already? Thank You Future TB regimens: is the fight lost already? 19
Today’s talk
GLOBAL TB PROGRAMME
Regimens of equal duration
Phillips, PLoS ONE 2013
Logs odds ratio of a poor outcome plotted against log odds ratio of a positive culture.
Fitted line is weighted by the precision of the estimates, and this precision is
represented by the diameter of the circles around each point. The dotted line represents the 95% confidence interval on the slope.
Analysis of culture results as surrogate endpoints across all trials.
PZA Exposure – Hepatotoxicity (Analysis based on n=4490 , studies from 1954 – 2010) AAC, November 2010, Volume 56, Number 11
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4. Data Science
Today’s talk
GLOBAL TB PROGRAMME
Regimens of equal duration
Phillips, PLoS ONE 2013
Logs odds ratio of a poor outcome plotted against log odds ratio of a positive culture.
Fitted line is weighted by the precision of the estimates, and this precision is
represented by the diameter of the circles around each point. The dotted line represents the 95% confidence interval on the slope.
Analysis of culture results as surrogate endpoints across all trials.
PZA Exposure – Hepatotoxicity (Analysis based on n=4490 , studies from 1954 – 2010) AAC, November 2010, Volume 56, Number 11
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