quantitative analysis of mgit time to positivity...
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Quantitative Analysis of MGIT Time
to Positivity Using a Two-Part
Longitudinal Model in Patients with
Pulmonary Tuberculosis: A Meta-
Analysis of 11 Clinical Studies
Including 30 Unique Regimens
October 15, 2017
Nastya Kassir, PharmD, PhD, FCP
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© Copyright 2016 Certara, L.P. All rights reserved.
Overview
1. Tuberculosis: Challenges and Opportunities
• ~10M new case of infected subjects & 1.4 million deaths per year…
• A plan to eradicate TB by 2035 !
• Strategic Partnership & Alliances• Non-Profit: Critical Path to Tuberculosis Regimen (CPTR), B&M Gates Foundation, TB Alliance
• Private: Pharma’s and Biotechs
• A Series of Initiatives to Optimize TB Drug Development
2. Introducing Time to Positivity (TTP), a Promising Biomarker for TB
• TTP from Liquid Culture.
• Modeling of Biomarker (TTP) & Interactive Platform for Drug Developers
• Prognostic value of TTP for Clinical Response in Phase III
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Introducing Time to Positivity (TTP)
as a Promising Biomarker for TB
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Liquid Culture of TB: Time to Positivity (TTP)
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TTP (time to positivity) = the time to detectable growth of TB in liquid culture.
o Reflecting the detection of critical metabolic activity of TB
o Reduced variability, easier technical requirements.
Time (Weeks)
Current Hypothesis: rate of TTP may be prognostic of clinical response in Phase III
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Part 1
Interactive Platform for Comparison of TTP
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Interactive Platform for Comparison of TTP
• Current Hypothesis:
o Rate of TTP may be prognostic of clinical response in Phase III
• Data Repository for Strategic Positioning
o 11 Clinical Studies in Patients with TB
o 30 Treatments
o ~2000 patients
• R Shiny App
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Interactive Platform – 1 of 5
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Interactive Platform – 2 of 5
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Interactive Platform – 3 of 5
“Fast Gamma” “Slow Gamma”
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Interactive Platform – 4 of 5
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Interactive Platform – 5 of 5
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https://pharmacometrics.shinyapps.io/cpittp/
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Part 2
Two-Part Longitudinal Model for
TTP
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Objectives
Develop TTP Model
• Develop a quantitative description of TTP change over time,
as a function of relevant sources of variability
Create a Parametric Time-to-Event Model
• Develop a parametric time-to-event model to predict the
probability of TTP=42
• Testing of subject-level gamma values as covariates
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TTP Model: Gompertz Function
• A Gompertz model resulted in the best goodness-of-fit.
TTP(time) = Alpha * exp[-Beta * exp(-Gamma*Time)]
• TTP handling
• TTP42 retained in the analysis
• TTP42 set to missing
• TTP42 censored + M3 Method (likelihood method)
• …
the maximum value that can
be reached with the incubation
time (i.e,. TTP=42 days)
Baseline TTPA constant related
to the proliferative
ability of Tuberculosis in
culture (rate of growth)
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Gompertz Function & Possible Linkage to Response
Effect of Beta on TTP Profile
Left-Right Shift, Same Steepness
Effect of Gamma (rate of
growth) on TTP Profile
Steepness
It could be hypothesized that the parameter describing these TTP profiles (sub-
population) may be predictive of clinical response in a Phase III study.
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TTP Model: TTP 42 set to Missing
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Probability of TTP=42 (No TB Growth)
• A parametric time-to-event model for predicting the
probability of TTP = 42 days
• The subject-level gamma parameter can be expressed in
terms of a hazard function:
ℎ 𝑡 = ℎ0 𝑡 × exp 𝛽𝐺𝑎𝑚𝑚𝑎
𝐺𝑎𝑚𝑚𝑎 − 0.05
0.01
• ℎ0 𝑡 : Baseline hazard function
• 𝛽: log-hazard ratio
• gamma: gamma parameter describing the first-order rate of
TTP growth for subjects.
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Baseline Hazard Function
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Visual Predictive Check for Probability of TTP42
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Conclusion
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Conclusion
• Time to Positivity (TTP) from Liquid Culture Media
o An early biomarker that measures metabolic activity of TB (rate of growth)
o A two-piece model including Gompertz and parametric time-to-event functions
adequately described the time-dependent changes in TTP as well as the
probability of no TB growth.
o Subject-level gamma values improved predictions of the probability of no TB
growth.
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Acknowledgements
• Certara Team
o JF Marier, PhD, FCP
o Samer Mouksassi, PharmD, PhD, FCP
o Benjamin Rich, PhD
o Grygoriy Vasilinin, PhD
• CPTR Team
o Klaus Romero, MD, MS, FCP
o Allan Berg, PharmD, PhD, FCP
o Lindsay Lehmann, MBA
o Debra Hanna, PhD
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