Quantitative Analysis of MGIT Time to Positivity...

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

© 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


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


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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“Fast Gamma” “Slow Gamma”

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https://pharmacometrics.shinyapps.io/cpittp/

https://pharmacometrics.shinyapps.io/cpittp/


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.


TTP Model: TTP 42 set to Missing


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.


Baseline Hazard Function


Visual Predictive Check for Probability of TTP42


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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Quantitative Analysis of MGIT Time to Positivity...

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