Stratified medicine in the treatment of TB Patrick Phillips, PhD Division of Pulmonary and Critical Care, Department of Medicine Division of Biostatistics, Department of Epidemiology and Biostatistics

Treatment Stratification https://www.myabaris.com/tools/life-expectancy-calculator-how-long-will-i-live/

Personalized medicine: “molecular profiling technologies for tailoring the right therapeutic strategy for the right person at the right time”. Overambitious promise of individualized unique drug targeting and development. Stratified medicine: reflects the effects of medicines at population level. This population approach better aligns with the public health approach used in TB. European Commission DR. Workshop report, Stratification biomarkers in personalized medicine, 2010

Bringing stratified medicine to TB – a paradigm shift in trial design and overall objectives Cure all patients with TB Not 90-95% of patients, but target cure >99% Identify a pragmatic treatment strategy that is superior to standard of care Pursue cure for all and keep markers simple. Abandon “One Size Fits All” approach Use baseline and/or on-treatment markers to stratify patients into risk groups Patients in different risk groups receive different durations or compositions of regimens

Relapse rates in 2/3/4-month regimens in DS-TB Total patients HR throughout, with S&Z added (Fox, 1981) NIRT (Jawahar, 2013) Gati Moxi OFLOTUB (Merle, 2014) RIFAQUIN (Jindani, 2014) REMoxTB (Gillespie, 2014) Moxi & INH Moxi & EMB (Johnson, 2009) Smear neg, no cavities Daily SHRZ, Smear negative (Hong Kong, 1981, 1989)

Relapse rates in 2/3/4-month regimens in DS-TB Total patients Proportion of patients cured HR throughout, with S&Z added (Fox, 1981) NIRT (Jawahar, 2013) Gati Moxi OFLOTUB (Merle, 2014) RIFAQUIN (Jindani, 2014) REMoxTB (Gillespie, 2014) Moxi & INH Moxi & EMB (Johnson, 2009) Smear neg, no cavities Daily SHRZ, Smear negative (Hong Kong, 1981, 1989)

Evaluating the same shorter regimen for all Shorter novel regimen ‘one size fits all’ 8.7% unfavorable 6-month HRZE, 8% unfavorable Low risk 3% 2% Moderate risk 8% 7% Non-inferiority depends primarily on efficacy in the high risk patients High risk 16% 20%

Evaluating a treatment stratification approach Novel regimen with treatment stratification, 3-4% unfavorable 6-month HRZE, 8% unfavorable Low risk 3% Radically shorter duration 2% Moderate risk 8% Shorter duration 5% High risk 16% 5% Longer duration

Evaluating a treatment stratification approach Novel regimen with treatment stratification, 3-4% unfavorable 6-month HRZE, 8% unfavorable 1. Target Treatment Shortening, with no reduction in efficacy in low risk group Low risk 3% Radically shorter duration 2% Moderate risk 8% Shorter duration 5% 2. Target Improved Efficacy, with a more potent regimen in high risk group High risk 16% 5% Longer duration

The CURE-TB Strategy – Stratified Medicine to Cure All in DS TB Illustrative example using RPT at 1200mg Randomise Strata (risk of relapse) Control Treatment strategy 1 (Baseline factors only) Treatment strategy 2 (On treatment biomarker to adjust duration) Low 2HRZE/4HR (6 months) 2HPZE (2 months) (2+ months) Moderate 2HPZE/2HP (4 months) (4+ months) High 2HPZE/4HP (6+ months) Low risk of relapse Moderate risk of relapse High risk of relapse From the TBTC CURE-TB Working Group

Advantages of stratified medicine in TB Each patient receives the therapy that gives them the best opportunity for cure Phase III trials with superiority rather than non-inferiority designs. Superiority more robust for interpretation and generalizability Two-pronged attack to achieve cure for all Shorter duration for those for which it is appropriate Reducing health system costs, improving adherence Longer duration for those that need it Improving population-level outcomes, reducing onward transmission

Objections to stratified medicine in TB We don’t have good enough stratification factors TB-REFLECT analysis is providing robust evidence Stratification algorithm can evolve over time as new data and markers emerge Treatment stratification will lead to market fragmentation Informal stratification is already practiced in many resource-rich settings Formalization of an evidence-based treatment strategy allows for clear strategies for market access. It’s too complex to implement in a resource poor setting Begin with simple markers Utilize readily available digital technology for stratification

Acknowledgements Payam Nahid, Rada Savic, and the TBTC CURE TB Working Group The CURE TB MDR-TB Consortium