New drugs and regimens for treatment of drug-sensitive TB (DS-TB) Patrick Phillips Patrick.Phillips@ucsf.edu @PPJPhillips
Outline Overview of regimen development strategies 1-3 year horizon: Ongoing phase III trials 5-10 year horizon: Ongoing and imminent phase IIB/C trials The Universal Regimen vs. Precision Medicine 2
WHO Target regimen profiles for TB treatment (2016) https://www.who.int/tb/publications/trp_profiles/en/ Aim: - To assist drug regimen developers in identifying important regimen features and aligning these with patient and programmatic needs at country level Three separate target profiles: - Rifampicin-susceptible TB (DS-TB) - Rifampicin-resistant TB (RR-TB) - Pan-susceptible TB ( Pan-TB ) 3
Pan-susceptible TB and The Universal Regimen A regimen for Pan-TB (a.k.a. The Universal Regimen) is intended to treat both DS-TB and RR-TB - Doesn t include a rifamycin (or isoniazid) - Disease that is susceptible to drugs in the regimen Very attractive to drug developers as it unifies treatment of TB leading to a bigger market share - Completely new regimen with no pre-existing resistance 4
Regimen development strategies Global numbers of patients, millions (% of total) Drugs likely to have more side effects Lower hurdle for efficacy improvements Rifamycin-containing regimen Substitution of 1-3 old drugs to shorten therapy Completely new regimen without a rifamycin May or may not include older drugs DR-TB 0.5m (5%) DS-TB 9.5m (95%) Pan-TB 10m (99+%) 5
Regimen development strategies Global numbers of patients, millions (% of total) Drugs likely to have more side effects Potentially a lower hurdle for efficacy improvements Rifamycin-containing regimen Substitution of 1-3 old drugs to shorten therapy Completely new regimen without a rifamycin May or may not include older drugs DR-TB 0.5m (5%) DS-TB 9.5m (95%) Pan-TB 10.0m (99%) Approach for bedaquiline, delamanid and pretomanid 6 Regulatory approval Historically an easier pathway for regulatory approval for a new drug May no longer be so smooth
Regimen development strategies Global numbers of patients, millions (% of total) Drugs likely to have more side effects Potentially a lower hurdle for efficacy improvements Rifamycin-containing regimen Substitution of 1-3 old drugs to shorten therapy Completely new regimen without a rifamycin May or may not include older drugs DR-TB 0.5m (5%) DS-TB 9.5m (95%) Pan-TB 10.0m (99%) Likely more favored approach today for a new regimen Regulatory approval 7
Ongoing phase III trials for DS-TB and Pan-TB New regimens in 1-3 years? Moxifloxacin NIRT 000024 Study 31/A5349 High-dose rifapentine High-dose rifampicin RIFASHORT TRUNCATE-TB For the purposes of this presentation, a Phase III trial is one with at least 6 months post-treatment follow-up which is powered for some sort of comparison using long-term outcomes. New drugs STAND SimpliciTB 9
10 1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India Previous randomized trials Regimen 3-month 3RHZO 4-month 3RHZO/1HR 5-month 3RHZO/2HR 4-month 2RHZO/2HR Total patients 529 randomized Relapse n(%) 83 7 (8%) 81 3 (4%) 86 2 (2%) 81 12 (13%) Narayanan P. Shortening short course chemotherapy: a randomised clinical trial for treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase. Indian J Tuberc. 2002;49:27-38. 429 randomized 2(RHZE) 3 /4(HR) 3 2(MHRZ) 3 /2(MHR) 3 2(GHRZ) 3 /2(GHR) 3 R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol M Moxifloxacin G Gatifloxacin O Ofloxacin X 3 Thrice-weekly Jawahar MS et al. Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One. 2013;8(7):e67030 Comment: Concerns about the conduct and analysis of this study https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/b42ab7ea- 3b02-495e-adbf-1204ff6e27df
1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India Previous phase III trials with moxifloxacin (REMoxTB) R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol M Moxifloxacin G Gatifloxacin O Ofloxacin X 3 Thrice-weekly 1931 randomized 2RHZE/4HR 2RHZM/2MHR 2RMZE/2MR Gillespie SH et al. Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis. N Engl J Med. 2014;371(17):1577-87. 11
1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India Sites South India R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol M Moxifloxacin X 3 Thrice-weekly Sample size: 1371 Recruitment: May 2007 Oct 2016 Results: 2019 Newly diagnosed pulmonary DS-TB, HIV negative CTRI Registration: PROVCTRI/2008/091/000024 Control 2(RHZE) 3 /4(RH) 3 3-month 3RHZEM 4-month 2RHZEM/2RHM 4-month 2RHZEM/2(RHM) 3 4-month 2RHZEM/2(RHEM) 3 12
1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India Preliminary results (not peer-reviewed) (http://www.nirt.res.in/pdf/ar/annual%20report%202017-18.pdf) - Faster culture conversion with moxifloxacin 94% vs 77% (p < 0.001) - Improved end of treatment outcomes with moxifloxacin 91% - 93% vs 86% (p < 0.05) - 84 (7%) recurrences to date across all arms 13
2. Study 31/A5349 Rifapentine and Moxifloxacin CDC TB Trials Consortium (TBTC) / NIH AIDS Clinical Trials Group (ACTG) Phase II experience with rifapentine 334 + 531 randomized 334 randomized Dose for Study 31 / A5349: 1200mg with food Dorman SE et al. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care Med. 2015;191(3):333-43 Savic RM et al. Defining the Optimal Dose of Rifapentine for Pulmonary Tuberculosis: Exposure-Response Relations From Two Phase 2 Clinical Trials. Clin Pharmacol Ther. 2017 14
2. Study 31/A5349 Rifapentine and Moxifloxacin CDC TB Trials Consortium (TBTC) / NIH AIDS Clinical Trials Group (ACTG) Sites: Global Sample size: 2516 ClinicalTrials.gov Registration: NCT02410772 Recruitment: Jan 2016 Oct 2018 Results: Q2 2020 R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol M Moxifloxacin P Rifapentine Control 2RHZE/4RH Newly diagnosed pulmonary DS- TB 4-month 2PHZM/2PHM 4-month 2PHZE/2PH 15
2. Study 31/A5349 Rifapentine and Moxifloxacin CDC TB Trials Consortium (TBTC) / NIH AIDS Clinical Trials Group (ACTG) 16
3. RIFASHORT High-dose Rifampicin INTERTB & St. George s, University of London Phase II experience with rifampicin R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol Q SQ109 M Moxifloxacin R 35 R 35 mg/kg 365 randomized Boeree MJ et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017;17(1):39-49 Svensson EM et al. The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis. Clin Infect Dis. 2018;67(1):34-41. 17
3. RIFASHORT High-dose Rifampicin INTERTB & St. George s, University of London Sites: Sample size: 654 Botswana, Uganda, Nepal, Guinea, Peru Recruitment: Feb 2017 Q4 2019 Results: Q3 2021 Newly diagnosed pulmonary DS- TB, HIV negative ClinicalTrials.gov Registration: NCT02581527 R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol Control (R 10mg/kg) 2RHZE/4RH 4-month (R 1200mg) 2RHZE/2RH 4-month (R 1800mg) 2RHZE/2RH 18
4. TRUNCATE-TB Old and new drugs University College London (UCL) & National University of Singapore (NUS) A trial to evaluate a novel strategy, not just novel regimens 19
4. TRUNCATE-TB Old and new drugs University College London (UCL) & National University of Singapore (NUS) Sites: Sample size: 900 Singapore, Thailand, Philippines ClinicalTrials.gov Registration: NCT03474198 Recruitment: Q1 2018 Q4 2019 Results: Q1 2021 R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol Lz Linezolid C Clofazimine Lv Levofloxacin B Bedaquiline R 35 R 35 mg/kg Control 2RHZE/4RH 2/3-month R 35 HZELz Newly diagnosed pulmonary DS-TB 2/3-month R 35 HZEC 2/3-month PHZELv 2/3-month BHZELz 20
5. STAND & SimpliciTB Global Alliance for TB Drug Development Phase II experience with pretomanid (Pa) 240 randomized Bacterial decline in solid culture media over 8 weeks Pa 100 MZ HRZE 181 randomized Regimen Population % neg on liquid cultures at 8 weeks % neg on solid cultures at 8 weeks Pa 200 MZ BPaZ DS-TB 66% 89% BPaZ DS-TB 75%* 84% BPaMZ BPaMZ HRZE control MDR-TB Z-sensitive MDR-TB Z-resistant 96%* 100%* 78%* 95%* DS-TB 51% 86% R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol B Bedaquiline Pa Pretomanid Bacterial decline in liquid culture media over 8 weeks 21
5. STAND Old and new drugs Global Alliance for TB Drug Development Sites: Sample size: Global 284 (1200 planned) ClinicalTrials.gov Registration: NCT02342886 Recruitment: Q1 2015 Q4 2015 Results: 2019 Newly diagnosed pulmonary DS-TB R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol M - Moxifloxacin Pa Pretomanid Control 2RHZE/4RH 6-month 6Pa 200 MZ 4-month 4Pa 200 MZ 4-month 4Pa 100 MZ 22
6. SimpliciTB Old and new drugs Global Alliance for TB Drug Development & PanACEA Sites: Global Sample size: 300 ClinicalTrials.gov Registration: NCT03474198 Recruitment: Q1 2018 Q4 2019 Results: Q1 2021 R Rifampicin H Isoniazid Z Pyrazinamide E Ethambutol M - Moxifloxacin Pa Pretomanid B - Bedaquiline Control 2RHZE/4RH Newly diagnosed pulmonary DS- TB 4-month BPaMZ 23
New regimens for DS-TB 1-3 year horizon (estimated) 4-month PaMZ 3/4-month M 4-month P or MP 4-month BPaMZ B Bedaquiline C Clofazimine E Ethambutol H Isoniazid Lv Levofloxacin Lz Linezolid M - Moxifloxacin P Rifapentine Pa Pretomanid R Rifampicin Z Pyrazinamide 2/3-month R 35 Lz, R 35 C, PLv, BLz 4-month R 1200/1800mg 2019 2020 2021 2022 24
Ongoing or imminent phase IIB/C trials for DS-TB and Pan-TB New regimens in 5-10 years? Phase IIC trials (long-term outcomes) - CLO-FAST (ACTG A5362) 3/4-month regimens with clofazimine and high-dose rifapentine - PanACEA STEP 4-month regimens with various combinations of sutezolid, high-dose pyrazinamide and high-dose rifampicin (40mg/kg?) - TBTC CRUSH-TB Phillips PP, et al. A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Med. 2016;14(1):51. 4-month regimens with bedaquiline/pyrazinamide backbone 25
Ongoing or imminent phase IIB/C trials for DS-TB and Pan-TB New regimens in 5-10 years? Platform phase IIC trials (multi-arm multi-sponsor) 26
Ongoing or imminent phase IIB/C trials for DS-TB and Pan-TB New regimens in 5-10 years? Platform phase IIC trials (multi-arm multi-sponsor) STAMPEDE Trial in prostate cancer (thanks to Matt Sydes) 27
The Universal Regimen and Precision Medicine One-Size-Fits-All, or The Right Regimen for the Right Patient? 28
The Universal Regimen and Precision Medicine One-Size-Fits-All, or The Right Regimen for the Right Patient? Imperial MZ, et al. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nature Medicine. 2018 29
Stratified medicine and the treatment of TB TBTC CURE-TB (Protocol in development) Strategy 1: Baseline Risk Markers Strategy 2: Baseline/On Treatment Markers 30