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New drugs and regimens for treatment of drug-sensitive TB (DS-TB)
Patrick Phillips
@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
Patrick Phillips • [email protected] • @PPJPhillips2
Patrick Phillips • [email protected] • @PPJPhillips3
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’)
Patrick Phillips • [email protected] • @PPJPhillips4
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
Regimen development strategiesGlobal numbers of patients, millions (% of total)
DR-TB
• 0.5m (5%)
DS-TB
• 9.5m (95%)
Pan-TB
• 10m (99+%)
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
Patrick Phillips • [email protected] • @PPJPhillips5
Drugs likely to have more
side effects
Lower hurdle for efficacy
improvements
Patrick Phillips • [email protected] • @PPJPhillips6
Regimen development strategiesGlobal numbers of patients, millions (% of total)
DR-TB
• 0.5m (5%)
DS-TB
• 9.5m (95%)
Pan-TB
• 10.0m (99%)
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
Regulatoryapproval Historically an easier pathway for
regulatory approval for a new drug
May no longer be so smooth…
Approach for
bedaquiline,
delamanid
and
pretomanid
Patrick Phillips • [email protected] • @PPJPhillips7
Regimen development strategiesGlobal numbers of patients, millions (% of total)
DR-TB
• 0.5m (5%)
DS-TB
• 9.5m (95%)
Pan-TB
• 10.0m (99%)
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
Regulatoryapproval
Likely more
favored
approach
today for a
new regimen
Patrick Phillips • [email protected] • @PPJPhillips9
Ongoing phase III trials for DS-TB and Pan-TBNew regimens in 1-3 years?
MoxifloxacinHigh-dose
rifapentine
High-dose
rifampicinNew drugs
NIRT 000024
Study 31/A5349
RIFASHORT
TRUNCATE-TB
STAND
SimpliciTB
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.
Patrick Phillips • [email protected] • @PPJPhillips10
1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India
RegimenTotal
patients
Relapse
n(%)
3-month
3RHZO83 7 (8%)
4-month
3RHZO/1HR81 3 (4%)
5-month
3RHZO/2HR86 2 (2%)
4-month
2RHZO/2HR81 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.
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
2(GHRZ)3/2(GHR)3
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
M – Moxifloxacin
G – Gatifloxacin
O – Ofloxacin
X3 – Thrice-weekly
2(MHRZ)3/2(MHR)3
2(RHZE)3/4(HR)3
Comment: Concerns about the conduct and analysis of this studyhttps://journals.plos.org/plosone/article/comment?id=10.1371/annotation/b42ab7ea-
3b02-495e-adbf-1204ff6e27df
Previous randomized trials429 randomized
529 randomized
Patrick Phillips • [email protected] • @PPJPhillips11
1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India
Gillespie SH et al. Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive
Tuberculosis. N Engl J Med. 2014;371(17):1577-87.
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
M – Moxifloxacin
G – Gatifloxacin
O – Ofloxacin
X3 – Thrice-weekly
2RHZM/2MHR
2RHZE/4HR
Previous phase III trials with moxifloxacin (REMoxTB)
1931 randomized2RMZE/2MR
Patrick Phillips • [email protected] • @PPJPhillips12
1. NIRT 00024 - Moxifloxacin ICMR National Institute for Research in TB (NIRT), Chennai, India
Newly diagnosed pulmonary DS-TB,
HIV negative
Control2(RHZE)3/4(RH)3
3-month
3RHZEM
4-month
2RHZEM/2RHM
4-month
2RHZEM/2(RHM)3
4-month
2RHZEM/2(RHEM)3
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
M – Moxifloxacin
X3 – Thrice-weekly
Sites South India
Sample size: 1371
Recruitment: May 2007 – Oct 2016
Results: 2019
CTRI Registration:
PROVCTRI/2008/091/000024
Patrick Phillips • [email protected] • @PPJPhillips13
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
Patrick Phillips • [email protected] • @PPJPhillips14
2. Study 31/A5349 – Rifapentine and MoxifloxacinCDC TB Trials Consortium (TBTC) / NIH AIDS Clinical Trials Group (ACTG)
Phase II experience with rifapentine
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
334 randomized
334 + 531 randomized
Dose for Study 31 /
A5349: 1200mg with
food
Sites: Global
Sample size: 2516
Recruitment: Jan 2016 – Oct 2018
Results: Q2 2020
Patrick Phillips • [email protected] • @PPJPhillips15
2. Study 31/A5349 – Rifapentine and MoxifloxacinCDC TB Trials Consortium (TBTC) / NIH AIDS Clinical Trials Group (ACTG)
Newly diagnosed pulmonary DS-
TB
Control2RHZE/4RH
4-month
2PHZM/2PHM
4-month
2PHZE/2PH
ClinicalTrials.gov Registration:
NCT02410772
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
M – Moxifloxacin
P – Rifapentine
Patrick Phillips • [email protected] • @PPJPhillips16
2. Study 31/A5349 – Rifapentine and MoxifloxacinCDC TB Trials Consortium (TBTC) / NIH AIDS Clinical Trials Group (ACTG)
Patrick Phillips • [email protected] • @PPJPhillips17
3. RIFASHORT – High-dose RifampicinINTERTB & St. George’s, University of London
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
Q – SQ109
M – Moxifloxacin
R35 – R 35 mg/kg Phase II experience with rifampicin
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.
365 randomized
Sites: Botswana, Uganda,
Nepal, Guinea, Peru
Sample size: 654
Recruitment: Feb 2017 – Q4 2019
Results: Q3 2021
Patrick Phillips • [email protected] • @PPJPhillips18
3. RIFASHORT – High-dose RifampicinINTERTB & St. George’s, University of London
Newly diagnosed pulmonary DS-
TB, HIV negative
Control(R 10mg/kg)2RHZE/4RH
4-month(R 1200mg)2RHZE/2RH
4-month(R 1800mg)2RHZE/2RH
ClinicalTrials.gov Registration:
NCT02581527
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
Patrick Phillips • [email protected] • @PPJPhillips19
4. TRUNCATE-TB – Old and new drugsUniversity College London (UCL) & National University of Singapore (NUS)
A trial to evaluate a novel strategy, not just novel regimens
Sites: Singapore, Thailand,
Philippines
Sample size: 900
Recruitment: Q1 2018 – Q4 2019
Results: Q1 2021
Patrick Phillips • [email protected] • @PPJPhillips20
4. TRUNCATE-TB – Old and new drugsUniversity College London (UCL) & National University of Singapore (NUS)
Newly diagnosed pulmonary DS-TB
Control2RHZE/4RH
2/3-month
R35HZELz
2/3-month
R35HZEC
2/3-month
PHZELv
2/3-month
BHZELz
ClinicalTrials.gov Registration:
NCT03474198
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
Lz – Linezolid
C – Clofazimine
Lv – Levofloxacin
B – Bedaquiline
R35 – R 35 mg/kg
Patrick Phillips • [email protected] • @PPJPhillips21
5. STAND & SimpliciTBGlobal Alliance for TB Drug Development
Bacterial decline in solid
culture media over 8 weeks
Bacterial decline in liquid
culture media over 8 weeks
Phase II experience with pretomanid (Pa)181 randomized
Pa100MZ
Pa200MZ
HRZE
Regimen Population
% neg on
liquid cultures
at 8 weeks
% neg on
solid cultures
at 8 weeks
BPaZ DS-TB 66% 89%
BPaZ DS-TB 75%* 84%
BPaMZMDR-TB
Z-sensitive96%* 100%*
BPaMZMDR-TB
Z-resistant78%* 95%*
HRZE
controlDS-TB 51% 86%
240 randomized
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
B – Bedaquiline
Pa – Pretomanid
Sites: Global
Sample size: 284 (1200 planned)
Recruitment: Q1 2015 – Q4 2015
Results: 2019
Patrick Phillips • [email protected] • @PPJPhillips22
5. STAND – Old and new drugsGlobal Alliance for TB Drug Development
Newly diagnosed pulmonary DS-TB
Control2RHZE/4RH
6-month6Pa200MZ
4-month4Pa200MZ
4-month4Pa100MZ
ClinicalTrials.gov Registration:
NCT02342886
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
M - Moxifloxacin
Pa – Pretomanid
Sites: Global
Sample size: 300
Recruitment: Q1 2018 – Q4 2019
Results: Q1 2021
Patrick Phillips • [email protected] • @PPJPhillips23
6. SimpliciTB – Old and new drugsGlobal Alliance for TB Drug Development & PanACEA
Newly diagnosed pulmonary DS-
TB
Control2RHZE/4RH
4-monthBPaMZ
ClinicalTrials.gov Registration:
NCT03474198
R – Rifampicin
H – Isoniazid
Z – Pyrazinamide
E – Ethambutol
M - Moxifloxacin
Pa – Pretomanid
B - Bedaquiline
Patrick Phillips • [email protected] • @PPJPhillips24
New regimens for DS-TB1-3 year horizon (estimated)
2019 2020 2021 2022
4-month BPaMZ
4-month R 1200/1800mg
2/3-month R35Lz, R35C, PLv, BLz
B – Bedaquiline
C – Clofazimine
E – Ethambutol
H – Isoniazid
Lv – Levofloxacin
Lz – Linezolid
M - Moxifloxacin
P – Rifapentine
Pa – Pretomanid
R – Rifampicin
Z – Pyrazinamide
4-month P or MP
4-month PaMZ
3/4-month M
Patrick Phillips • [email protected] • @PPJPhillips25
Ongoing or imminent phase IIB/C trials for DS-TB and Pan-TBNew 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
4-month regimens with bedaquiline/pyrazinamide backbone
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.
Patrick Phillips • [email protected] • @PPJPhillips26
Ongoing or imminent phase IIB/C trials for DS-TB and Pan-TBNew regimens in 5-10 years?
Platform phase IIC trials (multi-arm multi-sponsor)
Patrick Phillips • [email protected] • @PPJPhillips27
Ongoing or imminent phase IIB/C trials for DS-TB and Pan-TBNew regimens in 5-10 years?
Platform phase IIC trials (multi-arm multi-sponsor)
STAMPEDE Trial in prostate cancer (thanks to Matt Sydes)
Patrick Phillips • [email protected] • @PPJPhillips28
The Universal Regimen and Precision Medicine One-Size-Fits-All, or The Right Regimen for the Right Patient?
…
Patrick Phillips • [email protected] • @PPJPhillips29
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
Patrick Phillips • [email protected] • @PPJPhillips30
Stratified medicine and the treatment of TBTBTC CURE-TB (Protocol in development)
Strategy 1: Baseline Risk Markers
Strategy 2: Baseline/On Treatment
Markers