new drugs and regimens for treatment of drug-sensitive tb ... - phillips.pdf1-3 year horizon:...

New drugs and regimens for treatment of drug-sensitive TB (DS-TB)

Patrick Phillips

[email protected]

@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


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’)


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


Drugs likely to have more

side effects

Lower hurdle for efficacy

improvements



DR-TB

• 0.5m (5%)

DS-TB

• 9.5m (95%)

Pan-TB

• 10.0m (99%)


side effects

Potentially a lower hurdle

for efficacy improvements


regimen


to shorten therapy


without a rifamycin


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



DR-TB

• 0.5m (5%)

DS-TB

• 9.5m (95%)

Pan-TB

• 10.0m (99%)


side effects

Potentially a lower hurdle

for efficacy improvements


regimen


to shorten therapy


without a rifamycin


drugs

Regulatoryapproval

Likely more

favored

approach

today for a

new regimen


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.


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

https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/b42ab7ea-3b02-495e-adbf-1204ff6e27df



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


2RHZM/2MHR

2RHZE/4HR

Previous phase III trials with moxifloxacin (REMoxTB)

1931 randomized2RMZE/2MR



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


Sites South India

Sample size: 1371

Recruitment: May 2007 – Oct 2016

Results: 2019

CTRI Registration:

PROVCTRI/2008/091/000024



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

http://www.nirt.res.in/pdf/AR/Annual Report 2017-18.pdf


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



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


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


3. RIFASHORT – High-dose RifampicinINTERTB & St. George’s, University of London


TB, HIV negative

Control(R 10mg/kg)2RHZE/4RH

4-month(R 1200mg)2RHZE/2RH

4-month(R 1800mg)2RHZE/2RH


NCT02581527

R – Rifampicin

H – Isoniazid

Z – Pyrazinamide

E – Ethambutol


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


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


NCT03474198

R – Rifampicin

H – Isoniazid

Z – Pyrazinamide

E – Ethambutol

Lz – Linezolid

C – Clofazimine

Lv – Levofloxacin

B – Bedaquiline

R35 – R 35 mg/kg


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)


Results: 2019


5. STAND – Old and new drugsGlobal Alliance for TB Drug Development

Newly diagnosed pulmonary DS-TB

Control2RHZE/4RH

6-month6Pa200MZ

4-month4Pa200MZ

4-month4Pa100MZ


NCT02342886

R – Rifampicin

H – Isoniazid

Z – Pyrazinamide

E – Ethambutol

M - Moxifloxacin

Pa – Pretomanid

Sites: Global

Sample size: 300


Results: Q1 2021


6. SimpliciTB – Old and new drugsGlobal Alliance for TB Drug Development & PanACEA


TB

Control2RHZE/4RH

4-monthBPaMZ


NCT03474198

R – Rifampicin

H – Isoniazid

Z – Pyrazinamide

E – Ethambutol

M - Moxifloxacin

Pa – Pretomanid

B - Bedaquiline


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


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.



Platform phase IIC trials (multi-arm multi-sponsor)



Platform phase IIC trials (multi-arm multi-sponsor)

STAMPEDE Trial in prostate cancer (thanks to Matt Sydes)


The Universal Regimen and Precision Medicine One-Size-Fits-All, or The Right Regimen for the Right Patient?

…


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


Stratified medicine and the treatment of TBTBTC CURE-TB (Protocol in development)

Strategy 1: Baseline Risk Markers

Strategy 2: Baseline/On Treatment

Markers

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