Unified Drug Sensitive/Drug
Resistant Development
Pathway for Novel TB Drug
Regimens
Stephen Murray, MD, PhD
& Daniel Everitt, MD
Global Alliance for TB Drug Development
CPTR, Oct 2012
TBA Update
Current MDR Development Approach
• Add single agent to Standard of Care
– Complex regimen with long period of treatment and follow up
• Greater unmet need on a per patient basis has resulted in calls for
accelerated approval of drugs for MDR/XDR TB
– But how will we know how to use the drugs? And for how long?
– Will still have to perform Ph 3
• Requires separate development program from DS-TB
• Standard of care (SOC) treatment (control group) for MDR-TB is
lengthy, difficult, toxicity prone, not efficacious and expensive.
• A new regimen for MDR-TB could be much shorter than SOC, but
the timepoint for comparison will still be defined by the SOC
control group (24 mos vs 6 mos)
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Unified DS/DR Development Path
Paradigm Shift
• Patients should be treated based on what they are sensitive to-rather than on what they are resistant to
– “MDR” as a label doesn’t apply in setting of new chemical entities
• Proposed Indication: “Drugs X, Y, and Z in combination are
indicated for the treatment of tuberculosis caused by M.tb strains
that are sensitive to drugs X, Y, and Z.”
– Only patients sensitive to drugs X, Y, Z included in clinical trials
– Traditional “MDR” or “DS” not an exclusion
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Unified Drug Sensitive/Drug Resistant
Regimen Development Path
Stage
Testing
Model
Study
Attributes
Go/No-Go
Criteria:
Pre clinical
Phase 1
Mouse Model
Healthy
Subjects
• Single drug
• Combo in
regimen
• Relapse-free
sterilizing
activity
• Single and
repeat dose
• Safety,
tolerability
• PK
• Drug
Interactions
Phase 2
Monotherapy
EBA
• Single drug
• Dose ranging
• DS patients
only
PK to support
daily dosing
Combination/
Regimen EBA
• Optimized
dose
Regimen
• Test final
regimen
• DS patients
only?
Clear effect to
reduce CFU count
Phase 3
Regimen 2Month Study
• DS and DR
sensitive to
regimen
• DS vs HRZE
standard
• DR for
consistency
As good as
HRZE standard
Registration
• 2 to 4 month
treatment,
eg
• DS vs HRZE
for noninferiority
• DR for
consistency
Better Than HRZE
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NiX-TB
New Chemical Entities in XDR-TB
Proposed Collaborative
“Rescue” Study for
XDR/TDR.
Background
• DS-TB is a curable disease
• MDR-TB is a curable disease with treatment options
• XDR- / TDR-TB is a disease where existing treatment options are
limited
– Optimal therapy should consist of at least 3 effective drugs to which M.tb is
susceptible
– New chemical entities without pre-existing resistance are currently in
development, but not yet available
– Aim is to help XDR-TB patients now, under carefully controlled conditions,
while learning how to use the drugs/regimens
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Proposed “Rescue” Study in XDR-/TDR-TB
• Foundation: a number of drugs without pre-existing resistance
could have promising data by END2013
– Bedaquiline, delamanid, PA-824, sutezolid, SQ109
– Clofazimine?
• Proposal: initiate global study of combinations of NCEs in patients
with XDR-/TDR-TB at select centers with aim of cure
– Potential collaborators: Tibotec, Otsuka, TB Alliance, Pfizer, Sequella
– Once collaborators have committed, mouse relapse data of combination(s) to
predict duration of treatment
– By providing complete regimen, prevent emergence of resistance
– Pre-approval study; not intended for MDR-TB or to expand access beyond XDR
• Not compassionate use: highly selected centers, more intensive
data collection, long-term follow up with definitive outcomes, learn
to use regimen, learnings to be rapidly incorporated into treatment
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Ongoing Novel
Combination
Studies
NC-002: First Novel Combo “SSCC” Study
In Patients with M.TB Sensitive to Pa, M, and Z
Participants with newly diagnosed smear positive DS TB
Pa(200mg)-M-Z
N=60
DS
Pa(100mg)-M-Z
N=60
2 months of treatment
Randomize
DR
Rifafour
N=60
Pa(200mg)-M-Z
N=50
Serial 16 hour pooled sputum samples for CFU Count
Z = pyrazinamide at 1500mg
Pa = PA-824
M = moxifloxacin
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NC-002 - Many “firsts” in Steps Forward for TB
Drug Development
• Moves a novel regimen from a 2 week EBA study to a 2 month
“SSCC” study
– Allows us to look at the predictability of 2 week EBA data within a 2 month
study
• Enrolls DS and DR subjects in a single trial treated with the same
regimen – moves to a new paradigm beyond the traditional
“MDR” definition
• Evaluates “MDR” patients in an EBA study
• Evaluates fixed dose PZA in a rigorous trial
• Consistent quantitative CFU data across myco labs
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Third Novel Combo EBA: NC-003
Participants with newly diagnosed smear positive DS TB
Z
C
J-C-Z
J-Pa-C
14 daily doses
J-Pa-Z
J-Pa-C-Z
Rifafour
15 per group
Randomize
Serial 16 hour pooled sputum samples for CFU Count
Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207
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Phase 3 Studies of Regimens to Shorten
Treatment Duration
• REMox
– Standard 6 month HRZE regimen compared to 2 arms of 4 month therapy:
• Moxifloxacin substituting for ethambutol, or
• Moxifloxacin substituting for isoniazid
– Fully enrolled with 1931 subjects; all have completed treatment
– Top line results expected at end, 2013
• Oflotub Phase 3 Study – Analysis is moving forward
– Design – HRZE X 6 months
vs gatifloxacin substitution for ethambutol X 4 months
• ~ 2000 patients
– Sponsored by TDR / WHO
– Database issues resolved by transfer to new database
– Results expected Summer, 2013
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