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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 - PowerPoint PPT Presentation
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CPTR, Oct 2012TBA Update
Stephen Murray, MD, PhD& Daniel Everitt, MDGlobal Alliance for TB Drug Development
Unified Drug Sensitive/Drug Resistant DevelopmentPathway for Novel TB Drug Regimens
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• 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)
Current MDR Development Approach
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• 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
Paradigm ShiftUnified DS/DR Development Path
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Mouse Model
• Single drug• Combo in
regimen• Relapse-free
sterilizing activity
Healthy Subjects
• Single and repeat dose
• Safety, tolerability
• PK• Drug
Interactions
Monotherapy EBA
• Single drug• Dose ranging• DS patients
only
Combination/Regimen EBA
• Optimized dose Regimen
• Test final regimen
• DS patients only?
Regimen 2-Month Study
• DS and DR sensitive to regimen
• DS vs HRZE standard
• DR for consistency
Registration
• 2 to 4 month treatment, eg
• DS vs HRZE for non-inferiority
• DR for consistency
Unified Drug Sensitive/Drug Resistant Regimen Development Path
As good as HRZE standard
Phase 2Pre clinical Phase 1 Phase 3
Better Than HRZE
Stage
Testing Model
Study Attributes
Go/No-Go Criteria: PK to support
daily dosingClear effect to
reduce CFU count
NiX-TB
Proposed Collaborative “Rescue” Study for XDR/TDR.
New Chemical Entities in XDR-TB
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• 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
Background
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• 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
Proposed “Rescue” Study in XDR-/TDR-TB
Ongoing Novel Combination Studies
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Participants with newly diagnosed smear positive DS TB
NC-002: First Novel Combo “SSCC” StudyIn Patients with M.TB Sensitive to Pa, M, and Z
Pa(200mg)-M-ZN=60
Pa(100mg)-M-ZN=60
RifafourN=60
Pa(200mg)-M-Z
N=50
Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin
2 months of treatment
Randomize
Serial 16 hour pooled sputum samples for CFU Count
DS
DR
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• 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
NC-002 - Many “firsts” in Steps Forward for TB Drug Development
Third Novel Combo EBA: NC-003Participants with newly diagnosed smear positive DS TB
C
J-C-Z
J-Pa-C
J-Pa-C-Z
Rifafour
Z
Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207
14 daily doses
Randomize
15 per group
Serial 16 hour pooled sputum samples for CFU Count
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J-Pa-Z
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• 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
Phase 3 Studies of Regimens to Shorten Treatment Duration
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