Transcript PRESENTATION - FINAL - Critical Path to TB Drug Regimens

Rifapentine Development Progress
CPTR 2012 Workshop
Rifapentine Development Progress – October 4, 2012
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Latent TB infection (LTBI) and active TB
●
Preventing TB by treating M. tuberculosis
infection (LTBI) = conerstone of strategy
for TB elimination
● TB develops in 5-10% of infected
persons, risk increased when
impaired cellular immunity
(esp. HIV infection)
4M TB regimen
2M TB regimen
10D regimen
LTBI ttt
2M TB regimen +
LTBI ttt
●
Interest in new efficient and improved
regimens
From Abu-Raddad L et al. PNAS 2009;106(33):13980-85
● shorter,
● With high competion rate
● With good effectiveness and tolerability
Rifapentine Development Progress – October 4, 2012
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Rifapentine
A rifamycin with advantageous properties
Rifapentine has properties that favors M. tuberculosis exposure
to rifamycin bactericidal activity
Rifapentine
Rifampin
0.06 µg/mL
0.25 µg/mL
Intra/Extracellular ratio
24
5
T1/2
13h
3h
MIC
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Latent TB Treatment Shortening
TBTC S26 Design
INH 300 mg
Daily
9 months
270-day dosing
Phase III, Randomized, Open-Label
Non-inferiority trial
n=8053 high-risk TST reactors
Low-medium incidence settings
33-month follow-up from randomization
Self-AdminisTered
3 MO
9 MO
33 MO
# of TB events
RPT 900mg + INH 900mg
Once-weekly
3 months
12-day dosing
Directly Observed Therapy
Primary objective Evaluate the effectiveness of weekly
RPT/INH for 3 months under DOT
Secondary objectives  Safety evaluation
 Adherence assessment
 Efficacy evaluation based on perprotocol evaluation
Rifapentine Development Progress – October 4, 2012
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TBTC S26 – The Prevent TB Study
Primary endpoint : TB rates by Mo33 – mITT
0.6
Arm A
Arm B
0.4
INH (n 3745)
RPT/INH (n 3986)
15 TB cases
0.2
15 TB cases
7 TB cases
6 TB cases
0.0
Cumulative TB rate (%)
0.8
1.0
Cumulative TB Event Rate
0
200
400
600
800
1000
Number of days from enrollment
Non-inferiority demonstrated as 97.5% upper-bound of diff = 0.08% (<0.75%= NI margin)
Rifapentine Development Progress – October 4, 2012
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TBTC S26 – The Prevent TB Study
TBTC S26 Tolerance Results on MITT Population
Outcome
9INH
N=3,745
3RPT/INH
N=3986
P-value
Treatment completion
2,585 (69%)
3,273 (82%)
< 0.001
Permanent drug d/cany reason
1,160 (31%)
713 (17.9%)
< 0.001
Permanent drug d/cadverse event
139 (3.7%)
196 (4.9%)
0.009
Permanent drug d/cadverse event Gr 3/4
62 (1.7%)
79 (2.1%)
NS
Drug related
hepatoxicity
103 (2.7%)
18 (0.4%)
<0.001
Possible
Hypersensitivity
17(0.5%)
152 (3.8%)
<0.001
Death
39 (1.1%)
31 (0.8%)
NS
Rifapentine Development Progress – October 4, 2012
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TBTC S26 – The Prevent TB Study
Conclusion
●
●
The largest US Government study on tuberculosis preventive therapy in low
to medium TB incidence setting
Showed that
● Supervised weekly RPT/INH regimen for 3 Mo is non inferior as standard selfadministered daily INH for 9 Mo ( both in mITT & PP) in preventing new cases of
TB disease
● Completion rate is higher with 3HP than 9INH  82% vs 69%
● 3RPT/INH regimen is safe  Lower rate of hepatotoxicity attributable to study
drug
●
●
S26 confirms that RPT can be used effectively in low/medium TB incidence
settings to prevent TB cases
CDC recommendation in MMWR :
● « The combination regimen of INH and RPT given as 12 weekly DOT doses is
recommended as an equal alternative to 9 months of daily self-supervised INH for
treating LTBI in otherwise healthy patients aged ≥12 years who have a predictive
factor for greater likelihood of TB developing ».
Rifapentine Development Progress – October 4, 2012
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TBTC S26 – The Prevent TB Study
Limitations
●
Few HIV-infected participants
● Enrollment of this population was extended to December 2010
● Tolerability and effectiveness data pending
●
Complete tolerability assessment in young children also pending
● Enrollment of children 2-11 years old extended to December
2010
●
Costs ?
Rifapentine Development Progress – October 4, 2012
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LTBI treatment : New shorter treatment regimen
Well documented
TBTC
S26
TBTC
S33
Phase III
Phase IV
3RPT/INH to
prevent TB
i@ADHERE
The Prevent TB study
in low to medium TB
incidence settings
ZA study
(NIAID)
DOT vs SAT
#8053
#1000
Phase III
Prevent TB in adults with
HIV infection (no ART)
(high TB incidence setting)
Brazil study
#1148
Phase III
Prevent TB in adults
(in low to medium TB
incidence settings)
#399
Rifapentine Development Progress – October 4, 2012
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S33-@ i ADHERE - TBTC-CDC
Assess adherence to RPT- based -short course treatment to prevent TB
Eligible patients
Same criteria as S26 except
Adults only >45kg
Randomization
n=300
n=300
DOT
Medication Event
Monitoring
System
n=300
SAT
RPT 900mg +
INH 900mg
once weekly- 12 wks
Weekly reminder SMS
RPT 900mg +
INH 900mg
once weekly- 12 wks
RPT 900mg +
INH 900mg
once weekly- 12 wks
Enhanced SAT*
Primary Endpoint
Completion of 11 therapeutic doses/12 planned
Monthly visits
FU x16 weeks after initiation of treatment
Secondary Endpoints
- Devlpt active TB/ Resistance
- DC all reasons/ due to Gr 3 or 4 toxicity AEs/ Death
Rifapentine Development Progress – October 4, 2012
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New regimen for latent TB
Sanofi involvment
●
Regulatory
● Seek for efficacy supplement for Priftin®
● Extend registration to other countries that could use US dossier
●
Pharmaceutical
● Development of FDC containing P+H
●
Clinical development
● Interaction studies
●
Price
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Active & Latent TB treatment shortening using
rifapentine-based regimens development approach
Substituting RPT for RIF
CDC / TBTC Partnership
3 - 4 months
Registration ISTs
Current Regulatory
Requirements
Active TB
Combining
+ new TB drug(s)
CPTR Drug Coalition
TB Alliance
< 3 months
Registration ISTs
Upcoming Regulatory
Requirements
RPT-based regimens
for Treatment Shortening
Phase II TBTC S29x
Preclinical
DDI
EBA
Ph III – TBTC S26
Latent TB
CDC / TBTC
RPT = P = Rifapentine
RIF = R = Rifampin
H = Isoniazid
3-mo PH1/7
DOTS
CDC / TBTC Partnership
1-mo PH7/7
self-adm.
NIAID / TBTC
ATS Recommendations
Pragmatic ISTs
Phase III TBTC S26
Submission dossier
Phases III
A 5279
Rifapentine Development Progress – October 4, 2012
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Active TB development plan
Selecting the optimal dose for the pivotal Phase III
Preclinical
Safety & Toxicity
studies
Phase I
Dose exploration
S29
Phase II
Safety & Efficacy
10 mg/kg
Independant Phase II
Dose exploration
Endpoints: Safety
Endpoints: Early MCB
PK / PD
PIP
Phase III
S29B
S29X
Interaction studies
Primary endpoints
Safety &
Efficacy
2-month conversion
Primary endpoint
Safety
Rifapentine Development Progress – October 4, 2012
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TBTC Study 29X Phase IIb
Dose exploration
●
TBTC S29 amendment = TBTC S29 eXtension
Study 29
n = 531
Study 29X
n = 320
FPI = July 2011
• Open-label
• 5/7 + DOTS
• Fasting
• Primary endpoint: Efficacy & Safety
• Double-blind for RPT arms
• 7/7 + DOTS on week days
• Fed
• Primary endpoint: Safety
Rifapentine Development Progress – October 4, 2012
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Active TB development plan
Selecting the optimal dose for the pivotal Phase III
Preclinical
Safety & Toxicity
studies
Phase I
Dose exploration
S29
Phase II
Safety & Efficacy
10 mg/kg
Independant Phase II
Dose exploration
Endpoints: Safety
Endpoints: Early MCB
PK / PD
PIP
Phase III
S29B
S29X
S31
Interaction studies
Primary endpoints
Safety &
Efficacy
1-year relapse
Rifapentine Development Progress – October 4, 2012
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Access to Medicines & Tuberculosis
Promoting Access to Shorter Treatment against Active & Latent TB
●
Bringing rifapentine where it should be in TB management:
● Active TB:
• Pursue efficient development of a 3-4 mo. RPT-based regimen in
partnership with CDC & in line with registration standards.
• Contribute to the identification of <3-month regimen within CPTR.
● Latent TB:
• Ensure worldwide broad access of the short course RPT/INH regimen
at tiered price.
• Pursue efforts for futher treatment shortening
● Pharmaceutical development:
• FDC
• Pediatric formulation
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