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Rifapentine (Priftin®): A significant step forward in TB control Marilyn Maroni
XX International Workshop on TB – Barcelona – November 22, 2016
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Tuberculosis A top infectious disease killer worlwide
Source: WHO – Media Center – Tuberculosis – Factsheet/ Updated October 2016
(* DS-TB: Drug Sensitive-Tuberculosis; MDR-TB: Multidrug Resistant-Tuberculosis)
1st leading cause of death in the world from a single infectious agent, after HIV
In 2015, 10,4 million new TB cases, including 1 million in children (either DS-TB or MDR-TB*)
11% in TB/HIV co-infected persons
1.8 million people, including 200 000 children died from the disease
TB is a leading killer of people living with HIV, 35% of HIV deaths are due to TB.
Over 95% of TB deaths occur in low & middle-income countries, and it is among the top 3
causes of death for women aged 15 to 44
November 22, 2016 XX International Workshop on TB - Barcelona- MM 2
WHO Tuberculosis Strategy A world free of TB
A world free of TB (Zero deaths, disease and suffering due to TB)
End the global TB epidemic
Pillar 1 Integrated, people-
centered care and
prevention
Pillar 2 Bold policies and
supportive systems
Pillar 3 Intensified research
and innovations
VISION
GOAL
35% in TB deaths
20% in TB incidence
75% in TB deaths,
50% in TB incidence
2020
2025
95% in TB deaths,
90% in TB incidence
2035
2015
In 2014, the World Health Assembly, held by WHO, unanimously approved a 20 year
over-arching strategy to End the global tuberculosis epidemic
Source : WHO, End TB strategy
November 22, 2016 XX International Workshop on TB - Barcelona- MM 3
WHO Tuberculosis Strategy Prospect for TB elimination
Improvements in active TB
treatment would lead to by factor
10
Vaccination to prevent infection
could also reduce incidence by
factor 10
Mitigation of risk factors will
contribute to TB control but play a
small part
Treating both active TB & LTBI is the
only way to approach elimination
(average decrease rate of 20%
annually ) Source: Dye et al – Prospect for TB elimiation.
Annu.Rev. Public Health 2013. 34:271-86
Eliminating Tuberculosis by 2050, requires a simultaneous attack on two
components of the M. tuberculosis life cycle : cut transmission, by treating active
cases; and also neutralize the reservoir of latent infection, by preventing activation
in high risk group.
November 22, 2016 XX International Workshop on TB - Barcelona- MM 4
Tuberculosis Natural history of « Mycobacterium Tuberculosis »
CONTACT
No infection
50%
50%
INFECTION
Host immune reaction
Control TST Conversion / IGRA +
Latent TB
Infection REACTIVATION Active TB
Disease
Within the first 2 years
- High Bacterial load
- Age<5yrs
- Immunosuppression
- HIV (8-10% /year)
Primary
95% 5%
CONTAGIOUS
(droplets)
5-10% No symptoms, no transmission
Persistent immune response
Dormant bacilli resume replication
LTBI POOL IS
THE RESERVOIR
FOR FUTURE TB
CASES
• Estimated 1/4 of the world population is infected by LTBI
• Many groups at risk to develop active TB Anti-TNFα treatment, Dialysis, Patients preparing for transplantation,
Prisoners, Recent immigrants from high prevalence countries, Homeless
persons, Health workers. November 22, 2016 XX International Workshop on TB - Barcelona- MM 5
FOR THE COMMUNITY
Eliminate the reservoir of M.Tb: major element of the
strategy for eliminating TB
Prevent the later transmission if individuals develop active
disease
FOR THE INDIVIDUALS
To prevent the development of active TB (if host immunity
decreases)
AT THE PROGRAM LEVEL
Savings in resources over the long term WHICH are then
available to be spent on other important areas, such as case
management and contact investigation.
WHO Tuberculosis Strategy Why treating LTBI ?
Curing your LTBI condition to prevent activation is a strong individual act with a
great impact on community health.
November 22, 2016 XX International Workshop on TB - Barcelona- MM 6
WHO guidelines for LTBI management A global approach to tackle the disease
Systematic testing and treatment of LTBI should be
performed in: • People living with HIV
• Adult and child contacts of pulmonary TB cases
• Patients initiating anti-TNF treatment
• Patients receiving dialysis
• Patients preparing for organ or haematologic tranplants
• Patients with silicosis
Systematic testing and treatment of LTBI should be
considered for: • Prisoners
• Health workers
• Immigrants from high TB burden countries
• Homeless persons
• Illicit drug users
Source : Guidelines on the management of latent tuberculosis infection, WHO 2014
• People living with HIV
• Children below 5 years of age who are household or close contacts of people with TB
Regimen Treatment Duration Frequency Intakes
3 HP Rifapentine + Isoniazid 3 months Weekly 12
6 INH Isoniazid 6 months Daily 180
9 INH Isoniazid 9 months Daily 270
3-4 RH Rifampicin + Isoniazid 3-4 months Daily 90-120
3-4 R Rifampicin 3-4 months Daily 90-120
In High income and upper-middle income countries with estimated with estimated
TB incidence less than 100 per 100 000 population
For resource-limited countries and other middle-income countries not targeted in the
WHO guidelines for management of LTBI
XX International Workshop on TB - Barcelona- MM November 22, 2016 7
Rifapentine
| 8 XX International Workshop on TB - Barcelona- MM November 22, 2016
MOA : Binds to β subunit of bacterial RNA polymerase
Anti M. tuberculosis activity Bactericidal , Active against M. tuberculosis at all stages of replication
Concentration-Time dependent activity
Predictors of activity: AUC / MIC
Mechanism of resistance : Mutations in rpoB gene – 10-8
The « revival » of rifapentine
Since mid 90s : partnership Sanofi / CDC
• Sanofi donates
• Priftin® to Division of TB Elimination for worldwide TB trials
• Funds to the CDC Foundation to supplement US Federal funding
• Cooperative Research and Development Agreements (CRADA)
•CDC Study Sponsor
• Independence for study conduct, collection & analysis of data
• Reports SAEs to FDA and local HA (in compliance with regulations)
• Provides Sanofi with copy of the complete analysis data set and raw data
• Sanofi : right to access and utilize the data and study reports for all legitimate business (regulatory)
| 9 XX International Workshop on TB - Barcelona- MM November 22, 2016
Focus on 3HP regimen TBTC-S26 – PREVENT TB STUDY
• 2001 to 2013 : Designed and
conducted by US-CDC - Sanofi
donated rifapentine
• Randomized, open-label, non-
inferiority trial
• 33 months of follow-up from date
of enrollment
• Including children 2-17 years old
& HIV infected patients not
taking ART
• Countries with Low and Medium
TB incidence settings (USA,
Canada, Brazil, and Spain)
9 months of daily self administered INH
for treatment of Latent TB Infection
in high-risk TST reactors
3 months of directly observed once-
weekly rifapentine (RPT) + Isoniazid
(INH)
TBTC-S26
vs
November 22, 2016 XX International Workshop on TB - Barcelona- MM 10
3RPT/INH : 12 weekly doses
• INH 15-25 mg/kg up to 900mg max
• RPT up to 900 mg max graduated
dosing for persons≤50Kg
9INH: 270 daily doses
• INH 5-15 mg/kg up to 300 mg max
S26 Main study (8053 patients)-
(#250 in Barcelona)
S26 HIV substudy
(403 patients)
S26 Paediatric substudy
(1058 patients)
Note: Five children included in the paediatric substudy were HIV-infected at enrollment
and were therefore also included in the HIV substudy. Of these 5 children,
1 child was enrolled in the TBTC-S26 main study, and the remaining 4 children were
enrolled during the extended enrollment for the paediatric and HIV sub-studies
Patients enrolled in TBTC-S26 main study
And HIV sub-studies (ITT populations)
And pediatrics
Weight Range Rifapentine Dose
10.0-14.0 kg 21.4-30.0 mg/kg 300 -mg
14.1-25.0 kg 18.0-31.9 mg/kg 450 mg
25.1-32.0 kg 18.8-23.9 mg/kg 600 mg
32.1-50.0 kg 15.0-23.4 mg/kg 750 mg
>50.0 kg ≤18.0 mg/kg 900 mg
212 4
1
Study dose
Focus on 3HP regimen TBTC-S26 – PREVENT TB STUDY
More than 8000 patients including 1058 children and 403 HIV+ patients
vs
November 22, 2016 XX International Workshop on TB - Barcelona- MM 11
Focus on 3HP regimen : PREVENT TB Study (S26)
XX International Workshop on TB - Barcelona- MM
Efficacy results & completion rates
Study treatment arm N #TB cases TB per 100 p-y Cumulative
TB rate (%)
Treatment
completion
rate (%)
TBTC-S26 main study
9INH 3745 15 0,16 0,43 2585 (69,0)
3RPT/INH 3986 7 0,07 0,19 3273 (82,1)
TBTC-S26 pediatric substudy
9INH 436 3 b 0,27 0,78 353 (81,0)
3RPT/INH 472 0 0,00 0,0 416 (88,1)
TBTC-S26 HIV substudy c
9INH 193 6 1,25 3,50 123 (63,7)
3RPT/INH 206 2 0,39 1,01 183 (88,8)
Number of TB cases and event rates by treatment arm : TBTC-S26 main and substudies
(MITT population, 33 month analysis)
a. 95% CI for the difference in cumulative TB disease rates (%).
b. All 3 children who developed TB in the paediatric substudy had participated in the main study and are also counted in number of TB cases for the main study.
c. 4 of the 8 patients who developed culture-confirmed TB in the HIV substudy had participated in the main study and are also counted in number of TB cases for the main
study.
Better effectiveness with 3HP regimen than with 9INH
November 22, 2016 12
Hypersensitivity reaction was rather rare in the 3RPT/INH arm and
hepatotoxicity more frequently reported with 9INH as compared to the
main study
Pediatric
substudy
(1032 patients)
HIV-infected
substudy
(393 patients)
Main study
(8053)
3-months of weekly RPT/INH showed good tolerability in more than 8000
exposed patients (4000 patients in each treatment group) with latent TB
infection showing
• Less hepatotoxicity events as compared to the standard 9INH regimen
(0.6% vs 3.0%)
• Hypersensitivity reactions (flu-like syndrome) were reported with higher
incidence/rate in the 3RPT/INH regimen (4.0% vs 0.5%, with 9INH)
→ The frequency of severe reactions was low and did not result in any
patient’s death
The incidence of hypersensitivity reaction was lower compared with
the TBTC-S26 main study and no children experienced
hepatotoxicity
Focus on 3HP regimen TBTC-S26 – PREVENT TB STUDY / Safety results
The safety pattern observed in the TBTC-S26 study was generally consistent with
the profile previously described and established for RPT US labeling in active TB
indication
November 22, 2016 XX International Workshop on TB - Barcelona- MM 13
TBTC-S26 main and sub-studies provide evidence that
Weekly 3RPT/INH regimen given by DOT is as efficient and well tolerated as self-administered daily INH for 9 months to prevent the development of active TB
In infected patients at high risk of progression to TB disease including children 2-17 years old and HIV co- infected not taking ART
Adherence and treatment completion rate are higher
with weekly 3RPT/INH regimen than 9INH which likely increases effectiveness
Focus on 3HP regimen TBTC-S26 – PREVENT TB STUDY / Conclusion
Based on the review of safety and efficacy data, the benefit-risk balance for
rifapentine new regimen is considered positive in the target population
November 22, 2016 XX International Workshop on TB - Barcelona- MM 14
Rifapentine is currently approved and marketed in the USA
registered in 2014
In patients at high risk of progression to tuberculosis disease
in association with Isoniazid
registered in 1998
in association with one or more anti-TB drugs.
On going phase 3 clinical study with an optimized regimen to shorten treatment duration to 4 months
in association with one or more anti-TB
drugs.
To be registered in other countries 2016 onwards
Focus on Rifapentine (Priftin®) Regulatory status
Latent TB Active TB
November 22, 2016 XX International Workshop on TB - Barcelona- MM 15
Focus on rifapentine and 3HP regimen
* Priftin® is indicated in adults and children 2 years and older for the treatment of latent tuberculosis infection caused by M.
tuberculosis in patients at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis
patients, recent conversion to a positive tuberculin skin test, HIV-infected patients, or those with pulmonary fibrosis on radiograph).
Source : http://en.sanofi.com/Images/37707_20141202_priftin_en.pdf
Rifapentine approved by USFDA*
3HP regimen First choice in US-CDC guidelines
3HP regimen recommended in WHO guidelines
Rifapentine included in WHO Essential Medicines List
Rifapentine called for WHO prequalification (under review)
2011
2014
2015
XX International Workshop on TB - Barcelona- MM November 22, 2016 16
Sanofi plans for rifapentine in LTBI
•Ensure access to the in-need patients • Extend registration to countries
• Include into national TB guidelines
• Implement in high TB incidence areas
• Increase awareness for LTBI management as a major contributor to TB elimination
• Simplify treatment
• Fixed Dose Combinations (RPT/INH – 3 instead of 9 tablets)
• Pediatric forms
•Action levers • Prepare a ready to use full CTD
• Establish partnership with governments and medical communities (training)
• Educational tools for HCPs
• Support local Investigator Sponsored Studies
XX International Workshop on TB - Barcelona- MM | 17 XX International Workshop on TB - Barcelona- MM November 22, 2016
Rifapentine donations to support Investigator Sponsored Studies
Study/Design objective Countries sponsor
Nb.patients
receiving 3HP
status Start date
Rd, open-label,
coontrolled
comparative
Safety &
compliance in
Asian patients
Taiwan Dr Wang 160 Ongoing
(follow-up)
LPO Dec16
HALT-TB
Rd, open label,
controlled
comparative
Pilot study safety
and compliance
in EU
UK University
College
London (Prof
Abubakar)
50 Recruiting FPI Mar 15
IMPAACT
2001
Single arm,
Safety, PK
PK & safety Haiti, India,
Kenya,
Malawi,
RSA, USA,
Zimbabwe
DAIDS/NIH 80 HIV+ &
non HIV
pregnant
women
(2nd and 3rd
trimester) &
post-partum
Planned FPI Q42016
CORTIS
Rd, partially
blinded,
comparative
w/SOC (surv)
Efficacy to
reduce the rate
of incident TB
disease in COR+
persons
South
Africa
University of
Cape Town/
B&M Gates
Foundation
(Dr Hatherill)
500 non HIV Recruiting FPI Q3 16
Rd: randomized
| 18 XX International Workshop on TB - Barcelona- MM November 22, 2016
Formulations developed by Sanofi GOA
development center (India)
For adults and Children > 12 years
Film Coated
RPT/INH tablets
P300mg/H300mg
3 tablets per dosing Instead of 9
P150mg/H150mg P100mg
For children
Dispersible
RPT/INH tablets
Dispersible
RPT tablets
Adjusted doses
Good taste (mango flavor)
Focus on Rifapentine – Development of Fixed Dose Combination (FDC) RPT/INH and dispersible tablets
| November 22, 2016 XX International Workshop on TB - Barcelona- MM 19
Simplified 3HP regimen: adult Fixed Dose Combinations (300mg/300mg) development plan
Study/Design
GCP
objective Countries Sponsor Nb.patients
receiving RPT
status Start date
BEQ13851
Open label,
Rd, 2-arm, 4-
period, 2-
sequence
cross-over PK
& safety study
BEQ of FDC
tablet (RPT
300mg/INH300m
g) vs standalone
formulations of
RPT (Priftin 150
mg tablet) and
INH (300 mg
tablet) given at
300 mg
RSA ATM (full
package sub
contracted PXL)
46 adult
healthy
volunteers
planned Q22016
Periodic 3HP
Observationnal
Rd, pragmatic,
controlled, 3
arms
- Feasibility ,
safety and
effectiveness of
3HP in high
burden settings
- May be
supportive to
registration in
RSA
RSA UNITAID/KNCV
Dr G.
Churchyard
- 1800 HIV+
(single round)
- 1800 HIV+ (2
rounds- 2nd
year with FDC)
planned FPI Q416
| 20 XX International Workshop on TB - Barcelona- MM November 22, 2016
Adapted regimen for children : dispersible forms FDC (150mg/150mg) & Rifapentine (100mg) development plan
Study/Design
GCP
objective Countries Sponsor Nb.patients
receiving RPT
status Start date
BDR14479
Open label, Rd,
3-period, 3
sequence, 3-
arm, crossover
study
- Relative BA of
dispersible
formulations vs
standard (2 Priftin
150 mg tablets + one
INH 300 mg tablet)
co-administered in
fed condition
- Food effect
RSA ATM (full
package sub
contracted
Parexel)
24 adult healthy
volunteers
planned Dec2016
TBTC-S35
Stepwise
approach
Single arm, age
deescalating
cohort safety
PK study
- PK, safety and
tolerability in children
& determine the age-
specific dose of RPT
(< 2 years)
- bridge data with the
pivotal study S26
- support registration
in <2 years old group
in Europe (PIP)
RSA CDC (Pr
Hesseling-
University of
Cape Town)
72 children 0-12
years old HIV+ &
HIV- WD FDC + RPT (100mg) if needs
planned FPI Q117
| 21 XX International Workshop on TB - Barcelona- MM November 22, 2016
THANK YOU
Ph
ase III
Independant Phase II Dose exploration
HIV & non HIV population Active TB (smears +) 2 months treatment
RPT 7/7 Phase I
Dose exploration
Preclinical Safety & Toxicity
studies
Phase II Safety & Efficacy
10 mg/kg
S29B
S29
S29X
S31
Rifapentine in active TB phase 3 study TBTC-S31/ACTG A5349 - Design
TBTC-S31 “Rifapentine-containing treatment shortening
regimens for pulmonary tuberculosis
a randomized, open-label, controlled, NI phase 3 clinical trial”
increases in antimicrobial activity of RPT :
exposure dependent, robust and ‘in-range’
for treatment shortening
ANALYZED
Start FPI. Q12016
Supportive
Phase I studies*
- 2500 patients
All treatment is daily 7/7
Flat RPT dose of 1200 mg daily
Moxi dose of 400 mg
Food guidance: food with RPT, no food with RIF
| 23 XX International Workshop on TB - Barcelona- MM November 22, 2016
The rifamycins
24
Cornerstone of TB treatment
rifampicin
Rifampin
Catalytic site
The rifamycins chemical compound
Isolated for Amycolatopsis rifamycinica
Planar naphtoquinone ring.
Positions 3 & 4 extensively modified by hemisynthesis
MOA
Binds to b subunit of bacterial RNA polymerase
In DNA channel 12Ǻ away from active site
Proximity with region 3 of s factor
Allosteric effect and dissociation of DNA-RNA hybrid
Anti M. tuberculosis activity
Bactericidal
Active against M. tuberculosis at all stages of replication
Concentration-Time dependant activity
Predictors of activity: AUC / MIC
Mechanism of resistance
Mutations in rpoB gene – 10-8
In all but one condon determining the 12 a.a.
binding site.
Rifamycins are inhibitors of bacterial transcription
Recommended