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