1. Rifapentine Development Progress – October 4, 2012 | 1 I. CIEREN-PUISEUX – ACCES TO MEDECINE Rifapentine Development Progress CPTR 2012 Workshop

2. Rifapentine Development Progress – October 4, 2012 | 2 I. CIEREN-PUISEUX – ACCES TO MEDECINE 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) ● Interest in new efficient and improved regimens ● shorter, ● With high competion rate ● With good effectiveness and tolerability LTBI ttt 2M TB regimen + LTBI ttt 2M TB regimen 10D regimen 4M TB regimen From Abu-Raddad L et al. PNAS 2009;106(33):13980-85

3. Rifapentine Development Progress – October 4, 2012 | 3 I. CIEREN-PUISEUX – ACCES TO MEDECINE RifapentineRifampin MIC0.06 µg/mL0.25 µg/mL Intra/Extracellular ratio245 T 1/2 13h3h Rifapentine A rifamycin with advantageous properties Rifapentine has properties that favors M. tuberculosis exposure to rifamycin bactericidal activity

4. Rifapentine Development Progress – October 4, 2012 | 4 I. CIEREN-PUISEUX – ACCES TO MEDECINE Latent TB Treatment Shortening TBTC S26 Design INH 300 mg Daily 9 months 270-day dosing Self-AdminisTered INH 300 mg Daily 9 months 270-day dosing Self-AdminisTered Phase III, Randomized, Open-Label Non-inferiority trial n=8053 high-risk TST reactors Low-medium incidence settings 33-month follow-up from randomization Phase III, Randomized, Open-Label Non-inferiority trial n=8053 high-risk TST reactors Low-medium incidence settings 33-month follow-up from randomization 9 MO 33 MO RPT 900mg + INH 900mg Once-weekly 3 months 12-day dosing Directly Observed Therapy RPT 900mg + INH 900mg Once-weekly 3 months 12-day dosing Directly Observed Therapy 3 MO # of TB events Primary objective  Evaluate the effectiveness of weekly RPT/INH for 3 months under DOT Secondary objectives  Safety evaluation  Adherence assessment  Efficacy evaluation based on per- protocol evaluation Primary objective  Evaluate the effectiveness of weekly RPT/INH for 3 months under DOT Secondary objectives  Safety evaluation  Adherence assessment  Efficacy evaluation based on per- protocol evaluation

5. Rifapentine Development Progress – October 4, 2012 | 5 I. CIEREN-PUISEUX – ACCES TO MEDECINE 6 TB cases 15 TB cases Non-inferiority demonstrated as 97.5% upper-bound of diff = 0.08% (<0.75%= NI margin) TBTC S26 – The Prevent TB Study Primary endpoint : TB rates by Mo33 – mITT INH (n 3745) RPT/INH (n 3986) 7 TB cases 15 TB cases

6. Rifapentine Development Progress – October 4, 2012 | 6 I. CIEREN-PUISEUX – ACCES TO MEDECINE 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 completion2,585 (69%)3,273 (82%)< 0.001 Permanent drug d/c- any reason 1,160 (31%)713 (17.9%)< 0.001 Permanent drug d/c- adverse event 139 (3.7%)196 (4.9%)0.009 Permanent drug d/c- adverse 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 Death39 (1.1%)31 (0.8%)NS

7. Rifapentine Development Progress – October 4, 2012 | 7 I. CIEREN-PUISEUX – ACCES TO MEDECINE 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 self- administered 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 ».

8. Rifapentine Development Progress – October 4, 2012 | 8 I. CIEREN-PUISEUX – ACCES TO MEDECINE ● 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 ? TBTC S26 – The Prevent TB Study Limitations

9. Rifapentine Development Progress – October 4, 2012 | 9 I. CIEREN-PUISEUX – ACCES TO MEDECINE LTBI treatment : New shorter treatment regimen Well documented Phase IV 3RPT/INH to prevent TB i@ADHERE DOT vs SAT Phase III The Prevent TB study in low to medium TB incidence settings Phase III Prevent TB in adults with HIV infection (no ART ) (high TB incidence setting) TBTCS26TBTCS26 ZA study (NIAID) (NIAID) #1000 Phase III Prevent TB in adults (in low to medium TB incidence settings) Brazil study #8053 #1148 #399 TBTCS33TBTCS33

10. Rifapentine Development Progress – October 4, 2012 | 10 I. CIEREN-PUISEUX – ACCES TO MEDECINE 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 DOT SATEnhanced SAT* RPT 900mg + INH 900mg once weekly- 12 wks Weekly reminder SMS 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 Medication Event Monitoring System n=300 RPT 900mg + INH 900mg once weekly- 12 wks

11. Rifapentine Development Progress – October 4, 2012 | 11 I. CIEREN-PUISEUX – ACCES TO MEDECINE 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

12. Rifapentine Development Progress – October 4, 2012 | 12 I. CIEREN-PUISEUX – ACCES TO MEDECINE NIAID / TBTC RPT-based regimens for Treatment Shortening RPT-based regimens for Treatment Shortening Active TB Latent TB Substituting RPT for RIF 3 - 4 months Substituting RPT for RIF 3 - 4 months Combining + new TB drug(s) < 3 months Combining + new TB drug(s) < 3 months 3-mo PH 1/7 DOTS 1-mo PH 7/7 self-adm. CDC / TBTC Partnership CPTR Drug Coalition TB Alliance CDC / TBTC CDC / TBTC Partnership ATS Recommendations Phase II TBTC S29x Preclinical DDI EBA Preclinical DDI EBA Phase III TBTC S26 Submission dossier Ph III – TBTC S26 RPT = P = Rifapentine RIF = R = Rifampin H = Isoniazid Phases III A 5279 Registration ISTs Current Regulatory Requirements Registration ISTs Upcoming Regulatory Requirements Pragmatic ISTs Active & Latent TB treatment shortening using rifapentine-based regimens development approach

13. Rifapentine Development Progress – October 4, 2012 | 13 I. CIEREN-PUISEUX – ACCES TO MEDECINE Phase III Independant Phase II Dose exploration Endpoints: Safety Endpoints: Early MCB PK / PD Interaction studies Phase I Dose exploration Preclinical Safety & Toxicity studies Phase II Safety & Efficacy 10 mg/kg S29BS29B S29S29 S29XS29X PIP Active TB development plan Selecting the optimal dose for the pivotal Phase III Primary endpoint Safety Primary endpoint Safety Primary endpoints Safety & Efficacy 2-month conversion Primary endpoints Safety & Efficacy 2-month conversion

14. Rifapentine Development Progress – October 4, 2012 | 14 I. CIEREN-PUISEUX – ACCES TO MEDECINE Study 29 Study 29X Open-label Open-label 5/7 + DOTS 5/7 + DOTS Fasting Fasting Primary endpoint: Efficacy & Safety Primary endpoint: Efficacy & Safety Double-blind for RPT arms Double-blind for RPT arms 7/7 + DOTS on week days 7/7 + DOTS on week days Fed Fed Primary endpoint: Safety Primary endpoint: Safety n = 531 n = 320 FPI = July 2011 ● TBTC S29 amendment = TBTC S29 eXtension TBTC Study 29X Phase IIb Dose exploration

15. Rifapentine Development Progress – October 4, 2012 | 15 I. CIEREN-PUISEUX – ACCES TO MEDECINE Phase III Interaction studies Phase I Dose exploration Preclinical Safety & Toxicity studies Phase II Safety & Efficacy 10 mg/kg S29BS29B S29S29 S29XS29X S31S31 Active TB development plan Selecting the optimal dose for the pivotal Phase III Primary endpoints Safety & Efficacy 1-year relapse Primary endpoints Safety & Efficacy 1-year relapse PIP Independant Phase II Dose exploration Endpoints: Safety Endpoints: Early MCB PK / PD

16. Rifapentine Development Progress – October 4, 2012 | 16 I. CIEREN-PUISEUX – ACCES TO MEDECINE Access to Shorter Treatment against Active & Latent TB 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