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

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):

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

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

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

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%)< Permanent drug d/c- any reason 1,160 (31%)713 (17.9%)< 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

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 ».

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

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 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

Rifapentine Development Progress – October 4, 2012 | 10 I. CIEREN-PUISEUX – ACCES TO MEDECINE 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

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

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 months Substituting RPT for RIF 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

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

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

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

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