Rifapentine Development Progress CPTR 2012 Workshop Rifapentine Development Progress – October 4, 2012 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 1 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 2 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 Rifapentine Development Progress – October 4, 2012 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 3 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 4 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 5 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 6 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 7 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 8 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 9 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 10 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 11 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 12 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 13 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 14 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 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 15 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 Rifapentine Development Progress – October 4, 2012 I. CIEREN-PUISEUX – ACCES TO MEDECINE | 16