ACCESS TO MEDICINES. Update on tuberculosis field activities

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1 ACCESS TO MEDICINES Update on tuberculosis field activities

2 Update on clinical activities 1/3 Latent TB Prevent study (S26) main study (8053 patients) PK substudy construction of a POPPK model Paediatric population (#1058) HIV population (#400) snda submission in progress Claimed Indication would be treatment of LTBI in patients at high risk for developing active TB (including HIV+ and children) i@adhere (S33) in progress 519/900 patients enrolled 2

3 Update on clinical activities 2/3 Latent TB (continued) ACTG 5279 : Ultra Short-Course RPT/INH for the Prevention of Active TB in HIV-Infected Individuals with LTBI Comparison of efficacy of a 4-week daily regimen of weight-based RPT/INH to standard 9-Mo daily INH regimen for TB prevention in HIV infected individuals requiring ART 1113/3000 patients enrolled Active TB Close collaboration with CDC-TBTC towards a shortened regimen to design a phase 3 study that could be used for registration of a shorter regimen for active TB Substituing RPT for RIF in combination w/standard companion drugs 3

4 Update on clinical activities 3/3 DDI ATRIPLA TM /Priftin TM Open-label, randomized, 2 periods, parallel groups, PK-DDI study, repeated doses in HIV infected volunteers (otherwise healthy) receiving chronic Atripla (CD4>350) Cohort 1 : Priftin TM daily regimen : 15mg/kg OD for 21 days Atripla 3 weeks Screening Atripla 2 weeks Period 1 Atripla TM Cohort 2 : Priftin TM weekly regimen : 900mg OW (3 weekly administrations) 3 weeks Period 2 Atripla +Priftin EOS 3-5 days after last dose of RPT Atripla Atripla 4

5 Sanofi INT12291 : Cohort 2 results 12 subjects receiving RPT 900 mg ow for 3 consecutive weeks in coadministration with Atripla 1 tablet/d After 3 weekly 900 mg doses of RPT + Atripla emtricitabine and tenofovir no change in steady state exposure (C min,c max & AUC 0-24 ) efavirenz decrease of 15% on C min and AUC 0-24 while C max not affected well tolerated (AEs of mild intensity in accordance with RPT known safety profile ) No modification of CD4 cell counts or viral loads Comparison Atripla+ RPT vs Atripla alone Parameters Treatment ratio estimates After one dose After 3 consecutive weekly doses After one dose 90% CI After 3 consecutive weekly dose C max (0.94 to 1.08) (0.82 to 1.03) C min (0.95 to 1.05) (0.79 to 0.93) AUC (0.93 to 1.01) (0.79 to 0.93) 5

6 Update on Industrial Activities Different combinations are in development Latent TB Active - TB 2 FDC 2 FDC Film Coated Water Disp Film Coated Water Disp 300mg/300mg 150mg/150mg 225/75mg 300/75mg 90/50mg 120/50mg Rifapentine water dispersible Strengh 100mg New FDC pediatric formulation containing Rifampin In order to be in accordance with WHO guidelines (Rapid advice : treatment of tuberculosis in children.world Health Organization

7 Sanofi Portfolio RIFAMPICIN FAMILY RIFAPENTINE FAMILY Sanofi TB R&D objectives DS TB RIFADIN RIFINAH (R+H) PRIFTIN 2FDC (P+H) MDR TB TERIZIDONE RIFATER (R+H+Z) RIFAFOUR (R+H+Z+E) ETHIONAMIDE Improving the efficacy of the drugresistant TB treatments (MDR and XDR-TB) Shortening treatments duration in DS and MDR/XDR-TB By killing the different phenotypes of M. tuberculosis present in human By targeting host pathogen interaction By host modulation LEVOFLOXACIN AMIKACIN 7

8 Update on registration : RPT for LTBI US registration WHO Prequalification WHO guidelines Submission ATM countries GDF eligibility Registration ATM countries Public Market National TB Programs Private Market 8

9 THANK YOU

10 BACK UP

11 RIFAQUIN trial (INTERTB - St George s University Medical School-London-UK): Phase 3, complex design, open-label, randomized and active-controlled To compare 2 strategies using combination of RPT & Moxi for Either reducing the lenght of treatment course Or reducing the total number of drug doses 3 arms : DOT control Regimen 1 2HRZE 2MRZE 2 4HR RPT 900mg + Moxi 400 mg x2/wk Regimen 2 2MRZE 4 RPT 1200mg + Moxi 400 mg once a wk Participating countries: RSA, Zimbabwe, Zambia, Botswana Non-inferiority design (NI margin : 6%) 11

12 RIFAQUIN trial (INTERTB - St George s University Medical School-London-UK): Results Protocol amendment : end of FU set when LPI completed their M12 visit 827 randomized patients with newly diagnosed smear+ TB (1100 initially planned) 275 in control arm; 275 in 6Mo (2Xwk) arm; 277 in 4Mo (OaW) arm Including 26% HIV+ not taking ART with median CD4 cell counts 312/mm 19% excluded from mitt : 592 evaluable patients Secondary endpoint : culture status at Mo2 Culture result 2 -month Intensive Phase RZE + H RZE + M Negative 187 (85%) 394 (90%) Positive 32 (15%) 42 (10%) Total p =

13 RIFAQUIN trial : mitt primary outcomes Overall Status Outcome Control regimen 4-month regimen 6-month regimen Unfavourable during treatment Unfavourable post- treatment Total favourable 161 (86%) 141 (74%) Failure (culture confirmed) 2 2 Death 1 0 Treatment change for adverse event 1 2 Lost to follow-up 5 7 Inadequate treatment 2 0 Other treatment change Relapse (culture confirmed) 4 18 Relapse (limited bacteriology) 2 7 Total unfavourable 27 (14%) 50 (26%) Total assessable (86%) (14%)

14 RIFAQUIN trial : conclusion The 6-month regimen with once-weekly 1200mg rifapentine and moxifloxacin in the continuation phase was non-inferior to control, even at the 2.5% level, also safe and well tolerated. The 4-month regimen with twice-weekly 900mg rifapentine and moxifloxacin was safe and well tolerated but significantly inferior to control in terms of efficacy. The benefit seen in the moxifloxacin arms in culture status at 2 months was marginal confirming previous studies Analysis ongoing (genotype and MIRU) : No increase risk of acquired RIF resistance in relapses apparently 14

15 Access to Medicines: 4 Strategic Levers In support of Operations, in partnership with external stakeholders, we mobilise Sanofi s core skills to improve access to medicines by: Developing products for meeting current and future patient needs Utilising our industrial network in the North and South Making medicines affordable, through tiered-pricing Developing information and educational tools 15

16 Our fields of activity 16

17 Access to Medicines - Geographic Focus Malaria Mental Health Leishmaniasis Buruli Ulcer TB Epilepsy HAT Chagas 17

18 Access to Medicines - Summary A mini-pharma company leveraging the strengths of major parent pharma company Partnerships are critical; we do not work alone 4 strategic levers ; 3 disease area programmes Not just Drugs - importance of IEC 18

19 Rifapentine in active TB : towards an ultra-short course regimen- TBTC S31 Pivotal study Hypothesis: A 4 (3) month rifapentine-based (high dose) treatment regimen is not inferior to the 6-month rifampin-based standard treatment regimen Target Profile: Rifapentine-based regimen, in combination with companion drugs As part an ultra-short course regimen : 3 or 4 months targeted For drug-susceptible pulmonary TB Cavitary & non-cavitary diseases For non-hiv and HIV populations For adult and pediatric populations Also: extrapulmonary TB and other populations at risk 19 TB Annual F2F Meeting Toulouse March 2011

20 Mean ± SD (Geometric mean) [CV%] C min (ng/ml) C max (ng/ml) T a max (h) AUC 0-24 (ng.h/ml) t 1/2z (h) CL ss /F (L/h) a Median (Min - Max) Efavirenz alone Efavirenz + Rifapentine Day 1 Day ± ± ± 2250 (2130) [83.6] (2130) [87.7] (1820) [85.8] 5960 ± ± ± 2500 (5470) [47.5] (5510) [48.8] (5020) [45.5] ( ) ( ) ( ) ± ± ± (79900) [68.3] (77600) [71.6] (68600) [71.8] 24.3 ± ± ± 20.6 (21.2) [59.9] (27.2) [63.9] (25.8) [66.7] 8.75 ± ± ± 6.70 (7.51) [51.3] (7.74) [53.9] (8.74) [62.1] 20

21 ACTG 5279 : NIH /NIAID Prevent TB with ultra-short-course P-based regimen in HIV+ Title : «Phase 3 Clinical Trial of Ultra Short-Course RPT/INH for the Prevention of Active TB in HIV-Infected Individuals with LTBI» Multicenter, Randomized, Open-label study, two balanced groups, non-inferiority design 3000 patients, 1500 per trt group Follow-up 36 months To compare efficacy of a 4-week daily regimen of weight-based RPT/INH to standard 9-Mo daily INH regimen for TB prevention in HIV infected individuals requiring ART By Amendment : evaluation of DDI between RPT and NNRTi (Efavirenz and Nevirapine) in real time Jan 2013: Evaluation of first 30 patients > no concerns (trough EFV cc>1 mg/ml) GO to complete the EFV-PK cohort up to 90 / suspend study until data obtained and allow continuing EFV patients enrollment and starting NVP-PK cohort recruitment Status: end September June: 1050 patients enrolled 21