Treatment shortening for (drug-susceptible) pulmonary TB: Building a case for rifapentine Susan Dorman, MD XXI Jornadas Internacionales sobre Tuberculosis 20 November 2017 Disclosures • Sanofi aventis donated rifapentine to the CDC for some of the studies described in this talk Need for Shorter Treatment for DS-TB (in addition to improving access to, delivery of TB care) • Shorter, highly potent regimens have potential to: • Increase adherence, decrease default rates • Decrease drug resistance • Decrease TB Control Program costs • Strategies for developing shorter regimens • New drugs • Optimize use of existing drugs Existing drugs that may not be used optimally • Rifamycins • Is 10 mg/kg the optimal dose for rifampin? • Is rifampin the optimal drug in its class? • Fluoroquinolones • Which fluoroquinolone? • As replacement for ethambutol? • As replacement for isoniazid? • Pyrazinamide • How to get drug into more bacteria • How to minimize toxicity and maximize activity • Linezolid, β-lactams, others Rifamycins Rifamycins •Inhibit bacterial DNA-dependent RNA polymerase •Key “sterilizing” component of TB tx •Rifampin, rifapentine, rifabutin, rifalazil Current use of rifampin and the case for pharmacodynamic (PD) optimization A lot of Evidence of MED in humans PD in mice3 bacteria • Early bactericidal activity2 RIF dose n EBA0-2 300 mg 3 0.06 600 mg 8 0.19 1200 mg 8 0.41 • In DAILY combo therapy with INH: Doses <9 mg/kg associated with positive sputum cx at 8, 16, 20 wks Few/no bacteria 1 Jindani et al, Am Rev Respir Dis 1980;121:939 2 Long et al, Am Rev Respir Dis 1970;119;879 3 Jayaram et al, AAC (2003); 47:2118 Current use of rifampin and the case for pharmacodynamic (PD) optimization A lot of Evidence of MED in humans PD in mice bacteria • Early bactericidal activity2 RIF dose n EBA0-2 300 mg 3 0.06 600 mg 8 0.19 1200 mg 8 0.41 Range of human AUC/MIC after 600 mg oral dose • In DAILY combo therapy with INH: Doses <9 mg/kg associated with positive sputum cx at 8, 16, 20 wks Few/no bacteria 1 Jindani et al, Am Rev Respir Dis 1980;121:939 2 Long et al, Am Rev Respir Dis 1970;119;879 3 Jayaram et al, AAC (2003); 47:2118 Existing drugs that may not be used optimally • Rifamycins • Is 10 mg/kg the optimal dose for rifampicin? • Is rifampicin the optimal drug in its class? • Fluoroquinolones • Which fluoroquinolone? • As replacement for ethambutol? • As replacement for isoniazid? • Pyrazinamide • How to get drug into more bacteria • How to minimize toxicity and maximize activity • Linezolid, β-lactams, others rifapentine rifampicin Rifapentine (RPT, P) Half-life = 14-18 h (vs. 2-4 for RIF) MIC90 = 0.06 mg/ml (vs. 0.25 for RIF) Developed as a rifamycin for highly intermittent (600 mg once or twice per week) active TB treatment; US FDA approved for this indication in 1998, but activity of these intermittent regimens is not sufficient for their use in patients at high risk for treatment failure Preclinical: DAILY rifapentine is highly active in mouse model of TB R, rifampin 8 R10HZ Proportion (%) of mice relapsing after Rx for: P, rifapent in e Regimen 7 R20HZ 8 wks 10 wks 12 wks 6 R40HZ R10 HZ Not Done Not Done 100% (15/15) 5 P10HZ R20 HZ Not Done 100% (15/15) 67% (10/15) 4 P20HZ R40 HZ Not Done 27% (4/15) 0% (0/15) 3 P10 HZ 100% (15/15) 33% (5/15) 0% (0/15) 2 P20 HZ 40% (6/15) 0% (0/15) 1 0 0 2 4 6 8 10 12 Replacing RIFAMPIN 10 mg/kg/d with Treatment duration (weeks) RIFAPENTINE 10 mg/kg/d: • increases bactericidal & sterilizing activity • halves the time needed for cure From Nuermberger et al ClinicalTBTC S29B: Multiple Phase dose 1: RPT Safety PK and PK of escalating rifapentine daily doses in healthy volunteers 5 mg/kg RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RPT No evidence of dose-dependent increase in frequency of known rifamycin-associated toxicities, e.g. hepatotoxicity or cytopenias Max tolerated dose at least 20 mg/kg/d. 10 20 30 40 50 60 70 Time from dose (h) Dooley et al; Clin Pharmacol Ther 2012;91:881 Clinical Phase 2: TBTC Study ‘29X’ STUDY OBJECTIVE For regimens that include “high” doses of RPT (in addition to H+Z+E) administered daily during intensive phase treatment of smear positive, drug susceptible pulmonary TB: • Determine safety & tolerability • Estimate antimicrobial activity, using a surrogate endpoint for ‘cure’ • PK/PD relationships • Which PK parameter is associated with effect or toxicity? • For the key PK parameter, what range should we target? • Are there covariates that influence that PK parameter? • What strategies can we use to get the most people at that PK parameter target Sputum smear (+) PTB suspect Phase 2 Randomization (n=320) RPT 20 mg/kg RPT 15 mg/kg RPT 10 mg/kg RIF 10 mg/kg RPT placebo RPT placebo INH+PZA+EMB INH+PZA+EMB INH+PZA+EMB INH+PZA+EMB 7/7 for 8 weeks 7/7 for 8 weeks 7/7 for 8 weeks 7/7 for 8 weeks Study visits every 2 weeks for safety assessments & sputum culture Double-blind with respect to RPT dose, but not RPT vs RIF RPT given with high-fat food to maximize absorption ASSESS FOR PRIMARY ENDPOINTS: Tolerability/safety: discontinuations, AEs Efficacy (surrogates): % culture neg at week 8, time to stable cx conversion ATS/CDC/IDSA-recommended continuation phase regimen Current TB treatment “intensive phase” “continuation phase” RIF 10 mg/kg/d RPT 10 mg/kg/d isoniazid rifampin isoniazid RPT 15 mg/kg/d pyrazinamide rifampin 10 mg/kg ethambutol RPT 20 mg/kg/d 1 2 3 4 5 6 months Sites enrolling in SettingTBTC Study 29 and 29x Phase 2 TB Trials Consortium Enrollment Phase 2 • Inclusion criteria (summary) • Age 18 years or older • Sputum smear (+) PTB suspect • < 5 days TB tx, prior 6 months • HIV testing; those on ART excluded (drug-drug interactions) • Karnofsky > 60 •AST <3x ULN • Informed consent • Randomization stratified by • Enrollment site • baseline cavitation, yes vs. no 801 Not enrolled: 1135 Screened Phase 2 Refused (127) Not eligible (573) Other or unknown (101) 334 Enrolled 80 not eligible for MITT: 334 Intention-to-Treat • Did not grow Mtb (6) • Resistant to INH, rifamycins and/or analysis PZA (44) • Other (30) 254 Modified Intention-to- 19 not eligible for Per-Protocol: Treat analysis • Drug toxicity led to d/c regimen (5) • Died (2) • Withdrew consent or physician advised to d/c regimen (7) 235 Per Protocol analysis • Contaminated week 8 cx (1 • Other (2) Clinical Phase 2: TBTC Study 29X Phase 2 Results: Study Population (ITT) Assigned treatment arm --> RIF 10 RPT 10 RPT 15 RPT 20 N=85 N=87 N=81 N=81 Median age (range) 33 (19,78) 29 (19,66) 31 (18,69) 31 (19,70) Median weight (range) 54 (41,77) 54 (40,76) 55 (40,81) 54 (41,82) Male (%) 55 (65) 63 (72) 58 (72) 54 (67) Cavitary pulmonary TB (%) 69 (81) 67 (77) 61 (75) 60 (74) HIV-positive (%) 5 (6) 6 (7) 4 (5) 11 (14) Enrolled at African site (%) 45 (53) 49 (56) 48 (59) 48 (59) *A well-tolerated regimen was pre-defined as one for which the 90% one-sided confidence limit of the Clinical Phase 2: TBTC Study 29X % of participants who permanently discontinued Results: Tolerability (ITT) that regimen was < 30% Assigned treatment arm ---> RIF CTRL RPT 10 RPT 15 RPT 20 N=85 N=87 N=81 N=81 Regimen permanently discontinued 11 5 5 9 (12.9%) (5.7%) (6.2%) (11.1%) Upper bound of 90% one-sided CL* 19.0 10.5 11.3 17.1 based on microbiology 4 2 3 3 death 0 0 1 1 toxicityother than death 3 0 1 2 w/draw consent, refuse to continue 23 0 0 Other 2 0 0 3 Safety: No differences in adverse events (number, type, severity) between arms % of participants whose sputum is Mtb negative at the end of intensive phase treatment (MITT), by ASSIGNED TREATMENT ARM RIF RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg SOLID CX (n/n) 81.3 (52/64) 92.5 (62/67) 89.4 (59/66) 94.7 (54/57) % difference vs. RIF 11.3 8.1 13.5 (95% CI) (-1.7, 24.3) (-5.5, 21.8) (0.7, 26.3) value 0.10 0.14 0.05 LIQUID CX (n/n) 56.3 (36/64) 74.6 (50/67) 69.7 (46/66) 82.5 (47/57) % difference vs. RIF 18.4 13.5 26.2 (95% CI) (0.8, 35.9) (-4.5, 31.4) (8.9, 43.5) value 0.04 0.16 <0.01 RIF in S29: solid 79.2%, liquid 62.6% % of participants whose sputum is Mtb negative at the end of intensive phase treatment (MITT), by RIFAPENTINE AUC TERTILE low AUC medium AUC high AUC RIF RPT RPT RPT AUC < 297 AUC 297-461 AUC > 461 SOLID CX (n/n) 81.3 (52/64) 85.5 (47/55) 96.7 (58/60) 93.3 (70/75) % difference vs. RIF 4.2 15.4 12.1 (95% CI) (-10.8, 19.2) (3.2, 27.6) (-0.5, 24.6) value 0.27 <0.01 0.02 LIQUID CX (n/n) 56.3 (36/64) 56.4 (31/55) 86.7 (52/60) 80.0 (60/75) % difference vs. RIF 0.1 30.4 23.8 (95% CI) (-19.5, 19.7) (13.9, 46.9) (7.1, 40.4) value 0.50 <0.01 <0.01 RIF in S29: solid 79.2%, liquid 62.6% Clinical Phase 2:TBTC Study 29X Phase 2 Arm- vs.