Treatment shortening for (drug-susceptible) pulmonary TB:

Building a case for

Susan Dorman, MD XXI Jornadas Internacionales sobre 20 November 2017 Disclosures

• 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

• • Is 10 mg/kg the optimal dose for rifampin? • Is rifampin the optimal drug in its class? • Fluoroquinolones • Which fluoroquinolone? • As replacement for ? • As replacement for ? • • How to get drug into more bacteria • How to minimize toxicity and maximize activity • , β-lactams, others Rifamycins

Rifamycins •Inhibit bacterial DNA-dependent RNA polymerase •Key “sterilizing” component of TB tx

•Rifampin, rifapentine, , 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 ? • 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 g/ml (vs. 0.25 for RIF) Developed as a 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. Dose- vs. Exposure-Response

PD outcome P-value P-value P-value Description Arm effect Dose effect Exposure (AUC) effect Stable culture conversion, solid 0.6 0.17 0.0002 media Stable culture conversion, liquid 0.36 0.17 0.001 media ‘Is 20 mg/kg ‘Is 1200 mg ‘Is AUC better than 15 mg/kg better than 900 mg driving the effect?’ better than 10 mg/kg?’ better than 600 mg?’ Efficacy: PKPD relationship is steep Emax curve Phase 2

Maximal effect

50% effect

Legend: Median exposure: 600 mg group Median exposure: 900 mg group Median exposure: 1200 mg group

23 AUC (mcg*h/L) Courtesy of Rada Savic Key Findings from Phase 2 Studies of RPT

• The RPT regimens were well-tolerated and appeared safe; there were no specific toxicities that increased with increasing RPT dosage • Efficacy, whether assessed by % culture negative at end-of-intensive phase or time to stable culture conversion, was greater for the highest RPT dosages than for RIF • Exposure (AUC) was the strongest driver of the efficacy response; AUC- response curve is steep • PK and PK/PD analyses support flat dosing using 1200 mg ‘with food’ • Pulmonary cavitation is an important covariate – presence of cavity(s) increases by almost 3-fold the RPT AUC required for half-maximal response Conclusion from Phase 2 Studies of RPT

For rifapentine, the robust antimicrobial activity and observed good tolerability and safety justify assessment of daily high-dose rifapentine in regimens of shorter than 6 months duration in a phase 3 Clinical Phase 3: TBTC S31/ACTG 5349 Primary Objectives Evaluate efficacy of a rifapentine-containing regimen to determine whether the single substitution of RPT for RIF makes it possible to reduce to 4 months the duration of treatment (direct follow-on to S29X) 2PHZE/2PH

Evaluate efficacy of a 4 month regimen that substitutes a) RPT for RIF and b) MOX for EMB to determine whether reduction to 4 months duration is possible (optimized regimen using existing drugs) 2PHZM/2PHM DESIGN: Notes: multicenter • All treatment: daily 7/7 3 arms (1:1:1) Screen for eligibility • Flat P dose of 1200 mg Open label • M dose of 400 mg Non-inferiority design Consent, enroll • Food guidance: food with RPT, no Target enrollment: 2500 food with RIF Randomize 1:1:1

Regimen 1 Regimen 2 Regimen 3 (control) (investigational) (investigational) 2RHZE/4RH 2PHZE/2PH 2PHZM/2PHM (26 wks) (17 wks) (17 wks)

Evaluation for primary outcome (cure) at 12 months after randomization SECONDARY: Evaluate safety and tolerability of the regimens, intensive PK of ALL TB drugs and EFV, biobanking Eligibility (summary) Phase 3 • Inclusion • Sputum that is smear positive and/or is Xpert positive with semiquant result of medium or high • Age 12 or older • HIV testing • CD4 ≥ 100 • Usual lab parameters • Informed consent

• Exclusion • More than 5 days of treatment directed against active TB • TB or suspected TB involving CNS, bones/joints, miliary • Wt less than 40 kg • Karnofsky score of 50 or less • Known drug resistant TB Phase 3 Study 31 / A5349 Status First patient in: Jan 2016 Current enrollment: 1468 (59%) 30 sites

Targets Last patient enrolled: Q3 2018 Last patient out: Q1 2020 Results: Q3 2020 Summary

• Rifapentine-based regimens hold promise for shortening the treatment of DS-pulmonary TB to meaningfully less than 6 months

• A phase 3 clinical trial evaluating such regimens is over half-enrolled; results expected in 3 years What else is on the horizon?

• DS-TB: high dose rifampin for treatment shortening • DS-PTB: identification of subpopulations of patients that can be cured reliably with <6 months tx, and subpopulations that require >>6 months tx

• DS and DR TB: B-Pa824-Moxi-PZA

• DR-TB • Shortened regimens • Injection-sparing regimens • Optimization of drug use for EPTB (e.g. TB meningitis) Thank you

Site coordinators & clinicians, and participants The S29X Protocol Team: Neil Schluger, Jason Stout, Lorna Bozeman, Stefan Goldberg, John Johnson, Betial Haile, Emily Hecker, Grace Muzanye, Masa Narita, Payam Nahid, Susan Ray, Chad Heilig, Andrew Vernon, Marc Weiner The S31 Protocol Team: Payam Nahid, Sue Swindells, Stefan Goldberg, Ekaterina Kurbatova, Richard Chaisson, Kwok-Chiu Chang, Michael Chen, Mark Cotton, Dalene von Delft, Kelly Dooley, Melissa Engle, Courtney Fletcher, Phan Ha, Lara Hosey, John Johnson, Daniel Johnson, Marilyn Marone, Cynthia Merrifield, Jose Miro, Sachiko Miyahara, Nguyen Viet Nhung, April Pettit, Anthony Podany, Kathleen Robergeau, Wadzanai Samaneka, Andrew Vernon, Mark Weiner, Lisa Wolf The TBTC Data Center: Pei-Jean Feng, Ruth Moro, Chad Heilig, Lorna Bozeman, Stefan Goldberg, Bill Mac Kenzie, Erin Sizemore, Kimberly Chapman, Deron Burton, Anne Purfield, Nicole Brown Ekaterina Kurbatova Sanofi Aventis (for donation of rifapentine and support for PK analyses) Others: Rada Savic, Kelly Dooley, Chuck Peloquin for PK/PD analyses; Bill Burman, Eric Nuermberger, Jacques Grosset FUNDERS: CDC TB Trials Consortium, NIH AIDS Clinical Trials Group, FDA Orphan Products R01