Short treatment forv : Is It in Sight?

Susan E. Dorman, MD Professor of Medicine Medical University of South Carolina

24 April 2018 ESCMIDECCMID, eLibrary Madrid © by author No Disclosures

ESCMID eLibrary © by author Perspective…

• 2014, Baltimore, Maryland

• 82 year old woman referred to Health Department TB Clinic

• Recently hospitalized for RUL pneumonia. Treated with for presumed community-acquired bacterial pneumonia.

• M. tuberculosis identified in culture after she was discharged ESCMID eLibrary © by author Perspective…

• Broke down in tears on hearing of TB diagnosis • “I can’t go through that again”

• Dx’d with pulmonary TB at age 22 (1954) • Sanitorium in North Carolina for about 2 years • “Injections and pills” for approx. 18 months (INH/PAS/SM?) 6-month “short-course” TB treatment was, at one time, considered miraculous ESCMID eLibraryShould we do better? Can we? © by author Current treatment of Drug-susceptible Pulmonary TB

“intensive phase” “continuation phase”

rifampin isoniazid rifampin 10 mg/kg

1 2 3 4 5 6 months 6 monthsESCMIDall oral eLibraryintrinsic efficacy > 95% © by author How did we get to the current short course regimen of 2HRZE/4HR ?

ESCMID eLibrary © by author Treatment shortening of DS-PTB

Era and Months of therapy required for cure Regimen 3 6 9 12 15 18 1950s-1960s Isoniazid + (+/- PAS) 1970s Isoniazid + Rifampin 1980s Isoniazid + Rifampin + PZA FutureESCMID ??? eLibrary © by author PATHOGEN HOST (Drug-susceptible M. tuberculosis) Shortening treatment for DS pulmonary TB to ANTIMICROBIAL <6 months: AGENT/S What experience (or other tools) already exists? What do we know ESCMID eLibraryalready? © by author Certain hosts reliably can be cured with HOST shortened antimicrobial regimens Smear-neg/culture-neg “paucibacillary” pulmonary TB: 1.9% with relapse after a 4-month treatment course Hong Kong Chest Service. Am Rev Respir Dis, 1989; 139:871 Dutt AK et al. Am Rev Respir Dis, 1989;139:867 Teo SK et al. Ann Acad Med Singapore, 2002;31:175

We suggest that a 4 month treatment regimen is adequate for treatment of HIV- uninfected adult patients with AFB smear- and culture-negative pulmonary TB (conditional recommendation; very low certainty in the evidence)

-American Thoracic Society/Infectious Diseases Society of America TB Treatment ESCMIDGuidelines, 2016 eLibrary © by author ANTI- Certain shortened antimicrobial regimens MICROBIAL AGENT(S) will cure most, but not all, hosts

Table. % of participants with “favorable” outcome (per-protocol analysis group) Control FQ for EMB Phase 3 6-month 4-month regimen regimen REMox TB1 (moxifloxacin for EMB) 92% 85% OFLOTUB2 ( for EMB) 89% 82%

1. Gillespie S et al. NEJM 2014;371:1577 ESCMID eLibrary2. Merle CS et al. NEJM 2014;371:1588 © by author Drug-susceptible pulm TB: How can we cure ALL patients in << 6 months? PATHOGEN HOST (Drug-susceptible M. tuberculosis)

ANTIMICROBIAL New antimicrobial agents AGENT(S) Optimize use of existing agents ESCMID eLibrary © by author “Old” drugs that may not be used New Drugs optimally • • • • PZA • New chemical entities •

Hypothetical Model of TB Chemotherapy • (Isoniazid) M. Iseman, D. Mitchison 3 anatomic/metabolic populations of bacilli in cavitary TB

A: rapidly multiplying, INH>RIF>EMB B: slowly multiplying, acid pH, PZA>RIF>INH A C: sporadically multiplying, RIF>INH

i

l

l

i

c

a

b “Persisters”

# B C

1 2 3 4 5 6 ESCMIDmonths of therapy eLibrary © by author Rifamycins

• Inhibit bacterial DNA-dependent RNA polymerase

• Key “sterilizing” component of TB tx

• Rifampin, , , rifalazil ESCMID eLibrary © by author Current use of rifampin and the case for pharmacodynamic (PD) optimization

Evidence of MED in humans • Early bactericidal activity1

RIF dose n EBA0-2 PD in mice Why300 mg do we3 use 0.06 such600 amg low dose8 of0.19 Range of human 1200 mg 8 0.41 exposures rifampin? after 600 mg p<0.05 oral dose • In DAILY combo therapy with INH2 • Doses <9 mg/kg associated with positive sputum cx at 8, 16, 20 wks

1Jindani et al, Am Rev Respir Dis 1980; 121:939 2 ESCMIDJayaram et al, AAC (2003); 47:2118 eLibraryLong et al, Am Rev Respir Dis 1979; 119:879 © by author Getting more out of the class

•Is rifampin 10 mg/kg the optimal dose? • PanACEA Consortium (M. Boeree et al) • Amina Jindani

•Is rifampin the optimal agent within the rifamycin class? • US CDC TB Trials Consortium, with NIH AIDS Clinical Trials Group ESCMID eLibrary © by author Is rifampin the optimal drug in the rifamycin class?

Rifapentine (RPT, P)

• MIC90 = 0.06 g/ml (vs. 0.25 for RIF) • Half-life = 14-18 h (vs. 2-4 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 ESCMIDfor treatment failure eLibrary © by author Preclinical: DAILY rifapentine is highly active in the mouse model of TB

Proportion (%) of mice relapsing after Rx R, rifampin for: Regimen 8 P, rifapentine R10HZ 8 wks 10 wks 12 wks 7 R20HZ R10 HZ Not Done Not Done 100% (15/15) 6 R40HZ P10 HZ 100% 33% (5/15) 0% (0/15) 5 P10HZ (15/15) P HZ 40% (6/15) 0% (0/15) 4 P20HZ 20 3

CFU per Lung

10 2 Replacing RIFAMPIN 10 mg/kg/d with RIFAPENTINE 10 mg/kg/d Log 1 0 increases regimen bactericidal & 0 2 4 6 8 10 12 sterilizing activity, and halves the Treatment duration (weeks) time needed for cure ESCMID eLibraryFrom Nuermberger et al © by author Re-developing rifapentine for TB: getting the dose right

• How much is safe and well-tolerated? • What are the pharmacokinetics at higher doses? • Pharmacodynamics • Which PK parameter is associated with effect or toxicity? • For that key PK parameter, what range should we target to maximize effect and minimize toxicity? • Are there covariates that influence that PK parameter • What strategies can we use to get the most people at that PK parameter target? ESCMID eLibrary © by author Clinical Phase 1: Safety and PK of escalating rifapentine daily doses in healthy volunteers

45 TBTC S29B: Multiple dose RPT PK No evidence of dose- 40 dependent increase in 5 mg/kg RPT 10 mg/kg RPT 35 frequency of known rifamycin- 15 mg/kg RPT 20 mg/kg RPT 30 associated toxicities, such as

25 hepatotoxicity or cytopenias.

20 Maximum tolerated dose at Meanconcentration (mcg/ml) 15 least 20 mg/kg/d.

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5

0 0 10 20 30 40 50 60 70 Dooley et al; Clin Pharmacol Ther 2012;91:881 ESCMIDTime from dose (h) eLibrary © by author Clinical Phase 2: Efficacy (using surrogate endpoint), safety, tolerability, and PK of escalating rifapentine daily doses in adults with pulmonary TB Sputum smear (+), suspected PTB (n=320)

Randomization (n=320) +INH+PZA+EMB RPT 15 mg/kg RIF 10 mg/kg RPT 20 mg/kg RPT 10 mg/kg Daily for 8 weeks Study visits every 2 weeks for safety assessments & sputum culture

Tolerability/safety: discontinuations, AEs Efficacy (surrogates): % culture neg at week 8, time to stable cx conversion

ESCMIDATS/CDC/IDSA-recommended eLibrary continuation phase regimen © by author Clinical Phase 2: Efficacy (using surrogate endpoint), safety, tolerability, and PK of escalating rifapentine daily doses in adults with pulmonary TB • Randomized, partly double-blind, multicenter (320 participants) • Key Findings • 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 • PK and PK/PD analyses supported flat dosing using 1200 mg without food • Pulmonary cavitation was an important covariate – presence of cavity/s increased by ESCMID2 to 3-fold the RPT AUC required for eLibrary half-maximal response © by author RPT exposure- response relationship tx based on phase 2 clinical trial data

% with negative cultures cultures negative with % Target RPT AUC at completion of 8 weeks of of weeks 8 of completion at

R. Savic, Clin Pharm Ther 2017;102:321 ESCMIDAUC0-24 (ug*h/mL) eLibraryDorman AJRCCM 2015;191:333 © by author RPT: magnitude of the efficacy effect in phase 2 trials* is sufficient to warrant * * proceeding to phase 3

Difference in % with cx conversion at week 8 between investigational and control regimens (phase 2)

Historical phase 2 PZA trials: 12

Phase 2 RPT trial: 12

*solid culture, per-protocol analysis group; upper 2 AUC tertiles for RPT ESCMIDWallis RS PLoS One 2015 10(4) e0125403eLibrary © by author S31/A5349 US CDC TB Trials Consortium, and Screen for eligibility Phase 3 NIH AIDS Clinical Trials Group Consent, enroll • International

• Multicenter Randomize 1:1:1 • Open label • Non-inferiority design • Enroll adolescents & HIV+ in Regimen 1 Regimen 2 Regimen 3 addition to adults & HIV- (control) (investigational) (investigational) • All treatment: daily 7/7 2RHZE/4RH 2PHZE/2PH 2PHZM/2PHM • Flat P dose of 1200 mg 26 weeks 17 weeks 17 weeks • M dose of 400 mg

• Food guidance: food with Evaluation for primary outcome at 12 months after randomization RPT, no food with RIF SECONDARY: Evaluate safety and tolerability of the regimens, intensive PK of • Target ESCMID accrual 2500 ALL TB drugs andeLibrary EFV, biobanking © by author Target 2500 2500 S31/A5349 Cumulative enrollment 2000 Actual 1897 (76%)

1500

1000 Number of participants 500

Jan 2016

0

Expected cumulative accrual Actual cumulative accrual ESCMIDtime eLibrary © by author Shortened treatment for drug- susceptible pulmonary TB: is it in sight? si

• Truly transformative shortening (e.g. tx duration 1 month) likely will rely on new drugs (new mechanisms of action) +/- host directed therapies • Investment in basic research, time

• In the interim, clinically meaningful tx shortening may be feasible by optimizing the use of existing drugs • Results from rifamycin trials in about 2 years ESCMID eLibrary © by author With thanks and attribution to many, including:

• TB Trials Consortium of the US Centers for Disease Control and Prevention especially Andrew Vernon, Stefan Goldberg, Payam Nahid, Rada Savic, Marc Weiner • NIH NIAID AIDS Clinical Trials Group especially Sue Swindells • NIH NIAID Division of Microbiology & Infectious Diseases • Johns Hopkins Center for TB Research especially Dick Chaisson, Eric Nuermberger, Jacques Grosset, Ian Rosenthal, Kelly Dooley, Bill Bishai • Sanofi for rifapentine donation • Study participants ESCMID eLibrary © by author RPT 3rd AUC tertile RPT 2nd AUC tertile

RPT 1st AUC tertile

Rifampin Compared with participants with low RPT exposures and participants on control rifampin regimen, participants with high RPT AUC had faster culture conversion and were more likely to convert cultures to negative by week 8

Stable culture conversion

SOLID MEDIA conversion has been observed observed been has conversion Probability that stable culture culture stable that Probability MITT BY RIFAPENTINE AUC TERTILE

ESCMIDWeeks on treatment eLibraryDorman, AJRCCM 2015 © by author