Co-Administration of Pretomanid with Rifampin Or Rifabutin Among Patients with Pulmonary Tuberculosis

Co-administration of pretomanid with rifampin or rifabutin among patients with pulmonary tuberculosis

Interim PK results from “Assessing Pretomanid for Tuberculosis” (APT) Trial

Elisa Ignatius, Mahmoud Tareq Abdelwahab, Bronwyn Hendricks, Nikhil Gupte, Kim Narunsky, Grace Barnes, Rodney Dawson, Kelly E. Dooley, Paolo Denti, and the APT study team

12TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF TUBERCULOSIS DRUGS September 10, 2019 London, UK Disclosures

• Pretomanid donated by TB Alliance • Rifabutin donated by Pfizer

• I have no personal financial disclosures. Background

• TB control challenged by duration and complexity of treatment regimens

• Pretomanid is a novel nitroimidazole with activity against replicating and dormant bacilli

• Highly effective in combination with linezolid and bedaquiline for XDR-TB • Treatment shortening for drug-sensitive TB

• Extensively metabolized Brief history

2001 2002 2004 2005 2006-2015 2016 2018 2019

• Nature • In-licensed • Preclinical • IND filed • Phase I-III • NixTB • ZeNix • FDA publication from Chiron trials • NDA • EMA • WHO August 14, 2019: FDA approves BPaL for XDR-TB and treatment intolerant/non-responsive MDR-TB (6 months)

OBJECTIVE Describe the effect of co-administration with rifabutin or rifampin on the pharmacokinetic parameters of pretomanid

https://www.tballiance.org/pathway-potential-new-tb-treatments A Phase 2 Randomized, Open-Label Trial of Pretomanid-Containing Regimens versus Standard Treatment for Drug-Sensitive Sputum Smear-Positive Pulmonary Tuberculosis (APT)

Rationale: New chemical entities of the nitroimidazole class are being developed for TB. Pretomanid is extremely potent in animal models as part of combination therapy. Is pretomanid a good candidate for TB treatment shortening in people with drug-sensitive TB? Design: Phase IIB, randomized, open-label, three-arm trial assessing the safety and efficacy of Pretomanid added to first-line drugs over 12 weeks among adult patients with pulmonary TB Arm Weeks 0-8 Weeks 9-12 Weeks 13-24* 1 PaHRZ PaHR HR 2 PaHRbZ PaHRb HR 3 (standard Rx) HRZE HR HR

R=rifampicin; Rb=rifabutin; Pa=pretomanid; H=isoniazid; E=ethambutol; Z=pyrazinamide Duration: 12 months (3 months experimental treatment, then 3 months standard treatment; additional 6 months of follow-up) Sample size: 183 participants Adults with new sputum smear-positive pulmonary TB

Randomization 1:1:1

Pretomanid 200 mg Pretomanid 200 mg ETHAMBUTOL Outcomes Weeks 0-8 Isoniazid Isoniazid Isoniazid Rifampin 600 mg Rifampin 600 mg Rifabutin 300 mg Primary: Pyrazinamide Pyrazinamide Pyrazinamide Once daily for 56 doses Once daily for 56 doses Once daily for 56 doses - Efficacy (liquid culture) - Safety, tolerability

Pretomanid 200 mg Pretomanid 200 mg Isoniazid Secondary: Isoniazid Isoniazid Weeks 9-12 Rifampin Rifampin Rifabutin - Discontinuation rate Once daily for 28 doses Once daily for 28 doses Once daily for 28 doses - Efficacy (solid culture) - Conversion at 8, 12 wks Collect sputa for solid and liquid cultures at days 0, 7, 14, 21, 28, 42, 56, 70, 84. - Rate of △TTP over 12 wks Safety visits at Days 7, 14, 21, 28, 42, 56, 70, 84 - DDI: Pa + RIF vs Rb Semi-Intensive PK analysis at Day 14 & Sparse PK analysis at Days 28, 56, 84 Ophthalmologic examination at baseline - Pretomanid PK/PD

Weeks 13-24 Continue TB treatment with conventional continuation phase regimen. Study visits at 4 and 6 months

Post-treatment Post-treatment follow-up visit at 12 months Eligibility

Inclusion criteria Exclusion criteria • Suspected pulmonary TB, smear • Pregnant, breast feeding positive or GeneXpert positive • Disorders for which study drugs are contraindicated • Age >= 18 years (severe hepatic damage, acute liver disease, allergy to • Weight >= 40kg, <= 80kg drugs, uncontrolled gouty arthritis) • Karnofsky score at least 60 • Planned treated with tacrolimus, cyclosporine • HIV negative, OR HIV positive with • Pulmonary silicosis CD4 >350, not on ART • CNS TB • Ability to adhere • QTc >450ms • Post-menopausal or on double barrier • Neuropathy, epilepsy, lens opacity conception for self or partner (if male) • Resistance to first line TB drugs • ALT >3xULN, tbili >2xULN, Cr >ULN • Hg <7.0 g/dL, platelet<100,000/mm3 • > 5 days treatment with TB treatment Baseline characteristics

Table 4.1 Baseline Characteristics of Patients at Enrollment

PaHRZ PaHRbZ HRZE ALL

Number 90

Age - Median (IQR) 32 (22 – 40) 31 (23 – 38) 30 (24 – 33) 31 (23 – 39)

Sex (% Males) 25 (83%) 23 (74%) 20 (69%) 68 (76%)

Race/Ethnicity % White 0 0 0 0 Black 16 (53%) 20 (65%) 18 (62%) 54 (60%) Colored 14 (47%) 11 (35%) 11 (38%) 36 (40%)

HIV Status - % Positive 2 (7%) 2 (6%) 2 (7%) 6 (7%)

Cavitation >1cm 25 (83%) 25 (81%) 26 (87%) 75 (83%) Materials and methods

• PK samples: pre-dose, 1, 2, 5, 8, and 24 hours post-dose on day 14 • 57 participants, 339 samples

• LC-MS/MS assay, 0.1 mg/L as lower limit of quantification • NONMEM 7.4 with FOCE-I • PsN • R software and STATA • Xpose4 and Pirana Model structure

Dose Bioavailability (F) Central volume

Ka Central compartment

Series of transit compartments CL Mean Transit Time (MTT) + Number of Trans Cmpts (NN) Model parameters

Parameter description Typical values Central Volume of distribution Vc(L)a 81 Absorption rate constant Ka (1/h) 0.764 Mean transit Time (h) 1.43 Number of Transit Compartment (NN) 4.49 Bioavailability (F) 1 FIXED Proportional error (%) 6.84 Additive Error (mg/L) 0.032 Rifampin effect on clearance (%) 78.7 Sex [Female] effect on clearance (%) -20.8 Between subject variability of clearance (%CV) 20.5 Between occasion variability of Absorption rate constant (%CV) 41.7 Between occasion variablity of mean transit time (%CV) 78.1 Between occasion variability of bioavailability (%CV) 11.6

Parameters were scaled by median weight/fat free mass VPC plot by arm Model-predicted PK metrics

AUC0-24 (mg*h/L) Cmax(mg/L)

58.9 (48.1-64.6) 3.4 (2.94-3.74)

] 4

g m

29.9 (23.6-35.1) [ 2.15 (1.86-2.47)

]

[

e c

C 50 3

e P

2 25

Rifampin Rifabutin Rifampin Rifabutin Prior pretomanid data

Compiled PK parameters for pretomanid Volunteers1 Patients3 (CL-010) Patients3 (CL-007) (d7) (d14) (d14) Fasting Fasting Fasting Rif-Pa Pa 50 100 150 200 200 600 1000 1200

AUC0-24 (mg*h/L) 13.7 42.5 12 17 25 36 30 69 130 130

Cmax (mg/L) 1.2 2.5 0.75 1.1 1.5 2.1 2.0 4.2 6.6 7.0

CLF (L/h) 14.7 4.7 4.8

|------49% ------| |-- 66% --| Compiled PK parameters for pretomanid APT (patients) Volunteers1 Patients2 (CL-010) Patients2 (CL-007) Health volunteers3 (d14) (d7) (d14) (d14) (single dose) Fed Fasting Fasting Fasting Pa (fast) Pa (fed) Pa-H-Rif-Z Pa-H-Rb-Z Rif-Pa Pa 50 100 150 200 200 600 1000 1200

AUC0-24 (mg*h/L) 28.1 51.6 29.9 58.9 13.7 42.5 12 17 25 36 30 69 130 130

Cmax (mg/L) 1.1 2.0 2.2 3.4 1.2 2.5 0.75 1.1 1.5 2.1 2.0 4.2 6.6 7.0

CLF (L/h) 7.6 3.9 7.2 4.0 14.7 4.7 4.8

1. Medians: Dooley et al. “Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir- Ritonavir, Efavirenz, or Rifampin” 2. Geometric means; Lyons. “Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients” (2018) 3. FDA Briefing Document: https://www.fda.gov/media/127592/download. DSMB meeting - August 2019 • Safety Evaluation A Data and Safety Monitoring Board (DSMB) will review the study protocol and oversee progress of the trial. The DSMB will review safety data once 50% of the participants have completed study treatment. Since this is an open-label study, the DSMB will have access to treatment group assignment. The DSMB will be comprised of at least the following: an expert in statistics, an expert in clinical trials, and an expert in clinical TB. No early stopping rules will be formally adopted. • Time to culture conversion Unadjusted hazard ratio for time to culture conversion will be estimated using Cox-proportional hazards model. A hazard ratio of at least 1.20 will ensure enhanced efficacy of each experimental treatment arm. The interim analysis is powered at 95% to ensure the end of study power at 90%. An experimental arm that does not meet efficacy criteria at the interim analysis may be dropped, following a formal review of all data by the study team leadership and the DSMB. • PK analysis

PK parameters (e.g. area under the concentration-time curve over 24 hours (AUC0-24), minimum concentration (Cmin), maximum concentration (Cmax), and oral clearance (Cl/F)), will be estimated for PA-824 from semi-intensive sampling data, using a noncompartmental approach using standard PK software, like Phoenix WinNonLin. Using all PK data (sparse and semi-intensive), a PK/PD model will be developed to evaluate the PK values for PA-824 when given with rifampicin vs. with rifabutin. Results may be helpful as accessory information that will put interim efficacy results into pharmacologic context. Upcoming analyses

• Efficacy (liquid culture) of PaHRZ and PaHRbZ vs HRZE • Safety, tolerability of regimens

• Secondary: • Discontinuation rate • Efficacy (solid culture) • Culture conversion at 8, 12 wks • Rate of △TTP over 12 wks • Final analysis of drug-drug interactions of Pa + Rif vs Rb • Correlation of pretomanid PK/PD

• Building more comprehensive PBPK model including data from other studies, DDI Conclusions

• Co-administration with rifampin increases pretomanid clearance compared to rifabutin

• Pretomanid AUC with rifampin in a fed state is comparable to pretomanid monotherapy in a fasting state

• Pretomanid AUC with rifabutin in a fed state is higher than that seen in pretomanid monotherapy in a fasting state

• Safety acceptable, efficacy met the hazard ratio threshold to continue References 1. Lyons MA. Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother [Internet]. 2018;62(7):1–19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29661865 2. Diacon AH, Dawson R, Du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 2012;56(6):3027–31. 3. Dooley KE, Luetkemeyer AF, Park JG, Allen R, Cramer Y, Murray S, et al. Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrob Agents Chemother. 2014;58(9):5245–52. 4. Salinger DH, Subramoney V, Everitt D, Nedelman JR. Population Pharmacokinetics of Pretomanid. Antimicrob Agents Chemother [Internet]. 2019 Aug 12; Available from: http://aac.asm.org/lookup/doi/10.1128/AAC.00907-19 5. Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents Chemother. 2010;54(8):3402–7. 6. Singh R, Manjunatha U, Boshoff HIM, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science [Internet]. 2008 Nov 28;322(5906):1392–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19039139 7. Stephen C. Piscitelli, Keith A. Rodvold, Manjunath P. Pai 2011. Humana Press, an imprint of Springer Science+Business Media, New York. Drug Interactions in Infectious Diseases, 3rd Edition. 8. Dogra M, Palmer BD, Bashiri G, Tingle MD, Shinde SS, Anderson RF, et al. Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver. Br J Pharmacol [Internet]. 2011 Jan;162(1):226–36. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20955364 9. Baptista R, Fazakerley DM, Beckmann M, Baillie L, Mur LAJ. Untargeted metabolomics reveals a new mode of action of pretomanid (PA- 824). Sci Rep [Internet]. 2018 Mar 23;8(1):5084. Available from: http://dx.doi.org/10.1038/s41598-018-23110-1 Acknowledgements

University of Cape Town Johns Hopkins University Rodney Dawson Kelly Dooley Bronwyn Hendricks Nikhil Gupte (Statistician) Kim Narunsky Grace Barnes (Global Study Coordinator) Helen McIlleron Mahmoud Tareq Abdelwahab Paolo Denti Medical University of South Carolina Colleen Whitelaw Susan Dorman David Carman Debbie Carstens Acknowledging: Wendy Simons FDA Orphan Drugs Program Global Alliance for TB Drug Development TB Alliance Pzifer FDA R01 R01FD004794 T32 GM066691