TB Drugs in the Pipeline Carl M. Mendel, MD TB Alliance IUATLD Meeting San Antonio, February 24, 2012

TB Alliance TB Alliance PHARMA BIOTECH ACADEMIA INSTITUTES GOVERNMENTS FOUNDATIONS Founded in 2000 Not-for-profit Product Development Partnership (PDP) headquartered in New York, with office in Pretoria Entrepreneurial, virtual approach to drug discovery and development Largest portfolio of TB drug candidates in history

TB Alliance Mission Develop new, better treatments for TB that are: Faster-acting and less complex Compatible with anti-retrovirals for HIV/AIDS coinfection Active against drug sensitive and drug resistant strains Ensure that new regimens are affordable, adopted for use, and made widely available Coordinate and act as catalyst for global TB drug discovery and development activities

TB Alliance Portfolio Clinical Development Discovery Target Or Cell-Based Screening Natural Products IMCAS Whole-Cell Hit to Lead Program GSK TBA-354 U. of Auckland/ U. Ill Chicago PA-824 Novartis Moxifloxacin (+ H, R, Z) Bayer Topoisomerase I Inhibitors AZ/NYMC AZ Mycobacterial Gyrase Inhibitors TMC207 Tibotec Moxifloxacin (+ R, Z, E) PA-824/Pyrazinamide TB Drug Discovery Portfolio NITD Riminophenazines IMM/BTTTRI TMC207/Pyrazinamide Gyrase B Inhibitors Pyrazinamide Analogs Yonsei PA-824/ Moxifloxacin/ Pyrazinamide Folate Biosynthesis Inhibitors AZ RNA Polymerase Inhibitors Energy Metabolism Inhibitors AZ/U. Penn Lead identification Lead Optimization Clinical Phase I Clinical Phase II Clinical Phase III Preclinical TB Regimen Development JHU/U. Ill Chicago Novel TB regimen development Current first-line TB treatment consists of: isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E) Clinical Development Discovery Preclinical Development THPP Series GSK Diarylquinolines Tibotec/U. of Auckland PA-824/TMC207

TB Drug/Regimen Discovery and Development Process Drug Candidate Pool Discovery Phase II  Phase III Identification of New Drug Candidates Selection of Potential New Regimens Compound 1 Compound 2 Compound 3 Compound 5 Compound 4 Regimen A Regimen B Regimen C Single Compound Preclinical Development  Phase I  EBA Regimen Identification

Modes of Action Bio- reduction DNA Reactive Species mRNA H+ ADP ATP Peptide H+ ADP ATP Bio- reduction Multiple Targets PA-824 OPC-67683 DNA Gyrase Gatifloxacin Moxifloxacin RNA Polymerase Rifapentine Ribosome PNU-100480 AZD-5847 ATP Synthase TMC-207 Cell-Wall Synthesis SQ-109

TB Regimen Testing: A New Approach

Approach to Novel Regimen Development Use animal model(s) to identify most promising combinations Conduct full preclinical, Phase I and Phase II EBA evaluations of each drug singly Explore drug-drug interactions and, as appropriate, preclinical tox of the combination Take combination (regimen) into clinical development (Phase II, III)

NC-001

NC-001 (first novel combination EBA study) NC-001: Use of EBA to Test Principles Learned From Animal Models and to Begin Clinical Development of Novel Regimens NC-001 (first novel combination EBA study) J-Z synergy Pa-Z additivity Pa-J antagonism Pa-M-Z an enhanced novel regimen EBA = early bactericidal activity Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

First Novel Combo EBA: NC-001 Pa-Z-(M pbo) J-Z J -(Z pbo) J-Pa 2 weeks of treatment Rifafour Pa-M-Z Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207

All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0)

All Treatment Groups: Bi-linear Regression Mean of TTP Over Day; Change from Baseline (Day X – Day 0)

NC-001 Conclusions Validation of mouse data: J-Z synergy, Pa-Z additivity, Pa-J antagonism Pa-M-Z an enhanced novel regimen in 2-wk study All three compounds contribute to observed effect EBA can distinguish between treatments Just as it has previously distinguished between doses CFU and TTP give similar results Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

Post NC-001 Study: Next Steps Develop Pa-M-Z for both DS- and DR-TB (in setting of appropriate resistance testing) 2-month “SSCC” study (NC-002) as next step In patients whose M.tb is sensitive to Pa, M, and Z Build on J-Z and Pa-Z backbones Explore J-Pa building block Continue to examine potential regimens in mouse models and bring promising new regimens into clinical development Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

NC-002: First Study to Examine DS- and MDR-TB Together Using the Same Treatment for Both

NC-002 Objectives Pa-M-Z vs Rifafour in DS-TB Pa-M-Z in MDR-TB consistent with Pa-M-Z in DS-TB DS vs MDR in 2-wk EBA 2-wk EBA vs 2-mo “SSCC” Feasibility of multicenter “EBA” study Pa = PA-824; M = moxifloxacin; Z = pyrazinamide

2 months of treatment (plus 2-wk EBA substudy) First Novel Combo SSCC: NC-002 In patients with M.tb sensitive to Pa, M, and Z Pa(100mg)-M-Z 2 months of treatment (plus 2-wk EBA substudy) Rifafour Pa(200mg)-M-Z Pa(200mg)-M-Z (MDR) Pa = PA-824; M = moxifloxacin; Z = pyrazinamide Z dose = 1500mg

Unified DS/DR Development Path

Current MDR Development Path Issues Requires separate development program from DS-TB Standard of care (SOC) treatment (control group) for MDR-TB is Lengthy (24+ months) Toxicity-prone / difficult Of limited efficacy Expensive A new regimen for MDR-TB could be much shorter than SOC, but the timepoint for comparison will still be defined by the SOC control group

Unified DS/DR Development Path: Paradigm Shift Indication: “Drugs X, Y, and Z in combination are indicated for the treatment of tuberculosis caused by M.tb strains that are sensitive to drugs X, Y, and Z.” Patients should be treated based on what they are sensitive to--rather than what they are resistant to “MDR” label doesn’t apply in setting of new chemical entities

Unified DS/DR Regimen Development Path Better than HRZE Complete regimens as good as HRZE SD, MD; DDI if needed 2-wk Combo EBA Mouse model 2-wk EBA 2-mo SSCC Ph3 cidal sterilizing DS + DR sensitive to test regimen DS vs HRZE MDR not randomized Best doses used in combos All final regimens tested here MDR also 2-4 mos DS vs HRZE MDR for consistency Dose ranging in cidal Only combos in sterilizing Dose ranging here for single drugs DS only

Coming This Year SQ109 EBA study results PNU100480 EBA study results NC-002 (Pa-M-Z x 2 mos in DS and MDR pts) NC-003 2-wk EBA study examining four new regimens: J-Pa-Z, J-Pa-C, J-Z-C, J-Pa-Z-C TBA-354 (nitroimidazole) FIM study Expansion of biobanking initiative Gatifloxacin Ph 3 results

Thank You! And Thank You To Our: Funders Partners Stakeholders Staff Patients 25

TB Alliance Supporters Bill & Melinda Gates Foundation United States Food and Drug Administration European Union United Kingdom Department for International Development United States Agency for International Development