Accelerating the development of faster acting and affordable drug combinations to fight tuberculosis.

Community Advocacy for New Tools and Strategies to Address TB/HIV: TB Treatment Christo van Niekerk

Tuberculosis (TB) Tuberculosis, an ancient and relentless pandemic, continues to ravage continents, societies and families. Yet today the world still depends on outdated drugs delivered in a complex multi-drug regimen for six or more months. No new drugs have been introduces in 30 years

Global Epidemic 2 billion people are infected with M. tb 9 million new active TB cases a year 2 million people die/year; 1/15 sec ~ 400,000 new cases of MDR-TB a year 12 million persons are TB/HIV co-infected Biggest killer of women of childbearing age Economic toll: $12 billion a year Current TB therapy, though efficacious, is inadequate to control the global TB epidemic - too long and too complex

Factors Contributing to Current TB Epidemic HIV epidemic failing public health infrastructures increasing poverty and homelessness IV drug use (living conditions)

Tuberculosis (TB) A disease caused by a bacterium (bug): Mycobacterium tuberculosis (M. tb; MTB) 50 years after introduction of an effective drug, TB remains 2 nd only to AIDS as the leading infectious cause of death in the world

Natural History of TB (in the absence of HIV infection) 50% 10% 90%

Clinical Presentations Latent TB Infection Pulmonary TB –Smear positive (cavitating) –Smear negative Extra Pulmonary TB TB in children –Miliary TB –TB meningitis –Pulmonary TB –Other

Latent Tuberculosis Infection Every second, someone in the world breathes in tiny TB bacteria in the air and becomes newly infected. While one third humanity is infected with TB bacteria, only one in ten people develop an active case of the disease. Those who do not get sick carry latent TB infection.

Latent Tuberculosis Infection Of the approximately 2 billion people who are latently infected, 10% will develop active TB at some point in their lives. For those who are HIV+, risk is almost 10% per year. (In some countries, over 70% of TB patients are also HIV+)

State of the Field Lengthy months of 4 drugs taken in combination Outdated – drugs discovered in 1940s, 1950s, armamentarium dwindling Cumbersome - direct monitoring by healthcare workers, <50% of smear+ cases receive standard of care Poor results - Incomplete treatment results in drug-resistant strains, and relapse TB and HIV treatment not easily co- administered We need a new treatment!

TB and HIV A total of 12 million people worldwide are co- infected with both diseases, with a majority of them living in Southern Africa. In sub-Saharan Africa, two-thirds of TB patients are co-infected with AIDS. When someone with latent TB becomes co- infected with HIV, the risk of developing active TB increases by a factor of For those who are HIV+, risk is almost 10% per year. (In some countries, over 70% of TB patients are also HIV+)

TB and HIV The are several important associations between epidemics of HIV and TB: TB is harder to diagnose in HIV positive people TB progresses faster in HIV-infected people TB in HIV positive people is more likely to be fatal if undiagnosed or left untreated TB occurs earlier in the course of HIV infection than other opportunistic infections TB is the only major AIDS-related opportunistic infection that poses a risk to HIV-negative people.

History of TB Control 1882: Koch discovered the bacterium (M. tb) 1891: Koch discovered the diagnostic (tuberculin) 1921: Calmette & Guerin introduced the vaccine (BCG) 1948: Waksman et al introduced the drug (streptomycin) 2005: more people developed TB than in any previous year; WHO declared targets of 70% case detection, 85% cure not met 2015: target for Millennium Development Goals “In an increasingly connected world of jetliners, mass transportation and displaced populations, TB anywhere is TB everywhere.”

TB Treatment Evolution st regimen: Streptomycin PAS Isoniazid 1963 Rifampin (R) discovered 1974 BMRC Trials add R & Z Pyrazinamide (Z) discovered – but liver toxicity Rx lasts from months Standard Regimen by 1960s based on 1952 drugs 1970 BMRC Trials add R Rx shortened to 9 months Standard Therapy 2 months: R, H, Z, E + 4 months: R, H Rx shortened to 6 months Strepto- mycin 1 st used for TB

Isoniazid Rifampin Pyrazinamide Ethambutol Rifabutin* Rifapentine First-Line Drugs Second-Line Drugs Antituberculosis Drugs Streptomycin Cycloserine p-Aminosalicylic acid Ethionamide Amikacin or kanamycin* Capreomycin Levofloxacin* Moxifloxacin* Gatifloxacin* *Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

History of the TB Alliance Cape Town Declaration – Feb 2000 –Hosts: Rockefeller Foundation & MRC S. Africa –Over 120 organizations (health, science, philanthropy and private industry) Results –Support goals of Stop TB Initiative –Create Scientific Blueprint –Develop Pharmacoeconomic Analysis Build a global alliance for TB drug development

The TB Alliance International Public-Private Partnership (PDP) Independent, not-for-profit organization Based in New York, Brussels and Pretoria Entrepreneurial, virtual R&D approach –Out-source R&D to public or private partners

The TB Alliance Mission  Develop new, better drugs for TB  Ensure affordability, access and adoption (AAA)  Coordinate and catalyze TB drug development activities worldwide

Affordability, Access and Adoption (AAA) Develop cost effective, affordable new anti- tuberculosis drugs for all those who need them most Ensure equitable access of new TB treatments, especially for patients in high-burden countries. Working closely with communities, governments and National TB Programme coordinators to ensure the future drugs will be adopted into TB Programmes

TB Alliance Strategic Challenges Need for combination therapy, not single drug(s) - implementation of new paradigm Maintaining a robust pipeline Long development times Need for TB Regulatory guidance Ensuring/supporting AAA

Operating Principles Scientific, ethical, financial rigor Best business practices Flexible and collaborative Active portfolio management Commitment to AAA

Developing Leads Two-Pronged Strategy –Existing Compounds, Analogs, Derivatives –Novel Families or Classes Worldwide Sourcing –Companies, Academia, Compound Libraries, Natural Products Obtaining Rights –Licensing, Purchase, Donations, Co-development, Co-Investment, etc.

1.Active disease 2.TB/HIV co-infection 3.MDR-TB 4.Latent infection (LTBI) TB Alliance Priorities Based on impact and feasibility

Active TB – Near Term Goal 130 doses Shorten: 6 months to 2-3 months Simplify: daily to weekly 10 doses

Long-term Goal Active Disease 7-10 days of treatment But - very difficult to achieve without advances in understanding the biology of “persistence”

TB Alliance Portfolio DiscoveryPreclinicalClinical Testing Nitroimidazole Analogs (University of Auckland/Novartis Institute for Tropical Diseases/ National Institute of Allergy & Infectious Diseases) Quinolones (KRICT/Yonsei University) Nitroimidazole PA-824 (Chiron) Compounds, Analogs and Derivatives Contracted Program Program in discussion Screening and Target Identification (AstraZeneca) Nitroimidazole OPC (Otsuka) Moxifloxacin (Bayer) Global Alliance for TB Drug Development March InhA Inhibitors (GlaxoSmithKline) Isocitrate Lyase Inhibitors (GlaxoSmithKline) Focused Screening (GlaxoSmithKline) Pleuromutilins (GlaxoSmithKline) Nitroimidazole Backup Compound (Otsuka) Oxazolidinones (Pfizer) Bifunctional Molecules (Cumbre) Macrolides (University of Illinois at Chicago) Malate Synthase Inhibitors (GlaxoSmithKline/Rockefeller University) Protease Inhibitors (Medivir) Riminophenazines (Institute of Materia Medica) Capuromycins (Sankyo/Sequella) Diamine SQ-109 (Sequella) New Targets (University of Pennsylvania/Evotec) Proteasome Inhibitors (Cornell University) Quinolone DW-224 (Dongwha)

ResearchDevelopmentAccess & Adoption Mouse Model of TB (Johns Hopkins University) Biomedical Info Resources / Database (IntellectuAll Limited) Clinical Trials Infrastructure Regulatory Support TB Alliance Strategic Initiatives Global Alliance for TB Drug Development March 2006 Biomarkers (BG Medicine/Colorado State University) Differential Pricing Analysis Procurement, Distribution, And Market Analysis Epidemiology Studies

Global TB Drug Portfolio September 2005 DiscoveryPreclinicalClinical Testing Dihydrolipoamide Acyltransferase Inhibitors Cornell University, NIAID InhA Inhibitors GlaxoSmithKline, TB Alliance Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Macrolides TB Alliance, University of Illinois at Chicago Methyltransferase Inhibitors Anacor Pharmaceuticals Translocase I Inhibitors Sequella Inc., Sankyo Synthase Inhibitor FAS20013 FASgen Inc. Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance Diarylquinoline TMC207 Johnson & Johnson Nitroimidazo-oxazole OPC Otsuka Natural Products Exploration BIOTEC, California State University, ITR, NIAID, TAACF, University of Auckland Dipiperidines (SQ-609) Sequella Inc. Diamine SQ-109 Sequella Inc. Gatifloxacin OFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR Cell Wall Inhibitors Colorado State University, NIAID Novel Antibiotic Class GlaxoSmithKline, TB Alliance Picolinamide Imidazoles NIAID, TAACF) Pleuromutilins GlaxoSmithKline, TB Alliance Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance Screening and Target Identification AstraZeneca Thiolactomycin Analogs NIAID, NIH Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance Nitrofuranylamides NIAID, University of Tennessee Pyrrole LL-3858 Lupin Limited Nitroimidazole PA-824 Chiron Corporation, TB Alliance Non-Fluorinated Quinolone TaiGen Carboxylates TB Alliance, Wellesley College Nitroimidazo-oxazole Back-up Otsuka STOP TB New Drugs Working Group

Clinical Development Pipeline CompoundDevelopment StageSponsor / Coordinator gatifloxacinPhase III EC / OFLOTUB Consortium; IRD * ; WHO TDR  ; Lupin Ltd. moxifloxacinPhase II / III Bayer; TB Alliance; CDC  ; University College of London; Johns Hopkins University TMC 207Early Bactericidal ActivityJohnson & Johnson (Tibotec) OPC-67683Early Bactericidal ActivityOtsuka Pharmaceutical Co., Ltd. PA-824Phase ITB Alliance LL-3858Phase ILupin Ltd. * Institut de Recherche pour le Developement  World Health Organization, Tropical Disease Research  Centers for Disease Control and Prevention

TB and HIV While policymakers are currently developing better technical frameworks to improve today’s strategies for TB control in HIV hotspots, better drugs that eliminate TB in HIV patients are key to halting the dual infection.

Mechanism of drug-drug interactions during metabolism The cytochrome P450 enzyme system consists of an array of isoenzymes. Approximately 50 % of all drugs are substrates of CYP3A4, including HIV protease inhibitors (PIs) and non- nucleoside reverse transcriptase inhibitors (NNRTIs). Antituberculosis drugs and HIV

Rifampicin should be avoided because of its strong inducing effect resulting in an increased risk of virological failure and development of resistance. Serious side effects can occur in combination with Protease inhibitors Rifampin should be avoided if concurrent ART with NNRTIs (nucleoside reverse transcriptase inhibitors.)

Objective: Provide more effective and safer drug therapy Approach: –Prioritize novel mechanisms of action (should be effective in MDR-TB and TB/HIV) –Screen MDR-TB strains –Test for and prioritize compounds without P450 interactions –Even compounds that do not shorten treatment of active disease may be efficacious for MDR-TB and safe for co-therapy with ARVs Success will be a consequence of efforts for active disease MDR-TB and TB/HIV

Drug-resistant TB or MDR-TB One of the most serious aspects of TB Completely a man-made problem Difficult to treat; cure rate less than 50% By definition, resistant to at least both INH and Rifampicin Due to inappropriate prescribing and/or poor adherence to proper regimen

Drug Resistance TB Develops in two ways: primary drug resistance –infecting organisms are already resistant secondary drug resistance –resistant mutants are selected for during treatment

Drug Resistance TB(2) Resistance is created by: –Microbial factors –Physician factors –Patient factors Conclusion: all TB disease should be treated initially with at least 3 drugs (INH, RIF, PZA usually)

Accelerating the development of faster acting and affordable drug combinations to fight tuberculosis.

Why Need to Treat for So Long? Hypothesis (Dogma): –Subpopulation of bacteria are in a slow- growing (or non-growing) state; drugs don’t affect them – need to wait until burst of growth –Referred to as “persisters” –Same as “latent” bacteria???

“TB Crystal Ball” All present first-line drugs (HRZE) have suboptimal profiles –Pharmacokinetics (H,R,E) –cytochrome P450 interactions (R,H) –poor sterilizing activities (H,Z,E) –antagonistic interactions (E with HRZ; H with RZ) Will any of present first-line drugs ultimately be part of optimized regimens ? H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol