NEW DRUGS FOR TUBERCULOSIS: THE NEED, THE HOPE AND THE REALITY Neil W. Schluger, M.D. Professor of Medicine, Epidemiology and Environmental Health Sciences Columbia University Global tuberculosis incidence Overall: 2 2 billion with with latent infection 16 16 million prevalent cases/year 8-12 8-12 million incident cases/year 2-3 2-3 2 million deaths/year deaths 8-9 million new cases/year WHO, Global Report 2012 December 12, 2012 1
HIV prevalence among new cases of TB WHO, Global Report 2012 Distribution and prevalence of MDR-TB Total MDR cases: Total MDR 500,000 cases >500,000 Zignol WHO et 2010 al. Bull Global WHO 2012; Report 90: 111-119D December 12, 2012 2
Why do we need new drugs to treat TB? Shorter overall treatment duration Lower relapse rates Development of regimens with fewer adverse effects, particularly less hepatotoxicity Development of regimens that can be given easily and safely in combination with antiretroviral therapy Development of regimens that are effective in treating MDR TB/XDR TB Current therapy for tuberculosis 2HRZE/4HR Induction phase: 2 months isoniazid, rifampin, pyrazinamide, ethambutol Continuation phase: 4 months isoniazid, rifampin Advantages: 100% effective Low relapse rate (3 4%) Inexpensive Universally available Can be given intermittently Disadvantages 6 months duration High relapse rate (15%) Adverse effects common Interactions with HIV treatment Not useful against MDR strains December 12, 2012 3
drug discovery/development and its impact on treatment Pyrazinamide Ethionamide Streptomycin Kanamycin/amikacin Capreomycin Isoniazid PAS Thioacetazone Cycloserine Rifampin EMB 1968 1967 1966 1965 1957 1956 1955 1952 1946 1944 The evolution of treatment for active TB 1952 24 months HS 1986 6 months 2HRZE/4HR 250 regimens tested in 25,000 patients in order to determine optimal: drug combinations doses dosing intervals treatment duration December 12, 2012 4
TB drugs in clinical development Sponsor Drug Stage Sanofi-Aventis Rifapentine Phase 4 Bayer/GA Moxifloxacin Phase 2/3 EU, WHO Gatifloxacin Phase 2/3 Tibotec TMC207 Phase 2 Otsuka OPC67683 Phase 2 Global Alliance PA-824 Phase 2 Sequella SQ-109 Phase 2 Lupin LL-3858 Phase 2 Pfizer PNU100480 Phase 2 AstraZeneca AZD-5847 Phase 1 December 12, 2012 5
RMZ has greater sterilizing activity than RHZ or RHZM in murine TB Nuermberger, AJRCCM, 2004;169:421 RHZ RHZM RMZ Activity of enhanced-dose rifapentine in the mouse model R 10 HZ (5/7) R 10 MZ (5/7) P 10 HZ (5/7) PLoS Medicine 2007: 4: e344 December 12, 2012 6
TBTC Phase 2 study design Hypothesis: Addition or substitution of DRUG X during intensive phase will result in a significantly greater proportion of patients whose sputum is culture negative at 2 months, compared with the standard regimen Smear positive tuberculosis STANDARD REGIMEN NOVEL REGIMEN 8 WEEKS SPUTUM CULTURE 8 WEEKS 4HR 4HR TBTC trials of novel regimens for active tuberculosis TBTC Study Patients enrolled Novel regimen Standard regimen Improvement in 2 month culture conversion 27 1 336 HRZM HRZE 0% 28 2 433 MRZE HRZE 5.5% 29 3 389 HRptZE 10 mg/kg) 29X 334 HRptZE (15-20 mg/kg) HRZE 3.0% HRZE? 1. AJRCCM 2006; 174: 331-8 2. AJRCCM 2009; 180: 273-80 3. J Infect Dis. 2012; 206: 1030-40 December 12, 2012 7
Resistance to quinolones among TB cases: a growing problem? Ramachandran R et al. Int J Tuberc Lung Dis 2009; 13(9):1154 1160 REMOX TB Trial Three arm trial sponsored by the MRC and the TB Alliance Treatment shortening, moxifloxacin based Arms: 2HRZE/4HR 2EMRZ/4HR 2MHRZ/2MHR Enrollment completed 2/12 Results expected in 12-18 months December 12, 2012 8
High dose rifamycin based treatment shortening trials Rifaquin Sponsored by the EDCTP Study arms 2EHRZ/4HR 2EMRZ/2P2M2 (moxi 400 mg b.i.w.; Rpt 900 mg b.i.w) 2EMRZ/4P1M1 (moxi 400 mg. q.w.; Rpt 1200 q.w.) Enrollment completed, currently in follow up Utility of linezolid in the treatment of MDR and XDR TB: New York City experience All patients resistant to H/R; 10/16 resistant to injectables; 6/16 resistant to quinolones Anger et al. J Antimicrob Chemother 2010; 65:775-783 December 12, 2012 9
Adverse effects associated with administration of linezolid for tuberculosis Lee et al. N Engl J Med 2012;367:1508 18. TB drugs in clinical development Sponsor Drug Stage Sanofi-Aventis Rifapentine Phase 4 Bayer/GA Moxifloxacin Phase 2/3 EU, WHO Gatifloxacin Phase 2/3 Tibotec TMC207 Phase 2 Otsuka OPC67683 Phase 2 Global Alliance PA-824 Phase 2 Sequella SQ-109 Phase 2 Lupin LL-3858 Phase 2 Pfizer PNU100480 Phase 2 AstraZeneca AZD-5847 Phase 1 December 12, 2012 10
Mice inoculated i.v. with M. tuberculosis 12 days later, drug treatment started Mice killed 1 (yellow) or 2 (blue) months later Surviving bacteria in lungs counted Science 2005; 307: 223-227 Activity of TMC207 in a murine model of therapy: daily therapy Tibotec data presented at ICAAC, December 2005 December 12, 2012 11
Activity of TMC207 in a murine model of therapy: weekly therapy Log 10 CFU Tibotec data presented at ICAAC, December 2005 Bedaquiline (TMC207), an ATP synthase inhibitor, in the treatment of MDR-TB Diacon et al. N Engl J Med 2009; ;360:2397-405. December 12, 2012 12
Time to culture conversion in patients with MDR Tb treated with bedaquiline: C208 trial Source: Janssen briefing document prepared for FDA hearing, Nov. 28, 2012 Excess deaths in experimental arm of C208, bedaquiline clinical trial in MDR TB Source: Janssen briefing document prepared for FDA hearing, Nov. 28, 2012 December 12, 2012 13
Chemical Structure of OPC 67683 N O O N O OCF 3 O 2 N N OPC 67683 : (R) 2 Methyl 6 nitro 2 {4 [4 (4 trifluoromethoxyphenoxy) piperidin 1 yl]phenoxymethyl} 2,3 dihydroimidazo[2,1 b]oxazole December 12, 2012 14
Effects of OPC 67683 on Mycolic Acid Biosynthesis Compound Subclass mycolic acid IC50 (µg/ml) 95% CI (µg/ml) OPC 67683 Fatty acid α Methoxy Keto >0.25 >0.25 0.036 0.021 0.020 0.068 0.009 0.059 INH Fatty acid α Methoxy Keto >4 1.851 0.61 0.69 1.109 3.090 0.537 0.738 0.422 1.129 PNAS 2012; 109: 14188 14193 December 12, 2012 15
Three drug combination containing OPC 67683 vs. standard regimen Infection 1M Start of treatment 0 1M 2M 3M 4M 5M 6M CFU CFU CFU CFU CFU CFU Compound Dose (mg/kg) mouse Cmax (µg/ml) human Cmax (µg/ml) OPC 67683 2.5 0.297 RFP 5 4.52 4.5 1/6 0/6 4/5 INH EB PZA 10 100 100 3.06 3.51 63.2 4.5 3.7 59.3 Vehicle : 5% Gum Acacia ; RHEZ : 2RHEZ + 4RH ; ORZ : 2ORZ + 2OR Sputum culture conversion in patients with MDR-TB treated with delaminid (OPC-67683) Gler et al. N Engl J Med 2012;366:2151-60. December 12, 2012 16
Early bactericidal activity using novel drugs and combinations DS-TB patients Diacon et al. Lancet 2012; 380: 986 93 December 12, 2012 17
Combining novel agents in the treatment of TB in a murine model Taseen R et al. Antimicrob Agents Chemother 2011; 55: 5485 5492 The challenge of tuberculosis clinical trials Type Endpoint Size Duration of study What is being studied? Phase 1 Safety/tolerability small days-weeks drug Phase 1 PK/PD PK/PD data; drug interactions small days-weeks drug(s) Phase 2a EBA small days-weeks drug Phase 2b 2-month culture conversion medium months regimen Phase 3 Failure/relapse large years regimen Phase 4 Detection of uncommon side effects large years regimen December 12, 2012 18
COMPANION GRAPHS December 12, 2012 19
Annual Global Plan Research Funding Targets vs. 2011 Investments $800,000,000 $740,000,000 $600,000,000 $400,000,000 $420,000,000 $340,000,000 $380,000,000 $200,000,000 $250,038,877 $0 $120,361,419 Fundamental research $55,043,541 New diagnostics New drugs New vaccines $80,000,000 $95,446,326 $84,140,175 Operational research Global Plan Annual Targets 2011 Investments Total TB R&D Funding: 2005 2011 $700,000,000 $649,648,183 $619,209,536 $630,446,462 $525,000,000 $350,000,000 $473,920,682 $491,476,917 $417,824,708 $357,426,170 $175,000,000 $0 2005 2006 2007 2008 2009 2010 2011 2011 TB R&D investments witnessed an 82% increase over 2005 levels, but only 3% growth since 2010. December 12, 2012 20
NIH funding for AIDS research Source: Treatment Action Group Report on TB Research Funding New drugs for TB: conclusions More drugs in clinical development than at any time in the last 40 years Bedaquiline on the verge of approval the first new TB drug since rifampin Multiple challenges in TB drug development Combining novel agents Clinical trials capacity Length of trials Funding December 12, 2012 21