Status of the TB Drug Pipeline -Discovery

Transcription

1 File IND Status of the TB Drug Pipeline -Discovery V. Balasubramanian 1

2 Prevalence and Deaths Prevalence Deaths AFR- Africa AMR-America EMR-Eastern Mediterranean EUR- Europe SEAR- South East Asia WPR- Western Pacific MDG- Millennium goal By 2015 (worldwide): 10 million cases 1 million deaths Ref: Global TB control. Surveillance Planning Financing. WHO Report

3 MDR and XDR TB MDR: Resistant to Inh and Rif. No particular second line regimen Varies with patient and doctor Efficacy inferior to first-line Poor compliance Safety issues Cost XDR: Also resistant to fluroquinolone and a macrolide Almost nothing available for treatment 3

4 Summary: Present Treatment Drug sensitive patients - need accelerated treatment options to improve quality of life First line treatment is failing MDR, XDR patients - Question of life! There isn t an effective second line treatment ~10% TB are HIV positive patients Need compatible treatments 4

5 Discovery Pipeline Beauty is in the eye of the beholder 5

6 Demand and Supply 6

7 Recent reviews 7

8 8

9 Scanning the patents.. In the last 2 years, Opportunity! Number of Compounds TB Compounds Antibacterial Anticancer Patents 9

10 Recent reviews de Souza, M.V Recent Patents Anti-Infect Drug Discovery. 1: Tomoika, H Current Pharmaceutical Design. 12: Phillips, O.A. & Sharaf, L.H Expert Opinion on Therapeutic Patents. 17: Portero, J and Rubio, M Expert Opinion. Ther. Patents. 17:

11 Opportunities 1 Cell Wall Inhibitors PA-824 OPC67683 SQ-109 InhA inhibitors Prothionamide FabB/F inhibitors Hydroxamate derivatives Capuramycin analogs Proteasome Inhibitors Bortezomib analogs Metabolic Pathway Inhbitors Isocitrate lyase inhibitors PAS Analogs Sulfonyl Ureas ADP TCA H + ATP? PABA DHFA DNA Gyrase Inhibitors New quinolones; (KRQ-10018) 2-Pyridones (ABT-255) PO 4 ADP ST-Kinases ATP RNA Synthesis Inhibitors Rifametane Spiropiperidyl rifamycins Protein Kinase Inhibitors Tetrahydrobenzothiophenes ATP Synthase TMC207 FAS H + Membrane Potential Pyrazinamide analogs 11 Protein Synthesis Inhibitors Oxazolidininones Capreomycin New Macrolides Peptide deformylase inhibitors Pleuromutilins

12 Opportunities 2 Unknown mechanism with in vivo efficacy Phenazines: safer than Clofazamine Phenothiazines: Thioridazine Pyrrole derivates (BM212 analogs) Nitrofuranylamides Thiazinones Note: this is not an exhaustive list.. 12

13 Thiazinones Outcome of whole cell screening NEW BENZOTHIAZINONE DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS WO Vadim Makarov, Stewart Cole, Ute Moellmann 13

14 Potency & Cidality 14

15 In vivo efficacy Balb/c mice I.v infection with H37Rv 5 x 10 6 cfu/0.5 ml Treatment onset at day 1 post infection per oral in CMC; once daily for 4 wks As good as Inh in this animal model 15

16 Attacking Persistence Non-replicating bacilli 16

17 DlaT Inhibitors Inhibitors of dihydrolipoamide acyltransferase (DlaT) 17

18 In vivo Phenotype of dlat Required to cause disease in guinea pigs Used as a defense mechanism by Mtb to resist RNI attack by host 18

19 Enyzme inhibition IC um 19

20 Inhibitor kill NRP of Mtb ph5.5 DMSO ctrls Cpd - Nitrite Cpd - Nitrite Cpd + Nitrite Cpd + Nitrite Time & Conc. Dependent killing Synergistic with Nitrite Only NRP killed 20

21 Inhibitor kills intracellular Mtb Exposure for 2 days +verapamil Primary human lung or skin fibroblasts Monkey kidney Vero cells 21

22 In short Significant efforts in finding new inhibitors Many small molecule opportunities emerging Challenges remain in converting potent MICs to lead candidates that are efficacious in animals and with safety margins that permit clinical testing. Challenges remain in finding paths to develop agents that target persistence 22

23 Diseases in the Developing World AstraZeneca s commitment 23

24 Our commitment AstraZeneca is committed to making a contribution to improving health in the developing world Our approach is two-fold: Dedicated research into finding a new treatment for tuberculosis (TB) Helping local communities strengthen their healthcare capabilities 24

25 Dedicated research We have a dedicated TB research centre in Bangalore, India 80+ scientists focused on finding new therapies Fully integrated with AstraZeneca s world-wide drug discovery network Close collaboration with infection research centre in Boston, US, and with academic leaders in the field 25

26 Discovery We are focused on finding new therapies that will: Act on drug-resistant strains Shorten the duration of treatment Eradicate disease (including the latent form) to reduce the chances of relapse Be compatible with HIV/AIDS therapies We have a robust pipeline of projects that are expected to deliver a potential new medicine by

27 Joining Forces Only major pharmaceutical company involved in New Medicines for Tuberculosis (NM4TB) programme The European Commission considers NM4TB as its flagship programme in TB drug discovery.. and fully expects delivery of a drug candidate in 2010 Dr. Hannu Laang, Scientific officer European Commission Poverty-related diseases May 22nd

28 Joining Forces Organisational partner support the delivery of Global Plan to Stop TB Co-funded Open Forum I, II & III on TB Drug Development Involved in TB drug development working groups and strategy Gates Foundation Award for PK/PD studies Increasing focus on HIV/TB coinfection and role of businesses Recognised AstraZeneca as one of top private funders of TB R&D 28

29 Development Once a candidate drug is identified, we expect development of any compounds discovered by AstraZeneca to: Follow development pathways agreed in discussion with external experts & regulatory authorities Be performed principally in countries with high rates of infection Be performed in collaboration with external groups with relevant expertise Be overseen by AstraZeneca to ensure compliance with global pharmaceutical, ethical and regulatory standards 29