Status of the TB Drug Pipeline -Discovery
Transcript of Status of the TB Drug Pipeline -Discovery
2TB Forum_May 2008
Prevalence and Deaths
By 2015 (worldwide):10 million cases1 million deaths
AFR- AfricaAMR-AmericaEMR-Eastern MediterraneanEUR- EuropeSEAR- South East AsiaWPR- Western PacificMDG- Millennium goal
Prevalence Deaths
Ref: Global TB control. Surveillance Planning Financing. WHO Report 2008
3TB Forum_May 2008
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
4TB Forum_May 2008
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
9TB Forum_May 2008
Scanning the patents…..In the last 2 years,
TB Compounds Antibacterial Anticancer10
100
1000
10000
Patents
Num
ber
of C
ompo
unds
Opportunity!
10TB Forum_May 2008
Recent reviews• de Souza, M.V. 2006. Recent Patents
Anti-Infect Drug Discovery. 1:33-44.• Tomoika, H. 2006. Current
Pharmaceutical Design. 12: 4047-4070• Phillips, O.A. & Sharaf, L.H. 2007.
Expert Opinion on Therapeutic Patents. 17: 429-435.
• Portero, J and Rubio, M. 2007. Expert Opinion. Ther. Patents. 17: 617-637
11TB Forum_May 2008
Opportunities…1
PABA
DHFA
PO4ATP
ADP
ST-Kinases
Cell Wall InhibitorsPA-824
OPC67683SQ-109
InhA inhibitorsProthionamide
FabB/F inhibitorsHydroxamate derivatives
Capuramycin analogs
Metabolic Pathway InhbitorsIsocitrate lyase inhibitors
PAS AnalogsSulfonyl Ureas
DNA Gyrase InhibitorsNew quinolones; (KRQ-10018)2-Pyridones (ABT-255)
RNA Synthesis InhibitorsRifametaneSpiropiperidyl rifamycins
Protein Synthesis InhibitorsOxazolidininonesCapreomycinNew MacrolidesPeptide deformylase inhibitorsPleuromutilins
ATP
ADP
H+
H+
Membrane PotentialPyrazinamide analogs
?
TCA
Protein Kinase InhibitorsTetrahydro-benzothiophenes
Proteasome InhibitorsBortezomib analogs
ATP SynthaseTMC207FAS-20013
12TB Forum_May 2008
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…..
13TB Forum_May 2008
Thiazinones
NEW BENZOTHIAZINONE DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS
WO2007134625. 2007. Vadim Makarov, Stewart Cole, Ute Moellmann
Outcome of whole cell screening
15TB Forum_May 2008
In vivo efficacy• Balb/c mice• I.v infection with H37Rv 5 x 106 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
18TB Forum_May 2008
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
20TB Forum_May 2008
Inhibitor kill NRP of Mtb
Cpd - Nitrite
Cpd + Nitrite
DMSO ctrlsBCG @ pH5.5
Cpd - Nitrite
Cpd + Nitrite
Time & Conc. Dependent killingSynergistic with NitriteOnly NRP killed
21TB Forum_May 2008
Inhibitor kills intracellular Mtb
+verapamil
Primary human lung or skin fibroblastsMonkey kidney Vero cells
Exposure for 2 days
22TB Forum_May 2008
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
24TB Forum_May 2008
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
25TB Forum_May 2008
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
26TB Forum_May 2008
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 2010
27TB Forum_May 2008
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 officerEuropean Commission
Poverty-related diseasesMay 22nd 2006
28TB Forum_May 2008
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 co-infection and role of businesses
• Recognised AstraZeneca as one of top private funders of TB R&D
29TB Forum_May 2008
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