1TB Forum_May 2008

File

IND

Status of the TB Drug Pipeline - Discovery

V. Balasubramanian

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

5TB Forum_May 2008

Discovery Pipeline

“Beauty is in the eye of the beholder”

6TB Forum_May 2008

Demand and Supply

7TB Forum_May 2008

Recent reviews…

8TB Forum_May 2008

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

14TB Forum_May 2008

Potency & Cidality

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

16TB Forum_May 2008

Attacking Persistence

Non-replicating bacilli

17TB Forum_May 2008

DlaT Inhibitors

Inhibitors of dihydrolipoamide acyltransferase(DlaT)

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

19TB Forum_May 2008

Enyzme inhibitionIC50 45 uM

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

23TB Forum_May 2008

Diseases in the Developing World

AstraZeneca’s commitment

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