a model to address drug discovery for neglected diseases_osdd

7/28/2019 A model to address drug discovery for neglected diseases_OSDD

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A model to address drug discovery for neglecteddiseases!

Tanjore S Balganesh, Zakir T Thomas and

Samir K Bramhachari

- Predictive

Sciences

- Multidisciplinary

An Initiative of

The Council of Scientific and Industrial Research,

Ministry of Science and Technology,

Govt. of India
http://www.osdd.net/


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New model

OSDD

Public funding

Innovation AffordableHealth care

THE FOUR HORSEMEN OF THE APOLCALYPSE

A WAY FORWARD

ADDRESSINGCOMPLEX DISEASES


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HOW TO APPROACH COMPLEX PROBLEMS IN

AN INNOVATIVE WAY!!!

OSDD PARADIGM :
http://www.osdd.net/http://www.osdd.net/


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Testing new paradigms

Networking-

Crowd sourcing

Openness- datasharing through

appropriate

portal

OSDD

AN EXAMPLE


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Literature

AnnotationTools

Genomic

Databases

Curated

Annotations

Raw

Annotations

Community of >800

student researchers

Collaborative Curation

Innovative Crowd Sourcing Model for MtbSystems Biology

87% of Mtb genome annotated


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Within weeks, 830 volunteered to re-annotate the entire M.

tuberculosis genome. The work started in December2009 and wascompleted by April 2010, packing nearly 300 man-years into 4

months!Source: Munos B. Can Open-Source Drug R&D

Repower Pharmaceutical Innovation?

Clin Pharmacol Ther 2010;87:534

536

Source: Hiroaki Kitano

Nature Chemical Biology 7, 323

326 (2011)

Social engineering for

virtual 'big science' in

systems biology


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OSDD One Month

Campaign onPublic Awareness of

Need of

New Drugs for TB

180 Videos

On YouTube

From across

the country conveying

the message more

forcefully than we

could ever have


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CROWD SOURCING IS A VIABLE

APPROACH


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CHANGING PRARADIGMS

WHERE IS SCIENCE GOING?


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Evolving Paradigms in Science

FIRST SECOND THIRD FOURTH

1000 years ago Last few 100 years Last few decades Today

Describing

Natural

Phenomena

Using Models,

Generalizations

Simulating

complex

phenomena

Unify theory, experiment and

simulation

Data from observations

and/or high fidelity

simulations

Analysis of database using

data management and

statistics

Empirical

Theoretical

Computational

Data Intensive

Scientific Discovery
http://www.osdd.net/http://www.osdd.net/


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Evolving Paradigms in Drug Discovery

FIRST SECOND THIRD FOURTH

Early discoverySubstrate driven

chemistry Last few decadesToday

Serendipity

Natural products

Chemical to drug

Synthetic

chemistry

Pharmacology

Rationale

Drug design and

development

Unify theory, experiment and

simulation

Data from observations

coupled to high fidelity

simulations

- Empirical

SAR driven

Computational

biology

Molecular

structure

Pattern

recognition

PredictiveSciences

Complexity


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BUILDING ON THE CHANGES

THE OPEN INNOVATION MODEL


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The Current Innovation Model

Fuzzy Front-End Research Development

Inputs-

RESTRICED

GEOGRAPHY

Inputs

POOR SUCCESS RATES

LACK OF INNOVATIONX

Technology

Hits / Lead Molecules

Image Source: Clorox, Andy Gilinkski, www.imaginatik.com

X??

X

X

X

X

X

ISOLATED ISLAND EFFORTS


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Open Innovation Model

CROWD SOURCING

Porous-walled funnel facilitates free flow of ideas / projects

Bring in more eyeballs to look at the inside

Enables Redundancies and Parallelization

Fuzzy Front-End Research Development

Inputs

Inputs XLaunch

X

Technology


External

endorsement/

relationships


Date intensive

science=-

DIVERSE IDEAS


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The Open Innovation Model-

OSDD


Bring in more eyeballs to look at the inside

Enables Redundancies and Parallelization

Fuzzy Front-End Research DevelopmentInputs

Inputs

INNOVATION

Technology



OSDD

OSDD

INDIVIDUAL PIs

IDEAS

INTEGRATED

OSDD PROJECT

INTEGRATED TEAM EFFORT

Marrying The TWO CULTURES

- Academic

- Delivery focused

- OSDD THE FACILITATOR

THE FACILITATION

- Expertise

- Discovery Platforms

CLIMBINGTHE MAGIC MOUNTAIN


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The Open Innovation Model- OSDD


Bring in more eyeballs to look at the inside Enables Redundancies and Parallelization

Fuzzy Front-End Research DevelopmentInputs

Inputs

INNOVATION

Technology

Lead Molecules

OSDD

OSDD

OSDD

Phase 2

With GATB

DiscoveryINSERM/TresCantos

OSDD

INDIVIDUAL PIs

IDEAS

INTEGRATED TEAM EFFORT

GLOBALISING THE EFFORT

CLIMBING

THE MAGIC MOUNTAIN


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TENETS OF OSDDOPEN DATASHARING

PARTNERSHIP

GENERIC

MANUFACTU-

RING


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PRIORITIES

TB with emphasis on MDR TB

Malaria

Leishmania


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Strategies towards TB small molecule

delivery

Systems biology and molecular simulation.

Build diversity libraries- Why and How?

Building early discovery project portfolio Finding Novel combinations- the approach


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iOSDD890


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iOSDD890From Social

Network to

Biological

Network


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Genome Scale Reconstruction of Metabolism in Mtb


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Minimizing off-target interaction - Polypharmacology

Can we design inhibitors which will bind to multiple targets synergistically tokill the bug?

Subtractive Genomics andProteomics Approach

Target Validation

Sequencecomparison

Structurecomparison

Interactome

Metabolic MapFBA

RegulatoryNetwork

Validation &Downstream

studies

Target Identification

+

Inhibitor

Target1

Target1

Off-targetbinding

sites


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Build diversity libraries- Why and

How?


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PLAYING TO OUR STRENGTHS

Best synthetic chemistry brains in the world.

CSIR itself has more than 2000 chemists in the

organization

Diverse chemistry skills

Carbohydrate

Terpine

Heterocyclic

Natural product


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OSDD OutreachProgramme

Chemically DiverseCompound Library

Initiative (CDCLi)

Fund US $ 0.9 Million

120 CompoundsDeposited in Mol Bank 120 Screened against

TB 47 Screened against

Malaria

2 Found Active inMalaria Screen

Started in September 2011 Started in end 2012

Fund US $ 0.4 Million

57 Projects 59 PIs Involved

45 Projects 29 Pis leading 64 Students

1100 CompoundsDeposited (6 months) 1100 Screened againstM. smegmatis

28Found Active

Crowd Sourcing Chemical Synthesis & Screening for OSDD


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Building early discovery project

portfolio

- Facilitating Discovery

- SOP based progression- Ensures quality of data

Open Drug Discovery Platform


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Open Drug Discovery Platform

Clones &

StrainsRepository

Mtb Clonesin E coli(SASTRAUniv)

MtbStrains: DSand MDR

Target

Validation

GeneKnockout inMtb

Gene

Knockdown in

Mtb

Mechanism

of Action

Microarray

WholeGenomesequencingapproachof mutants

Toxicology

In vitro andin vivo inanimalmodels

Compound

Screening

In M smeg(IICT)

In Mtb:MIC andMBC

Biochem

Assays

Cloning,expression&purification

EnzymeAssays

Standardization &throughputamenable

DMPK

In vitro andin vivo

Metabolicstability

CaCO2perme-

ability

Pre clinical

Efficacy inanimalmodels


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Discovery Portfolio

MS1.5

GlmU1

Decisionpoint

LAT

MS 2.0

Pkn G

FasII

LigA

DapA

Dap B

GlmU2

PknB

MS 3.0

LEAD

LAMS

CDRI-830CDRI-1

IIM-1

Target based approach

Whole cell screening approach

Natural

Product

Synthetic

compound

Whole

genome

analysis -

InteractomeAnd

Metabolic

Map analysis

Onecompd.

DapA

Dap B


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Finding Novel combinations the

approach

THE BEST OF TIMES AND THE WORST OF TIMES

First Novel Combo EBA: NC-001- DS patients


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First Novel Combo EBA: NC-001- DS patients.

GATB data

Pa-Z-(M pbo)

J-Z

J -(Z pbo)

J-Pa

2 weeks of treatment

Rifafour

Pa-M-Z

Pa = PA-824: M = Moxifloxacin; Z = Pyrazinamide; J = TMC207

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All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day;


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All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day;

Change from Baseline (Day XDay 0).

GATB data

-2.5

-2

-1.5

-1

-.5

0

.5

0 2 4 6 8 10 12 14Day

TMC207 TMC207 & Pyrazinamide

TMC207 & PA-824 PA-824 & Pyrazynamide

PA-824 & Pyr & Moxifloxacin Rifafour e275

Bi-linear Regression: logCFU change from baseline


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Advantages of new protocol

Current MDR TB regimen cumbersome

6 drugs with injection, side effects, costly, longduration (2 years), compliance poor

PaMZ regimen offers potential of effective,simpler and shorter regimen

Potent activity in EBA studies on DS TBpatients

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12, 2013 33

d d d


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Proposed study design in

collaboration with GATB Phase II open label, stratified RCT

Site: LRS Institute of TB and Respiratory Diseases,

New Delhi

Study population: newly diagnosed pulmonaryMDRTB

Application currently with DCGI.

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12, 2013 34


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Objectives

Primary objectives: To evaluate the anti-mycobacterial activity and

safety of a combination of PA-824, M and Z for the

first 8 weeks in subjects with newly diagnosed

pulmonary MDR-TB

To evaluate the anti-mycobacterial activity and

safely of PA-824, when added to the Category IV

regimen of RNTCP for the first 8 weeks, in subjects

with newly diagnosed pulmonary MDR-TB

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WILL ALSO HELP IN BUILDING CLINICAL TRIAL CAPABALITIES; AN OSDD DELIVERABLE


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OSDD challenges - going forward

Building credibility Delivering on the initiatives

Completing the process Treading the newer aspects of the path

Maintaining the momentum Keeping the ideas coming

Replicating the model

Evolution of a mature pathway Expanding the model

Apply the path to other neglected diseases

a model to address drug discovery for neglected diseases_osdd

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