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Open Source Drug Discovery
(OSDD)
Third Asia-Pacific NIS Forum
Diagnosis of NIS and Development of STI
Strategies in the Open Innovation Framework
April 8, 2015
Bangkok, Thailand
Dr Sarala Balachandran
Chief Scientist, CSIR &
Project Director, OSDD
Outline
Introduction to OSDD
Why focus on TB
Various disciplines and website
Clinical trial being undertaken
Future Plans
Open Source Drug Discovery
A CSIR led team India consortium with global partnership for
affordable healthcare
How can we work together
Involve the scientific community with out borders in a
seamless manner
Encourage and train youngsters
Share the knowledge created
The first disease target: Tuberculosis (TB)
TB Drug Discovery
Why Open Source Drug discovery ?
 Many eye balls make the bug shallow!
 Lack of market incentive for TB
 Successful Open Source Models
 Human Genome Sequencing Initiative
 Open Source Software Initiative (eg: Linux OS)
 Android
 The WWW
Open Source Drug Discovery (OSDD) Model
“Team India Consortium with International Participation”
Open Synthesis and
Exchange
of Knowledge
Candidate
Targets
in silico SCREENING
Mycobacterium tuberculosis
Lead
Molecules PRECLINICAL & CLINICAL
TRIAL
in vivo VALIDATION
Wiki Portal
Academia
& Hospitals
Exchange of Ideas/Results
Community Participation
Lead Organization
Council of Scientific and
Industrial Research (CSIR), India
Current Partners
Contract
Research
Organisations
Drug
OSDD: Attribution and IP
• All contributions on the OSDD portal
(www.osdd.net) attributed to the authors with
date and time stamp
• Real time data sharing
• Click wrap license agreement
– All contributions treated as Protected Collective
Information
• mandates sharing,
• attribution,
• contribute back
OSDD View on Patents
• Two patent applied molecules in hit to lead phase
• Patent only to ensure that:
– Quality assurance in downstream processes
– Subsequent innovations remain in open source
– Affordability : through non exclusive licenses
Connect…
Integrate…
People
• Brainstorm Beyond Boundaries
• Harnessing the Innovation at the
Fringes
Science 2.0
Courtesy: HHMI
Seamless access to Information
& Tools
Ensuring relevancy in an ever
exploding information base
Information
Process
• Discussions to Discovery
• End to End Integration
Challenge … is balancing the three dimensions
OSDD An Alternative Model Of Drug Discovery And
Development
• Drug Discovery is risky, prone to failure, expensive and long drawn
• Drug Discovery and Development: Driven by pharmaceutical industry,
patents and market economics
• This Approach is not feasible for neglected diseases like TB, Malaria etc,
where there is no economic benefit
• Can we bring pharmaceutical research into the open where
academia, industry and researchers from different disciplines
collaborate as a goal oriented community?
The Open Innovation Model: OSDD strategy
• Porous-walled funnel facilitates free flow of ideas / projects
• Bring in more eyeballs to look at the inside
• Enables Redundancies and Parallelization
Inputs
Fuzzy Front-End
Research
Development
OSDD the leader
- Expertise
- Discovery Platforms
INDIVIDUAL PIs
IDEAS
Hits / Lead Molecules
OSDD
Platforms driving the
process
INTEGRATED
OSDD PROJECT
OSDD
Marrying The TWO CULTURES
Technology
Inputs
New Combination GATB
-
GLOBALISING
THE EFFORT
-
Academic
Delivery focused
OSDD THE FACILITATOR
Image Source: Clorox, Andy Gilinkski,
www.imaginatik.com
OSDD Philosophy
• Open Access of Data, Resources and Results to foster
collaboration to accelerate drug discovery
• Real time data sharing: All contributions on the OSDD
portal attributed to the authors with date and time stamp
• Click wrap license agreement: All contributions treated as
Protected Collective Information
mandates sharing, attribution, contribute back
• Patent only to ensure that: Quality assurance in downstream
processes
• Subsequent innovations remain in open source
• Affordability: through non exclusive licenses; generic
manufacturers
OSDD Strategy To Drug Discovery & Development
OSDD Distributed Virtual Laboratory &
Some Current Partners
Screening
Clinical Trials
LRS
IIT K
Compound
Repository
Screening for TB &
Malaria @CDRI
Compound
synthesis
Screening
IICB
Compound Repository
TB Screening
Screening
CLRI
NIIST
OSDD is Now an Internationally Reputed Drug Discovery Initiative
Pioneered by Government of India
Novel Combination of TB Drugs
Pre-Clinical Compound offered to OSDD
Assisting to progress OSDD’s in house
molecule
Support to Cheminformatics
3 Hit to Lead Candidates offered to OSDD
OSDD : Then & Now
Then
(March 2009)
Current
718 from 22 Countries
(as on 24th Feb 2009)
~8000 from 130
Countries
PIs
13
187
Institutions
7
75
Projects
13
984
Implementing
Team Size
3
7 (3)
TB
TB, Malaria,
Leishmaniasis
NONE
Several
Community
Target Diseases
International
Collaborations
OSDD: Coordination of Activities
 Crowd sourcing for solving challenges
(genome annotation for systems level
understanding)
 Streamlining processes & resources
(repositories/computational resources)
 Focused effort to targeted deliverables
(CROs & Academic Collaborations)
Top Down
Centrally Coordinated Projects
 Individual Driven
 Volunteer contributions
 Progression of target based & ligand
based approaches
 Contribution of resources and skills
Community Developed Projects
Bottom Up
Process of Project Proposal Review, Approval and
Implementation
Principal Investigator: Posts a project proposal on Sysborg
Open
Peer
Review
Scientific
Expert
Review
(4 weeks)
(4 weeks)
Periodic Monitoring & 6 monthly Review
Scientific Inputs from Science Support Group
Budget
Review
(2 weeks)
Ongoing work
Community effort is ongoing to further understand the biology of Mtb
System level analysis of metabolic impact of critically approved drugs
In-silico druggable target identification
Dedicated chemical synthesis lab
Targeted synthesis
Diversity oriented synthesis
Large scale mol bank
Screening facility against M smegmatis and M tuberculosis
DMPK analysis and in vivo will be facilitated
Clinical trials
The requirement of clinical trials for new TB drugs
Pitfalls of the current regimen:
Current MDR regimen:
Limited efficacy
Levofloxacin
Side effects
Pyrazinamide
Long duration of treatment
Ethambutol
Non-compliance
Ethionamide
Solution for the above problem:
Cycloserine
Kanamycin
Combination regimen brought forward
by TB Alliance
Public funding is required for affordable
pricing of drugs in infectious diseases
Why CSIR-OSDD is conducting clinical
trials
• So far we do
not have any
clinical trials
for new
drugs for TB
in India,
which will
directly
benefit
Indian MDR
patients
• The one
which
addresses
MDR TB
Sirturo
(Bedaquiline,
TMC-207) is
approved in
US, but has
not reached
India so far
• The
combination
of drugs in
which Sirturo
is to be given
has not been
studied and
hence lack of
clarity on the
best
combination
for the same
OSDD-TBCT-001
PaMZ is a novel combination regimen as compared to
introducing one drug at a time.
From the studies so far it shows promise to be effective in
both DS and DR patients, also from pre-clinical studies it
seems that it might even reduce the treatment duration
The agreement between OSDD and TB Alliance allows us to
have complete freedom to develop, manufacture and make
available to the patients at an affordable pricing in India
This expertise/infrastructure developed in-house will lay out
a platform for us to take further candidates from our pipeline
in a fast track manner
Phase IIb clinical trials with PA-824 regimen
Study flow diagram
PA-824+M+Z
PA-824 +
Category IV
regimen
Category IV
regimen
If successful,
will pave way
for simple, safe,
patient friendly
regimen
without
injectable
Does PA-824
add to
efficacy of
Category IV
regimen?
Control
HOSPITALIZATION
A Phase II, Open Label, Randomised Clinical Trial to evaluate the Anti Bacterial
Activity, Safety, Tolerability & Pharmacokinetics in Adult Males with newly
diagnosed
MDR TB: A three arm study.
23
Advantages of PaMZ regimen over
Current MDR Treatment
 Reduce number of drugs
 No injectable
 Hopefully will decrease the duration
 Better efficacy expected
 Simplified regimen
Why PA-824
Active against both replicating and hypoxic, non-replicating Mtb
Sterilizing activity in human pulmonary TB
PaMZ regimen offers promise of simpler and shorter regimen
Bactericidal activity in mouse
6
5
4
3
2
0
-.5
Untreated
RHZ
-1
7
PaMZ
PaM
-1.5
8
PaZ
-2
9
MZ
-2.5
logCFU change from baseline
.5
Bi-linear Regression: logCFU change from baseline
0
1
2
4
6
8
10
12
14
Day
0
0
4
8
TMC207
TMC207 & PA-824
PA-824 & Pyr & Moxifloxacin
TMC207 & Pyrazinamide
PA-824 & Pyrazynamide
Rifafour e275
Presentation
made to
Technical
Presentation
committee
made to IND and approval
committee on
obtained
st
21 August 2013
DCGI
and approval
submission obtained
made on
21.3.2013
Apex
committee
approval
obtained
Letter of
approval
from DCGI
obtained on
13.1.2014
National Research
Committee under
RNTCP held at
NITRD on 30th
September
Import licence
obtained Approval obtained
under OR head
Ethics
committee
approval 24th
January 2014
Challenges to be met
Agreement
with TB
Alliance
done
Agreement
with NITRD
ongoing
Repackaging
of IP done
Insurance
cover of
trial done
IM & SIV
carried out
Recruitment
of patients
started in
March 2015
OSDD : A Global Community About 8000 members from over 130 countries
Statistics as of January 2015
From insilico studies to laboratory
work to medicines for the patients