Slide deck for CDD's 2017 Q1 webinar featuring Dr. Chris Cooper (TB Alliance) and Dr. Matt Segall (Optibrium).

1. Make Better Drug Discovery Decisions
through Collaborative Analytics
Wednesday, March 29, 2017

2. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery
Kellan Gregory
Director of Product
Excellence, CDD
Moderators
Frank Cole
US Head of Sales, EAST
CDD

3. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery
Dr. Chris Cooper
Sr. Director of Chemistry,
TB Alliance, New York, NY
Panelists
Dr. Matthew Segall
CEO Optibrium Ltd
Cambridge, UK

4. • TB is the leading infectious disease
killer, and a top 10 killer worldwide.
• TB kills 1 person nearly every 18
seconds; 1.8 million die each year.
• 10.4 million new cases annually.
• Leading killer of people with AIDS.
• Drug resistance is on the rise—
580,000 annual cases.
• 1 million children become ill with TB
each year and 210,000 die.
TB Pandemic
Chris Cooper

5. Current TB Therapy
LONG
TB treatment today takes 6-30 months.
OLD
Arsenal of drugs developed mostly in 1960s.
COMPLEX
Many pills must be taken daily; drug-resistant
treatment includes daily injections.
EXPENSIVE
Drug-resistant (DR) TB drugs can cost >$10,000
per treatment.
INADEQUATE
Breeds resistance & default; incompatible with
some HIV treatments; DR-TB treatment often
fails.
One day of treatment for
drug-resistant TB
5

6. 6
Catalyzing and advancing new TB cures
TB Alliance: A Product Development Partnership (PDP)
6
 Not for profit organization founded in 2000,
with offices in New York, USA; and Pretoria,
South Africa (total staff: 48)
 Developing new TB drugs—and redefining
the way TB drugs are developed
 Virtual business model promotes innovation and
efficient, rapid progress
 Leverage global pipeline of drugs to find the most
promising TB regimens
 Transform TB treatment with new regimens that
treat drug-sensitive and drug-resistant TB
 Ensure beneficial new TB regimens are quickly and
widely adopted
 Largest TB drug pipeline in history

7. 7
Achieving maximum impact will
require:
• Short, simple regimens that are
adopted, available and affordable.
• Ideally, a universal regimen
consisting of all novel drugs that is
effective in all people with active
TB.
• All TB treatments are appropriately
formulated for children.
Discover, develop and deliver better and faster TB regimens
Our Vision: Better TB Medicines for All
7

8. Success will require novel drug combinations
Product Development Strategy
Current
Treatment
6-30
Months
New Treatments in
Development
3-6
Months
Aspirational
Goal
7-10
Days
8

11. 11
Leveraging the best science from around the world
A Global Network of Partners

12. 12
In Vitro ADME/Tox Testing (CRO #4)
• Solubility (clogD), plasma protein binding, %F.
• Metabolic stability, CYP450, hERG, Cytotoxicity liabilities, etc.
Mouse PO PK (CRO #4).
Analogue Synthesis
(CRO #1)
SAR/SLR
In Vitro Testing (Research Institute #3)
• Whole Cell Activity – Replicating and non-replicating
In Vivo PoC (Chronic Efficacy in Mice) (Research Institute #6)
In Vivo PoC (Acute Efficacy in Mice) (Research Institute #5)
In Vitro Testing (University #2)
• Activity against isolated enzyme
• MoA, MoR
“Typical” TB Alliance Lead Optimization Project
Multiple data sources
Lab-to-lab variability, as well as
site-to-site
Multiple data types
Assimilate, integrate and
analyze relevant data
Improve decision-making

13. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
CDD Vault Full Solution

14. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
CDD Vault -- Advantage

15. Whole Solution: Biology Assay Data , QC, & SAR

16. Structured Discovery Data

17. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery
Beautiful Data Visualization

18. © 2017 Optibrium Ltd. US Patent Numbers 9,224,098 and 9,367,812
Optibrium™, StarDrop™, Card View™, Nova™, Auto-Modeller™, Glowing Molecule™ and MPO Explorer™ are trademarks of Optibrium Ltd.
Multi-parameter Optimisation in Drug Discovery
Targeting compounds with a high chance of success
Matt Segall, CEO Optibrium Ltd. – matt@optibrium.com
18

19. © 2017 Optibrium Ltd. 19
The Objectives of Drug Discovery
Multi-parameter optimisation
• Identify chemistries with an
optimal balance of properties
• Quickly identify situations
when such a balance is not
possible
−Fail fast, fail cheap
−Only when confident
−Avoid missed opportunities
Absorption
Metabolic
stability
Potency
Safety
Property 1
Property2
X
Solubility
Absorption
Solubility
Metabolic
stability
Potency
Safety
Property2
Property 1
Drug
X
Hit
No good drug
M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310

20. © 2017 Optibrium Ltd.
Challenge 1: Data overload
Visualisation is important but not enough…
20
How can you make a confident decision by looking at these?
*Segall and Champness (2010) GEN, 30 (Sep 1) http://bit.ly/cSx4Tm

21. © 2017 Optibrium Ltd.
Challenge 2: Uncertainty in Data
• Experimental variability/error
− Single measurements: assay
variability
o pKi/pIC50 ~ 0.3 – 0.7 log units
(factor of 2-5 in Ki/IC50)
− Multiple replicates: mean
and standard error in mean
• Statistical uncertainty in
predictions
− Standard error of prediction
o logP ~ 0.4 -0.5 log units
o logS ~ 0.7 – 0.8 log units
o pKi ~ 0.9 – 1.0 log units
− Need to consider domain of
applicability
21
RMSE=0.8 log units
Segall and Champness (2015) J. Comput.-Aided Mol. Des. 29(9) p. 809
0
0.1
0.2
0.3
0.4
0.5
0.6
5 7 9 11 13 15
Probability
Solubility

22. © 2017 Optibrium Ltd.
Probabilistic Scoring
Integrated assessment of data against project criteria
Uniquely accounts for the uncertainties in all compound-
related data (experimental or calculated)
User-defined scoring profile Compounds ranked by
likelihood of success
M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310

23. © 2017 Optibrium Ltd.
Probabilistic Scoring
User-defined scoring profile Compounds ranked by
likelihood of success
Histograms for quick visual guide to
compound properties
M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310
Integrated assessment of data against project criteria
Uniquely accounts for the uncertainties in all compound-
related data (experimental or calculated)

24. StarDrop™

25. © 2017 Optibrium Ltd.
StarDrop – Core Features
Guiding decisions from selection to design…
• Probabilistic Scoring
− Define your property profile and quickly target high quality compounds
• Chemical space and selection
− Balance quality and diversity to avoid missed opportunities
• Card View™, data visualisation and SAR analysis
− Understand the structure-activity relationships in your chemical series
• Interactive design and Glowing Molecule™
− Guide the design of balanced compounds
25

26. © 2017 Optibrium Ltd.
StarDrop Plug-in Modules
Extend Core Capabilities
torch3D™ is a trademark of Cresset BioMolecular Discovery Ltd. BIOSTER™ is a trademark of Digital Chemistry Ltd.
Derek Nexus™ is a trademark of Lhasa Limited. SeeSAR™ is a trademark for BioSolveIT GmbH.
ADME QSAR
Auto
Modeller™
P450
High quality predictive models of
key ADME properties
Build and validate robust models
tailored to your chemistry
QM simulations identify sites of
metabolism and lability for P450s
Derek
Nexus™
Nova™ BIOSTER™
Knowledge-based prediction of
>40 toxicity endpoints
Generate and prioritise new,
relevant compound ideas
Explore >25k transformations with
the Nova module
torch3D™ SeeSAR™
MPO
Explorer™
Apply 3D SAR to identify and
optimise novel actives
Visualise protein-ligand
interactions in 3D
Develop multi-parameter
optimisation strategies

27. © 2017 Optibrium Ltd.
Conclusion
A complete platform for data visualisation, analysis and
compound design
• Website: www.optibrium.com/stardrop
− Detailed information
− Case studies
• Online community: www.optibrium.com/community
− Publications, presentations and posters
− Demo videos, tutorials and hints and tips
− Download free add-ons for StarDrop including CDD Vault plug-in
• Email:
− matt@optibrium.com
27

28. In Vitro ADME/Tox Testing (CRO #4)
• Solubility (clogD), plasma protein binding, %F.
• Metabolic stability, CYP450, hERG, Cytotoxicity liabilities, etc.
Mouse PO PK (CRO #4).
Analogue Synthesis
(CRO #1)
SAR/SLR
In Vitro Testing (Research Institute #3)
• Whole Cell Activity – Replicating and non-replicating
In Vivo PoC (Chronic Efficacy in Mice) (Research Institute #6)
In Vivo PoC (Acute Efficacy in Mice) (Research Institute #6)
In Vitro Testing (University #2)
• Activity against isolated enzyme
• MoA, MoR
“Typical” TB Alliance Lead Optimization Project
Multiple data sources
Lab-to-lab variability, as well as
site-to-site
Multiple data types
Assimilate, integrate and
analyze relevant data
Improve decision-making
Chris Cooper

29. Integration of CDD
• Available to all TB Alliance research partners
(CRO’s, universities, research institutes) to
facilitate direct data upload.
• CDD Vault integrated across TB Drug
Accelerator (TBDA) consortium -> enhanced
project coordination for global TB network.
• Initial raw data can be uploaded to private
“sandbox” -> permits data QC prior to
publication.

30. Integration of CDD
• Single data source for:
– Compound batch registration
– Chemical structures, descriptors
– In vitro biochemical data
– In vivo pharmacokinetic data
– In vivo efficacy data
– Tox. data, etc.
– Biological/pharmacological
protocols
• CDD Visualization-> Provides
simple graphical interface view
of data parameters/trends.

31. In Vitro ADME/Tox Testing (CRO #4)
• Solubility (clogD), plasma protein binding, %F.
• Metabolic stability, CYP450, hERG, Cytotoxicity liabilities, etc.
Mouse PO PK (CRO #4).
Analogue Synthesis
(CRO #1)
SAR/SLR
In Vitro Testing (Research Institute #3)
• Whole Cell Activity – Replicating and non-replicating
In Vivo PoC (Chronic Efficacy in Mice) (Research Institute #6)
In Vivo PoC (Acute Efficacy in Mice) (Research Institute #6)
In Vitro Testing (University #2)
• Activity against isolated enzyme
• MoA, MoR
“Typical” TB Alliance Lead Optimization Project
Multiple data sources
Lab-to-lab variability, as well as
site-to-site
Multiple data types
Assimilate, integrate and
analyze relevant data
Improve decision-making

32. Integration of Optibrium (StarDrop)
• Provides intuitive graphical depictions of important SAR/SLR
trends (physicochemical, potency/efficacy, toxicities, etc.).

33. Integration of Optibrium (StarDrop)
!!!!!!
• Multidimensional chemistry space models -> provide guidance
for new analogue design and synthesis.
Integration of CDD + StarDrop has improved the quality and
speed of med. chem. decision-making across TB Alliance
discovery portfolio

34. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery
Q&A

35. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery
Dr. Chris Cooper
Sr. Director of Chemistry,
TB Alliance, New York, NY
Christopher.cooper@tballiance.org
Thank You Panelists
Dr. Matthew Segall
CEO Optibrium Ltd
Cambridge, UK
matt@optibrium.com

36. Copyright © 2016 All Rights Reserved Collaborative Drug Discovery
Thank you all
for your participation
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info@collaborativedrug.com