Download eTOXsys – Highly Relevant Proprietary Data and Predictive Models

eTOXsys – Highly Relevant Proprietary Data
and Predictive Models for Drug
Development
Scott McDonald
Director of Member Services
[email protected]
Summary
• Background – eTOX
• eTOXsys overview
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Interface
Data
Ontology
Models
SEND
• Use cases
• Sustainability
Who is involved
4
Project aims by 31st December 2016
Predict more complex toxicity endpoints by:
• Sharing high quality proprietary toxicity data previously
accessible for modelling only by the owning company
• Development of several models representing the
different components in the mechanism leading to a toxic
effect
• Integrated tool into an overall decision-making tool
Data
Models
Integrated
System
Value proposition
• Improved early drug candidate safety assessment
• Results can be applied to:
• Targeted in vitro screening
• Triggering the inclusion of specific target organs in early in
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vivo studies
Extrapolation from short term to long term effects
Raising hypotheses with regards to on-target and off-target
toxicities
Interaction with MedChem and Pharmacology with regards
to hypothesis on structural moieties responsible for effects
A facilitated target safety review
Data
Confidentiality levels
Confidential Shared Data
In-House Data
Only accessible via secrecy
agreement
Only accessible to EFPIA
data owner
Non-Confidential Shared
Data
Public Data
Accessible to eTOX
consortium
Accessible outside eTOX
consortium
Data
Database contents = Latest release 2016.2
Non-confidential
Structures
1,449
Other
routes; 53
Other
injection;
251
Dermal; 58
Confidential
Structures
466
Non-confidential
Studies
7,509
Baboon; 4
Inhalation;
259
Dog; 2035
Guinea pig; 9
Intravenous;
1068
Hamster; 6
Rat; 4515
Marmoset; 38
Monkey; 449
Oral; 5788
82-100 days;
593
101-364 days;
400
Mouse; 349
Pig; 16
>365; 86
Rabbit; 81
36-81 days; 147
<20 days; 3944
20-35 days;
2333
Data
Top 10 organs affected by histopathology
Liver
806
658
Thymus
852
426
Kidney
990
391
Spleen
884
373
Adrenal gland
867
291
Stomach
265
Lung
265
Mesenteric lymph node
799
1005
727
249
Bone marrow
202
Testis
199
0
200
523
873
400
Negative structures
600
800
Positive structures
1000
1200
Ontobrowser & the eTOX ontology
Data
Predictive Models
• eTOX computational modellers have developed a range
of models
• ADME, organ toxicity and target safety pharmacology
• Built on chemical space highly relevant to drug
development
• Verified and well documented
Modular Approach
• Integrated but modular package
• Access to other databases will be technically enabled
• Predictive models will be available and users can choose
the ones they want
eTOXsys – the integrated system
eTOXsys – data query
eTOXsys – data query
eTOXsys – data query
eTOXsys – data query
eTOXsys
eTOXsys
eTOXsys
Predictive models
Predictive models
Predictive Models
Predictive models
Predictive models
SEND
• Standard for Exchange of Nonclinical Data, captured at
individual animal level
• FDA require the data for a NDA to be submitted in SEND
format for studies which start after the 18th of December
2016
• eTOX donated data captured at dose group level
• Lhasa has developed a tool that will permit the import of
data in SEND format into eTOXsys
Use case 1 – Framework for early drug
development candidate assessment
• Framework of four key approaches, each accessible through
eTOXsys, was introduced to early small molecule drug
development
• 60 projects have been assessed to May 2016 at the transition
point from hit to lead against this framework
• Results for target search
• Identical targets found for 10 projects (17%)
• Similar/related targets (down-stream targets, antagonists  agonists)
for 10 projects (17%)
• Results for chemical similarity search:
• >50% similarity in 34 projects (57%)
• >60% similarity in 8 projects (13%)
• 70% similarity in 3 projects (5%)
Use case 1 – Framework for early drug
development candidate assessment
• The eTOX database represents a valuable tool for early
assessment of drug candidate and target assessment
• Results of the database search can be used:
• To identify tool compounds for comparison of the safety
profile
• To optimise the design of early in vivo screening studies
(inclusion of non-routine organs and tissues)
• To initiate discussions between Medicinal Chemistry,
Pharmacology and Toxicology for compound optimisation
Use Case 2 – Relevance of histopathology findings
observed in a rat toxicity study
• Renal papillary necrosis was observed in a rat toxicity
study
• eTOXsys was searched for compounds with the same
effect
• 49 compounds (81 studies) were identified (all 49 affected
rats, only 3 for dogs)
• 30 compounds with annotated pharmacology: 53% were
EGF or VEGF inhibitors
• Further literature research established a link between
EGF receptors and renal papillary necrosis
Use Case 2 – Relevance of histopathology findings
observed in a rat toxicity study
• Inhibiting epidermal/vascular growth factors (on- or offtarget) could be related with the induction of renal
papillary necrosis
• Rats are more susceptible to chemically induced renal
papillary necrosis compared to dogs/other species
• Both conclusions used for assessment of the relevance of
renal papillary necrosis observed in rats for the human
situation
Use Case 2 – Relevance of histopathology findings
observed in a rat toxicity study
Use Case 3 – Consideration of potential target
related effects in preclinical screening
• Investigation of antagonists for specific receptors within
the P2Xn receptor family due to their prominent role in
nociception
• Searching eTOXsys for structurally similar compounds
led to the retrieval of Fluopyram, a fungicide
• Reported treatment-related effects included:
• Liver (hypertrophy) in the mid-dose
• Thyroid (hypertrophy) in the high dose
• These effects are mechanistically well characterised and
considered to be species-specific without relevance for
human safety (Rouquié et al. 2014)
Use Case 3 – Consideration of potential target
related effects in preclinical screening
• The study director was advised to include thyroid in the
screening panel (not normally included)
• If comparable liver or thyroid effects are observed during
screening of pivotal 4-week toxicity studies, these can be
de-risked based on the knowledge obtained from
eTOXsys and the literature
Summary - eTOXsys
• eTOXsys delivers:
• Access to proprietary data that is not available elsewhere
• An ontology and mining platform built specifically for this type
of data
• Well documented and verified models tested over a chemical
space that is highly relevant for drug development
• SEND compatibility
Sustainability
• eTOX project ends in December 2016
• Moves to sustainability phase in January 2017
• Molecular Networks and Lhasa Limited will continue to
work closely together
• Lhasa Limited will act as the ‘business broker’
• Framework is being put in place to allow non-eTOX
participants to gain access to eTOXsys
Sustainability
• Product development
• Promotion
• Licensing
• Distribution
• Training
• Support
Summary – eTOXsys and Sustainability
• eTOXsys delivers:
• Access to proprietary data that is not available elsewhere
• An ontology and mining platform built specifically for this type
of data
• Well documented and verified models tested over a chemical
space that is highly relevant for drug development
• SEND compatibility
• Sustainability allows:
• This valuable resource to be used more extensively
• Provides ongoing updates
• Users will be well supported and trained
Next Steps
• Please let us know if you would like further information on
eTOXsys
• Join us for our Virtual ICGM:
• Wednesday 16th November at 4pm (UK time)
• https://www.lhasalimited.org/events/webinar-etoxsys-highlyrelevant-proprietary-data-and-predictive-models-for-drugdevelopment/4075
Acknowledgements
• All those involved in the eTOX project
Questions?