product update - lhasa limited · product update dr nicholas marchetti product manager...
TRANSCRIPT
Two Years On…
• At the last ICGM
• Derek and Sarah for Web• Lhasa Carcinogenicity Database
Latest Release: Derek Nexus 5
• Significant work on the Skin Sensitisation endpoint
• Leading to the implementation of Potency predictions for
LLNA EC3
• Classification of Sensitisers
• Derek ICH M7 Classification
• Presents additional information to help perform expert review
Updates to the Derek Knowledge Base
• Focus on skin sensitisation and mutagenicity (in vitro)
endpoints
• 22 new/modified mutagenicity (Ames) alerts
• 11 new/modified skin sensitisation alerts
Updates to the Derek Knowledge Base
• Using data from
• Secondments to Lhasa members
Updates to the Derek Knowledge Base
• Using data from
• Recent Publications (e.g. acid chloride, alert 315)
Updates to the Derek Knowledge Base
• Using data from
• Proprietary Data Sets
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Latest Release: Model Building for Sarah Nexus 2.0
• New functionality to enable users to build predictive
models for mutagenicity
• Also allows for users to supplement the Lhasa model with
their own data
• Predictions can be run using different models can be
manually compared to understand the impact of the
additional compounds
• The best prediction settings can
be automatically determined for
your chemical space
Latest Release: Sarah Nexus 2.0 Updates
• Changes to prediction
algorithm
• Hypotheses with
Connection Points
• Hypothesis weighting
when combined to give
an overall prediction
Balanced accuracy has increased by 3 percentage points
Future Plans: Derek, Sarah and ICH M7
• Derek
• Negative Predictions for Skin Sensitisation
• Improvements to ICH M7 Interface to help build a
submission-ready package
• Sarah
• Improved Chemical Engine implemented for model building
and prediction
• Display of strain information for data underlying Training Set
and derived Hypotheses
• Improved functionality to allow comparison between
predictions using multiple models
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Zeneth
• Introduction of a novel methodology to better predict
likelihood of degradation pathways occurring
• Improvements to support additional drawing packages
and operating systems
• Longer-term project to meet additional use cases and
more closely align with member workflows
Pathway likelihood
• Existing method – lowest step likelihood
• Only 5 likelihood levels for many combinations
• Loss of information descending tree
• New method – ‘Multiplied likelihoods’
15
Change to Prediction Methodology
• Current methodology is often not granular enough to discriminate
between two “equivalent” outcomes where in reality one is less
likely than the other
Pathway likelihood
Processing constraints
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Pathway likelihood
Lowest step
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Pathway likelihood
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Multiplied step
Zeneth Update
• Zeneth 2016.1.1 Knowledge Base
• Released 22nd August 2016
• 46 new transformations
• 51 improved transformations
• Summary:
Transformation Type Number added Total number
Oxidations 17 143
Hydrolyses 7 87
Condensations/additions 13 90
Eliminations/fragmentations 7 56
Isomerisations/rearrangements 1 32
Photochemical reactions 1 38
Total 46 446
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Latest Release: Meteor Nexus
• A hybrid of a machine-learnt approach to rank expert
system-generated metabolites based on known metabolic
reactions
• reduces the number of “false positive” predictions
• Ability to overlay toxicity predictions directly on to the tree
Future Plans
• Development of additional visualisations to allow the
predictions to be useful in a wider variety of applications
• Further refinement of the hybrid methodology to improve
predictions
• Supplementation of the dataset to increase accuracy of
observed metabolites
Derek and Sarah for Web
• Web-based interface to Derek and Sarah
predictions
• Workflow tool, integrated into your corporate directory
service
• Includes reporting, notification and management of
historical predictions
• Demo later in the ICGM
Mirabilis
• Collaboration between Lhasa Limited and pharmaceutical
industry partners
• To develop a systematic approach for the risk
assessment of potentially mutagenic impurities remaining
in a final drug product when introduced or created during
synthesis
• See presentation later in the ICGM
Mirabilis: Next Steps
• First full release of Mirabilis to be released to the current
consortium by the end of 2016
• Further release scheduled for 2017
• Implementing feedback already gathered within consortium
• Seeking further feedback following initial release
• Improvements to the Knowledge Base
Setaria: Introduction
• Workflow based Intelligent Knowledge Organisation
Solution
• Stores Project-relevant data
• Stores and organises Experimental outcomes and in silico
predictions for easy retrieval
• Designed specifically for the pharmaceutical use case
• Result of a bespoke development for one Lhasa member
• Now in an evaluation phase to see how applicable the
workflow is in the wider pharmaceutical market
Setaria: Next Steps
• Evaluating the system with members
• Development of generic, customisable business rules to
suit alternative workflows and ways of working
• See presentation later in the ICGM
Building the Chemical Foundations
• Mirabilis
• Fundamental component allowing mapping of reaction types
onto end-user synthetic schemes
• Sarah
• Key part of the curation/standardisation engine
• Ensures that no matter how you draw the compound, you will
always get the best prediction
• Comprehensive coverage of Tautomers, Resonance Forms
and…
• Seeking member feedback on standalone deployment
Building on the Foundations
• Fundamental part of our upcoming development of our
Forced Degradation product, Zeneth
• Will be used to continue the development of our Next
Generation methodologies as they are improved in
Meteor
Lhasa Carcinogenicity Database
• Searchable repository of 6529 long-term carcinogenicity
studies covering 1529 chemicals
• Builds upon work by Lois Swirsky Gold et al.
• Recalculates TD50 values following the non-lifetable
statistical method using a new R script
• Will be published
• Data will be expanded upon in the future
A trusted solution to ICH M7
..developed through collaboration
Impurity
identification
Database
searching
ICH
M7
Expert prediction
Statistical
prediction
Expert assessment
Classification
Reporting
Purge mitigation
Control
Test
Archiving
A trusted solution to ICH M7
..developed through collaboration
Database
searching
ICH
M7
Expert in silico
prediction
Statistical in
silico prediction
Expert
assessment
Classification
Reporting
Purge mitigation
Impurity
identification
Test
ControlArchiving
Data
sharing
Questions?