Product Update

Dr Nicholas MarchettiProduct Manager

nik.marchetti@lhasalimited.org

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

9

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

18

Pathway likelihood

19

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?