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12 May 2020

2020 Webinar: The Application of Adverse Outcome Pathways (AOPs) for Risk Assessment.


Lhasa Webinar 800x369px

Lhasa Limited's CEO, Dr. Chris Barber and Principal Global Alliance Manager, Dr. Crina Heghes, presented on the application of adverse outcome pathways (AOPs) for risk assessment. Links to access the slides and recordings can be found at the bottom of this page.

Here are the questions which were raised during the webinar Q&A session, along with considered answers from the presenters:

1. Are the carc AOPs for humans or rats?
We include all the pathways that are relevant for both human and rodents. We are aware that some of the pathways are not as relevant for humans and we capture this knowledge within the context of a pathway. We will then use this to reason to come to a conclusion on the human risk. We capture the rodent ones because generally people still carry out assays related to this species and any positive findings in this need to be negated.

2. What would be the advantage of joining the consortium?
By joining our consortium, you can direct the development of the product. From a software point of view, the consortium would be asked what their consensus is with regards to some of the questions brought up here. Equally importantly is the pre-competitive knowledge sharing. Kaptis provides the framework for pre-competitive collaboration such as sharing screening sequences for adverse events, it also aims to capture relevant public data and knowledge and systematically organise that knowledge into a searchable tool. We anticipate that members will validate our pathways with their proprietary data and this would be shared through Kaptis.

3. Do you talk to regulators about Kaptis?
Yes, as with all our products, we work closely with regulators to make sure we incorporate their feedback on how our products would help them. We have been talking and presenting to US FDA, US EPA, HMRA, and Health Canada. We are currently in the process of giving access to Health Canada. Also, the EMA have invited us to attend their Innovation Task Force Briefing Meeting forum and present on such topic as well.

4. What public sources do you use?
We use public sources to develop our AOPs such as ChEMBL for in vitro data and PubMed for relevant tox data and mechanistic data.

5. Is Kaptis helpful in impurities qualification?
Kaptis supports decision-making by linking molecular initiating events to adverse outcomes using a concept called Adverse Outcome Pathways which are essentially biological or mechanistic relationships between a target a chemical may interact with, the assays that are used to evaluate the efficacy of that interaction and the down-stream impact on a whole animal or human.  A typical decision may be ‘which assay should I select to understand the potential hazard of a chemical to cause this toxic outcome?’.  These biological pathways are generally considered independent of the chemical that is interacting and so can be equally well applied to an impurity or to a drug product.  Given a concern for an impurity to cause a particular adverse outcome, Kaptis will allow the user to select appropriate screens (e.g. in silico or in vitro) to qualify that risk.

6. Is there a list of targets already present in Kaptis?
Our initial work has focused upon 2 apical endpoints – carcinogenicity (both genotoxic and non-genotoxic carcinogens) and developmental and reproductive toxicity.  So far, we have developed 37 AOPs (many with multiple pathways) for carcinogenicity endpoint and 56 MIEs linked to DART adverse outcomes and are currently developing these into AOP networks. The list of targets is growing as Lhasa scientists have tackle further areas following the prioritisation of consortium members

7. How comprehensive is the data screened?
Our task will never be complete as there is not comprehensive understanding of the full biological complexity of the response to a chemical in an animal or human, we are using all quality public and proprietary knowledge to make these pathways as comprehensive as possible.  Our ambition is to ensure that the knowledge collected, curated and organised in Kaptis is the most comprehensive knowledgebase available.  We are fortunate to have a close relationship with our members and their feedback will help us improve Kaptis’ performance.

8. It would be interesting to know how reporting could be realised? How will the read-out be performed?
We are still working on reporting with the consortia.  Because Kaptis is envisaged to be used in a number of contexts to answer a number of different questions and because of the depth and complexity of the underlying data stored within Kaptis, a simple single report is not likely to be possible.  We are designing the software to be interactive – to allow the user to undertake a high level analysis (at the whole pathway level), to dive into the details around a particular key event, or to focus on a particular key event relationship or assay.  This is likely to require a flexible user-defined report to be produced to capture the right information to explain a decision, report on the analysis, and provide supporting details.



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