All discovery and preclinical programmes have unanswered biological questions and thus target validation continues as a project proceeds into the clinic and beyond. In the early stages, target validation is focused on in vitro and in vivo proof of concept, pharmacological efficacy, and target safety. As the programme progresses towards the clinic, investigations shift towards patient stratification and selection, the generation of a relevant preclinical package, and the identification of exploratory biomarkers. Emma’s industrial experience spans all of these areas. Using her broad expertise and biological insight she has led multiple successful investigations to build scientific support for preclinical programmes and to build on clinical strategy. Examples include:

​​​

• in vitro and in vivo proof of concept for novel targets: delivering first in class targets to the discovery pipeline and supporting partnering and fundraising milestones

  • Design of key in vitro experiments to address go/no go efficacy and safety questions, with detailed budgets and timelines

  • Evaluation of in vivo models, identification of the best CRO provider and management of CRO activities

  • Translational pharmacology, alignment of in vitro and in vivo hypothesis with data from patient tissues and clinical studies.

  • Assembly and leadership of external multi-disciplinary scientific advisory teams to provide expert insight and niche technical expertise.

​

• Biological mechanism of action for small molecule and biologics targets: delivering a drug discovery plan and supporting preclinical and business development strategies for targets or assets with unclear biological mechanisms of action.

  • Definition of the key questions, based on review of all existing proprietary and public data

  • Formulation of a clear and compelling hypothesis, visualizing the preclinical and clinical paths and illustrating the potential value of the programme to key stakeholders

  • Design of a lead optimization workflow with key primary and secondary assays to select for desired biological activity.

  • Design of a validation plan for key pharmacokinetic and pharmacodynamic markers to illustrate in vivo proof of mechanism, ensuring alignment to in vitro and patient data

​

• Design of target validation workflows for novel platform technologies: data-led implementation and evolution of an integrated process for target evaluation in the absence of any prior established standard.

  • Review of existing data to identify biochemical, biological and pharmacological parameters that are critical to desired efficacy and safety endpoints

  • On-boarding of new capabilities (e.g.  ‘omics’ technologies, bioinformatics and human tissue approaches) to improve, refine and accelerate target validation

  • Identify and provide biological validation for first-in-class targets.

  • Evaluation of key in vitro safety and efficacy models in the context of normal and disease patient tissue to support IND packages

  • Continuous assessment and refinement of the overall process in response to emerging data

​

• Patient selection and stratification for first-in-class targets: mapping targets, pathways and biological mechanisms of action to unmet need and key patient groups. Building the clinical, competitive and commercial case and enabling clinical progression and indication expansion

  • Utilization of ‘omics’ data to associate expression of a target with key patient groups (e.g. driver mutations, molecular phenotypes, patient groups of high unmet need).

  • Experimental exploration of indication expansion and targeted therapy opportunities.

  • Discovery and validation of patient selection assays for use in early trials

​​

• Hypothesis invalidation, an example: adoption of a 'fast fail' approach to potential literature targets, minimizing the risk and expenditure of pursuing targets based on false assumptions.

  • In an example case, (GPCR lipid mediator) a review of proprietary data and public literature identified key 'killer experiments'  designed to interrogate assumptions

  • The literature findings were shown to be reproducible but the in vitro pharmacology of the natural ligand had not been fully investigated in the original publication.

  • Further evaluation revealed inconsistent biological responses across the concentration range, rendering the approach unsuitable for further development.

  • Defining and addressing the right biological questions from the outset is crucial to success