In a DDW Sitting Down With podcast with Lu Rahman, Ruth Roberts and Claire Sadler, ApconiX, discuss the benefits of performing a target safety assessment (TSA) during drug discovery and development when a biological target is going to be acted on by a drug.
The background
In this podcast, Professor Ruth Roberts, co-Founder of ApconiX, and Claire Sadler, Project Toxicologist, ApconiX, outline how TSAs can be used throughout the drug discovery and development pathway, offering examples of best practice and potential next steps.
According to Roberts: “A target safety assessment is an integrated, evidence-based report that brings together all public domain information to identify the potential risks associated with modulating a biological target.
“Most TSAs we do are for pharmaceutical companies, such as drug therapeutics, but TSAs are also applicable to other industries including veterinary science and agrochemicals.”
In the work carried out by ApconiX, its TSAs support decision-making during the drug discovery and development pathway.
“We look at the likely occurrence and impact of the potential consequences from a toxicology perspective of modulating a biological target and provide clear and concise guidance on mitigating risks,” explains Roberts.
The value of a TSA
According to Sadler, a TSA is of value to any company thinking about modulating a biological target. “This is usually the primary target but can be extended to consider other targets that might be modulated unintentionally,” she explains.
TSAs can be invaluable during product development: For due diligence purposes or for portfolio selection, grant applications and for planning the drug discovery and development programme.
Roberts explains that the foundation of a TSA is understanding the target’s normal biology. “Over 40% of drug safety failures are due to the drug target. Knowing the potential hazards of modulating a target enables informed decision making,” she says. “When focusing on a primary drug target, you are looking in terms of the benefit of modulation for a specific disease. A TSA gives you the understanding of the challenges that may come along with that and you are able to proceed with a fair understanding of the risks as well as the potential benefits. A TSA allows you to go into a project with your eyes open,” she adds.
Using a TSA and when should one be carried out?
TSAs can be used to make choices between targets being accepted into a portfolio. According to Sadler, “this is particularly helpful to those with complex portfolios and to investors. Later in a project TSAs can be used to build a safety strategy to identify potential hazards and assess risks.”
By carrying out a TSA as early as possible, before investment has been made at the target selection phase, means that informed decision making can take place. Sadler points out that should be revisited through the drug discovery and development programme. “Bearing in mind the timescales of getting a drug to market, knowledge will be gained throughout the programme and scientific understanding of a target will increase,” she says, adding that starting early but building upon knowledge is important to a successful programme and adds that the best times to update a TSA is when a programme moves to the next stage.
How to approach a TSA
TSAs should be tailored to answer any specific questions. That could be around a multiple target portfolio decision or a clinical finding. Sadler advises on ensuring the context of the project is fully understood including the target, the indication, the modality, the project stage, patient population and any pre-existing known information.
When gathering available public domain information, toxicology expertise is important to scrutinise the evidence and put into the context of the drug programme. This is because a hazard can be perceived very differently depending on, for example, the disease indications.
“Some targets are highly novel and there is very little information known about them. In this case the TSA may have to be tailored to expand across the pathway for example and consider related targets,” says Sadler. Other targets are well understood and the challenge here is that there may be tens of thousands of pieces of literature so understanding the optimal information to draw out requires specialisation and skill.
According to Roberts, when gathering evidence for a TSA it is important to consider all publicly available information. “Having a number of pipelines allows the systematic search and curation of all publicly available evidence sources. It is an end-to-end process that takes together such areas as alignments, homologies, knockouts, overexpression and clinical trial data,” she says.
Roberts notes that although bioinformatics is the basis of a TSA, it is only the start. “The expert getting to grips with the information and interpreting that information in the context of the project is the key to a high quality TSA,” she reveals.
Investment
“A TSA is an expert review,” says Roberts. “In drug discovery cost terms, it is a relatively moderate investment. The scale or depth of a TSA can be adjusted depending on project needs,” she says and adds that “the return on investment far outweighs the cost of a TSA.”
A range of different expertise is required to create a TSA. This includes toxicology expertise, especially around mechanistic toxicology, safety and secondary pharmacologists, immunotoxicologists and organ system specialists, as well as drug project experience and specialised bioinformatics.
The review process and next steps
TSAs should be peer reviewed by expert project toxicologists to give opinion on the interpretation of the evidence collected, says Sadler. Customer review is also important. Clients will often have a view on the relevance of findings from their own expert position.
Having received a TSA, the first steps might be to look at the high impact, high likelihood of risks that have been identified. “Further discussion may be beneficial if there are areas of concern. Using the knowledge gained from a TSA, the risk assessments may be front loaded by adding extra end points to efficacy studies that may come before toxicology studies,” says Sadler, giving an example: “This may suggest in-vitro or in-silico approaches or even the design of the modality may be influenced. For example, brain penetration may be avoided if there is a CNS risk, a discussion with the medicinal chemists may be beneficial here in terms of tractability.”
DDW Volume 24 – Issue 3, Summer 2023
