The Target Safety Assessment (TSA) workflow developed by TNO, enables the identification of the potential toxicological effects of drugs at an early stage. The computer-based method was recently tested in collaboration with a pharmaceutical company and clearly demonstrated its added value to the early safety assessment of drugs.
Many drugs exert their action by interacting with body proteins. Activating or inhibiting these proteins is not without (toxicological) risks. The early identification of safety issues is therefore a key factor when developing innovative drugs.
Consequences of no-go drugs
“Bringing new drugs to the market is not an easy process. Even in a late phase of development many products fail, adverse effects. The later in the process a compound drops out, the more expensive it is for the pharmaceutical company. Fail fast, fail cheap is therefore a well-known concept,” explains Jennifer McCormack-Venhorst, project leader at TNO.
“The higher goal is, and remains, to provide the patient with innovative drugs more quickly”
The process of new drugs
The search for new drugs begins with the selection of a target (a specific protein) for a therapeutic indication, followed by finding and optimising candidate drugs. If the developed compound demonstrates sufficient efficacy and safety, it can be tested in clinical studies. “We come into the picture at the very start of this process and identify what is known about the selected target. What kind of effects does this specific protein have? What happens when we influence the protein? Among the aspects we study in detail are the binding site and specificity of the target,” McCormack-Venhorst says.
The Target Safety Assessment workflow jointly developed with pharmaceutical companies encompasses all the aspects of a safety assessment. “Undesired effects can arise due to the candidate drug’s lack of selectivity. The role played by the protein in biological pathways, is also important: interactions between proteins may activate or inhibit several processes, which can lead to undesired effects. We also look at this aspect,” McCormack-Venhorst adds.
Drawing up the toxicity profile
With all the information that is obtained, a toxicity profile is made. “The data and insights that are derived from the workflow are combined in an extensive report in which the toxicity per organ and type of data (in vivo, in vitro, clinical) is shown and ranked by the severity, level of evidence and relevance, among other things, for the patient population. This profile allows us to give advice to the company which can be used to decide on the next steps”, explains McCormack-Venhorst.
TNO started the Target Safety Assessment last year. Various pharmaceutical companies took the opportunity to assess the added value this could deliver, and interest was tangible. “We carried out a pilot for a company. The investigated target was a heat shock protein that is involved in the right folding of proteins, and is a target for cancer medication. The pilot went very well”, says McCormack-Venhorst.
The satisfied pharma company – which must remain anonymous given the significance of the vested interests – endorses the Target Safety Assessment workflow: “This method can provide clear added value to the early safety assessment of drugs. TNO has produced a high-quality workflow. And, what’s more, the cooperation was enjoyable.”
“This method can provide clear added value to the early safety assessment of drugs”