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Liz Hudson

How Well Do You Understand Off-Target Liability?

A Q&A with Sr. Principal Scientific Advisor and drug discovery and development industry expert Stan Spence on understanding off-target liability

Understanding how a drug works has always been important. But in today’s era of precision medicine, where drugs are increasingly personalized for a patient or small groups of patients, drug developers must show exactly how their therapies work and where their targets land. But science wouldn’t be science without surprises and drug development rarely, if ever, goes exactly as planned.

Understanding the diversity of off-target effects of treatments at the molecular level can reveal both unwanted side effects and unexpected benefits. “Sponsors don't always find the perfect molecule. Sometimes it’s incredibly difficult for a company to create a backup molecule without an off-target ‘hit’,” says Stan Spence, Senior Principal Scientific Advisor at Charles River Laboratories. “Then it's a question of what can be done to further characterize, understand, and mitigate the expected off-target effects.”

Stan brings more than 30 years of experience in pharmaceutical and biotechnology drug development to the Charles River Scientific Advisory board, beginning in toxicology within Preclinical Safety Assessment group at Merck and continuing in his career to contribute to the development several marketed drugs. Stan has also served as a senior director at Centocor and Wyeth, Executive Director of Preclinical Safety at Novartis, and VP of Nonclinical Development at C4 Therapeutics.

With experience in presenting nonclinical strategies to the FDA/EMA/PMDA, Stan has been an invited speaker at numerous societal scientific meetings and at the FDA and NIH. Stan’s experience includes the nonclinical development of a wide range of small molecules and biological therapeutics, plus reproductive, developmental, and juvenile toxicology. He joins us today for this Q&A.

What is off-target liability?

Generally, off-target liability includes any binding, inhibition, degradation, or activation of receptors, ion channels, transporters, enzymes, and proteins other than your intended pharmacological target that are known to be involved in clinical adverse drug reactions.

The commercial liabilities of a drug candidate with unknown off-target effects are multi-faceted. There is inherent risk attached to progressing a candidate without a comprehensive understanding of its binding profile. A candidate with serious off-target liabilities is more likely to fail anywhere along the continuum of drug development. 

Is there a difference between de-risking for the clinic and de-risking for the patient?

No, the keystone of successful drug development always puts the patient first, and this requires the drug to be effective and safe. For life-threatening indications such as cancer some liabilities can be accepted into early clinical development provided the risk assessment supports the likelihood that the off-target effects would be manageable, meaning not life-threatening, and occur at exposures that reasonably exceed the intended therapeutic exposure. However, this pushes a known risk to the most expensive phase of development, the clinic, and may lead to clinical toxicities and late-stage failures that could have been avoided. Although an IND for a drug intended to treat a life-threatening indication can be accepted with significant risks, drug development teams should be making decisions based on a weight of evidence with the likelihood of clinical success at the forefront of every decision.

What are the major implications of off-target effects?

Unintended off-target pharmacology can result in toxicities that lead to drug attrition, which can occur at any stage of drug development depending on the target and the drug platform. Therefore, identifying off-target liabilities should be done early in the drug development process to help select the drug candidate with the highest likelihood of success. While most off-target liabilities can be de-risked in toxicology studies, some off-target toxicities may not manifest until late-stage clinical development. Given this, it is paramount to identify and quantify these liabilities early in the drug development process to avoid exposing patients to potentially unmanageable toxicities and to avoid costly late-stage clinical failures.

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How does identifying off-targets earlier or later in the pipeline impact drug development research, particularly in smaller and start-up biotech?

Late-stage attrition represents the worst-case scenario with significant financial implications that can have a profound impact on a small company's viability and should be avoided at all costs. Disciplined portfolio decisions based on a “weight of evidence” allow funds that would otherwise be spent on a molecule with a low likelihood of clinical success to be re-directed back to research to create an improved molecule with a higher likelihood of clinical success. This also allows for better management of company expenditures to extend a cash runway.

What sort of strategies can help manage hazard versus risk in drug projects and target biology?

Early identification of on- and off-target liabilities allow scientists to develop a hazard assessment by making an inventory of all the toxicities that might manifest. The hazard assessment provides the basis for the blueprint of the toxicology or nonclinical development program. For some off-target liabilities the causal relationship to a given toxicity is well understood and a development decision can be made quickly. Other off target liabilities may influence species selection for the toxicology program and/or require purposefully designed follow-up assays and/or the inclusion of non-standard endpoints in early toxicology studies to better understand the risk or likelihood that a given toxicity will manifest in the clinical setting. Thereafter, a well-informed portfolio decision can be taken based on that weight of evidence approach considering the in vivo toxicology profile and comparison of exposure to the modelled human therapeutic exposure. Overall, this informs the likelihood of clinical success.

Is off-targeting binding always a negative event?

Off-target binding in pharmacology is not always a negative result. Some off-target binding can be inconsequential whereas other off-target binding might improve the drug’s effectiveness. It really depends on the indication, the on- and off-target biology, and the potency of off-target effects.

Aside from terminating non-viable candidates quickly and using that knowledge to generate improved drug candidates, knowing your binding profile allows you to better manage hazard versus risk in drug projects and target biology that can drive better decision-making and prioritization of research activities.

Sponsors don't always find the perfect molecule. Sometimes it’s incredibly difficult for a company to create a backup molecule without an off-target “hit.” Then it's a question of what can be done to further characterize, understand, and mitigate the expected off-target effects. I think this is where Charles River can add tremendous value. A detailed assessment of off-target binding can also, in some cases, lead to repurposing a molecule or deriving new molecules purposefully intended to bind to a new target of interest that could take your research in exciting new directions.

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Liz Hudson was a Senior Marketing Manager at Charles River Laboratories focusing on the Early Discovery business. This blog was updated January 20, 2026.