IQ DILI Initiative NONCLINICAL TRANSLATION Working Group – Nonmember Solicitation
** Responses due by 22 September 2025 **
Background and Rationale
Traditional risk assessment approaches for predicting and understanding mechanisms of drug-induced liver injury (DILI) have largely focused on small molecule therapeutics. However, as the drug landscape continues to evolve, small molecules now represent just one of many therapeutic modalities in portfolios across industry. One primary area of focus for the Nonclinical Translation working group is oligonucleotide therapeutics, an emerging class of drugs designed to address targets and pathways previously considered “undruggable” by traditional small molecules. Although significant progress has been made in evaluating the nonclinical safety of oligonucleotide therapeutics, hepatotoxicity remains a safety concern as the liver represents a major organ of uptake and exposure for some oligonucleotides. Their distinct mechanism of action and metabolic pathways present challenges, including hybridization-dependent and -independent off-target effects, exaggerated on-target pharmacology, immune-mediated responses to foreign nucleotides and differences in cellular processing; all of which can potentially contribute to liver injury. These complexities underscore the need to re-evaluate the relevance and effectiveness of traditional nonclinical safety approaches to assess DILI risk for emerging therapeutic modalities.
Project Details
Considering these challenges and collective experience, the Nonclinical Translation Working Group is in a unique position to review the current state of knowledge regarding the mechanisms of hepatotoxicity for oligonucleotide therapeutics and to identify gaps to further enhance nonclinical capabilities in addressing hepatotoxicity risk. This project will involve a comprehensive literature search to review and summarize known mechanisms of toxicity, evaluate the relevance and limitations of current methodologies, and assess translatability of nonclinical findings to clinical outcomes. A significant component will be sharing company experience and engaging in discussions to identify and address unmet needs in nonclinical DILI assessment of oligonucleotide therapeutics. A nonmember participant with expertise in nonclinical drug safety, DILI and emerging modalities would be an invaluable addition, offering expertise, expanding perspectives and enhancing the group’s ability to navigate this rapidly evolving therapeutic landscape.
Qualifications for the Candidate (all are required)
Note: Qualifications below must be based on specific scientific or technical expertise.
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- Experience in pharmaceutical industry or academia in the nonclinical development and safety assessment of new drugs
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- Involvement in the design/conduct/analysis/interpretation of nonclinical studies and risk assessment for DILI
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- Expertise in the nonclinical mechanisms of hepatic injury, with a particular focus on oligonucleotide therapeutics is highly desired
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- Demonstrated experience with authoring scientific publications in the field of nonclinical hepatology, DILI mechanisms and/or oligonucleotide safety
Boundaries of Engagement
Respondents, please note this is a volunteer role. When this project is completed, membership with this IQ working group ends. However, there may be additional opportunity to contribute to additional project initiatives aimed focused on other new modalities.
Submission Deadline
Respondents must submit a Statement of Interest (SoI) and current curriculum vitae (CV) by 22 September 2025.
