Human Safety NAMs

Early derisking (discovery & lead optimization) with new approach methodologies: Which molecules should move forward?

The earliest stages of drug discovery offer the greatest opportunity to influence program outcomes, yet safety considerations are often introduced too late to meaningfully shape decisions. During hit to lead and lead optimization, human relevant safety liabilities, such as liver or cardiac toxicity, can already be present, even when efficacy signals appear promising. Understanding these risks earlier allows teams to evaluate not only whether a molecule is active, but whether it is likely to be viable.

Human safety NAMs support early safety decision-making by applying scalable NAM models complemented by in silico methods specifically designed for discovery use. Model complexity is selected based on the biological question at hand, ensuring that studies remain efficient while still capturing relevant mechanisms. By integrating multiple readouts, our scientists account for diverse toxicity pathways that may not be apparent in initial assays.

Incorporating human-relevant safety insights at this stage helps teams compare risk across lead series, make informed decisions at predefined checkpoints, focusing resources on molecules with the greatest likelihood of success. The result is greater confidence in lead prioritization and reduced investment in low value or high risk programs.

This approach moves safety from a late-stage filter to an early decision driver, reducing reliance on downstream failure.

Candidate selection using human safety NAMs: Which candidate offers the best balance of efficacy and safety?

As programs advance and the number of viable molecules narrows, decision making increasingly depends on understanding trade-offs between efficacy and safety. At this stage, subtle yet meaningful differences in human-relevant safety profiles can be used to exclude candidates that otherwise appear similar based solely on pharmacology.

IQVIA supports candidate selection by enabling direct, side by side assessment of multiple molecules using consistent human based safety models. This approach allows teams to evaluate comparative risk across candidates, identify liabilities linked to mechanism or modality, and anticipate potential challenges before committing to a single preclinical candidate.

By integrating these insights with existing pharmacology and PK/PD data, IQVIA Laboratories Discovery Sciences teams help our customers make more informed decisions. This reduces the likelihood of advancing a candidate that later fails for predictable safety reasons and improves overall portfolio confidence.

IND-enabling safety using human safety NAMs: How can we generate a safety package appropriate for progression to first in human (FIH) studies?

For some drug modalities, particularly antibody-based therapeutics (such as multi-specifics or antibody-drug conjugates [ADCs]) and advanced cell or gene therapies, meaningful pharmacology may be limited or absent in non-human species. In these cases, NAMs can be used to generate human safety data, which can play a critical role in enabling progression to clinical development.

Based on the drug modality, mechanism of action, and target biology, we design panels of human cell and organoid models to capture on target toxicity, off-target effects, exaggerated pharmacology and potential off target liabilities. Screening is typically conducted across multiple donors to address biological variability and strengthen confidence in the findings.

Human-relevant safety data generated using this approach has been accepted by regulators to support progression to first-in-human studies, both as a complement to reducing animal testing and, in some cases, in the absence of traditional animal safety studies. Our labs have supported 13 IND-enabling programs (5 bispecific and 8 CAR-T), with 10 advancing to FIH, demonstrating a focus on programs with high human selectivity and a scientifically justified, regulator-aligned strategy.

Mechanistic toxicology & clinical signal investigation using NAMs: Why are we seeing this signal and can it be mitigated?

Unexpected safety findings can arise during advanced preclinical development or even after a program has entered the clinic. When this occurs, understanding the underlying mechanism is essential to determining whether a program should proceed, be modified, or be stopped altogether.

We support mechanistic investigations using human cell based models based on new approach methodologies (NAMs) that represent relevant organs and biological systems. Studies are designed to reflect clinically relevant exposure and kinetics, allowing hypotheses about mechanism, dose dependence, or tissue specificity to be tested directly. This targeted, hypothesis-driven approach avoids unnecessary repetition of animal studies while providing insights directly relevant to human biology.

A mechanistic understanding can accelerate root-cause analysis, inform mitigation strategies, and, where appropriate, enable the design or selection of backup molecules without the toxic mechanism. In doing so, it helps preserve program value that might otherwise be prematurely terminated.