Drug Discovery Derisking: Attrition, Target Selection, and Integrated Development Strategies

Clinical success rate and timelines of a drug discovery program are highly dependent on target, modality, and indication. For compounds entering Phase 1, “big pharma” has a higher likelihood of approval compared to drug discovery companies overall, and Phase 2 is where lack of desired efficacy or safety have ended more than two-thirds of all programs.

The choice of target is paramount to any drug discovery campaign, and no target is without risk. Targets with limited validation can create valuable first-in-class opportunities for those willing to take on risk. New targets can have genetic validation, but that is no guarantee. Best-in-class opportunities require a differentiated approach; they may entail less biological risk than first-in-class and come with more competition, but they can provide a bigger payoff. Even great molecules may face inherent challenges attributable to the target, such as lack of efficacy or on-target toxicities.

The success of target validation and lead optimization depends heavily on how closely a biological model mimics the complexities of human disease. Discrepancies between experimental environments and clinical pathology often lead to late-stage attrition in drug development. A webinar scheduled for Wednesday, April 22, 2026, 11:00 AM – 12:00 PM Eastern Time, will discuss strategies for integrating high-throughput CRISPR screens and advanced biological models to accelerate drug discovery workflows. Topics include criteria for selecting disease-relevant models, high-throughput CRISPR screening methods for identifying novel targets, advanced in vitro and in vivo models for enhancing translational success, and practical approaches to align model selection with tissue and safety requirements. The webinar will be presented by Lonza’s market development manager and associate director of market strategy.

One of the most complicated transitions in drug development is moving a molecule from discovery to candidate nomination and GMP manufacturing. Integrated development strategies, which combine chemistry, biology, pharmacology, toxicology, CMC, regulatory, and manufacturing expertise, are critical to minimizing risk, maintaining timeliness, and increasing the possibility of therapeutic success. Fragmented approaches frequently cause needless setbacks; when teams work in silos, crucial insights are lost, late-stage surprises manifest, and projects stop.

An integrated model solves five key development pitfalls: siloed data and misaligned teams; overlooking translational relevance; delayed consideration of formulation and pharmacokinetics; regulatory misalignment; and underestimating manufacturing scalability. Solutions include centralized data management, interdisciplinary reviews, incorporation of translational medicine considerations into candidate nomination, predictive modelling to determine dose feasibility, introduction of regulatory strategies during candidate evaluation, and engagement of process chemistry and manufacturing specialists in lead selection. By integrating scientific rigor and operational foresight, businesses can protect overall development investment, strengthen regulatory positioning, minimize late-stage attrition, improve GMP readiness, and improve timelines to IND.

Ten FDA programs exist to accelerate drug discovery. AstraZeneca dramatically improved their overall success rate in the 2012-2016 time period by focusing on proof of mechanism and safety early. Biologics are growing; however, small molecules still represent the largest drug modality.