The success of early CAR-T cell therapies was partly luck. Future therapies face a high bar, as an ideal target must meet three criteria: 1) be abundant on cancer cells, 2) be indispensable for the cancer's survival, and 3) be dispensable for the patient's healthy tissues to avoid lethal toxicity.

A critical disconnect exists in drug development: the decision to start a trial is most influenced by the number of academic publications on a target. However, this metric has no bearing on the trial's likelihood of success. The best predictor of success is actually strong human genetic evidence linking the target to the disease.

Human genetics doesn't just provide a drug target; it often specifies the therapeutic approach required. Discovering a protective loss-of-function mutation immediately tells researchers to develop an inhibitor (like an antibody or siRNA), accelerating the path from target discovery to molecule design.

CEO Dan Schmitt outlines a three-part test for a new drug: it must effectively engage its intended biological target, avoid interacting with other enzymes to prevent toxicity, and be deliverable to a patient in sufficient quantities to be effective. This framework simplifies the core challenges of drug development.

The catastrophic failure rate in drug development isn't just bad luck; it's a structural problem. It originates from the very first decision: researchers, biased by existing literature and simplistic models, fixate on a single biochemical target, ignoring the body's complex, multi-faceted nature.

Novartis's cardio drug failure in a secondary prevention trial highlights a critical development challenge: even for genetically-validated targets, intervening late in a chronic disease's progression may be ineffective. The damage may already be too extensive, suggesting earlier treatment is needed to show a benefit.

Gilead has tightened its criteria for advancing projects, demanding a deep mechanistic understanding before committing significant resources. This involves validating the target, understanding its biological impact preclinically, and identifying biomarkers—moving beyond just a promising hypothesis to a de-risked scientific thesis.

Many blood cancers are better understood as "regulatory problems" driven by epigenetic failures—the systems controlling which genes are turned on or off. This shifts the therapeutic focus from targeting DNA mutations to developing drugs, like IDH inhibitors, that correct these underlying control mechanisms.

Haya's approach redefines the drug target. Instead of focusing on single proteins or pathways, they identify the "causal unit" of disease as the cellular behaviors that dictate how patients feel, function, and survive, and then work backwards to find a target.