A compound improves efficacy but accumulates in one organ. How would you frame the go or no-go decision?

Why

Accumulation is not automatically disqualifying. Some drugs concentrate in tissue by design, and lysosomal trapping of basic lipophilic compounds is common and often tolerated. What matters is whether the accumulated material produces a functional or structural change, and whether that change reverses when dosing stops.

The decision needs four kinds of evidence. Exposure data give the tissue to plasma ratio and whether levels plateau or keep rising with repeat dosing. Toxicology gives histopathology, organ function markers and a no-observed-adverse-effect level, from which a margin over the efficacious exposure follows.

Recovery groups show reversibility. Mechanism tells you whether the effect is on-target, which would follow the whole series, or a property of this molecule, which chemistry might fix. Context changes the threshold.

A single-dose therapy for a fatal disease tolerates much more than a chronic treatment for a mild one. Wong and colleagues' data are a reminder that most programs fail later anyway, so the real comparison is between carrying a known liability forward and spending the same resources on an alternative series. The decision should be written as a criterion in advance, with the experiment that would resolve it.