Salivary gland toxicity has been the defining liability of PSMA-targeted radiopharmaceuticals — lutetium vipivotide tetraxetan included — so the single most clinically consequential number in Aktis Oncology’s first-in-human AKY-2519 dataset is 4.2 Gy RBE at the predicted therapeutic dose schedule of 8 MBq × 4 administrations of actinium-225. That figure sits well below the salivary gland exposure benchmarks associated with approved agents and, if it holds through therapeutic dosing, removes the toxicity constraint that forces dose reductions and interruptions in current PSMA practice.
The imaging and dosimetry assessment enrolled 16 mCRPC patients across two sequential phases. The first used gallium-68–labeled AKY-2519 with PET/CT to characterize biodistribution and compare directly against PSMA-11; the second used low-dose, non-therapeutic lutetium-177–labeled AKY-2519 with SPECT/CT at 3, 24, and 144 hours to generate absorbed dose coefficients convertible to an actinium-225 therapeutic estimate. Predicted kidney dose landed at 16 Gy RBE and liver at 9.9 Gy RBE — both manageable relative to clinical benchmarks — while tumor uptake and retention persisted for at least six days post-administration. That retention duration matters: actinium-225’s daughters require extended tumor residency to deliver meaningful alpha-particle dose, and six-day retention is mechanistically compatible with that requirement. No adverse events or infusion reactions were reported with either imaging surrogate.
The strategic framing here is explicit. Aktis is enrolling both PLUVICTO-naïve and PLUVICTO-experienced mCRPC patients in its ongoing Phase 1b, positioning AKY-2519 not as a replacement for lutetium vipivotide tetraxetan but as a sequential or combinable option for a population that either cannot tolerate PSMA-directed therapy or has exhausted it. B7-H3 expression is preserved in PSMA-low and PSMA-negative disease, which represents a population with essentially no approved radioligand option. A second Phase 1b across lung, colorectal, and other B7-H3-expressing solid tumors is set to open in the second half of 2026, broadening the addressable population well beyond prostate.
The datapoint to track is the salivary gland absorbed dose in patients who proceed to therapeutic actinium-225 dosing. Predicted estimates from lutetium-177 surrogates are an approximation; confirmed dosimetry in actual therapeutic administrations, expected with preliminary Phase 1b data in 2027, will determine whether that 4.2 Gy RBE figure survives contact with clinical reality and whether the differentiation claim against approved radiopharmaceuticals is durable.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
