bottlenecksBottleneck

Actinium-225 supply

There is barely enough of the radioactive metal actinium-225 in the world to treat a few hundred patients a year, even though several new cancer drugs need it. New ways of making it are being built, but they are not yet running at full scale.

Actinium-225's legacy supply comes from milking thorium-229 'cow' generators held at only four sites worldwide: Oak Ridge National Laboratory (US), the Joint Research Centre in Karlsruhe (Germany), the Institute for Physics and Power Engineering (Russia, irregular), and formerly SCK CEN (Belgium). Together they yield roughly 63 GBq (1.7 Ci) a year, which a 2025 review estimates is enough for only 100 to 200 patient treatments globally, against research and trial demand alone estimated at around 185 GBq (5 Ci) a year.

The scarcity has already stopped a clinical programme: in June 2024 Bristol Myers Squibb's RayzeBio paused new-patient enrolment in the phase 3 ACTION-1 trial of RYZ101 (225Ac-DOTATATE) specifically because it could not secure enough actinium-225, with the company citing a single global supplier for the trial. Every alpha-emitting PSMA and DOTATATE programme in development competes for the same small pool.

The fix is a shift from thorium-229 decay to direct production: accelerator irradiation of radium-226 or thorium-232 targets. The US DOE Isotope Program runs a tri-laboratory accelerator effort (Brookhaven, Los Alamos, Oak Ridge); commercial entrants are building cyclotron and electron-accelerator routes using radium-226 stocks. None of these has yet demonstrated tens of curies a year of GMP-grade material, which is the scale several late-stage alpha-emitter programmes will need if they reach approval.

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Scale of the problem

~63 GBq (1.7 Ci) per year across 4 sites

Legacy thorium-229 generator supply, worldwide

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100–200 globally

Patients that legacy supply can treat per year

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~185 GBq (5 Ci)/year

Estimated annual demand from research and clinical trials alone

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June 2024, cited as due to actinium-225 shortage

RayzeBio (BMS) paused new enrolment in phase 3 ACTION-1 trial

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Root causes

Only four sites worldwide hold a usable thorium-229 stockpile, and one (Russia's IPPE) does not supply regularly.
Direct accelerator production of actinium-225 from radium-226 or thorium-232 is technically demanding and has not yet been demonstrated at industrial scale outside pilot facilities.
Radium-226 feedstock itself is scarce and its supply chain (legacy sealed sources, mining by-product) is not yet organised for pharmaceutical use.
Alpha-emitter production and purification require heavier shielding and faster processing than beta emitters because of short-lived, highly active daughter nuclides.

Current efforts

US DOE Isotope Program tri-laboratory accelerator effort (Brookhaven National Laboratory, Los Alamos National Laboratory, Oak Ridge National Laboratory) producing actinium-225 by proton irradiation.
Commercial accelerator-route entrants (e.g. cyclotron irradiation of radium-226, announced by CNL/ITM-linked ventures from October 2024) aiming for GMP-grade supply.
Bayer's supply agreement with an accelerator-route producer to secure actinium-225 for its own clinical programmes from H2 2024.
BMS/RayzeBio advancing on-site accelerator production to de-risk its own trial supply after the ACTION-1 pause.

Success criteria

Multiple independent, non-Th-229-dependent producers scaling to tens of curies a year of GMP-grade actinium-225, enough that a single supplier problem no longer stops a phase 3 trial.