Pharma companies have been increasingly investing in developing targeted alpha therapies for cancer treatment, using alpha-emitting isotopes such as Ac-225. However, the industry faces an ongoing Ac-225 supply shortage, so companies are moving to secure their supply chains. Eli Lilly’s recent investment in isotope manufacturer Ionetix highlights large pharma’s growing interest in Ac-225 and in securing a stable supply for its pipeline. Like Eli Lilly, several other companies have invested in or partnered with manufacturers to secure supply.
Ac-225 is emerging as a leading isotope for targeted cancer therapy
Among recent advances in cancer therapy, few have shown as much promise as targeted alpha therapies. Targeted alpha therapies (TAT) use alpha-emitting isotopes to target and destroy cancerous tissue while limiting damage to surrounding healthy tissue. This is possible because alpha radiation travels only a short distance in human tissue, less than 0.1 mm or fewer than 10 cell diameters. They also have high energy levels of 5-9 MeV, which helps destroy malignant cells selectively.
Several alpha-emitting isotopes are currently being explored for TAT, the most common among them being Ac-225, At-211, Pb-212, and Bi-213. Of these, Ac-225 (actinium-225) is considered the most potent medical-grade radioisotope as it has a high decay energy of 5.9 MeV and a half-life of 10 days. It is the isotope of choice in several clinical trials, with about 15 Ac-225-based ongoing clinical trials currently in the USA. However, adoption has been slow because supply remains tight.
Ac-225 does not occur naturally. Producers derive it from Th-229 (thorium-229), a byproduct of uranium-233 (U-233), which was left over from atomic weapons production in the 1950s and 1960s. The US Department of Energy (DOE) supplied the initial batch of Ac-225. However, the supply cannot keep up with the growing demand for trials.
Isotope makers are racing to expand future Ac-225 output
Currently, there are two commercialized routes to produce Ac-225. The first and traditional route separates Ac-225 from Th-229, taken from the US government’s legacy reserves of U-233. The US government holds about 453kg of U-233, of which only about 256kg is of high quality and will produce about 24g of medical-grade thorium.
Legacy reserves are supporting supply, but only to a point
The government previously started a program to extract a small amount of Th-229 (150mCi). That yielded about 1.2 Ci of Ac-225 per year, enough to treat 1,200 patients. However, in 2019, the US DOE entered into a public-private partnership with Terra Power and Isotek to downblend its stock of U-233 to extract Th-229, which can further be used to develop Ac-225. In 2021, TerraPower entered into an agreement with Cardinal Health, a US-based commercial alpha contract manufacturing organization (CMO), to develop and produce Ac-225 for drug development and commercial sales. This will likely improve Ac-225 supply over time.
The other route uses cyclotron production. In this process, producers irradiate a Ra-226 target with a proton and knock off two neutrons. Several isotope manufacturers are adopting this technology and expanding capacity.
Cyclotron makers are expanding output, but shortages remain
Niowave, a US-based supplier of medical and industrial radioisotopes, uses a closed-loop cycle to produce high-purity Ac-225 and other alpha emitters from Ra-226 using a superconducting electron linear accelerator. Ionetix, another cyclotron technology company and isotope manufacturer, uses the same approach. It produced its first batch of Ac-225 in June 2024. The company commissioned its first cyclotron at its current facility in 2023. It plans to install a second one there in early 2025. By 2025, the company should be able to produce about 1Ci per week. The company also aims to establish another site in the USA for Ac-225 production in 2026.
While isotope manufacturers are trying to raise output over the long term, the current Ac-225 supply remains limited and is barely enough to support ongoing clinical trials. In 2024, the worldwide supply of Ac-225 is estimated to be about 2Ci per annum, which is merely enough to treat 2,000 patients.
Pharma companies are investing upstream to secure Ac-225 supply
Given its currently limited availability and immense potential, leading pharmaceutical players are adopting various strategies to secure their Ac-225 supply to support their targeted alpha therapies drug pipelines. Several players, including Fusion Pharmaceuticals, Telix Pharmaceuticals, and Bayer, are partnering with Ac-225 producers to reduce supply risk in their trials. Recently, Eli Lilly also moved to secure its actinium supply.
Fusion, which has three Ac-225-based drugs in trials, was one of the first movers and has signed several agreements to secure supply.
Fusion entered into a partnership with TRIUMF, Canada’s national particle accelerator center, in December 2020. In this partnership, Fusion would provide the latter with up to US$18.5 million (CA$25 million) to upgrade its production facilities and scale up production of Ac-225. In return, Fusion would get preferred access to the resulting isotope at favorable pricing.
Later, in June 2022, Fusion collaborated with Niowave, a US radioisotope manufacturer. Under the agreement, Fusion would invest up to US$5 million in Niowave to help expand its Ac-225 production capacity. In return, Fusion will get access to a pre-determined percentage of Niowave’s capacity of the resulting Ac-225, as well as preferred access to any excess stock produced.
Then, in November 2023, Fusion entered into an agreement with BWXT Medical, a US-based supplier of nuclear components and a subsidiary of BWX Technologies. Under the agreement, BWXT Medical would provide Fusion with preferential access to Ra-225 (parent isotope of Ac-225) and access to high-specific-activity generator technology. This would let Fusion produce Ac-225 at its own manufacturing facility for clinical trials. In addition, BWXT Medical would supply Fusion with predetermined amounts of actinium under a preferred partner agreement.
Telix Pharmaceuticals also entered into an agreement with Cardinal Health in May 2024 for global Ac-225 supply.
Bayer signed an agreement with PanTera (a Belgian radioisotope production JV created by Ion Beam Applications and SCK CEN) in February 2024 to secure large-scale production of Ac-225. PanTera uses both the Ra-226 and Th-229 production mechanisms to produce Ac-225. It is collaborating with TerraPower to supply Th-229.
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Eli Lilly also invested in a nuclear isotope manufacturing company, Ionetix, in August 2024. Eli Lilly has made a US$10 million convertible loan investment in the company to secure its supply of Ac-225. Point Biopharma, which Eli Lilly acquired in 2023, had already invested US$10 million in Ionetix. That brought Eli Lilly’s total debt facility with Ionetix to US$20 million. TLilly can convert that debt into equity once Ionetix’s valuation exceeds US$300 million.
These investments by Eli Lilly and Fusion Pharmaceuticals are rare cases where major pharmaceutical companies are investing up the supply chain to secure actinium availability for their cutting-edge drug pipelines.
EOS Implic-Action: Ac-225 access will shape which targeted alpha drugs advance
Targeted alpha therapies are emerging as promising next-generation cancer drugs, but they face supply constraints in alpha-emitting isotopes, especially Ac-225. Companies that want to advance these therapies must secure an isotope supply to keep clinical trials running smoothly.
In the past, large pharmaceutical companies such as BMS have had to halt enrolment in their clinical trials due to the unavailability of Ac-225. Such interruptions delay trials, raise costs, and can jeopardize overall success.
Companies are taking stronger steps to secure Ac-225
Considering these limitations, companies with ongoing or planned Ac-225-based trials need to secure isotope supply for the full trial period and for future commercial production if the drug wins approval. Some companies are signing supply agreements with isotope manufacturers. Others are going further and investing in upstream suppliers. Some, including Fusion and now BMS, are moving towards building on-site production of Ac-225.
Investment risk remains high while trials stay early
Still, building a secure Ac-225 supply chain brings its own costs and risks. Most pharmaceutical companies are undertaking significant investments (ranging between US$5-25 million) to guarantee their supply of Ac-225.
However, TAT is still at an early stage. Most Ac-225 trials are in phase 1 or phase 1/2 and remain far from FDA approval. Moreover, BMS is running the only phase 3 Ac-225 trial for neuroendocrine cancer, and has now halted due to supply issues. Because the treatment is still early in development, it is too soon to know whether these heavy Ac-225 investments will produce FDA-approved drugs and adequate returns. That risk is especially serious for smaller players.
So companies developing Ac-225-based targeted alpha therapies need to secure supply, but they also need to match investment levels to their size, pipeline, and financial position.