Lead seeks to lead in radiopharma

Lead rightfully has a bad reputation for contaminating soil and causing harmful health effects. But in the radiopharmaceutical industry, lead’s image is on the rise.

In the past 3 years, several companies in the nuclear medicine space have turned their attention to lead-212, whose decay leads to α-particle emissions that hold the promise of irreversibly damaging cancer cells. Experts say that the abundance of raw material needed to make lead-212, the relative ease of synthesis, and the isotope’s keen ability to harm cancer cells make it a superior option to actinium-225, the main α-emitting isotope being studied as a radiopharmaceutical.

Andy Hsieh, a biotech analyst at the investment firm William Blair, recalls that he first learned about lead-based radioisotopes in 2022 and was utterly blown away. “Everything in the α-therapy space was actinium for the longest time. Then we realized there was another option—lead-212,” he says.

Radiopharmaceutical-based cancer treatments, also known as radioconjugates, differ from traditional external radiation therapy in that they are injected and release emissions inside the body. These drugs typically have four components: a radioactive isotope, a chelating agent, a linker, and a targeting molecule that ensures that the drug is delivered to cancer cells and not to healthy tissues.

The isotopes differ in the type of emission they release. The only radiopharmaceuticals currently approved are β-emitting compounds such as Novartis’s Pluvicto and Luthathera, both of which are made using lutetium-177. But α therapies emanate higher levels of energy than β drugs do, so they result in a more potent attack. While β-emitting compounds nick just one strand of cancer cells’ DNA, α therapies break both strands, causing permanent damage.

“One can say that α therapies blast the cells, whereas β therapies work more by stinging the cancer cells,” says Julien Dodet, CEO of the French biotechnology firm Orano Med, which is developing lead-212-based radioconjugates.

Dodet, among others, argues that α therapies have a greater cancer-killing potential than β therapies do; others say the choice between the two depends on the kind and location of the cancer being treated. Similarly, investors are divided on which of the two α-therapy isotopes will emerge as the winner. “The debate between lead-212 and actinium-225 has now become a major theme in the field,” says Alexandra Ramsey, an equity research associate at William Blair.

Some companies say that the advantages of lead are clear. Perspective Therapeutics in Seattle generates lead-212 from thorium-228, which CEO Thijs Spoor says is easy to stockpile. “The Department of Energy has much of it, and it can be easily mined,” he says.

In contrast, the preferred precursors to actinium-225 play hard to get, says Michael Schultz, Perspective’s chief scientific officer. Several starting materials, including uranium-233 and thorium-232, can make the isotope; the industry favorite is radium-226, but “a minimal amount” is available for use worldwide, Schultz says.

“This means that people are literally going around dissolving the dials of old fluorescent watches that were made in the 1940s and ’50s.”

RayzeBio, a unit of Bristol Myers Squibb that is studying radiotherapies based on actinium-225, recently announced that it had to halt a clinical trial because of an actinium shortage. While it is unclear what led to the shortage, the company is investing in its capability to produce actinium-225 at its own 5,900 m²facility in Indianapolis.

Meanwhile, Spoor and Schultz have other reasons to praise lead-212. Manufacturing the isotope is relatively straightforward, as well as less capital intensive and safer than making actinium-225, Spoor says. It can be captured by running decaying thorium-228 through a fairly simple chromatographic separation.

In contrast, making actinium-225 requires expensive cyclotrons, electron accelerators, or nuclear reactors, Schultz says. Moreover, actinium’s preferred starting material, radium-226, poses several safety risks. “It has a 1,600-year half-life,” he says. “So if you had some kind of a leak of that material in a production facility, you could be shut down for a long time.”

Lead-212 patrons point out that the isotope also has benefits in the clinic. When a patient receives lead-212-based radiotherapy, the isotope, through its natural decay chain, releases β and γ particles. In turn, that produces the the daughter element bismuth-212, an α-particle emitter. The γ rays can be easily imaged by single-photon emission computed tomography, according to Schultz. “You can actually see where the emissions are happening in a patient’s body,” he says. “This quality will be game changing, as it allows doctors to customize a therapy for each patient.”

For Emanuele Ostuni, founder and CEO of Cambridge, Massachusetts–based ArtBio, the most exciting element of the lead-212 story is its short half-life. While lead-212 decays by half in 1o h, actinium-225 takes about 10 days. Because of its shorter half-life, “lead-212 has better safety profiles and response rates,” Ostuni says. And Spoor concurs. From a textbook radiobiology perspective, he says, high-dose radiation over a short period is the best way to kill cancer cells.

John Babich, chief scientific officer at Ratio Therapeutics, a Boston developer of actinium-225-based radiopharmaceuticals, says he is isotope agnostic. From a therapeutic point of view, he says, any isotope retained in the tumor for a prolonged period leads to efficient killing of cancer cells. “For this reason, the longer half-life of actinium-225 becomes very attractive as it will deliver more energy,” Babich says. But he adds that right now there isn’t enough data to tell if one of the two α therapies is inherently better than the other.

Some proponents of actinium-225 also argue that because the isotope has a relatively long half-life, therapies can be manufactured in a centralized facility and supplied to hospitals across a wide area. In contrast, lead-212 needs to be generated in units closer to hospitals.

Amid the lead versus actinium debate, investment in the α-emitter space has increased tremendously since 2023, Hsieh says. “More tumor killing and a better safety profile by lead-212 has made the field very interesting.”

The German biotech ITM Isotope Technologies recently raised $200 million to develop its radiopharmaceutical portfolio. While the company’s top candidates are β-emitting, lutetium-based drugs, some of the new funds will go toward making α-emitting, actinium-based therapies.

In May, ArtBio hired Minnesota’s Nucleus RadioPharma to help manufacture its drugs in clinical trials. Ostuni says ArtBio now has four service providers. Drug services firms like Nucleus are ramping up to meet future demand. CEO Charles Conroy says Nucleus will spend over $100 million in the next 18 months to support the growing need for radiotherapies. “This market will continue to grow and evolve,” he says. “We will ensure there is enough to support the demand.”

Others, such as Orano Med, are developing in-house facilities. The company recently poured $20 million into its 2,800 m² site focused on manufacturing lead-212 radiopharmaceuticals on an industrial scale. “I think this investment will give us a competitive advantage because we will have the capacity to make 5,000 doses a year,” Dodet says.

The US Food and Drug Administration has yet to approve an α radiotherapy, but Dodet is confident that the market will see one soon. He says the α-therapy market has a place for all isotopes. “I don’t think there is a big difference between actinium and lead in terms of potential to develop new exciting drugs,” Dodet says. “The big difference will be how to make these drugs in large quantities when the time comes.”