By Jonathan D. Grinstein PhD

When one studies strongly radioactive substances special precautions must be taken. Dust, the air of the room, and one’s clothes all become radioactive. — Marie Curie

The term “radioligand therapy” has an outdated ring to it. Indeed, the use of radioactivity for diagnoses and medical treatments has been around for more than 100 years, such as the use of iodine-131 for thyroid cancer.

But the therapeutic use of radioligands, a radioisotope linked to a cell-targeting compound, is a fairly new medicine. The first FDA-approved radioligand therapy (RLT)—the combinatorial use of Locametz (gallium-68 gozetotide) and Pluvicto (lutetium-177 vipivotide tetraxetan) for metastatic prostate cancer diagnosis and treatment, respectively—was approved 18 months ago, in 2022.

There’s a major bottleneck to RLTs, however: they are hard to manufacture and deliver viably at commercial scale. Therapeutic radioisotopes are produced in special nuclear reactors or generators and then shipped to a production facility where the radioisotope is bonded to the cell-targeting compound.

Nucleus Radiopharma, a CDMO specializing in radiopharmaceuticals, sees this as an opportunity to develop the necessary supply chain and infrastructure. The idea for Nucleus came about because, while the science has been developing, the supply chain and infrastructure to support the science haven’t.

“Who’s going to go build and invest hundreds of millions of dollars in the infrastructure until the science has proven it?” Charles Conroy, CEO at Nucleus RadioPharma, told GEN Edge. “Now, it’s a little bit like a dog-caught car because you see the science and you’re like, ‘This is fantastic. We need to get this out and get it to tons of patients.’ But you just can’t. It’s a very intricate thing to build, and these are very hard drugs to develop and ship. You need to have a special skill set, equipment, and all those wonderful things to get these things out. That’s why Nucleus came into being.”

Owning the supply chain

Each radioisotope has a different half-life and releases energy differently, making some better for diagnostics and others for therapeutics. Typically, the diagnostic radioisotopes have longer half-lives and lower amounts of radiation energy, whereas the therapeutic ones have short half-lives and greater amounts of energy. Treatment also depends on what is being targeted; some targets may require more radiation than others to be eliminated.

“It depends on how long you want [the radioisotopes] to sit in the body; different isotopes are used for different treatments,” said Conroy. “For things like an Alzheimer’s treatment, it takes longer to destroy an amyloid plaque, for example, than it takes to destroy a cancer cell.”

To be a successful RLT-CDMO, Conroy said that it’s critical to have a proper supply of all types of radioisotopes. That’s especially the case because radioactive materials, whether lutetium or actinium, are currently in short supply.

“We work with a bevy of manufacturers across the industry to ensure we can bring products in,” said Conroy. “We take that product and test it for the pharma companies we work with. We test on a broad range of radioisotopes to ensure that if there’s a different type of supply, we can make that available.”

That’s why Nucleus partnered with SHINE Technologies, an advanced nuclear technology company and North America’s largest producer of lutetium-177. Nucleus recently announced that SHINE will provide lutetium-177 for targeted RLTs for neuroendocrine tumors and prostate cancer over several years.

The steady availability of this radioisotope is fundamental to the goal at Nucleus: to become the backbone of an uninterrupted RLT supply for cancer treatments.

Too hot to handle

It is one thing to create an RLT in the lab; it is another to use it in clinics worldwide. Conroy said that Nucleus is building their radioligand-supporting CDMOs with commercialization strategies in mind.

“There are lots of things that can be put together in the lab that’s one floor away from the patient; they can take them from the lab, run them across the hall, and give them to the patient,” said Conroy of the work being done at the Mayo Clinic. “But that’s not great if we can’t commercialize that and make sure it can be used across the country. We’ve seen some good clinical candidates, but they can’t be commercialized how they ship today.”

The Nucleus team has started working on formulations with different buffers and chelating agents to ensure the drugs can be shipped and have the longest shelf life possible.

In October, Nucleus announced that it had raised a $56 million Series A—led by Eclipse and GE Healthcare—to establish manufacturing facilities around the country, including Rochester, Minnesota, near the Mayo Clinic, and build novel technology for the development, manufacturing, and distribution of radiopharmaceuticals.

“This is the biggest raise that a CDMO has ever done in this space,” said Conroy. “Up to this point, the structure just hasn’t been there, so we’re the first to build out this infrastructure to make sure that we can get [RLTs] to patients.”

Conroy said that the field has been waiting for someone to take the steps to own the manufacturing and commercialization of RLTs. With such a high demand, Nucleus has already booked about 50–60% of the Rochester plant’s capacity once it opens. It won’t be until Q3 of 2024, at the earliest, that Nucleus starts creating any doses in that facility, as they will need to acquire equipment and certifications from regulatory authorities.

While getting the Rochester location up and running, Nucleus is already considering expanding to new sites on both coasts, “just to make sure that we can be close to where the clinical trials are and where the patients are,” said Conroy. “Each of those investments will be over $25 million in each of those buildings, but those are probably 24–30 months away from being open. We’re going to be running with Rochester for a while.”

Cost and regulation

While radioligand therapies may be significantly less complex and elegant than cell and gene therapies, they aren’t many orders of magnitude cheaper. Conroy said that a course of therapy to a patient—typically five doses—can be somewhere in the $250,000 range. But because the therapeutic application typically follows a diagnostic one using the same targeting molecule, Conroy said there’s an extremely high likelihood that they’ll be effective, which payers and patients both like to see.

Right now, the major application of radioligand therapy has been for prostate cancer, but Conroy expects to see drugs for other kinds of cancers, including breast and renal, in the next five years.

“When you talk about prostate, pancreatic, breast, and renal cancer, it’s going to be hundreds of thousands of patients. Most of these therapies are four to six doses, so hundreds of thousands of doses will surely be produced,” said Conroy. “This thing will be pretty big over the next few years. We’re talking about the size of this industry tripling in five years.”

And big pharma has taken notice. In October 2023, Eli Lilly acquired POINT and their pipeline of clinical and preclinical-stage RLTs in development for cancer treatment for $12.50/share (an aggregate of approximately $1.4 billion). Two months earlier, Genentech entered into a $1-billion deal with PeptiDream to co-develop radiopharmaceuticals. And, according to Conroy, there are currently hundreds of clinical trials for RLTs from around 75 companies.

The craze has also spread across the pond. It may not have taken hold like a reverse of Beatlemania, but there has been some activity in Europe.

With a $23-million seed round in June 2023, F-Prime Capital and Omega Funds announced the founding of an early-stage radiopharmaceutical company named ARTBIO. By combining an alpha-emitting isotope (Pb212) with ligands that bind to known tumor targets, ARTBIO was made to make very specific cancer treatments. The company calls these treatments alpha radioligand therapies (ART).

But more pertinent to the team at Nucleus RadioPharma is that ARTBIO is also creating an entirely new approach to ART manufacturing to overcome production and distribution challenges.

While Conroy did speak to eventual plans for Nucleus RadioPharma to bring its RLT-CDMOs to Europe, the early-stage company will first have to show that it can serve the purported long queue of suitors lining up at their doors coast-to-coast in the U.S.

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