At the intersection of radiation and precision, Novartis, Bayer, AstraZeneca and more hope to cash in on a radiopharmaceuticals market that could top $16 billion by 2033.
For years, chemotherapy and radiation therapy formed the backbone of oncology care, despite their steep burden of side effects. Then came precision medicine, which sought to improve the safety and tolerability of cancer therapy by tailoring treatment to the patient’s specific needs and using certain molecules to deliver cancer-killing chemicals directly to the tumor, sparing the surrounding tissues.
Now, armed with recent advancements in targeting technologies, the pharmaceutical industry is applying the principles of precision medicine to radiation, unlocking a new paradigm of oncology called radiopharmaceuticals.
Currently, Novartis enjoys market dominance with its two FDA-approved therapies: Lutathera, indicated for gastroenteropancreatic neuroendocrine tumors, and Pluvicto, for metastatic castration-resistant prostate cancer (mCRPC). In 2024, Novartis reported over $2.1 billion for these products combined.
Its closest challenger is Bayer, which owns Xofigo, a radium-223 based radiotherapy that according to Dominik Ruettinger, global head of research and early development for oncology, “was the first alpha emitting [targeted radionuclide therapy] approved.” It won the FDA’s blessing in 2013, while Novartis’ Lutathera cleared regulatory hurdles roughly five years later, in 2018. But despite its first-to-market advantage, Bayer has fallen far behind. The company didn’t even bother to report Xofigo’s sales figures last year.
Behind these two pioneers, AstraZeneca, Eli Lilly, Bristol Myers Squibb and more are scrambling to capitalize on a market opportunity that by some estimates could top $16 billion in value by 2033.
In order to compete, however, they will need to innovate on the modality—improving the technology and optimizing the composition of the radiotherapy itself and push into new indications and earlier treatment settings. In a Feb. 7 note to investors, Jefferies analysts said that this year, companies will likely “explore more modalities, isotopes, and $1B+ cancer targets.”
Seeking Alpha Power
Very broadly speaking, targeted radiotherapies are composed of three parts: the actual radionuclide that delivers cancer-killing radiation, the targeting molecule and a linker that binds these two components. Each piece of the radiopharma molecule presents an opportunity for drugmakers to improve on, but experts told BioSpace most of the innovative effort is presently focused on the first two elements.
First, the radioactive payload. The current standard in the space is the emission of beta particles, which are small, highly energetic particles—essentially electrons or positrons—that bombard the target tumor cell, weakening and, ultimately, destroying it. Lutathera and Pluvicto are beta-emitters, underscoring the therapeutic efficacy of this class of radioisotopes.
But the field is already quickly moving away from beta and testing newer, more powerful alpha-emitting isotopes. Unlike their beta counterparts, alpha particles are orders of magnitude larger—nearly 8,000 times larger, according to Oliver Sartor, director of Radiopharmaceutical Clinical Trials at the Mayo Clinic—which lends to their stronger cancer-killing activity.
The most common alpha-emitter being studied right now is actinium-225, which “holds the promise of being a next-generation radioisotope in cancer treatment,” Puja Sapra, AstraZeneca’s senior vice president for Biologics Engineering and Oncology Targeted Discovery, told BioSpace in an email. Actinium-225 “delivers greater radiation dose over shorter distance, with potential for more targeted delivery and potential to reduce damage to surrounding healthy tissue compared to beta emitters,” she said.
AstraZeneca has two clinical-stage radiopharma assets, both of which are actinium-225-based. The more mature of the two is FPI-2265—the star of the $2 billion acquisition of Fusion Pharmaceuticals in March 2024—which targets the prostate-specific membrane antigen (PSMA) and is in Phase IIb development for mCRPC. A readout from this study is expected this year, Sapra told BioSpace in March.
The Fusion buy also gave AstraZeneca AZD2068, another actinium-225-based radioconjugate that targets the EGFR and cMET proteins. The asset is in early-stage studies for solid tumors, with results expected in 2026.
Bayer is also investing in actinium-225, which forms the heart of what it calls a “targeted alpha therapy” program. An advantage of this approach, according to Ruettinger, is its “high energy and a short penetrating range,” which damages the DNA of cancer cells and triggers their death. “At the same time, because the energy travels a short range, damage to nearby normal tissues is much reduced,” he told BioSpace in an email. Bayer’s Xofigo is an alpha-emitter.
Like AstraZeneca, Bayer’s clinical pipeline consists of two actinium-225-based molecules, BAY 3546828 and BAY 3563254, both of which target PSMA. BAY 3546828 is currently recruiting for a Phase I trial, while BAY 3563254 is being studied in a first-in-human trial that launched in March 2024. Bayer is proposing both molecules for mCRPC.
Beyond actinium-225, however, the company is also “open to using other isotopes,” Ruettinger said. To this end, Bayer has several preclinical programs exploring various payloads, with a particular focus on different half-lives.
“A fast-growing tumor with a high cell division rate may require treatment with an isotope with short half life, while an isotope with longer half life may be better suited for patients with low tumor burden, such as in an adjuvant setting,” Ruettinger explained.
Precision Targeting
Another area of active innovation in radiopharma involves the targeting moiety, which is used to deliver the therapeutic element to the cancer cells. “There are largely three flavors of ways to target the radioisotopes to the tumor,” Shiva Malek, Novartis’ global head of Oncology, told BioSpace in an interview. These include peptides, small molecules and biologics, including antibodies.
Though different in how they work, all three share a goal: to direct the payload to the target tumor, precisely deliver a cancer-killing dose of radiation and, crucially, minimize toxic off-target effects.
Of these three “flavors,” Novartis has chosen to focus on peptides, which Malek said is due to their favorable pharmacokinetic properties. “They’re rapidly cleared from the body,” she explained. “You don’t want an RLT [radioligand therapy] sitting in your bone marrow or circulating for a long time. You want it cleared pretty rapidly.”
Of course, Malek continued, “you want to have really high affinity for your tumor antigen,” so the therapy reaches the tumor. For Novartis, peptides achieve a good mix of safety and targeting efficacy.
For Lilly, however, the process of selecting a targeting ligand isn’t so straightforward. “The optimal ligand will be the one that has excellent performance for a specific target,” Daniel Pryma, the company’s vice president for Global Clinical Development, Radioligand Therapy, told BioSpace in an email. The payload is also a big consideration, according to Pryma, who noted that the pharma’s discovery efforts take into account “rational pairing” between “target, ligand, isotope and patient populations.”
Lilly has two radiopharma assets in the clinic, both from its $1.4 billion acquisition of Point Biopharma in October 2023. The lead candidate is PNT2001, which targets PSMA and uses a small molecule ligand, also directed against PSMA, according to Lilly’s pipeline page. The pharma is additionally developing PNT2002—Point’s lead asset—which is also designed to seek out PSMA but uses a peptide ligand.
A Regimen that is ‘Greater Than Its Parts’
Aside from improving the structure of the radiopharma molecule itself, some companies are looking to package targeted radiotherapy into combination regimens as a way to break into clinical practice.
Such an approach, according to Malek, could elevate the efficacy of radiopharma therapies even further, particularly when combining them with agents that can “exacerbate DNA damage,” such as chemotherapy and T cell engagers.
“We don’t fully understand where we’re going to get the best combinations,” Malek said, but this is a question that Novartis has already started to chip away at. The pharma is running a handful of combination studies testing its current radiotherapies—which Malek said have “clear monotherapy activity”—with standard of care and immunotherapies, in prostate cancer.
AstraZeneca is similarly exploring combination approaches, Sapra said, with an eye toward making its radioconjugates “the backbone for novel cancer therapies.” The company’s focus is on developing combination regimens “that can attack a tumor from multiple angles” and offer superior selectivity to and efficacy against specific cancer types.
For instance, Sapra explained that targeted radiotherapies could work well with antibody-drug conjugates (ADCs) by opening up new tumor types or tumor locations that ADCs would otherwise not be able to access. Similarly, she theorized that radioconjugates, which damage the DNA, might be synergistic with anti-cancer therapies that prevent the cells’ DNA repair mechanism.
Ultimately, AstraZeneca’s goal with combinations is to demonstrate improved efficacy and clinical utility, in turn achieving a regimen whose overall value is “greater than its parts.”
A Fertile Field
The radiopharma space is still in its infancy, with high potential for growth.
One area of growth, according to William Blair, is a move into earlier treatment settings. Recent dosing optimization studies “show that radiation can still be used further up, and we’re not going to [negatively] impact the quality of life too much,” analysts told BioSpace.
In this regard, Novartis appears to be leading the pack. In March, the pharma won a label expansion pushing Pluvicto into an earlier treatment setting in prostate cancer—even before classic chemotherapy—which would “basically triple the total addressable market for Pluvicto,” the analysts noted.
New indications are also ripe for radiopharma expansion, according to William Blair, an opportunity many of the main players are leaning into. Bayer, for instance, is working on an asset that targets the GPC3 protein to treat hepatocellular carcinoma (HCC). “GPC3 is an oncofetal protein overexpressed in 70-75%of HCC lesions,” Ruettinger said, noting that this asset will also carry the alpha-emitting actinium-225.
BMS is also targeting HCC, according to Ben Hickey, president of RayzeBio, a BMS company. The pharma’s RYZ801, which also targets GPC3 and carries actinium-225, is part of BMS’ mid-term plans for its radiopharma pipeline. Farther out on the horizon, BMS is also planning to target the CA9 protein—typically highly expressed in malignant kidney tissues—to treat renal cell carcinoma. This program is still in the preclinical phase, Hickey said.
There’s also the prospect of using the radiopharma platform beyond cancer. “Autoimmune conditions could be one of these applications,” William Blair analyst Andy Hsieh told BioSpace in an email. Hsieh was quick to qualify, however, that use in this field remains “theoretical at the moment.”
There is at least some precedent, however. “We’ve seen some ADCs, antibodies, or T cell engagers expanding from cancer to autoimmune conditions,” Hsieh said, adding that targeted radiotherapy could follow suit. But even at this theoretical stage, there are already barriers, such as the “high-risk nature” of autoimmune drug development, and the “complex supply chain” in this market.
“The efficacy bar would need to be exceedingly high . . . in order for Big Pharma to invest in” the autoimmune potential of radiopharma, according to Hsieh. “We see the prospect of that as an unlikely event.”
