https://www.nature.com/articles/s41587-024-02295-z
Precision radiation opens a new window on cancer therapy
Published: 12 June 2024 / Nature Biotechnology
Targeted radiopharmaceuticals offer resistance-free potency, pre-treatment imaging and widespread combination potential. Big pharma and investors are piling in.
Move over, antibody–drug conjugates. Targeted radiopharmaceuticals are emerging as a new favorite among big pharma buyers and investors. This modality, which uses cancer-seeking ligands to deliver highly targeted radiation to tumor cells, has attracted several large acquisitions and a flurry of public and private investments.
Radiopharmaceuticals offer advantages over other cancer therapies. Their mechanism of action — blasting tumor cells with DNA-shredding radiation — minimizes drug resistance and unlocks rich combination opportunities, particularly with immunotherapies. Radiopharmaceuticals also allow investigators to visualize tumor location and therapy uptake, thanks to the use of imaging isotopes ahead of, or alongside, therapeutic isotopes. This ‘theranostic’ approach improves patient selection and dosing accuracy, ultimately accelerating development, according to proponents. “You get a level of information you can’t get with any other modality. You can’t quantify where your ADCs [antibody–drug conjugates] or your CAR-Ts (chimeric antigen receptor-T cells) are,” says one CEO. Radiopharmaceuticals also broaden the range of viable drug targets: some radioactive isotopes are so potent that even low-expression targets may draw enough radioactive molecules to destroy the cancer cell.
These advantages, coupled with strong efficacy data from Novartis’s marketed radiopharmaceuticals Lutathera (lutetium-177 dotatate) for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and Pluvicto (lutetium-177 vipivotide tetraxetan) for metastatic castration-resistant prostate cancer, have triggered multi-billion-dollar biotech acquisitions (Table 1). The target companies have mid- to late-stage clinical assets, plus treatment infrastructure and manufacturing capabilities. They offer big pharmas with little or no in-house expertise a leg up into field that “has the potential to be bigger than even ADCs,” according to Julien Dodet, CEO of Orano Med, a Texas-based subsidiary of Paris, France-headquartered nuclear fuel group Orano. Market leader Novartis isn’t sitting still: in early May 2024 it paid $1 billion up front for preclinical Mariana Oncology.
There are challenges. Radiopharmaceuticals are difficult to make and distribute, owing to unstoppable radioactive decay. “It’s like shipping a melting ice cube without refrigeration,” says Y-mAbs Therapeutics’ CEO Michael Rossi, previously head of radioligand imaging at Lutathera developer Advanced Accelerator Applications after its 2018 acquisition by Novartis. Securing a reliable supply of isotope is non-trivial. Downstream, there are too few nuclear medicine specialists and treatment facilities to administer radiopharmaceuticals. Some hospitals already struggle to manage radioactive biowaste.
Yet radiopharmaceuticals’ newfound momentum comes as other targeted medicines reach a ceiling. There is a dearth of ‘pan-cancer’ genetic targets, and immunotherapies work for only a minority of cancer patients. ADCs are growing fast, but limited by toxicity. This emerging category of precision radiation may expand the reach and efficacy of checkpoint inhibitors and other treatment classes.
Radiopharmaceuticals also offer lots of room to innovate — across choice of isotope, ligand, target and conjugation. Multiple permutations and combinations are under investigation across a growing cohort of startups and newly prominent specialist groups. Some have tied their hats to a particular type of radiation or isotope. Others focus on ligands, such as macrocyclic peptides or antibodies. Some remain isotope- or ligand-agnostic, claiming expertise in pulling together the whole.
Assembling a radiopharmaceutical is not straightforward. The radioactive isotope will shred anything in its vicinity; it must be stabilized or ‘caged’ by a chelator until it reaches its destination. Once there, the isotope should remain long enough to be effective, before its progeny (and the ligand) are excreted, with minimal accumulation in the kidney. “Creating a good radiopharmaceutical, with rapid clearance, that doesn’t stick to anything else, is more art than science,” admits Germo Gericke, chief medical officer at Berlin-based Ariceum and former chief medical officer at Advanced Accelerator Applications. As yet, no one technology or molecule appears to drive a meaningful, distinctive advantage over any other. “It’s early days, so everyone is still learning,” says Alpha-9 Oncology CEO David Hirsch. “We just need more data.”
Beyond beta radiation
The data are coming. Novartis’s Lutathera and Pluvicto, approved in 2018 and 2022, respectively, both use the isotope lutetium-177 to deliver beta radiation — a medium-powered, mid-range stream of electrons that can travel 2–10 mm (several dozen cell diameters), cleaving one or both DNA strands. In Lutathera, the beta radiation is directed at the somatostatin type 2 receptor (SSTR2) found across the surface of slow-growing NETs. The ligand is the somatostatin analog oxodotreotide. In Pluvicto, the targeting moiety is vipivotide, a peptide that inhibits prostate-specific membrane antigen (PSMA), expressed on fast-growing prostate cancer cells.
Both drugs significantly improved overall survival relative to standard of care in phase 3 trials in patients with advanced disease. More recently, in the NETTER-2 trial, Lutathera reduced the risk of death or progression by 72% when used as a first line with octreotide (a somatostatin analog) for newly diagnosed GEP-NET. Pluvicto produced more than a doubling of radiographic progression-free survival in the pre-chemotherapy setting; Novartis expects to file for an additional approval for Pluvicto in early-line disease during 2024. Peak sales are forecast at over $2 billion annually.
Novartis now wants to expand these drugs — and a wider radiopharmaceuticals pipeline — across even more tumors and disease stages. It is not alone (Table 2). Venture financing in radiopharmaceuticals more than quintupled in the five years ending 2023, according to data and analytics firm GlobalData.
Many next-generation radiopharmaceuticals harness alpha radiation: powerful, short-range helium nuclei that rip through both strands of in-range DNA, causing mostly irreparable damage and leaving no room for resistance. Yet, as they penetrate only one or two cell diameters, they leave nearby healthy cells unharmed. Alpha rays will “will blow almost anything apart,” according to Jason Lewis, professor and Emily Tow chair at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, who has consulted for or is on scientific advisory boards at several radiopharmaceuticals companies. Patients who develop ‘radio-resistance’ to beta-emitting Lutathera or Pluvicto as cancer cells’ rapid genomic alterations outmaneuver the toxic rays may benefit from an alpha emitter.
Alpha emitters with the same targets as Lutathera and Pluvicto are among the most advanced pipeline radiopharmaceuticals, positioned as next-line therapies for patients showing signs of disease after treatment with beta radiation. RayzeBio’s (now Bristol Myers Squibb’s) RYZ101 delivers alpha-emitting actinium-225 (Act-225) to SSTR2 receptors; it’s in phase 3 for GEP-NET that no longer responds to Lutathera. Fusion’s (now AstraZeneca’s) lead candidate, acquired in February 2023 from RadioMedix, uses Act-225 to target PSMA. Act-225 also features in clinical programs at Bayer, Convergent Therapeutics and Actinium Pharmaceuticals. Novartis’s Mariana Oncology acquisition brings a preclinical Act-225 lead in small cell lung cancer.
Another alpha advantage relates to its ability to harness the immune system — critical for a durable anti-cancer effect. Hitting tumor cells with any kind of ionizing radiation generates neoantigens, potentially sensitizing tumors to immunotherapy. Alpha’s short-range, high-energy punch makes it a more effective cancer cell killer — and thus a better neoantigen generator — than the lower-energy beta-radiation.
Another potential advantage of alpha radiation is convenience: patients receiving Lutathera or Pluvicto must stay away from pregnant women and children for at least a week after therapy, as Lu-177 has a week-long half-life and emits beta and gamma radiation, both of which travel further than alpha particles. Reduced isolation requirements are a “big plus” for alpha emitters, notes Dominik Rüttinger, head of research and early development, oncology at Bayer, which has since 2013 been selling alpha-emitting Xofigo (radium-223 dichloride) for prostate-cancer-linked bone metastases. (Xofigo has no separate ligand: radium, like calcium, finds its way naturally to fast-growing bone cells, just as beta-emitting iodine-131 naturally accumulates in the thyroid; the latter has been used to treat thyroid cancer since the 1940s.)
Almost two dozen clinical trials of alpha-emitting radiopharmaceuticals are underway, though no targeted alpha therapy using Act-225 or Pb-212 has yet been approved.
Despite the “huge amount of enthusiasm” for alpha-emitters, “there is not much human data,” cautions MSKCC’s Lewis. A phase 1 dose-finding trial of Johnson & Johnson’s Act-225-based prostate cancer candidate, presented at the American Society of Clinical Oncology conference in early June, revealed 4 patient deaths due to treatment-related adverse events among 57 patients who received the drug, alongside “profound and durable” responses among heavily pretreated patients. For Act-225 in particular, “the jury is still out on long-term safety,” says Gericke at isotope-agnostic Ariceum.
The alpha-isotope battle: actinium-225 or lead-212?
A major concern relates to actinium-225’s decay chain. The isotope decays into several ‘daughter’ isotopes that emit further alpha rays. That could add potency but could also pose a safety risk if these daughters escape the tumor environment. RayzeBio in 2023 released imaging data from a dosimetry substudy of RYZ101 suggesting that most of the alpha radiation remained within tumors. Though reassuring, the data were from just a handful of patients. Act-225 and its daughters release imaging (gamma) rays only at certain points in their decay chain, so its activity is hard to measure accurately.
Meanwhile, lead (Pb)-212 has emerged as another popular alpha emitter. Its decay chain is clean — it emits just one alpha particle — so there is less risk of stray radiation. It can also be paired with a gamma-emitting isotope, Pb-203, suitable for imaging. Using the same element for imaging and therapy ensures matched biodistribution, explains Thijs Spoor, CEO of Perspective Therapeutics. “Using different elements means you don’t know if you’re seeing exactly the same [uptake] pattern as for therapy.”
There are trade-offs: Pb-212’s eleven-hour half-life poses substantial logistical and transportation challenges. Act-225, which takes over 10 days to decay to half its starting quantity, places a greater burden on waste management.
Pb-212’s proponents argue that the short, high-energy punch delivered by its faster decay may potentiate this isotope’s ability to sensitize the immune system. Since Pb-212 clears out fast, tumor-infiltrating lymphocytes can assemble and do their work without the risk of damage from longer-lasting radiation, as may occur with Act-255. Spoor points to preclinical data showing significantly more tumor-infiltrating lymphocytes, including CD8+ T cells, after a single injection of Perspective’s melanocortin 1 receptor (MC1R)-targeting melanoma candidate, also being tested in combination with Bristol Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab).
“Combining radiopharmaceuticals with immuno-oncology drugs is a rich, under-explored area,” sums up Emanuele Ostuni, founding CEO of Artbio, whose Pb-212-based prostate cancer candidate has just entered the clinic.
The precise immunologic effects of a given radiation type or radioisotope remain incompletely understood. Preclinical studies combining a range of radiopharmaceuticals with checkpoint inhibitors show promising increases in overall survival, though emerging clinical data are patchy.
Supply dynamics also feed the Act-225 versus Pb-212 race. A few years ago, Pb-212 was harder to procure than Act-225, which helps explain why Act-225-based candidates are more advanced. Since then, the tables have turned. Producing Act-225 requires specialist equipment such as a cyclotron or nuclear reactor, requiring a separate supply chain — and leading to bottlenecks: Bristol Myers Squibb and RayzeBio’s phase 3 RYZ101 trial was recently delayed due to an Act-225 shortage. Developers are frantically signing supply deals to secure source material as their candidates advance through the clinic and demand ramps up. Some are buying the suppliers: Melbourne, Australia-based Telix Pharmaceuticals in April 2024 bought Vancouver, British Columbia-based ARTMS and its cyclotron-based isotope production platform for $57.5 million up front. Meantime, companies including Orano Med, Perspective and Artbio have developed their own, in-house Pb-212-generation methods. In early 2024, Orano Med broke ground on a Pb-212-based radioligand production facility in France slated to become Europe’s first industrial-scale facility of its kind. A US site will come online in early June.
The US Food and Drug Administration (FDA) appears open to an ‘alpha-first’ therapy approach, at least in the rare, underserved GEP-NET indication. In February 2024, RadioMedix and Orano Med’s Pb-212-based GEP-NET candidate, AlphaMedix, became the first targeted alpha-emitting therapy to receive FDA breakthrough therapy designation. It is in phase 2 for patients who have never received Lutathera. FDA also granted fast track status to Perspective Therapeutics’ Pb-212 based, phase 1/2a neuroendocrine tumor candidate in a first-line setting.
Evolving ligand design
As isotope pros and cons emerge, ligand design is also evolving.
There are ground rules for twinning ligand and isotope. “You need to match the isotope half-life to the kinetics of the targeting agent,” explains Neil Bander, co-founder and CSO at Convergent Therapeutics. Slower-decaying isotopes are better suited to ligands that hang around for longer, such as antibodies; shorter-lived small molecules or small peptides are better matched with fast-decaying isotopes.
How ligand and target interact also influences isotope choice: Convergent’s phase 2 prostate cancer candidate links the full-sized antibody rosopatamab to the slow-decaying Act-225. Since the target PSMA receptor internalizes the antibody (and conjoined isotope), Act-225’s multistep decay chain may be more likely to remain contained. Telix’s phase 3 prostate cancer radiopharmaceutical uses the same antibody, instead tethered to slow-decaying lutetium-177.
Full-sized antibodies are hard to equal for specificity. But their size and staying power can be a drawback: radioactive isotopes should not linger too long. Smaller peptides offer an attractive middle ground, combining antibody-style specificity and target affinity with greater tumor cell penetration and faster clearance.
Peptides can also be designed for the job at hand. “Many older radiopharmaceuticals are repurposed: a compound bound a given target, and scientists attached a chelator to conjugate a radioisotope,” says Christiane Smerling, head of nuclear medicine and imaging at 3B Pharmaceuticals. Now companies are tailoring peptides for an optimal mix of target affinity, tumor penetration, payload capacity and clearance. Limiting accumulation in the kidney is particularly important: the kidneys tend to reabsorb amino acids, risking a buildup of radioactive isotope. Companies like 3B have found ways to ‘mask’ peptides from the kidney so that they are instead excreted in urine; its licensees include Fusion, Debiopharm and Novartis, which in 2023 licensed rights to 3B’s fibroblast activation protein (FAP)-targeting technology, tweaking an earlier deal with Clovis Oncology. Other peptide designs are also in play (Box 1).
Small molecules also have a place in the radiotherapeutics resurgence. Radionetics is hunting small molecule–isotope combinations that hit G-protein-coupled receptors. “The gap between what small molecules and peptides can do is shrinking,” says senior vice president, biology Ana Kusnetzow.
A “crazy number” of potential targets
More isotopes and a broadening range of tailored ligands have opened radiopharmaceuticals’ target range well beyond SSTR2 and PSMA. Once again, there are matching principles: target type and location may favor one or other type of radiation.
FAP, expressed across many cancers, has attracted particular interest. FAP sits not on cancer cells themselves, but in surrounding tissues. Killing the actual cancer cells “may require some cross fire,” suggests Novartis global head of oncology development Jeff Legos. He thinks Lu-177’s longer range beta radiation is ideal for the job. Novartis’s FAP-targeted Lu-177 based asset, now in phase 1/2, was acquired from Clovis Oncology in 2022.
Ariceum is targeting the poly-ADP ribose polymerase (PARP) enzyme with a radiopharmaceutical for recurrent glioblastoma, an aggressive brain cancer. Since PARP sits right on top of cellular DNA, very short-range radiation would be ideal, and it should also reduce the risk of hitting neighboring neurons in the brain. Ariceum is attaching a PARP inhibitor (itself a potent class of anticancer drugs) to radioactive iodine-123, which emits ultra-short-range Auger radiation and gamma rays helpful for imaging. The PARP enzyme sits within the range of the Auger emission, says Ariceum CEO Manfred Rüdiger, and is also upregulated in response to DNA damage. So irradiating DNA should lead to more PARP expression and more isotope binding, “like a chain reaction,” says Rüdiger. The company plans to start a phase 1 trial in the United Kingdom in June 2024.
Auger radiation, a low-energy stream of electrons, has so far attracted less industry interest than beta and alpha radiation. But it may have its place among future treatments, suggests Samantha Terry, reader in radiobiology at King’s College London. Auger electrons are unlikely to be helpful for large tumors but could deliver a targeted “final blow” to the most stubborn cancer cells, mopping up the last remnants of cancer.There are many other targets in the radiopharmaceuticals pipeline. Carbonic anhydrase IX is the focus of Telix’s phase 2 advanced kidney cancer program combining Lu-177 with girentuximab; gastrin-releasing peptide receptor is the target of Novartis’s phase 1 Lu-177–NeoB and Orano Med’s phase 1 Pb-212-based candidate. Würzburg, Germany-based Pentixapharm has diagnostic and therapeutic assets targeting CXC chemokine receptor 4 (CXC4), including a phase 1/2 therapy for central nervous system lymphoma using beta-emitting yttrium-90. Johnson & Johnson’s Act-225-based phase 1 prostate cancer program goes after human kallikrein 2; Aktis Oncology’s lead hits nectin 4. Preclinical targets include RayzeBio’s glypican-3 (liver cancer) and melanocortin 1 receptor (melanomas), and delta-like ligand 3 at newcomer Abdera Therapeutics.
This could be just the start. Alpha radiation is so potent that only a handful of molecules need reach the cancer cell to eliminate it, says Orano Med’s Dodet. This opens up “a crazy number of potential molecular targets,” he continues, including low-expression targets.
Such binding efficiency, alongside radiopharmaceuticals’ ‘see what you treat’ theranostic quality, is what is getting developers so excited. “You get real-time images that show which patients benefit the most,” says Novartis’s Legos, rather than having to wait for archival tissue samples. Plus, radiopharmaceuticals are “simpler than ADCs,” adds Perspective’s Spoor. “All they need to do is hit the outside of the cell. Then it’s destroyed.”
High hurdles
There is a way to go. Even if some next-generation radiopharmaceuticals are approved, they will face unique logistical challenges. Isotope supply, product assembly, scaled-up manufacturing and delivery to patients within isotope decay timeframes all require considerable expertise, facilities and coordination. Novartis’s four radiopharmaceutical manufacturing sites — including a second US site approved by the FDA in January 2024 – allow it to make a quarter of a million Pluvicto doses per year. But even this well-resourced pharma giant has faced bumps in the road. Other, smaller developers hope that Novartis is, in the words of one biotech CEO, “laying the highway on which others will drive.”
But Novartis is selling only two products, both using the same radioisotope. Others will require different distribution and treatment infrastructure. Products using short-lived Pb-212, for example, must be produced close to treatment centers and will require substantial shielding because of strong gamma ray emission. Hospitals and treatment centers will have to store Act-225-based product waste for 100 days, per guidelines requiring safe isotope storage for at least ten half-lives. Patients may need to stay in the hospital longer.
Another complication is that radiopharmaceuticals must be administered by trained nuclear medicine physicians, which “every major academic institution in the US is having trouble recruiting,” says MSKCC’s Lewis. Lutathera’s and Pluvicto’s successes are drawing in more trainees, but the need for coordination between oncologist and nuclear medicine specialists, who may be working at different sites or with different healthcare providers, is another challenge. “There is a lot to learn from cell therapy,” says Bayer’s Rüttinger, alluding to that field’s similarly complex manufacturing logistics. (Artbio’s Ostuni was formerly Novartis’s head of Europe for cell and gene therapies.)Some early-stage biotechs assume such challenges will be resolved once their programs mature. Others, like Y-mAbs, are developing approaches that may help address them. Y-mAbs’ two-stage radiopharmaceutical technology, licensed from MSKCC and the Massachusetts Institute of Technology, involves ‘prepainting’ tumor cells with antibody-based tetramers that bind the target and then disassemble. Unbound fragments are rapidly excreted, and bound components behave as a ‘molecular Velcro’, attracting a chelator–isotope complex delivered in the second step.
The first stage can be performed by oncologists as no radioactivity is involved. This means physicians can participate in treatment, making them more likely to use radiopharmaceuticals, says CEO Rossi. The second step will require authorized users, but it will be quicker, Rossi claims, than the five- or six-hour infusion required for Lutathera, as it involves only the ‘inert’ caged radioisotope. Since most of the ligand complex is excreted before the isotope is administered, the radioactivity is not expected to stay too long. “With Lutathera, the [ligand–chelator] is married to Lu-177 in the factory and shipped as a conjugate. In our case, that assembly happens inside the patient,” Rossi explains.
Y-mAbs’ Lu-177-based disialoganglioside GD2-targeting program is in phase 1 for small cell lung cancer, melanoma and sarcomas to determine treatment dose, sequence and spacing. GD2 is present on a range of metastasized tumors; the company sells the GD2-targeting antibody Danyelza (naxitamab) for children with relapsed or refractory high-risk neuroblastomas in bone or bone marrow.
Nuclear medicine’s theranostic property means fast results — from this and other radiopharmaceutical trials. “We get to watch the drug work in the organ and to calculate what absorbed doses look like,” says Rossi. All radiopharmaceutical doses are subtherapeutic in terms of the ligand; it is the isotope that drives efficacy. “We’re not looking to change physiology” or cell pathways. Instead, it is about letting loose the physics of an isotope in a very targeted fashion.
A new treatment pillar?
The next wave of radiopharmaceutical approvals will likely share a target and/or isotope with Lutathera or Pluvicto, offering incremental improvement such as more convenient dosing, a next-stage treatment option or slightly better efficacy. ITM Isotope Technologies Munich’s Lu-177-based GEP-NET phase 3 candidate uses a slightly different ligand from Lutathera and has different dosing. Point Biopharma has late-stage look-alikes of both Novartis drugs; the FDA in January 2024 accepted Point licensee Lantheus Holdings’ application for a generic Lutathera.
Beyond that, the field’s proponents are betting on approvals for radiopharmaceuticals with a far wider range of radioisotopes, ligands and targets, treating a broader range of disease types and stages. Participants envision a new pillar of oncology treatment, whose importance will grow as cancers are diagnosed earlier, among younger patients where the tolerability bar will be higher. “You have a very precise warhead that finds the tumor wherever it is. That could get into the mainstream,” says Ariceum’s Gericke.
By 2028, annual radiopharmaceutical therapy sales are expected to exceed $6 billion, according to Evaluate forecasts. Including diagnostic agents such as the widely used technetium-99m doubles that figure (Fig. 1). That’s why investors continue to pile in: ITM, an isotope supplier and radiopharmaceuticals developer, recently raised a second $200 million-plus financing round within 12 months of its last.
Countries including Australia, Belgium and the Netherlands are using strategic investments and tax breaks to gain competitive edge in a field that requires (and drives) specialist manufacturing, distribution, isotope supply and treatment ecosystems. Nations with efficient and flexible trial approval processes, cancer-focused clusters of excellence and coordinated treatment and imaging centers are attracting radiopharmaceutical developers. Europe, unusually, has a head start over the United States in this field, according to Joachim Rothe, partner at Ariceum co-founder EQT Life Sciences.
An approved Act-225- or Pb-212-carrying radiopharmaceutical would provide further momentum to a field already riding high on investor interest, mergers and acquisitions, and licensing deals. “This is still a young industry. There is a lot more to come,” says 3B’s Smerling.
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