The big idea behind radiopharmaceuticals is taking the hallmarks of two cancer therapies – radiology and chemotherapy – and merging them, and this is what makes the technology a disrupter.
A radioactive isotope is attached to a targeting molecule that delivers radiation to the cancer cell with a high degree of specificity and selectivity. Often called “theranostics,” a small amount of radioactivity is first used to image a patient with a positron emission tomography (PET) scan to detect the degree to which a target is expressed. What results is a molecule that has a therapeutic benefit, but most of the benefit is the radioactive dose that is delivered in a very specific way.
“It's not a new idea,” Telix Pharmaceuticals Ltd. CEO Christian Behrenbruch said, “but essentially the whole field of medicine and molecular medicine in cancer is about developing very specific molecules and targeting agents for certain pathways expressed in cancer. The field is about greater specificity and more biomarker-driven management of patients.”
Radiopharma therapy is an emerging class of cancer therapeutics that deliver radiation directly to the tumor while minimizing radiation exposure to normal tissue. In this way, targeted radiopharmaceuticals are created by linking a therapeutic radioisotope to a targeting molecule that precisely recognizes tumor cells and binds to certain receptors on the tumor cell surface.
The radioisotope accumulates at the tumor site and decays, releasing a small amount of ionizing radiation, with the goal of destroying tumor tissue. The precise localization enables targeted treatment with potentially minimal impact to healthy surrounding tissue.
The ability to target tumors directly results in lower toxicity compared to other systemic therapies. Radiopharmaceuticals can also speed up dosing optimization because radioligands and their biodistribution can easily be tracked through imaging agents.
“You see what you treat, and you treat what you see, early on in drug development. We know it works because we can measure how much is being absorbed,” said Steffen Schuster, CEO of ITM Isotope Technologies Munich (ITM) in Munich, Germany.
In the 1950s there was one therapy (iodine), and it was the only one until the early 2000s. Then there were a few drugs for the neuroendocrine space and for the prostate cancer space.
In the last decade, radiopharma players like Bayer AG and Novartis AG have proven that this new technology can produce marketable drugs. Their successes have smoothed the way for new entrants to discover different ways to deliver tumor-killing radioactive payloads to cancers while leaving healthy cells untouched.
Bayer’s Xofigo (radium-223 dichloride), an alpha-emitting therapy, was approved in 2013 for bone metastases in patients with prostate cancer. Norwegian firm Algeta ASA, the originator company, was acquired by Bayer in 2013 for $2.5 billion.
The field opened with the approval of Lutathera (lutetium (177Lu) oxodotreotide) in 2018 for neuroendocrine tumors. Advanced Accelerator Applications SA developed Lutathera, and Novartis acquired the company for $3.9 billion. Viewed as the global leader in the radiopharma space, Novartis has spent nearly $6 billion on acquisitions, setting the global stage for the field by clearing clinical and regulatory hurdles.
FDA approval of Novartis’ Pluvicto (lutetium (177Lu) vipivotide tetraxetan) in March 2022 for treating adults with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) took radiopharmaceuticals from being a niche modality into mainstream oncology treatment to become one of the core pillars of treatment. It is the indication’s first FDA-approved targeted radioligand therapy that contains a radioisotope.
Novartis acquired Pluvicto from Endocyte Inc. for $2.1 billion in 2018, and analysts predict Pluvicto will likely be more than a $3 billion drug. Pluvicto uses lutetium-177, which is a beta emitter. Once it enters the bloodstream, Pluvicto binds to prostate cancer cells expressing PSMA13, and emissions from the radioisotope disrupt the tumor cells’ ability to replicate and/or kill the cells.
The approval was based on the phase III Vision study showing participants treated with Pluvicto plus standard-of-care (SOC) treatment had a 38% lower risk of death and a statistically significant reduction in the risk of radiographic disease progression or death compared to SOC alone.
What’s in a moiety?Alpha emitters such as Bayer’s Xofigo can deliver huge doses of radiation to a tumor, but only at close quarters, while beta emitters such as Lutathera and Pluvicto have greater range and accuracy but don’t cause such widespread damage to cancers.
Ratio Therapeutics Inc.’s founders, Jack Hoppin and John Babich, liken alpha radiation to a cannonball, while suggesting beta emitters are more like accurate rifle shots. They hope their company’s Trillium technology will allow for targeted delivery of destructive alpha radiation, but with much greater precision.
Trillium is a trifunctional small-molecule scaffold that can be fine-tuned to alter its plasma clearance, target affinity and therapeutic payload. Each component of the scaffolding can be independently optimized to boost tumor uptake over normal tissue uptake, thereby maximizing therapeutic index.
Ratio is also developing technology to take advantage of the tumor killing power of the alpha emitter, Actinium-225, for its Macropa chelator platform. It has already been successfully incorporated into the Trillium platform, as well as in several peptides and antibodies.
Boston-based Ratio raised more than $20 million in seed financing, and it has development alliances with Bayer and Lantheus Holdings Inc.
“Back in the old days, people used to think that betas, because they traveled further, were more effective for big tumors, and alphas, because they travel at shorter distance but provide a bigger punch, were better for smaller tumors,” Fusion Pharmaceuticals Inc. CEO John Valliant told BioWorld.
But published data on the actinium PSMA showed remarkable responses, even in large bony lesions, “so some of the old dogma doesn’t really hold true on these,” he said, adding that because alphas are larger compared to betas, they cause double-strand DNA breaks and massive trauma to the cancer cell, and so “you can actually use alphas at less of a radiation dose than a beta and see effects where betas don’t work.
“In our field, people used to love one type of targeting molecule over another – some people liked antibodies and some liked small molecules and wouldn’t like ‘the other.’ The approach that we take is to use the best delivery vehicle for a given target, so the PSMA program that we have now is a small molecule. Two of our phase I assets are antibodies, another is a small molecule, and we wanted to be able to use any type of targeting molecule that would give us the best results,” he said.
Spun out of the Centre for Probe Development and Commercialization (CPDC) at McMaster University in Hamilton, Ontario, Fusion created its fast-clear linker to clear actinium from the body quickly if it is not taken up by the tumor. The objective is to get the radiation in the tumor and nowhere else, Fusion Chief Scientific Officer Christopher Leamon said. “If it doesn’t stick to the tumor, we want it out of the body, and we have a variety of targeting ligands that include antibodies and small molecules,” he said.
The fast-clear linker is attached to the chelator portion that actinium binds with. During metabolism in normal tissues, the antibody is broken down, and a piece of the antibody contains a small piece of the chelator and fast-clear linker. Once it is broken down, the liver releases the actinium with the fast-clear linker back through the circulation and it is cleared through the kidneys, which is a faster removal from the body. The liver does this naturally, he said, but the fast-clear linker does it three times faster.
Germany’s ITM is not tied to one moiety; rather, it is playing the field and choosing what is most appropriate for each indication, CEO Steffen Schuster said. The company’s most advanced therapeutic is ITM-11, a peptide called edotreotide labeled with lutetium-177, which is in phase III trials in patients with gastroenteropancreatic-neuroendocrine tumors (GEP-NETs).
“We like lutetium for slow-growing tumors. We think it is more appropriate because you have the range,” Schuster said, explaining that for alphas, the range is about 2 mm compared to betas that travel across two to three cell diameters. Lutetium is also well-tolerated by healthy tissue, he said.
The company uses no-carrier-added (nca) lutetium-177, which has much less toxic waste than carrier-added (Lu-177) and requires more careful handling of patient waste.
Promise of alpha therapiesPharma companies like alpha emitters because they don't really look like radioactive drugs, Telix’s Behrenbruch said. The shielding material in alpha emitters is paper – compared to lead for lutetium or iodine – and the high-energy and short radiation distance has “phenomenal killing power.”
"There are roughly two or three types of radionuclides that are alpha emitters that have huge potential to move radiation oncology into something that looks like a regular drug. One of them is astatine, and the other is actinium.
“These are the next frontier of radiation biology,” he said, explaining that the old world of radiation biology consists of radionuclides like iodine and yttrium, which Sirtex Medical Ltd.'s SIR-Spheres Y-90 microspheres contain. The current model is lutetium 177 (177Lu), a user-friendly isotope that is stable, has short radiation, and allows for dosing in an out-patient setting, which increases the number of patients that can be treated.
Astatine does not rely on a nuclear reactor or proliferative nuclear sources, and it's a cleaner isotope to use. There are only a handful of sites around the world that are suited to conduct astatine trials, and Telix said that by funding a few studies, the company was able to unlock additional industry funding.
The promise of alpha therapies is likely to change treatment paradigms, Advancell Co. Ltd. CEO Andrew Adamovich said.
“We always thought targeted alpha therapy delivered some incredible results,” he said, pointing to the killing power of alpha emitter actinium-225. But delivering the supply of these alpha-emitting particles has been problematic because they have a long half-life, which means only small amounts can be produced.
“The challenge has always been scaling production of these alpha-emitting isotopes, and there are a lot of companies trying to do that,” he said.
Sydney, Australia-based Advancell ended up choosing lead-212 (212Pb) as its isotope, largely because the half-life of the isotope is 10.6 hours, and it is well-suited to the targeting molecule it is attached to. When it decays, it emits one alpha particle, and Advancell was able to overcome the degradation issues that other companies had with seeing off-target effects.
The company developed its own 212Pb generator that allows it to make lead product, Alpha 212, daily in clinical amounts. The quantities of lead used are nanomolar, and the chelation chemistry attached to the targeting molecule rids the body of lead poisoning.
“Without even getting into the downstream toxic daughter issue, as actinium decays toward stability, it emits alpha particles,” and the toxicity issues are not fully known, Advancell’s CEO Andrew Adamovich said, noting that lead-212 does not have those issues.
“We looked at these issues when we were first looking at setting up Advancell, and we looked at lead-212 as an alternative, which was more attractive from a risk perspective, from a production perspective, and from a clinical perspective,” he said.
PSMA is a well-defined target, so Advancell is starting with metastatic prostate cancer. It also has programs in melanoma and pancreatic and breast cancers.
All of the technology was developed in Australia, and the therapy will be a low-cost treatment that will be easily accessible.
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