Much of the radiopharmaceutical industry’s alpha-therapy pipeline is built around a familiar concept: find a molecular target expressed by cancer cells, attach an alpha-emitting isotope to a targeting molecule, administer the drug systemically and rely on biology to carry radiation to tumors.
Oncoinventis pursuing a different strategy.
Its lead radiopharmaceutical, Radspherin, uses radium-224-loaded calcium carbonate microparticles administered directly into the peritoneal cavity following surgical removal of visible tumors. Rather than searching for cancer through the bloodstream, the therapy is designed to exploit the anatomy of a compartment where microscopic residual disease can remain after surgery. New clinical dosimetry results published in the Journal of Nuclear Medicine provide evidence that the approach may also have another important characteristic: relatively little radiation appears to reach normal organs.
The study evaluated nine patients from first-in-human Phase 1 studies of Radspherin in ovarian and colorectal cancer. Investigators found that absorbed radiation doses to normal organs were below levels commonly associated with complication risks, including in the kidneys and red bone marrow, two tissues that can become important constraints in radiopharmaceutical therapy.
The findings do not establish Radspherin’s efficacy. Nine patients also represent a small dosimetry cohort. But they help answer an important question surrounding Oncoinvent’s approach: if an alpha-emitting therapy is placed directly where residual disease is most likely to remain, can therapeutic radiation largely stay there?
So far, the dosimetry data suggest that may be possible.
Radspherin is unusual because it is receptor-independent. There is no PSMA, somatostatin receptor, FAP or other molecular target guiding the radiopharmaceutical to cancer cells. Instead, billions of biodegradable calcium carbonate microparticles containing radium-224 are distributed inside the peritoneal cavity following cytoreductive surgery.
Radium-224 decays through a chain that produces multiple alpha emissions. Alpha particles deposit large amounts of energy over extremely short distances, creating the potential to destroy nearby malignant cells while limiting radiation exposure farther away. That short range is particularly interesting in the post-surgical setting Oncoinvent is targeting. Patients with ovarian and colorectal cancers that spread throughout the peritoneum can undergo extensive cytoreductive surgery intended to remove visible disease. But even when surgeons achieve complete macroscopic resection, microscopic cancer cells can remain scattered throughout the abdominal cavity and eventually seed recurrence.
Radspherin is intended to attack that residual disease. Rather than asking a radiopharmaceutical to travel throughout the body and locate tumors, Oncoinvent is attempting to place the radioactive material directly into the anatomical compartment where microscopic cancer cells are believed to remain.
That distinction could matter considerably.
Radiopharmaceutical therapy always involves a balance between delivering sufficient radiation to disease and limiting unintended exposure to healthy tissue. For systemic therapies, circulating radioactivity and uptake in non-target tissues can place practical limits on administered activity. The kidneys and bone marrow are particularly important because excessive radiation exposure can create renal or hematologic toxicity.
Oncoinvent’s new study examined whether those same limitations might emerge with intraperitoneal radium-224 microparticle therapy. The answer, at least in this small early-stage dataset, was encouraging. Investigators reported low absorbed doses across normal organs, including kidneys and red bone marrow. The results were also consistent with the favorable safety profile previously reported from the company’s early clinical studies.
But measuring that exposure was not straightforward.
Alpha therapy presents a growing challenge for the nuclear medicine field because conventional imaging-based dosimetry approaches cannot necessarily be transferred directly from beta-emitting radiopharmaceuticals.
Caroline Stokke, senior author of the publication, Head of Nuclear Medicine Physics at Oslo University Hospital and Chair of the European Association of Nuclear Medicine Dosimetry Committee, highlighted that problem.
“This work also reflects the methodological complexity of dosimetry for alpha therapies, where imaging cannot always be directly applied.”
Researchers therefore combined several methods, including blood sampling and biokinetic modeling, to estimate radiation exposure to normal tissues.
“In early-phase clinical studies, dosimetry is essential to understand how radiation exposure relates to potential toxicity and identify potential dose-limiting tissues,” Stokke said.
The work points to a broader issue facing the radiopharmaceutical industry. As targeted alpha therapies move deeper into clinical development, determining where alpha radiation actually goes — and translating microscopic energy deposition into clinically meaningful absorbed-dose estimates — is becoming increasingly important.
The significance of the Radspherin results becomes clearer when viewed against one of the fundamental challenges of systemic radiopharmaceutical therapy. A radiopharmaceutical administered intravenously must travel through the body before reaching its target. Even highly selective agents can expose blood, kidneys, salivary glands, marrow or other tissues to radiation.
That does not make systemic therapy inherently problematic; several radiopharmaceuticals have already demonstrated that targeted radiation can be delivered safely and effectively. But normal-organ exposure remains part of the therapeutic equation. Radspherin is attempting to change the geometry of that equation. Instead of improving the targeting molecule, Oncoinvent largely removes the need for one.
The abdominal cavity itself becomes part of the delivery mechanism. The microparticles are intended to remain regionally distributed while radium-224 and its decay products deliver short-range alpha radiation near the peritoneal surfaces. If the treatment can maintain sufficient local radiation while producing minimal systemic exposure, it could create a wider separation between the radiation delivered to the intended treatment area and the dose received by critical normal organs.
Kari Myren, Oncoinvent’s chief medical officer, said the results support that hypothesis.
“Unintended radiation exposure to normal organs, especially for the kidneys and red bone marrow, frequently represents a limitation for obtaining therapeutic doses of radiopharmaceuticals.”According to Myren, the results indicate “very low radiation exposure to healthy organs after treatment.”
That remains an early-stage conclusion. But if confirmed in larger studies, the implications extend beyond safety. A therapy that avoids substantial systemic exposure could potentially reduce some of the dose-limiting constraints associated with radiopharmaceutical treatment while integrating into an existing surgical pathway.
The dosimetry publication does not stand alone. Oncoinvent has completed early-stage studies of Radspherin in both ovarian and colorectal cancers and is now testing the therapy in a randomized Phase 2 ovarian cancer trial. Earlier this year, the company reported final 24-month follow-up from its Phase 1 ovarian cancer study. Twenty-one patients were enrolled across dose levels, with no dose-limiting toxicities and no Grade 3 or higher adverse events considered related to Radspherin.
The recommended dose was established at 7 MBq. The efficacy signal was also notable, although it came from a small, uncontrolled early-stage study: among 10 patients treated at the recommended dose, Oncoinvent reported that only one experienced peritoneal recurrence through 24 months.
Those results should be interpreted cautiously. Phase 1 trials are primarily designed to evaluate safety, and small patient populations can produce efficacy signals that do not hold up in randomized studies. That is why the company's ongoing Phase 2 study is considerably more important.
The randomized trial is evaluating Radspherin in patients with peritoneal metastases from ovarian cancer. Patients receiving Radspherin after pre-operative chemotherapy and complete surgical resection are being compared with patients receiving chemotherapy and surgery without Radspherin, with progression-free survival as the primary efficacy measure.
In June, Oncoinvent said the study had reached 50% enrollment. The trial should begin to show whether the biological and dosimetric rationale behind Radspherin translates into a measurable clinical benefit.
There is also a strategic reason to watch the program beyond ovarian cancer. Peritoneal metastases occur across several malignancies, including ovarian, colorectal and gastric cancers. If localized alpha therapy can successfully eliminate microscopic residual disease following surgery, the concept may not necessarily depend on the biology of a single tumor type.
That is an important distinction from receptor-targeted radiopharmaceutical development. A PSMA-targeted therapy depends on PSMA expression. A somatostatin receptor-targeted therapy depends on receptor expression. Other emerging radiopharmaceutical platforms similarly depend on identifying targets with favorable tumor expression and manageable normal-tissue distribution.
Radspherin's hypothesis is different: the common denominator is not a receptor. It is the location of the disease. That potentially makes the peritoneal cavity itself the target.
However, there are limitations to that strategy. Local administration restricts the approach to cancers and clinical situations where disease can be addressed within an accessible anatomical compartment. Radspherin is not designed to seek distant metastases throughout the body, and it would not replace systemic therapy for patients with widespread disease. But within the right clinical setting, that limitation could become an advantage.
Radiopharmaceutical development is increasingly becoming a search not simply for better isotopes, but for better ways of controlling where radiation goes. Most of the industry is pursuing that objective through increasingly sophisticated targeting molecules, chelators, linkers, pharmacokinetics and isotope combinations. Oncoinvent is pursuing it through anatomy.
The distinction makes Radspherin one of the more unconventional alpha-therapy programs moving through the clinic. Its success will ultimately depend not on dosimetry alone, but on whether the ongoing randomized trial demonstrates that adding a localized alpha treatment after surgery meaningfully delays recurrence.
The new Journal of Nuclear Medicine publication nevertheless addresses an important part of that equation. The objective of radiopharmaceutical therapy is not simply to deliver radiation. It is to create as large a therapeutic separation as possible between the radiation absorbed by cancer and the radiation absorbed by healthy tissue.
For Radspherin, the early evidence suggests that normal-organ exposure may be quite low. The next question is the one that matters most: whether keeping alpha radiation local can keep the cancer from coming back.
