Radiation therapy has long existed as a modality for treating cancer. Until recently, most radiation was delivered from an external source that needed to penetrate the tissues to reach the location of the tumor. While often effective, external beam radiation has also been associated with significant collateral damage to healthy tissues, leading to side effects such as hair loss, digestive tract impacts, and sexual problems. Now, however, interest is rapidly growing in systemically administered radiopharmaceuticals that target radiation directly to cancer cells throughout the body, thus potentially reducing side effects. GlobalData forecasts that the total market value of radiopharmaceuticals in oncology will grow from $738 million in 2020 to $3.6 billion by 2026.
Similar to targeted therapies that deliver an effector drug to a specific tumor via an antigen or cellular receptor, radiopharmaceuticals combine a radioisotope with a targeting molecule that binds a specific tumor protein or selectively accumulates within a specific tissue. This approach, in many cases, also allows a tumor to be first visualized with an imaging isotope prior to treatment with the cancer-killing isotope, which confirms the selectivity of the targeting molecule.
The first radiopharmaceutical to enter widespread clinical use was radioactive iodine (I-131), which has been used since the 1940s to treat both hyperthyroidism and malignant thyroid disease. I-131 and certain other clinically used radioisotopes (notably lutetium-177, samarium-153, and yttrium-90) are emitters of beta particle radiation. Beta particles, the size of electrons, travel relatively long distances (0.5 – 12 millimeters) through tissues and emit a low level of energy that breaks the bonds of water molecules, generating free-radicals that damage cellular DNA, leading to cell death by apoptosis.
Beta emitters have proven useful for the treatment of certain cancers including large, heterogenous tumors and non-solid tumors. The yttrium-labeled anti-CD20 antibodies Zevalin and Bexxar were approved by the FDA in 2002 and 2003; while highly effective, they ultimately faced a number of challenges due to the complexity of the treatment, reimbursement issues, and other commercial reasons. At ASCO 2021, Novartis presented positive results from the Phase III VISION trial of its lutetium-177-labeled PSMA-617 (prostate-specific membrane antigen) radiopharmaceutical, AAA-617, in progressive PSMA-positive, metastatic, castration-resistant prostate cancer. In patients who had previously failed three lines of therapy, adding AAA-617 to standard of care improved median overall survival by four months (from 11.3 months to 15.3 months) and progression-free survival by over 5 months (from 3.4 months to 8.7 months). Additionally, AAA-617 therapy extended the time the patients went before experiencing a skeletal event related to bone metastases (such as a fracture, need for bone surgery or radiation, or spinal cord compression) from 6.8 months to 11.5 months. Novartis is now studying AAA-617 in two Phase III trials for earlier stage metastatic prostate cancers, comparing the drug with other forms of radiation treatment as well as other cancer therapies. Germany’s Isotopen Technologien München (ITM) is also conducting Phase III studies with a lutetium-177 radiolabeled molecule that targets neuroendocrine receptors as a potential treatment for gastroenteropancreatic neuroendocrine tumors.
However, beta emitters are less useful for treating disseminated cancers or minimal residual disease. As a result, attention has increasingly turned to another class of isotopes, alpha particle emitters (which include nine possible choices based on certain radioisotopes of actinium, bismuth, lead, radium, terbium, or thorium). Alpha particles are heavier than beta particles, about the size of a helium nucleus. They travel much shorter distances through tissues (40-90 micrometers), emitting nearly 1000-fold higher energy than beta emitters, and causing direct damage to the DNA of targeted tumor cells. As a result, alpha emitters kill tumor cells more efficiently than beta emitters, with less off-target damage to healthy cells. The type of scaffold chosen for targeting (i.e. antibodies, antibody fragments, peptides, natural selective accumulation) determines the route by which these radiopharmaceuticals are cleared from the body, their pharmacokinetics, tissue biodistribution, and radiation dosimetry, thus providing a wide range of options for creation of the best therapeutic for a particular cancer type.
In May 2013, the alpha-emitter 223Radium dichloride, developed by Algeta ASA and Bayer Health and marketed as Xofigo®, was approved by the FDA as the first radiopharmaceutical that significantly prolongs survival in castration-resistant prostate cancer patients with widespread bone metastatic disease. Since then, there has been growing interest in radiopharmaceuticals based on alpha emitters from both companies and investors, especially for the treatment of solid tumors.
For example, RayzeBio has raised more than $150 million in two rounds of venture financing (including a $105 million Series B closed in December 2020) to develop seven radiotherapies against validated targets based on its proprietary peptide mimetic binders and the alpha emitting isotope 225actinium. In March 2021, Aktis Oncology closed a $72 million Series A financing that included participation by both Bristol Myers Squibb and Novartis – a leader in radiopharmaceutical development since their 2019 acquisitions of Advanced Accelerator Applications and Endocyte, the original developer of AAA-617. Aktis has created a platform that facilitates the identification of agents that hit well-validated cancer targets, readily penetrate tumors, and clear quickly from other parts of the body. The intent is to enable physicians to see if a particular targeting molecule can effectively engage with an individual patient’s cancer before administering a therapeutic isotope.
Other companies pursuing alpha emitter radiopharmaceuticals include Actinium Pharmaceuticals, Clovis, and Fusion Pharmaceuticals. The latter company completed a $212.5 million initial public offering in June 2020 to support the development of alpha-emitters using its proprietary linker technology, both as single agents and in combination with checkpoint inhibitors and other anti-cancer drugs.
The ultimate success of radiopharmaceuticals still faces some challenges. The supply of clinically useful radionuclides is currently constrained, especially for alpha particle emitters – something that is likely to be overcome in the future with greater investment in their production. Treatment using these agents is perceived as highly complex, one of the issues that ultimately impacted Zevalin and Bexxar’s success in the marketplace. And there remains negative public perception and fear of radioactivity in general. But the growing positive clinical experience with these agents clearly suggests that they will be valuable additions to the armamentarium against cancer.