Radiopharmaceuticals Bring in Big Money to Target Irreversible Tumor Damage

Radiopharmaceuticals

Pictured: Illustration of cancer cells being held in the crosshairs of a scope/iStock, wildpixel

The final big M&A deal of 2023—BMS’s purchase of RayzeBio for $4.1 billion—centers on the development of radiopharmaceuticals, and with good reason. While targeted cancer treatment approaches such as immunotherapies have taken off, experts say they don’t work for all patients and, in some cases, lead to severe toxicities. Radiopharmaceuticals, a targeted therapy in which radiation-emitting isotopes are delivered to cancer cells, may be the answer to some of these challenges.

“Trial after trial has shown the benefits of radiopharmaceuticals, which is driving the excitement in this field,” Delphine Chen, director of molecular imaging and therapy at the Fred Hutchinson Cancer Center told BioSpace. “We are seeing good responses even in patients who have undergone multiple prior therapies, something we don’t see with other therapies.”    

Unlike traditional radiotherapy, where the radiation is administered from outside the patient’s body, radiopharmaceutical therapy targets cancer cells using specific delivery vehicles such as monoclonal antibodies carrying radioactive isotopes. The isotopes emit radioactive β-particles or highly concentrated α particles, which cause irreparable damage to the DNA of cancer cells.

Investment Accelerates

Radiopharmaceuticals have been around for nearly a century, and in the 1940s, radioactive iodine was used to treat thyroid cancers.

“It’s not like it’s a completely novel space,” Dominik Ruettinger, senior vice president and global head of Research & Early Development for Oncology at Bayer, told BioSpace. “But earlier, it didn’t quite work. It was mainly side effects that affected the kidneys and bone marrow that stopped these super early programs.”

While still used for thyroid cancers, radiopharmaceuticals didn’t gain traction in other indications, due in part to complicated treatment protocols. But over the past two decades, this began to change. In the early 2000s, the FDA approved two β-particles emitting radiopharmaceutical therapies, Zevalin (Ibritumomab) and Bexxar (tositumomab), to treat some people with non-Hodgkin lymphoma, a type of blood cancer.

Increased investment followed. In 2014, Bayer acquired Algeta, a Norwegian biotech company focused on developing α particle–emitting radiopharmaceuticals, for $2.9 billion. In 2018, Novartis spent $6 billion to acquire two radiopharmaceutical companies, Endocyte and Advanced Accelerator Application S.A. Novartis’ Pluvicto, approved in 2022 for metastatic castration-resistant prostate cancers, and Lutathera, approved in 2018 to treat gastroenteropancreatic neuroendocrine tumors, stemmed from these acquisitions.

Pluvicto’s approval as the first targeted radioligand therapy for advanced prostate cancer followed successful Phase III data, which showed the drug extended overall survival by four months compared to standard-of-care for relapsed prostate cancer patients. Pluvicto has raked in more than $700 million, and Novartis expects it to become a multibillion-dollar drug, CEO Vas Narasimhan said during an investor call in October 2023.

Also, in June 2021, Bayer agreed to acquire Noria Therapeutics and PSMA Therapeutics. Through this transaction, the German multinational obtained exclusive rights to a differentiated α radionuclide investigational compound based on actinium-225 and a small molecule directed toward prostate-specific membrane antigen (PSMA). More recently, Eli Lilly entered the space, acquiring Point Biopharma and its PSMA-targeted treatment, Lu-PNT2002, for $1.4 billion last October. Point and partner Lantheus Holdings revealed topline data from a Phase III trial in December, showing that the drug elicited a 3.5-month progression-free survival advantage over the control.  

A Targeted Advantage

Of the myriad targeted cancer therapies that have been developed over the last decades, 97% have failed. One reason, research shows, is that the drugs selected for clinical investigation target the wrong pathway. Radiopharmaceuticals work independently of signaling pathways, Ruettinger said.

“Radiopharmaceutical therapies work regardless of the mutational status of cancer, and [regardless] of therapies a patient may have been exposed to before,” he told BioSpace. “That is what people are so excited about.”

While the clinical data looks promising, there are no head-to-head comparisons between radiopharmaceutical and other modalities, Ken Song, president and CEO of RayzeBio told BioSpace in an email. “But the level of efficacy and safety seen thus far with [radiopharmaceutical therapies] highlights the potential of it as a modality that effectively treats patients across multiple cancer types.” Song added that because radiopharmaceuticals have shown benefits across two diverse cancer types—prostate cancer and neuroendocrine tumors—he is hopeful they may work for many other cancer types as well.

Seeking ‘Irreversible Damage’

Most of the current radiopharmaceuticals on the market, including Novartis’ Pluvicto and Lutathera, use an isotope called lutetium-177a β-emitting particle, which generally creates a single-stranded DNA break. These emissions travel long distances, and over a period of three days patients and their excretions emit radiations, posing a hazard to those who come into contact with them.

However, RayzeBio—along with several other companies, including Perspective Therapeutics and ArtBio—is developing α-emitting radiopharmaceuticals for solid tumors, which do not require patient isolation. In contrast to β particle–emitting isotopes, α-particle isotopes don’t travel long distances, negating the need for isolation. In addition, they deliver a more concentrated dose of toxic radiation than α particles and create double-stranded DNA breaks.

“With double-stranded breaks in the DNA, the damage is pretty much irreversible and there are no known mechanisms for cancer cells to repair such damage, which makes it so compelling,” Ruettinger noted.

Overcoming Roadblocks

Despite all these developments, two of the biggest challenges in scaling radiotherapies have been manufacturing and supply. Due to the short half-life of the radioisotopes, radiopharmaceuticals need to be delivered to a patient within 10 days of manufacturing, Ruettinger said, making the distribution of the drug a big challenge from a logistics point of view. The other problem, he said, is the supply of isotopes.

In April 2023, Pluvicto reportedly experienced a supply shortage amidst rising demand. The company subsequently resolved the shortage following FDA approval for commercial production of the drug at the Novartis RLT manufacturing facility in Millburn, NJ, in 2023.

The drug is made in small batches and must be given to patients within five days, making it nearly impossible to stockpile, Ruettinger pointed out. A company spokesperson told BioSpace in an email that Novartis is aiming for a production capacity of 250,000 doses in 2024 and beyond.

Fred Hutch’s Chen said she believes these challenges will be resolved with time. “I agree that radiopharmaceutical therapy is poised to become big in the coming years.”

Aayushi Pratap is a New York-based health and science journalist.

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