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Radioligand therapy, a 'game-changer' for cancer treatment, forces manufacturers to race against a ticking clock

Novartis manufacturing associate checking punches at compressing machine.

Source: Novartis

In 2010, a volcano erupted in Iceland. For Dr. Oliver Sartor, a cancer research professor at the Tulane University School of Medicine, it was a problem. 

Ash from the eruption disrupted flights across Europe — including a time-sensitive shipment of experimental radioligand therapy that Sartor was expecting from Norway.

Radioligand therapy, also called radionuclide or radiopharmaceutical therapy, is a targeted form of cancer treatment that delivers radiation directly to cancer cells. While other forms of cancer treatment can target any rapidly dividing cells in the body, radioligand therapy’s precision helps limit damage to healthy, surrounding tissue. 

It’s an effective form of treatment that many experts and patients are excited about, but there’s a significant catch — the medication expires within days after it’s manufactured.

A radioligand is made of a radioisotope, which emits radiation that damages cells, and a targeted ligand — a molecule that binds to specific markers on cancer cells. The radioactive component has a very short half-life, or the time it takes for the radioactivity to decrease by 50%. Once the radioactivity decays, it can no longer kill the cancer cells as effectively, which means radioligand therapy has a limited window of viability. By the time it is packaged and ready to ship, the treatment has to reach patients in a matter of days.

“It takes planning,” Sartor told CNBC. “It’s not something you just sort of walk in and say ‘Oh, I think I’ll give you [this] today.'”

Pharmaceutical company Novartis believes the returns will be worth the challenge of mastering this race against time.

Novartis currently produces two radioligand therapy treatments called Lutathera, which treats neuroendocrine tumors, a rare form of cancer in the digestive tract, and Pluvicto, for patients with a specific type of prostate cancer. They were both approved by the Food and Drug Administration.

As of October, Novartis had treated more than 16,000 neuroendocrine patients and 4,000 prostate cancer patients in the U.S. Pluvicto was approved only last March and demand is increasing. As many as 60,000 U.S. patients could ultimately benefit from the medicine, said Jeevan Virk, head of radioligand therapy at Novartis.

The drugs are expensive. The list price (wholesale acquisition cost) of Pluvicto is around $42,500, while Lutathera is around $53,200, and most patients require between four to six doses. Novartis, which generated more than $50 billion in net sales last year, believes Pluvicto holds multibillion-dollar peak sales potential.

But in order to realize that potential, Novartis has to move the medication through the supply chain seamlessly. 

Expensive to produce and ship fast

Nuclear medicine has been used to treat cancer for decades, and radioligand therapy itself is not new. The therapy has previously been used to treat cancers like lymphoma, but it was not always widely accepted or used by members of the medical community.

“I think it was challenging for it to find its place,” said Dr. Delphine Chen, director of molecular imaging and therapy at Fred Hutchinson Cancer Center in Seattle.

Dr. Leo I. Gordon, a professor of cancer research at Northwestern University’s Feinberg School of Medicine, said the hesitation often comes down to finances.

Producing radioligand therapy is expensive, and companies have to be willing to shoulder the costs and navigate a challenging supply chain in the hope that they can eventually make a profit.

“I’m not sure it’s a great message to send that everything is based on profit mode and all,” he said, “but it certainly does exist in medicine, oncology and the world.”

For lymphoma, it’s not a long-term investment any company has been willing to make, Gordon said. But since Pluvicto and Lutathera outperform existing treatments available for certain prostate and neuroendocrine cancers, they are being seen to have significant commercial promise.

“There’s a lot of excitement around it,” said Chen, who has administered both drugs to patients. “A lot of patients feel better on it, so that’s really exciting and gratifying to me as a physician to be able to offer something that actually is helpful with minimal toxicity.”

Novartis manufactures radioligand therapy at three sites in Italy, Spain and New Jersey, and has a fourth facility slated to open in Indiana next year. Virk said between 70 to 150 people work in each facility, and the site in Indiana will be Novartis’ largest to date. 

For both Pluvicto and Lutathera, the manufacturing process begins with a mineral. The minerals are enriched into a stable isotope and exposed to radiation in nuclear reactors, where they ultimately become radioactive after around two to three weeks. During the irradiation, the enriched isotopes are placed into capsules to keep them secure. 

The strength of the radiation starts to decay as soon as the capsules are taken out of the reactors, which means Novartis begins a race against a ticking clock. The radioactive atoms have a half-life of just six and a half days. 

The capsules are transferred to an isotope-precursor production facility where they are further purified and concentrated into a radioactive liquid salt solution. At the end of this stage, which takes around 48 hours, there is enough radioactivity in one vial to treat between 30 and 50 patients. 

The final step takes place in a labeling facility where the radioactive atoms are attached to targeting molecules, or the medicine itself, and that takes around 24 hours. After the final product has been packaged and inspected for quality, it is ready to be shipped.

The drugs have different shelf lives depending on how much radiation Novartis can load into one vial. Pluvicto expires five days after it’s packaged at the factory, while Lutathera has a 72-hour shelf life. 

“We basically need to get the product distributed around the world, just in 72 hours, from those three production sites,” Virk said. “This includes anywhere from Tokyo to Anchorage, so it’s an incredible distance that needs to be covered.”

Patients feel the difference

Radioligand therapy is administered through an IV infusion, and though it does help limit damage to healthy tissue, patients can experience some side effects. 

Chen of the Fred Hutchinson Cancer Center said patients who receive Pluvicto can experience some nausea, vomiting, diarrhea, constipation, and fatigue in the short term. “Most of them have had only mild nausea that we’ve observed, and so Pluvicto is very well tolerated compared to chemotherapy,” she said. 

Chen said patients can experience many of the same symptoms with Lutathera, but the diarrhea can be exacerbated, and some patients contend with worsening bowel obstruction. In rare cases, patients may be unable to maintain their blood pressure. 

But for many patients, these side effects are worth it.

Vanue Lacour Jr. was first diagnosed with prostate cancer in 2007, and underwent a “tough” surgery to remove his prostate after his diagnosis. He stayed cancer-free for eight years, but in 2015, he learned he had relapsed with an advanced form of prostate cancer that had spread into his bones. 

“I was determined to win,” the 80-year-old told CNBC. “I’m determined to live.” 

Lacour began a grueling round of chemotherapy that he described as a “very, very hard, harsh medicine.” He incurred painful damage to nerves in his foot and leg that he still lives with today. 

The chemotherapy helped stabilize his cancer, but Lacour said his doctors were not satisfied. In 2018, Lacour enrolled in a clinical trial for Pluvicto and received six doses over eight months. Now, he is officially in remission. 

“I had no real side effects,” Lacour said. “I’m getting back to doing a lot of the things I like to do.”

Radioligand therapy has also helped Josh Mailman, who learned he had a softball-sized neuroendocrine tumor of the pancreas in 2007. The cancer had also spread to his liver. 

“I didn’t know how much time I had,” the 61-year-old Oakland, California, resident told CNBC. “There were very few treatments for pancreatic neuroendocrine tumors at the time.”

Mailman decided to join a support group, and he said the other members encouraged him to learn as much as possible about his disease. In 2008, he traveled to a medical conference in Toronto where he heard about radioligand therapy for the first time. As his symptoms worsened over the next six months, his doctor agreed to give Mailman his first dose of radioligand therapy under compassionate care in 2009. 

Mailman received three doses of radioligand therapy in 2009 and 2010, and he said it kept his cancer stable for the next six years. He has since had two follow-up treatments — one in 2016 and one in 2020, after the FDA approved Lutathera.

“I’m still here 15 years later,” he said. “It’s been a game-changer in the neuroendocrine tumor space.”

Because of his success with radioligand therapy, Mailman has become deeply involved in patient advocacy, where he works to raise awareness about nuclear medicine and neuroendocrine tumors.

“I would say I’m retired, my wife disagrees,” Mailman joked.

Mailman also runs virtual patient groups twice a week, where patients, friends and family members can come together to discuss their diagnosis and treatments. Mailman said radioligand therapy is discussed in more than 90% of the sessions. 

“Either someone’s going to have it, someone had it, someone wants to know more about it,” he said.

During one session CNBC observed in early November, more than a dozen patients met and discussed their experiences with and concerns about radioligand therapy. Patients who had already received it answered questions about their side effects and shared tips about how to overcome fear about needles and radiation. 

It is common for patients to express unease about the radiation, said Chen, but there are clear precautions in place to limit exposure and protect others. 

The road ahead

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