In 2010, a volcano erupted in Iceland. It was an issue for Dr. Oliver Sartor, a professor of cancer research at Tulane University School of Medicine.
A time-sensitive supply of experimental radioligand therapy that Sartor was expecting from Norway was delayed due to the eruption’s ash.
A focused kind of cancer treatment, radioligand therapy, also known as radionuclide or radiopharmaceutical therapy, delivers radiation to cancer cells. Other cancer therapies can target any rapidly proliferating cells in the body, but radioligand therapy’s accuracy helps prevent harm to healthy, nearby tissue.
There is a huge drawback, however, in that the medication expires just days after it is made, which is why so many professionals and patients are enthusiastic about this successful method of treatment.
A targeted ligand, a chemical that binds to particular markers on cancer cells, plus a radioisotope that produces radiation that destroys cells make up a radioligand. The radioactive component has a very short half-life, or the time it takes for the radioactivity to decrease by 50%. Radioligand therapy has a finite window of viability because once the radioactivity decays, it can no longer efficiently destroy the cancer cells. The therapy must arrive at patients within a few days after it is packaged and prepared for shipping.
“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.
I think radioligand therapy has arrived in a way that is meaningful for patients today. I’m anxious for patients to be able to receive the therapy in an FDA-approved manner, and also to do the next generation of clinical trials to ensure that even more people will have access in the future.
Professor Dr. Oliver Sartor
Expensive to produce and ship fast
Since the beginning of nuclear medicine, radioligand treatment has been utilized to treat cancer. Although the therapy has been employed in the past to treat diseases like lymphoma, it wasn’t always well-liked or utilized by 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.
Companies must be prepared to bear the costs of producing radioligand therapy and negotiate a complex supply chain in the hopes that they will eventually turn 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. In nuclear reactors, the minerals are enriched into a stable isotope and subjected to radiation. After about two to three weeks, they became radioactive. The enriched isotopes are enclosed in capsules during the irradiation to keep them safe.
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 moved to an establishment that creates isotope precursors, where they are refined further and concentrated into a radioactive liquid salt solution. One vial has enough radioactivity at the end of this phase, which takes about 48 hours, 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.”
Pluvicto and Lutathera are packaged inside a small lead container, roughly the size of a credit card. Lead is a strong insulator, so it doesn’t allow the radiation to escape. The drugs are also placed inside an additional container called a Type-A container, which is made of Styrofoam and helps with temperature control.
The risk of radiation exposure is so minimal that radioligand therapy is often transported via commercial airlines and cargo planes. When doses have to be transported on the ground, Virk said Novartis often uses a private courier van service to ensure they reach their destination as quickly as possible.
The process is timed to the minute, said Virk, and there’s a team of around 30 to 40 people at Novartis who oversees the complex logistics.
“It’s a 24/7 operation as you might imagine, because we really have customers around the globe that depend on ensuring that patients get their doses,” he said. “That’s really the fuel that keeps us going.”
Mistakes can happen, and things do go wrong in the supply chain occasionally, Virk said. However, mistakes are expensive because the production process must restart if the shipments do not get to the patients in time and the dosages cannot be saved.
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
As demand for radioligand therapy increases, Novartis’ challenge is to scale up access and awareness about the medication.
Virk, head of radioligand therapy at Novartis, said the company is working with health care systems, governments and other regulatory agencies around the world to improve its operations.
“From my perspective, radioligand therapy as a platform is still very much in its infancy,” he said. “So we’re really excited about the drug, but very acutely aware that we’re just at the beginning of this radioligand therapy revolution.”
Sartor from the Tulane University School of Medicine stated that although there is still work to be done, especially in terms of supply chain optimization, radioligand therapy actually benefits patients.
“I think radioligand therapy has arrived in a way that is meaningful for patients today,” he said. “I’m anxious for patients to be able to receive the therapy in an FDA-approved manner, and also to do the next generation of clinical trials to ensure that even more people will have access in the future.”
