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 on the Tulane University School of Medicine, it was an issue.
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 type of cancer treatment that delivers radiation on to cancer cells. While other types of cancer treatment can goal any rapidly dividing cells within the body, radioligand therapy’s precision helps limit damage to healthy, surrounding tissue.
It’s an efficient type of treatment that many experts and patients are enthusiastic about, but there’s a big catch — the medication expires inside days after it’s manufactured.
A radioligand is manufactured from 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 really short half-life, or the time it takes for the radioactivity to diminish by 50%. Once the radioactivity decays, it could not kill the cancer cells as effectively, which suggests radioligand therapy has a limited window of viability. By the point it’s packaged and able to ship, the treatment has to achieve patients in a matter of days.
“It takes planning,” Sartor told CNBC. “It isn’t something you only type of walk in and say ‘Oh, I feel I’ll offer you [this] today.'”
Pharmaceutical company Novartis believes the returns will likely be well worth the challenge of mastering this race against time.
Novartis currently produces two radioligand therapy treatments called Lutathera, which treats neuroendocrine tumors, a rare type of cancer within the digestive tract, and Pluvicto, for patients with a selected sort of prostate cancer. They were each approved by the Food and Drug Administration.
As of October, Novartis had treated greater than 16,000 neuroendocrine patients and 4,000 prostate cancer patients within the U.S. Pluvicto was approved only last March and demand is increasing. As many as 60,000 U.S. patients could ultimately profit from the medication, 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 4 to 6 doses. Novartis, which generated greater than $50 billion in net sales last yr, believes Pluvicto holds multibillion-dollar peak sales potential.
But with the intention to realize that potential, Novartis has to maneuver the medication through the provision chain seamlessly.
Expensive to supply and ship fast
Nuclear medicine has been used to treat cancer for many years, and radioligand therapy itself shouldn’t be latest. The therapy has previously been used to treat cancers like lymphoma, however it was not at all times widely accepted or utilized by members of the medical community.
“I feel it was difficult for it to search out 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 all the way down to funds.
Producing radioligand therapy is dear, and corporations should be willing to shoulder the prices and navigate a difficult supply chain within the hope that they’ll eventually make a profit.
“I’m undecided it’s an incredible message to send that every thing is predicated on profit mode and all,” he said, “however it actually does exist in medicine, oncology and the world.”
For lymphoma, it isn’t 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’re being seen to have significant business promise.
“There’s lots of excitement around it,” said Chen, who has administered each drugs to patients. “A whole lot of patients feel higher on it, in order that’s really exciting and gratifying to me as a physician to give you the option to supply something that really is useful with minimal toxicity.”
Novartis engineers in packaging facility.
Source: Novartis
Novartis manufactures radioligand therapy at three sites in Italy, Spain and Recent Jersey, and has a fourth facility slated to open in Indiana next yr. Virk said between 70 to 150 people work in each facility, and the location in Indiana will likely be Novartis’ largest so far.
For each Pluvicto and Lutathera, the manufacturing process begins with a mineral. The minerals are enriched right into a stable isotope and exposed to radiation in nuclear reactors, where they ultimately develop into radioactive after around two to a few weeks. Throughout the irradiation, the enriched isotopes are placed into capsules to maintain them secure.
The strength of the radiation starts to decay as soon because the capsules are taken out of the reactors, which suggests 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’re further purified and concentrated right into a radioactive liquid salt solution. At the top of this stage, which takes around 48 hours, there’s enough radioactivity in a single vial to treat between 30 and 50 patients.
The ultimate step takes place in a labeling facility where the radioactive atoms are attached to targeting molecules, or the medication itself, and that takes around 24 hours. After the ultimate product has been packaged and inspected for quality, it’s able 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 on the factory, while Lutathera has a 72-hour shelf life.
“We mainly must get the product distributed world wide, 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 should be covered.”
Novartis scientist in lab packing materials for transportation.
Source: Novartis
Pluvicto and Lutathera are packaged inside a small lead container, roughly the dimensions of a bank card. Lead is a powerful insulator, so it doesn’t allow the radiation to flee. The drugs are also placed inside an extra container called a Type-A container, which is manufactured from Styrofoam and helps with temperature control.
The danger of radiation exposure is so minimal that radioligand therapy is commonly transported via business airlines and cargo planes. When doses should be transported on the bottom, Virk said Novartis often uses a personal courier van service to make sure they reach their destination as quickly as possible.
The method is timed to the minute, said Virk, and there is a team of around 30 to 40 people at Novartis who oversees the complex logistics.
“It is a 24/7 operation as you would possibly imagine, because we actually have customers across the globe that rely upon ensuring that patients get their doses,” he said. “That is really the fuel that keeps us going.”
Mistakes can occur, and things do go incorrect in the provision chain occasionally, Virk said. But errors are costly, because if the shipments don’t reach patients in time, the doses cannot be salvaged, and the manufacturing process has to begin over.
Patients feel the difference
Radioligand therapy is run through an IV infusion, and though it does help limit damage to healthy tissue, patients can experience some unintended effects.
Chen of the Fred Hutchinson Cancer Center said patients who receive Pluvicto can experience some nausea, vomiting, diarrhea, constipation, and fatigue within the short term. “Most of them have had only mild nausea that we have observed, and so Pluvicto could be very well tolerated in comparison with chemotherapy,” she said.
Chen said patients can experience most of the same symptoms with Lutathera, however the diarrhea might be exacerbated, and a few patients contend with worsening bowel obstruction. In rare cases, patients could also be unable to keep up their blood pressure.
But for a lot of patients, these unintended effects are value 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 a complicated type of prostate cancer that had spread into his bones.
“I used to be 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 weren’t satisfied. In 2018, Lacour enrolled in a clinical trial for Pluvicto and received six doses over eight months. Now, he’s officially in remission.
“I had no real unintended effects,” Lacour said. “I’m getting back to doing lots of the things I wish 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 the way much time I had,” the 61-year-old Oakland, California, resident told CNBC. “There have been only a few treatments for pancreatic neuroendocrine tumors on the time.”
Mailman decided to hitch a support group, and he said the opposite 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 primary time. As his symptoms worsened over the following six months, his doctor agreed to present 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 following 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 has been a game-changer within the neuroendocrine tumor space.”
Due to his success with radioligand therapy, Mailman has develop into deeply involved in patient advocacy, where he works to boost awareness about nuclear medicine and neuroendocrine tumors.
“I might say I’m retired, my wife disagrees,” Mailman joked.
Mailman also runs virtual patient groups twice every week, where patients, friends and relations can come together to debate their diagnosis and coverings. Mailman said radioligand therapy is discussed in greater than 90% of the sessions.
“Either someone’s going to have it, someone had it, someone desires to know more about it,” he said.
During one session CNBC observed in early November, greater than a dozen patients met and discussed their experiences with and concerns about radioligand therapy. Patients who had already received it answered questions on their unintended effects and shared recommendations on learn how to overcome fear about needles and radiation.
It’s common for patients to specific unease concerning the radiation, said Chen, but there are clear precautions in place to limit exposure and protect others.
Completion was expected within the second half of next yr, the Swiss pharma group said.
Arnd Wiegmann | Reuters
The road ahead
As demand for radioligand therapy increases, Novartis’ challenge is to scale up access and awareness concerning the medication.
Virk, head of radioligand therapy at Novartis, said the corporate is working with health care systems, governments and other regulatory agencies world wide to enhance its operations.
“From my perspective, [radioligand therapy] as a platform continues to be very much in its infancy,” he said. “So [we’re] really excited concerning the drug, [but] very acutely aware that we’re just originally of this radioligand therapy revolution.”
Sartor on the Tulane University School of Medicine said there continues to be work to be done, particularly when it comes to optimizing the provision chain but that radioligand therapy makes an actual difference for patients.
“I feel radioligand therapy has arrived in a way that’s meaningful for patients today,” he said. “I’m anxious for patients to give you the option to receive the therapy in an FDA-approved manner, and likewise to do the following generation of clinical trials to be certain that much more people may have access in the long run.”