In 2010, a volcano erupted in Iceland. For Dr. Oliver Sarter, a cancer research professor at Tulane University School of Medicine, it was a problem.
Ash from the eruption disrupted flights across Europe, including time-sensitive shipments of experimental radioligand treatments Sarter had expected from Norway.
Radioligand therapy, also called radionuclide or radiopharmaceutical therapy, is a targeted cancer treatment that delivers radiation directly to cancer cells. While other forms of cancer therapy can target rapidly dividing cells in the body, the precision of radioligand therapy helps limit damage to healthy surrounding tissue. .
Although this is an effective treatment that many professionals and patients aspire to, it has significant pitfalls. This drug expires a few days after manufacture.
A radioligand consists of a radioisotope that emits radiation that damages cells, and a targeting ligand, a molecule that binds to a specific marker in cancer cells. The half-life of radioactive components is very short, the time it takes for the radioactivity to decrease by 50%. As the radioactivity decays, it can no longer effectively kill cancer cells. This means that radioligand therapy has a limited survival time. The treatment must be delivered to the patient within days before it is packaged and ready for shipment.
“You need a plan,” Sarter told CNBC. “It’s not something you just walk in and say ‘Oh I think I’ll give it to you’ [this] today. ‘”
Pharmaceutical company Novartis believes it is worth the challenge of overcoming this race against time.
Novartis currently makes two radioligand therapeutics called Lutathera, which treats neuroendocrine tumors, a rare form of cancer of the gastrointestinal tract, and Pluvicto, for patients with certain types of prostate cancer. Approved by the Food and Drug Administration.
As of October, Novartis has treated more than 16,000 neuroendocrine patients and 4,000 prostate cancer patients in the United States. Pluvicto was only approved last March and demand is on the rise. As many as 60,000 US patients may ultimately benefit from the drug, said Geevan Burke, head of radioligand therapy at Novartis.
Medicines are expensive. Pluvicto’s list price (wholesale purchase cost) is about $42,500, while Lutathera is about $53,200, and most patients need 4-6 doses of him. Novartis Generates Over $50 Billion net sales We believe Pluvicto has peak sales potential of billions of dollars last year.
But to realize that potential, Novartis needs to move medicines seamlessly through its supply chain.
Expensive to produce and ship quickly
Nuclear medicine has been used to treat cancer for decades, and radioligand therapy itself is not new. was not always widely accepted or used by members of the
Dr. Delphine Chen, director of molecular imaging and therapy at Fred Hutchinson Cancer Center in Seattle, said:
Leo I. Gordon, Ph.D., a cancer research professor at Northwestern University Feinberg School of Medicine, said the hesitation often comes down to finances.
Radioligand therapies are expensive to produce, and companies must bear the costs and navigate challenging supply chains before they can ultimately turn a profit.
“I don’t know if it’s a great message that everything is based on profit mode, but it certainly exists in medicine, oncology and the world.”
Lymphoma is not a long-term investment that any company is willing to make, Gordon said. However, Pluvicto and Lutathera hold great commercial promise because they outperform existing treatments available for certain prostate and neuroendocrine cancers.
“There’s a lot of excitement in that,” said Cheng, who has given patients both drugs. , is really exciting and satisfying for me as a doctor.
A Novartis engineer in a packaging facility.
Source: Novartis
Novartis manufactures radioligand therapy at three facilities in Italy, Spain and New Jersey, and plans to open a fourth facility in Indiana next year. Virk said he has 70 to 150 people working at each facility, and that the Indiana facility will be Novartis’ largest facility to date.
For both Purvict and Lutacera, the manufacturing process begins with minerals. The minerals are enriched into stable isotopes, exposed to radiation in nuclear reactors, and finally become radioactive after about two to three weeks. During irradiation, the concentrated isotope is encapsulated to keep it safe.
As soon as the capsule is removed from the reactor, the intensity of the radiation begins to decay. This means Novartis will start competing with ticking watches. The half-life of radioactive atoms is only six and a half days.
The capsules are transferred to the Isotope Precursor Manufacturing Facility where they are further purified and concentrated into a radioactive liquid salt solution. At the end of this stage, which takes about 48 hours, one vial has enough radioactivity for him to treat 30 to 50 patients.
The final step takes place in a labeling facility where radioactive atoms are attached to the target molecule or drug itself, which takes about 24 hours. After the final product is packed and inspected for quality, it is ready for shipment.
The shelf life of the drug depends on the amount of radiation Novartis can put in one vial. Pluvicto expires five days after he is factory packaged, while Lutathera he has a 72 hour expiration date.
“Basically, we need to distribute the product worldwide within 72 hours from these three production sites,” says Virk. “This includes anywhere from Tokyo to Anchorage, so it’s an incredible distance that needs to be covered.”
Novartis scientists work with lab packaging for shipping.
Source: Novartis
Pluvicto and Lutathera come in small lead containers about the size of a credit card. Since lead is a strong insulator, it does not allow radiation to escape. The medicine is placed inside an additional container called a Type-A container that is made of Styrofoam and helps with temperature control.
Because the risk of radiation exposure is so small, radioligand therapy is often transported on commercial airlines and cargo planes. When doses need to be transported by ground, Novartis often uses his service of dedicated courier vans to get them to their destination as quickly as possible, Virk said.
This process happens in minutes and Novartis has a team of around 30-40 people overseeing the complex logistics.
“As you can imagine, this is a 24/7 operation because we have customers all over the world who depend on making sure their patients are on their medication,” he said. rice field. “That’s the fuel that keeps us going.”
Virk said mistakes can happen and sometimes things go wrong in the supply chain. However, errors are costly because if the shipment is not made in time for the patient, the dose cannot be recovered and the manufacturing process has to start over.
patients feel the difference
Radioligand therapy is administered by IV infusion and helps limit damage to healthy tissue, but patients may experience some side effects.
Chen of Fred Hutchinson Cancer Center said patients receiving Pluvicto may experience nausea, vomiting, diarrhea, constipation and fatigue in the short term. “Most of them had only mild nausea that we observed, so Pullvict is very well tolerated compared to chemotherapy.
Chen says patients can experience many of the same symptoms as Lutacera, but diarrhea can get worse, and some patients struggle with worsening bowel obstructions. may not be maintained.
But for many patients, these side effects are worth it.
Vanue Lacour Jr. was first diagnosed with prostate cancer in 2007 and underwent “harsh” surgery to remove his prostate after diagnosis. After being cancer-free for his eight years, he learned in 2015 that advanced prostate cancer had returned, metastasizing to his bones.
“I’m determined to win,” the 80-year-old told CNBC. “I’m determined to live.”
Lacour began a grueling round of chemotherapy that he describes as “very, very difficult, harsh drugs”. .
Chemotherapy helped stabilize his cancer, but Lacour said his doctors weren’t happy. In 2018, Lacour enrolled in his Pluvicto clinical trial and over eight months he received six doses. He is now officially in remission.
“There were no real side effects,” Lacourt said. “I’m getting back to doing a lot of the things I love to do.”
Radioligand therapy also helped Josh Mailman, who learned in 2007 that he had a softball-sized neuroendocrine tumor in his pancreas. The cancer had also spread to his liver.
“I didn’t know how much time I had,” a 61-year-old man from Oakland, Calif., told CNBC. “At the time, there were few treatments for pancreatic neuroendocrine tumors.”
Mailman decided to join a support group, he said, encouraging other members to learn as much as possible about his illness. In 2008, he attended a medical conference in Toronto, where he first heard about radioligand therapy. As his symptoms worsened over the next six months, his doctors agreed to give Mailman his first dose of radioligand therapy in 2009 under compassionate care.
Mailman said he underwent three rounds of radioligand therapy in 2009 and 2010, after which his cancer remained stable for the next six years. Since then, after the FDA approved his Lutathera, he has had two follow-up treatments, one each in 2016 and 2020.
“I’m still here after 15 years,” he said. “This was a game changer in the neuroendocrine tumor space.”
The success of radioligand therapy has made Mailman deeply involved in patient advocacy, working to raise awareness about nuclear medicine and neuroendocrine tumors.
“I would say I’m retired, but my wife disagrees,” Mailman joked.
Mailman also runs a virtual patient group twice a week where patients, friends and family can come together to discuss diagnosis and treatment. Mailman says radioligand therapy is discussed in more than 90% of his sessions.
“Someone’s going to get it, someone’s had it, someone’s wanting to know more about it,” he said.
One session CNBC observed in early November brought together more than a dozen patients to discuss their experiences and concerns about radioligand therapy. Patients who had already taken it answered questions about side effects and shared tips on how to overcome their fear of needles and radiation.
It’s common for patients to express concerns about radiation, Chen said, but clear precautions are in place to limit exposure and protect others.
According to the Swiss pharmaceutical group, completion is expected in the second half of next year.
Arndt Wiegmann | Reuters
road ahead
As demand for radioligand therapy increases, Novartis’ challenge is to increase access and awareness of its medicines.
Virk, head of radioligand therapy at Novartis, said the company is working with health systems, governments and other regulatory bodies around the world to improve operations.
“From my point of view, [radioligand therapy] The platform is just getting started,” he said. [we’re] very excited about the drug, [but] We are very keenly aware that this radioligand therapy revolution is just the beginning. ”
Sartor of Tulane University School of Medicine said there is still work to be done, especially when it comes to optimizing the supply chain, but radioligand therapy can make a real difference for patients.
“I think radioligand therapy has arrived in a way that makes sense for patients today,” he said. We are eager to conduct next-generation clinical trials to ensure that patients receive treatment.”
