Ahead Of The Curve On Radiopharmaceuticals
By Ben Comer, Chief Editor, Life Science Leader
Like the resurgent interest in antibody-drug conjugates (ADCs), following improvements in linker technology, payload capacity and precision targeting, radiopharmaceuticals are also having something of a moment. Despite the negatives – a complicated supply chain, short half-life, and the radioactive fear factor – analysts are forecasting continued growth in radiopharmaceuticals (from approximately $5-7 billion in 2022 to $9-$13 billion in 2032), amid a shift in focus from diagnostics to therapeutics. In late December, Bristol Myers Squibb announced plans to acquire radiopharmaceutical therapeutics company RayzeBio, in a deal worth $4.1 billion; Eli Lilly closed its $1.4 billion acquisition of radiopharmaceuticals company POINT Biopharma on December 27.
Tiffany Olson isn’t surprised; she anticipated the current expansion in use of radiopharmaceuticals nearly a decade ago. As the former president of Cardinal Health’s Nuclear and Precision Health Solutions group, Olson oversaw Cardinal’s manufacturing partnership with Bayer for Xofigo, a radiopharmaceutical treatment for an advanced form of prostate cancer. That experience “showed that you can really market these types of therapeutics successfully,” says Olson.
Cardinal had already placed a substantial bet on radiopharmaceuticals back in 2002, purchasing Syncor International Corp, a nuclear pharmacy company that prepared and delivered radiopharmaceutical therapies and diagnostics, in a deal worth just over $1 billion. The acquisition brought Cardinal a capability to manufacture radiopharmaceuticals, distribute them through nuclear pharmacies, and even make certain diagnostics using Syncor’s cyclotrons.
But the market for radiopharmaceuticals went through peaks and valleys during the aughts; when Olson joined Cardinal as head of its radiopharmaceuticals group in 2013 – after leading Roche Diagnostics and Eli Lilly’s diagnostic division – her strategy boiled down to: “What can we do to help accelerate the growth, and also be on top of the growth curve” in radiopharmaceuticals? “At the time, we were participating in part of the supply chain: preparing the pharmaceutical, putting it into a pill or syringe, and delivering it,” says Olson. “But we were seeing growth in areas further upstream, or adjacent to what we were doing. We decided to go to where we believed the growth is going to be.”
In 2017, Olson convinced Cardinal to place a bet on gallium, despite the fact that “virtually no products required gallium” at the time, says Olson. “We signed an exclusive distribution agreement with a manufacturer in Belgium who made a gallium generator, and people thought we were crazy.” That bet turned into a winner as gallium use increased in recent years as a diagnostic imaging tool, something Olson and her team anticipated by looking at research programs and industry pipelines. A year after Cardinal’s gallium distribution deal, a major Big Pharma turned more eyes toward the growing opportunity in radiopharmaceuticals.
At the beginning of 2018, Novartis acquired French radiopharmaceuticals company Advanced Accelerator Applications (AAA) in a deal worth $3.9 billion, and closed the year with the purchase of Endocyte, an American radiopharmaceuticals company, for $2.1 billion. Between those two acquisitions in 2018, Novartis essentially paid what the entire radiopharmaceuticals market was worth at the time, roughly $6 billion, says Olson. “That is when interest in radiopharmaceuticals exploded, and money started coming in to fund new research projects.”
Not New, But Improved
Using radioactive agents in diagnostics and as therapeutics is not a new concept or modality, but like ADCs, radiopharmaceuticals have become more precise, improving both on safety and efficacy, with the potential to move into earlier lines of therapy for certain tumor types. When Olson joined Cardinal in 2013, she immediately saw the potential in theranostic pairing, or using radiopharmaceuticals as both a diagnostic and therapeutic for cancer patients. “When I first came into the [nuclear medicine] industry, it was probably around 90% diagnostics, and 10% therapeutics,” says Olson. “Now, we are seeing this huge seismic shift into therapeutics, which have the ability to target cancer at the cellular level.”
Currently approved radiopharmaceutical therapies for cancer are typically administered after a patient has failed traditional chemotherapy, however several companies – including Novartis – are pursuing clinical programs aimed at advancing radiopharmaceuticals into earlier lines of therapy. In comparison to chemotherapy, which kills off all fast-growing cells, and radiation, which impacts a broad area surrounding a tumor, radiopharmaceuticals – particularly when a diagnostic is paired with a therapeutic agent – can better target tumor cells without damaging healthy cells in the vicinity, notes Olson. “Right now, I don’t see radiopharmaceuticals replacing traditional cancer therapies, but they will increasingly complement and augment those therapies … with cancer, it’s all about doing the least amount of harm while getting rid of the cancer.”
Novartis CEO Vas Narasimhan predicted 2023 sales of over $1 billion for Pluvicto, Novartis’s radiopharmaceutical therapy for PSMA-positive, metastatic castration-resistant prostate cancer. While the final end-of-year numbers are not yet in, it appears likely that Pluvicto will become the first radiopharmaceutical blockbuster product. Additionally, Novartis announced positive Phase 3 data in September supporting first-line use of Lutathera in gastroenteropancreatic neuroendocrine tumors, an indication for which the drug was first approved in 2018. The new trial demonstrated improved progression-free survival, which is significant; the FDA has lately emphasized the importance of progression-free and “mature overall survival” data as a key metric for new approval decisions in radiopharmaceuticals.
Despite a long history on the market, radiopharmaceuticals have only targeted a small number of tumor types to date, including thyroid cancer, prostate cancer and specific neuroendocrine tumors. That is likely to change in the coming years, and current therapies in established target areas also will face new competition. Olson sits on the board at Telix Pharmaceuticals, an Australian radiopharmaceuticals company, which is currently developing radiopharmaceutical diagnostics and therapies targeting kidney and brain cancers, in addition to prostate cancer. Olson says radiopharmaceuticals in prostate and renal cancers will propel growth in the sector over the next couple of years, although new studies exploring pan tumor biomarkers, such as carbonic anhydrase-IX for example, could open new doors to radiopharmaceutical therapies.
Supply Chain And Other Headwinds
Because the isotopes used for radiopharmaceutical diagnostics and therapeutics decay rapidly, a “just-in-time” supply chain is needed to effectively deliver products to patients – you can’t just have a year’s worth of isotopes sitting on a shelf somewhere, says Olson. “It is important to have a robust source for isotopes … many times there can be issues.” For example, technetium-99m, the most commonly used radioisotope (produced from “mother” isotope molybdenum-99) in nuclear diagnostic imaging, has a surprisingly few number of commercial sources. Molybdenum-99 is produced in a research reactor; there are seven such research reactors worldwide, and none in the United States, although that could change soon, says Olson.
Technetium-99m generators are produced from molybdenum-99, and once a generator arrives at a hospital, “you have basically two weeks to use it … and there’s about a four-week lead time to get that generator made,” says Olson. “You can’t just walk in and say to the reactor, ‘I need some more molybdenum-99 today.’ It must come out of the reactor, get processed into chemical grade, and be put in a generator and sent to authorized pharmacists that can elute it.” In other words, multiple purchases from multiple suppliers is required to deliver the end product, and patient administration requires an “authorized user,” safe delivery area, and product tracking.
Even though BWXT Medical, a nuclear medicine supplier, is poised to enter the technetium-99m generator supply market, for many years there have only been two sources of technetium-99m generators, says Olson. With seven research reactors worldwide, four processors, and two generator suppliers (with BWXT being a potential third) for technetium-99m generators, it’s not a surprise that there can be “a lot of uncertainty about the supply chain” for radiopharmaceuticals, says Olson. Challenges associated with obtaining the most commonly used nuclear diagnostic agent (technetium-99m) was part of the reason for Cardinal’s decision to establish an exclusive distribution agreement for gallium generators, before demand caught up to available supply.
Two other challenges are worth noting as potential headwinds on the burgeoning field of radiopharmaceuticals. The first is pharmacist and physician training requirements to become an “authorized user” of radioactive materials. Currently, physicians need 800 hours of training to inject a radiopharmaceutical, which is “a lot,” says Olson. A urologist oncology, for example, will physically inject a radiopharmaceutical like Novartis’s Pluvicto, but he or she will not be reading scans. Should that injection process require 800 hours of training? “Everyone agrees that training is needed, but what level of training? That question is controversial but important, particularly in the context of pushing radiopharmaceutical access out into community-based settings,” says Olson. The second challenge deals with reimbursement for diagnostic imaging in the hospital. New diagnostics are often awarded a billing code (“A” code) in Medicare that is good for three years, and then disappears. After three years, the lack of a direct billing code creates a strong disincentive for using that diagnostic. This issue could be addressed by the bipartisan Facilitating Innovative Nuclear Diagnostics (FIND) Act – which aims to address the diagnostic reimbursement gap – but so far, the companion bills in the U.S. House and U.S. Senate have not reached the floor for a vote.
Expanding and securing the supply chain, adjusting physician and pharmacist training requirements, and establishing more favorable reimbursement for innovative diagnostics will be key issues to watch as the radiopharmaceuticals subsector grows in the coming years. Olson retired from Cardinal Health in 2021 and now does board work, speaking and advising. She started her own leadership consulting firm, focused on working with executives to develop strategy, grow businesses, and improve leadership skills. She will continue watching the radiopharmaceuticals space from her various board positions, including the Education and Research Foundation for Nuclear Medicine and Molecular Imaging, and through industry events.
Leadership: Engaging The Introverts
As a former division leader at Roche Diagnostics and Eli Lilly, Olson came to Cardinal Health with experience leading teams; her leadership philosophy consists of three things, in this order: listen, learn, lead. “If I can come into a new job, or really any new circumstance, and listen to customers, and listen internally to understand the issues and challenges so I can learn as much as possible about the situation …. then I am able to lead,” says Olson. “But for me, leading is not necessarily telling people what to do. It’s getting people to understand and to align on a specific goal.”
Olson says she learned early on that she didn’t want to be – and never has been – the smartest person in the room. “As a team, you want everyone to have their different specialties, and to be able to feel comfortable talking about those specialties. As a leader then, it’s my job to make sure people are heard, and to bring the group together.”
Asked about the most difficult aspect of being a leader, Olson says competing projects that go against one’s own project can make people feel conflicted, because they don’t have time for everything. Part of the solution is helping people to prioritize what is most important, right now, so they don’t feel overwhelmed. Fostering trust, and making sure people feel safe to contribute also can be a very challenging, says Olson. “When I was at Cardinal, I had several introverts on my team, and they tended to sit back and listen.” Olson worked with those introverts directly, letting them know that they would be asked to contribute during upcoming meetings. “I would tell them, ‘You won’t be the first person that I ask, but I would like to know your opinion on the topic, so know that I will ask you in the meeting.’ Then they would inevitably say something brilliant, but as the leader, you have to figure out how to bring that out in people, and everyone is different.”
Cancer Survivor
Last November, Olson took the stage at the American Cancer Society’s Discovery Ball to talk about her experience as a 17-year cancer survivor, the first time she had spoken publicly about her journey. Olson was CEO at Roche Diagnostics when she was diagnosed with breast cancer, and recalls walking into a large infusion room with 30-plus chairs to receive chemotherapy. “That made me realize that cancer doesn’t discriminate, because in that room there were young and old people, rich and poor, educated and not educated, and a long list of skin colors and ethnicities. That is why health equity is so important, not just in terms of healthcare discrimination, but in research, because that is how we will find solutions.” As a leader, Olson says her experience with cancer made her more empathetic about what other people go through, especially regarding health issues. “I was a young mom with two young kids, so it just made me appreciate more what other people experience, and what everyone can bring.”