In more ways than one, 2018 was a year of expansion for Novartis International. In January the company completed its $3.9 billion acquisition of nuclear medicine company Advanced Accelerator Applications (AAA), and in October it completed the $2.1 billion purchase of biopharmaceutical enterprise, Endocyte.

But in addition to scaling its company footprint, the Swiss-based pharmaceutical provider expanded its stake in another area — the emerging and promising field of theranostics. With AAA providing it access to its neuroendocrine tumor treatment, 177-Lu-Lutathera, and Endocyte giving it the same for its prostate cancer drug, 177-Lu-PSMA-617.

Interest in theranostics has driven a lot of business activity in recent years and energized not just companies but providers in nuclear medicine in working to develop radiotherapeutic molecules that can diagnose, determine a personalized course of action for, and treat various forms of cancer. The word itself is a portmanteau of diagnostics and therapeutics.

“The strong growth of radiotherapeutics represented around 14 percent of the total nuclear medicine market in 2018 - up from 3 percent in 2012 – and is expected to represent 60 percent, or even more, of the $26 billion U.S. nuclear medicine market by 2030,” Paul-Emmanuel Goethals, co-founder of MEDraysintell, a business intelligence firm specializing in nuclear medicine, told HCB News. “They are driving the growth of radiotheranostics, and their overall development along with that of conventional therapeutics will boost development of associated PET and SPECT tracers.”

Origins, and where it is today
Although the term was first coined in the 1990s, the concept of theranostics dates back to the 1940s when iodine was applied in both diagnostic imaging and therapy for benign and malignant thyroid tumors.

“You can give someone I-123, and using molecular imaging, you can see where the iodine goes and visualize metastatic thyroid cancer,” said Dr. Thomas Hope, a nuclear medicine physician and associate professor of radiology at the University of California, San Francisco. “Then, you can give them I-131, which has a different type of radiation emitted that can treat the thyroid cancer.”

This practice refers to a specific example of theranostics known as radiotheranostics. While in this scenario the same radionuclide is used for diagnosis and therapy, other forms of radiotheranostics involve different radionuclides paired together with a targeting ligand. One radionuclide is used to image the tumor, while the other is used to treat it.

Today, work in the field has extended to other types of cancer, most notably neuroendocrine tumors, with the FDA approving the use of the theranostic Lutathera for this condition in January 2018. The drug utilizes the amino acid peptide, DOTATATE, to image and target the somatostatin receptor, a common receptor of many cancer cells, before the radionuclide, lutetium-177 emits radiation to treat the tumor.

A promising frontier in theranostics is prostate cancer, with PSMA-617 showing promise and undergoing Phase III trials in the U.S. The therapy targets and binds a ligand to the prostate-specific membrane antigen (PSMA), and applies Lutetium-177 to destroy the tumor. It is designed for late-stage patients who have exhausted all treatment options available to them, though some argue its use should extend to those in earlier stages.

"Using something like peptide radiotherapy becomes more beneficial because, unlike many chemotherapies, it doesn't depend on rapid cell replication to be able to kill the cells. It targets the cell with enough radiation right where it is, just through the binding of the cell surface membrane,” said Dr. Geoffrey B. Johnson, chair of nuclear medicine at the Mayo Clinic in Rochester, Minnesota. “Many people believe the benefits, and the low amount of toxicity related to this therapy could be used at any stage for prostate cancer patients, even after the initial diagnosis.”

Reimbursement, and other challenges
While a source of excitement, the application of theranostics is still not well understood or even heard of in some medical circles. If it is to be integrated as a standard form of cancer care, changes and greater awareness must take place on a multitude of levels.

For U.S. providers, a key hurdle preventing adoption of theranostics is uncertainty over who is responsible for it. In many parts of Europe the responsibility falls to nuclear medicine — which is considered separate from radiology — but according to Dr. Wolfgang Weber, professor of nuclear medicine at the Technical University of Munich, no standards in the U.S. exist to dictate which area of study it falls under. This, in turn, leads to more problems, with providers unable to acquire the correct infrastructure or set up appropriate training programs for their staff.

“This problem lies partially in the fact that the application of radioisotopes for therapy is not really something that has been in the focus of radiology in recent years in the U.S.,” said Weber. “In Germany, it’s very clear that it’s a study of nuclear medicine, and there are a reasonable number of people who are trained in doing this."

He adds that while radiology in the U.S. is extremely efficient, it consequently is dominated by physicians who work primarily in a reading room, reviewing images of patients and writing reports based on what they see.
“Talking to patients, deciding if a treatment is right for them, and following up with them after therapy is outside the experience of many radiologists,” said Weber.

Another challenge is the perishable nature of radioactive drugs, which adds to the cost of producing these drugs in a field where reimbursement guidelines have still not been completely settled. This deters many from fully investing in it.

“Once you have something approved, it has to also be reimbursed, which, especially for diagnostics, does not have the same payoff as a therapeutic,” said Dr. Ken Herrmann, chair and a professor of nuclear medicine in the department of nuclear medicine at the University of Essen. “Just because a diagnostic is approved by the FDA doesn’t mean it’s reimbursed.”

Hope stresses that theranostics is a form of “treatment”, not a “cure”, and that it cannot be used to combat all forms of cancer.

“Its success depends on its ability to target cancer, and there are certain cancers that can’t be targeted because they don’t have cell surface proteins that we can target,” he said. “Additionally, the biodistribution of the agent may not be optimized yet.”

The road ahead
Securing approval of new theranostic agents requires generating awareness of meaningful scientific evidence. While regulatory processes can be long, access to literature and clinical validations of these therapies can help speed up approval time.

Outside of the U.S., theranostics are sometimes used on a “compassionate-use” basis, in which new, unapproved drugs are used to treat seriously ill patients with no other available treatment options, according to Hope. This helps to validate substances, leading to publication of literature and evidence that can be used in assessments of the same drug in other countries.

“If you take a drug that’s currently in Phase III trials, such as Lutetium-177-PSMA-617, the drug never went through Phase I and Phase II trials in the U.S.,” said Hope. “The company was able to go straight to Phase III trials because there was a Phase II trial performed in Australia, and there’s also extensive experience in Germany using PSMA-617, which presumably allowed the FDA to let the company move forward to a Phase III trial based on that.”

The success of theranostics for treating thyroid and neuroendocrine cancers, along with its expected benefits for prostate, have prompted a number of ideas involving its use in treating other forms of cancer.

"If you look at Lutathera, there is growing evidence that it could be used for many other tumors," said Johnson. "For example, it is used in many places off-label or in some parts of Europe where it's reimbursable for thoracic carcinoid tumors, as well as medullary thyroid cancer. We have also been exploring its use in pheochromocytoma, glomus tumors, pituitary neuroendocrine tumors, and meningiomas."

To Goethals, with MEDraysintell, reimbursement will be the main driver determining growth in theranostics.

“Reimbursement will be directly linked to the ability of the industry to demonstrate that the expensive drug to be used has the highest chance to be efficient in this specific patient,” he said “Radiodiagnostic agents will be used to make the distinction between responders and non-responders and only on the basis of the imaging or selection agent, treatment will be allowed/reimbursed.”

But to Herrmann, tapping into that growth requires rethinking the structure of nuclear medicine and its role within the healthcare ecosystem.

“We need to make sure there are enough people in nuclear medicine in general, which could potentially be done by making nuclear medicine departments independent in the U.S.,” said Herrmann. “We have to redesign the profile of nuclear medicine, become more clinical and active with patients, and become better trained as real doctors instead of just focusing on diagnostics.”