Radionuclide-based Human Therapeutics

Delivered January 26th, 2018

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A Table of Radionuclide-based Products Marketed in the US

Radionuclide therapeutic products are primarily used as parts of outpatient treatments in the United States. Though the list of FDA approved radionuclide therapeutic products is limited, research identified the following five products available in the U.S.: Xenon Xe 133, Lymphoseek, Cardiolite, Xofigo, and Metastron. These products have been arranged in a table in this spreadsheet.

In order to identify these products, we researched the existing therapies based on radionuclides in the United States. Upon finding the names of these products, we performed an extensive search of the patents, company websites and the National Institutes of Health (NIH) site to arrive at information on inventor and administration channel. 

Xenon xe 133 Xenon Xe 133 is a gas, administered by inhalation used for evaluation and imaging studies targeting the pulmonary system and cerebral flow. The drug is administered as an outpatient treatment, with patients exhaling the gas through a single breath upon completion of their studies. 

The drug is currently licensed to, and sold by, Lantheus Holdings, Inc. It was invented by Donald Ray Van Deripe, intended to be used in cancer treatments.

lymphoseekLymphoseek, also known as Technetium Tc-99m tilmanocept, is primarily used as a radioactive agent, used to help mark lymph nodes during diagnostic and surgical procedures.  It is injected into the patient after being diluted in 0.9% sodium chloride shortly before use.

Lymphoseek is currently sold by Cardinal Health, after having acquired licensing rights from inventors at Navidea Biopharmaceuticals, Inc.
 
cardioliteAnother outpatient imaging product, Cardiolite - also known as Sodium Pertechnetate Tc99m - is administered intravenously. It is primarily used for detecting myocardial abnormalities, evaluating function and identifying coronary disease. 

Cardiolite is currently licensed and sold by Lantheus Medical Holdings. It was originally invented by Alan Davidson and Alun Jones.

xofigoThe radionuclide therapeutic, Xofigo consists of radium Ra 223 dichloride. It is primarily used as a treatment for prostate cancer which is recurrent after surgical interventions. Xofigo is administered through injection every 4-6 weeks.

Currently, Xofigo is currently licensed and sold by Bayer Health but was invented by Roy Larson.

Metastron Metastron is a radionuclide treatment used in cases of metastatic bone cancer. The active agent is Strontium Chloride, SR-89, and 
is administered to outpatients intravenously.

Metastron was also invented by Roy Larson. The drug is now licensed and sold by GE Healthcare.

ConclusionThere are few radionuclide therapies in the U.S. A majority of these therapies - including Xenon Ze 133, Lymphoseek and Cardiolite - are used as diagnostic agents, supporting imaging studies to detect abnormalities. Another few, Metastron and Xofigo, are primarily used in the treatment of cancers.

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Distribution and Commercialization of Radionucleotide-based Human Therapeutics in the U.S.

We have compiled details on the distribution and commercialization of five major FDA approved radionucleotide-based human therapeutics products identified for marketing in the US. We focused on Xenon Xe 133, Lymphoseek, Cardiolite, Xofigo, and Metastron. We researched information from company-operated sources to determine ownership, manufacturing, and patient administration information for each product. 
XENON XE 133
 Xenon Xe 133 is currently manufactured by, licensed to, and distributed by Lantheus Holdings, Inc. Lantheus specializes in the design and supply as well as the validation of radiopharmaceutical products with limited half-lives. The company focuses on providing reliable “on-time delivery” of its products, making it a diagnostic imaging industry leader. 

The drug is administered to patients by licensed medical practitioners as an inhalant during out-patient diagnostic procedures for “the evaluation of pulmonary function and for imaging the lungs.” Lantheus also notes that the gas may also be used “to assess cerebral flow.” 
LYMPHOSEEK
 Lymphoseek is licensed under Cardinal Health, which owns sole production and distribution rights. Cardinal Health maintains VAWD Accreditation and specializes in a reliable and “highly regulated” distribution to pharmaceutical providers through localized Cardinal Health Pharmacies.

As a diagnostic agent, Lymphoseek is administered to patients on an out-patient basis to “locate lymph nodes draining a primary tumor site in patients with solid tumors.” Lymphoseek can additionally be used to guide “sentinel lymph node biopsy using a handheld gamma counter” in patients suffering from cancers involving the oral cavity, breast tissue, or for melanoma.
CARDIOLITE
 Lantheus Holdings, Inc. is the company that manufactures, distributes, and is the current license holder for Cardiolite. Lantheus currently manages all distribution of Cardiolite to pharmaceutical companies and directly to medical professionals through its customer service department. 

Cardiolite has been in use since 1991 and is known as “the first technetium-labeled myocardial perfusion imaging tracer” used in the US. It is administered by medical practitioners to patients on an out-patient basis to aid in detecting “known or suspected coronary artery disease (CAD).” 
XOFIGO
 Xofigo was originally developed and licensed under Bayer, but in 2009, Algeta “signed an agreement for the development” and co-promotion Xofigo “with Bayer in the US.” Bayer maintains exclusive international distribution rights of Xofigo. Algeta is a Norwegian company that focuses on alternative cancer therapies.

The drug, administered intravenously to patients with “castration-resistant prostate cancer, [or] symptomatic bone metastases,” is currently being marketed to US medical practitioners and patients. It is administered to patients as an outpatient or prescribed treatment.
METASTRON
 Metastron is licensed to General Electric Health through the Illinois Emergency Management Agency. Under authorization by this agency, General Electric Health produces and markets the distribution of the intravenous medication. GE Health is known as a leading global supplier of pharmaceutical products with a focus on maintaining “lowest cost” manufacturing, “structural simplification,” and enhanced “design productivity.” The organization's main aim is to produce the highest quality materials at the lowest cost to consumers.

Metastron is administered by medical practitioners to adult patients on an outpatient basis “for the relief of bone pain associated with painful skeletal metastases” as diagnosed by a licensed therapist. 
CONCLUSION
Each radionuclide-based product we researched is owned and distributed by US based license holders, except for Xofigo, which co-owned and distributed by the Norwegian company, Algeta. These products are administered on an out-patient basis and are distributed and marketed to both patients and medical practitioners. 

Xenon Ze 133, Lymphoseek and Cardiolite are primarily marketed and distributed to medical providers as diagnostic agents, while Metastron and Xofigo are also marketed directly to patients for the treatment of cancer symptoms.

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Issues Related to the Distribution, Commercialization, and Handling of Radionuclide-based Human Therapeutics in the US

An overall review of the market suggests that the current issues surrounding radionuclide-based human therapeutics are mainly economic and regulatory in nature.  These categories overlap in some cases. For instance the difficulty and expense of getting human therapies approved by government regulators is both a regulatory and economic issue.

However, many of these issues are endemic to any development of human therapies, as the cost and regulatory environment operates on all products being developed to fight disease in humans.  However, there are some barriers specific to radionuclide-based therapies.  These include the availability of radioisotopes for research and clinical use, as well as the cost and difficulty associated with disposal. 

Many of these issues are not limited to the U.S., but do apply to the U.S. market.

General Issues
The economic limitations related to this field include limited market size, market share, price resistance and the likelihood of insurance reimbursement.  Furthermore, there is the substantial cost of pursuing the clinical trials required for regulatory approval.

In the post-approval market, radionuclide-based human therapeutics face other barriers. There are issues of exclusivity in terms of patent protection and market competition from other therapies targeting the same diseases.

Supply Issues
The ability to use radionuclide-based human therapeutics is limited in part by the availability of the radionuclide.  

A key bottleneck in the supply chain comes from a lack of updated modern nuclear reactors.  A number of key radionuclides used for human diagnostic and therapeutic purposes are created using nuclear reactors.  However, many current reactors are aging or have been decommissioned, making them a poor source of large volumes of the necessary product.

According to government data, the average age of U.S. commercial reactors is about 36 years. There was a new reactor that entered operation in 2016, but that represented the first new on to come online in 20 years.  Prior to that, the next youngest reactor in the U.S. entered service in 1996.

This presents a secondary regulatory challenge associated with the market for radionuclide-based human therapeutics.  The nuclear industry itself is a highly-regulated field.  In that regard, it is similar to the process for drug and therapy development.  Given that the supply chain for this type of therapy relies on another industry, itself the subject of a high level of regulatory scrutiny, it creates an additional regulatory risk not present in other types of therapy.

Disposal Issues
Another issue specific to radionuclide-based human therapeutics is the issue of waste disposal.  This is complicated by a similar feedback loop as the one feeding the issue of supply.  Namely, that the overall market for nuclear-related functions is somewhat fixed, meaning that supply for many of the services involved in nuclear waste disposal are inflexible, so any additional increase in demand creates a price increase until the general market conditions catch up.

This has long been a problem for the market for radionuclide-based human therapeutics.  During its development as a market, these price pressures have been evident.  Increased use of radionuclides in human therapy has resulted in higher demand for disposal of the related radioactive waste.   

However, the situation surrounding the overall nuclear market is one of general stagnation.  As noted above, there has been one new reactor brought on line in the last 20 years.  In a climate of stagnant or even reduced radioactive waste generation, there comes a higher cost of disposal and a lower availability of disposal options as demand increases.

ConclusionThe issues facing development and marketing of radionuclide-based human therapeutics are largely economic or regulatory in nature.  Many of these issues track similar issues that face the development of any human therapy.  However, some issues are specific to the radionuclide market, such as supply risks related to creation of radioactive material and additional costs related to disposal.