Current R&D focuses on Lead-212 to treat aggressive cancers
A “cowboy” country-and-western song performed by Chad Brock that includes the dramatic lyrics “Thunder is only noise, lightning does the work” finds new metaphorical meaning in the application of ionizing radiation to aggressive cancer tumors. This metaphor is brought to down to earth in the world of nuclear medicine by the new work of Areva NC, the French state-owned global nuclear giant, which is developing innovative uses for one of the world’s most unique isotopes.
For the past year, Areva has been working with the U.S. National Cancer Institute (NCI) in Bethesda, MD. The objective is to develop Lead-212 as a medical-quality radioactive isotope for use in new treatments for several types of aggressive cancers. The firm formed a new business unit in 2009 to fund the R&D clinical trials and develop a radiopharmaceutical drug based on the very short-lived isotope.
According to the NCI survival rates for Pancreatic cancer, which is one of the aggressive cancer types, are among the lowest of all cancers. The American Cancer Society estimates that in 2009 there will be approximately 43,000 cases and 35,000 deaths from the disease. The five-year survival rate is less than 5% of those diagnosed with the disease. The primary risks factors for pancreatic cancer include age, tobacco smoke, diabetes, and inherited predisposition to DNA mutations that cause the disease. Almost all patients are over age 45 and the average age at the time of diagnosis is 72.
Interview with Areva’s nuclear medicine CEO
In an exclusive interview with this blog, Patrick Bourdet, (right) CEO of Areva's new business unit, said the R&D work with the NCI is taking place under the auspices of a Cooperative Research & Development Agreement (CRADA). He said that Lead-212 has a very short half-life, as little as 8-10 hours, but it can used to target cancer cells to kill them directly.
According to Bourdet, the way the therapy would work is that the Lead-212 a Beta emitter, and its daughter decay product Bismuth-212, an Alpha emitter, binds to a specific peptide of the cancer cells.
Bourdet also noted that pancreatic cancer was not the only disease that has the potential to be treated by Lead-212 therapy should clinical trials prove to be successful. Other examples targeted by the R&D work at NCI include melanoma, ovarian, and colon cancer.
However, Bourdet said the R&D work has not yet entered clinical trials and that it will be several years before a therapeutic drug is available to physicians. He said that clinical trials could begin later this year or in early 2010.
How it works - target acquisition of cancer cells
Alpha emitters such as Bismuth-212, which is a decay product of Lead-212, are very effective at destroying single cancer cells. The Lead-212 is produced from a Radium-224 generator system which in turn is produced by the decay of natural Thorium-232 to Thorium-228 and to subsequent daughter products.
Chart source: PNNL
Two scientists at Argonne National Laboratory (ANL), John Hines and Bob Alcher, first develop a device for production of Bismuth 212 in 1989.
According to the Health Physics Society, Lead-212 and Bismuth-212 are currently used for experimental treatment of metastatic cancer in laboratory animals.
Antibodies or peptides labeled with Lead-212, or its daughter Bismuth-212, target cell-surface antigens on cancer cells.
The alpha particles from Bismuth-212 are particularly effective in destroying cancer cells. The high level of ionization breaks cancer cell DNA chains so completely they cannot repair themselves.
In short, the alpha-emitting Bismuth-212 that decays “in vivo” from the very short-lived Lead-212 destroys the fast-spreading metastases of cancer that are difficult to treat with other combinations of surgery, chemotherapy, and external-beam radiation therapy.
The institutions using the Lead-212 and Bismuth-212 daughters of Radium-224 in cell-directed immunotherapy against cancer are the University of Missouri at Columbia, MO (melanoma treatment) and the National Cancer Institute in Bethesda, MD (ovarian cancer treatment).
Building the business unit from scratch
Areva is doing something unusual for a global nuclear energy company. It is building the business unit from scratch. The firm has core competencies in things like uranium mines, nuclear reactors, and management of spent nuclear fuel, but none in nuclear medicine and radiopharmaceutical drugs. When a new product opportunity in the nuclear medicine field is not a core competency, the easy answer is to spin it to someone who knows the business. The plan is to let them take risks with the high costs of years of clinical trials, and reap licensing revenues if there is a success.
Bourdet says in this case the firm sought strategic business advice from AEC Partners, which is a strategic business consulting firm in the life sciences field, with offices in Paris and New York. After working with AEC, Areva decided to enter the nuclear medicine market with a new business unit which Bourdet now leads.
The business unit will be a supplier of Radium-224 which in turn produces Lead-212. If clinical trials are successful, the production facility and treatment center will have to be co-located because of the extremely short half-life of Lead-212.
Shortening the journey for clinical trials
Medical trials with humans require an enormous amount of groundwork. Bourdet says the three phases of clinical trials could take up to six years to complete. The three phases address safety, medical utility, and the development of a product (industrialization). However, Bourdet also said the U.S. Food & Drug Administration (FDA) offers a "shorter option for fast trials for treatments that hold the potential for very high-benefit therapeutic results." Accelerated approval of such treatments by the federal government depends on expected improved survival rates from the disease.
Areva has no investment or licensing partners at this time to share the cost of the clinical trials. However, Areva is confident enough of the outcome to have selected Goodwin Biotechnology (GBI) of Plantation, FL, to begin process development of a new radiopharmaceutical drug using Lead-212. GBI is a contract manufacturing organization that specializes in making therapeutic drugs used in all phases of clinical trials for new medicines.
From nuclear submarines to nuclear medicine
Asked why he chose to get into this business, with its long-term risks and rewards, Bourdet said the company is backing him "because we have an unprecedented opportunity to boost the survival rates from some of the most deadly cancers known to medical science."
Bourdet comes to the job with more than 20 years’ experience in the nuclear industry He started his career in 1986 in nuclear submarines with Technicatome (now AREVA TA) and the French Atomic Energy Commission-Nuclear Propulsion Dept (CEA-DPN). He joined COGEMA (now AREVA NC) in 1998 at the La Hague site in Normandy, France, working in production facilities, and joined the AREVA NC headquarters in the sales and marketing Department in 2005.
The following year, he was appointed to lead the AREVA TAO (Thorium of AREVA for Oncology) project focused on cancer research. He negotiated the Cooperative Research and Development Agreement (CRADA) signed in 2008 with the NCI. In April 2009, Bourdet was appointed President and CEO of AREVA Med, a new company focused on the development of powerful drugs to combat cancer.
There is no drug right now and the clinical trials are still in the future, but Bourdet is hopeful that the outcome will be consistent with expectations. The goal is that patients with aggressive cancers will no longer be facing a death sentence, but rather will have an avenue of hope offered to them by a most unusual source - radioactive lead. That's a pretty good future for a new business.
Update 09/24/09 - Areva Med recognized by foundation
NEW YORK, September 24, 2009 ~ AREVA, through its subsidiary AREVA Med LLC, announced today that the Clinton Global Initiative has recognized its efforts to develop innovative production methods to produce medical-grade Lead-212. This isotope is used to combat cancer in promising alpha radio-immunotherapy treatments.
Since the signature of a cooperation and research agreement with the U.S. National Cancer Institute and the University of Alabama, AREVA Med has increased its efforts to demonstrate the benefits of the medical-grade lead-212.
Relying on its long experience in radiochemistry and nuclear engineering, AREVA has developed new processes to extract rare isotopes derived from its industrial activities.
AREVA CEO Anne Lauvergeon said:
“On behalf of all AREVA employees, I am honored that our efforts in nuclear medicine have been recognized by the renowned Clinton Global Initiative, which supports projects that are innovative and beneficial for people at a global scale. This recognition demonstrates our spirit of commitment worldwide. It is also a tribute to our American partners, including the U.S. National Cancer Institute and the University of Alabama at Birmingham.”
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