THE UNMET NEED
In August 2004, the FDA approved new drug applications for Ca-DTPA (trisodium calcium diethylenetriaminepentaacetate) and Zn-DTPA (trisodium zinc diethylenetriaminepentaacetate) injections for the treatment of individuals who had been contaminated with radioactive americium, curium or plutonium. Both of these agents are salts of DTPA which is a chelating agent that forms stable complexes with these transuranic elements, thereby increasing their excretion from the body.
Ca-DTPA and Zn-DTPA had been used extensively over more than forty years as investigational agents in the treatment of individuals exposed to varying levels of radionuclides. The FDA found these agents to be safe and effective based on data maintained in a U.S. Registry of individuals with internal radioactive contamination from acute occupational exposure as well as from a careful review of published literature articles. Both Ca-DTPA and Zn-DTPA were found to increase the urinary excretion of plutonium, americium, and curium.
The difficulty of both Ca-DTPA and Zn-DPTA is that they need to be administered by intravenous injection (IV) by a health care professional. In a mass casualty situation, which could occur in a nuclear accident such as observed recently with the Fukushima Nuclear Power plants in Japan or in the instance of a terrorist attach with a dirty bomb, IV administration is impractical and a high percentage of the exposed population would likely go untreated. Capture is developing an oral chelating agent that could be easily distributed and administered to the entire affected population.
The proposed product in development by Capture, C2E2, is a diethyl ester of DTPA, which has been shown to be orally bioavailable and to chelate transuranic radionuclide elements in contaminated animals. Since C2E2 is itself a chelating agent and is relatively stable in vivo in rats and dogs, it is not considered a prodrug of DTPA.
Heavy Metal Toxicity
In addition to C2E2's utility in cases of exposure to radioactive elements, C2E2 has been shown to bind and enhance the elimination of non-radioactive toxic heavy metals such as lead (Pb) and gadolinium (Gd). It is well known that even small amounts of lead can cause serious health problems. Children younger than 6 years are especially vulnerable to lead poisoning, which can severely affect mental and physical development. Gd deposition toxicity concerns have recently been noted by FDA (for reference see "Gadolinium-based Contrast Agents for Magnetic Resonance Imaging (MRI): Drug Safety Communication - FDA Evaluating the Risk of Brain Deposits With Repeated Use", July 27, 2015 FDA Safety Announcement). Gd deposition can occur with the dosing of Gadolinium Based Contrast Agents (GBCAs) as part of Magnetic Resonance Imaging (MRI) medical procedures. Reported signs and symptoms of Gd deposition toxicity include mental confusion, joint pain, muscle weakness, skin problems and Nephrogenic Systemic Fibrosis (NSF, a potentially life threatening illness). It is estimated that GBCAs were used in 42% of the 40 million (8.4 million) MRI procedures in 2016. No current therapies exist for patients that may experience Gd toxicity.
C2E2 is an orally administered agent that can reduce long term exposure to certain heavy metals by enhancing their elimination from the body. Because of its efficacy and ease of use, Capture Pharmaceuticals anticipates the wide use of C2E2 to prevent the consequences of heavy metal exposure.