Development of Cobinamide as a Cyanide Antidote: Completion of pre-IND Studies

SUMMARY Cyanide is a rapidly acting, lethal poison. It contributes to the 5000 to 10,000 fatalities from smoke inhalation each year in the U.S. In addition, several billion pounds of cyanide are used worldwide in a variety of industries, most notably mining of precious metals. Accidental exposures can, therefore, happen and because cyanide is easy to synthesize from simple chemicals, cyanide release by terrorists is an ever-present danger. The two FDA- approved treatments for cyanide poisoning, Cyanokit® and Nithiodote®, must be given by intravenous injection over 10-15 min, which is not practical for treating mass casualties as could occur in a major industrial accident or a terrorist attack. Moreover, the hydroxocobalamin in Cyanokit® must be reconstituted from a solid and the sodium nitrite in Nithiodote® is contraindicated in smoke inhalation victims due to methemoglobin generation. Thus, neither treatment is ideal for treating cyanide-poisoning, and an easy-to-administer antidote is needed. Cobinamide is a hydroxocobalamin analog that is considerably more potent as a cyanide antidote than the parent compound; it is also effective against other cellular asphyxiants such as hydrogen sulfide, methanethiol, and sodium azide. We have developed a cobinamide formulation, bis(aminotetrazolyl)cobinamide, that is absorbed rapidly after intramuscular (IM) injection and that has an excellent safety profile. Based on studies in mice, rabbits, and pigs, we calculate that enough cobinamide could be given by IM injection to rescue a human from a lethal exposure to cyanide. We are developing a safe pre-filled syringe system that would allow cobinamide to be administered quickly and easily in a pre-hospital setting. We have had several interactions with the FDA and the Biomedical Advanced Research and Development Authority (BARDA); from these meetings, we have learned that to advance cobinamide further as a cyanide antidote, we need to accomplish the following. First, we need to transition from laboratory-scale manufacturing to commercial manufacturing and generate good manufacturing practice (GMP) grade material. Second, we need to conduct 7-day repeat dose toxicity studies in two animal species (rats and dogs). To date, we have given bis(aminotetrazolyl)cobinamide only as a single injection, and it is possible that cumulative toxicity could occur with repeated injections. Third, we need to conduct several in vitro tests of cobinamide, including genotoxicity studies and evaluation for arrhythmogenicity. And fourth, we need to generate a Target Product Profile (TPP) to guide future drug development. We anticipate completing this work in the first 2-2½ years. We will then have a pre-IND meeting with the FDA to discuss our TPP and specify the definitive good laboratory practice (GLP) toxicity studies that will serve as a basis for future human safety studies. In the last 6-12 months, we will initiate these GLP toxicity studies, conducting a 14-day toxicity study in a single species (rats); definitive toxicity studies in a second species (dogs) will be conducted in the future under other support. As part of the proposal, we present a full Commercialization Plan that includes securing future funding and the steps required to market launch the planned drug product.