TV-1380 attenuates cocaine-induced changes in cardiodynamic parameters in monkeys and reduces the formation of cocaethylene.

BACKGROUND: TV-1380 is a rationally mutated, human BChE fused to human serum albumin that has high hydrolytic enzymatic activity against cocaine and as well as an extended elimination half-life. OBJECTIVE: The present studies examined the safety of TV-1380 and its protective effect when given to monkeys alone or concomitantly with cocaine and ethanol. METHODS: A set of studies was conducted in monkeys with TV-1380. The parameters tested included telemetric assessment of cardiovascular parameters, clinical pathology, plasma analysis of cardiac troponin I, ex-vivo analyses of cocaethylene and PK analysis of serum concentrations of TV-1380, cocaine and its metabolites, and histopathological examinations. RESULTS: TV-1380 treatment in monkeys was well tolerated. TV-1380 pretreatment prior to cocaine significantly attenuated the cardiac effects of cocaine and reduced cocaine-induced elevations in serum cardiac troponin I. TV-1380 changed the metabolic fate of cocaine resulting in decreased exposure to benzoylecgonine, while increasing the exposure to ecgonine methyl ester in plasma.TV-1380 reduced the plasma levels of the toxic metabolite cocaethylene formed after co-administration of ethanol and cocaine. CONCLUSION: The results of this study demonstrate that TV-1380 not only accelerates the elimination of cocaine, but also protects the treated animal from the cardiac effects of cocaine, and inhibits the formation of the toxic cocaethylene metabolite when cocaine is given together with ethanol, supporting further clinical development of modified BChE products as possible treatments for cocaine abuse.

Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence.

BACKGROUND: TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. METHODS: Intra-muscular injections of TV-1380 (150mg or 300mg) or placebo were administered once weekly to participants (n=66-69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of "no use" confirmed by urine testing. RESULTS: Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150mg and 300mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5-12 (8.1% and 14.6% for the 150mg and 300mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p=0.0056 for 300mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. CONCLUSIONS: While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.

Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects.

Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43-77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel ) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis.