Studies With An Engineered Cocaine Hydrolase (TV 1380)

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Presentation transcript:

Studies With An Engineered Cocaine Hydrolase (TV 1380) Phil Skolnick, Ph.D., D.Sc. (hon.) Director, DTMC NIDA Council Presentation, September 2016

Pathways of cocaine metabolism

Cocaine as BChE substrate Cocaine docked into human butyrylcholinesterase

BChE - cocaine hydrolase A199S/F227A/S287G/A328W/Y332G 10000 CocH F227AS/S287G/A328W/Y332A 1000 A199S/S287G/A328W/Y332G cocaine kcat 100 A328W/Y332A 10 wild type BChE 1 1 2 3 4 5 (2002) (2003) (2004) (2008) Successive Mutation Generations Brimijoin, et al., Neuropsychopharmacol. 2008

TV-1380 Eliminates cocaine by hydrolysis in rats Rats were given TV-1380 (3 mg/kg) or saline, through the tail vein. Ten minutes later they received 30 µCi 3H-cocaine (3.5mg/kg), also through the tail vein. tissues were collected at 10 min (6 rats). Vehicle treated TV-1380 treated Cocaine levels Benzoic acid levels cocaine/benzoate cpm brain heart plasma heart plasma brain Brimijoin et al., 2008

Addict Biol 2013 Jan;18:30-39

TV-1380 Reduces Cocaine self-administration in Monkeys Saline Mean of 3 monkeys self-administering 30 ug/kg/inj cocaine. TV-1380 (5mg/kg, IM) was injected on day 20 and first session conducted 2 hrs thereafter. Additional 4 consecutive daily sessions. Response rate is total responses divided by session time with the timeout time excluded. C. Schindler , et al

J. Clin. Psychopharmacol., 2015

Shram, et al., 2015

Study design Study population – cocaine recreational users (males and females) Day -3 (baseline) Day 1 Day 2 (~TV1380 Cmax) Day 5 Day 8 (TV1380 dosing interval) Treatment drug; IM Cocaine (40mg; i.v.) Placebo 50mg 100mg 300mg TEVA 1380 safe and well tolerated after multiple doses…..(4)

TEVA 1380 Reduces Cocaine Cmax Following A 40 mg/kg (i.v.) Challenge Data from Shram, et al., 2015 Jenkins, et al. J. Anal. Tox. (2002)

The concentration of cocaine in blood necessary to produce positive subjective effects (in experienced smokers) is 150-200 ng/ml (Jenkins AJ, et al. J Anal Toxicol. 2002;26(7):382-392). If the enzyme can prevent cocaine from reaching those levels, the euphoric effect can be abolished or blunted

Is There A Path Forward For Cocaine-Degrading Enzymes?

Is There A Path Forward For Cocaine-Degrading Enzymes?

COMPLETE SUPPRESSION OF COCAINE-INDUCED INCREASES IN LOCOMOTOR ACTIVITY 2 MONTHS FOLLOWING GENE TRANSFER OF AN ENGINEERED MURINE BUTYRLCHOLINESTERASE (Geng, et al., 2013)