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

2. Pathways of cocaine metabolism

3. Cocaine as BChE substrate
Cocaine docked into human butyrylcholinesterase

5. 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

6. 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

7. Addict Biol 2013 Jan;18:30-39

8. 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

9. J. Clin. Psychopharmacol., 2015

10. Shram, et al., 2015

11. 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)

13. 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)

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

20. Is There A Path Forward For Cocaine-Degrading Enzymes?

21. Is There A Path Forward For Cocaine-Degrading Enzymes?

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