Crossing the Rubicon: NIDA/Pharma Collaboration

Crossing the Rubicon: NIDA/Industry Partnerships

Phil Skolnick, Ph.D., D.Sc. (hon.)

Director, DPMCDA

NIDA/Industry (esp. Big Pharma) Collaboration Is A Relatively Recent Phenomenon

Why now?

• Retreat from psychiatric drug development – most potential candidates to treat SUDs are repurposed from psychiatry portfolios (few bespoke SUD programs).

C&E News, March, 2012

An Increased Level Of Interest In Collaboration Is A Relatively Recent Phenomenon

Why now?

• Retreat from psychiatric drug development – most potential candidates to treat SUDs are from a psychiatry portfolio (few bespoke SUD programs).

• SUDs now represent a “rescue” indication for these molecules.

• Data demonstrating the market potential of medications to treat SUDs.

Why Has The Pharma/Biotech Sector Remained (Largely) Indifferent To SUDs?

•Perceived small market size (ROI) •Regulatory hurdle: current focus on abstinence (as opposed to reduced use)

•A fractured advocacy message (meds vs no meds and views in between)

•Corporate image and liability issues

•Uncertainty about reimbursement

Source: Drugs.com, citing use of the IMS Health “Multinational Integrated Data Analysis System” (MIDAS)

U.S. Suboxone® Sales Reached $1.49 Billion in 2012— More Than Viagra® or Adderall ®

U.S. Retail Sales of

Suboxone®

$1.50 B

$1.00 B

$500 M

$1.25 B

$250 M

$750 M

Source: U.S. Substance Abuse and Mental Health Services Administration

“2011 National Survey on Drug Use & Health” ~ 67,500 randomly selected individuals

2011 U.S. Estimates of Current (past month) Drug Use

Use During

Past Month

Methamphetamine 439,000

Heroin 281,000

Cocaine 1.4 Million

Marijuana 18.1 Million

Rx Pain Relievers (nonmedical use) 4.5 Million

Rough Estimate of U.S. Market for a

First-in-Class Cocaine Addiction Treatment

1.4 M regular users

If 20% seek treatment each year,

then market = 280,000/year

If average treatment duration is 6 months &

the medication costs $700/mo, then sales

>$1 BB per year

C OO

CH3

O

C

CH3 N

O

O

N

C

O

CH3

OOC

C OO

CH3

O

CCH3 N

O

NCH3

C

O

OC

H H C OO

CH3

N

buty ry lcholinesterase

buty ry lcholinesterase

HO

OH

OH

HOC

O

(-)-Norcocaine

5%

(-)-Cocaine(-)-Ecgonine methy l ester

~45%

(-)-Benzoy lecgonine

~45%

Benzoic acid

Benzoic acid

(-)-Norecgonine methy l ester

~5%

+

HO

+ CH3OH

Methanol

N-d

em

eth

ylase

liv er

carboxy lesterase

+

Pathways of cocaine metabolism

Cocaine docked into human butyrylcholinesterase

Cocaine as BChE substrate

1

10

100

1000

10000

1

Successive Mutation Generations

wild type BChE

A328W/Y332A

3 2 4

cocain

e k

ca

t

(2003)

BChE - cocaine hydrolase

5

A199S/S287G/A328W/Y332G

(2004) (2008) (2002)

F227AS/S287G/A328W/Y332A

A199S/F227A/S287G/A328W/Y332G

CocH

Brimijoin, et al., Neuropsychopharmacol. 2008

0

500

1000

1500

2000

2500

3000

3500

4000

brain heart plasma brain heart plasma

Cocaine levels

coca

ine/

ben

zoat

e cp

m

TV-1380 Eliminates cocaine by hydrolysis in rats

Vehicle treated

TV-1380 treated

Benzoic acid levels

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).

Brimijoin et al., 2008

S D SSD D

Lever

Pre

ssin

g

acquisition maintenance extinction reinstatement

elapsed time (weeks)

1 2 3 4 5

Cocaine 1st time

Cocaine stop

Cocaine 2nd time

Effects of An Engineered Esterase In A Rat Relapse Model

TV-1380 Eliminates Responding Following Re-exposure to Cocaine

leve

r p

ress

er

resp

on

ses

From: Dr. Merav Bassan, TEVA

Addict Biol 2013 Jan;18:30-39

Serum TV-1380 Concentrations over Time

Mean TV-1380 Concentration (ng/mL)

0

1000

2000

3000

4000

5000

Hours Post-TV-1380 Administration

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240

Figure 14.2.1.7.1.1 : Arithmetic Mean Time Course of Serum TV-1380 Concentration (ng/mL) on Day 1

TV-1380 PK Population, Y Axis Scale = Linear

Note: BLQ concentrations were replaced by half of LLOQ value 134 for summary calculations.

2: TV-1380 50 mg 3: TV-1380 100 mg

4: TV-1380 300 mg

2 2 2 3 3 3

4 4 4

2222

22222 2 2

22

2 22 2 2 2 233

3

3

33

3333

3

3

3

33

3 3 3 3 344

4

4

4

4

444 4 4

4

4

4

4

4

44

4 4


10

100

1000

10000

Hours Since Hours Post-TV-1380 Administration

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240


Cocaine PK Population, Y Axis Scale = Log

2: TV-1380 50 mg 3: TV-1380 100 mg

4: TV-1380 300 mg

2 2 2 3 3 3

4 4 4

22

2

2

22222 2 2

2

2

22

2

2 2

2 23

3

3

3

33

333 3 33

3

3

3

33

3 3

3

4

4

4

4

44444 4 4 4

44

4

44

44

4


10

100

1000

10000

Hours Since Hours Post-TV-1380 Administration

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240



2: TV-1380 50 mg 3: TV-1380 100 mg

4: TV-1380 300 mg

2 2 2 3 3 3

4 4 4

22

2

2

22222 2 2

2

2

22

2

2 2

2 23

3

3

3

33

333 3 33

3

3

3

33

3 3

3

4

4

4

4

44444 4 4 4

44

4

44

44

4

Hours

Mea

n T

V-1

38

0 C

on

cen

trat

ion

(n

g/m

L)

© 2012 Teva Pharmaceutical Industries Ltd.

Opinions or conclusions expressed by Dr. Skolnick in connection with

this presentation, a final draft of which has not been reviewed by Teva

Pharmaceutical Industries Ltd. do not necessarily reflect the views of the

company.

Time course of plasma cocaine concentration (40 mg/kg, i.v.)

Mean Cocaine Concentration (ng/mL)

0.1

1.0

10.0

100.0

1000.0

Hours Since Hours Since Infusion

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Figure 14.2.1.1.1.2 : Arithmetic Mean Time Course of Plasma Cocaine Concentration (ng/mL) on Day -3Cocaine PK Population, Y Axis Scale = Log

1: Placebo 2: TV-1380 50 mg

3: TV-1380 100 mg 4: TV-1380 300 mg

1 1 1 2 2 2

3 3 3 4 4 4

1

1111111

11

1

1

1

1

12

2222222

22

2

2

2

2

23

3333333

33

3

3

3

3

34

444444444

44

4

4

4


0.1

1.0

10.0

100.0

1000.0


0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Figure 14.2.1.1.1.4 : Arithmetic Mean Time Course of Plasma Cocaine Concentration (ng/mL) on Day 2



3: TV-1380 100 mg 4: TV-1380 300 mg

1 1 1 2 2 2

3 3 3 4 4 4

1

1

111111

1

1

1

1

1

1

12

2222

2

22

2

2

2

2

2

2 23

33

33

3

3

3

3

3

3 3

3 3 34

44

44

4

44

44

4 4 4 4 4


0.1

1.0

10.0

100.0

1000.0


0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24




3: TV-1380 100 mg 4: TV-1380 300 mg

1 1 1 2 2 2

3 3 3 4 4 4

1

1111

111

11

11

1

1

12

22

222

22

2

2

2

2

2 2 23

3333

3

3

3

3

3

3

33

3 34

444

4

4

4

4

4

4 4 4 4 4 4 Mean Cocaine Concentration (ng/mL)

0.1

1.0

10.0

100.0

1000.0


0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24




3: TV-1380 100 mg 4: TV-1380 300 mg

1 1 1 2 2 2

3 3 3 4 4 4

1

1

111111

11

1

1

1

1

12

2

2222

22

2

2

2

2

2

2 23

3

333

3

33

3

3

3

3

3

3 34

4444

4

4

4

4

4

4

4 4 4 4


0

100

200

300

Hours Since Infusion

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Figure 14.2.1.1.1.1 : Arithmetic Mean Time Course of Plasma Cocaine Concentration (ng/mL) on Day -3Cocaine PK Population, Y Axis Scale = Linear

Note: BLQ concentrations were replaced by half of LLOQ value 1 for summary calculations.


3: TV-1380 100 mg 4: TV-1380 300 mg

1 1 1 2 2 2

3 3 3 4 4 4

1

1

11

1

1

1

1

1

1

11

1 1 12

2

22

2

2

2

2

2

2

22

2 2 23

33

3

3

3

3

3

3

3

33

3 3 34

4

44

4

4

4

4

44

44

4 4 4

Me

an C

oca

ine

Co

nce

ntr

atio

n (

ng/

mL)

hours(post Cocaine infusion)

Day -3 (baseline)

Day 8 Day 5

Day 2 (Cmax)

© 2012 Teva Pharmaceutical Industries Ltd.

Opinions or conclusions expressed by Dr. Skolnick in connection with

this presentation, a final draft of which has not been reviewed by Teva

Pharmaceutical Industries Ltd. do not necessarily reflect the views of the

company.

Crossing the Rubicon: NIDA/Pharma Collaboration

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