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
Mean TV-1380 Concentration (ng/mL)
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
Figure 14.2.1.7.1.2 : Arithmetic Mean Time Course of Serum TV-1380 Concentration (ng/mL) on Day 1
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
Mean TV-1380 Concentration (ng/mL)
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
Figure 14.2.1.7.1.2 : Arithmetic Mean Time Course of Serum TV-1380 Concentration (ng/mL) on Day 1
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
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
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 14.2.1.1.1.4 : Arithmetic Mean Time Course of Plasma Cocaine Concentration (ng/mL) on Day 2
Cocaine 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
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
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 14.2.1.1.1.6 : Arithmetic Mean Time Course of Plasma Cocaine Concentration (ng/mL) on Day 5
Cocaine 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
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
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 14.2.1.1.1.8 : Arithmetic Mean Time Course of Plasma Cocaine Concentration (ng/mL) on Day 8
Cocaine 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
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
Mean Cocaine Concentration (ng/mL)
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.
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
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.