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The Open Drug Discovery Journal, 2009, 1, 1-35
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Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
Narender R. Gavva*
Department of Neuroscience, Amgen, Inc., Thousand Oaks, CA, USA
Abstract: TRPV1 antagonists have been considered as potential treatments for pain associated with inflammatory diseases and cancer. During Phase I clinical trials
with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicits marked, but reversible, and generally plasma concentration-dependent
hyperthermia. Furthermore, in a Phase Ib study, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long-lasting hyperthermia with
maximal body temperature surpassing 40 ºC, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals.
Since TRPV1 blockade elicited hyperthermia is a major hurdle, we investigated the possibility of eliminating hyperthermia while maintaining antihyperalgesia by two
approaches: i) peripheral restriction of TRPV1 antagonists, ii) characterization of TRPV1 modulators that exhibit differential pharmacology. Results from the
preclinical studies of both approaches will be discussed.
*Address correspondence to this author at the Department of Neuroscience, Amgen Inc., Thousand Oaks, CA, USA; Tel: (805)447-0607; E-mail: [email protected]
1877-3818/09
2009 Bentham Open
2 The Open Drug Discovery Journal, 2009, Volume 1
Narender R. Gavva
Presented at the 2nd annual Pain therapeutics summit, Oct 6-7, 2008, New Brunswick, NJ
Setbacks in the Clinical Development of
TRPV1 Antagonists: What Next?
Narender R. Gavva Ph.D.
Department of Neuroscience
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Outline
 Introduction
 Functional assays
 AMG 517 preclinical studies
 TRPV1 antagonism - hyperthermia
 Mechanisms of hyperthermia
 AMG 517 clinical trial results
 Peripherally restricted antagonists – hyperthermia
 Differential pharmacology of antagonists – no hyperthermia
 Conclusions
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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Narender R. Gavva
TRP channels are integrators of multiple
noxious stimuli
Dhaka et al (2006) Annu Rev Neurosci. 29:135-61
•
Narender Gavva
Agonists of TRPA1 and TRPV1 cause pain in humans and pain behavior in rodents
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
TRPV1: A polymodal detector of painful stimuli
TRPV1 Expression
in E19 Rat
TRPV1 is activated by:
White Areas Show
Expression In DRG
Neurons in Rats
•
•
•
•
•
Chemical ligands (capsaicin, RTX etc)
Heat
GPCR signaling
Phosphorylation
TRPV1
Low pH
Ca2+, Na+
Moiseenkova-Bell et al 2008
PNAS. 105:7451-5
TRPV1
positive DRG
neurons
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Rat sensory neurons
responding to capsaicin
(calcium imaging)
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TRPV1 – Target validation
TRPV1 knockout mice show reduced thermal hyperalgesia
Wt
KO
Davis et al (2000) Nature 405:183-7; Caterina et al (2000) Science, 288, 306-13
•
•
TRPV1 expression in the spinal cord is up-regulated after SCI – Zhou et al (2002) J Surg Res. 107:140-4
TRPV1 expression increased in inflamed human oesophagus – Mathews et al (2004) Eur J Gastroenterol
Hepatol.16:897-902
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Various distinct chemical scaffolds act as
TRPV1 antagonists
H
N
AMG9810
O
O
F
AMG0347
F
F
O
N
AMG2674
Cl
N
O
N
HO
Cl
N
N
H
N
O
NH
F
F
H
N
N
Gavva et al 2005 JPET, 313:474-484
F
OH
CF3
S
F
N
N
H
N
O
O
N
S
N
O
JYL1421 (SC0030)
F
F
O
N
O
SB-705498
N
N
O
HN
N
S
N
N
HO
CF3
H
N
Cl
N
O
Br
Narender Gavva
N
BCTC
N
AMG 517
Doherty et al., 2007 JMC 50:3515-27
Gavva et al., 2007 JPET 323:128-137
NH
N
F
O
NVS Pyridopyrimidine
F
F
F
ABT-102
Pain Therapeutics Summit – Oct 7th 2008
AMG8562
N
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Narender R. Gavva
Strategy for SAR development
H
N
O
O

High-throughput screening of our corporate
database identified several N-aryl cinnamides
as TRPV1 antagonists

Constrained analogs of s-cis cinnamides
provided an entry into a novel chemical series
of TRPV1 antagonists

Further optimization lead to the clinical
candidate AMG 517
O
rTRPV1 (Cap) IC50 = 79 nM
rTRPV1 (pH) IC50 = 350 nM
H
N
N
O
N
O
rTRPV1 (Cap) IC50 = 120 nM
rTRPV1 (pH) IC50 = 680 nM
NHAc
F3C
N
O
N
S
N
rTRPV1 (Cap) IC50 = 0.9 nM
rTRPV1 (pH) IC50 = 0.5 nM
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
AMG 517 blocks all modes of TRPV1 activation


AMG 517 is a potent antagonist of rodent, dog, monkey and human TRPV1
AMG 517 does not block TRPA1, TRPV2, TRPV3, TRPV4, and TRPM8
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517: Pharmacokinetic profile
Intravenous dosing
Oral dosing
Species
AUC0-inf
(ng.hr/mL)
Rat
8800
120
4000
31
51
Dog
7400
140
7000
41
23
Monkey
37000
30
2300
62
52
50
4500
60-120
CL
(mL/hr/kg)
Human
(projected)
Vss
(mL/kg)
t1/2
(h)
F (%)
250
Dog
Rat
Monkey
 Good Oral Bioavailability
 Low Clearance
 Long Half-life
 Linear PK (1-10 mg/kg)
Mean AUC 0-inf (µg*h/ml)
200
150
100
50
0
0
Narender Gavva
1
2
3
Pain Therapeutics Summit – Oct 7th 2008
4
5
6
Dose (mg/kg)
7
8
9
10
11
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
AMG 517 blocks capsaicin-induced
flinching in rats
Dose
AMG 517 p.o.
60 min
Inject Capsaicin
Into the Paw
Count # of
Paw Flinches
in 1 min
Narender Gavva
Gavva et al., 2007 JPET 323:128-137
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517 blocks inflammation-induced
thermal hyperalgesia
Inject CFA
into the paw
Dose
AMG 517, p.o.
2h
50
Plasma levels
AMG 517
10000
** **
**
40
1000
**
30
20
100
10
0
0.01
0.1
1
10
AMG 517 (mg/kg, p.o.)
Record thermal
sensitivity
Narender Gavva
Gavva et al., 2007 JPET 323:128-137
Pain Therapeutics Summit – Oct 7th 2008
10
100
Concentration (ng/ml)
22 h
% inhibition of thermal
hyperalgesia
60
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
TRPV1 antagonists block capsaicin-induced
hypothermia and cause hyperthermia by themselves
•
On-target challenge model
•
•
Capsaicin, a TRPV1 agonist produces an “on-target” decrease in body temperature
Pretreatment with a TRPV1 antagonist should block capsaicin-induced hypothermia
Vehicle/Vehicle
Vehicle/Capsaicin
AMG9810/Vehicle
AMG9810/Capsaicin
vehicle or capsaicin
40
40
Vehicle or
AMG9810
39
Temperature ( C)
Temperature ( C)
vehicle or AM G9810
38
37
36
35
39
38
37
36
34
-30 -20 -10 0 10 20 30 40 50 60 70 80 90 100
-30 -20 -10 0 10 20 30 40 50 60 70 80 90 100
Time (min)
Time (min)
Gavva et al., J Neurosci. 2007 Mar 28;27(13):3366-3374
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517 causes hyperthermia in
multiple species
Rat radiotelemetry
Cynomolgus monkeys
AMG 517 (0.3 mg/kg)
AMG 517 (1 mg/kg)
40
AMG 517 (3 mg/kg)
Vehicle
Temperature (  C)
Temperature (C)
39
38
37
baseline
39
38
37
Treatme nt
Veh or AMG 517
36
30 mg/kg AM G 517 (n = 3)
10 mg/kg AM G 517 (n = 3)
Vehicle (n = 6)
36
10 20 30 40 50 60 70
0
Time (min)
3
6
9
12
15
18
21
Time (hr)
Gavva et al., JPET 2007 323:128-137

TRPV1 antagonists caused hyperthermia in rodents, dogs, monkeys
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Agonists and antagonists do not cause body
temperature changes in TRPV1 knockout mice
Agonist-induced hypothermia
Antagonist-induced hyperthermia
Steiner et al., J Neurosci. 2007 Jul 11;27(28):7459-68

Agonist-induced hypothermia & antagonist-induced hyperthermia are
entirely TRPV1 mediated
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517 causes hyperthermia by
vasoconstriction and increased thermogenesis
Individual effectors
Skin vasomotor tone
Nonshivering
thermogenesis
Shivering
Gavva et al., 2008 Pain 136:202-210
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Antipyretic acetaminophen suppresses TRPV1
antagonist-induced hyperthermia
Rat radiotelemetry
Veh/Veh (n=7)
Veh/Acet (n=8)
Temperature (C)
39
AMG8163/Veh (n=7)
AMG8163/Acet (n=8)
38
37
36
0
30
60
90
120 150 180 210 240 270
Time (min)


Narender Gavva
Gavva et al., JPET 2007 323:128-137
AMG8163 is a ‘boc’ analogue of AMG 517
Similar to AMG 517, AMG8163 blocks all modes of TRPV1 activation
Pain Therapeutics Summit – Oct 7th 2008
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Narender R. Gavva
Repeated administration of AMG 517 attenuates
hyperthermia
Monkey radiotelemetry
3 9.0
0 mg/ kg /day
3 0 mg /k g/day
AMG 517
3 8.5
3 8.0
3 7.5
3 7.0
B d T
3 6.5
3 6.0
t
(C)


0
6
12
18
24
30
36
42
48
54
60
66
72
T im e P o st-Do se (h ou rs)
Trea tm en t a t 0, 24 , 4 8, an d 7 2 h ou rs
TRPV1 is tonically activated and plays a role in body temperature regulation
Role of TRPV1 in thermoregulation can be compensated
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Clinical trial design
 Vehicle of all studies: A suspension in a 100 ml of 2% Pluronic 108 in OraPlus®
followed by two 75 ml water washes
 1st Phase I – single dose safety & pharmacokinetic study
– Double-blind, placebo-controlled, randomized, single dose, dose-escalation
sequential cohort study
– Healthy subjects received 1, 2, 5, 10, 20, or 25 mg AMG 517
– End points: number and incidence of treatment emergent-events, oral and
tympanic body temperature measurements
 2nd Phase I – Repeated dose study
– Double-blind, placebo-controlled, randomized, single dose, dose-escalation
sequential cohort study
– Placebo, 2, 5, or 10 mg of AMG 517
– treatment emergent-events, difference in max body temperature on day 1 versus
subsequent days, through day 7
 Phase Ib – Dental pain study
– Double-blind, placebo-controlled, randomized, Parallel group, multi-center study
– Inclusion criteria: moderate to severe post-operative pain
– Single doses of placebo, 2, 8, or 15 mg of AMG 517
More details can be found in: Gavva et al., 2008 Pain 136:202-210
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517 has a long half-life in healthy subjects
1000
1 mg (n=6)
2 mg (n=6)
5 mg (n=6)
10 mg (n=6)
20 mg (n=8)
25 mg (n=7)
100
10
1
2
0
8
4
93
6
10
08
10
80
11
52
12
24
12
96
13
68
86
79
72
4
2
0
8
6
6
64
57
50
43
36
28
21
14
4
0.1
0
72
Plasma AMG 517 Concentration (ng/mL)
Plasma concentration versus time
Time (h)

Plasma half life: ~ 300 hrs
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Gavva et al., 2008 Pain 136:202-210
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
AMG 517 elicits transient hyperthermia in
humans
Body temperature & Cmax versus time
38.4
AMG 517 Concentration
Temperature
38.0
100
37.6
37.2
10
36.8
1
Temperature (°C, Tympanic)
AMG 517 Concentration (ng/mL)
1000
36.4
0.1
36.0
0
4
8
12
16
20
24
Time (hr) Post-dose
(mean + SD of the max body temperature [tympanic] presented)
Gavva et al., 2008 Pain 136:202-210
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517 caused plasma concentrationdependent hyperthermia in healthy subjects
Body temperature versus Cmax
Maximum body temperature (°C)
40
Placebo (n=12)*
1 mg (n=6)
2 m g (n=6)
5 mg (n=6)
10 mg (n=6)
25 mg (n=7)
20 mg (n=8)
39
38
37
0
50
100
150
200
250
300
350
Cmax
(ng/mL)
Gavva et al., 2008 Pain 136:202-210


Single dose, oral suspension in a 100 mL of 2% Pluronic 108 in OraPlus®
Plasma half life of AMG 517 in humans: ~ 300 hrs
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Trend of hyperthermia attenuation after
repeated administration of AMG 517
Body temperature versus time
o
Maximum Tympanic Temperature (Mean + SE, C)
39
Placebo (N=7)
AMG 517 2mg (N=12)
AMG517 5mg (N=6)
AMG517 10mg (N=6)
38
37
36
-1
1
2
3
4
5
6
7
Study Day
(mean + SD of the max body temperature [tympanic] presented)
Gavva et al., 2008 Pain 136:202-210
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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AMG 517 caused marked hyperthermia in
subjects who underwent molar extraction
Molar extraction subjects
40
o
Temperature ( C)
41
39
38
37
36

placebo
2mg
8mg
15mg
AMG 517
TRPV1 antagonists causing hyperthermia in rodents, dogs, monkeys, and
humans indicates an evolutionarily conserved role of TRPV1 in thermoregulation
Gavva et al., 2008 Pain 136:202-210
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
First approach to address hyperthermia:
Peripheral restriction of antagonists
Hypothesis
 Thermoregulation is CNS mediated
 Can we minimize hyperthermia by restricting antagonists to the
periphery?
Strategy
 Reduce brain exposure: peripherally restricted TRPV1 antagonists
• Increase polar surface area (PSA)
• Decrease logP
• Increase number of hydrogen-bond donors
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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Profiles of peripherally restricted TRPV1
antagonists
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Effect of AMG13731 and AMG21629 on
rat body core temperature
AMG13731 (10 mg/kg)
AMG13731 (3 mg/kg)
Vehicle
40
Temperature (C)
Temperature (C)
40
39
38
37
36
Vehicle or drugs, p.o.
-30
0
30
90
120
Vehicle
39
38
37
36
60
AMG21629 (3mg/kg)
Vehicle or drugs, p.o.
-30
0
30
90
120
Time (min)
Time (min)
NH2
F 3C
N
N
O
NH N
N
NH2
S
F3 C
N
AMG13731
O
N
N
O
NH
AMG21629
HN
F
NHSO2Me
Tamayo et al 2008 J Med Chem. 51:2744-57

60
OMe
Site of action for TRPV1 antagonist-induced hyperthermia is outside the BBB
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Evaluation of compounds exhibiting differential
pharmacology - 2nd Approach
Profile A
Profile B
Profile C
Profile D

Narender Gavva
Capsaicin
pH 5
Heat
Block
Block
Block
Block
Partial block
Block
Block
Potentiate
No effect
Block
Potentiate
Potentiate
Profiles defined by agonist-induced
45Ca2+
Pain Therapeutics Summit – Oct 7th 2008
Body
temp
uptake assays
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
AMG8562, a profile C compound that does
not cause hyperthermia in rats
In vitro data
Rat radiotelemetry
25
0
-11 -10 -9 -8 -7 -6
AMG8562 [log M]
150
-5
75
50
25
0
-11 -10 -9 -8 -7 -6
AMG8562 [log M]
Heat
125
-5
0
Vehicle
or compound
Veh
or AMG8562
p.o. p.o.
-5
Lehto et al 2008 JPET 326:218-229
Narender Gavva
30 mg/kg (n=6)
37
25
0
-11 -10 -9 -8 -7 -6
AMG8562 [log M]
1 mg/kg (n=6)
38
36
50
10 mg/kg (n=6)
3 mg/kg (n=6)
100
75
Vehicle (n=6)
Pain Therapeutics Summit – Oct 7th 2008
90
12
0
15
0
18
0
21
0
24
0
27
0
50
39
150
125
100
60
75
pH 5
30
100
200
175
Temperature (  C)
% max 45Ca2+ uptake
Capsaicin
% max 45Ca2+ uptake
% max 45Ca2+ uptake
125
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Narender R. Gavva
AMG8562 is modestly effective in
capsaicin-challenge and pain models
Capsaicin-induced flinch
CFA-induced thermal hyperalgesia
Latency (sec)
Number of flinches
1
**
** **
10
100
AMG8562 (mg/kg, p.o.)
0.1
1000
8
*
6
**
100
10
4
1
2
0
0.1
30
100
AMG8562 (mg/kg, p.o.)
Acetic acid-induced writhing
Number of writhes
50
10000
40
1000
30
*
20
*
100
10
10
10
30
100
AMG8562 (mg/kg, p.o.)
Pain Therapeutics Summit – Oct 7th 2008
Ibuprofen
1
vehicle
0
Plasma concentration (ng/ml)
Number of writhes
Plasma concentration (ng/ml)
Narender Gavva
*
AMG8163
0.1
1
AMG8163
**
10
Vehicle
10
10000
Pre-CFA
100
*
Latency (sec)
1000
Vehicle
Total flinches in 1 min
10000
12
Plasma concentration (ng/ml)
14
12
10
8
6
4
2
0
Plasma concentration (ng/ml)
Plasma concentration (ng/ml)
Plasma concentration (ng/ml)
Lehto et al 2008 JPET 326:218-229
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
AMG8562, exhibits profile B modulation of
human TRPV1
pH 5 activation
100
80
60
40
20
0
-10
-9
-8
-7
AMG8562 [log M]
-6
Heat activation
125
% max 45Ca2+ uptake
% max 45Ca2+ uptake
% max 45Ca2+ uptake
Capsaicin activation
100
75
50
25
0
-10
-9
-8
-7
AMG8562 [log M]
-6
100
80
60
40
20
0
-10
-9
-8
-7
AMG8562 [log M]
Lehto et al 2008 JPET 326:218-229

Profile B modulators cause hyperthermia in rats
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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Narender R. Gavva
Current status of TRPV1 antagonists in the clinic
Compound
name
Company
Route of
Indication
administration
Stage
Current
status
ABT-102
Abbott
Oral
Phase I
Initiated ?
AMG 517
Amgen
Oral
Dental pain
Phase Ib
Terminated
AZD1386
AstraZeneca
Oral
Dental pain
Phase II
Completed
GRC 6211
Lilly/Glenmark
Oral
Dental pain
Phase II
Suspended
JTS-653
Japan Tobacco
Oral
Overactive
bladder
pain
Phase I
On going
MK 2295
Merck/Neurogen
Oral
Dental pain
Phase II
Completed
SB-705498
GSK
Oral
Migraine
Phase II
Terminated
Rectal pain
Phase II
Terminated
Dental pain
Phase II
Completed
unknown
unknown
unknown
PF-4065463
Narender Gavva
Evotec/Pfizer
unknown
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
Conclusions
•

Genetic and pharmacological evidence suggests that TRPV1 contributes to
hyperalgesia
TRPV1 antagonists block capsaicin-induced flinch (on-target challenge)
and act as anti-hyperalgesics
•
AMG 517, a selective TRPV1 antagonist caused plasma concentration
dependent hyperthermia in humans
•
Antagonist-induced hyperthermia showed a complete and clear attenuation
after repeated dosing in preclinical species but not in humans
•
Mechanisms of hyperthermia include antagonist-induced vasoconstriction
and increased thermogenesis
•
Peripherally restricted TRPV1 antagonists caused hyperthermia
•
Profile C modulators of TRPV1 did not cause hyperthermia and
demonstrated modest efficacy in pain models
•
Clinical trial results of other TRPV1 antagonists are eagerly awaited
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
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Narender R. Gavva
Outstanding questions and next steps
Preclinical
•
‘Profile C’ modulators of both rodent and human TRPV1
•
Efficacy after repeated dosing of TRPV1 antagonists
•
TRPV1 function in non-pathophysiological states (e.g.,
thermosensation)
Clinical
•
Development by different routes of administration (e.g., topical
application)
•
Development of short half-life antagonists
•
Development of antipyretic + TRPV1 antagonist combination
•
Development of TRPV1 antagonists in primary indications
(e.g., Osteoarthritis)
Narender Gavva
Pain Therapeutics Summit – Oct 7th 2008
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
The Open Drug Discovery Journal, 2009, Volume 1
35
The Team
Departments
Neuroscience
Chemistry
Process Chemistry
TRPV1 Core Team
Neuroscience
PKDM
Modeling
E-phys
Sample Bank
Regulatory Affairs
Toxicology
Pharmaceutics
Clinical
Analytical
Legal
Project Management
Marketing
Leyla Arik
Anthony Bannon
James Davis
Narender Gavva
Charles Henley
Gal Hever
Rongzhen Kuang
David Immke
Sonya Lehto
Lana Klionsky
Ella Magal
Licheng Shi
Rami Tamir
Jue Wang
Judy Wang
Weiya Wang
Gary Zajic
Dawn Zhu
Yunxin Bo
Ning Chen
Balan Chenera
Darin D’Amico
Liz Doherty
Lillian Liao
Mark Norman
Nobuko Nishimura
Vassil Ognyanov
Dan Retz
Mark Stec
Nuria Tamayo
Phi Tang
Kevin Yang
Charles Bernard
Chris Borths
Tracy Bostick
Margaret Faul
Andrew Hague
Tony King
Bobby Raihi
Thomas Storz
Jason Tedrow
Oliver Thiel
Narender Gavva
Christopher Banfield
Anthony Bannon
Gudarz Davar
Celia Dominguez
Margaret Faul
Anu Gore
David Hovland
Pat Kesslak
Sonya Lehto
Jean-Claude Louis
Mark Norman
Sekhar Surapaneni
James Treanor
Collaborators
Andrej Romanovsky, Andras Garami
St. Joseph's Hospital and Medical Center, Phoenix, AZ
Frank Porreca, Todd Vanderah
University of Arizona, Tucson, AZ
Narender Gavva
Received: January 28, 2009
Pain Therapeutics Summit – Oct 7th 2008
Accepted: January 29, 2009
© Narender R. Gavva; Licensee Bentham Open.
This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: //creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, noncommercial use, distribution and reproduction in any medium, provided the work is properly cited.