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The Open Drug Discovery Journal, 2009, 1, 1-35 1
1877-3818/09 2009 Bentham Open
Open Access
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]
2 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next?
Presented at the 2nd annual Pain therapeutics summit, Oct 6-7, 2008, New Brunswick, NJ
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 3
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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
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TRP channels are integrators of multiple noxious stimuli
Dhaka et al (2006) Annu Rev Neurosci. 29:135-61
• Agonists of TRPA1 and TRPV1 cause pain in humans and pain behavior in rodents
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TRPV1Ca2+, Na+
TRPV1: A polymodal detector of painful stimuli
Rat sensory neurons responding to capsaicin (calcium imaging)
TRPV1 is activated by:• Chemical ligands (capsaicin, RTX etc)• Heat• GPCR signaling • Phosphorylation• Low pH
White Areas Show Expression In DRG Neurons in Rats
TRPV1 positive DRG neurons
TRPV1 Expressionin E19 Rat
Moiseenkova-Bell et al 2008 PNAS. 105:7451-5
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TRPV1 – Target validation
• 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
TRPV1 knockout mice show reduced thermal hyperalgesia
Davis et al (2000) Nature 405:183-7; Caterina et al (2000) Science, 288, 306-13
WtKO
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 7
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Various distinct chemical scaffolds act as TRPV1 antagonists
F
FF
N
O
N
SN
HNOAMG 517
HN
OO
O
NO
NH
N N
Cl
AMG9810
BCTC
N NH
NH
O
O
Cl
NVS Pyridopyrimidine
N
NH
NNNHO
Cl
CF3
FF
F
AMG2674N
N O
HN
OH
F
FF
AMG0347
N N
N
F
S
S
O
O
JYL1421 (SC0030)
SB-705498
Gavva et al., 2007 JPET 323:128-137Doherty et al., 2007 JMC 50:3515-27
ABT-102
Gavva et al 2005 JPET, 313:474-484
HN
CF3
NO
HO
F
F F
N N
NN
O
Br AMG8562
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Strategy for SAR development
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
HN
O
O
HN
O
O
N N
F3C
O
N N
SN
NHAc
rTRPV1 (Cap) IC50 = 79 nMrTRPV1 (pH) IC50 = 350 nM
rTRPV1 (Cap) IC50 = 120 nMrTRPV1 (pH) IC50 = 680 nM
rTRPV1 (Cap) IC50 = 0.9 nMrTRPV1 (pH) IC50 = 0.5 nM
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 9
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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
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AMG 517: Pharmacokinetic profile
Intravenous dosing Oral dosing
Species AUC0-inf
(ng.hr/mL) CL
(mL/hr/kg) Vss
(mL/kg) t1/2 (h) F (%)
Rat 8800 120 4000 31 51
Good Oral Bioavailability *h/m
l)
200
250DogRatMonkey
Rat 8800 120 4000 31 51
Dog 7400 140 7000 41 23
Monkey 37000 30 2300 62 52
Human (projected) 50 4500 60-120
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Good Oral Bioavailability Low Clearance Long Half-life Linear PK (1-10 mg/kg)
Dose (mg/kg)
0 1 2 3 4 5 6 7 8 9 10 11
Mea
n A
UC
0-in
f (µg
*
0
50
100
150
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 11
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AMG 517 blocks capsaicin-induced flinching in rats
Count # ofPaw Flinches
in 1 min
DoseAMG 517 p.o.
Inject CapsaicinInto the Paw
60 min
Gavva et al., 2007 JPET 323:128-137
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AMG 517 blocks inflammation-induced thermal hyperalgesia
DoseAMG 517, p.o.
Inject CFAinto the paw
Record thermal sensitivity
22 h
2 h 0.01 0.1 1 10 100
0
10
20
30
40
50
60AMG 517Plasma levels
10
100
1000
10000
****
** **
AMG 517 (mg/kg, p.o.)
% in
hibi
tion
of th
erm
alhy
pera
lges
ia
Concentration (ng/m
l)
Gavva et al., 2007 JPET 323:128-137
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 13
• On-target challenge model• Capsaicin, a TRPV1 agonist produces an “on-target” decrease in body temperature
P i h TRPV1 i h ld bl k i i i d d h h i
TRPV1 antagonists block capsaicin-induced hypothermia and cause hyperthermia by themselves
• Pretreatment with a TRPV1 antagonist should block capsaicin-induced hypothermia
38
39
40
Vehicle/VehicleVehicle/Capsaicin
AMG9810/VehicleAMG9810/Capsaicin
vehicle or AMG9810
vehicle or capsaicin
ure
( C
)
39
40 Vehicle orAMG9810
ure
( C
)
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
-30 -20 -10 0 10 20 30 40 50 60 70 80 90 10034
35
36
37
Time (min)
Tem
pera
tu
-30 -20 -10 0 10 20 30 40 50 60 70 80 90 10036
37
38
Time (min)
Tem
pera
tu
Gavva et al., J Neurosci. 2007 Mar 28;27(13):3366-3374
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AMG 517 causes hyperthermia in multiple species
30 mg/kg AMG 517 (n = 3)
Cynomolgus monkeysAMG 517 (0.3 mg/kg)
Rat radiotelemetry
0 3 6 9 12 15 18 21 2436
37
38
39
40 10 mg/kg AMG 517 (n = 3)30 mg/kg AMG 517 (n = 3)
Vehicle (n = 6)
Treatment
Tem
pera
ture
( C
)36
37
38
39Vehicle
AMG 517 (1 mg/kg)AMG 517 (3 mg/kg)
Tem
pera
ture
( C
)
Veh or AMG 517
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0 3 6 9 12 15 18 21 24Time (hr)
Gavva et al., JPET 2007 323:128-137
TRPV1 antagonists caused hyperthermia in rodents, dogs, monkeys
10 20 30 40 50 60 7036
baseline Time (min)
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 15
Agonists and antagonists do not cause body temperature changes in TRPV1 knockout mice
Agonist-induced hypothermia Antagonist-induced hyperthermia
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Agonist-induced hypothermia & antagonist-induced hyperthermia are entirely TRPV1 mediated
Steiner et al., J Neurosci. 2007 Jul 11;27(28):7459-68
16 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
AMG 517 causes hyperthermia by vasoconstriction and increased thermogenesis
Skin vasomotor toneIndividual effectors
Nonshivering thermogenesis
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Shivering
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 17
Antipyretic acetaminophen suppresses TRPV1 antagonist-induced hyperthermia
39Veh/Veh (n=7) AMG8163/Veh (n=7)
AMG8163/A t ( 8)
Rat radiotelemetry
36
37
38
39 AMG8163/Acet (n=8)Veh/Acet (n=8)
Tem
pera
ture
(C
)
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0 30 60 90 120 150 180 210 240 27036
Time (min) 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
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Repeated administration of AMG 517 attenuates hyperthermiaMonkey radiotelemetry
3 9.0 0 mg/kg /day 3 0 mg /kg/day AMG 517
Bd
T
3 6.0
3 6.5
3 7.0
3 7.5
3 8.0
3 8.5
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TRPV1 is tonically activated and plays a role in body temperature regulation Role of TRPV1 in thermoregulation can be compensated
T ime Post-Dose (hou rs)Trea tm en t a t 0, 24 , 48, and 72 hou rs
0 6 12 1 8 2 4 3 0 36 42 48 54 60 66 72t(C
)
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 19
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 studyDouble blind placebo controlled randomized single dose dose escalation– 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
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
– 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
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AMG 517 has a long half-life in healthy subjects
/mL) 1000
1 mg (n=6)
Plasma concentration versus timeA
MG
517
Con
cent
ratio
n (n
g/
1
10
100
g ( ) 2 mg (n=6) 5 mg (n=6) 10 mg (n=6) 20 mg (n=8) 25 mg (n=7)
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Gavva et al., 2008 Pain 136:202-210
Time (h)
0 72 144
216
288
360
432
504
576
648
720
792
864
936
1008
1080
1152
1224
1296
1368
Plas
ma
A
0.1
Plasma half life: ~ 300 hrs
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 21
AMG 517 elicits transient hyperthermia in humans
1000 38.4
AMG 517 Concentration
Body temperature & Cmax versus timeA M
G 5
17 C
once
ntra
tion
(ng/
mL)
1
10
100
Tem
pera
ture
(°C
, Tym
pani
c)
36 4
36.8
37.2
37.6
38.0Temperature
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Time (hr) Post-dose
0 4 8 12 16 20 24
A
0.1 36.0
36.4
(mean + SD of the max body temperature [tympanic] presented)
Gavva et al., 2008 Pain 136:202-210
22 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
AMG 517 caused plasma concentration-dependent hyperthermia in healthy subjects
C)
40Placebo (n=12)*1 mg (n=6)2 mg (n=6)
Body temperature versus Cmax
Max
imum
bod
y te
mpe
ratu
re (°
C
37
38
39
g ( )5 mg (n=6)10 mg (n=6)25 mg (n=7)20 mg (n=8)
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Single dose, oral suspension in a 100 mL of 2% Pluronic 108 in OraPlus® Plasma half life of AMG 517 in humans: ~ 300 hrs
Cmax
(ng/mL)
0 50 100 150 200 250 300 350
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 23
Trend of hyperthermia attenuation afterrepeated administration of AMG 517
E, o C
)39
Placebo (N=7)AMG 517 2mg (N=12)
Body temperature versus timeum
Tym
pani
c Te
mpe
ratu
re (M
ean
+ SE
37
38
AMG 517 2mg (N 12)AMG517 5mg (N=6)AMG517 10mg (N=6)
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Study Day
Max
imu
36-1 1 2 3 4 5 6 7
(mean + SD of the max body temperature [tympanic] presented)
Gavva et al., 2008 Pain 136:202-210
24 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
AMG 517 caused marked hyperthermia in subjects who underwent molar extraction
41
Molar extraction subjects
36
37
38
39
40
placebo 2mg 8mg 15mgAMG 517
Tem
pera
ture
(o C)
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
TRPV1 antagonists causing hyperthermia in rodents, dogs, monkeys, and humans indicates an evolutionarily conserved role of TRPV1 in thermoregulation
AMG 517
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 25
First approach to address hyperthermia: Peripheral restriction of antagonists
Hypothesis
Thermoregulation is CNS mediated
Strategy
Thermoregulation is CNS mediated
Can we minimize hyperthermia by restricting antagonists to the periphery?
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Reduce brain exposure: peripherally restricted TRPV1 antagonists • Increase polar surface area (PSA)• Decrease logP• Increase number of hydrogen-bond donors
26 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
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 27
Effect of AMG13731 and AMG21629 onrat body core temperature
39
40
Vehicle
AMG13731 (10 mg/kg)AMG13731 (3 mg/kg)
C)
39
40AMG21629 (3mg/kg)
Vehicle C)
NH2
-30 0 30 60 90 12036
37
38
39
Vehicle or drugs, p.o.
Time (min)
Tem
pera
ture
(
-30 0 30 60 90 12036
37
38
39
Vehicle or drugs, p.o.
Time (min)
Tem
pera
ture
(
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
N N
ON
F3C
NH
FNHSO2Me
SN
NH2
AMG13731N N
O
F3C
NHN
ONH2
HN
OMe
AMG21629
Site of action for TRPV1 antagonist-induced hyperthermia is outside the BBB
Tamayo et al 2008 J Med Chem. 51:2744-57
28 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
Evaluation of compounds exhibiting differential pharmacology - 2nd Approach
B dCapsaicin pH 5 Heat Body temp
Block Block Block
Block Partial block Block
Block Potentiate No effect
Profile AProfile BProfile C
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Block Potentiate Potentiate
Profile CProfile D
Profiles defined by agonist-induced 45Ca2+ uptake assays
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 29
AMG8562, a profile C compound that does not cause hyperthermia in rats
Capsaicin pH 5125 200
In vitro dataRat radiotelemetry
Heat
-11 -10 -9 -8 -7 -6 -50
25
50
75
100
AMG8562 [log M]
% m
ax45
Ca2+
upt
ake
-11 -10 -9 -8 -7 -6 -50
255075
100125150175
AMG8562 [log M]
% m
ax45
Ca2+
upt
ake
125
150
ake
37
38
39 Vehicle (n=6)1 mg/kg (n=6)
10 mg/kg (n=6)
3 mg/kg (n=6)30 mg/kg (n=6)
Tem
pera
ture
( C
)
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
-11 -10 -9 -8 -7 -6 -50
25
50
75
100
AMG8562 [log M]
% m
ax45
Ca2+
upt
a
Lehto et al 2008 JPET 326:218-229
0 30 60 90 120
150
180
210
240
270
36Veh or AMG8562 p.o.
T
Vehicle or compound p.o.
30 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
AMG8562 is modestly effective in capsaicin-challenge and pain models
14 10000
Number of flinches
Plasma concentration (ng/ml)
in
Plas m
10
12 10000
Latency (sec)
Plasma concentration (ng/ml) Plasma
Capsaicin-induced flinch CFA-induced thermal hyperalgesia
Vehi
cle
AMG
8163
Vehi
cle0
2468
1012
0.1
1
10
100
1000
0.1 1 10 100
AMG
8163
AMG8562 (mg/kg, p.o.)
** ** ** **
*
Tota
l flin
ches
in 1
m
ma concentration (ng/m
l)
0
2
4
6
8
10
0.1
1
10
100
1000
Vehi
cle
Pre
-CFA 30
AM
G81
63
AMG8562 (mg/kg, p.o.)
**
100
**
Late
ncy
(sec
)
a concentration (ng/ml)
Number of writhesPlasma concentration (ng/ml) P
Acetic acid-induced writhing
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
0
10
20
30
40
50
1
10
100
1000
10000
10 100
Plasma concentration (ng/ml)
vehi
cle
Ibup
rofe
n*
*
30
AMG8562 (mg/kg, p.o.)
Num
ber o
f writ
hes
Plasma concentration (ng/m
l)
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 31
AMG8562, exhibits profile B modulation of human TRPV1
0
20
40
60
80
100
% m
ax45
Ca2+
upt
ake
0
25
50
75
100
125%
max
45C
a2+ u
ptak
e
0
20
40
60
80
100
% m
ax45
Ca2+
upt
ake
Capsaicin activation pH 5 activation Heat activation
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Lehto et al 2008 JPET 326:218-229
-10 -9 -8 -7 -60
AMG8562 [log M]-10 -9 -8 -7 -6
0
AMG8562 [log M]-10 -9 -8 -7 -6
AMG8562 [log M]
Profile B modulators cause hyperthermia in rats
32 The Open Drug Discovery Journal, 2009, Volume 1 Narender R. Gavva
Compound name
Company Route of administration
Indication Stage Current status
ABT 102 Abb tt O l Ph I I iti t d ?
Current status of TRPV1 antagonists in the clinic
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 SuspendedJTS-653 Japan Tobacco Oral Overactive
bladder pain
Phase I On going
MK 2295 Merck/Neurogen Oral Dental pain Phase II Completed
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
g p p
SB-705498 GSK Oral Migraine Phase II Terminated
Rectal pain Phase II Terminated
Dental pain Phase II Completed
PF-4065463 Evotec/Pfizer unknown unknown unknown unknown
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 33
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
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
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
34 The Open Drug Discovery Journal, 2009, Volume 1 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)
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
• Development of short half-life antagonists
• Development of antipyretic + TRPV1 antagonist combination
• Development of TRPV1 antagonists in primary indications (e.g., Osteoarthritis)
Setbacks in the Clinical Development of TRPV1 Antagonists: What Next? The Open Drug Discovery Journal, 2009, Volume 1 35
Received: January 28, 2009 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, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
Chemistry
Yunxin Bo Ning Chen
TRPV1 Core Team
Narender GavvaCh i t h B fi ld
The Team
Departments
NeurosciencePKDM
Process Chemistry
Charles BernardChris Borths
Neuroscience
Leyla ArikA th B Ning Chen
Balan CheneraDarin D’AmicoLiz DohertyLillian LiaoMark NormanNobuko NishimuraVassil OgnyanovDan RetzMark StecNuria Tamayo
Christopher BanfieldAnthony BannonGudarz DavarCelia DominguezMargaret FaulAnu GoreDavid HovlandPat KesslakSonya LehtoJean-Claude LouisMark Norman
PKDMModelingE-physSample BankRegulatory Affairs Toxicology PharmaceuticsClinicalAnalyticalLegalProject Management
Chris BorthsTracy BostickMargaret FaulAndrew HagueTony KingBobby RaihiThomas StorzJason TedrowOliver Thiel
Anthony BannonJames DavisNarender GavvaCharles HenleyGal HeverRongzhen KuangDavid ImmkeSonya LehtoLana KlionskyElla MagalLicheng Shi
Narender Gavva Pain Therapeutics Summit – Oct 7th 2008
Phi TangKevin Yang
Sekhar SurapaneniJames Treanor
Project ManagementMarketing
CollaboratorsAndrej Romanovsky, Andras GaramiSt. Joseph's Hospital and Medical Center, Phoenix, AZFrank Porreca, Todd VanderahUniversity of Arizona, Tucson, AZ
gRami TamirJue WangJudy WangWeiya WangGary ZajicDawn Zhu