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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

Narender Gavva Pain Therapeutics Summit – Oct 7th 2008

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



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



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



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



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



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



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


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


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



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



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


• 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

)


-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


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


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)


Agonists and antagonists do not cause body temperature changes in TRPV1 knockout mice

Agonist-induced hypothermia Antagonist-induced hyperthermia


Agonist-induced hypothermia & antagonist-induced hyperthermia are entirely TRPV1 mediated

Steiner et al., J Neurosci. 2007 Jul 11;27(28):7459-68


AMG 517 causes hyperthermia by vasoconstriction and increased thermogenesis

Skin vasomotor toneIndividual effectors

Nonshivering thermogenesis


Shivering

Gavva et al., 2008 Pain 136:202-210


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

)


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


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


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

)


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


– 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


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)


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


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


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


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)


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


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)


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


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)


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


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?


Reduce brain exposure: peripherally restricted TRPV1 antagonists • Increase polar surface area (PSA)• Decrease logP• Increase number of hydrogen-bond donors


Profiles of peripherally restricted TRPV1 antagonists



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

(


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


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


Block Potentiate Potentiate

Profile CProfile D

Profiles defined by agonist-induced 45Ca2+ uptake assays


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

)


-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.


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


**

100

**

Late

ncy

(sec

)

a concentration (ng/ml)

Number of writhesPlasma concentration (ng/ml) P

Acetic acid-induced writhing


0

10

20

30

40

50

1

10

100

1000

10000

10 100

Plasma concentration (ng/ml)

vehi

cle

Ibup

rofe

n*

*

30


Num

ber o

f writ

hes

Plasma concentration (ng/m

l)

Lehto et al 2008 JPET 326:218-229


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


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


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


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


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


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


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)


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


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

open access setbacks in the clinical development of trpv1 ... · pdf filesetbacks in the...

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