Discontinued drugs in 2006: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs

1. Background

2. Survey of compounds in

pulmonary-allergy,

dermatological, gastrointestinal

and arthritis drugs discontinued

in 2006

3. Expert opinion

Discontinued drugs in 2006: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs Cevdet Ozdemir & Cezmi A Akdis † † Swiss Institute of Allergy and Asthma Research (SIAF) Obere Strasse 22 CH-7270, Davos, Switzerland

This perspective is the second in a series discussing drugs dropped from development in 2006, with a focus on pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs. A survey of discontinued drugs from 2006 is provided, based on data from the Pharmaprojects database, along with an analysis of biology, mechanisms of action and economic considerations in developing new drugs.

K eywords: asthma, arthritis, atopic eczema, discontinued drugs, new drugs, psoriasis

Expert Opin. Investig. Drugs (2007) 16(9):1327-1344

1. Background

Long-term courses of therapy for the most prevalent disorders of airways, such as asthma and chronic obstructive pulmonary disease and the increasing prevalence of allergic diseases, especially in pediatric age groups, have attracted the attention of the pharmaceutical industry to develop new agents for these disorders. The profound impact of allergic and asthmatic diseases on both quality of life and social costs justify the need for the development of new efficient therapeutic approaches aimed at reducing treatment time. Use of basic knowledge derived from molecular biology, genetic engineering and biotechnology is leading to the development of novel concepts to cure allergic and autoimmune diseases. Widely used inhaled corticosteroids, inhaled β 2 -adrenergic agents, antihistaminics, xanthine oxidase inhibitors and anticholinergic agents are on the market and new compounds are in the pipeline. New-generation antihistamines are also being developed for the symptomatic treatment of allergic diseases. In addition, treatments that aim to act specifically on the interaction of the immune system with allergens, such as different modes of allergen-specific immunotherapy, are also under development [1] .

Cell adhesion molecules play critical roles in the recruitment and migration of cells to sites of inflammation. These receptors have moved the attention of the pharmaceutical industry as targets for the development of drugs to treat inflamma-tory and autoimmune diseases. Today, one of the most promising developments in the area of allergy is monoclonal antibody therapy against IgE, which may be also effective in the treatment of other allergies such as food allergy and asthma in addition to allergic rhinitis.

Gastrointestinal disorders still require investment to develop better agents with effective clinical applications and fewer side effects. Management of inflamma-tory bowel disease is much more than drug therapy, dose and timing. The goals remain of induction of remission, limitation of side effects, modification of the pattern of disease and avoidance of complications. This is also applicable for rheumatologic disorders.

The Phase I clinical trial of TeGenero’s TGN-1412 (anti-CD28) in the UK has stirred up a storm of controversy after trial participants suffered serious adverse

Perspective

10.1517/13543784.16.9.1327 © 2007 Informa UK Ltd ISSN 1354-3784 1327

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Discontinued drugs in 2006: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs

1328 Expert Opin. Investig. Drugs (2007) 16(9)

events soon after taking the drug. Although this event could have a number of implications for drug developers, it needs to be weighed against the need for new medicines, especially in chronic disorders. the mechanism of action of TGN-1412 seems the most likely reason for the severe reactions of the trial participants [2] .

2. Survey of compounds in pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs discontinued in 2006

A brief summary of the discontinued products by class based on information from Pharmaprojects [101] and web analysis is provided in Table 1.

2.1 Pulmonary-allergy 2.1.1 Valategrast Valategrast hydrochloride (R-411; Roche) is a dual antagonist of α 4 β 1 - α 4 β 7 integrins that targets the inflammatory process in respiratory airways. It entered Pharmaprojects as a new product in 2001 and Phase I and II studies have been conducted. It had shown good efficacy in animal disease models [3] . Following oral administration, R-411 was rapidly and completely biotransformed into its active metabolite, RO-0270608, most of which was eliminated by biliary excretion. R-411 had shown acceptable pharmacokinetics and good safety in healthy volunteers [4] . To test drug interactions, a single daily dose of R-411 300 mg in tablet form was given for 8 consecutive days to 12 healthy volunteers and it was shown that it did not affect major CYP isoform activities, thus indicating a low potential for drug interactions [5] .

R-411 inhibited eosinophil and T H 2 cell excitation and survival, and inhibited eosinophil migration from blood to pulmonary tissues. The idea of combining R-411 with monte-lukast (leukotriene antagonist) in the pharmaceutical dosage forms, therefore, provided a therapeutic treatment that had the combined effect of reducing circulating eosinophil counts and reducing eosinophil egress into pulmonary tissues, thereby providing an early onset of bronchodilation as well as sustained anti-inflammatory effects [102] . Development of R-411 was discontinued for the treatment of asthma after clarification of the regulatory framework for that class of compounds [101] .

2.1.2 DW-908e The cell surface integrin very late antigen-4 (VLA-4; α 4 β 1 ; CD49d/CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti- inflammatory drugs for the treatment of asthma [6] .

DW-908e (Daiichi Sankyo) was suggested to inhibit immune cell infiltration to the inflammatory area by inhibit-ing binding between adhesive VLA-4 molecules expressed on eosinophils and vascular cell adhesion molecule-1 expressed on vascular endothelial cells. It had α 4 β 1 -integrin antagonist

activity and was an orally active agent. It was discontinued during Phase I trials after the US FDA placed a clinical hold on drugs that target VLA-4 following two cases of progressive multifocal leucoencephalopathy in patients taking natalizumab [101] .

2.1.3 S-5751 Prostanoids – prostaglandins and thromboxane A2 (TXA2) – the COX metabolites of arachidonic acid, are implicated in the inflammatory cascade that occurs in asthmatic airways [7] . Genetic analysis supports the view that prostaglandin receptors have a pivotal role in mediating aspects of allergic diseases that are resistant to existing therapy.

S-5751 (Shionogi) was an orally administered prostaglandin D 2 receptor antagonist. The development of S-5751 was ceased during Phase II trials in 400 bronchial asthma patients because results failed to reach the primary end point of change in forced expiratory volume/s and no significant benefit over placebo was observed with high or low doses [101] .

2.1.4 ASF-1020 Inhaled corticosteroids and inhaled long-acting β 2 -agonists are frequently used in the treatment of patients with asthma .

ASF-1020 (Astion) was an inhaled small molecule with a non-steroidal, anti-inflammatory effect combined with long-acting β 2 -agonistic activity for the treatment of asthma. COX inhibition and prostaglandin synthase inhibition had also been the target of that drug. Animal studies demonstrated proof of concept with an anti-inflammatory effect comparable to systemic glucocorticosteroids. It was suggested that ASF-1020 also had potential in chronic obstructive pulmonary disease. Astion discontinued development of ASF-1020 during Phase I/II trials [101] .

2.1.5 QAK-423 QAK-423 (Novartis) was a novel compound for the treatment of asthma and chronic obstructive pulmonary disease. It was discontinued after Phase I trial [101] .

2.1.6 HL-10 Several Phase II studies performed on patients with acute lung injury or acute respiratory distress syndrome and a Phase III study performed on a pediatric population have shown beneficial effects of surfactants on oxygenation and survival [8] .

HL-10 was a mixture of phospholipids and surfactants (SP-B and SP-C) derived from porcine lung, being developed by Leo for the treatment of acute lung injury and adult respiratory distress syndrome. Trials were discontinued due to lack of efficacy during a Phase III trial in patients with adult respiratory distress syndrome [101,103] .

2.1.7 Org-4419 Org-4419 (Cypress Bioscience and Organon/Azko Nobel) was an antagonist of α 2 -adrenoceptor, 5-HT2 and 5-HT3. It was a combination of an undisclosed approved drug and

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis

Expert Opin. Investig. Drugs (2007) 16(9) 1329

Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s.

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

Clin

dam

ycin

, Shi

re; H

yacn

e;

HyC

linda

NN

O

OO

OS

Cl

O

Shire

Skye

Phar

ma

Acn

ePr

otei

n 50

S rib

osom

al

subu

nit

inhi

bito

r

Uns

peci

fi ed

IIISt

rate

gic

HyC

linda

is a

top

ical

gel

fo

rmul

atio

n of

the

an

tibio

tic c

linda

myc

in,

whi

ch w

as u

nder

de

velo

pmen

t by

Shi

re

for

the

trea

tmen

t of

ac

ne, p

rior

to

Skye

Phar

ma

disc

ontin

uing

all

topi

cal d

rug

deve

lopm

ent

prog

ram

s (d

irect

com

mun

icat

ion,

Sh

ire, 2

Mar

200

0;

Cow

en 7

th A

nnua

l G

loba

l Hea

lth C

are

Con

fere

nce,

Lon

don

2006

). It

used

Sk

yePh

arm

a’s

topi

cal

Hya

luro

nan

Indu

ced

Targ

etin

g sy

stem

(HIT

te

chno

logy

[qv]

; Pre

ss

rele

ases

, Sky

ePha

rma,

28

Oct

199

9 an

d 28

Feb

200

1).

HL-

10Le

oA

RDS

Not

app

licab

leN

ot a

pplic

able

IIIEf

fi cac

yLe

o ha

s di

scon

tinue

d de

velo

pmen

t of

HL-

10,

a m

ixtu

re o

f ph

osph

olip

ids

and

surf

acta

nts

(SP-

B an

d SP

-C) d

eriv

ed f

rom

po

rcin

e lu

ng, f

or t

he

trea

tmen

t of

ALI

and

A

RDS,

due

to

a la

ck o

f ef

fi cac

y (d

irect

co

mm

unic

atio

n, L

eo,

10 M

ay 2

006)

. It

was

be

ing

deve

lope

d in

col

-la

bora

tion

with

Hal

las

Phar

ma,

Old

enbu

rg,

Ger

man

y.

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.



Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

5D12

; ant

i-CD

40 m

Ab,

Ta

nox

Nov

artis

Tano

xC

rohn

’s d

isea

se,

psor

iasi

sC

D40

ant

agon

ist

CD

40 m

olec

ule,

TN

F re

cept

or

supe

rfam

ily

mem

ber

5

IIU

nspe

cifi e

dC

hiro

n (n

ow N

ovar

tis) h

as

disc

ontin

ued

deve

lopm

ent

of 5

D12

, a h

uman

ized

an

ti-C

D40

mA

b fo

r th

e tr

eatm

ent

of a

utoi

mm

une

dise

ases

(dire

ct c

omm

unic

atio

n,

Tano

x, 5

Oct

200

6).

AD

-452

Sose

iRA

; os

teoa

rthr

itis

IL-1

ant

agon

ist,

IL

-6 a

ntag

onis

t,

IL-8

ant

agon

ist,

TN

F an

tago

nist

Uns

peci

fi ed

IIEf

fi cac

ySo

sei R

&D

(Sos

ei) (

form

erly

A

rale

is) h

as d

isco

ntin

ued

deve

lopm

ent

of A

D-4

52, a

si

ngle

-isom

er f

orm

ulat

ion

of

a m

arke

ted

oral

cel

l cyt

okin

e m

odul

ator

, as

a D

MA

RD f

or

the

trea

tmen

t of

RA

and

ost

eo-

arth

ritis,

fol

low

ing

failu

re t

o m

eet

effi c

acy

end

poin

ts in

a

Phas

e IIb

tria

l in

RA (4

th

ERBI

Con

fere

nce,

Cam

brid

ge

2002

; Pre

ss r

elea

se, S

osei

, 21

Nov

200

6). I

t do

wnr

egul

ates

in

fl am

mat

ory

cyto

kine

s in

clud

ing

IL-1

, IL-

6, IL

-8 a

nd

TNF

(JP

Mor

gan

23rd

Ann

ual

Hea

lthca

re C

onfe

renc

e,

San

Fran

cisc

o 20

05).

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

Am

oxap

ine

+ p

redn

isol

one

com

bina

tion;

CRx

-119

pr

edni

solo

ne +

am

oxap

ine

com

bina

tion

Com

bina

toRx

RA;

perio

dont

itis

Uni

dent

ifi ed

ph

arm

acol

ogic

al

activ

ity

Uns

peci

fi ed

IIEf

fi cac

yC

ombi

nato

Rx h

as d

isco

ntin

ued

deve

lopm

ent

of C

Rx-1

19, a

se

lect

ive

ster

oid

ampl

ifi er

, for

the

tr

eatm

ent

of R

A, f

ollo

win

g a

shift

of

res

ourc

es t

o pr

oduc

ts s

how

-in

g hi

gher

effi

cac

y (P

ress

rel

ease

, C

ombi

nato

Rx, 1

0 A

ug 2

006)

. It

also

had

pot

entia

l in

psor

iasi

s,

Cro

hn’s

dis

ease

, ulc

erat

ive

colit

is,

asth

ma,

ato

pic

derm

atiti

s an

d ot

her

infl a

mm

ator

y co

nditi

ons.

It is

a

com

bina

tion

of a

red

uced

-dos

e co

rtic

oste

roid

(pre

dnis

olon

e) w

ith

an a

ntid

epre

ssan

t (a

mox

apin

e; q

v)

whi

ch e

nhan

ced

its t

hera

peut

ic

effe

cts

with

out

incr

easi

ng s

ide

effe

cts.

It h

ad a

diff

eren

t mec

hani

smfr

om C

Rx-1

39, C

Rx-1

02 a

nd

CRx

-170

(all

qv) (

JP M

orga

n 22

nd

Ann

ual H

ealth

care

Con

fere

nce,

Sa

n Fr

anci

sco

2004

; BIO

200

5,

Phila

delp

hia)

. It

also

mod

ulat

ed

seve

ral c

ytok

ines

incl

udin

g TN

F-α.

It

was

a o

nce-

daily

adm

inis

tere

d pr

oduc

t th

at c

ould

be

deliv

ered

or

ally

or

by in

hala

tion.

O N

Cl

N

N

HH

OO

O

O H

O

H

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

APC

-205

9C

eler

a G

enom

ics

Col

itis,

ul

cera

tive;

as

thm

a

Tryp

tase

inhi

bito

rTr

ypta

se α

/β1

IISt

rate

gic

Cel

era

Gen

omic

s (f

orm

erly

Axy

s be

fore

th

e ac

quis

ition

) has

dis

cont

inue

d de

velo

pmen

t of

APC

-205

9, a

try

ptas

e in

hibi

tor,

for

the

tre

atm

ent

of u

lcer

ativ

e co

litis

and

ast

hma,

due

to

a sh

ift in

fo

cus

to d

iagn

ostic

s (d

irect

co

mm

unic

atio

n, C

eler

a, 7

Nov

200

6).

Cel

era

and

Baye

r w

ere

focu

sed

on o

ral

tryp

tase

inhi

bito

rs (q

v; P

ress

rel

ease

, A

xys,

7 M

ay 2

001)

.

ASF

-102

0A

stio

nA

sthm

aβ 2

-adr

enor

ecep

tor

agon

ist;

C

OX

inhi

bito

r;

pros

tagl

andi

n sy

ntha

se in

hibi

tor

Adr

ener

gic,

β 2

-rec

epto

r,

surf

ace

IIU

nspe

cifi e

dA

stio

n ha

s di

scon

tinue

d de

velo

pmen

t of

ASF

-102

0, a

n in

hale

d sm

all m

olec

ule

with

a n

on-s

tero

idal

ant

i-infl

am

mat

ory

effe

ct c

ombi

ned

with

long

act

ing

β2

agon

istic

act

ivity

for

the

tre

atm

ent

of

asth

ma.

It a

lso

had

pote

ntia

l in

CO

PD

(Com

pany

Web

Pag

e, A

stio

n, 1

2 A

ug

2005

; dire

ct c

omm

unic

atio

n, A

stio

n,

19 N

ov 2

006)

.

Balic

atib

, A

AE-

581

Nov

artis

Ost

eopo

rosi

sC

athe

psin

K in

hibi

tor

Cat

heps

in K

IIU

nspe

cifi e

dN

ovar

tis h

as d

isco

ntin

ued

deve

lopm

ent

of b

alic

atib

(AA

E-58

1), a

n or

ally

-act

ive

once

-dai

ly c

athe

psin

K in

hibi

tor

for

the

trea

tmen

t of

ost

eopo

rosi

s (A

nnua

l Re

port

, Nov

artis

, 200

4; P

ress

rel

ease

, N

ovar

tis, 2

8 N

ov 2

006)

. It

inhi

bite

d ca

thep

sin

K in

ost

eocl

asts

, lea

ding

to

red

uced

col

lage

n br

eakd

own

and

decr

ease

d bo

ne r

esor

ptio

n (P

ress

re

leas

e, N

ovar

tis, 3

0 O

ct 2

001

and

17 O

ct 2

002)

.

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.



Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

CD

P-48

4; P

EG-IL

-1β

MA

b,

Nek

tar;

PEG

-IL-1

β M

Ab,

UC

BU

CB

Nek

tar

Ther

apeu

tics

RAIL

-1β

anta

goni

stIL

-1 r

ecep

tor,

ty

pe II

IIU

nspe

cifi e

dU

CB

(Cel

ltech

bef

ore

the

acqu

isiti

on) h

as d

isco

ntin

ued

deve

lopm

ent

of C

DP-

484,

a

pegy

late

d an

tibod

y fr

agm

ent

IL-1

β in

hibi

tor,

for

th

e tr

eatm

ent

of R

A, a

nd

pote

ntia

lly o

ther

imm

une/

infl a

mm

ator

y di

sord

ers.

It

was

pre

viou

sly

susp

ende

d du

e to

a P

hase

I tr

ial f

ailin

g to

m

eet

the

crite

ria t

o pr

ocee

d w

ith P

hase

II d

evel

opm

ent

(Pre

ss r

elea

se, U

CB,

27

Jul

2005

; dire

ct c

omm

unic

atio

n,

UC

B, 1

5 D

ec 2

006)

.

Cic

losp

orin

+ lo

ratid

ine

co

mbi

natio

n; C

Rx-1

40;

lora

tidin

e +

cic

losp

orin

co

mbi

natio

n

Com

bina

toRx

Psor

iasi

sC

alci

neur

in

inhi

bito

rPe

ptid

ylpr

olyl

is

omer

ase

A

(cyc

loph

ilin

A)

IIEf

fi cac

yC

ombi

nato

Rx h

as

disc

ontin

ued

deve

lopm

ent

of C

Rx-1

40, a

n en

hanc

ed

calc

ineu

rin in

hibi

tor,

for

the

tr

eatm

ent

of p

soria

sis.

It is

a

com

bina

tion

of a

re

duce

d-do

se c

alci

neur

in

inhi

bito

r (c

iclo

spor

in) a

nd a

n an

tihis

tam

ine

(lora

tidin

e),

whi

ch s

elec

tivel

y bo

osts

im

mun

omod

ulat

ory

activ

ity

with

out

incr

easi

ng s

ide

effe

cts

(Com

pany

Web

Pag

e,

Com

bina

toRx

, 6 A

pr 2

005;

Pr

ess

rele

ase,

Com

bina

toRx

, 22

Feb

200

6).

O

ON

NN

NN

OO

N

O

OO

O

N

ON

N

ON

OO

NN

N

O

Cl

O

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

Del

miti

de

acet

ate,

A

llotr

ap-1

258,

RD

P-12

58,

RDP-

58,

RSP-

58

Gen

zym

ePr

octe

r &

G

ambl

eC

oliti

s,

ulce

rativ

e;

Cro

hn’s

di

seas

e;

chem

othe

rapy

-in

duce

d in

jury

, G

I; ps

oria

sis;

ec

zem

a,

atop

ic;

mul

tiple

sc

lero

sis,

ge

nera

l; Ba

rret

t’s

esop

hagu

s

TNF-

α an

tago

nist

; pr

otei

n sy

nthe

sis

anta

goni

st

TNF

rece

ptor

-ass

ocia

ted

fact

or 6

; mye

loid

di

ffer

entia

tion

prim

ary

resp

onse

gen

e (8

8);

IL-1

rec

epto

r-as

soci

ated

ki

nase

1

IIU

nspe

cifi e

dG

enzy

me

(San

gSta

t be

fore

the

ac

quis

ition

) has

dis

cont

inue

d de

velo

pmen

t of

del

miti

de a

ceta

te

(RD

P-58

; for

mer

ly A

llotr

ap-1

258)

, an

ora

lly a

ctiv

e, r

atio

nally

des

igne

d de

cape

ptid

e in

hibi

tor

of T

NF-

α m

RNA

tra

nsla

tion,

for

the

tre

at-

men

t of

ulc

erat

ive

colit

is, H

IV-

and

canc

er-r

elat

ed G

I com

plic

atio

ns

and

MS

(Ann

ual R

epor

t, G

enzy

me,

20

05).

It al

so h

ad p

oten

tial i

n ps

oria

sis,

ato

pic

derm

atiti

s,

cong

estiv

e he

art

failu

re, p

reve

ntio

n of

GvH

D, c

irrho

sis,

Bar

rett

’s

esop

hagu

s, a

nd a

s an

inha

led

trea

tmen

t fo

r re

spira

tory

co

nditi

ons

such

as

asth

ma,

CO

PD

and

pulm

onar

y fi b

rosi

s (P

ress

re

leas

e, S

angS

tat,

27

Sep

2002

; 6t

h W

orld

Con

gres

s on

Infl a

mm

a-tio

n, V

anco

uver

, 200

3). I

t pr

even

ts

tran

slat

ion

of t

he T

NF

prot

ein

rath

er t

han

bind

ing

to t

he p

rote

in

to in

hibi

t fu

nctio

n (A

nnua

l Rep

ort,

Sa

ngSt

at, 1

999;

JP

Mor

gan

H&

Q

20th

Ann

ual H

ealth

care

C

onfe

renc

e, S

an F

ranc

isco

200

2).

Del

miti

de a

ceta

te r

educ

es

infl a

mm

atio

n by

tar

getin

g TR

AFY

K,

a TR

AF6

/MyD

88/IR

AK

pro

tein

co

mpl

ex im

plic

ated

in s

ever

al

infl a

mm

ator

y di

seas

es (P

ress

re

leas

e, S

angS

tat,

21

May

200

3).

Seco

nd-g

ener

atio

n co

mpo

unds

w

ere

unde

r de

velo

pmen

t (R

DP-

59;

qv) (

Pres

s re

leas

e, S

angS

tat,

10

Jul

200

1).

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.



Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

FK-7

78;

mal

onon

itrila

mid

es;

MN

As,

Ast

ella

s;

MN

As,

sa

nofi -

aven

tis

Ast

ella

sTr

ansp

lant

re

ject

ion,

ge

nera

l

Hyd

roor

otat

e de

hydr

ogen

ase

inhi

bito

r; t

yros

ine

kina

se in

hibi

tor

Dih

ydro

orot

ate

dehy

drog

enas

eII

Effi c

acy

Ast

ella

s ha

s di

scon

tinue

d de

velo

pmen

t of

FK

-778

, the

lead

in

a s

erie

s of

syn

thet

ic

MN

As

for

the

trea

tmen

t of

org

an

tran

spla

nt r

ejec

tion,

as

it w

as n

ot

supe

rior

to e

xist

ing

trea

tmen

ts

in P

hase

II t

rials

(Com

pany

Web

Pa

ge, A

stel

las,

11

Aug

200

6).

It w

as o

rigin

ally

lice

nsed

fro

m

sano

fi -av

entis

(Ave

ntis

bef

ore

the

mer

ger;

pre

viou

sly

Hoe

chst

M

ario

n Ro

usse

l), w

hich

lice

nsed

al

l rig

hts

to A

stel

las.

It is

der

ived

fr

om t

he a

ctiv

e m

etab

olite

of

lefl u

nom

ide

(qv)

, A77

,172

6. It

in

hibi

ts T

- an

d B-

cell

func

tion

via

the

inhi

bitio

n of

dih

ydro

ortic

ac

id d

ehyd

roge

nase

and

tyr

osin

e ki

nase

(Tra

nspl

anta

tion

(200

4)

77:S

88).

Org

-441

9C

ypre

ss

Bios

cien

ceA

kzo

Nob

elA

pnoe

aα 2

-adr

enor

ecep

tor

anta

goni

st;

5-H

T 2 a

ntag

onis

t;

5-H

T 3 a

ntag

onis

t

Adr

ener

gic,

α2A

rec

epto

r;

5-H

T 3A

IIEf

fi cac

yC

ypre

ss B

iosc

ienc

e an

d O

rgan

on

(Azk

o N

obel

) hav

e di

scon

tinue

d de

velo

pmen

t of

Org

-441

9, a

co

mbi

natio

n of

mirt

azap

ine

(qv)

and

ano

ther

und

iscl

osed

ap

prov

ed d

rug

for

the

trea

tmen

t of

obs

truc

tive

slee

p ap

noea

, fo

llow

ing

lack

of

effi c

acy

in

Phas

e IIa

tria

ls.

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

S-57

51

S

O

O

N

OO

Shio

nogi

Alle

rgy,

ge

nera

l; as

thm

a

Pros

tagl

andi

n D

2 an

tago

nist

Pros

tagl

andi

n D

2 re

cept

or (D

P)II

Effi c

acy

S-57

51 is

an

oral

pr

osta

glan

din

D2

rece

ptor

an

tago

nist

, whi

ch w

as u

nder

de

velo

pmen

t by

Shi

onog

i as

an a

ntia

llerg

ic.

TAK

-715

N

NO

S N

Take

daA

rthr

itis,

rh

eum

atoi

dP3

8 ki

nase

in

hibi

tor

Mito

gen-

activ

ated

pr

otei

n ki

nase

14

IIU

nspe

cifi e

dTa

keda

has

dis

cont

inue

dde

velo

pmen

t of

TA

K-7

15 a

s a

p38

MA

P ki

nase

inhi

bito

r fo

r th

e tr

eatm

ent

of R

A a

s it

did

not

satis

fy c

riter

ia f

or f

urth

er

deve

lopm

ent

(Scr

ip D

aily

O

nlin

e, 3

1 Ju

l 200

6,

S009

2889

8).

Taliz

umab

; an

ti-Ig

E M

Ab;

H

u-90

1, T

anox

; H

u-90

1;

TNX

-901

Tano

xA

llerg

y,

food

Imm

unog

lobu

lin

E in

hibi

tor

Imm

unog

lobu

lin

heav

y co

nsta

nt

epsi

lon

IIU

nspe

cifi e

dTa

nox

has

disc

ontin

ued

deve

lopm

ent

of t

aliz

umab

(T

NX

-901

; Hu-

901)

, a

hum

aniz

ed a

nti-I

gE

mA

b fo

r th

e tr

eatm

ent

of

seve

re p

eanu

t al

lerg

y (D

irect

co

mm

unic

atio

n, T

anox

, 5

Oct

200

6). T

anox

was

als

o de

velo

ping

ano

ther

ant

i-IgE

m

Ab,

om

aliz

umab

(qv)

(Pre

ss

rele

ase,

Tan

ox, 1

3 Ju

l 199

9;

Ann

ual R

epor

t Pr

otei

n D

esig

n La

bs, 2

000)

.

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.



Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

Val

ateg

rast

hyd

roch

lorid

e;

inte

grin

ant

agon

ists

, Ro

che;

R-4

11;

Ro-0

2706

08;

Ro-0

2724

41;

Ro-0

2724

41/0

02;

Ro-2

7-24

41/0

02

Hof

fman

n-La

Roc

heA

sthm

aα 4

β 1-in

tegr

in

anta

goni

st;

α 4β 7

-inte

grin

an

tago

nist

Inte

grin

, α4

(ant

igen

CD

49d,

α 4

sub

unit

of V

LA-4

re

cept

or);

inte

grin

,β 1

(fi b

rone

ctin

re

cept

or, β

po

lype

ptid

e, a

ntig

en

CD

29 in

clud

es

MD

F2, M

SK12

); in

tegr

in, β

7

IISt

rate

gic

Roch

e ha

s di

scon

tinue

d de

velo

pmen

t of

va

late

gras

t hy

droc

hlor

ide

(R-4

11),

an o

ral,

once

-dai

ly

adm

inis

tere

d du

al

α 4β 1

- an

d α 4

β 7-in

tegr

inan

tago

nist

for

the

tr

eatm

ent

of a

sthm

a af

ter

clar

ifi ca

tion

of t

he

regu

lato

ry f

ram

ewor

k fo

r th

is c

lass

of

com

poun

ds (P

ress

re

leas

e, R

oche

, 17

Oct

200

6).

Ro-0

2706

08 is

the

act

ive

met

abol

ite (J

. Clin

. Ph

arm

acol

. (2

004)

44:

138,

PM

ID:1

5545

307)

.

HC

l

N

Cl

N

O

O

O

N

OC

l

Cl

AZD

-934

3A

stra

Zene

caG

astr

o-es

opha

geal

re

fl ux

Uni

dent

ifi ed

ph

arm

acol

ogic

al

activ

ity

Uns

peci

fi ed

IU

nspe

cifi e

dA

stra

Zene

ca h

as

disc

ontin

ued

deve

lopm

ent

of

AZD

-934

3, a

n in

hibi

tor

of t

rans

ient

lo

wer

eso

phag

eal

sphi

ncte

r re

laxa

tions

, fo

r th

e tr

eatm

ent

of

gast

ro-e

soph

agea

l re

fl ux

dise

ase

(Com

pany

pip

elin

e,

Ast

raZe

neca

, 8

Jun

2006

).

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

CRA

-028

129;

ca

thep

sin

S in

hibi

tors

, C

eler

a;

cath

epsi

n S

inhi

bito

rs,

Sano

fi

Cel

era

Gen

omic

ssa

nofi -

aven

tis;

Baye

rPs

oria

sis

Cat

heps

in S

in

hibi

tor

Cat

heps

in S

ISt

rate

gic

Cel

era

Gen

omic

s (f

orm

erly

A

xys

befo

re t

he a

cqui

sitio

n)

and

sano

fi -av

entis

(Ave

ntis

be

fore

the

mer

ger;

pr

evio

usly

Rho

ne-P

oule

nc

Rore

r) h

as d

isco

ntin

ued

deve

lopm

ent

of C

RA-0

2812

9,

an o

rally

act

ive

smal

l m

olec

ule

inhi

bito

r of

the

cy

stei

ne p

rote

ase

cath

epsi

n S,

fo

r th

e tr

eatm

ent

of

infl a

mm

ator

y an

d au

toim

mun

e di

seas

es,

incl

udin

g ps

oria

sis,

ast

hma,

C

OPD

, ath

eros

cler

osis

, RA

an

d al

lerg

ic r

hini

tis, d

ue t

o C

eler

a sh

iftin

g its

foc

us t

o di

agno

stic

s (P

ress

rel

ease

, A

xys,

30

Nov

199

9; C

ompa

ny

Web

Pag

e, C

eler

a, 2

6 A

ug

2003

; Pre

ss r

elea

se, C

eler

a,

20 S

ep 2

005;

Dire

ct c

omm

u-ni

catio

n, C

eler

a,

7 N

ov 2

006)

.

CS-

526

Dai

ichi

San

kyo

Nov

artis

; U

be In

dust

ries

Ulc

er,

gast

ricH

+/K

+ t

rans

port

ing

ATP

ase

inhi

bito

rA

TPas

e,

H+ /

K+

exch

angi

ng,

α po

lype

ptid

e

IU

nspe

cifi e

dSa

nkyo

(Dai

ichi

San

kyo)

has

di

scon

tinue

d de

velo

pmen

t of

CS-

526

as a

n an

tiulc

er

agen

t (A

limen

t Ph

arm

acol

.Th

er. (

2006

) 23:

23,

PMID

:167

0090

0).

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.



Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


Tab

le 1

. Dis

con

tin

ued

PA

DG

IA d

rug

s (c

on

tin

ued

).

Dru

g n

ame(

s)O

rig

inat

or

Lice

nse

eIn

dic

atio

nPh

arm

aco

log

y d

escr

ipti

on

Targ

etD

evel

op

men

t Ph

ase

reac

hed

Rea

son

fo

r d

isco

nti

nu

atio

nN

ote

s

DW

-908

eD

aiic

hi S

anky

oA

sthm

aα 4

β 1-in

tegr

in

anta

goni

st;

VC

AM

-1

anta

goni

st

Inte

grin

, β1

(fi br

onec

tin

rece

ptor

, β p

olyp

eptid

e,

antig

en C

D29

incl

udes

M

DF2

, MSK

12);

inte

grin

, α4

(ant

igen

C

D49

d, α

4 su

buni

t of

VLA

-4 r

ecep

tor)

; va

scul

ar c

ell a

dhes

ion

mol

ecul

e 1

IA

dver

se e

vent

sD

aiic

hi P

harm

aceu

tical

(Dai

ichi

Sa

nkyo

) has

dis

cont

inue

d de

velo

pmen

t of

DW

-908

e,

a co

mpo

und

in a

ser

ies

of o

rally

ac

tive

antia

llerg

ic a

gent

s fo

r th

e tr

eatm

ent

of im

mun

olog

ical

/alle

rgic

di

seas

es s

uch

as a

sthm

a (S

crip

Dai

ly

Onl

ine,

10

May

200

4, S

0084

3080

&

7 N

ov 2

006,

S00

9395

34).

Com

poun

ds in

the

ser

ies

inhi

bite

d im

mun

e ce

ll in

fi ltr

atio

n to

the

in

fl am

mat

ory

area

by

inhi

bitin

g bi

ndin

g be

twee

n ad

hesi

ve V

LA-4

m

olec

ules

exp

ress

ed o

n eo

sino

phils

an

d V

CA

M-1

exp

ress

ed o

n va

scul

ar

endo

thel

ial c

ells

(Com

pany

pip

elin

e,

Dai

ichi

, Oct

200

3). I

t w

as t

o be

as

sess

ed b

y D

aiic

hi M

edic

al R

esea

rch

(Dai

ichi

Pha

rmac

eutic

al) (

Dai

ichi

Sa

nkyo

) in

the

US

(Ann

ual R

epor

t,

Dai

ichi

, 200

4).

QA

K-4

23N

ovar

tisA

sthm

a;

CO

PDU

nide

ntifi

ed

phar

mac

olog

ical

ac

tivity

Uns

peci

fi ed

IU

nspe

cifi e

dN

ovar

tis h

as d

isco

ntin

ued

deve

lopm

ent

of Q

AK

-423

for

the

tr

eatm

ent

of a

sthm

a an

d C

OPD

(C

ompa

ny p

rese

ntat

ion,

Nov

artis

, 19

Jan

200

6).

SLV

-317

; SL

V-3

21So

lvay

Irrita

ble

bow

el

synd

rom

e

NK

1 an

tago

nist

Tach

ykin

in

rece

ptor

1I

Uns

peci

fi ed

Solv

ay h

as d

isco

ntin

ued

deve

lopm

ent

of S

LV-3

17 a

nd

SLV

-321

, NK

1 an

tago

nist

s, u

nder

de

velo

pmen

t fo

r th

e tr

eatm

ent

of

dise

ases

of

the

GI s

yste

m

(Com

pany

pre

sent

atio

n, S

olva

y,

3 O

ct 2

006)

.

Sour

ce o

f da

ta: P

harm

apro

ject

s, c

opyr

ight

© In

form

a U

K L

td 2

007

[101

].A

LI: A

cute

lung

inju

ry; A

RDS:

Adu

lt re

spira

tory

dis

tres

s sy

ndro

me;

DM

ARD

: Dis

ease

-mod

ifyin

g an

tirhe

umat

ic d

rug;

GI:

Gas

troi

ntes

tinal

; GvH

D: G

raft

-ver

sus-

host

dis

ease

; HIT

: Hea

d Im

pact

Tel

emet

ry;

mA

b: M

onoc

lona

l ant

ibod

y; M

NA

: Mal

onon

itrila

mid

e; M

S: M

ultip

le s

cler

osis

; PA

DG

IA: P

ulm

onar

y-al

lerg

y, d

erm

atol

ogic

al, g

astr

oint

estin

al a

nd a

rthr

itis;

RA

: Rhe

umat

oid

arth

ritis

; VC

AM

: Vas

cula

r ce

ll ad

hesi

on m

olec

ule;

V

LA: V

ery

late

ant

igen

.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

mirtazapine, which had a tetracyclic chemical structure and was classified as a noradrenergic and specific serotonergic antidepressant for the treatment of obstructive sleep apnea. It was discontinued following lack of efficacy in Phase IIa trials [101] .

2.1.8 Talizumab Food-induced anaphylaxis is an IgE-mediated condition that is estimated to affect many people.

Talizumab (TNX-901; Tanox) was a humanized IgG1 monoclonal antibody against IgE that could bind with high affinity to an epitope in the CH3 domain, thus masking a region responsible for binding to both Fce RIs and low-affinity Fce receptors (FcεRII or CD23). In addition to inhibiting the binding of IgE to mast cells and basophils, anti-IgE also markedly downregulated the expression of Fc ε RIs on basophils and might inhibit allergen-specific activation of T cells through interference with Fcε RI- or Fc ε RII-facilitated allergen presentation [9] . The drug was well tolerated in a double-blind, randomized Phase II trial in peanut allergic patients and was found to be the primary end point of increasing the symptom threshold to peanuts. It was administered subcutaneously. It was discontinued during Phase I/II clinical trials [101] .

2.2 Gastrointestinal 2.2.1 5D12 CD40, a TNF receptor family member, is expressed on den-dritic cells, B cells and to some degree on epithelial cells during inflammation. Non-stimulating antibodies directed to CD40 seem to have minimal binding to epithelium-expressed CD40 and may provide an alternate means of blocking CD40/CD154 interactions [10] . 5D12 (Tanox), a humanized anti-CD40 monoclonal antibody (mAb), was a potent antagonist of the CD40–CD40L pathway [11] .

5D12 was in preclinical studies in a kidney transplant model and in psoriasis. A European Phase I/II safety and efficacy trial of 20 patients was carried out for Crohn’s disease, but development was discontinued in 2006 [101] .

2.2.2 Delmitide acetate Delmitide acetate (RDP-58; formerly Allotrap-1258; Genzyme) was a decapeptide with inhibitory effects on TNF synthesis and developed for the potential treatment of Crohn’s disease and ulcerative colitis; Phase II trials for both indications commenced in October 2001. RDP-58 inhib-ited synthesis of pro-inflammatory cytokines by disrupting cell signaling at the preMAPK MyD88–IRAK–TRAF6 protein complex [12] .

It was suggested that it also had potential in psoriasis, atopic dermatitis, congestive heart failure, graft-versus-host disease, cirrhosis, Barrett’s esophagus and as an inhaled treatment for respiratory conditions such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. In a mouse lipopolysaccharide-induced model of acute lung inflammation, delmitide acetate instilled into the lung 24 h

prior to induction of inflammation reduced TNF- α , IFN- γ and IL-12 levels in bronchoalveolar lavage fluid. The number of infiltrating cells and activated neutrophils was also reduced. In a mouse lipopolysaccharide-induced model of chronic lung inflammation, delmitide acetate significantly reduced peri-bronchial leucocyte infiltration. A topical gel formulation had been in toxicology studies for psoriasis and atopic dermatitis. In a mouse model of skin inflammation, topical application of delmitide acetate reduced TNF- α expression, edema and infiltration of inflammatory cells [101] .

2.2.3 APC-2059 Inhibition of tryptase represents a breakthrough approach to the treatment of disease associated with mast cell-mediated inflammation [104] . APC-2059 (Celera Genomics) is a tryptase inhibitor developed for the treatment of ulcerative colitis and asthma. It was a dibasic inhibitor with subnanomolar activity and had been advanced to Phase II clinical trials for the treatment of both psoriasis and ulcerative colitis [13] . Phase I testing of a different (intravenous) formulation of APC-2059 had been initiated for the treatment of inflammatory bowel disease [104] . Development of APC-2059 had been discon-tinued due to a shift of the company in focus to diagnostics. A topical cream formulation for mild-to-moderate psoriasis was discontinued after interim evaluation of a Phase II trial, which revealed no difference between placebo and treated areas of skin. In a Phase II trial in ulcerative colitis patients with moderate-to-severe flares, APC-2059 was safe and well tolerated, and reduced disease activity in some patients [14,101] .

2.2.4 SLV-317 and SLV-321 Neurokinin-1 receptors have been identified in the CNS as well as in peripheral organs, including the gastrointestinal and respiratory system, the genitourinary tract and the vascular endothelium. SLV-317 (Solvay) was rapidly absorbed and well tolerated in a double-blind placebo-controlled study [101] . It was shown that SLV-317 caused a substantial reduction of substance P-induced venodilation, which was already almost fully established at the time of the first measurement (30 min after dosing) and which was still pronounced at the end of the measurements [15] . It was discontinued.

2.2.5 AZD-9343 AZD-9343 (AstraZeneca) was an antispasmodic, an inhibitor of transient lower esophageal sphincter relaxations, for the treatment of gastro-esophageal reflux disease. It was discontinued during Phase I trials [101] .

2.2.6 CS-526 CS-526 (Daiichi Sankyo) was an anti-ulcer agent. It was one of the potassium-competitive acid blockers (P-CABs), which exploit the requirement for potassium binding to (and exchange within) the proton pump as part of the acid secretion process. These agents bind ionically to the proton pump at or near the potassium-binding site in a K + -competitive manner,



Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


thereby blocking acid secretion through a direct, reversible mechanism. That resulted in a very rapid onset of effect, with initial research showing that almost complete acid blockade could be achieved within 30 min of administration. CS-526 had provided effective acid inhibition equivalent to that observed with other proton pump inhibitors in rat studies [16,17] . It was discontinued in Phase I trials [101] .

2.2.7 AD-452 AD-452 (Sosei) was a low-molecular disease-modifying anti-rheumatic drug that was expected to reduce joint inflammation, destruction and pain while preserving mobility [105] .

It was indicated for the treatment of rheumatoid arthritis and osteoarthritis, but was discontinued after it failed to meet its primary or secondary efficacy end points in a Phase IIb clinical trial [106] .

2.2.8 TAK-715 TAK-715 (Takeda) was a p38 MAPK inhibitor, synthesized as a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles, that had been implicated in the pro-inflammatory cytokine signal pathway, the inhibitors of which are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

Inhibition of p38 MAPK and LPS-stimulated release of TNF- α from human monocytic THP-1 cells by TAK-715 was demonstrated in vitro ; its inhibition of LPS-induced TNF-α; production was demonstrated in vivo in mice. TAK-715 had showed good bioavailability in mice and rats and efficacy in a rat adjuvant-induced arthritis model. It was advanced into clinical Phase II trials [18] , but was discontinued as it did not satisfy criteria for further development [101] .

2.2.9 Amoxapine plus prednisolone combination CRx-119 was a combination of a low dose of the steroid prednisolone and amoxapine [107] . It was suggested to selectively amplify prednisolone’s anti-inflammatory and immunomodulatory effects without replicating the steroid toxicity [108] . It had potential for the treatment of rheumatoid arthritis, psoriasis, Crohn’s disease, ulcerative colitis, asthma, atopic dermatitis and other inflammatory conditions. It also modulated several cytokines including TNF- α . It was a once-daily administered product that could be delivered orally or by inhalation [101] . CRx-119 was generally well tolerated and there were no drug-related serious adverse events reported. The most common adverse event observed with CRx-119 was drowsiness, a known side effect of amoxapine.

2.2.10 CDP-484 Neutralization of IL-1 as a clinically effective mechanism for the treatment of immunity-related disorders had been supported by the recent FDA approval. CDP-484 (UCB), an antibody fragment that blocked the effects of the pro-inflammatory protein IL-1, was suggested as a new treatment for rheumatoid arthritis and other immunity-related

and inflammatory disorders. It had a high affinity in binding to IL-1. It was PEGylated and was expected to possess a prolonged duration of effect in patients [109] . CDP-484 was discontinued due to a Phase I trial in which it failed to meet the criteria to proceed with Phase II development [101] .

2.2.11 Balicatib The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. Cathepsin K inhibitors may reduce bone resorption, but do not affect bone formation, perhaps in part because inhibition of osteoclastic resorption in that manner did not impair osteoblastogenesis and in part because there might be transitory increases in parathyroid hormone. Balicatib (Novartis) was an orally active once-daily cathepsin K inhibitor for the treatment of osteoporosis, with low nanomolar potency against cathepsin K and excellent in vitro specificity against a large panel of thiol proteases, as well as serine or metalloproteases. It was ∼ 10- to 100-fold more potent in cell-based enzyme occupancy assays. It inhibited cathepsin K in osteoclasts, leading to reduced collagen breakdown and decreased bone resorption and had been shown to reduce bone turnover [19] . It was in Phase IIb trials when development was discontinued [101] .

2.2.12 FK-778 FK-778 (Astellas) exerts its immunosuppressive activity via the suppression of de novo pyrimidine biosynthesis, thus inhibiting the action of dihydroorotate dehydrogenase, an enzyme that is critical in the process, and consequently inhibiting cell prolifera-tion. It was shown that FK-778 directly reduced endothelial adhesion molecule upregulation, inhibited lymphocyte activa-tion and attenuated lymphocyte–endothelium interactions, which were critical early steps in graft rejection [20] . These effects were separate from the blockade of pyrimidine synthe-sis. The antiproliferative potency of FK-778 on smooth muscle cells may be an important mechanism to inhibit the fibropro-liferative lesions of chronic organ rejection. FK-778 inhibits formation of the immunologic synapse. It was discontinued, as it was not superior to existing treatments in Phase II trials [21] .

2.3 Dermatological 2.3.1 HyClinda HyClinda (Shire) was a topical gel formulation of the antibiotic clindamycin, which was under development for the treatment of acne. It used the topical hyaluronan-induced targeting system (HIT technology [qv]). It was pharmaco-logically described as a protein 50S ribosomal subunit inhibitor. It was discontinued while in Phase III development prior to SkyePharma’s discontinuation of all topical drug development programs [101] .

2.3.2 CRA-028129 Cathepsin S is expressed in antigen-presenting cells and plays a role in invariant chain processing and major MHCII antigen presentation leading to CD4 + T-cell activation.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.



An oral cathepsin S inhibitor that blocks MHC-II antigen presentation could result in a T-cell-selective immuno-suppressant agent with improved safety over the existing standard of care for the treatment of rheumatoid arthritis, bronchial asthma, psoriasis, multiple sclerosis and other autoimmune-based inflammatory diseases [22] . CRA-028129 (Celera Genomics) was discovered and developed as a part of a proprietary non-partnered program to develop inhibitors of cathepsin S [111] .

It was in a Phase I trial for psoriasis in 70 subjects in New Zealand. Celera had identified two biomarkers of cathepsin S inhibition, which would have been used to deter-mine the pharmacodynamic behavior of CRA-028129 [101] , but was discontinued while in a Phase I trial for psoriasis, due to Celera shifting its focus to diagnostics. The cathepsin K inhibitor balicatib (AAE-581) passed Phase II clinical trials in 2005 [23] , but was also discontinued, as described above.

2.3.3 CRx-140 Ciclosporin (CsA) is a potent immunomodulator, but its clinical use is limited by side effects. CRx-140, which was devel-oped by CombinatoRx as a combination of low-dose ciclospo-rin and loratadine, was shown to selectively amplify certain elements of ciclosporin’s anti-inflammatory and immunomod-ulatory properties, without amplifying its toxicities. It was an orally available, syncretic agent indicated in psoriasis [112] . CRx-140 was generally well tolerated, but in a randomized, blinded, controlled, Phase II clinical trial of CRx-140 in patients with psoriasis, statistical significance of the primary and secondary efficacy end points of reduction in Physician Global Assessment and Psoriasis Area Severity Index versus active control was not achieved and it was discontinued.

2.3.4 TGN-1412 TGN-1412 (TeGenero) caused near-fatal side effects in its first trial on human subjects in March 2006 [2] . In the Pharmaprojects database it is not listed as discontinued under its ‘world status’, but its ‘pharma status’ is given as ‘ceased’.

3. Expert opinion

In order for a new drug to enter onto the market, a long path must be traveled, including in vitro experiments, animal

models and human studies, which take many years. Following preclinical studies, introduction of the drug to humans must be closely monitored, usually in healthy volunteers in Phase I studies. Here, it is aimed to determine the metabolic and pharmacologic actions, bioavailability, bioclearance, distribu-tion of the drug and the side effects associated with increasing doses and, if possible, to gain early evidence of effectiveness. Technical innovation in pharmaceutical manufacturing has been relatively slow compared with that in drug R & D, with many methods used for process analysis remaining largely unchanged for decades. To address this problem and ensure the safety and efficacy of drug production, the FDA has developed process analytical technology guidelines for quality testing [113] .

Most of the discontinued drugs mentioned in this review could reach Phase II, which includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with a certain disease or symptom. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored and conducted in a relatively small number of patients. Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence to sug-gest effectiveness of the drug has been obtained in Phase II, and are intended to gather the additional information about efficacy and safety that is needed to evaluate the overall benefit–risk relationship of the drug. Phase III studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information to the scientific community.

Among physicians, factors for the selection of a newly developed drug are the efficacy, side effects, compliance and price in some communities. However, cost effectiveness, superiority over existing therapies, novel mechanism of action, intellectual property rights and sufficient data for licensing without problems are essential in the decision-making process by drug companies. With a world population of > 6 billion as the actual market, concept development based on pharmacoeconomics as a new science discipline is becoming more and more important in drug development.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Ozdemir & Akdis


Bibliography 1. AKDIS M, AKDIS CA: Mechanisms of

allergen-specifi c immunotherapy. J. Allergy Clin. Immunol. ( 2007 ) 119 (4): 780 -791.

2. SHERIDAN C: TeGenero fi asco prompts regulatory rethink. Nat. Biotechnol. ( 2006 ) 24 (5): 475 -476.

3. RENZETTI LM, TANNU S, CONNAUGHTON S et al. : Attenuation of airway infl ammation and hyperresponsiveness in murine and primate models of asthma by RO0270608, a dual α 4 β 1 – α 4 β 7 integrin antagonist. Am. J. Resp. Crit. Care. Med. ( 2003 ) 167 (7): A640 .

4. HIJAZI Y, WELKER H, DORR AE et al. : Pharmacokinetics, safety, and tolerability of R411, a dual α 4 β 1 – α 4 β 7 integrin antagonist after oral administration at single and multiple once daily ascending doses in healthy volunteers. J. Clin. Pharmacol. ( 2004 ) 44 : 1368 -1378.

5. HIJAZI Y, WELKER H, DORR AE, FRANK K, RENZETTI LM, PATEL I: Evaluation of the effect of multiple-dose administration of R411, a dual α 4 β 1 – α 4 β 7 integrin antagonist on the major CYP isoform activities in healthy volunteers. Eur. J. Clin. Pharmacol. ( 2006 ) 62 : 83 -85.

6. SINGH J, ADAMS S, CARTER MB et al. : Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma. Curr. Top. Med. Chem. ( 2004 ) 4 (14): 1497 -1507.

7. ROLIN S, MASEREEL B, DOGNÉ JM: Prostanoids as pharmacological targets in COPD and asthma. Eur. J. Pharmacol. ( 2006 ) 533 (1-3): 89 -100.

8. KESECIOGLU J, HAITSMA JJ: Surfactant therapy in adults with acute lung injury/acute respiratory distress syndrome. Curr. Opin. Crit. Care ( 2006 ) 12 (1): 55 -60.

9. LEUNG DY, SAMPSON HA, YUNGINGER JW et al. : Avon Longitudinal Study of Parents and Children Study Team Effect of anti-IgE therapy in patients with peanut allergy. N. Engl. J. Med. ( 2003 ) 348 (11): 986 -993.

10. MATTHEWS JB, RAMOS E, BLUESTONE JA: Clinical trials of transplant tolerance: slow but steady progress. Am. J. Transplant. ( 2003 ) 3 : 794 -803.

11. BOON L, LAMAN JD, ORTIZ-BUIJSSE A et al. : Preclinical

assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys. Toxicology ( 2002 ) 174 : 53 -65.

12. TRAVIS S, YAP LM, HAWKEY C et al. : RDP Investigators Study Group. RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Infl amm. Bowel Dis. ( 2005 ) 11 (8): 713 -719.

13. TREMAINE WJ, BRZEZINSKI A, KATZ JA et al. : AXYS ULCERATIVE COLITIS STUDY GROUP: Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study. Aliment. Pharmacol. Ther. ( 2002 ) 16 : 407 -413.

14. RICE KD, WANG VR, GANGLOFF AR et al. : Dibasic inhibitors of human mast cell tryptase. Part 2: structure–activity relationships and requirements for potent activity. Bioorg. Med. Chem. Lett. ( 2000 ) 16;10 (20): 2361 -2366.

15. HESSE C, LUNTZ SP, SIEDLER H, et al. : Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals. Br. J. Clin. Pharmacol. ( 2006 ) 61 (4): 414 -419.

16. VAKIL N: Review article: new pharmacological agents for the treatment of gastro-oesophageal refl ux disease. Aliment. Pharmacol. Ther. ( 2004 ) 15;19 (10): 1041 -1049.

17. ITO K, KINOSHITA K, TOMIZAWA A et al. : The anti-secretory and anti-ulcer properties of R-105266, a novel acid pumpantagonist. Gut ( 2001 ) 49 (Suppl. 3) (Abstract 3061).

18. MIWATASHI S, ARIKAWA Y, KOTANI E et al. : Novel inhibitor of p38 MAP kinase as an anti-TNF- α drug: discovery of N -[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent. J. Med. Chem. ( 2005 ) 22;48 (19): 5966 -5979.

19. FALGUEYRET JP, DESMARAIS S, OBALLA R et al. : Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. ( 2005 ) 48 (24): 7535 -7543.

20. SCHREPFER S, DEUSE T, KOCH-NOLTE F, DETTER C, REICHENSPURNER H: FK778: new cellular and molecular mechanisms of action. Transplant. Proc. ( 2006 ) 38 (3): 757 -761.

21. KAPLAN MJ: FK-778 Astellas. Curr. Opin.Investig. Drugs ( 2005 ) 6 (5): 526 -536.

22. LINK JO, ZIPFEL S: Advances in cathepsin S inhibitor design. Curr. Opin. Drug. Discov. Dev. ( 2006 ) 9 (4): 471 -482.

23. VASILJEVA O, REINHECKEL T, PETERS C, TURK D, TURK V, TURK B: Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr. Pharm. Des. ( 2007 ) 13 (3): 385 -401.

Websites 101. http://www.pharmaprojects.com

The Pharmaprojects database. Copyright © Informa UK Ltd 2007.

102. http://www.wipo.int/pctdb/fr/ia.jsp?LANGUAGE = FR & IA = EP2005%2F013462 & DISPLAY = DESC Combinations of valategrast and montelukast for treating asthma. World Intellectual Property Organization (Accessed June 2007).

103. http://www.leopharma.com/41256A84002BE7FC/0/59400A0E93DD0652C1256EAD007340E5?OpenDocumentLEO Pharma. HL 10 Project Closed (Accessed June 2007).

104. http://fi ndarticles.com/p/articles/mi_m0EIN/is_1999_Jan_5/ai_53509263) Axys Pharmaceuticals initiates Phase I clinical trial of lead topical tryptase inhibitor APC-2059, for the treatment of psoriasis (Accessed June 2007).

105. http://www.japancorp.net/article.asp?Art_ID = 10810) Sosei UK subsidiary starts Phase IIb clinical trial of AD-452, investigational drug for the treatment of rheumatoid arthritis (Accessed June 2007).

106. http://www.prnewswire.com/cgi-bin/stories.pl?ACCT = 104 & STORY = /www/story/11-21-2006/0004478282 & EDATE = Sosei announces the results of the Phase IIb clinical trial of AD-452 (Accessed June 2007).

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.



107. http://www.biospace.com/news_story.aspx?StoryID = 15009 CombinatoRx, Inc. reports preliminary data for CRx-119 in an exploratory immuno-infl ammatory disease model; does not meet primary endpoint of reduction of C-reactive protein (Accessed June 2007).

108. http://library.corporate-ir.net/library/14/148/148036/items/191669/CRXX_BIO_2006.pdf Combinator. Bio 2006 Conference (Accessed June 2007).

109. http://ir.ucb-group.com/phoenix.zhtml?c = 137495 & p = irol-newsArticle & ID = 845000 & highlight = Celltech new product pipeline (Accessed June 2007).

110. http://www.celera.com/celera/pr_1127168705 Press release: Celera Genomics initiates Phase I clinical trial for cathepsin s inhibitor for the treatment of psoriasis. Celera Genomics initiates Phase I clinical trial for cathepsin S inhibitor for the treatment of psoriasis (Accessed June 2007).

111. http://www.corporate-ir.net/media_fi les/irol/14/148036/030606b.pdf A Phase II trial of a new anti-infl ammatory combination drug, CRx-140, in patients with severe psoriasis. Gottlieb A, Zhang Y,Nichols M, CRx-140 Group at CombinatoRx, Inc. and CRx-140 Group of Investigators (Accessed June 2007).

112. http://www.fda.gov/Cder/guidance/5815dft.htm Process Analytical Technology (PAT): A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. (Accessed June 2007).

Affi liation Cevdet Ozdemir1 MD & Cezmi A Akdis †2 MD †Author for correspondence 1 Marmara University, Division of Pediatric Allergy and Immunology, Istanbul, Turkey 2 Swiss Institute of Allergy and Asthma Research (SIAF) Obere Strasse 22 CH-7270, Davos, Switzerland Tel: +41 81 4100848; Fax: +41 81 4100840;E-mail: [email protected]

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

Of

Pitts

burg

h on

11/

05/1

4Fo

r pe

rson

al u

se o

nly.

Documents

Discontinued drugs in 2006: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs