Peroxisome

Peroxisome Proliferator-Activated
Proliferator-Activated
Receptor
Receptor (PPAR)
(PPAR) Agonists
Agonists

Preclinical
Preclinical and
and Clinical
Clinical Cardiac
Cardiac Safety
Safety
Considerations
Considerations

Jeri
Jeri El-Hage,
El-Hage, Ph.D.
Ph.D.
Div.
Div. of
of Metabolism
Metabolism andand Endocrinology
Endocrinology Products
Products
Center
Center for
for Drug
Drug Evaluation
Evaluation and
and Research,
Research, FDA
FDA

Endocrinologic and Metabolic Drugs

 PPAR
PPAR Agonist
Agonist Therapeutics
Therapeutics
•• PPAR
PPAR gamma
gamma agonists
agonists -- insulin
insulin sensitizers
sensitizers for
for type
type 22 diabetes
diabetes
–– Approved
Approved drugs
drugs –– Actos
Actos (pioglitazone),
(pioglitazone), Avandia
Avandia
(rosiglitazone)
(rosiglitazone)

PPAR
PPAR alpha
alpha agonists
agonists –for
–for dyslipidemia,
dyslipidemia, increase
increase HDL,
HDL,
decrease
decrease TG,
TG, no
no effects
effects on
on LDL.
LDL.
Approved
Approved drugs
drugs –– fibrates
fibrates (( fenofibrate,
fenofibrate, clofibrate)
clofibrate)

PPAR
PPAR dual
dual agonists
agonists (alpha/gamma)
(alpha/gamma) –– being
being developed
developed for
for
combined
combined treatment
treatment ofof type
type 22 diabetes
diabetes and
and dyslipidemia
dyslipidemia
Muraglitazar,
Muraglitazar, Tesaglitazar,
Tesaglitazar, Ragaglitazar,
Ragaglitazar, Naveglitazar
Naveglitazar

PPAR
PPAR delta
delta agonists
agonists –– being
being developed
developed for
for obesity
obesity

PPAR
PPAR pan
pan agonists
agonists (alpha/delta/gamma)
(alpha/delta/gamma) –– being
being developed
developed
for
for type
type 22 diabetes
diabetes and and dyslipidemia
Endocrinologic and Metabolic Drugs
dyslipidemia
 PPAR
PPAR Agonist
Agonist Development
Development Chronology
Chronology
•• Troglitazone
Troglitazone –– approved
approved 1997.
1997. Removed
Removed from from market
market for
for safety
safety
concern
concern (i.e.,
(i.e., drug-induced
drug-induced liver
liver failure)
failure) in
in 2000.
2000.

•• Pioglitazone
Pioglitazone and
and Rosiglitazone
Rosiglitazone –– approved
approved by
by FDA
FDA in
in 1999.
1999.

•• Seven
Seven yearsyears since
since last
last approval
approval despite
despite intense
intense interest
interest in
in this
this
therapeutic
therapeutic area,
area, i.e.,
i.e., dozens
dozens of
of compounds
compounds in in development
development
(( >> 50
50 INDs).
INDs).

•• Numerous
Numerous development
development programs
programs terminated
terminated –– all
all for
for safety
safety
issues.
issues.

•• Toxicities
Toxicities observed
observed in
in animals
animals are
are also
also observed
observed clinically
clinically ..
(( e.g.,
e.g., cardiac,
cardiac, skeletal
skeletal muscle,
muscle, renal,
renal, bone
bone marrow).
marrow).

Most
Most agonists
agonists in
in development
development are are non-thiazolidinediones.
non-thiazolidinediones.
Liver
Liver toxicity
toxicity has
has not
not been
been aa clinical
clinical safety
safety issue.
issue.

Endocrinologic and Metabolic Drugs

 Discontinuations
Discontinuations for
for Clinical
Clinical Cardiac
Cardiac Safety
Safety
•• Indirect
Indirect -- PPAR
PPAR gamma-mediated
gamma-mediated fluid
fluid accumulation,
accumulation, weight
weight gain,
gain,
and
and edema
edema leading
leading to
to excess
excess CHF
CHF (dose
(dose and
and duration
duration dependent,
dependent,
may
may be
be pharmacologic
pharmacologic effect
effect on
on kidney
kidney))
–– Approved
Approved drugs
drugs –– re-labeled
re-labeled to
to describe
describe CHF
CHF risk
risk

–– Pro-active
Pro-active study
study –– Pioglitazone
Pioglitazone (( Lancet
Lancet 366:9493,
366:9493, Oct.
Oct. 2005)
2005)

–– Muraglitazar
Muraglitazar Advisory
Advisory Committee
Committee -- Sept.
Sept. 2005
2005
–– Numerous
Numerous other
other non-approved
non-approved drugs
drugs with
with clinical
clinical safety
safety signal
signal
for
for excess
excess edema/CHF
edema/CHF (gamma
(gamma and
and dual
dual agonists).
agonists).

Direct
Direct cardiotoxicity(?)
cardiotoxicity(?) –– death,
death, MI,
MI, stroke,
stroke, TIA.
TIA.
Clinical
Clinical –– Muraglitazar
Muraglitazar Advisory
Advisory Committee,
Committee, Sept
Sept 2005
2005
Preclinical
Preclinical evidence
evidence for
for direct
direct cardiotoxicity
cardiotoxicity with
with dual
dual and
and alpha
alpha
agonists.
agonists.
Endocrinologic and Metabolic Drugs
 Discontinuations
Discontinuations for
for Clinical
Clinical Safety
Safety
Non-cardiac
Non-cardiac

•• Skeletal
Skeletal muscle
muscle toxicity
toxicity –– rhabdomyolysis
rhabdomyolysis in in
Phase
Phase 11 trials
trials
–– Led
Led to
to discontinuation
discontinuation ofof 11 dual
dual ,, 11 alpha
alpha
agonist
agonist

•• Renal
Renal toxicity
toxicity –– >> 50%
50% increases
increases inin creatinine,
creatinine,
excess
excess renal
renal failure
failure
–– Led
Led to
to discontinuation
discontinuation ofof 22 dual
dual agonists.
agonists.

Endocrinologic and Metabolic Drugs

 Nonclinical
Nonclinical Safety
Safety Issues
Issues ::
Rodent
Rodent Carcinogenicity
Carcinogenicity Findings
Findings

•• Drug-
Drug- related
related increases
increases in
in tumors
tumors with
with gamma
gamma and
and dual
dual
agonists
agonists

Mouse
Mouse (CD-1,
(CD-1, B6C3F1)
B6C3F1)
hemangiosarcomas
hemangiosarcomas observed
observed with
with 10/13
10/13 compounds
compounds

Rat
Rat (( SD,
SD, Wistar,
Wistar, Fischer)
Fischer) --
–– Bladder
Bladder tumors
tumors –– 5/7
5/7 dual
dual agonists
agonists (negative
(negative in
in Wistar
Wistar rats)
rats)
–– Sarcomatous
Sarcomatous tumors
tumors of
of adipose,
adipose, skin,
skin, renal
renal tubules,
tubules,
muscle
muscle (( uterus,
uterus, stomach)-
stomach)- more
more common
common with
with dual
dual agonists
agonists
–– According
According to
to the
the International
International Agency
Agency for
for Research
Research onon Cancer
Cancer
(IARC)
(IARC) and
and Environmental
Environmental Protection
Protection Agency
Agency (EPA)
(EPA) criteria
criteria ::
–– Multi-species,
Multi-species, multi-strain,
multi-strain, multi-sex,
multi-sex, multi-site
multi-site carcinogens
carcinogens ==
“probable
“probable human
human carcinogen”
carcinogen”

Class-related
Class-related tumor
tumor findings
findings led
led to
to development
development of of policy
policy
requiring
requiring completion
completion of
of rodent
rodent carcinogenicity
carcinogenicity studies
studies prior
prior to
to
the
the initiation
initiation of
of Phase
Phase 33 clinical
clinical studies
studies (( >> 66 months
months duration).
duration).
Endocrinologic and Metabolic Drugs
 Discontinuation
Discontinuation for
for Nonclinical
Nonclinical Safety
Safety Issues
Issues
•• Five
Five dual
dual agonists
agonists discontinued
discontinued (by(by sponsors)
sponsors) for
for multi-species,
multi-species,
multi-sex,
multi-sex, multi-site
multi-site increases
increases in
in tumors
tumors with
with no
no safety
safety margins
margins
for
for clinical
clinical exposures.
exposures.

Three
Three compounds
compounds terminated
terminated prior
prior to
to CDER
CDER recommendations
recommendations for
for
completion
completion of
of carcinogenicity
carcinogenicity testing
testing prior
prior to
to Phase
Phase 3.
3. (June
(June
2004).
2004).

Development
Development of of 22 additional
additional compounds
compounds terminated
terminated for
for rodent
rodent
carcinogenicity
carcinogenicity findings
findings (( multispecies,
multispecies, multisite
multisite tumors
tumors atat all
all
doses
doses )) since
since the
the CDER
CDER policy
policy was
was implemented.
implemented.

•• Brain
Brain lesions
lesions –– not
not monitorable
monitorable or
or reversible
reversible
ventricular
ventricular dilation,
dilation, brain
brain vacuolation
vacuolation –dog
–dog (n
(n == 11 drug)
drug)
brain
brain hemorrhages
hemorrhages –– monkey
monkey (n
(n == 11 drug)
drug)
Endocrinologic and Metabolic Drugs
 PPAR
PPAR Safety
Safety Summary
Summary

•• PPAR
PPAR gamma-mediated
gamma-mediated fluid
fluid accumulation,
accumulation, edema,
edema, weight
weight
gain
gain with
with consequent
consequent increased
increased frequency
frequency of
of CHF
CHF is
is the
the
major
major dose-limiting
dose-limiting adverse
adverse event.
event.

•• The
The fluid
fluid accumulation
accumulation andand resultant
resultant adverse
adverse cardiac
cardiac
effects
effects are
are observed
observed preclinically
preclinically and
and clinically
clinically with
with
virtually
virtually all
all compounds
compounds with
with PPAR
PPAR gamma
gamma activity
activity
(gamma,
(gamma, dual
dual ,, and
and pan
pan agonists).
agonists).

•• Clinical
Clinical safety
safety issues
issues responsible
responsible for
for the
the discontinuation
discontinuation
of
of more
more compounds
compounds than
than rodent
rodent carcinogenicity
carcinogenicity issues.
issues.

While
While the
the approved
approved drugs
drugs are
are associated
associated with
with increased
increased
edema
edema and
and CHF,
CHF, there
there is
is no
no evidence
evidence of
of direct
direct
cardiotoxicity
cardiotoxicity with
with the
the approved
approved PPAR
PPAR gamma
gamma agonists.
agonists.

Endocrinologic and Metabolic Drugs

 PPAR
PPAR Gamma-Mediated
Gamma-Mediated Cardiac
Cardiac Toxicity
Toxicity

•• Fluid
Fluid accumulation
accumulation in
in all
all species
species (( mouse,
mouse, rat,
rat, dog,
dog, rabbit,
rabbit, monkey,
monkey,
human).
human).

•• Fluid
Fluid accumulation
accumulation leads
leads to
to weight
weight gain,
gain, edema,
edema, cardiac
cardiac
hypertrophy
hypertrophy with
with resultant
resultant heart
heart failure
failure in
in all
all species.
species.

•• Dogs
Dogs more
more sensitive
sensitive to
to PPAR
PPAR toxic
toxic effects
effects than
than other
other species,
species, thus
thus
not
not helpful
helpful for
for establishing
establishing safety
safety margins
margins forfor clinical
clinical doses.
doses. Led
Led
to
to recommendation
recommendation that that general
general toxicity
toxicity testing
testing be
be conducted
conducted inin
rats
rats and
and monkeys.
monkeys.

•• Fluid
Fluid accumulation,
accumulation, weight
weight gain,
gain, cardiac
cardiac hypertrophy
hypertrophy observed
observed
with
with short
short latency
latency (( within
within 1-3
1-3 months).
months).

•• Drug-induced
Drug-induced heartheart failure
failure and
and death
death observed
observed with
with chronic
chronic
treatment
treatment (( >> 66 months
months in in animals
animals andand man).
man).
–– Led
Led to
to recommendation
recommendation for for 11 year
year non-rodent
non-rodent toxicity
toxicity study
study in
in
attempt
attempt toto define
define NOAEL
NOAEL exposures
exposures for for chronic
chronic clinical
clinical dosing.
dosing.
Endocrinologic and Metabolic Drugs
 PPAR-Related
PPAR-Related Cardiac
Cardiac Toxicity:
Toxicity: Nonclinical
Nonclinical
•• Atrial
Atrial thrombi,
thrombi, pericardial/thoracic
pericardial/thoracic effusions,
effusions, cardiomyopathy,
cardiomyopathy,
interstitial
interstitial expansion,
expansion, and
and CHF-related
CHF-related deaths
deaths observed
observed inin rats
rats
and
and monkeys
monkeys with
with chronic
chronic treatment
treatment (( 11 yr
yr in
in monkey,
monkey, >> 11 year
year in
in
rats
rats and
and mice).
mice).

•• Dual
Dual and
and alpha
alpha agonists
agonists also
also associated
associated with
with direct
direct
cardiomyopathy
cardiomyopathy in
in mice,
mice, rats,
rats, dogs,
dogs, and
and monkeys.
monkeys.

•• No
No adverse
adverse effect
effect levels
levels (NOAEL)
(NOAEL) for for fluid
fluid accumulation
accumulation and
and
resultant
resultant adverse
adverse cardiac
cardiac effects
effects (CHF,
(CHF, death)
death) decrease
decrease markedly
markedly
with
with increased
increased treatment
treatment duration
duration in in animals
animals and
and humans.
humans.
–– Safe
Safe doses
doses in
in Phase
Phase 22 clinical
clinical trials
trials do
do not
not predict
predict safe
safe doses
doses
for
for Phase
Phase 33 or
or chronic
chronic treatment.
treatment.

•• Division
Division defines
defines NOAELs
NOAELs for
for cardiac
cardiac toxicity
toxicity using
using data
data from
from the
the
longest
longest duration
duration nonclinical
nonclinical studies
studies (( 11 yr
yr monkey,
monkey, 22 year
year rat).
rat).
Therefore,
Therefore, data
data from
from rodent
rodent carcinogenicity
carcinogenicity studies
studies used
used to
to
determine
determine NOAELs
NOAELs for
for cardiac
cardiac safety,
safety, as
as well
well as
as safety
safety margins
margins
for
for carcinogencity.
carcinogencity.
Endocrinologic and Metabolic Drugs
 Effect
Effect of
of Treatment
Treatment Duration
Duration on
on LOAEL
LOAEL
Preclinical
Preclinical Examples
Examples

Study 1 Mos 3 Mos 6 Mos Chronic

Duration/ (1 yr Monkey;
Dose mg/kg mg/kg mg/kg 2 yr rodent)
Gamma
Mouse 20 (21 X) 0.5 ( 2X)
Rat 10 (12X) 4 (3X) 1 ( 1X)
Monkey 10 ( 20X) 3 (8X) 1 (3X) 0.3 (1X)

Dual
Rat 3 (3X) 0.4 (1X) 0.1 ( ½ X)
Dog 4 (25 X) 0.4 (3X) ------ --------
Monkey 1.2 (9X) 0.4 (3X)

Endocrinologic and Metabolic Drugs

 Effect
Effect of
of Treatment
Treatment Duration
Duration on
on LOAEL
LOAEL
Clinical
Clinical Examples
Examples
Duration 12 -16 Wks 24-26 Wks 52 Wks

Gamma
Edema 20 mg 10 mg 2.5 mg
CHF ------- 10 mg 5 mg
Gamma
Edema 20 mg 5 mg No data
CHF -------- 10 mg No data
Dual
Edema 20 mg 5 mg 2.5 mg
CHF --------- 10 mg 5 mg
Dual
Edema 5 mg 2 mg 0.5 mg
CHF ------- -------- 1 mg
Endocrinologic and Metabolic Drugs
 Implications
Implications of
of Cardiac
Cardiac Toxicity
Toxicity for
for
Carcinogenicity
Carcinogenicity Testing
Testing
•• Doses
Doses which
which increase
increase heart
heart weights
weights ≥≥ 25%
25% in
in rodents
rodents at
at 33 months
months result
result
in
in premature
premature cardiac
cardiac mortality
mortality in
in 2-
2- year
year carcinogenicity
carcinogenicity studies.
studies.

•• Rats
Rats more
more sensitive
sensitive to
to developing
developing failure
failure secondary
secondary to
to fluid
fluid
accumulation
accumulation and
and cardiac
cardiac hypertrophy
hypertrophy than
than mice.
mice.

•• 20-25%
20-25% increases
increases in
in heart
heart weight
weight accepted
accepted toto establish
establish the
the maximum
maximum
tolerated
tolerated dose
dose (MTD)
(MTD) for
for carcinogenicity
carcinogenicity testing
testing in
in both
both rodent
rodent species.
species.

•• This
This paradigm
paradigm developed
developed based
based on
on experience
experience with
with PPAR
PPAR gamma
gamma
agonists
agonists and
and successfully
successfully predicts
predicts MTD
MTD for
for most
most gamma
gamma only
only
compounds
compounds ..

•• However,
However, use use of
of 20-25%
20-25% increase
increase inin heart
heart wt
wt to
to define
define the
the high
high dose
dose
(MTD)
(MTD) for
for dual
dual agonists
agonists hashas been
been less
less successful.
successful. Premature
Premature mortality
mortality
still
still observed
observed with
with high
high dose
dose inin 22 year
year rat
rat studies
studies with
with most
most dual
dual
agonists
agonists .. Data
Data suggest
suggest addition
addition of
of alpha
alpha activity
activity to
to dual
dual agonist
agonist
enhances
enhances cardiac
cardiac toxicity
toxicity ..
Endocrinologic and Metabolic Drugs
 Implications
Implications of
of Cardiac
Cardiac Toxicity
Toxicity for
for Clinical
Clinical
Study
Study Design
Design
•• Patients
Patients with
with NYHA
NYHA class
class 33 and
and 44 cardiac
cardiac disease
disease have
have
usually
usually been
been excluded
excluded from
from Phase
Phase 33 trials.
trials.

•• Phase
Phase 22 and
and 33 protocols
protocols should
should include
include prospective
prospective
monitoring
monitoring for
for fluid
fluid accumulation,
accumulation, weight
weight gain,
gain, edema
edema

•• Stopping
Stopping criteria
criteria should
should be
be predefined.
predefined.

•• Monitor
Monitor diuretics
diuretics use
use or
or dose
dose changes.
changes.

•• DSMB
DSMB adjudication
adjudication of
of cardiac
cardiac morbidity
morbidity and
and mortality
mortality
(( e.g.,
e.g., CHF,
CHF, MI,
MI, stroke,
stroke, TIA,
TIA, death).
death).

Endocrinologic and Metabolic Drugs

 Implications
Implications of
of Cardiac
Cardiac Toxicity
Toxicity for
for Clinical
Clinical
Studies
Studies (slide
(slide 1)
1)
•• Phase
Phase 33 studies
studies should
should bebe designed
designed as as one
one year
year controlled
controlled
trials
trials with
with collection
collection of
of open
open label
label safety
safety data
data for
for up
up to
to 22
years
years inin aa significant
significant number
number of of patients
patients (( e.g.,
e.g., minimum
minimum of of
500
500 subjects
subjects for
for 18
18 months
months andand 200
200 for
for 22 years).
years).

•• Phase
Phase 33 dose
dose selections
selections based
based on
on drug
drug exposures
exposures at
at
NOAELs
NOAELs in in the
the chronic
chronic preclinical
preclinical studies
studies and
and Phase
Phase 22
safety
safety data
data have
have been
been associated
associated with
with excess
excess cardiac
cardiac
toxicity
toxicity (edema,
(edema, heart
heart failure
failure and
and cardiac
cardiac morbidity)
morbidity) in
in
numerous
numerous failed
failed Phase
Phase 33 programs.
programs.

•• Phase
Phase 33 trials
trials only
only justified
justified ifif safety
safety margin
margin isis fully
fully adequate
adequate
at
at doses
doses expected
expected toto have
have sufficient
sufficient clinical
clinical effect
effect
•• (i.e,
(i.e, ifif edema
edema isis observed
observed at at doses
doses close
close to
to those
those required
required for
for
efficacy,
efficacy, drugdrug may
may not
not be
be aa good
good candidate
candidate forfor further
further
development).
development).

Endocrinologic and Metabolic Drugs

 Implications
Implications of
of Cardiac
Cardiac Toxicity
Toxicity for
for Clinical
Clinical
Studies
Studies (slide
(slide 2)
2)
•• Phase
Phase 33 clinical
clinical safety
safety data
data suggest
suggest that
that humans
humans with
with type
type
22 diabetes
diabetes are
are more
more sensitive
sensitive to
to the
the chronic
chronic cardiotoxic
cardiotoxic
effects
effects of
of PPAR
PPAR agonists
agonists than
than the
the young
young healthy
healthy animals
animals
used
used in
in preclinical
preclinical toxicology
toxicology studies.
studies. (( i.e.,
i.e., drug
drug exposures
exposures
at
at NOAELs
NOAELs in in rodents
rodents and
and monkeys
monkeys over
over estimate
estimate safety
safety
margins).
margins).

•• Cardiac
Cardiac toxicity
toxicity is
is progressive
progressive in
in humans
humans and
and animals
animals ..
(( i.e.,
i.e., seen
seen at
at lower
lower doses/AUC
doses/AUC exposures
exposures with
with longer
longer
treatment
treatment duration).
duration).

Doses
Doses without
without cardiac
cardiac safety
safety signals
signals after
after chronic
chronic treatment
treatment
are
are usually
usually 55 to
to 10-
10- fold
fold lower
lower than
than doses
doses considered
considered safe
safe
after
after 12-16
12-16 weeks
weeks of of treatment.
treatment.

Endocrinologic and Metabolic Drugs

 Recommendations
Recommendations for
for Phase
Phase 33 Study
Study
Designs
Designs
•• Evaluation
Evaluation of of cardiac
cardiac safety
safety data
data from
from chronic
chronic preclinical
preclinical
studies
studies and
and Phase
Phase 22 clinical
clinical studies
studies will
will be
be conducted
conducted prior
prior
to
to the
the initiation
initiation of
of Phase
Phase 33 trials.
trials. (coincident
(coincident with
with the
the
submission
submission of of the
the rodent
rodent carcinogenicity
carcinogenicity data).
data).

•• Cardiac
Cardiac safety
safety assessment
assessment may may result
result in
in dose
dose limitations
limitations
and/or
and/or the
the recommendation
recommendation for for collection
collection of of cardiac
cardiac
outcomes
outcomes data
data in
in Phase
Phase 33 trials
trials ..

•• Currently,
Currently, recommendations
recommendations for for Phase
Phase 33 cardiac
cardiac outcome
outcome
studies
studies will
will be
be made
made on
on aa case-by
case-by -case
-case basis
basis dependent
dependent
on
on the
the cardiac
cardiac safety
safety profile
profile of
of each
each compound.
compound.

Endocrinologic and Metabolic Drugs