Dr. Gelzleichter: Evaluation of Carcinogenic Risk for Biotechnology

crunchkingofprussiaBiotechnology

Dec 6, 2012 (4 years and 8 months ago)

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©2012, Genentech

Nor Cal SOT

Evaluation of Carcinogenic Risk for
Biotechnology
-
Derived Therapeutics

Tom
Gelzleichter

September 27
th
, 2012

©2012, Genentech

1. Limitations
on utility of standard rodent bioassays for biologics

2. Historical
approaches for risk assessment of biologics

3. 2011
revisions to ICH S6

4. Examples
of revised approach

5. How
will these changes impact risk communication?


Topics

©2012, Genentech

Main Objective of Carcinogenesis Testing for
Pharmaceuticals

A product
-
specific
assessment of carcinogenic potential is
used to
communicate risk
and
provide input to the risk
management plan
along with labeling proposals, clinical
monitoring, post
-
marketing
surveillance

©2012, Genentech

2 year bioassays in general have limited utility for all chemical
classes

Interpretation difficult due to:


Lack of known negative controls (IARC only classifies one chemical as probably
not carcinogenic in humans)


Susceptibility determined by genotype, sex and test conditions


Examples: cigarette smoke, arsenic, benzene were challenging to find
rodent models that gave positive results


Lack of concordance across sexes, species (rarely are tumors found in all 4
genotypes
i
,.e., rat/mouse/M/F)


Inter
-
rodent
predictivity

(
rat:mouse
) 70
-
75%


Validation efforts have been heavily skewed towards certain chemical classes
(plus, nearly all have been
genotoxicants
)


Poor concordance for
immunotoxicants
, some hormones


Poor reproducibility (only 57% concordance when repeated)


Positivity rate is extremely high


In NTP studies, 68% of tested chemicals are positive in at least one of
the 4 genotypes


40% of marketed pharmaceuticals and food additives are positive


©2012, Genentech

Why are Chronic Rodent Bioassays
S
till
U
sed?


Most known human carcinogens are positive in at least one of the 4 genotypes
tested, when evaluated at MTD


Only 5
-
10% of positives are strictly rodent carcinogens


i.e
, has some positive predictive value


However, rate of false positives poorly understood




Limitations of the assay limit the utility


Typically used to inform label, informed consent


Rarely will regulatory agencies use this data in isolation for decision
-
making


©2012, Genentech

What About Biologics?

Rarely are long term studies in rodents feasible for biologics due to
antigenicity concerns or lack of binding

Lack of validation data


Limited data for
nongenotoxic

carcinogens


Virtually no validation efforts with large molecules (e.g.,
Tg
-
AC
transgenic model)


Known lack of concordance for immunosuppressive agents, many
hormones

Surrogate molecules: Discouraged given difficulties in verifying that
surrogate accurately reflects the biology of clinical candidate


Other data:


Data from in class or related drugs


Transgenic/
ko


Xenograft

studies

Limitations in data
interpretation and lack of
validation limit utility

©2012, Genentech


Challenges with
Nongenotoxic

Drugs:

What We’ve Learned From Risk Evaluation
of Immunosuppressive Agents

©2012, Genentech

Human Neoplasms Associated with 13 Immunosuppressive Drugs

Type

Drugs

Lymphoma

Dexamethasone, prednisone,

busulfan
, azathioprine,
methotrexate,
mycophenolate
,
cyclosporin

A,
tacrolimus

Squamous Cell Carcinoma

Prednisone,
busulfan
, azathioprine,

methotrexate,
mycophenolate
,
cyclosporin

A,
tacrolimus

Kaposi

Sarcoma

Dexamethasone, prednisone,
busulfan
, azathioprine,
methotrexate,
mycophenolate
,
cyclosporin

A

Urologic

Prednisone,

azathioprine,
mycophenolate
,
cyclosporin

A,
tacrolimus

Melanoma

mycophenolate

Multiple

cyclophosphamide

Source: Bugelski et al.(2010) Int. J. Toxicol. 29(5) 435
-
66

©2012, Genentech

Two year bioassay results for immunosuppresive drugs

Drug

Rat 2
yr

Mouse 2
yr

Abatacept

-

Lymphomas and mammary

tumors
(MLV/MMT virus)

Dexamethasone

Neg

-

Prednisone

-

Neg

Busulfan

-

Thymic

and ovarian

Cyclophosphamide

multiple

multiple

Azathioprine

Lymphoma

and squamous

Lymphoma,
hemangioendothelioma

Leflunomide

Neg

Lymphoma and lung

Methotrexate

Neg

Neg

Mycophenolate

Neg

Neg

Cyclosporine

Neg

Neg

Tacrolimus

Neg

Neg

sirolimus

Neg

Lymphoma and liver

everolimus

Neg

Neg


Of the 5 positives, 4 are known
genotoxicants


Poor concordance with known human
risks


Only 2 correctly predict specific tumor risks

©2012, Genentech

ICH Guidance for Biologics (Original ICH S6, 1997)

Standard
carc

bioassays are generally inappropriate for biotech drugs

When there is a concern, “a variety of approaches may be considered to
evaluate risk”

In case where product is biologically active and
nonimmunogenic

and
other studies have not provided sufficient information to assess risk,
then consider a singe rodent bioassay



©2012, Genentech

For Products that Support or Induce Proliferation (ICH S6, 1997)

Evaluate/review receptor expression in malignant and normal cells

Is there evidence that can stimulate growth of normal or malignant
cells?




Cause for concern?









Further studies in relevant model


Incorporate sensitive indices of
proliferation into chronic studies


If biologically active and
nonimmunogenic

consider

long
term assay


Yes No




In vitro evaluations may be
sufficient


©2012, Genentech



Question:
Given the limitations of chronic bioassays and ICH
guidance,
what type of
carc

studies
have
been
conducted for biologics
?







Answer:
In reality, very few chronic studies have been conducted that
have actually impacted product labels



©2012, Genentech

32 FDA
-
Licensed
MAb’s

to date: Two sponsors have
conducted preclinical studies that impacted label

Generic Name

Year Licensed by
FDA

Target

LT
Carc

studies on label?

Muromonab
-
CD3

1986

T cell CD3 Receptor

no

Abcixumab

1994

inhibition of glycoprotein IIb/IIIa

no

Daclizumab

1997

IL
-
2R
α
receptor (CD25)

no

Rituximab

1997

CD20

no

Basiliximab

1998

IL
-
2R
α
receptor (CD25)

no

Infliximab

1998

inhibition of TNF
-
α
signaling

no

Palivizumab

1998

an epitope of the RSV F protein

no

Trastuzumab

1998

ErbB2

no

Gemtuzumab

2000

CD33

no

Alemtuzumab

2001

CD52

no

Adalimumab

2002

inhibition of TNF
-
α
signaling

no

Efalizumab

2002

CD11a

no

Ibritumomab

2002

CD20

no

Tositumomab

2003

CD20

no

Bevacizumab

2004

VEGF

no

Cetuximab

2004

epidermal growth factor receptor

no

Omalizumab

2004

immunoglobulin E (IgE)

no

Natalizumab

2006

alpha
-
4 (
α4)
integrin,

xenograft models of a4+ cell
lines: no drug related impact

Panitumumab

2006

epidermal growth factor receptor

no

Ranibizumab

2006

VEGF
-
A

no

Eculizumab

2007

Complement system protein C5

no

Certolizumab pegol

2008

inhibition of TNF
-
α
signaling

no

Canakinumab

2009

IL
-
1
β

no

Golimumab

2009

TNF
-
alpha inihibitor

no

Ustekinumab

2009

anti
-
IL12/IL23

Decreased host defense to
tumors with surrogate; knockout
mice susceptible to tumors
[Data not from Sponsor
-
run
trials]

Ofatumumab

2009

CD20

7 month
cyno

tumorigenicity

data included in label
-

no drug
-
related effects noted

Denosumab

2010

RANK Ligand inhibitor

no

Tocilizumab
(Atlizumab )

2010

Anti
-

IL
-
6R

no

Belimumab

2011

inihibition of B
-

cell activating factor

no

Brentuximab vedotin

2011

CD30

no

Ipilimumab ( MDX
-
101 )

2011

blocks CTLA
-
4

no


Two Sponsors
conducted trials that
impacted label


One label impacted
by published
literature reports
(
ustekinumab
)

©2012, Genentech

Label Claims for Non
-
MAb

Therapeutics

Label Claim

2

yr

studies in one or two species

glargine

(insulin analog),
ocreotide

(
somatostatin

analog),
teriparatide

(parathyroid hormone analog), IGF
-
1, gonadotropin releasing hormone,
exenatide
,
liraglutide

(
incretin

mimetic),
pulmozyme

(
rhDNAse
),
abatacept

Two year
carc

studies have not been
performed…

But tumors
ID’ed

in chronic

tox

studies

aspart
,

glusine
, and
lispro

(insulin analogs), calcitonin,
pamlinitide

(amylin
hormone analog),

Hypothical

risk stated in label

asparaginase

(alkylating agent)

Two year
carc

studies in animals have
not been performed….

humulin
,
novolin
,
lente
,
ultralente
,
Exubera
,
detemir
,
genotropin
,
humantrope
,
norditropin
,
norIVitropin
,
nutropin
,
omnitrope
,
protropin
,
siazen
,
serostim
,
valtropin
,
iplex
,
bioclate
,
helixate
,
kogenate
,
recombinate
,
reFacto
,
BeneFIX
,

ceprotin
,
aldurazyme
,
elaprase
,
naglazyme
,
fabrazyme
,
aralast
,
prolastin
,
lactaid
,
arco
-
lase,
cotazym
,
creon
,
donnazyme
,
pancrease
,
viokase
,
zymase
,
adagen

octagam
,
albumarc
, albumin,
albuminar
,
albuRx
,
albutein
,
flexbumin
,
buminate
,
plasbumin
,
neupogen
,
neulasta
,
leukine
,
neumega
,
Gonal
-
F,
Follistim
,
ovidrel
,
luveris
,
infergen
,
roferon
-
A,
Pegasys
,
Intron A, Peg
-
Intron,
Alferon

N,
Avonex
,
rebif
,
betaseron
,
actimmune
,
proleukin
,
activase
,
retavase
,
TNKase
,
abbokinase
,
NovoSeven
,
Xigris
,
kepivance
,
regranex
,
granulex
,
natrecor
,
botox
,
myoblock

collagenase,
xiaflex
,
santyl
,
amphadase
,
hydase
,
vitrase
,
hylenex
,
oncaspar
,
elitek
,
refludan
,
angiomax
,
streptase
,
eminase
,
antril
,
kinaret
,
thioglobulin
,
fuzeon
,
somavert
,
crofab
,
digifab
,
ontak
,

©2012, Genentech

New ICH S6 Revision (ICH S6 R1, June 2011)

To better inform risk, a new paradigm has been
implemented by ICH




When an assessment is warranted (i.e., chronic dosing,
appropriate patient population, etc.) a
weight of
evidence approach

is now advocated


More emphasis on post
-
marketing surveillance


©2012, Genentech

What Can this Include?

Assessment of risk based on
published literature and internal data


Clinical


Market surveillance


Human epidemiology


Genetic diseases


Polymorphisms


Class effects

Mechanistic
data


Is there impact on pathways known to be associated with malignancy risk


Immunosuppression
, chronic inflammation


Downstream signaling through pathways associated with
risk

Transgenic models

KO models

Animal disease models

Xenograft

models

In vitro data

Chronic
tox

data

Alternative data (lifetime
phenotyping
, labeling for proliferation)

©2012, Genentech

Recommendations per ICH S6 R1, 2011


Outcome of Weight Based Assessment

Cause for concern


Hazard best
addressed by product
labeling and risk
management practices


Sponsor can propose
additional studies to
mitigate concern

Risk considered low


Additional rodent
bioassays not
warranted

Risk unclear


Consider studies as
discussed in ICH S6,
1997)

©2012, Genentech

Example: PCSK9 Inhibitor Class

FDA has provided guidance to all sponsors that are targeting PCSK9
(LDL
-
c lowering therapies)

Recommends a “Thorough Carcinogenicity Assessment”
as
described in ICH S6 (R1)


Requests that it is submitted early
in
development program (e.g., EOP2)



Includes formal evaluation of immunosuppressive potential
(recommends 12 week study in
cynos

in combo w/ statin)


Specific interest in NK cell activity, CD8+ T cell
cytolytic

activity


Includes evaluation of impact on bile acid synthesis


“…evidence of immunosuppression
and/or a sustained increase in bile
acid secretion and/or intestinal bile
acid load
would be disclosed in the
label as potential cancer
risks”

©2012, Genentech

Example: Studies to Mitigate Cause for Concern

GLP
-
1 analogs and C cell tumors


Rodent bioassays identified increases in C
-
cell tumors


Follow
-
up in vitro studies evaluated GLP
-
1 expression in rodent, monkey and human C
cells


GLP
-
1 expression was much lower in humans, monkeys relative to rodents


GLP
-
1 agonists stimulated measurable C
-
cell calcitonin release in rodents but not
human or monkey cells


Calcitonin levels evaluated in 5000 patients treated for up to two years with no
evidence of increase


Longitudinal studies have not identified causal association between GLP
-
1 analogs
and C cell pathology


However, FDA AERS database supports a potential risk of thyroid cancer with
exenatide


Current label (
liraglutide
):


In mice … a
dose
-
related increase in benign thyroid C
-
cell adenomas was
seen…


In rats … a
treatment
-
related increase in benign thyroid C
-
cell adenomas was
seen…


Human
relevance of thyroid C
-
cell tumors in mice and rats is unknown and could not
be determined by clinical studies or nonclinical studies


©2012, Genentech

Example: Class Effect Labeling



13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A carcinogenicity study was not conducted with
belatacept
. However, a murine carcinogenicity study was
conducted with
abatacept

(a more active analog in rodents) to determine the carcinogenic potential of CD28
blockade. Weekly subcutaneous injections of 20, 65, or 200 mg per kg of
abatacept

were associated with
increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors….

©2012, Genentech

Utility of General Tox Study Results

Predictivity

of 6
-

or 12 month general
tox

studies for 2
yr

bioassay (rats)


Histology evaluation (+ = increase in hyperplasia, hypertrophy, and atypical cellular
foci (e.g., multinucleated cells, dysplasia, etc.)


2
yr

rat bioassay (+ = increase in significant increase in tumors)


80
pharmacuticals

evaluated (all FDA approved, sufficient rat data available for
eval
)


30 rat carcinogens, 50
noncarcinogens



Positive
predictivity
: 63%

Negative
predictivity
: 88%

False negatives: 6%

Chronic
Tox

(rat)

2
yr

Bioassay

+

-

+

25

5

-

15

35

Reddy,
deGeorge
, et al., 2010.
Vet. Path
. 47(4) 614
-
629

©2012, Genentech

Where is carcinogenic risk communicated currently in label?

Boxed warning

Section 5: Warnings and Precautions


“Immunosuppression” or “Malignancies”

Section 6: Adverse Events


“Malignancies”

Section13: Nonclinical Toxicology

13.1 …carcinogenesis

“…must state whether long term studies in animals have been performed to evaluate the
carcinogenic potential and, if so, the species and results”

“…any precautionary statement on these topics must include
practical, relevant advice

to the prescriber on the significance of these animal findings.

Human data suggesting that the drug may be carcinogenic … as described in the
‘Warning and Precautions’ section,
must not

be included in this subsection of the
labeling.”

Section17: Patient Counseling Information


Source: Dan Mellon, FDA SOT 2012 Presentation
.

©2012, Genentech

Posited Strategy for Labeling Revisions (Proposed for SOT
Discussion Only: Not Formal FDA Position)

©2012, Genentech



©2012, Genentech





©2012, Genentech



Bottom Line:
Changes in risk communication in
not only product labels but informed consent
documents, investigator brochures, etc. are
anticipated but regulatory agencies have yet to
address what these changes will look like

©2012, Genentech

Summary


Historically, classical lifetime rodent bioassays have had limited utility
for malignancy risk assessment for biologics and have had little
impact on informing product labels


ICH has implemented new paradigm: Weight based assessment
that incorporates clinical, preclinical and mechanistic data


It remains to be seen how these risk assessments will be
communicated in product labels

©2012, Genentech




Page
28

© 2009, Genentech / Proprietary information


Please do not copy, distribute or use without prior written consent.



Thank You

Slide Credits
:

Dan Mellon(FDA)

Heather Taylor (Genentech)