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Preclinical Safety Assessment
Studies to Support Manufacturing
Process Changes for Vectibix
Barbara Mounho, Ph.D., D.A.B.T.
Amgen, Inc.
www.diahome.org
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Presentation
• Information presented taken from:
– Vectibix, European Public Assessment Report,
CHMP, 2007
– Vectibix, FDA Review, Application Number
12514, approval 09/27/2006
– Vectibix Prescribing Information, Thousand
Oaks, CA: Amgen, Inc; 2008
– www.Vectibix.com
– literature
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Overview
• Epidermal Growth Factor Receptor (EGFr)
and Vectibix®
– biology and rationale for targeting the EGFr pathway in cancer
• Manufacturing Process Change
– what changed and when in the clinical development program
•
Comparability Assessment Exercise
• Summary
– what did we learn from the comparability toxicology studies
– approach today
• applying a science-based decision tree in determining if toxicology
study needed in comparability package
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Overview of the EGFr
• EGFr (HER1 or ErB1) Belongs to the ErbB Family of Cell
Surface Receptors
– 170 Kd transmembrane glycoprotein
– extracellular ligand-binding domain (621 AAs)
– intracellular tyrosine kinase domain (542 AAs)
•
Expressed in Various Normal Cells of Epithelial Origin
– skin, lung, GI tract, liver
• Endogenous Ligands:
- EGF
- TGF
- amphiregulin - epiregulin
- betacellulin
- heparin-binding EGF
• Pivotal Role in Maintenance of Cellular Function & Survival
- cell proliferation & differentiation
- inhibition of apoptosis
- migration/motility
- enhanced cell survival
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Role of EGFr Pathway in Cancer
Ligand Binding and Dimerization
Results in Tyrosine Kinase Activation
EGF
TGF
Homodimer
Heterodimer
High
affinity
binding
ATP
Ligand Binding
ATP
ATP
Dimerization of the receptor
- homodimer
- heterodimer with other ErbB
family coreceptors
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- ATP binding
- Autophosphorylation of
the receptor tyrosine
kinase
- Activation signal
transduction pathways
Role of EGFr in Cancer
• Expression of EGFr Has Been Observed in Human Cancers
– colorectal
– head and neck
• EGFr Expression Correlates With:
– poor response to treatment
– disease progression
– poor survival
• In Normal Cells, the EGFr Signal is Strictly Regulated
• Malignant Cells, the EGFr Signal is Inappropriately Activated
• EGFr Pathway Activation in Tumor Cells Mediates
Several Processes
– cell survival and proliferation
– angiogenesis
– metastatic spread
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Targeting the EGFr for Anticancer Therapy
• Blocking the Activation of the EGFr Signaling
Pathway In Tumor Cells:
– inhibition of tumor cell growth
– may lead to cancer cell death
• Targeting the EGFr Pathway With Molecules
Such As Vectibix Offers Therapeutic
Potential for Anticancer Therapy
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Vectibix (panitumumab)
• Human IgG2 Kappa Monoclonal Antibody
– molecular weight = 147 kDa
– binds specifically to human EGFr (Kd = 5 x 10-11 M)
•
Indication*
– as monotherapy for the treatment of EGFr-expressing, metastatic
colorectal carcinoma with disease progression on or following
fluoropyrimidine-, oxaliplatin-, & irinotecan-containing chemotherapy
regimen
•
Administration/Dose
– intravenous (60 – 90 minute infusion)
– 6 mg/kg q2wks
•
Pharmacokinetics (PK)
– t½ = 7.5 days (mean)
* Indicated in patients with non-mutated (wild-type) KRAS in the EU
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Mechanism of Vectibix
Ligand
Ligand
VectibixEGFr dimerX
- Vectibix targets the extracellular domain of the EGFr preventing:
• the ligand from binding to the receptor
• receptor dimerization
• activation of the EGFr signaling pathway
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X
Vectibix Manufacturing Process History
• Initial Manufacturing Process Used a Hybridoma Cell Line
• Material Generated From Hybridoma Manufacturing Process
– initial preclinical studies (to support phase I)
• pharmacology
• PK
• toxicology
– phase I clinical study
• Prior to Phase III
– manufacturing process changed using chinese hamster ovary
(CHO) cell line
• higher productivity
(to support expected clinical & commercial demand)
• improve process robustness
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Vectibix Manufacturing Process History Cont’d.
• Manufacturing Changes Included
– hybridoma to CHO cell line
– modifications to the manufacturing processes to support the cell line
change
• cell culture process
• media components
• production bioreactor feeds
– manufacturing facility to support higher production yield
• What Did Not Change?
– genetic sequence expressing Vectibix
• DNA sequence used to create CHO cell line
generated from hybridoma cell line
– formulation
– excipients
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Same For Both
Manufacturing
Processes
Comparability Assessment
• Comprehensive Comparability Exercise Was Undertaken
– extent of the changes in the manufacturing process
– timing of changes (prior to phase III)
• Objective of Comparability Assessment
– support using CHO material in chronic and reprotoxicity studies
– to proceed into phase III clinical development with CHO material
• Comparability Assessment Included:
– analytical tests
– preclinical studies
• pharmacology
• PK
• toxicology
– clinical PK study
review
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Comparability Assessment
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Comparability Analytical Studies
• Analytical Studies Included Various Tests:
–
–
–
–
–
•
binding assay
bioassay
UV scan
HPLC
others
Results of Analytical Comparability Tests
– minor differences between the 2 materials
• expected due to cell line change
• well characterized and understood
– did not impact biological activity
• in vitro potency between the 2 materials was comparable
(binding and bioassay)
• Analytical Data Supported Using CHO-Derived Material
– pivotal toxicology studies
– phase III clinical trial
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Comparability Pharmacology Studies
• In vivo studies conducted with hybridoma and
CHO-derived material
– mouse xenograft studies using A431 human epidermoid
carcinoma cells
• Results
– both hybridoma and CHO material prevented and eradicated
established A431 tumor formation
• similar doses
• dose-dependent manner
– anti-tumor effects of hybridoma and CHO material
were comparable
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Comparability Pharmacokinetic Study
•
Study Design
N = 24 male monkeys
• single IV dose
• 12 administered hybridoma material (7.5 mg/kg)
• 12 administered CHO material (7.5 mg/kg)
CHO-Derived
Vectibix
Hybridoma-Derived
Vectibix
Parameter
Mean
SD
N
Mean
SD
N
AUC0-336h
(mg·day/mL)
619
83
12
664
143
12
Cmax
(mg/mL)
227
31
12
256
56
12
• The PK profiles of the hybridoma and CHO materials were
comparable (based on AUC and Cmax)
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Serum
Conc.
(mg/mL)
(mg/mL)
Vectibix Conc.
SerumPanitumumab
Monkey Comparability Pharmacokinetic Study
1000
100
10
1
Hybridoma (n = 12)
CHO (n = 12)
0.1
0
48
96
144
192
240
288
336
Time (hrs)
Time (h)
*Mean Vectibix concentration time profiles for the 2 materials are almost superimposable
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Overview of Toxicology Program
• All Studies Conducted in Cynomolgus Monkeys
(pharmacologically relevant species)
• Initial Studies Used Hybridoma-Derived Material
– tissue cross-reactivity
– 4 and 13-week repeated dose
• Comparability Studies (hybridoma and CHO)
– tissue cross-reactivity
– 4-week repeated dose
• Pivotal Studies Used CHO-Derived Material
– 6-month repeated dose
– reproductive toxicity
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Review
Toxicology Comparability Studies
• Toxicology Comparability Studies
– tissue cross-reactivity study
• compare tissue binding properties
– 4-week monkey toxicity study
• compare toxicity profile
• PK
• antibody response
(monkey anti-human antibody response MAHA)
• Objective: Moving Forward with CHO Material
– pivotal toxicology studies
– phase III clinical study
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Tissue Cross-Reactivity Study
• Study Design
– hybridoma- and CHO-derived Vectibix (biotinylated)
– panel of human and cynomolgus monkey tissues
• Results
– consistent with previous study using hybridoma material
– binding observed primarily in epithelial cells within the
different tissues for both materials
• skin, lung, breast, colon, eye
• human and monkey tissues
• Tissue Binding Properties of Hybridoma- and CHOMaterial Were Comparable
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4-Week Comparability Toxicity Study
• Administration: IV injection
once weekly for 4 weeks
• 3 monkeys/sex/group
terminated on day 28
• 1 monkey/sex/group
terminated on day 57
(4-week recovery)
• Blood samples for TK and
MAHA responses
Group
Number
(material)
Dose
Level
(mg/kg)
Number of
Monkeys
(M/F)
1
0 (vehicle)
4/4
2
(hybridoma)
7.5
4/4
3
(hybridoma)
30
4/4
4
(CHO)
7.5
4/4
5
(CHO)
30
4/4
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4-Week Comparability Toxicity Study – Results
• Primary Treatment-Related Toxicities
– related to pharmacological activity of Vectibix
– skin rash
– diarrhea
• Toxicities in This Study Consistent with Previous Studies Using
Hybridoma Material
– also consistent with those observed in clinical trials (skin rash; diarrhea)
– preclinical toxicity predictive of clinical toxicity
• No Remarkable Differences in Skin Rash or Diarrhea Between
Hybridoma and CHO groups
– severity
– incidence
• Toxicity Profile Between Hybridoma and CHO Material
Was Comparable
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SerumVectibix
Panitumumab
Conc. (mg/mL)
(mg/mL)
Concentration
Serum
4-Week Comparability Toxicity Study - PK Results*
(mg/mL)
Vectibix Concentration
Serum
SerumPanitumumab
Conc. (mg/mL)
7.5 mg/kg
10000
1000
100
10
1
0.1
0
1
2
3
4
5
6
30 mg/kg
10000
1000
100
10
2K
CHO
Female
CHO
Female
CHO
MaleMale
2K
CHO
Hybridoma Female
Hybridoma Male
1
0.1
7
0
1
2
3
4
5
6
7
Study Day
Study Day
• PK Between Hybridoma and CHO Groups Comparable
(exposure increased approximately dose proportionally)
– consistent with previous studies using hybridoma material
– consistent with monkey comparability PK study
*Clearance of Vectibix increases with presence of MAHA after repeated administration, thus, pharmacokinetic
comparisons were based on values after the first dose
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4-Week Comparability Toxicity Study – MAHA Responses
• The Number of MAHA Responses Between
Hybridoma and CHO Groups Was Comparable
Group Number
(material)
Dose Level
(mg/kg)
Incidence of MAHA
Responses (%)
1
0 (vehicle)
0
2
(hybridoma)
7.5
6/8 (75%)
3
(hybridoma)
30
4/8 (50%)
4
(CHO)
7.5
5/8 (63%)
5
(CHO)
30
2/8 (25%)
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Clinical Comparability Pharmacokinetic Study
• Phase I study
– open-label, multiple-dose, dose-rising trial in
patients with solid tumors
– patients administered 6 mg/kg of Vectibix q2wk
• N = 7 patients administered hybridoma material
• N = 10 patients administered CHO material
• Results
– The PK parameters (AUC0-tau and Cmax) of hybridomaand CHO-derived material were comparable*
*90% confidence interval of the ratios between the CHO and hybridoma material for the PK
parameters were within the 80% -125% interval
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Summary
• Initial Manufacturing Process Used Hybridoma Cell Line
– phase I
• Manufacturing Process Changed
– hybridoma to CHO cell line
– manufacturing process
– manufacturing facility
•
Comprehensive Comparability Exercise Was Undertaken
– extent of the changes
– time changes occurred in clinical development program
• prior to phase III
• Comparability Exercise
– analytical tests
– preclinical studies
– clinical pharmacokinetic study
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comparable
Summary Cont’d.
• Toxicology Comparability – What We Learned in Hindsight
– tissue cross-reactivity study
• binding properties of hybridoma- and CHO material were comparable
in human and monkey tissues
– monkey toxicity study
• toxicology tightly linked to the pharmacology (skin rash/diarrhea)
–
–
–
–
primary toxicities consistent with previous studies
no new or unexpected toxicities
toxicity profile well characterized and understood
preclinical toxicity predictive of clinical toxicity
• hybridoma and CHO groups
– toxicity profile
– exposure
– MAHA responses
comparable
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• chronic tox
• phase III
Summary Cont’d.
Is a Comparability Toxicology Study Needed?
• What Do We Do Today?
• Approach - Science-Based Comparability Decision Tree
• Questions Asked
• when did changes occur during clinical development program?
– prior to pivotal clinical trials (phase III) or post-marketing?
• what are the extent of the manufacturing changes?
– extensive vs. minor (e.g., cell line vs. excipient change)
• results of analytical tests?
– comparable
– differences detected
• what are the extent of the differences?
– extensive or minor
– are the differences well characterized and understood?
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Summary Cont’d.
Is a Comparability Toxicology Study Needed?
• Approach - Science-Based Comparability Decision Tree
• Questions Asked
– following unchanged?
– preclinical PK
– pharmacodynamics in pharmacology studies
– tissue binding properties (human and animal tissues)
– toxicology tightly linked to the pharmacology?
– related to the pharmacological activity (“on target”)
– toxicity profile well characterized and understood?
– toxicity endpoints sensitive enough to detect meaningful
differences?
– critical for study to provide reliable safety data
– preclinical toxicity predictive of clinical toxicity?
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Summary Cont’d.
Is a Comparability Toxicology Study Needed?
• Applying a Science-Based Comparability
Decision Tree Directs You In Determining
– would a toxicity study add relevant safety data
to the comparability package?
– each program is case-by-case
• approach for one molecule may not be the same as for
another molecule
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Summary Cont’d.
• Would We Do a Toxicology Comparability Study
for Vectibix?
– extensive changes in manufacturing process
– occurred before phase III
– analytical data showed minor differences
• in vitro potency comparable
– preclinical data comparable
• pharmacology
• PK
• tissue binding properties
– toxicology closely linked to the pharmacology
(skin rash/diarrhea)
– preclinical toxicity predictive of clinical toxicity
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Summary Cont’d.
• Applying a Science-Based Comparability Decision
Tree Approach for Toxicology Studies:
• requires detailed insight to data collected during the
preclinical and clinical development program
• data includes:
– analytical
– preclinical
» pharmacology
» PK
» toxicity
– clinical
» pharmacology
» PK
» toxicity
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Acknowledgments
•
•
•
•
•
•
•
•
•
•
•
•
Jeanine Bussiere
Mary Ellen Cosenza
Ruth Lightfoot-Dunn
Andrew Fox
Ralph Klinke
Julie Lepin
Richard Lit
Peggy Lum
David Reese
Bing-Bing Yang
Many, many others
Most of all – the patients
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References
•
Vectibix, European Public Assessment Report, CHMP, 2007.
•
Vectibix, FDA Review, Application Number 125147, approval 09/27/2006.
•
Vectibix Prescribing Information, Thousand Oaks, CA: Amgen, Inc; 2008.
•
Lacouture, M.E., and Lai, S.E. (2006). The PRIDE (papulopustules and/or paronychia, regulatory abnormalities
of hair growth, itching, and dryness due to epidermal growth factor receptor inhibitors) syndrome. Br. J. Dermatol.
155: 841-865.
•
Lenz, H.J. (2006). Anti-EGFr mechanism of action: anti-tumor effect and underlying cause of adverse events. Oncology.
20(5): 5-13.
•
Miettinen PJ, Berger JE, Meneses J, et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor
receptor. Nature. 1995;376:337-341.
•
O’keefe, P., Parrilli, M., and Lacouture, M.E. (2006). Toxicity of targeted therapy: focus on rash and other dermatologic side
effects. Oncology Nurse Ed. 20(13): 1-6.
•
www.Vectibix.com
•
Yarden, Y., Silwkowski, MX. (2001). Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127-137.
•
Yano, S., Kondo, K., Yamaguchi, M., et al. (2003). Distribution and function of EGFr in human tissue and the effect of EGFr
tyrosine kinase inhibition. Anticancer Res. 23: 3639-3650.
www.diahome.org