Download Document

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts
no text concepts found
Transcript
Preclinical Safety Assessment
Studies to Support Manufacturing
Process Changes for Vectibix
Barbara Mounho, Ph.D., D.A.B.T.
Amgen, Inc.
www.diahome.org
Disclaimer
The views and opinions expressed in the following PowerPoint slides are
those of the individual presenter and should not be attributed to Drug
Information Association, Inc. (“DIA”), its directors, officers, employees,
volunteers, members, chapters, councils, Special Interest Area
Communities or affiliates, or any organization with which the presenter is
employed or affiliated.
These PowerPoint slides are the intellectual property of the individual
presenter and are protected under the copyright laws of the United
States of America and other countries. Used by permission. All rights
reserved. Drug Information Association, DIA and DIA logo are registered
trademarks or trademarks of Drug Information Association Inc. All other
trademarks are the property of their respective owners.
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
- 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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
Comparability Assessment
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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)
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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%)
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
• 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?
www.diahome.org
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?
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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
www.diahome.org
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