planning for success: a cmc strategy for biosimilars … · planning for success: a cmc strategy...
TRANSCRIPT
-
Public
PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARS
Louise Angell Lead Scientist 10th Biosimilars & Follow-On Biologics Congregation 9th May 2017
Copyright @ 2017 Covance. All rights Reserved
-
Public
2
Overview
Covance history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)
Planning for Success: A CMC Strategy - London - May 2017
-
Public
Animal studies Toxicology PK/PD
Phase I / Phase III PK/PD Immunogenicity Efficacy (Similarity)
Pharmacovigilance Patient reported outcomes
Regulatory Strategy
BioA: PK and Immunogenicity (ADA, NAb)
Biomarkers
Consultancy Value communications
Input into clinical endpoints Policy re-imbursement advice
CMA
CMC
Preclinical
Clinical
BioA
Regulatory
Structural and
functional testing Continuous testing
multiple batches Stability
Batch release testing
CMC: Analytical characterisation
Covance History with Biosimilars
Pre-clinical Phase I Clinical
Phase III Clinical
Pre-registration Market
CCLS
3 Planning for Success: A CMC Strategy - London - May 2017
-
Public
Importance of CMC Pre-clinical phase Clinical phase
Analytic (physiochemical, structural and bioanalytical) In vitro functional (binding)
In vivo functional PK/PD (animal)
Toxicology
PK Efficacy Safety
PK = Pharmacokinetics PD = Pharmacodynamics
Amount of CMC data required
Novel biologic development
program
Biosimilar development program timeline
Science driven; end in mind; Extensive innovator characterisation to minimize downstream risk
4 Planning for Success: A CMC Strategy - London - May 2017
-
Public
5
Our history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)
Planning for Success: A CMC Strategy - London - May 2017
Overview
-
Public
Know the Target Product Profile (TPP)
6
Indications and Usage Dosage and Administration Dosage Forms and Strengths Contraindications Warnings and Precautions Adverse Reactions Drug Interactions Use in Specific Populations Drug Abuse and Dependence Overdosage Description Clinical Pharmacology Nonclinical Toxicology Clinical Studies References How supplied, Storage and Handling Patient Counselling Information
Safety, efficacy and quality of Innovator and Biosimilar must have no meaningful clinical difference
Image approved for use at Covance
Planning for Success: A CMC Strategy - London - May 2017
-
Public
Understand Mechanism of Action (MOA)
Understanding MOA of product, and the clinical relevance of any observed structural differences, enables the design of an initial control strategy to monitor and control residual risk Confirmation of identical amino acid sequence Assessment of post-translational modifications
including glycosylation (high mannose, afucosylation)
Product degradation (denature/ aggregation/ oxidation or deamidation)
Product related impurities, sequence variants Process related impurities eg Host Cell Protein
7
Image approved for use at Covance
Planning for Success: A CMC Strategy - London - May 2017
-
Public
Identify and Control Critical Quality Attributes (CQA)
8
Analytical and Manufacturing Controls
Assess and control risk
TPP
MOA CQA
BIOSIMILARS DO NOT GET MORE SIMILAR DURING THE DRUG DEVELOPMENT PROCESS
Planning for Success: A CMC Strategy - London - May 2017
-
Public
9
Our history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)
Planning for Success: A CMC Strategy - London - May 2017
Overview
-
Public
10
Covance Biosimilar Strategy
Assess Target Product Profile Determine Mechanism of Action Define Critical Quality Attributes Obtain Innovator Product and develop methods to support CQA
6-12
mon
ths
Pre-clinical phase Clinical phase
Amount of CMC data required
Planning for Success: A CMC Strategy - London - May 2017
Continual Biosimilarity Assessment
-
Public
Analytical Master File
11
Innovator 3
Covance has developed Analytical Master Files
Scientific rationale using TPP, MOA to justify CQA selection
Portfolio of Developed Methods
Extensive early characterization of Innovator
Risk-minimized, accelerated development approach
INNOVATOR SPECIFIC CMC ANALYTICAL SOLUTION MASTER
FILE
Planning for Success: A CMC Strategy - London - May 2017
Image approved for use at Covance
-
Public
12
Our history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)
Planning for Success: A CMC Strategy - London - May 2017
Overview
-
Public
Herceptin Mechanism of Action Her2 Binding and ADCC via FcRIII
*Shields, RL et al, J Biol Chem 2002; 277: 26733-40
Herceptin binds to HER2 receptor on target cell surface, and inhibits cell proliferation by blocking receptor dimerisation and hence downsteam signaling
NK cell binding to Herceptin Fc via FcRIII triggers degranulation and cell death
Lack of Fucose on Human IgG1 N-Linked oligosaccharide improves Binding to Human FcRIII and Antibody-dependent Cellular Cytotoxicity (ADCC)*
Quantification of % core glycan afucosylation (and % glycan occupancy and high mannose levels)
Covance Image
14
Planning for Success: A CMC Strategy - London - May 2017
Herceptin Is a registered trademark of Genentech Inc
-
Public
Case Study: A Biosimilar Solution
A biotechnology company Developed a Herceptin Biosimilar Ready to progress into clinical phase Structural characterisation and pre-clinical
assessment complete, with no significant difference from the innovator identified
Unexpected observation; limited in vitro ADCC activity
14
CLIENT THE CHALLENGES
Early in Biosimilar development phase
Link structure to function
Extensive structural characterisation
CQA
RISK BASED CMC STRATEGY
Client Biosimilar did not demonstrate the expected biological activity
Client unable to progress to clinical studies
18 month addition to Biosimilar development program
Image approved for use at Covance Herceptin Is a registered trademark of Genentech Inc
Planning for Success: A CMC Strategy - London - May 2017
-
Public
Understanding Critical Quality Attributes
15
Planning for Success: A CMC Strategy - London - May 2017
Attribute CQA Method
Identity Intact mass LC-MS
Identity Amino Acid Sequence Peptide map by LC-MS
Identity Glycosylation LC-MS
2 and 3 structure Di-sulphide bonding LC-MS
Purity Monomer, HMWs SE-HPLC
Purity Deamidation Peptide map
Purity Methionine Oxidation Peptide map
Purity Charge Distribution iCE
Potency Concentration UV-A280
Potency Fc Effector function Biacore
Potency Fab binding Cell based Bioassay
Potency ADCC Cell based Bioassay
Image approved for use at Covance
Data: Covance
Sheet1
AttributeCQAMethodState of Art TechnologyOrthoganol
IdentityIntact massLC-MSUPLC-UV-QTOF
IdentityAmino Acid SequencePeptide map by LC-MSUPLC-UV/FLR-QTOF Tryptic Peptide map with UPLC,Edman sequencing
IdentityGlycosylationLC-MSUPLC-FLR-QTOF N-Glycan detection by MALDI-MS
2 and 3 structureDi-sulphide bondingLC-MSCD
PurityMonomer, HMWsSE-HPLCHPLC/UPLC
PurityDeamidationPeptide map
PurityMethionine OxidationPeptide map
PurityCharge DistributioniCE
PotencyConcentrationUV-A280
PotencyFc Effector functionBiacore
PotencyFab bindingCell based BioassayBiacore
PotencyADCCCell based Bioassay-
Sheet2
Sheet3
-
Public
Proliferation Inhibition Assay
BT474 - Her2 receptor expressing breast cancer cell line
BT474 assay measures Fab binding to Her2
Herceptin serially diluted and added to BT474 cells
Herceptin Binds Her2 receptor and inhibits proliferation of cells
Measured as a function of adenosine triphoshate (ATP) concentration (via luciferase luminescence)
Relative Potency (Biological Activity) is calculated against a known standard
BT474 Cells
Data: Covance
16
Planning for Success: A CMC Strategy - London - May 2017
Herceptin Is a registered trademark of Genentech Inc
-
Public
x axis
10 100 1000 100005.8e6
6.8e6
7.8e6
8.8e6
9.8e6
1.08e7
1.18e7
Graph#2
4-P Fit: y = (A - D)/( 1 + (x/C)^B ) + D: A B C D Rel. Pot.Plot#1 (EU-Her: Concentration vs MeanValue) 1.2e+07 2.07 387 6.36e+06 1Plot#2 (US_Her: Concentration vs MeanValue) 1.2e+07 2.07 371 6.36e+06 1.04Plot#3 (TRS0020: Concentration vs MeanValue) 1.2e+07 2.07 384 6.36e+06 1.01
__________Curve Fit Option - Fixed Weight ValuePLA (Std. Curve: Plot#1) Degrees of Freedom: parallel = 24 free = 18 non-parallel = 6R^2 = 0.991 F-stat = 0.618 F-prob = 0.97
Relative Potency Assessment by Proliferation Inhibition
Shows that the biological activity (binding to Her2) was the same for each product; within 70 130% criteria
Research grade Trastuzumab
EU Herceptin
Log mAb Concentration (ng/mL)
Rel
ativ
e Lu
min
esce
nce
Uni
ts
US Herceptin
Data: Covance
Sample Mean Relative Potency, % (versus EU Innovator control)
US Innovator 100 RG Trastuzumab 90
17
Planning for Success: A CMC Strategy - London - May 2017
Herceptin Is a registered trademark of Genentech Inc
Data: Covance
-
Public
Antibody Dependent Cell Cytotoxicity (ADCC) Assessment
Herceptin serially diluted and added to SKBR3 cells (which express Her2) and NK cells (enriched from PBMCs)
Herceptin binds Her2 receptor on SKBR3 cells (Fab) and FcRIII on NK cells (Fc)
NK cells release cytokines to lyse SKBR3 cells
Relative Potency (Biological Activity) is calculated against a known standard
Measure release of Lactate Dehydrogenase (LDH) as function of cell lysis
SKBR 3 Cells
18
Planning for Success: A CMC Strategy - London - May 2017
Herceptin Is a registered trademark of Genentech Inc
Data: Covance
Data: Covance
-
Public
Relative Potency Assessment by ADCC
RG Trastuzumab significantly less potent in terms of ADCC function
Consistent with the MS based structural characterisation and differences in afucosylation level
Research grade Trastuzumab with less core glycan afucosylation
Herceptin EU and US
19
Planning for Success: A CMC Strategy - London - May 2017
Herceptin Is a registered trademark of Genentech Inc
Data: Covance
-
Public
Typical Fc-glycans of humanized IgG biopharmaceuticals
G0
G0F
Man5
G2F
G1
G1F
G2FS1
G2FS2
Galactose Sialic acid
N-Acetylglucosamine (GlcNAc) Mannose Fucose
G2
Absence of the N-glycan core-fucose (afucosylation) can result in increased binding affinity of antibodies to FcRIII and enhance ADCC
Covance image
Covance Image
20
Planning for Success: A CMC Strategy - London - May 2017
-
Public
Intact Mass Herceptin Mass Spectra [M+52H]52+
USA Herceptin
Research Grade Innovator
EU Herceptin
Protein ion current is shared between multiple charge states, [M+nH]n+ (typical of electrospray ionisation)
Glycan profile is defined at each charge state
C H 3
C H 3
C
H 2
C H 2
C C
C C
N N
N N
Covance Image
21
Planning for Success: A CMC Strategy - London - May 2017
Herceptin Is a registered trademark of Genentech Inc
All data: Covance
-
Public
Intact Mass Herceptin Deconvoluted MS data (MaxEnt1)
USA Herceptin
G0/G0F
2G0F G0F/G1F
2G1F & G0F/G2F
G1F/G2F
2G2F
Deconvolution converts MS data to a zero charge mass scale (Da)
Permits characterisation and comparison of glycan profiles (pairing of glycosylated heavy chains)
Mass accuracy in 150 kDa range typically within 60 ppm
22
Planning for Success: A CMC Strategy - London - May 2017
Sample Mean Relative
Potency % (versus EU Innovator)
N-Glycan Core Afucosylation % (excl. high mannose)
EU Herceptin N/A 14.7 (10.4) US Herceptin 94 10.2 (8.15)
RG Trastuzumab 45 4.35 (2.55)
Herceptin Is a registered trademark of Genentech Inc
Data: Covance
Data: Covance
-
Public
Summary slide
Successful Biosimilar
Development
TPP
MoA
CQA
Control
Characterise and compare
molecules
Understand structural effects on biological
activity
23
Apply early and robust CMC testing to maximise success of a biosimilar development program
A better understanding of the product leads to a higher predictability of the outcome
Planning for Success: A CMC Strategy - London - May 2017
-
Public
24
About Us Covance Inc., headquartered in Princeton, NJ, USA, is the drug development business of Laboratory Corporation of America Holdings (LabCorp). COVANCE is a registered trademark and the marketing name for Covance Inc. and its subsidiaries around the world
Planning for Success: A CMC Strategy - London - May 2017
PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARSOverviewSlide Number 3Importance of CMCOverviewKnow the Target Product Profile (TPP)Understand Mechanism of Action (MOA)Identify and Control Critical Quality Attributes (CQA)OverviewCovance Biosimilar StrategyAnalytical Master FileOverviewSlide Number 13Case Study: A Biosimilar Solution Understanding Critical Quality AttributesSlide Number 16Slide Number 17Antibody Dependent Cell Cytotoxicity (ADCC) AssessmentRelative Potency Assessment by ADCCTypical Fc-glycans of humanized IgG biopharmaceuticalsSlide Number 21Intact Mass HerceptinDeconvoluted MS data (MaxEnt1)Summary slideSlide Number 24