PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARS

Transcription

1 PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARS Louise Angell Lead Scientist 10th Biosimilars & Follow-On Biologics Congregation 9 th May Covance. All rights Reserved

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) 2

3 Covance History with Biosimilars Pre-clinical Phase I Clinical Phase III Clinical Preregistration Market CMC Structural and functional testing CMC: Analytical characterisation Continuous testing Stability multiple batches Batch release testing Preclinical Animal studies Toxicology PK/PD Clinical Phase I / Phase III PK/PD Immunogenicity Efficacy (Similarity) BioA CCLS Regulatory BioA: PK and Immunogenicity (ADA, NAb) Regulatory Strategy Biomarkers CMA Consultancy Value communications Input into clinical endpoints Policy re-imbursement advice Pharmacovigilance Patient reported outcomes 3

4 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 Amount of CMC data required Novel biologic development program PK = Pharmacokinetics PD = Pharmacodynamics Biosimilar development program timeline Science driven; end in mind; Extensive innovator characterisation to minimize downstream risk 4

5 Overview 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) 5

6 Know the Target Product Profile (TPP) 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 Image approved for use at Covance Safety, efficacy and quality of Innovator and Biosimilar must have no meaningful clinical difference 6

7 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 Image approved for use at Covance 7

8 Identify and Control Critical Quality Attributes (CQA) TPP Assess and control risk MOA CQA Analytical and Manufacturing Controls BIOSIMILARS DO NOT GET MORE SIMILAR DURING THE DRUG DEVELOPMENT PROCESS 8

9 Overview 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) 9

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 months Pre-clinical phase Clinical phase Amount of CMC data required Continual Biosimilarity Assessment 10

11 Analytical Master File INNOVATOR SPECIFIC CMC ANALYTICAL SOLUTION MASTER FILE Innovator 3 Image approved for use at Covance 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 11

12 Overview 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) 12

13 Herceptin Mechanism of Action Her2 Binding and ADCC via FcγRIII NK cell binding to Herceptin Fc via FcγRIII triggers degranulation and cell death Covance Image Lack of Fucose on Human IgG1 N-Linked oligosaccharide improves Binding to Human FcγRIII and Antibody-dependent Cellular Cytotoxicity (ADCC)* Quantification of % core glycan afucosylation (and % glycan occupancy and high mannose levels) Herceptin Is a registered trademark of Genentech Inc 14 Herceptin binds to HER2 receptor on target cell surface, and inhibits cell proliferation by blocking receptor dimerisation and hence downsteam signaling *Shields, RL et al, J Biol Chem 2002; 277:

14 Case Study: A Biosimilar Solution CLIENT 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 THE CHALLENGES Client Biosimilar did not demonstrate the expected biological activity Client unable to progress to clinical studies 18 month addition to Biosimilar development program RISK BASED CMC STRATEGY Early in Biosimilar development phase Link structure to function Extensive structural characterisation CQA Herceptin Is a registered trademark of Genentech Inc 14 Image approved for use at Covance

15 Understanding Critical Quality Attributes 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 Image approved for use at Covance Potency ADCC Cell based Bioassay Data: Covance 15

16 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 Data: Covance Herceptin Binds Her2 receptor and inhibits proliferation of cells BT474 Cells Measured as a function of adenosine triphoshate (ATP) concentration (via luciferase luminescence) Relative Potency (Biological Activity) is calculated against a known standard Herceptin Is a registered trademark of Genentech Inc 16

17 Relative Potency Assessment by Proliferation Inhibition Graph#2 1.18e7 Relative Luminescence Units 1.08e7 9.8e6 8.8e6 7.8e6 6.8e6 EU Herceptin Research grade Trastuzumab US Herceptin Shows that the biological activity (binding to Her2) was the same for each product; within % criteria Data: Covance 5.8e Log mab Concentration x axis (ng/ml) 4-P Fit: y = (A - D)/( 1 + (x/c)^b ) + D: A B C D Rel. Pot. Sample Mean Relative Potency, % (versus EU Innovator control) US Innovator 100 RG Trastuzumab 90 Plot#1 (EU-Her: Concentration vs MeanValue) 1.2e e+06 1 Plot#2 (US_Her: Concentration vs MeanValue) 1.2e e Plot#3 (TRS0020: Concentration vs MeanValue) 1.2e e Curve Fit Option - Fixed Weight Value Data: Covance PLA (Std. Curve: Plot#1) Degrees of Freedom: parallel = 24 free = 18 non-parallel = 6 R^2 = F-stat Herceptin = Is F-prob a registered = 0.97trademark of Genentech Inc 17

18 Antibody Dependent Cell Cytotoxicity (ADCC) Assessment Data: Covance SKBR 3 Cells 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 FcγRIII on NK cells (Fc) NK cells release cytokines to lyse SKBR3 cells Relative Potency (Biological Activity) is calculated against a known standard Data: Covance Measure release of Lactate Dehydrogenase (LDH) as function of cell lysis Herceptin Is a registered trademark of Genentech Inc 18

19 Relative Potency Assessment by ADCC Data: Covance Herceptin EU and US RG Trastuzumab significantly less potent in terms of ADCC function Research grade Trastuzumab with less core glycan afucosylation Consistent with the MS based structural characterisation and differences in afucosylation level Herceptin Is a registered trademark of Genentech Inc 19

20 Typical Fc-glycans of humanized IgG biopharmaceuticals G0F G0 G1F G1 Covance Image G2F G2 G2FS1 Absence of the N-glycan corefucose (afucosylation) can result in increased binding affinity of antibodies to FcγRIII and enhance ADCC Fucose Covance image Man5 N-Acetylglucosamine (GlcNAc) G2FS2 Mannose Galactose Sialic acid 20

21 Intact Mass Herceptin N N N N Mass Spectra [M+52H] 52+ C C USA Herceptin C H 3 C H 2 C H 2 C H 3 Covance Image C C EU Herceptin Protein ion current is shared between multiple charge states, [M+nH] n+ (typical of electrospray ionisation) Research Grade Innovator Glycan profile is defined at each charge state Herceptin Is a registered trademark of Genentech Inc All data: Covance 21

22 Intact Mass Herceptin Deconvoluted MS data (MaxEnt1) USA Herceptin Data: Covance Sample G0/G0F 2G0F G0F/G1F 2G1F & G0F/G2F G1F/G2F Mean Relative Potency % (versus EU Innovator) 2G2F N-Glycan Core Afucosylation % (excl. high mannose) EU Herceptin N/A 14.7 (10.4) US Herceptin (8.15) RG Trastuzumab (2.55) 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 Data: Covance Herceptin Is a registered trademark of Genentech Inc 22

23 Summary slide Apply early and robust CMC testing to maximise success of a biosimilar development program TPP Understand structural effects on biological activity Characterise and compare molecules Successful Biosimilar Development MoA CQA A better understanding of the product leads to a higher predictability of the outcome Control 23

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 24