Case study - Drug Information Association
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Comparability of a human IgG1 after cell line switching: A retrospective view Peter Lloyd Head of PK-PD, Novartis Biologics
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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.
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Outline of the presentation: Introduction to case study: IgG PK and mAb-ligand binding models: - consequences for characterisation of extent and duration of effect
Retrospective analysis: - can rodent replace NHP in PK studies to explore inherent IgG behaviour? - can immunogenic potential be detected with appropriate PK and PD analytical strategies? - can appropriate clinical strategies during clinical development provide more definitive information on comparability?
Summary: - “yes they can” www.diahome.org
Case study: IgG1 monoclonal Ab binds to and neutralises a soluble cytokine target - target not detected at baseline in systemic circulation
cross-reactivity established with marmoset and human target (similar affinity) PK assay for total drug in serum (marmoset / human) PD assay for total ligand in serum (human)
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Case study: Product A
Product B
Product C
Product D
NS0-derived ≥52 mg/mL
Sp2/0-derived ≥65 mg/mL
Sp2/0-derived ≥180 mg/mL
Sp2/0-derived ≥175 mg/mL
- human and marmoset crossreactivity
Comparability exercise: - phys - chem - PK (NHP)
Comparability exercise: - phys - chem - PK (NHP)
Comparability exercise: - phys - chem
-
-
-marmoset: 4 and 26 wk iv, 13 wk s.c. toxicology and EFD Clinical studies
Clinical studies
NS0 = expression cell line (mouse myeloma) Sp2/0 = expression cell line (mouse myeloma)
HSA = Human serum albumin
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Case study:
Research
Pre-clin
Phase I
Phase II
Phase III
cell line switch
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Phase IV
Case study: PK comparability non-human primate single sc dose x-over study n=16 marmosets
ACZ885 Concentration (ng/mL) mAb concentration (g/mL) Serum
100000 NS0 ACZ885 – NSO SP2/0 ACZ885 – SP2/0
PK comparability established: - AUC - Cmax and tmax
10000
1000
100 0
10
20
30
40
50
Time(days) (Days) Time
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Outline of the presentation: Introduction to case study: IgG PK and mAb-ligand binding models: - consequences for characterisation of extent and duration of effect
Retrospective analysis: - can rodent replace NHP in PK studies to explore inherent IgG behaviour? - can immunogenic potential be detected with appropriate PK and PD analytical strategies? - can appropriate clinical strategies during clinical development provide more definitive information on comparability?
Summary: www.diahome.org
A simple mAb PK model:
mAb iv dose
elimination mAb
slow clearance V ~ 7L t½ ~ 300 h (human)
FcRn protects IgG from degradation & explains long serum half-life Roopenian and Akilesh. Nature Reviews Immunology 2007; 7: 715
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Mouse, rat and cyno FcRn recognize human IgG man
IgG kinetics scale reasonably well using an allometric approach
non-human primate
NB only when target mediated disposition is absent rat
mouse
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A simple mAb PK-PD model: input ligand
mAb
+
ligand
mAb – ligand complex
dose elimination mAb
elimination ligand
slow clearance V ~ 7L t½ ~ 300 h www.diahome.org
elimination mAb – ligand complex
Components of the PK-PD model: Inherent pharmacokinetics of the mAb (IgG behaviour): - species differences often well understood and easily characterised; good prediction to man
Binding affinity to the target ligand: - species differences understood during characterisation of the mAb
Turnover of the ligand and clearance of the mAb-ligand complex: - species differences and behaviour of mAb-ligand complex sometimes not well understood - if cell surface ligand is not saturated with mAb then the mAb-ligand complex may be cleared very quickly (target mediated clearance) - for a soluble ligand the mAb-ligand complex will tend to follow IgG clearance mechanisms (eg case study)
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Case study: PK-PD model
soluble ligand
1.2
Single dose: 0.01 mg/kg 0.1 mg/kg 1.0 mg/kg 10.0 mg/kg
Free ligand concentration
1.0
0.8
0.6
0.4 mAb
ligand
complex
0.2
0.0 20
40
60
80
100
120
Time (days)
Assumptions
mAb with typical IgG kinetics; Kd = 0.37nM; soluble ligand, turnover (half-life 3h)
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Literature example: cell surface ligand anti-CD11a mAb – Raptiva (efalizumab) mAb
complex
ligand
Joshi et al An overview of the pharmacokinetics and pharmacodynamics of efalizumab: a monoclonal antibody approved for use in psoriasis J Clin Pharmacol 2006; 46: 10-20
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Summary: Ab-ligand PK-PD binding models – PK of monoclonal antibodies will generally follow “typical IgG behaviour” and scale reasonably well to man and/or exhibit Target Mediated Drug Disposition (TMDD) and be dependent on the amount of target present and its rate of turnover – Once maximum ligand binding is achieved then increasing the dose will primarily increase the duration of response – The shape of the exposure response curve can be simulated from preclinical data by adjusting parameters in the model (eg binding affinity, target expression) – The amount of ligand present and the rate at which it can be replaced (turnover) will be key drivers of the extent and duration of response www.diahome.org
Case study: consequences for comparability testing For an antagonistic mAb cleared primarily by IgG mediated clearance pathways, a study with PK endpoints will explore only inherent IgG characteristics this data could be generated equally well in rodents, as rodents clear human IgG by similar pathways to man
Differences in conventional non-compartmental PK parameters (Cmax, tmax) at high saturating doses may not impact on efficacy Binding to target is often not addressed in a PK-only study design
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Literature example: glycosylation pattern (rodent)
Milward et al Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice Biologicals 2008; 36: 41-47
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Case study: impact of immunogenicity non-neutralizing
neutralizing
anti-drug antibody
anti-drug antibody
drug mAb “typical IgG kinetics”
increase in IgG clearance no effect on target binding (total ligand, receptor occupancy)
increase in IgG clearance decrease in target binding (decrease in total ligand)
Target Mediated Disposition
increase IgG clearance (change in inflection point?) no effect on target binding
increase/decrease in clearance? (change in inflection point?) decrease in target binding
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Analytical strategy: impact of neutralizing immunogenicity
PK
PD (soluble target) *
a)
Immunogenicity a)
anti-human IgG
nIG may interfere in the PK and PD assays; detected as short PK t½. Immune complexes may also be cleared more rapidly. Decrease in total target may be apparent
mAb (drug) ligand residual bioactive drug
b)
drug-ligand complex / total target
residual bioactive drug
c)
capture Ab
or LC-MS
b)
NB: capture Ab has different ligand binding epitope compared with the drug and no steric interference
* - for cell surface target use receptor occupancy and/or PK profile
total drug (non-human only)
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c)
nIG may intefere in the PK and PD assays; detected as increase / decrease in exposure. Decrease in total target may be apparent
nIG does not interfere in the PK assay; although immune complexes may be cleared more rapidly. Decrease in total target may be apparent
Case study: population analysis of clinical data Phase III clinical study - incorporate comparability testing into clinical design; product A (NS0) and B (SP2/0) as covariates (n=35 patients per treatment) - serum total mAb and total ligand measured with sparse sampling strategy predict free ligand from PK-PD binding model - ligand capture (and therefore ligand suppression) will also detect neutralizing immunogenicity
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Case study: population analysis of clinical data Typical PK and PD profile from the PK-PD model Simulation of 150 mg s.c. single dose of Canakinumb
20
40
60
80
Time(days) Time (days)
100
10 5
10 5 0
Conclusions for materials derived from both cell lines:
- similar sc bav - similar in-vivo KD derived from clinical PK-PD binding model - no loss total ligand over time (ie no evidence of neutralizing immunogenicity)
1
NSO ----- SP2/0 NS0 cell line SP2/0 cell line
(pg/mL) concentration Serum ligandIL-1beta conc, pg/mL
Total ligand (PD profile)
1
Canakinumab conc, ug/mL concentration (g/mL) Serum mAb
mAb (PK profile)
0
20
40
60
80
100
Time(days) Time (days)
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Case study: summary Can rodent replace NHP in PK studies to explore inherent IgG behaviour? Industry perception and concern that NHP primate PK studies are necessary is driving acceptance that these will be the norm; however, for this case study (mAb targeted against a soluble ligand), preclinical studies in NHP with PK-only endpoint could probably be replaced by a PK study in rodent, even when the mAb does not bind the target in rodent (only the inherent IgG behaviour is characterised)
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Case study: summary Can immunogenic potential be detected with appropriate PK and PD analytical strategies? If total ligand capture can be easily measured, then neutralizing immunogenicity should be apparent as a decrease in total ligand;
this can easily be monitored in Phase III clinical trials; providing a robust assessment of immunogenic potential; additional neutralizing immunogenicity assays are probably not required
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Case study: summary Can appropriate clinical strategies during clinical development provide more definitive information on comparability? doses are often given at saturation of target ligand binding and differences in dose therefore affect duration of action rather than extent; conventional PK parameters to assess comparability (eg Cmax and tmax) may not be appropriate clinical studies with target capture and appropriate analytical strategy are more informative than pre-clinical studies regarding comparability of efficacy and immunogenic potential during drug development comparability testing can be built into clinical study design
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THANK YOU for your attention Acknowledgements: Jennifer Sims (Head Translational Sciences and Safety, Novartis Biologics) Phil Lowe (Modelling and Simulation, Novartis) Annette Zaar (Head of Immunogencity, Novartis Biologics) Fabienne Deckert (Head of PK-PD Bioanalytics, Novartis Biologics)
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