Immunogenicity Risk of Pre-existing Antibodies: A Cross-Company Readout

Transcription

1 Immunogenicity Risk of Pre-existing Antibodies: A Cross-Company Readout Li Xue, Ph.D. PDM-NBE Immunogenicity Sciences This document provides an outline of a presentation and is incomplete without the accompanying oral commentary and discussion. Conclusions and/ or potential strategies contained herein are NOT necessarily endorsed by Pfizer management. Any implied strategy herein would be subject to management, regulatory and legal review and approval before implementation.

2 Classification of Pre-Abs Autoantibodies Specific to self- antigens (e.g. cytokines, growth factors) or polyreactive IgGs and IgMs Cross-reactive antibodies Emerge due to prior environmental exposure, molecular mimicry between therapeutic products and environmental antigens, or homology with previous treatment with a structurally similar product Clinical significance of Pre-Abs is largely unknown

3 Examples of Known Clinical Impact IgE type pre-abs -- Risk for hypersensitivity Regional, IgE type pre-existing anti-galactose- α-1,3,- galactose Abs were associated with severe anaphylaxis in patients treated with Cetuximab Pre-Abs to glycan motifs in plant- produced biotherapeutics Pre-existing and neutralizing Abs to gene vectors risk for reduced therapeutic efficacy Dependent on the gene vector (e.g. AAV) and viral serotype Pre-Abs to some therapeutic antibody scaffolds risk for treatment ADA boosting in RA patients (Xue L., et al. 2013,AAPS J) Pre-existing antibody: biotherapeutic modality-based review. 2016, AAPS J

4 Anti-PEG Pre-Abs Varied Clinical Impact Product Pegloticase TM (PEG-porcine uricase) PEG- Asparaginase PEGASYS TM (PEG-IFN-α2a) PEG conjugation 10 KDa PEG X9 per each of 4 protein subunits. Total of 360 methoxy PEG (mpeg) 5KDa mpeg 40 KDa single branched bismpeg Study Population Patients with refractory gout Acute lymphoblastic leukemia patients HCV infected patients, Detection of Preexisting anti-peg Detection of treatment induced anti-peg Clinical impact of pre-existing anti-peg Yes Yes Rapid clearance, loss of efficacy, increased risk of infusion reactions Clinical impact of treatment induced anti- PEG Rapid clearance, loss of efficacy, increased risk of infusion reactions Yes Yes Inconclusive Rapid clearance Yes Yes No No PEG-IFN-β1a 20 KDa mpeg Multiple Sclerosis Yes Yes Unknown Unknown Peg-IFN- PEG-Intron (PEG-IFN-α2b) 20 KDa linear HCV infected mpeg subjects 12 KDa, mpeg HCV infected patients Yes Yes No No Yes Yes No No Pre-existing antibody: biotherapeutic modalitybased review. 2016, AAPS J

5 Immunogenicity Risk of Therapeutics Intrinsic Risk Factors Product sequence, structure Endogenous counterpart Posttranslational modifications Formulation, aggregation Target expression, distribution, mode of action Extrinsic Risk Factors Route of administration Treatment regimen Patient population Immunogenicity risk assessment requires collective evaluation of all risk factors in the context of anti-drug antibody (ADA) induction and ADA consequences Pfizer Confidential 5

6 Immunogenicity Risk Assessment of Pre-Abs Scope Prevalence at baseline Analytical impact on ADA identification and reporting Impact on post-treatment ADA boosting and consequences of ADA Aims To define clinical immunogenicity assay strategy To inform potential clinical impact and risk management strategies Pfizer Confidential 6

7 How to Assess the Immunogenicity Risk of Pre-Abs Determine Pre-Ab prevalence in treatment naïve subjects Relevant to product modalities, patient populations, production cell lines, ADA assay and reporting criteria Identify Pre-Ab impact on treatment ADA boosting and ADA consequences Base upon published scholarship, learnings from early or similar programs Specific program needs/overall risk-benefit profile Early Screening Pre-Abs emerged from prior treatment with similar compounds may present heightened immunogenicity risk Pre-Ab specificity: early hint for clinical impact

8 Cross-Company Clinical Pre-Ab Data Collection Cross-company clinical Pre-Ab / ADA data set 36 therapeutic compounds, 112 clinical studies sponsored by 8 organizations Aims To evaluate impact on post-treatment ADA boosting and relevance with product modalities and disease populations Statistician Ken Goldberg (Janssen R&D, Johnson & Johnson) Data contribution Li Xue, Boris Gorovits (Pfizer Inc.) Heather Myler (Bristol-Myers Squibb) Kaz Reynhardt, Marta Starcevic Manning (Amgen) Meina Liang (MedImmune) Shobha Purushothama, Lakshmi Amaravadi (Biogen) Mary Birchler (GlaxoSmithkline) Adrienne Clements Egan (Janssen R&D, Johnson & Johnson) Crystal Sung (Sanofi R&D)

9 Data Distribution by Product Modalities % Products PEGylated Protein 30% Immunotoxin 8% Gene therapy 8% Recombinant Protein 3% Human Antibody 28% Antibody Scaffolds 17% ADC 3% Non-human Antibody 3% Non-human Antibody 1% PEGylated Protein 10% Immunotoxin 3% Gene therapy 3% ADC 3% Recombinant Protein 6% Antibody Scaffolds 27% Human Antibody 47% % Studies Gene therapy 2% Antibody Scaffolds 9% Immunotox in 0% Nonhuman 1% ADC Antibody 1% PEGylated Protein 11% Recombina nt Protein 1% % Subjects Human Antibody 75% # Product # Study # Study Subjects Human Antibody Antibody Scaffolds Non-human Antibody ADC Gene therapy Immunotoxin PEGylated Protein Recombinant Protein Sum

10 Data Distribution by Patient Populations % Subjects Normal Human 2% Autoimmune 17% % Studies Normal Human 6% Autoimmune 16% Other 41% Cardiology 2% Other 41% Cardiology 2% Oncology 38% Oncology 35% % Products Oncology 22% Cardiology 5% Other 17% Normal Human 14% Autoimmune 42% # Product # Study # Study Subject Normal Human Autoimmune Cardiology Oncology Other Sum

11 Data Distribution by Route of Administration % Products IM Percutaneous 3% 3% IV, SC 14% IV 37% % Studies IV, SC 7% Percutaneous IM 1% 1% IV 31% SC 43% SC 60% IV, SC 3% IM 1% Percutaneous 0% % Subjects SC 68% IV 28% # Product # Study # Study Subjects IV SC IV, SC IM Percutaneous

12 Oneway Analysis of Combined Pre-Ab Prevalence by Modality Category Mean pre-ab prevalence for each product Greater than 20% prevalence observed for gene therapy, immunotoxin, mab scaffolds, and pegylated protein modalities

13 Oneway Analysis of Combined Pre-Ab Prevalence by Study Population Category Mean pre-ab prevalence for each product Greater than 20% prevalence observed in all surveyed study population categories

14 Oneway Analysis of Combined Pre-Ab Prevalence by Pre-Ab Specificity Category Mean pre-ab prevalence for each product Pre-Abs specific for toxin, gene vector, antibody fragment and PEG were observed in high prevalence

15 Oneway Analysis of Combined Pre-Ab Prevalence by Pre-Ab Isotypes Mean pre-ab prevalence for each product Of reported Pre-Ab isotypes, IgG type was more prevalent than IgM type

16 Factors Suggestive of Pre-Ab Prevalence Factors significantly suggestive of the baseline prevalence for a product in order of their nominal significance Modality category (p<0.0001, and nominally most significant) Pre-Ab specificity category (p=0.0003) Pre-Ab isotype (p=0.0007) Factors are not significant Study population category (require further evaluation)

17 Rates of Treatment ADA Induction/Boosting from Negative/Positive Baseline No significant difference between positive and negative baselines Pfizer Confidential 17

18 Rates of Treatment ADA Induction/Boosting from Negative/Positive Baseline No significant difference between positive and negative baselines Pfizer Confidential 18

19 Treatment ADA Boosting / Induction No significant difference between positive and negative baselines, P > 0.05

20 Treatment ADA Boosting from Pre-Ab + Subjects by Product Modalities % ADA Boosting in Pre-Ab + Subjects 52.3 ADA boosting from Pre-Ab + subjects observed for 5 of the 6 surveyed product modalities

21 Treatment ADA Boosting from Pre-Ab + Subjects by Study Populations % ADA Boosting in Pre-Ab + Subjects ADA boosting from Pre-Ab + subjects observed in all surveyed study populations; lowest boosting rate in cancer patients 3.5

22 Summary Preliminary analysis of current data set suggests that Prevalence of pre-abs is significantly determined by therapeutic modalities, pre-ab binding specificity/ isotypes Overall, subjects positive for pre-abs are not at higher risk to develop treatment emergent ADA response than subjects negative for pre-abs Frequency of Pre-Ab + subjects to develop boosted ADA response is varied with product modalities and patient populations Immunogenicity risk assessment of pre-abs is to be performed on a case by case basis in the context of a program s overall risk-benefit profile

23 Acknowledgements Ken Goldberg (Janssen R&D, Johnson & Johnson) Boris Gorovits (Pfizer Inc.) Heather Myler (Bristol-Myers Squibb) Kaz Reynhardt, Marta Starcevic Manning (Amgen) Meina Liang (MedImmune) Shobha Purushothama, Lakshmi Amaravadi (Biogen) Mary Birchler (GlaxoSmithkline) Adrienne Clements Egan (Janssen R&D, Johnson & Johnson) Crystal Sung (Sanofi R&D) AAPS TPIFG pre-existing antibody team AAPS TPIFG IPAPA

24 Further contribution to clinical Pre-Abs/ADA database and Pre-Ab risk analysis Please contact: Li Xue