The Role and Value of Nonclinical PK PD

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The Role and Value of Nonclinical PK, PD and Immunogenicity Assessments in a Comparability

The Role and Value of Nonclinical PK, PD and Immunogenicity Assessments in a Comparability Strategy Paul C. Francis, Ph. D.

Disclaimer The views and opinions expressed in the following Power. Point slides are those

Disclaimer The views and opinions expressed in the following Power. Point 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 Power. Point 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.

Outline • • General Strategy for Comparability Assessment Considerations for PK/PD Comparability Study Objectives

Outline • • General Strategy for Comparability Assessment Considerations for PK/PD Comparability Study Objectives Case Study 1 Case Study 2 Regulatory Feedback Summary / Conclusions

General Strategy for a Comparability Assessment • Comparability strategy for two Mabs (in Phase

General Strategy for a Comparability Assessment • Comparability strategy for two Mabs (in Phase 2) derived from different cell lines included: – Physical-chemical comparisons of the materials – In vitro biological assays – Concurrent in vivo comparison of biological effects • Strategy is consistent with regulatory guidelines – EMEA Guideline on Comparability of Biotechnology-Derived Medicinal Products After a Change in the Manufacturing Process, Non-Clinical and Clinical Issues – July 2007 – FDA Guidance Concerning Demonstration of Compatibility of Human Biological Products, Including Therapeutic Biotechnology -derived Products – April 1996

Prerequisites for Using a PK/PD Study to Assess Comparability • Molecule should only produce

Prerequisites for Using a PK/PD Study to Assess Comparability • Molecule should only produce PD-related effects at maximum dose tested in a repeat-dose study – No off-target-related toxicity at doses up to 10 X the maximum clinical dose • Robust in vivo PD marker needs to be available • PK profile should be well characterized in species to be tested • Immunogenicity assay for anti-drug antibodies should be available

Study Objectives • Directly compare the pharmacodynamic response (and recovery) and pharmacokinetic profile of

Study Objectives • Directly compare the pharmacodynamic response (and recovery) and pharmacokinetic profile of a Mab derived from two different cell lines – Ideally, test a dose that produces a robust, sub-maximal PD effect • Evaluate these parameters in cynomolgus monkeys administered two weekly doses followed by a non-dosing recovery period • Minimize animal usage and limit the overall study complexity and duration, resource needs, and costs

Case Study 1 Toxicology Profile for Mab 1 • Only binds to target in

Case Study 1 Toxicology Profile for Mab 1 • Only binds to target in humans, NHP’s, and rabbits • Repeat-dose studies in Cynomolgus monkeys – 6 -Week study: IV dosing (0. 1, 1. 0, 30 mg/kg) every 2 wk followed by 4 -mo recovery period – 6 -Month study: IV or SC dosing (0. 1, 1. 0, 30 mg/kg) every 2 wk followed by 4 -mo recovery period – Results were similar between 6 -wk and 6 -mo studies • • No treatment-related adverse effects at any dose level Reduced leukocyte counts in peripheral blood (expected PD effect) PD-related histopathology changes in lymphoid tissues in 6 -mo study Full recovery of PD changes in low-dose group, partial recovery at mid and high doses after 4 mo • Serum t 1/2 was dose-related and ranged from 7. 5 to 27 days • Negative for ADA • NOAEL = 30 mg/kg in both studies

Case Study 1 Study Design Elements • • • Species: Cynomolgus monkey, male and

Case Study 1 Study Design Elements • • • Species: Cynomolgus monkey, male and female Test Articles: derived from NS 0 cells derived from CHO cells Route: Subcutaneous injection No. Animals: 3/sex/group Dose Level: 0. 3 mg/kg (no control group) Dosing Duration: 1 week (dose on Days 1 and 8) Recovery Period: 12 weeks Endpoints: Clinical observations Body weight and food consumption Serum pharmacokinetics (PK) profile Pharmacodynamic (PD) endpoint Immunogenicity (ADA titers)

Serum Mab 1 Concentration ( g/m. L Serum Concentrations of Mab 1 in Cynomolgus

Serum Mab 1 Concentration ( g/m. L Serum Concentrations of Mab 1 in Cynomolgus Monkeys Following Subcutaneous Administration of 0. 3 mg/kg on Days 1 and 8 100 NS 0 CHO 10 1 D 8 0. 1 0. 001 0 336 672 1008 1344 Time (hr) 1680 2016

Immunogenicity of Mab 1 • 11 out of 12 animals were negative for ADA

Immunogenicity of Mab 1 • 11 out of 12 animals were negative for ADA • 1 animal administered CHO-derived Mab showed a low titer of ADA on Day 91, but there was no impact on the PK profile or PD response in this animal • Conclusion: No difference in the immunogenicity of NS 0 - or CHO-derived Mab 1

Mean (±SD) PK Parameters of Mab 1 in Cynomolgus Monkeys Following Subcutaneous Administration of

Mean (±SD) PK Parameters of Mab 1 in Cynomolgus Monkeys Following Subcutaneous Administration of 0. 3 mg/kg on Days 1 and 8 Parameter NS 0 CHO AUC 0 -∞ ( g-hr/m. L) 3122 ± 1054 2575 ± 352 Cmax ( g/m. L) 5. 7 ± 3. 9 4. 1 ± 0. 3 t 1/2 (hr) 371 ± 91 239 ± 102

Group Mean (±SD) of PD Marker Normalized to Baseline in Cynomolgus Monkeys Given 0.

Group Mean (±SD) of PD Marker Normalized to Baseline in Cynomolgus Monkeys Given 0. 3 mg/kg by SC Injection on Days 1 and 8 180 NS 0 CHO PD Marker (% of Baseline) 160 140 120 100 80 D 1 D 8 60 40 20 0 Baseline 7 14 21 28 42 Study Day 56 70 84 91

Case Study 2 Toxicology Profile for Mab 2 • Only binds to target in

Case Study 2 Toxicology Profile for Mab 2 • Only binds to target in humans and NHP’s • 4 -Week repeat-dose study in Cynomolgus monkeys – IV dosing (1. 0, 30, 100 mg/kg) every week followed by 6 -mo recovery period – Summary of results • No treatment-related adverse effects at any dose level • Reduced leukocyte counts in peripheral blood at all doses (expected PD effect) • Full recovery of PD changes by 20 weeks post dosing • PD-related histopathology changes in lymphoid tissues • Serum t 1/2 was dose-related; ranged from 2. 1 to 7. 3 days • All animals positive for ADA • NOAEL = 100 mg/kg

Case Study 2 Study Design Elements • Species: Cynomolgus monkey, male and female •

Case Study 2 Study Design Elements • Species: Cynomolgus monkey, male and female • Test Articles: derived from DG 44 CHO cells (Group 1) derived from GS CHO cells (Group 2) • Route: Intravenous injection • No. Animals: 3/sex/group • Dose Level: 1. 0 mg/kg (no control group) • Dosing Duration: 1 week (dose on Days 1 and 8) • Recovery Period: 8 weeks • Endpoints: Clinical observations Body weight and food consumption Serum pharmacokinetics (PK) profile Pharmacodynamic (PD) endpoint Immunogenicity (ADA titers)

Serum Mab 2 Concentration (ng/m. L Pharmacokinetics of Mab 2 from DG 44 CHO

Serum Mab 2 Concentration (ng/m. L Pharmacokinetics of Mab 2 from DG 44 CHO and GS CHO Cell Lines Following Intravenous Administration of 1. 0 mg/kg to Cynomolgus Monkeys on Days 1 and 8 100000 1000 D 1 D 8 100 DG 44 CHO GS CHO 10 1 0 100 200 300 Time (hr) 400 500 600

Immunogenicity of Mab 2 • 12 out of 12 animals were positive for ADA

Immunogenicity of Mab 2 • 12 out of 12 animals were positive for ADA at all time points sampled (Weeks 1, 4, and 8) • Conclusion: No difference in the immunogenicity of DG 44 CHO- or GS CHOderived Mab 2

Mean (±SD) PK Parameters of Mab 2 in Cynomolgus Monkeys Following Intravenous Administration of

Mean (±SD) PK Parameters of Mab 2 in Cynomolgus Monkeys Following Intravenous Administration of 1. 0 mg/kg on Days 1 and 8 Parameter DG 44 CHO GS CHO AUC 0 -∞ ( g-hr/m. L) 845. 0 ± 307. 9 691. 8 ± 318. 2 Cmax ( g/m. L) 17. 1 ± 5. 1 14. 8 ± 4. 8 t 1/2 (hr) 38. 9 ± 10. 1 19. 7 ± 11. 9

PD Marker (% of Baseline) Group Mean (±SD) of Biomarker Normalized to Baseline in

PD Marker (% of Baseline) Group Mean (±SD) of Biomarker Normalized to Baseline in Cynomolgus Monkeys Given 1. 0 mg/kg by IV Injection on Days 1 and 8 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 1 DG 44 CHO GS CHO D 8 8 15 22 29 36 43 Study Day 50 57 64 71

Regulatory Feedback • Case Study 1 – Preliminary results from PK/PD study and CM&C

Regulatory Feedback • Case Study 1 – Preliminary results from PK/PD study and CM&C comparability data submitted to FDA as part of an IND amendment – Currently under review by FDA • Case Study 2 – Preliminary results from PK/PD study and proposed CM&C comparability protocol submitted to FDA as pre-read for a Type C meeting – FDA indicated that they will make their assessment after the final PK/PD study report and CM&C comparability data have been submitted – Comments at the Type C meeting suggested that results from the PK/PD study would be accepted as supporting comparability as long as the preliminary data submitted in the Briefing Document was corroborated in the final study report

Conclusions • An acceptable comparability strategy for Mabs derived from different cell lines should

Conclusions • An acceptable comparability strategy for Mabs derived from different cell lines should include a CM&C assessment, in vitro assays, and an in vivo evaluation of biological effects and PK • If the Mab only produces any PD-related toxicity in a repeat -dose study, then limiting the primary parameters in the in vivo study to PK and PD may be acceptable • ADA titer can be helpful for interpreting the PK/PD results • Results may influence decision on whether a clinical comparability study is needed

Acknowledgements Jennifer Martin John Kamerud Wendy Komocsar Dan Wierda Holly Smith Jamie Blackbourne

Acknowledgements Jennifer Martin John Kamerud Wendy Komocsar Dan Wierda Holly Smith Jamie Blackbourne

Discussion Questions

Discussion Questions

Discussion Questions • Is immunogenicity an important comparability parameter in a nonclinical study? •

Discussion Questions • Is immunogenicity an important comparability parameter in a nonclinical study? • If a Mab produces non-PD-related toxicity, is it essential to include that endpoint in a comparability assessment? • Do in vivo comparability studies in non-human primates need to be statistically rigorous?