The Role and Value of Nonclinical PK PD
- Slides: 23
The Role and Value of Nonclinical PK, PD and Immunogenicity Assessments in a Comparability Strategy Paul C. Francis, Ph. D.
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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 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 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 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 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 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 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 • 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 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. 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 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 • 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 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 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 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 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 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 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
Discussion Questions
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?
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