Physiomics PLC · LSE:PYC
Physiomics — Physiomics Webinar 30 March 2023
19 slides from Physiomics's conference presentation, Mar 30, 2023
Slide 1: Mathematical modelling in the age of Project Optimus
Mathematical modelling in the age of Project Optimus 30 March 2023 Copyright © Physiomics Plc 2023 - www.physiomics.co.uk
Slide 2: FDA Project Optimus
FDA Project Optimus Draft guidance structure: A. Collection and Interpretation of Clinical Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Data • PKPD – modelling and simulation • Patient population is it relevant? • Analysis plan! B. Trial Designs to Compare Multiple Dosages • Recommend a par
Slide 3: Efficacy: Response across panels of cell-lines
Efficacy: Response across panels of cell-lines • Early in development we screen drugs across panels of cancer cell-lines for both small molecules and biologics (co-culture PBMCs and cancer cell-line) • What we learn from these early studies is inter- individual variability (IIV) clearly exists for e
Slide 4: Efficacy: Response across panels of cell-lines
Efficacy: Response across panels of cell-lines • Inter-individual variability (IIV) clearly exists for efficacy • We also know that there is IIV in concentration at a fixed dose • Dose X mg gives a range of concentrations (green region) • In all-comers we may not see a concentration-response – we ho
Slide 5: How do we handle IIV in PK, Efficacy and Safety/Tolerability?
How do we handle IIV in PK, Efficacy and Safety/Tolerability? • Dose Titration! • Design Phase 1 studies to identify the best titration strategy • Key advantage with regards Project Optimus – likely to negate the need for randomised parallel dose-response trial – very expensive! • Two marketed small
Slide 6: Venetoclax
Venetoclax • Target: BCL2 – apoptosis target • Tumour Lysis Syndrome is a key issue • Ramp-up is used for two different indications with different starting doses • In the Phase 1 numerous ramp up regimens were tested • Titration clearly helped in getting this drug approved Slide 6 Copyright © Physio
Slide 7: Axitinib
Axitinib • Target: VEGFR inhibitor – anti-angiogenic • The label discusses both up and down dose modifications to essentially choose an MTDi (individualised MTD) Slide 7 Copyright © Physiomics Plc 2023 - www.physiomics.co.uk
Slide 8: Axitinib
Axitinib • Target: VEGFR inhibitor – anti-angiogenic • The label discusses both up and down dose modifications to essentially choose an MTDi (individualised MTD) • Both Venetoclax and Axitinib are examples to a degree of individualised dosing and MTDi – note they don’t continue increasing the dose b
Slide 9: Efficacy in Oncology – Overall Survival (OS)
Efficacy in Oncology – Overall Survival (OS) The gold standard efficacy marker in oncology is overall Key Points survival • OS is a measure of multiple lines of Below is a schematic of a Phase III trial exploring the efficacy treatment of a new treatment A v Standard of Care (SoC) • Treatments post-
Slide 10: Efficacy in Oncology – Overall Survival (OS)
Efficacy in Oncology – Overall Survival (OS) The gold standard efficacy marker in oncology is overall We don’t know… survival Below is a schematic of a Phase III trial exploring the efficacy • How the resistance that emerges under of a new treatment A v Standard of Care (SoC) treatment A will respon
Slide 11: Efficacy in Oncology – Overall Survival (OS)
Efficacy in Oncology – Overall Survival (OS) The gold standard efficacy marker in oncology is overall What we do know… survival Below is a schematic of a Phase III trial exploring the efficacy • Eradicating as much of the disease for of a new treatment A v Standard of Care (SoC) as long as we can is
Slide 12: Efficacy in Oncology – Biomarkers
Efficacy in Oncology – Biomarkers If we now focus on the 1st treatment period… There are numerous measures of efficacy via biomarkers 1. Imaging: • Tumour Size both continuous and categorical • Time to new lesions • Location of lesions 2. Blood borne: • Circulating Tumour Cells • Circulating tumour
Slide 13: Efficacy in Oncology – Biomarkers
Efficacy in Oncology – Biomarkers • Dose/exposure of drug designed to affect disease burden, which we can’t measure precisely, we have numerous Drug measurements via biomarkers • What happens to these markers dictates decisions we make: • Should we progress the drug to next stage of development • Wh
Slide 14: Efficacy/Toxicity in Oncology – Biomarkers
Efficacy/Toxicity in Oncology – Biomarkers • Dose/exposure of drug designed to affect disease burden, which we can’t measure precisely, we have numerous Drug measurements via biomarkers • What happens to these markers dictates decisions we make: • Should we progress the drug to next stage of develop
Slide 15: Toxicity in Oncology – Biomarkers
Toxicity in Oncology – Biomarkers • Again toxicity can be measured using both quantitative and qualitative markers Drug • Effects on blood borne markers: liver enzymes, immune system (cytokines and cell types) etc. • Nausea and vomiting - a less dynamical marker Disease Patient • Grading systems Bur
Slide 16: Relationships between efficacy & safety
Relationships between efficacy & safety 1 1 Grade 3 Toxicity Grade 3 Toxicity Probability Probability Progression Free at X months Response - Imaging 0 0 Dose/Exposure Dose/Exposure 1 • It may be that the different efficacy measures do not all Grade 3 Toxicity agree exactly when compared to toxicity
Slide 17: FDA Project Optimus – Modelling & Simulation
FDA Project Optimus – Modelling & Simulation Draft guidance structure: A. Collection and Interpretation of Clinical PK, PD, & Pharmacogenomic Data ❖ Engage early and use all available data to help with designing Phase 1 dose-escalation and expansion studies B. Trial Designs to Compare Multiple Dosag
Slide 18: Summary
Summary • We know there is inter-individual variability in the IC50 for efficacy and safety – then in addition we have inter-individual variability in exposure – IIV is everywhere! • Dose titration is the only solution if you want to account for IIV • There is no single efficacy marker that is a tru
Slide 19: Thank you – Time for Questions
Thank you Time for Questions… Contact Us: Hayley Close Business Development hclose@physiomics.co.uk Copyright © Physiomics Plc 2023 - www.physiomics.co.uk