MIDD in Rare Disease: Experiences and Opportunities Gianluca Nucci - PowerPoint PPT Presentation

MIDD in Rare Disease: Experiences and Opportunities Gianluca Nucci Early Clinical Development Clinical Pharmacology Pfizer Inc

Disclosure I am employed at, and I am a stakeholder of, Pfizer Inc 2

Acknowledgments • Pinky Dua (Early Clinical Development Rare Disease CP Group Head) And a number of present and past colleagues. In particular: • Tong Zhu • Chay Lim • Neil Bhattacharya • Jack Cook • Lutz Harnisch 3

Outline • What is Model Informed Drug Development MIDD? • What are the challenges in Rare Disease and can MIDD help? • MIDD at Pfizer: • How we got where we are now? What have we accomplished? How has it evolved? • Case studies in Rare Diseases • Anti-myostatin (Domagrozumab) • Anti-TFPI (Marstacimab) • What are the remaining challenges? • Gene Therapy (GTx): A role for MIDD? • Conclusions 4

What is Model Informed Drug Development (MIDD)? “ quantitative framework for prediction and extrapolation, centered on knowledge and inference generated from integrated models of compound, mechanism and disease level data and aimed at improving the quality, efficiency and cost effectiveness of decision making ” 5

What are the challenges in Rare Disease? • Knowledge gaps : • Incomplete knowledge of disease (progression, endpoints, …) • Small number of patients (placebo, efficacy, dose response, …) • Many modalities (small & large molecules, GTx , enzyme replacement, …) • Patient Populations (pediatrics, adults) 6

What are the challenges in Rare Disease? … and can MIDD help? MIDD builds bridges in rare disease drug development … creates and integrates knowledge and disease understanding not possible with traditional methods 7

MIDD @ Pfizer: The Beginning (<2005) • High late-stage study failure (efficacy) • Root cause analysis → knowledge gaps: • study design, dose selection, quantitative understanding of endpoints and literature information • Technical Issues • not enough experts • Cultural Issues • clinicians, statisticians & clin pharm working in isolation 8

MIDD Implementation (> 2005) • Institutionalize MIDD to become Business as Usual • Senior leader sponsorship (top down) • Integral from governance bodies, to teams, to individual goals • Education of Clinical / Clin Pharm / Stats as departments and as partners (workshops) • Governance as well as colleagues 9

MIDD: A Paradigm Shift • Technical Ingredients • Cultural Ingredients • Agree on the key questions that need to be answered • Assumption-rich models & quantitative decision rules 10 Lalonde et al, http://www.nature.com/clpt/journal/v82/n1/full/6100235a.html

Technical Ingredients @ Work • Model Based Meta Analysis • PK/PD & CTS Denney, Tan, Nucci, ACoP 2013 Art Bergman & Beesan Tan https://doi.org/10.1016/j.diabres.2017.01.019 • Integrates emerging internal & external data • Informs drug development decisions • With reduced cost and improved speed 11

Sounds great and worked in Ph3 … but does it lead to better PoC success? Milligan et al. Clinical Pharmacology & Therapeutics ; doi:10.1038/clpt.2013.54 12

Evolution of MIDD to impact Phase 2 success (> 2014) • Get the right dose to test • Select the right target the mechanism (confidence in rationale) Target * Molecule * Dose → + PoC 13

Get the right dose: The 3 Pillars Proof of Mechanism Pillar 1: Exposure at the Pillar 2: Binding to Pillar 3: Expression of target site of action the pharmacological Pharmacology activity target Increased probability of survival if compounds are pillared 14 Morgan P et al. Drug Discov Today. 2012 May;17(9-10):419-24.

Get the right target: MIDD centric approach to target validation Quantitative Human QSP models understanding of linked to disease other compounds Clinical Target Validation Human Quantitative Pharmacology Human Genetics Experiments Early signal of efficacy 15

Confidence in PoC = Confidence in Target & Compound Clinical Pharmacology & Therapeutics (2013); 93 5, 379 – 381. doi:10.1038/clpt.2013.40

How Does It Look Like Today? MIDD impact Drug Discovery & Development: and RD productivity improving! Milligan et al. Clinical Pharmacology & Therapeutics ; doi:10.1038/clpt.2013.54 17

MIDD Case Studies in Rare Diseases • Domagrozumab (Doma) for Duchenne muscular dystrophy (DMD) • Marstacimab (anti-TFPI) for Hemophilia A or B 18

MIDD approaches for Doma in DMD • Fatal genetic neuromuscular disease with progressive loss of muscle integrity and function • Myostatin inhibits the myogenic process: its inhibition improved muscle mass in animals & knockouts • Doma is a monoclonal antibody against myostatin developed for DMD • The high unmet need of DMD requires reduced development timelines (yet inform objective decision making) • Doma FIH (#NCT01616277) in healthy adults followed by a phase II study in DMD boys (#NCT02310763) 19

Can we use adults PK and PKPD (Pillars) to select & support Pediatric Dosing Regimens? 1. Meta‐analysis of CL and Vss for mAb in adults and pediatrics 2. Develop a structural model to describe Doma and total myostatin data Bhattacharya et al. https://doi.org/10.1002/jcph.1015 20

Can we use adults PK and PKPD (Pillars) to select & support Pediatric Dosing Regimens? 3. Characterize the PK/PD determinants of Doma in healthy adults 4. Scale the model to Pediatrics and conduct CTS to select Ph2 Dose & regimens in DMD 21 Bhattacharya et al. https://doi.org/10.1002/jcph.1015

Can we use adults PK and PKPD (Pillars) to select & support Pediatric Dosing Regimens? • Yes! • Integration of internal data, literature information using meta‐analyses, pop PK/PD, and allometric scaling • Regulators agreed with us and interim PK checks were uneventful • Pfizer terminated Doma for DMD due to lack of efficacy – yet we were able to robustly test the mechanism 22 Bhattacharya et al. https://doi.org/10.1002/jcph.1015

MIDD approaches for anti-TFPI in Hemophilia (Hem) • Tissue Factor Pathway Inhibitor (TFPI) is a negative regulator of coagulation factors • An anti-TFPI mAb is expected to offer treatment in Hem-A and Hem-B not affected by antifactor inhibitors and with increased convenience • To speed development of anti-TFPI we proposed single dose escalation in healthy subjects (NCT02531815) followed by a multi dose hemophilia study (NCT02974855) to assess initial safety and efficacy 23

Can we use healthy subjects PK and PKPD (Pillars) to design and dose select in Hemophilia patients? 1. Develop nonlinear mixed effects model for PK and total soluble TFPI in healthy subjects 2. Identify and model PD biomarkers of interest based on mechanistic understanding 24 Lim, Zhu, Dua, ACoP 2018

Can we use healthy subjects PK and PKPD (Pillars) to design and dose select in Hemophilia patients? 3. Both direct and indirect response model used 4. PK simulated with different doses and EC90 estimates of key PD biomarkers to support “no regrets” dose selection 25 Lim, Zhu, Dua, ACoP 2018

Can we use healthy subjects PK and PKPD (Pillars) to design and dose select in Hemophilia patients? • Yes! • PK in patients as expected from healthy • Dose and regimen selection confirmed accurate by the PD biomarkers and efficacy 26 J. Mahlangu et al – ISTH, 2019

Remaining challenges: The example of GTx • GTx offers the hope of a cure for rare monogenic diseases • Initial results are potentially transformative • However GTx offers challenges/opportunities for MIDD • Many of the Rare Disease challenges are amplified • Initial studies only in patients with very small N, no Placebo • Critical role for quantitative linkage between expression and function • New challenges: • Mechanistic understanding of AAV vector • Dose selection when no redosing is possible • No PK (imaging?) • Immunogenicity • Duration of transgene expression 27

Quantitative Systems Pharmacology for AAV GTx • Main determinants of successful AAV gene replacement • Transduction efficiency of the vector into human target cells • Transcription/Translation efficiency of the transgene to produce protein • Initial QSP efforts underway (stay tuned) Biological map for mechanisms involved in AAV-based Extended model for AAV2/FIX combination gene replacement therapy IV dose (infusion) Courtesy of Pinky Dua Confidential. Internal Use Only.

Conclusions • MIDD has been a game changer at Pfizer impacting both collaboration culture and probability of success • MIDD is essential to inform Rare Disease drug development • integrates knowledge in a quantitative framework bridging the data/knowledge gaps of small populations • The sense of urgency and acceleration needed in Rare Disease may be addressed in part with: • innovative phase I study designs • extensive use of MIDD to integrate diverse data sources and bridge from healthy subjects to rare patients • Tremendous challenges and opportunities for MIDD impact are ahead of us • GTx being a critical modality that will require redefining the role of quantitative clinical pharmacology 29