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

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Disclosure

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

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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

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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

What is Model Informed Drug Development (MIDD)?

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“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”

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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)

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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

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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

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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

MIDD: A Paradigm Shift

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Lalonde et al, http://www.nature.com/clpt/journal/v82/n1/full/6100235a.html

• Agree on the key questions that need to be answered
• Assumption-rich models & quantitative decision rules
• Technical Ingredients
• Cultural Ingredients

Technical Ingredients @ Work

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• Integrates emerging internal & external data
• Informs drug development decisions
• With reduced cost and improved speed
• Model Based Meta Analysis
• PK/PD & CTS

Denney, Tan, Nucci, ACoP 2013

https://doi.org/10.1016/j.diabres.2017.01.019

Art Bergman & Beesan Tan

Sounds great and worked in Ph3 … but does it lead to better PoC success?

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Milligan et al. Clinical Pharmacology & Therapeutics ; doi:10.1038/clpt.2013.54

Evolution of MIDD to impact Phase 2 success (> 2014)

• Get the right dose to test

the mechanism

• Select the right target

(confidence in rationale)

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Target * Molecule * Dose → +PoC

Pillar 1: Exposure at the target site of action Pillar 2: Binding to the pharmacological target Pillar 3: Expression of Pharmacology activity

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Get the right dose: The 3 Pillars Proof of Mechanism

Morgan P et al. Drug Discov Today. 2012 May;17(9-10):419-24.

Increased probability of survival if compounds are pillared

Get the right target: MIDD centric approach to target validation

Clinical Target Validation

Quantitative understanding of

• ther compounds

Human Pharmacology Experiments Early signal of efficacy Quantitative Human Genetics Human QSP models linked to disease

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Confidence in PoC = Confidence in Target & Compound

Clinical Pharmacology & Therapeutics (2013); 93 5, 379–381. doi:10.1038/clpt.2013.40

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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

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MIDD Case Studies in Rare Diseases

• Domagrozumab (Doma) for Duchenne muscular dystrophy (DMD)
• Marstacimab (anti-TFPI) for Hemophilia A or B

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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)

Can we use adults PK and PKPD (Pillars) to select & support Pediatric Dosing Regimens?

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• 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

https://doi.org/10.1002/jcph.1015 Bhattacharya et al.

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• 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

https://doi.org/10.1002/jcph.1015 Bhattacharya et al.

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

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Can we use adults PK and PKPD (Pillars) to select & support Pediatric Dosing Regimens?

https://doi.org/10.1002/jcph.1015 Bhattacharya et al.

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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

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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

Lim, Zhu, Dua, ACoP 2018

Can we use healthy subjects PK and PKPD (Pillars) to design and dose select in Hemophilia patients?

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• 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

Lim, Zhu, Dua, ACoP 2018

Can we use healthy subjects PK and PKPD (Pillars) to design and dose select in Hemophilia patients?

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• Yes!
• PK in patients as

expected from healthy

• Dose and regimen

selection confirmed accurate by the PD biomarkers and efficacy

• J. Mahlangu et al– ISTH, 2019

Can we use healthy subjects PK and PKPD (Pillars) to design and dose select in Hemophilia patients?

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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

• Confidential. Internal Use Only.
• 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 gene replacement therapy Extended model for AAV2/FIX combination

IV dose (infusion)

Quantitative Systems Pharmacology for AAV GTx

Courtesy of Pinky Dua

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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