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Drug Development

forGene Therapy

Drug Development for Gene Therapy

Translational Biomarkers, Bioanalysis, and Companion Diagnostics

Edited by

Yanmei Lu

Sangamo Therapeutics Richmond, California USA

Boris Gorovits

Gorovits BioSolutions, LLC Andover, Massachusetts USA

Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750‐8400, fax (978) 750‐4470, or on the web at www.copyright .com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748‐6011, fax (201) 748‐6008, or online at http://www.wiley.com/go/permission.

Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762‐2974, outside the United States at (317) 572‐3993 or fax (317) 572‐4002.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data

Names: Lu, Yanmei, 1966- editor. | Gorovits, Boris, editor. Title: Drug development for gene therapy : translational biomarkers, bioanalysis, and companion diagnostics / edited by Yanmei Lu, Boris Gorovits. Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2024] | Includes bibliographical references and index. Identifiers: LCCN 2023049872 (print) | LCCN 2023049873 (ebook) | ISBN 9781119852780 (cloth) | ISBN 9781119852797 (adobe pdf) | ISBN 9781119852803 (epub) Subjects: MESH: Genetic Therapy–methods | Biomarkers, Pharmacological–analysis | Drug Development–methods Classification: LCC RB155 (print) | LCC RB155 (ebook) | NLM QU 560 | DDC 616/.042–dc23/eng/20231214 LC record available at https://lccn.loc.gov/2023049872 LC ebook record available at https://lccn.loc.gov/2023049873

Cover Design: Wiley Cover Image: © Jonathan Knowles/Getty Images

Contents

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List of Contributors xix Preface

xxiii

Section I

1 Introduction to AAV-based invivo Gene Therapy 3

Oscar Segurado

1.1

1.1.1 History

1.1.2 AAV-based

1.1.3 The

1.1.4 Cell

1.2

1.2.1 Effectiveness and Advantages of AAV Vectors for invivo Gene

1.2.2 Challenges of AAV Vectors for invivo Gene Therapy 14

1.3 Technology Platforms of AAV-based invivo Gene Therapy 14

1.3.1 cDNA Replacement 15

1.3.2 Genome Editing 15

1.3.2.1 ZFN 16

1.3.2.2 TALENs 16

1.3.2.3 CRISPR/Cas9 16

1.3.3 Base Editing and Prime Editing 17

1.3.4 RNAi Gene Silencing 17

1.3.5 Gene Addition 18

1.4 AAV Serotypes and Tissue Affinity 18

1.4.1 The Liver asa Biofactory 19

1.4.2 The CNS asa Biofactory 19

Introduction 3

Advantages and Disadvantages for AAV invivo 13

Therapy 13

Introduction 1

ofGene Therapy 3

invivo Gene Therapy: A Revolution in Medicine 4 AAV Vector Structure 11 Entry and Transduction Pathway 12

Contents

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1.4.3 The Muscle asa Biofactory 19

1.5

Precision Medicine: Screening and Monitoring Biomarkers, Companion Diagnostics 19

1.5.1 Gene

1.6

1.6.1 Predictions

1.6.2 Addressing

1.6.3 Addressing

1.6.4 Addressing

1.7

1.7.1 Patients

1.7.2 Physicians,

1.7.3 Payers

1.8

1.8.1 Can

1.8.2 Can

Therapy Clinical Trials: Spotlight onHemophilia A 20

Predictions forScientific and Medical Progress 22

forChallenges inthe Field 22 Durability 23 Immunogenicity 24 Malignancy 24

Predictions forMarket Adoption 24

and Patient Advocacy Groups 25

Clinical Guidelines, Regulatory Agencies 25

Final Thoughts 26

We Afford invivo Gene Therapies? 26 invivo Gene Editing Replace Gene Therapy? 27

References 28

2 Recent Development in invivo Clinical Gene Therapy Platforms 35

John Murphy and Jane Owens

2.1

2.1.1 rAAV-cDNA

2.1.1.1 Introduction:

2.1.1.2 Glybera

2.1.1.3 Luxturna

Introduction 35

Replacement Therapies 35

Approved rAAV-cDNA Replacement Therapies 36

(alipogene tiparvovec), Marketed by uniQure 36

(voretigene neparvovec-rzyl), Marketed by Spark

Therapeutics 38

2.1.1.4 Zolgensma

(onasemnogene abeparvovec), Marketed by Novartis 40

2.1.2 Introduction: rAAV-cDNA (gene) Therapy Candidates inClinical Development 46

2.1.2.1 AAV-Gene Replacement Clinical Trials forthe Eye 47

2.1.2.2 Clinical Trials forHeart Disease 47

2.1.2.3 Clinical Trials for Hematologic and Metabolic Disease (Targeting the Liver) 48

2.1.2.4 Clinical Trials forSkeletal Muscle 48

2.1.3 Introduction: rAAV-as aVehicle forinvivo Gene Editing 48

2.1.3.1 Non-nuclease Mediated Methods 48

2.1.3.2 Nuclease-mediated Homology Directed Repair 52

2.1.4 Nuclease-mediated Gene Disruption following AAV Delivery 54

2.1.5 Challenges and Opportunities withAAV asa Delivery Vehicle forNuclease-Mediated Gene Editing 56

References 56

Contents vii

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Section II Translational Biomarkers forGene Therapy 61

Biomarker and Bioanalytical Readouts for the Development of AAV

Gene Therapy

Yanmei Lu and Wibke Lembke

3.1

3.1.1 AAV-Mediated

3.1.2 Biomarker

3.2

3.2.1 Viral

3.2.2 Transgene

3.2.3 Transgene

3.2.4 Substrate

3.3

3.3.1 Assessment

3.3.1.1 AAV

3.3.1.2 AAV

3.3.1.3 Off-Target

3.3.2 Biomarkers

3.3.2.1 Hepatotoxicity

3.3.2.2 Thrombotic

3.3.2.3 Muscle

3.3.2.4 Immunogenicity

3.3.3 Safety

3.3.3.1 Dorsal

3.3.3.2 Other

3.4 Predictive and Diagnostic Biomarkers forStudy Enrollment and Patient

3.4.1 Preexisting Anti-Capsid Antibody 80

3.4.1.1 Companion Diagnostic 81

3.4.2 Preexisting Anti-Transgene Protein Antibody 81

3.5 Summary 82 References 82

Introduction 63

Pharmacokinetic (PK) and Pharmacodynamic (PD) Biomarkers 66

Biodistribution and Shedding 66

Safety and Monitoring Biomarkers and Readouts 71

Integration/Insertional Mutagenesis Risk 72 Germline Transmission Risk 73

Biomarkers forNonimmune Organ-Specific Toxicity 78

Target Organ Toxicity Biomarkers 79

Stratification 80

invivo Gene Therapy 63

Category and Utility 65

mRNA Expression 68 and Target Protein Activity and Concentration 68

and Other Distal PD Biomarkers 70

ofgenotoxicity 72

Gene Editing 73

forImmune-Mediated Toxicity 74

Microangiopathy 76

Toxicity 77

Assessment forrAAV Gene Therapy 77

Root Ganglia Toxicity 78

4 Nonclinical and Clinical Study Considerations forBiodistribution,

Shedding, and Pharmacokinetics/Pharmacodynamics 87

Manuela Braun and Kefeng Sun

4.1 Biodistribution and Viral Shedding 87

4.1.1 Introduction toBiodistribution and Viral Shedding 87

4.1.1.1 Definition and Terminology forBiodistribution and Shedding 88

Contents

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viii

4.1.1.2 Global Regulatory Guidance onConducting Biodistribution and Shedding Studies 88

4.1.2 Nonclinical

4.1.2.1 Design,

4.1.2.2 Examples

4.1.3 Clinical

4.1.3.1 General

Biodistribution and Shedding Studies forAAV Vectors 89

Execution, and Reporting 90

Biodistribution and Shedding Studies forAAV Vectors 96

Considerations inViral Shedding Studies inthe Clinical

Setting 97

4.1.3.2 Biodistribution

Characterization inHuman: Necessity and

Concerns 98

4.1.3.3 Examples

4.1.4 Gaps

and Challenges onBiodistribution and Shedding

Characterization 99

4.2

Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Clinical Dose Selection ofGene Therapy 100

4.2.1 Overview

onPK/PD and Dose Selection Strategies forGene

Therapy 100

4.2.1.1 AAV

Dosing Regimen– Safety Relationship and Safety-based Clinical

Dose Projection 101

4.2.1.2 AAV

Dose– Pharmacodynamics/Efficacy Relationship and Projection

ofPharmacologically-Active Dose (PAD) 102

4.2.2 Dose

4.2.3 Mechanistic

4.2.3.1 Modeling

4.2.3.2 Modeling

4.2.4 Clinical

4.2.4.1 Variability

Scaling Approaches: Allometric and Activity-Based Methods 102

Approaches toModeling Gene Therapy 105 and Simulation ofAAV Biodistribution 106 Transgene Product PK and PD ofthe Transgene Product 106

Pharmacology Considerations forGene Therapy 106

inTransgene Product Levels and/or Treatment

Response 106

4.2.4.2 Durability ofTransgene Expression and/or Treatment Response 107

4.2.5 Gaps and Challenges onPK/PD and Clinical Dose Selection 108

4.2.5.1 Interspecies difference inAAV Transduction and Immunogenicity 108

4.2.5.2 Availability ofClinical Samples and Bioanalytical Assays 109

4.2.5.3 Availability ofLong-Term Follow-Up Data 109

4.3 Summary 109 References 110

5 Immunogenicity of AAV Gene Therapy Products 117

Vibha Jawa and Bonnie Wu

5.1 Innate and Adaptive Immunity Induced by AAV-Based Gene Therapies 117

5.1.1 Innate Immune Response 117

5.1.2 Adaptive Immune Response 119

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5.2

5.2.1 Product-related

5.2.2 Process

5.2.3 Patient-Related

5.2.4 Nonclinical

5.2.5 Animal

5.2.6 Animal

5.2.7 Impact

5.3

5.3.1 Pre-existing

5.3.2 Treatment

5.3.3 Antibody

5.3.4 Risk

5.3.4.1 Gene

5.3.4.2 Gene

5.3.4.3 Gene

5.3.5 Product-

5.4 Clinical References 129

Preclinical Immunogenicity Risk Assessment 119

Risk Factors 120

and Manufacturing-Related Risk Factors 120

Risk Factors 121

Assessment ofImmunogenicity 121 Models forAssessing Innate Immunity 122 Models forAssessing Adaptive Immunity 122

ofImmunogenicity onAnimal Selection and Interpretation ofStudy Results 123 Clinical Manifestation Associated withImmunogenicity 123

Immunity Against AAV Vector May Compromise

Therapeutic Efficacy and Patient Safety 124

Induced Anti-AAV Capsid Antibodies may Prevent

Re-dosing 124

Specific toTransgene Protein could lead toToxicity or

Unwanted Immunity 125

ofImmunogenicity Associated withDifferent Administration

Routes 125

Delivery tothe Eye or Central Nervous System 126 Delivery toLiver 126 Delivery toMuscle 126

and Process-related Impurity Related Immunogenicity 127

Mitigation Strategy 127

Contents ix

Section III

6 Bioanalytical Methods to Detect Preexisting and Post-administration

Humoral Immune Responses Against AAV Capsid Proteins 137

Christian Vettermann and Boris Gorovits

6.1 Introduction 137

6.2 Considerations forAAV Total Antibody Assays 138

6.2.1 Nature ofAAV TAb Assay Analyte 138

6.2.2 Primary Analytical Methodologies applied forAAV TAb Detection 139

6.2.3 Tab Assay Critical Reagent Considerations 140

6.2.3.1 Positive and Negative Control Selection 140

6.2.3.2 Capture and Detection Reagents 141

6.2.3.3 Sample Testing Strategy 142

6.2.4 Key Assay Qualification/Validation Parameters 142

Bioanalysis for Gene Therapy 135

Contents

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6.2.4.1 Assay Sensitivity 142

6.2.4.2 Serotype

6.2.4.3 Precision

6.2.4.4 Matrix

6.2.4.5 Assay

6.2.5 TAb

6.3

Considerations forCell-based Transduction Inhibition Assays 145

6.3.1 Principle

6.3.2 AAV

6.3.3 Key

6.3.3.1 Screening

6.3.3.2 Limit

6.3.3.3 Precision

6.3.3.4 Specificity

6.3.3.5 Confirmatory

Specificity 142

143

Interference and Selectivity 143

Cut-Point 143

Assay Data Interpretation 144

and Methodology ofCell-based AAV TI Assays 145

TI Assay Development: Designing forClinical Relevance 146

Assay Validation Parameters 147

and Titer Cut-Points 147

ofDetection 148

150

Steps toEnsure Specific Detection ofNeutralizing AAV

Antibodies 150

6.3.3.6 Selectivity/Matrix

6.3.3.7 Stability

6.3.4 Sample

6.3.5 Data

6.3.6 Value

151

Testing Strategy and Monitoring Assay Performance 152

Interpretation: Preexisting TI Titer and Clinical Efficacy 152

and Challenges ofStandardizing TAb and TI Assays 156

References 157

Interference 151

7 Bioanalytical Methods to Study Biodistribution and Shedding of

AAV-Based Gene Therapy Vectors

Christian Vettermann and Russell Soon

7.1

Introduction 163

7.2 Choice ofPlatform: qPCR vs. Digital PCR 164

7.3 Aspects ofMethod Development 168

7.4 Back-Calculation Formulas and Extraction Efficiency Assessments 172

7.5 Sensitivity Requirements 177

7.6 Specificity Requirements 179

7.7 Standard Curve Performance, Colinearity, Precision, and Accuracy 180

7.8 Selectivity Assessment and Matrix Interference 181

7.9 Sample Stability Considerations 182

7.10 Data Reporting Formats, Acceptance Criteria, and Trending 184

7.11 Immunocapture qPCR: AnUltra-Sensitive Method toDetect Intact AAV Capsids 187

References 189

163

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