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Landscape Review and Evidence Map of Gene Therapy, Part 2

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Landscape Review and Evidence Map of Gene Therapy, Part 2 EMERGING TECHNOLOGIES AND THERAPEUTICS REPORT 1 Landscape Review and Evidence Map of Gene Therapy, Part II: Chimeric Antigen Receptor- T cell (CAR-T), Autologous Cell, Antisense, RNA Interference (RNAi), Zinc Finger Nuclease (ZFN), Genetically Modified Oncolytic Herpes Virus Andrea Richardson, Eric Apaydin, Sangita Baxi, Jerry Vockley, Olamigoke Akinniranye, Rachel Ross, Jody Larkin, Aneesa Motala, Gulrez Azhar, and Susanne Hempel RAND Corporation June 2019 Revision [February 2020] Since the completion of this report a gene therapy herein described as AVXS-101 has been approved by the FDA as Zolgensma therefore the report was revised in November 2019 to reflect that change. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. This publication was developed through a contract to support PCORI's work. Questions or comments may be sent to PCORI at [email protected] or by mail to Suite 900, 1828 L Street, NW, Washington, DC 20036. ©2019 Patient-Centered Outcomes Research Institute. For more information see https://www.pcori.org EMERGING TECHNOLOGIES AND THERAPEUTICS REPORT 2 Table of Contents Executive Summary ......................................................................................................... 6 Introduction of Report Series .......................................................................................... 8 History of Gene Therapies ............................................................................................ 8 Aim of the Report ......................................................................................................... 8 Methodology Overview ................................................................................................ 8 Data Sources ................................................................................................................ 9 Figure 1. Content and Data Sources ................................................................................. 10 Organization of the Report Series and Organization of This Report ........................... 10 Description of Interventions/ Technologies ................................................................... 11 Table 1. Intervention Classes With FDA-approved Therapies .............................................. 12 Table 2. FDA-approved Therapies .................................................................................... 13 Table 3. Potential Pipeline Gene Therapies ....................................................................... 14 CAR-T, Autologous Cell, ZFN, Antisense, RNAi, Genetically Modified Oncolytic Herpes Virus Gene Therapy .................................................................................................... 18 CAR-T Therapy Indications .............................................................................................. 18 Autologous Cell Therapy Indications ................................................................................. 19 Antisense Therapy Indications ......................................................................................... 20 RNAi Therapy Indications ................................................................................................ 20 ZFN Therapy Indications ................................................................................................. 21 Genetically Modified Oncolytic Viral Replication-competent, Attenuated Derivative of Herpes Simplex Virus Type 1 Therapy Indications ......................................................................... 22 Key Question 1a. What are the different types or modalities of the intervention that have been used in clinical practices and clinical research studies? ....................................................... 22 Key Question 1b. What are potential/presumed advantages and disadvantages in contrast to current practices? .......................................................................................................... 23 Key Question 1c. What are the safety issues or expected adverse events? ........................... 25 Context in Which Gene Therapy Is Used ........................................................................ 27 Key Question 2a. What is the approval process and current approval/certification status for gene therapies? ............................................................................................................ 27 Key Question 2b. Are any additional accompanying resources or technologies required? ....... 28 Key Question 2c. What is the current state of adoption in practice and settings? .................. 29 Key Question 2d. What are the operator factors, such as training and staffing? .................... 29 Ongoing Premarket and Postmarket Gene Therapy Studies .......................................... 30 Ongoing Trial Characteristics ..................................................................................... 30 Table 4. Ongoing Antisense Trials .................................................................................... 30 Table 5. Ongoing Autologous Cell Trials ............................................................................ 33 Table 6. Ongoing CAR-T Trials ......................................................................................... 37 Table 8. Ongoing ZFN and Genetically Modified Oncolytic Viral Therapy/Herpes Simplex Virus Type 1 Trials ................................................................................................................. 42 Key Question 3a. What are indication/patient inclusion criteria in ongoing trials? .................. 43 Key Question 3b. What are the types of interventions in ongoing trials? .............................. 44 Key Question 3c. What are the study designs/size in ongoing trials? ................................... 44 EMERGING TECHNOLOGIES AND THERAPEUTICS REPORT 3 Key Question 3d. What are the comparators in ongoing trials? ........................................... 44 Key Question 3e. What are the prior/concurrent treatments in ongoing trials? ...................... 44 Key Question 3f. What is the length of follow-up in ongoing trials? ..................................... 44 Key Question 3g. What are the outcomes measured in ongoing trials? ................................ 45 Current Evidence Supporting Gene Therapy .................................................................. 46 Published Trials Characteristics ................................................................................. 46 Table 9. Summary of Published Antisense, Autologous Cell, CAR-T, Genetically Modified Oncolytic Viral Therapy/Herpes Simplex Virus Type 1, RNAi, and ZFN .................................. 46 Key Question 4a. What are the indication/patient inclusion criteria in published studies? ....... 47 Key Question 4b. What are the types of interventions in published studies? ......................... 47 Key Question 4c. What are the study designs/size in published studies? .............................. 47 Key Question 4d. What are the comparators in published studies? ...................................... 47 Key Question 4e. What are the prior/concurrent treatments in published studies? ................ 48 Key Question 4f. What is the length of follow-up in published studies? ................................ 48 Key Question 4g. What are the outcomes measured in published studies? ........................... 48 Key Question 4h. What are the adverse events in published studies? .................................. 49 Evidence Map of Ongoing and Completed Trials ......................................................... 50 Figure 2. Gene Therapy Evidence Map—Antisense, Autologous Cell, CAR-T, Genetically Modified Oncolytic Viral Therapy/Herpes Simplex Virus Type 1, RNAi, and ZFN .................................. 51 Important Issues Raised by Gene Therapy .................................................................... 52 Key Question 5a. What are the implications of the current level of adoption and future diffusion, given current level of evidence—efficacy/safety, ethical, disparity, resource allocation, and decision making? ..................................................................................................... 52 Key Question 5b. What are the key issues pertaining to decisional uncertainty? ................... 53 Key Question 5c. What are potential areas of research focus for PCORI and others? ............. 54 Acknowledgements ....................................................................................................... 55 References ..................................................................................................................... 56 Appendix ....................................................................................................................... 98 Appendix A: Report Methodology ............................................................................... 98 Literature Searches ........................................................................................................ 98 Literature Review Procedure ........................................................................................... 99 Inclusion Criteria ............................................................................................................ 99 Data Extraction ............................................................................................................
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