Opportunities and Challenges for Manufacturing Scale Up of CAR T Cells. Mark Dudley Institute of Medicine March 1, 2016

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1 Opportunities and Challenges for Manufacturing Scale Up of CAR T Cells Mark Dudley Institute of Medicine March 1, 2016

2 Disclaimer This document represents proposals for discussion by Management. Strategies/Concepts/Projects described herein may need significant modifications before implementation, and no project should be considered final until it has been fully approved by the appropriate Novartis review process. Novartis will only implement programs that are fully consistent with all applicable laws and regulation as well as Novartis companies policies. 2 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

3 CTL019 Effective Therapy Results updated as of December 2015 Early results from UPENN/NVS studies Heavily pretreated patients, r/r disease, many pt transplant CRs mostly durable pall responses associated with CRS Indication Overall Response Percent Response Pediatric ALL 55/59 (all CR) 93% DLBCL + FL 15/26 (most CR) 58% CLL 10/24 (5 CR) 42% Complexity of Large Scale Manufacturing Academic manufacturing processes cannot fulfill global demands Manufacturing processes, product, and process characterization continue to evolve Regulatory requirements as they apply to cell and gene therapies often require clarification Current manufacturing processes are mostly manual; there is a lack of validated automated manufacturing solutions Complex logistics 3 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

4 Transition from Ph1 to Commercial Poor understanding of critical quality attributes and/or target product profile No predictive in vitro potency assay No preclinical model of toxicity CART19 Process Lymphocyte collection and enrichment CAR genetic modification T cell expansion Harvest/freeze and ship The aims of Phase 1 studies in cell and gene therapies may include safety endpoints, scientific discovery, demonstration of manufacturing success, or therapeutic proof of concept. Cell products manufactured for Phase 1 trials often rely on non-validated processing steps or exploratory reagents. In cell and gene therapies where the administered product may proliferate and expand in vivo after infusion, there may be a complex or poorly understood relationship between the dose of the administered product and its clinical impact. 4 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

5 Enabling Global Manufacturing Strategy Process Development Journey from Science to Industrialization small BIG Science Key Technologies Automation, & Integration Mfrg. Suite Design & Operations Global Manufacturing of the future Development Operations Cell Culture World Congress Stefan Wildt 23 Feb '16 Manufacturing Autologous Immunotherapy

6 Transition from Ph1 to Commercial Process Map Through strong collaboration of diverse technology transfer team participants from Academia, GMP production, Technical Development, Quality Assurance and Regulatory, we developed a step-based approach for process transfer 6 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

7 Transition from Ph1 to Commercial Chain of Custody Process scale out requires expanded logistics and infrastructure After gathering data from the academic process, we focused on further enhancing control and consistency of the process. Areas of enhancement included closing of process steps through customized consumable and equipment solutions to enhance sterility assurance 7 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

8 RESULTS Successful Technology Transfer Clean room gowning Patient-derived autologous CTL019 cells for treatment of pediatric patients with r/r ALL enrolled in a US-based, multicenter, phase II clinical trial have now been processed in the industry setting and infused into patients The cell expansion growth curves and release criteria on the cell products obtained in this large scale manufacturing facility were within range of those obtained at the academic facility CAR T cell expansion within expected range 8 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

9 CTL019 Manufacturing Challenges and Process Development Goals Lymphocyte Collection & Enrichment Control the variability of the incoming product: Indication + patientspecific + collection center Process characterization: Understand and control cell purity, phenotype, transduction rate, growth profile Genetic Modification with CAR Harvest & Formulation Activation, Expansion Product characterization: Understand and control Product CQA, ensure required yield and quality, integrate analytics to correlate with patient outcome Raw materials: Ensure robust and reliable raw materials sourcing, access to LV supply, GMP-quality ancillary reagents Process Development Goals 1. Imperatives: ensure clinical efficacy and product safety 2. Improve all unit operations, starting with most critical pain points 3. Use deep analytics to define design space, characterize and understand the product, and control and improve the process 4. Automate, functionally close and streamline the process Cell Culture World Congress Stefan Wildt 23 Feb '16 Manufacturing Autologous Immunotherapy

10 Clinical and Process Translation in Cell Therapies Translation from the Clinic to the Process to Improve Patient Outcomes Non-pivotal Correlation Pivotal Clinical trial Process development Development Operations Exploratory non-pivotal trials Validate new targets and receptor constructs. Identify biomarkers and clinical correlates Test combination therapies and novel immunotherapy agents Evaluate new process and technologies Scale Up and Confirmatory trials Cost reduction and improved quality/safety product profile Rapid production times and better patient/physician experience Improved process reliability, with fewer product manufacturing deviations and failures Possibility for increased understanding of products with potential to create new therapeutic opportunities 10 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

11 Summary: Scale Up in Cell Therapies Improving Patient Outcomes and Increasing Manufacturing Throughput Non-pivotal trial Process Innovation & Dev. Patient & Therapy Data Pivotal Trial Late Process Dev. Process & Product Data CTL019 is an effective therapy for some patients with CD19+ tumors in early phase clinical trials Manufacturing for Phase 1 trials is often complex, labor intensive, and utilizes incompletely qualified reagents and processes. Scale up and technical transfer has been successfully completed from UPENN to Novartis. This process was accomplished through a highly collaborative, multistep process Future Directions Highly controlled, standardized products enable deep analytics and correlative studies Conventional challenges as well as unique logistic and process challenges were addressed Emphasis was placed on safety and efficacy during scale up activities 11 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up

12 Acknowledgements Many thanks to: Stefan Wildt Nebojsa Milovic Jeffrey Boyd Bruce Levine Kathrin Jinivizian Margit Jeschke Megan Suhoski Zhaohui Zheng Daniel Stark Liza Loidolt Christopher Keir Patricia Wood 12 Institute of Medicine Mark Dudley March 1, 2016 Cell Therapy Scale Up