CGTP Summit 2024 / Cell and Gene Therapy Products Symposium 2024

Advancing Comparability Understanding of Cell-based Medicinal Products

Despite early success of adoptive cell therapies  and AAV-based gene therapies, it is quite evident that bringing such advanced medicines to the market has proven to be significantly challenging, most importantly due to CMC concerns. Amongst many challenges faced by CGT developers, comparability has continuously emerged as a recurring and inevitable hurdle due to the poorly understood and characterized nature of CGT products. During the first edition of the CGTP Summit in 2023, comparability considerations and current industry practices were discussed focusing on AAV-based gene therapies and CAR T-cell therapies. Reflecting on past success, the summit will continue the discussions on comparability with a focus on cell-based therapies.    

Cell-based medicinal products are inherently one of the most complex therapeutic modalities developed so far. Due to live cells   and inherent variability from where they are sourced and stage of development, cell-based medicinal products have proven to be difficult to characterize and standardize with currently available analytical methodologies. This summit will showcase presentations from the CGT industry and hold interactive panel discussions to tackle some of the challenges seen with conventional comparability strategies for cell-based products.   In this summit, we will focus on somatic cell products and cell-based gene therapy products.

Finally, this summit will feature an expert regulatory panel comprised of regulators from key regulatory agencies. To that effect, this summit will discuss the recently issued FDA draft guidance on manufacturing changes and comparability for human cell and gene therapy products. The purpose of this panel is to openly discuss the common comparability challenges, to engage in a productive dialogue about mitigating those challenges and opportunities for harmonization between regulatory agencies.   

Autologous Cell-Based Medicinal Products

Comparison of new manufacturing processes against established ones is crucial for ensuring the quality, safety, and efficacy of biotherapeutic products. The assessment of comparability for Chemistry, Manufacturing, and Controls (CMC) changes becomes particularly paramount in the pharmaceutical industry when transitioning from earlier to newer production methods. Autologous cell-based medicinal products (referred to autologous products herein), derived from a patient's own cells, present unique challenges when it comes to evaluating changes in CMC parameters due to their inherent variability and intricacies in manufacturing.

This abstract highlights the significance of an autologous session dedicated to discussing comparability assessment strategies for CMC changes in the context of evolving manufacturing processes. Such sessions serve as platforms for industry experts, regulators, and stakeholders to collaborate, share insights, and develop standardized approaches that ensure the safety and efficacy of autologous products.

This session's main objectives include outlining best practices for characterizing the critical quality attributes (CQAs) of autologous products, establishing robust comparability protocols, and addressing regulatory expectations for CMC changes in autologous therapies. Participants will delve into the complexities of autologous product manufacturing and explore analytical methodologies that can effectively capture the nuances of these personalized treatments.

Key topics to be covered during the session may include the identification of critical process parameters (CPPs) for autologous products, risk assessment strategies for CMC changes, and the utilization of advanced analytical techniques such as mass spectrometry, next-generation sequencing, and bioinformatics for comprehensive comparability evaluation. Case studies illustrating successful comparability assessments for autologous products will be presented to showcase real-world applications of the discussed methodologies.

In conclusion, the autologous session focusing on comparability assessment for CMC changes represents a critical initiative in advancing the field of personalized medicine. By fostering collaboration, innovation, and regulatory alignment, this session aims to drive the development of robust CMC strategies that support the continued advancement and commercialization of autologous products while upholding stringent quality and safety standards.

Session Speakers:

Comparability Considerations for In-Licensing an Early-Stage Academic Program

Annie Chiu, CARGO Therapeutics, Inc.

Comparability Study Considerations in the Development and Approval of AMTAGVI™ (Lifileucel)

Arvind Natarajan, IOVANCE Biotherapeutics, Inc.

Approaches for Establishing Comparability for Cell Therapy Products

Nitin Agarwal, Kite Pharma

Analytical Comparability for Autologous CAR-T Products

Hai Yue, Bristol-Myers Squibb Company

Additional Panelists:

Tal Salz, Dark Horse Consulting

Allogeneic Cell-based Therapies

Allogeneic cell therapy products are long sought for expanding the success of cell based therapeutic approaches. Off the shelf products, manufacturable in relatively large quantities could significantly increase access for patients while reducing the cost of manufacturing for companies. The complexities of commercially manufacturing allogeneic cell products remain challenging.  Manufacturing changes are needed inevitable for the continuous process improvement.  Allogeneic cell therapy has the added challenge of the need to periodically replace the donor starting materials.  This is due to limitations in batch size based on the expansion of a single donor and hence requiring robust comparability evaluations. In this session, we will discuss the complexities of implementing a comparability strategy during manufacturing for allogeneic cell-based products. Presentations will be based on case studies in the clinical and commercial space involving healthy donor and induced pluripotent stem cells (iPSC) derived products. Panel discussions will center around phase appropriate strategies to implementing changes required to optimize manufacturing and donor replacement for allogeneic products. 

Session Speakers:

Analytical Control Strategy and Multi-Level Comparability for Genome Editing Components for Cell Therapy Products

Julien Camperi, Genentech, a Member of the Roche Group

Regulatory Strategies & Comparability Assessment For Allogenic Cell Therapy Products With Variable Donor Starting Material 

Sangeetha Prakash, Takeda Pharmaceutical Company Limited

Case Study in Comparability for an iPSC-Derived, Genome-Edited Cell Therapy Product

Jennifer Dashnau, Century Therapeutics, Inc.

Additional Panelist:

Barbara Bonamassa, Italian Medicines Agency

Engaging Global Regulators in Discussion on Comparability for Cell-based Medicinal Products: Industry Challenges and a Path Towards Harmonized Solutions

In a rapidly evolving landscape of cell-based medicinal products, ensuring product comparability during manufacturing changes is a critical aspect of maintaining product quality, safety, and efficacy at any stage of product development. To gain insights and perspectives from global regulatory bodies on this topic, a regulatory panel is organized inviting key regulators such as the Food and Drug Administration (FDA), Pharmaceuticals and Medical Devices Agency (PMDA), Health Canada and Swedish Medical Products Agency. The primary objective of this panel is to openly discuss common comparability challenges seen by regulators, engage in a productive dialogue on mitigating these challenges, and explore opportunities for regulatory harmonization.

The panel will focus on key challenges witnessed by global regulatory bodies in assessing comparability studies for cell-based medicinal products, expectations from global regulatory bodies including considerations for establishing comparability, managing manufacturing changes, and ensuring product quality and safety. Regulators will also share their perspectives on the newly issued FDA draft guidance on comparability for cell and gene therapy products, highlighting areas of consensus and divergence with their own regulatory frameworks.

One of the key discussion points would be recognition of the need for greater harmonization and convergence among regulatory agencies to support the development and approval of cell-based medicinal products on a global scale. By aligning their expectations and requirements, regulators can enhance the predictability and consistency of regulatory reviews, reduce duplication of efforts for manufacturers, and ultimately expedite patient access to innovative therapies.

Overall, this panel aims to provide a valuable platform for regulators, industry stakeholders, and experts to come together, exchange insights, and collaborate toward a more harmonized regulatory approach for understanding comparability for cell-based medicinal products. The insights and recommendations generated through this dialogue have the potential to shape future regulatory guidance and facilitate the development and commercialization of advanced therapies for patients worldwide.

Panelists:

Andreea Barbu, Swedish Medical Products Agency

Yoshiaki Maruyama, PMDA

Christopher Storbeck, Health Canada

Andrew Timmons, CBER, FDA

This technical Seminar will be available to watch on demand 24/7 during the Symposium. Click on this session to access the presentation video. 

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Presented by: Promega Corporation 

This technical Seminar will be available to watch on demand 24/7 during the Symposium. Click on this session to access the presentation video.

NOTE: If prompted to login to view the video, enter your CASSS member credentials. 

Presented by: MilliporeSigma

In addition to the now well-known CAR T (chimeric antigen receptor T cells) and HSC (CD34+ hematopoietic stem cells) cell-based gene therapies, there are several other modes of gene modification as well as cell types already approved and on the horizon. CAR T and HSC genetically engineered therapeutics have typically relied upon lentiviral or gamma-retroviral vector transduction to introduce gene(s) of interest but other methods of gene modification can introduce, replace or inactivate genes in the cells of interest. Recently approved CASGEVY is the first approved therapy to rely on CRISPR/Cas9 gene-editing to modify HSCs. More complex genetically engineered cell therapies may require inclusion of multiple modes of gene modification in the same cell to ensure the desired product attributes. Challenges include effective delivery methods, effective targeting, effective cell selection and expansion, and development of appropriate analytical methods to assess more complex and novel genetic engineering approaches.   

Session Speakers:

Ingenui-T, a Rapid Autologous Chimeric Antigen Receptor (CAR)-T Manufacturing Solution Using Whole Blood, for Treatment of Autoimmune Disease

Sunetra Biswas, Kyverna Therapeutics, Inc.

CMC Development of PM359, a Prime Edited Hematopoietic Stem Cell Therapy for the Treatment of P47phox-Deficient Chronic Granulomatous Disease (CGD)

Barrett Nehilla, Prime Medicine, Inc.

Enabling the Advancement of Cell Therapies with Epigenetic Editing

Nathan Yee, Tune Therapeutics

Additional Panelist:

Zhaohui Ye, CBER, FDA

The field of Cell and Gene Therapy has witnessed expanding numbers of regulatory approvals in recent years. Of the approved products, a significant number are viral vector-based, either employing the viral vector for the delivery of a therapeutic transgene to cells ex vivo during the manufacturing process (e.g., LVV for modified cells), or via direct administration to the patient (e.g., AAV-based gene therapy product) to achieve a therapeutic effect. Given the rate of recent approvals, coupled with technological advances in molecular sciences, and partly driven by evolving regulatory expectations around controls, there is an evolution of product understanding, particularly in the application of analytical methods used to support process development and characterize or monitor product attributes. The aim of this session is to examine these changes in greater detail, including analytical method choices for optimal assessment of product characteristics, attribute criticality and monitoring. This may also include innovative approaches to determination of potency, including the use of surrogate metrics in the context of a potency assay matrix. A greater scientific understanding of viral vector-based Gene Therapy product attributes will improve the overall quality of these important therapeutic products. 

Session Speakers:

LYFGENIA's Journey: Lessons Learned in the Development of LVV-based Cell & Gene Therapy Products

Marc d'Anjou, bluebird bio, Inc. 

Potency Method Development, Bridging and Control Strategies for AAV Gene Therapy

Ping Carlson, Passage Bio

Gene Therapy Product Analytics: Potency Method Validation and Optimization

Wandong Zhang, BioMarin Pharamceutical Inc.

Additional Panelist:

Jessica Chery, CBER, FDA

Genome editing is a tool that enables a new generation of medicines by directly targeting with high precision the genetic cause of a disease. It also allows for immune evasion and prevents microenvironment responses: concepts vital to more potent, off the shelf, cell, and gene therapies. To ensure safe and efficacious administration of gene edited products to patients, minimizing unintended effects is paramount. This session will review approaches to characterize off target genotoxicity at different stages of development for different class of genome/epigenome editing medicines. Current regulatory standards will be discussed, and lessons learned may be applied to relieve bottlenecks for future therapies. 

Session Speakers:

Overview of Current Genomic Analytical Tools to Enable Advancement of Investigational in vivo Genome Editing Products into Clinical Studies

Jessica Seitzer, Intellia Therapeutics, Inc.

Analytical Control Strategies for Ensuring Genomic Integrity in CAR-T Cell Therapies

Athea Vichas, Bristol-Myers Squibb Company

Off-Target Analysis of Genome Editing Products

Yongwook Choi, CBER, FDA

Additional Panelist:

Jennifer Dashnau, Century Therapeutics, Inc.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together regulatory authorities and representatives from the pharmaceutical industry from across the globe to discuss a range of technical and scientific considerations for medicinal products and to develop ICH guidance. In this manner, ICH provides a harmonized approach to ensure that safe, effective and high-quality medicines are developed, registered, and maintained in a resource efficient manner whilst meeting high standards. As cell and gene therapy products have become ever more prevalent in the therapeutic landscape, the specific considerations applicable to such products are in need of specific recommendations for revisions to existing ICH guidelines and/or new guideline development. The ICH Cell and Gene Therapies Discussion Group (CGT DG) has been formed, and the Remit was endorsed by the ICH Management Committee in May 2023. In this session we will hear about the scope of ICH CGT DG activities and their progress toward targeted deliverables. 

Session Speaker:

ICH CGT DG: Progress Toward Delivering a Strategic Roadmap for ATMPs

Kathleen Francissen, Genentech, A Member of the Roche Group

Additional Panelist:

Melanie Eacho, CBER, FDA

Measurement of the biological activity is crucial for lot release, stability and any comparability exercise of all biological medicinal products. Potency assays should be implemented as early in clinical developments as possible because correlation with clinical performance could help in future identification of sub potent batches. However, development of an appropriate potency assay is often challenging, especially for products with complex or not well-defined mechanisms of action.  

Gene editing (GE) tools are used to achieve targeted modifications of genome sequences resulting in gene inactivation, modifications or insertions at specific locations, either in vivo or ex vivo. This allows the generation of very diverse cell phenotypes that can be used in the clinic to treat a high array of diseases. Thus, developing specific potency assays for gene edited medicinal products can have additional complications.  

This session will aim to review FDA’s recently released draft guideline on potency assurance for cell and gene therapy products. It will also cover issues to be considered when designing a potency assay for ex vivo genome-edited products or products that are intended to edit the genome in vivo, considering the different GE tools and possible mechanisms of actions. The session will also present the particular challenges of developing a potency assay for a GE product intended to knock-out a gene.  

Session Speakers:

Potency Assurance for Cellular and Gene Therapy Products

Andrew Byrnes, CBER, FDA

Potency Development for an in Vivo AAV Gene Editing Therapy

Debaditya Bhattacharya, ElevateBio

Approaches to Potency Assays for CRISPR Genome Editing Therapeutics 

Kristy Wood, Intellia Therapeutics, Inc.

Additional Panelist:

Keith Wonnacott, Lexeo Therapeutics, Inc.

Stem cell-derived medicines have seen somewhat of a renaissance over the last year, following a difficult period in terms of regulatory approval. New stem cell therapies, including many iPSC-based therapies, are now under development for a variety of indications and more traditional regenerative approaches have seen regulatory approval. Despite this, there remain difficult challenges for stem cell-derived products, including product characterization and potency assay development for mechanisms of action that often must be postulated fairly widely.  

This session will present case studies by stakeholders that are successfully navigating this field, together with viewpoints from regulators.  

Speaker:

Releasing Criteria and Potency Assay Development of an iPSC-Derived Neural Progenitor Cell Product Targeting CNS Diseases

Jing Fan, Hopstem Biotechnology Inc.

Navigating the Regulatory Path: Clinical Translation of iPSCs 

Saravanan Karumbayaram, CBER, FDA

Cellular Engineering to Address Manufacturing and Regulatory Concerns

Todd McDevitt, Genentech, a Member of the Roche Group

Panelist:

Andreea Barbu, Swedish Medical Products Agency