Cell and Gene Therapy Summit – Conversations Dedicated to Manufacturing Challenges, Investment Opportunities and Regulatory Harmonization
15 June 2023
Patient Access & Engagement
Regulatory & Standards
The Phacilitate Editorial team was this week invited to attend the ‘Cell and Gene Therapy Summit’ in London, as the third stop on Charles River’s 2023 tour. Here, Kadeja Johnson and Georgi Makin summarize their key takeaways from the conference, featuring interviews from some of the key opinion leaders invited to participate.
The invite-only event delivered on its goal to share insights with attendees from across the advanced therapeutics space, with presentations and panel discussions on its agenda.
Presenters Dr Paul Batty, Associate Professor in Hemophilia UCL IRIS; Dr Julie Warner, VP Regulatory Affairs, BOYD Consultants and Dr Ramin Baghirzade, Global Commercial Head of Gene Therapy, Charles River, kicked off the summit with presentations exploring key challenges associated with gene therapy development.
Dr Batty gave an insightful presentation on ‘Hemophilia & Gene Therapy: Current Challenges and Opportunities’ discussing the history of the monogenetic X-linked clotting disorder. Dr Batty highlighted the ongoing UCL/St Jude Children’s Research Hospital (St. Jude) hemophilia B study: AMT061 (HOPE-B). The study demonstrated that adults with hemophilia B significantly benefitted from the treatment developed by researchers at St. Jude, Memphis, by reducing the need for injections with clotting factor, a prior treatment, that prevents bleeds. Findings from the six-person study were significant in demonstrating gene therapy reduces the symptoms of the inherited disorder. Dr Batty analyzed the challenges within the study such as adverse effects, costs, factor expression and history of AAV vectors. It’s clear that with any new development, there will be challenges.
AAV is a brilliant concept for gene therapy but flawed. The natural history of AAV vectors can be unpredictable and varies from case to case:
Though there was bleeding reduction and treatment was well tolerated, there were occasional infusion reactions in patients in the trial.
There still needs to be a solution to improve access for patients where infrastructures need to be in place ready for clinical delivery and to expand the conversation to better understand the current vector’s natural behavioral history.
Platforms to accelerate development for in vivo and ex vivo could aid greatly in decreasing the pressure in development hence reducing costs. Charles River, as part of its expanding portfolio, has launched platforms to tackle industry-wide issues such as the nAAVigation Vector Platform, eXpDNA platform and plasmid DNA applications (DNA, in vivo gene, mRNA, transient protein, gene-modified cell therapies where cell engineering is involved).
Following Dr Batty’s presentation, Dr Julie Warner introduced the topic of ‘Aligning on Development Programs for Cell and Gene Therapy Across Regions’, primarily EU versus US, to open the discussion as to whether ‘full harmonization will ever be possible’ from a regulatory standpoint. Differentiation with the EU is clear and has its own considerations whereas the US has no clear distinction. It begs the question of whether ATMPs are regarded as GMOs across various regions. Are gene-edited organisms classified as GMOs within gene therapies?
According to the GMO EU directives, gene editing is not formally considered, ‘engineering’. As the gene therapy space advances, the need for regulatory authorities to comprehend the changing science limits progression. As of now, regulatory approaches, especially differentiation and classification are done case by case – there isn’t a definite guidance for all. Regulation no 1394/2007 states:
‘The evaluation of advanced therapy medicinal products often requires very specific expertise which goes beyond the traditional pharmaceutical field and covers areas bordering on other sectors such as biotechnology and medical devices’ – Clause 10.
Variation of guidelines paves a blurred line that leaves many developers unsure. The ICH, harmonization for better health, from the European Medicines Agency (EMA), has provided an adequate overarching guideline ‘Q13 on continuous manufacturing of drug substances and drug products’. As well as the EMA Multidisciplinary Guidelines that are provided for cell therapy and tissue engineering, gene therapy, pharmacogenomics and others. Without forgetting to mention the US’s FDA OTP has recently been divided into six divisions, is the harmonization between regulatory authorities feasible?
Yes. With careful planning mitigation and regulatory engagement is possible to achieve harmonization when you bring about the following considerations: legal framework, requirements, classifications and seeking regulation at the correct appropriate time. It is evident that there needs to be a combined harmonized regulatory opinion – a topic of conversation which doesn’t seem to have been resolved.
A point raised on mRNA remains unclear as to where its classification lies as well as the clinical and environmental risk considerations for GMO products.
Finally, Dr Ramin Baghirzade, discussed the further challenges facing the advanced therapies space that is being addressed, but at the same time are increasing – a tedious brain scratch that is often accompanied by a heavy sigh. As the market matures, and specifically the AAV market, more plasmids will be needed. It is difficult to predict and determine how plasmids will behave even with an intense study of their natural history. Optimization to expand the limited attention to process development is something that needs improvement when the complexities of common plasmids are in play (AAV and LVV).
Off-the-shelf products could be the start of a solution to accelerate process development – a much-desired prerequisite, as seen with the P helper that is readily available.
There are obviously hurdles when it comes to innovation The panel discussions from various speakers across the industry provided an insightful conversation in various areas of Gene Therapy Early Discovery to IND Filing, Gene Therapy IND Application to Commercialization, Gene Therapy Funding Status and the Future.
Each stage of the development process in Gene therapy require meticulous, effective preparation to maximize success, and success can mean many things from research breakthroughs to commercialization. Quality plasmids need to be the focus as it impacts the expanding plasmid market. Regulators want to understand what the risks entail, knowing the science and knowing the product greeting helps in conveying the need approval in the development process. It’s important to understand that regulations want a detailed package on plasmids and the process used to make sure those plasmids are tested properly for biosafety. It’s an exciting opportunity – the question now is timing. Doing it right in the beginning can help avoid unnecessary costs, which ultimately delay the processes.
Emphasis on demonstrating efficacy seemed to be a recurring theme, especially for small biotechs. The fragmented nature of cell and gene therapy stroked a fine balance between early-stage players. Therefore, how do we meet commercial reliability and patient needs? A good start was advice to be diligent and robust – if products were GMP ready, the potential to drive through to market application could be more feasible, especially with rare (pediatric) diseases.
There are obviously hurdles when it comes to innovation in this industry but the regulators are aware that there isn’t a lot of technical know-how in the regulatory space. Educating regulators is still a priority to driving the advanced therapies space forward. It is progressive and the ‘gold standard’ of regulation doesn’t always exist – especially with ‘new’ and young science where safety is always the first priority.
Though the challenges still remain, progression is gradual and every bit of progress is a big step in some way, shape, or form. The cost of advanced therapies is something that the majority of the global population will not be able to afford. This, however, is not deterring investment in this space. In one panel dedicated to funding and investment, panelists explained how while it may feel that investment is slowing down at the moment, the ‘glory days’ of high investment are not a preferable landscape to be returning to, and that operating with a degree of moderation is a far more sustainable model for approaching new funding opportunities. The opportunities for robust, patient-considerate developers and technological advances are very real, however, and questions were met with much enthusiasm.
The final presentation by Carina Thurgood, Co-Founder of the Maddi Foundation, demonstrated the importance for the continued support, development and investment in advanced therapies. Thurgood began pushing the necessity of raising awareness of Hereditary Spastic Paraplegia 15 (SPG15), to advance research and development of a Gene Therapy for this rare disease when her teenage daughter Madeleine Thurgood was diagnosed with a life-limiting genetic disease. In an exclusive interview with Phacilitate, Carina explained her family’s story, and the lengths to which they have explored opportunities for funding lifesaving research.
Overall, the Cell and Gene Therapy Summit provided excellent insight into the conversations happening within the gene therapy development, manufacturing and investment space, as well the associated challenges and opportunities. The evolved science in advanced therapies is both extraordinary and has been demonstrated to be potentially life-changing for many diseases, but as our knowledge increases, the challenges will not only be addressed and conversed, but effectively tackled – harmonization might just be a revolutionary stepping stone. Off-the-shelf GMP products, such as plasmids, could pave the way to harmonization as a baseline GMP-grade product, thus improving the development timeline for may AAV base gene therapies.