How AGC Biologics received approval from both US and European regulators for commercial manufacture of Lenmeldy – A cell-based gene therapy

In this podcast, we spoke with Luca Alberici, Senior Vice President and General Manager, Milan Facility, AGC Biologics about the road to their recent EC and FDA approval to commercially manufacture Lenmeldy™ and their future plans in cell and gene therapy. 

What is Lenmeldy?

We began the podcast by talking about AGC Biologics’ Milan site and their FDA approval to commercially manufacture Orchard Therapeutics’ Lenmeldy. Luca explained that Lenmeldy is a gene modified cell therapy product for the treatment of Metachromatic leukodystrophy (MLD), an ultra-rare hereditary disease characterized by accumulation of fats that causes neurodegenerative symptoms. It is a pediatric disease, and patients generally die by the age of five.  

With this therapy the patient’s stem cells are collected and modified through the use of a lentiviral vector to add a gene called ARSA that encodes for the right form of the enzyme that these patients are encoding wrong. These modified stem cells are then administered back to the patient so they can immune reconstitute not only the immune system, but the cells will also cross correct through secretion of the right form of the enzyme. After just a single shot of the therapy, there is an improvement in their condition and they develop normally, especially if treated in a pre-symptomatic phase. This is the power of gene therapy at its best.  

The Pathway to FDA Approval for Commercial Manufacture

We then discussed the pathway for receiving approval to commercially manufacture this product and how the AGC Biologics Milan team navigated this process. Luca described that it was quite a long journey. AGC Biologics were manufacturing this product at preclinical and clinical phases dating back roughly 15 years. They worked with a series of different sponsors, it was developed by the San Rafaelle Telethon Institute for Gene Therapy in Milan Italy, then GSK continued the clinical development before it was acquired by Orchard Therapeutics. AGC Biologics remained the manufacturer during this time and in 2020 received approval for commercial manufacture of the product in Europe, but FDA requirements are different so over the last two years, they partnered with Orchard Therapeutics and worked to meet the FDA requirements for approval.  

Luca explained that approval required a great deal of work on the process, the analytics, the quality system, supply chain, and raw materials. One of the most transversal aspects of the validation of a product is getting it ready to be manufactured for the market and it was great to go this last mile with a strong partner like Orchard Therapeutics. He also credits the infrastructure of AGC Biologics, which is a multi-site global organization and provided the Milan site great support in terms of general quality, standards, procedures, and simply by having faced multiple FDA inspections before. The combination of all these factors was what carried them to the finish line, it required extensive teamwork, not only at the Milan site but also the entire organization. 

The Only Site to Receive EC and FDA Commercial Manufacture Approval

I followed up by mentioning how with approval from the European Commission and the FDA, the AGC Biologics Milan facility is the only one in the cell and gene therapy industry to have commercial manufacturing authorization from both the FDA and the EC for LVV and cells. I asked Luca why there are so few CDMO’s who have achieved this and what makes the FDA and EMA approval process so challenging? He explained that the Milan site was the first site to receive clinical manufacturing approval for an ex vivo gene therapy in 2003, 21 years ago, when cell and gene therapy was almost nonexistent at the time. They were the first facility to receive approval for commercial manufacturing in Europe for a marketed product in 2015/2016, 10 years ago. Now they are the only site who can do viral vector and cell therapy, both approved from the main authorities, the EMA and FDA.  

Most of the time, different services are provided by separate facilities, but AGC Biologics handles everything internally. This approach dates back 28 years when market capacity for such processes was lacking, prompting AGC to build its internal capabilities for vector and cell supply across all geographies. They continue to benefit from their 30 years of accumulated experience. Few Contract Manufacturing Organizations (CMOs) are commercially authorized, and none have been authorized for a decade and for multiple products. AGC Biologics is the excess manufacturer for Strimvelis and has four other filings under review (two with the EMA and two with the FDA). Additionally, they have completed three PPQ filings that are expected to be reviewed in late 2024 or early 2025. 

Luca explained that there are currently only 15-20 approved cell and gene therapy products, and AGC Biologics manufactures 5-7 of them, handling about 30% of all late-stage and commercially approved assets. This is due to the newness and difficulty of cell and gene therapy, meaning only pioneering CDMOs have reached this stage. AGC Biologics is proud of their position, and customers continue to rely on them because they offer early innovation, strong manufacturing capacity for late stages, and the quality needed for commercial approval. 

Keys to a Strong Partnership

Next I asked Luca what he thought made the partnership with Orchard Therapeutics so successful. He emphasized that mutual trust and transparency have been crucial. They began collaborating with Orchard Therapeutics around 2017-2018, building daily on transparency, technical expertise, and science. Orchard Therapeutics owns the clinical portion and the product but relies on AGC Biologics for the manufacturing of the viral vector and cell therapy. They work together as an integrated value chain, fitting perfectly into the process of collecting cells from a patient, processing them, and then returning them to patients. 

Their partnership operates as a single team, continually innovating new solutions and processes. Transparency is key, with a “bad news first” policy to openly discuss any issues with their customers and find solutions together. This approach led to a realistic and ambitious plan that ensured they were well-prepared for regulatory inspections, resulting in their FDA approval. They aim to leverage this success for future approvals and product developments to treat more patients in need. 

Advice for Developers in Cell and Gene Therapy

Regarding advice for developers working on cell and gene therapy products, Luca highlighted the importance of being realistic and pragmatic. Balancing the life-saving potential of these therapies with the need to maintain quality and effectiveness is crucial. A conservative approach might not be viable economically or too slow to meet the needs of the therapy. Developers should rely on experienced partners who have demonstrated credibility in the market. 

The field has seen significant ups and downs, often driven by unmet expectations and poorly executed ventures. Many new CDMOs have emerged, some overpromising on timelines and costs. Some developers may have been thinking that cell therapy is easier than it is, or simply a copy and paste of other modalities and some CDMOs found themselves having extra capacity and therefore bid aggressively with timelines and cheaper prices. This has set back progress, underlining the importance of realistic expectations and partnering with trusted, experienced organizations to navigate the complexities of cell and gene therapy development successfully. Therefore partnerships are essential, not just with CDMOs but with all players in the value chain who have proven their credibility.  

The Future for AGC Biologics

I also asked what the future holds for AGC Biologics. Luca explained that in the coming year, they anticipate manufacturing 7-8 commercially approved products, significantly impacting the industry. Despite this growth, their focus remains on innovation and continuing to serve their early-stage customers, including academia, startups, and mid-sized biotechs in preclinical to Phase 1-2 stages. They are continuously innovating their proven processes in gene therapy (lentiviral and retroviral vectors) and cell therapy (stem cells and T cells) and are expanding their capabilities in AAV (adeno-associated virus) for in vivo gene therapy and investing in emerging cell types like exosomes, T regulatory and others. They enjoy partnership and bringing their customers into commercial manufacturing, but they always start very early in the process, and this is where their innovation is crucial. Milan develops the platform processes and then transfers these technologies to their other sites in Colorado, USA, and their upcoming site in Yokohama, Japan. 

AGC aims to establish manufacturing sites for cell therapy across three geographies (Europe, US, Japan) and for viral vectors in Europe and the US, with Milan as the innovation center. This strategy enhances their platform offerings and geographical reach, driving forward their comprehensive and strategic approach in the industry. 

I closed the interview by asking if Luca had anything else he would like to add. He emphasized that AGC is more than just a manufacturer; they are a Contract Development Organization (CDO) focused on development. While manufacturing is a significant part of their operations and they excel at it, their true value lies in their development capabilities. 

They can work with mature processes, adding value through suggestions, modifications, and scaling up. However, their strength is supporting clients with less mature processes. With 28 years of experience primarily in development, they have created processes from scratch for various cell types and developed comprehensive analytics. They have conducted over 160 tests, many of which are validated for market readiness. 

For viral vectors, their plug-and-play platforms for lentiviral and adeno-associated vectors allow clients to bring just their gene sequence, and they handle everything else. This integrated approach is crucial for small to medium-sized players, who often face the challenge of managing multiple suppliers. By partnering with AGC Biologics, they receive top-tier service across various verticals, simplifying the supply chain and reducing stress. 

For more information, please see 

Pin It on Pinterest