Laboratory in which genes are being edited.
The approvals in June of two gene therapies, Elevidys and Roctavian, indicated for Duchenne muscular dystrophy and hemophilia A, respectively, could be a harbinger for a record-setting year in the cell and gene therapy space.
However, the ever-increasing numbers of cell and gene therapy candidates in the pipeline, along with a steady growth of new approvals, are stretching manufacturing capacity to its limits. Multiple reports indicate the cell and gene therapy sector of the biopharmaceutical industry is experiencing a serious “capacity crunch.”
The challenging financial climate, with high interest rates in particular, is causing cash runway constraints for cell and gene therapy developers. Cycles in the credit markets entail a continually changing set of circumstances, which companies generally have little control over. Some years raising cash is easy; others it’s difficult. But for years acute shortages of manufacturing capacity have been persistently impacting cell and gene therapy development and commercial production of approved products.
BioPlan, a leading source of independent strategic information and analysis for the life sciences industry, estimates that there is presently a 500% shortage of cell and gene therapy manufacturing capacity, meaning that five times the current capacity would likely be used if it were available. In some cases, this is limiting the potential of approved products to launch on time, or, when launched, attain rapid uptake. In many others, it is slowing the development of products in the pipeline. These operational challenges can be just as impactful to growth as limited R&D funding, regulatory clinical holds, and market access hurdles.
Cell and gene therapies require enormous up-front investment outlays in complex manufacturing processes. Here, companies face considerable supply chain and distribution obstacles in their efforts to make sure just-in-time doses of cell and gene therapy products are available, whether in the clinical development or commercialization phases.
Further complicating matters is that there isn’t a one-size-fits-all method for manufacturing cell and gene therapies. Additionally, there are no “standardized, automated factories” to produce cell and gene therapies at scale.
The emerging critical mass of clinical- and real-world experience for the adeno-associated virus (AAV) vector gene therapy platform gives it perhaps a leg up on others, producing a safe and effective AAV-based treatment isn’t easy. The process of extracting and purifying AAV vectors is difficult, in part because AAVs are produced in live cells in cell cultures.
Of the next dozen or so therapies expected to launch in 2023 and 2024 the majority is of the AAV type, specifically in vivo gene therapies.
Companies can outsource manufacturing to contract development and manufacturing organizations (CDMOs). Indeed, CDMOs have played a vital role in cell and gene therapy production. As a leading CDMO, Catalent, for instance, has formed multiple long-term partnerships with biopharmaceutical companies. To illustrate, Catalent has served as the main commercial manufacturing partner for Sarepta Therapeutics in its quest to get its gene therapy to treat Duchenne muscular dystrophy across the finish line. Catalent also supports other candidates in Sarepta’s pipeline. To meet the increasing demand for gene therapies, Catalent is “ramping up” additions to its Maryland facilities.
However, CDMOs’ businesses are often stretched thin, which can mean significant wait times for manufacturing slots.
Starting with bigger pharmaceutical players—but also including some mid-sized ones—more and more firms are investing in in-house manufacturing to be able to meet the demands in clinical development and in anticipation of possible commercialization.
The decision last year by Legend Biotech and Johnson & Johnson to expand manufacturing aptly illustrates how companies are responding to and anticipating capacity issues. The companies’ newly approved CAR-T agent for multiple myeloma, Carvykti, may see robust indication expansion in the coming years, with potentially tens of thousands more patients being prescribed the product. As a result, the two companies forecast that they will require a substantial boost in manufacturing capacity. And so, last year, they committed $500 million to investing in building a new manufacturing facility in New Jersey.
While smaller firms, including Solid Biosciences and Sarepta Therapeutics, are outsourcing, larger companies are making substantial capital investments in cell and gene therapy manufacturing capability. Besides Legend Biotech and Johnson & Johnson, Pfizer, Novartis, Bayer, Biogen, and Biomarin are spending large sums on manufacturing. Together with Legend Biotech and Johnson & Johnson they lead the pack in terms of footprints and investments.
Manufacturing capability is critical throughout the cell and gene therapy development process, from late-stage clinical trials to market. But currently there is a sizable gap between the development and manufacturing capabilities.
The shortage of capacity and long lead times with CDMOs have resulted in some biopharmaceutical companies slowing R&D and even delaying entry into the field. To avert a greater problem five years from now, when there will be dozens of commercial products on the market, the industry will need to add much more capacity, either externally or internally.