Engineering and manufacturing expertise could ease the shortage of viral vectors used for drug delivery in the booming gene therapy market.
In both technology and medicine, bugs are typically something to be avoided. But in the new and booming era of cell therapy manufacturing, bugs are in big demand. That is to say, the industry is grappling with a scarcity of the customized viruses used to deliver disease-fighting engineered genes into a patient’s own cells. The FDA’s recent approval of a third novel gene therapy – Luxturna, developed by Spark Therapeutics for an inherited form of vision loss – accentuates the growing concern about the global supply of viral vectors.
Viral vectors form the basis of many cell and gene therapies, vaccines, and oncolytics. Think of them as the envelope containing genetic material that augments, replaces or suppresses a disease-causing gene mutation in a patient’s cells. Some treatments, like the CAR T cell therapies that recently brought the business into prime time, focus on the T cells of a patient’s immune system in a similar fashion to target and kill the molecular drivers of cancer and other diseases. To get this therapeutic genetic material into the patient’s cells, scientists conceal it within common viruses that have been disabled, which prevents them from replicating or causing illness. These viral vectors “infect” the targeted cells and in the process transfer the curative genetic material hidden within them.
The process of producing vectors in the quantities needed for clinical trials and the commercial marketplace is elaborate, expensive, and highly regulated. There is also a shortage of factories and expertise required to meet the demands, which has created a backlog for the gene-therapy companies and contract manufacturers that do. The skills needed to meet the manufacturing complexities, scale and quality assurance in the production of those viruses and other aspects of cell and gene therapies is creating a demand for engineering expertise, experts say.
In the early experimental days of gene therapy, when studies were confined to the laboratory workbench and the “patients” were mice, the supply of viral vectors was sufficient. But recently, the extraordinary performance of CAR T-cell therapies in human clinical trials has led to a robust pipeline of new drug candidates. More biotech companies are entering the game, emboldened by the landmark FDA approvals of the first two gene therapies treatments (Novartis’s Kymriah and Kite’s Yescarta) in the summer and autumn of 2017. All three approved treatments benefited from the FDA’s new fast-track review policy for promising cell and gene therapies for diseases with no other treatment options. As more companies move into this uncharted new space to take advantage of this bullish regulatory climate, the technical, regulatory and economic challenges of scaling up production are front and center. The scarcity of viral vectors is just one of the bugaboos, but it is at the core of the industry’s overall scalability issue.
Tipping the Production Scales
The gene therapies currently on the market are suitable for only a small subset of patients who fall into a certain age group and/or have unsuccessfully tried other available therapies. They are also focused on rare diseases affecting a relatively small number of cells within the body. Yet they are the harbingers of bigger things to come as the industry learns to develop novel therapies using larger numbers of engineered cells to treat a wider array of more common cancers and other diseases. As the industry advances, there will be a growing demand to produce gene therapies made with a much higher volume of viral vectors and on a much larger scale.
Because each treatment is derived from each patient’s own cells, and because each is designed as a one-time therapy, each batch of medicine is a custom manufacturing job. Consequently, that one infusion can cost patients and their insurers hundreds of thousands of dollars. Making these highly individualized treatments available to thousands more patients per year at a feasible price point will require creative technological solutions along the manufacturing process, beginning with the viral vector supply chain.
The process of producing vector stocks must be carried out in a Good Manufacturing Practice (GMP) facility in clean-room conditions with minimal open processing. Vector sterility is essential and the vectors are subjected to multiple filtration and sterilization steps.
First a batch of cells is grown in culture over several days to produce a quantity sufficient for production. These cells are then transfected with plasmids that encode them with the specific disease-fighting instructions they will deliver to the patient’s cells. After several more days of growth, the vector-containing cells are harvested, filtered to remove production cells and debris, and purified through downstream processing. The finished vectors are then cryopreserved for use up to several years later.
Biologically speaking, it takes only a few weeks to manufacture a batch of viral vectors. But the job of scaling up a research-sized process to commercial-level production under exacting regulatory standards can take months – not counting the time it takes to negotiate with a contract manufacturing organization (CMO) to do the work. As John Dawson, CEO of Oxford Biomedica (Oxford, UK) recently told the New York Times, those steps can take a year, and then it could be another six to 12 months to actually produce a finished batch of viruses. Gene therapy developers usually don’t have GMP facilities to make their own vectors for clinical trials so most hire out the work to one or CMO. As the market heats up, the waiting time for external production of viral vectors is getting much longer. Companies anxious to start testing their drug candidates in clinical trials are increasingly facing the expensive choice of investing in their own vector production facilities or finding creative ways around the CMO backlog.
For their part, contract development and manufacturing firms like Brammer Bio (Cambridge, MA) are aggressively expanding their production capacity. Brammer manufactures all the major types of virus platforms used in gene therapy, including lentiviral, retroviral, adenoviral and adeno-associated vectors. Through strategic mergers and facility acquisitions, Brammer has more than doubled its capacity for early-phase manufacturing capacity for both early and late-stage clinical trials. Investing more than $50 million in 2017 alone, the company has significantly expanded its facilities in Florida and the Boston area. “This added capacity is needed to meet the needs of a growing gene therapy pipeline,” said Brammer Chief Manufacturing Officer Christopher Murphy.
For production of its pediatric blood cancer drug Kymriah, Novartis contracted with Oxford BioMedica as its sole commercial and clinical supplier of lentiviral vectors. The three-year initial arrangement, which is extendable to five years, could bring Oxford BioMedica well over $100 million in revenues through upfront payments, performance incentives, and future royalties on sales. The two firms have been laying the groundwork for this deal since 2014 when they formally announced their collaboration to develop Kymriah using the company’s LentiVector platform.
One recent example of a company having it both ways is bluebird bio (Cambridge, MA). The drug developer will begin manufacturing its own lentiviral vectors in a newly acquired, 125,000 square foot facility in Durham, NC. At the same time, the company has inked multiyear agreements with several other manufacturing partners to address its vector supply issues. The firm is currently working to bring several gene therapies to market within four years, including drugs for cerebral adrenoleukodystrophy, multiple myeloma, and blood disorders like sickle cell disease, says Derek Adams, bluebird’s chief manufacturing and technology officer. Investing in a world-class manufacturing infrastructure is a crucial step,” he says.
By simultaneously establishing multiple lentiviral vector manufacturing partnerships and pursuing in-house manufacturing, he says, bluebird is positioned to produce products currently in development while preparing for future demands.
While the industry grapples with the supply issues, it is also aware of the need to develop lower-cost production methods. As firms begin to target diseases targeting large, solid organs, the price of vectors could run into the millions of dollars per patient, Dawson told the Times. He said companies are working to improve their methods to reduce costs in the short term to a few hundred thousand dollars and, in the future, to somewhere in the vicinity of $30,000.
Michael MacRae is an independent technical writer based in Portland, OR.
Read more about Cell Therapy on AABME.org.