Thinking back as recently as 2010 and 2011, there were only a handful of organizations with serious intentions of bringing gene therapy products to the market. I remember when pharma companies and venture capitalists used to dismiss gene therapies as too complicated, risky and inefficient.
Things have certainly changed. Close to $9 billion was invested globally in cell and gene therapies in 2018. Much of this has been driven by companies focusing on rare genetic diseases, which represent a relatively straightforward target if a single gene is responsible. These first “cures” have demonstrated that gene therapies can be effective and commercially viable.
Another factor in the (re)birth of the gene therapy field was the development of appropriate vectors (lentiviral and AAV, for example), which made commercial gene therapy possible. Despite the progress, however, manufacturing remains a key limiting step for widespread patient access. And so the next frontier for gene therapy is all about overcoming such manufacturing challenges.
In many cases, companies rush into manufacturing without realizing how important it is to the success of the product. Some question the validity of “the process is the product,” but I believe it is. When you embark on a gene therapy program, of course, you have to consider the quality of the design and preclinical studies to demonstrate efficacy, but you also have to seriously consider how you will manufacture the product. And you must be aware that any change in the process may affect the structure of the product, necessitating preclinical and clinical bridging studies.
Most will be familiar with QbD, but what about MbD – manufacturing by design? If you switch from one manufacturing technology to another, the molecular nature of your vector may also change. So deciding which technology to use and how you will use it early in development is key in gene therapy.
I believe there’s scope for improving gene therapy manufacturing across the whole value chain. Firstly, the viruses used in gene therapy are assembled in cell lines, and when you look at the productivity of the cell lines that are used today in terms of protein quantity, it’s far lower than you might get for the production of an antibody. Creating stable systems has been the holy grail of expression technology for the past 30 years and we’re still far away. If the industry as a whole can make greater strides towards stable systems, then the cost of manufacturing will fall.
Secondly, much of the transient transfection discussion focuses on the efficacy of transfection. Here, the role of the starting materials, the transfectants, is key and there is a need for the development of new and improved transfectants.
Finally, there is scope to increase yields through improvements in downstream purification steps, particularly capacity and separation so that viral species can be purified more precisely. Put simply, gene therapy preparations are mixtures of viruses, full and empty particles, together with contaminants from cell media. Analytical tools are the means by which manufacturers identify and quantify these different species at different steps – and, if these can be improved, efficiencies will increase and costs will go down.
These are some elements companies should be working on to improve productivity. Today, the cost of manufacturing for a single dose can be several hundreds of thousands of dollars. Our aim should be to reduce this by orders of magnitude in the coming years.
I am hopeful, especially when we look at the monoclonal antibody field, that it can be done. I can remember clearly how limiting the manufacturing technologies and processes were for antibodies 20 years ago. In contrast, just look at how seamless these processes are today. I have no doubt we’ll make progress – we already have. Nobody knew how to manufacture treatments for neuromuscular indications a few years ago taking into account the very important quantities necessary, and today process are available at least for clinical trials. But to make these therapies commercial realities for the most common indications, we must continue to innovate in manufacturing.
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