As many begin to show proof-of-concept in a range of disease indications, cell and gene therapies (CGTs) have quickly become one of the most talked-about areas of development in the pharmaceutical industry. The US Food and Drug Administration (FDA) has now approved more than 30 CGTs and plenty more are currently making their way through clinical trials globally.
Although CGTs have the potential to be breakthrough medications in a vast range of therapeutic areas, there are significant hurdles that must be overcome during the development process — before even considering commercialisation. Therefore, pharmaceutical companies and manufacturers must find ways to mitigate these issues to make such therapies available to patients as quickly as possible.
At Charles River’s recent Cell and Gene Therapy Summit in London, UK, a panel of experts sat down to talk about what companies should be considering when trying to develop and bring a cell and gene therapy to market. During their discussion, all participants unanimously agreed that companies should focus on problem solving early on; one way that CGT companies can approach this, they said, is by developing a clinically sound and simple potency assay.
Gene therapy trials have been delayed because of the lack of a suitable potency assay
Why a potency assay is essential
There are many reasons why potency assays should be considered early in the process of developing a cell and gene therapy. They can play a key role in the following stages and
- allow companies to determine how efficacious a therapeutic is: With a good potency assay, it can be determined if a CGT product is efficacious in a preclinical setting and, if so, how good it is. This can help developers and manufacturers to decide whether the product is worth committing to and whether it will be successful in human-based clinical trials.
- determine if the drug’s therapeutic window will be sufficient: For a drug to be financially viable, it must be tolerable in a patient population. Those in charge of medical reimbursement are also typically looking for a good therapeutic window — meaning the drug should be potent at low doses. Using an assay to ensure the drug is sufficiently potent can save CGT developers money, time and resources.
- highlight how a CGT may perform in human trials: Potency assays allow developers to assess the potential of their therapeutic to treat a disease early on. By using human-specific models, it can be better predicted if a therapy will need to be optimised while also indicating its overall functionality and viability as an effective treatment.
- reduce the costs associated with amending a CGT later down the line: When a company develops a good potency assay, it can allow them to determine the quality and efficacy of their product and whether any changes will have to be made. Going through this process before entering pivotal trials is a great way to make any necessary amendments to processes, materials and technologies early, saving companies money and time in the long-run.
- estimate how much product will need to be manufactured: Implementing a potency assay early in the process helps CGT developers to make more informed estimates regarding how much product they will need to manufacture. By determining this early, businesses can prevent the overproduction of the therapy in both clinical trials and commercial settings.
Looking towards commercialisation
Although many regulatory bodies do not require a company to have a robust potency assay for Phase I, the experts at the Charles River Cell and Gene Therapy Summit believe this is a key step to get a CGT candidate though the approval process. Nina Kotsopoulou, AAVantgarde’s Chief Technical Officer, comments: “You may not need a potency assay right at the beginning, but you’ll need it before you go into Phase III clinical trials. Many gene therapy trials have been delayed because of the lack of a suitable potency assay. Not only do you have to think about having a potency assay, but also how to validate it, so I would recommend considering this aspect of development ahead of schedule.”
Data should be collected as early as possible; don’t wait for your validation campaign to collect information about your process
“Potency assays are also immensely important when running a successful comparability study … as well as during the characterisation process. Data should be collected as early as possible; don’t wait for your validation campaign to collect information about your process. Even if a company chooses to work with a CDMO, they should have a lab of their own to do characterisation and potency and assay defining experiments.”
“Having a potency assay in Phase I,” Nina continues, “can help you bridge to Phase III, allowing you to alter your processes while reducing the chances of having to do another clinical study to bridge the gap.”
Franz Gerner, founder and Independent Consultant at South Mountain Advanced Therapies Consultants, agrees, stating: “Lately, I have observed a greater push from regulatory bodies when submitting an IND application to have a potency assay for Phase I, so this is something they are focusing on when assessing cell and gene therapies.”
The importance of high-quality raw materials
When selecting the core materials necessary for cell and gene therapy production, companies can either go for GMP-grade from the start or choose a cheaper intermediate prior to commercialisation. Franz Gerner, founder and Independent Consultant at South Mountain Advanced Therapies Consultants, believes that companies should focus on high-quality raw materials from the beginning: “I’ve observed the regulatory boards becoming more stringent on everything CMC-related — especially on the plasmid side of things,” he comments. 
“Viral vectors, which are sometimes an afterthought, are also an important consideration,” Franz continues: “The more potency per vector particle, the less manufacturing you have to do, thus reducing the overall cost of your CGT’s production. Therefore, optimising your viral vector early on can significantly enhance the expression and — in turn — the efficacy of your gene therapy.”
Nina Kotsopoulou echoes this sentiment, adding: “Although it does depend on geography to some degree, all regulators are getting more stringent about everything CMC-related. You might save some money by not doing your homework at the beginning, but then you have to spend a lot more on comparability studies and changing to higher grade materials further down the line.”
By investing early in raw materials, companies can positively influence their assay results while also determining how their product will behave when using commercial-friendly materials — which will be necessary if the CGT is approved anyway.
Potency assays for rare disease-targeting CGTs
Potency assays are an essential tool for any company looking to commercialise a cell and gene therapy, but they are especially crucial for those looking to break into the rare disease market; this is because of the unique challenges that developers in this field face. Small patient populations, difficulties when recruiting for clinical trials, as well as funding, grant and reimbursement obstacles, only scratch the surface of the testing climate of rare disease development … and companies pursuing this field must be prepared.
As the patient population is significantly smaller for rare diseases (meaning fewer people to treat), there is often less funding available from reimbursement agents and investors as it’s a more high- risk strategy. Not only is there difficulty in obtaining funding, but creating such therapies requires a company to invest more time and money into their development to make it work.
Therefore, creating a quality potency assay to determine a therapeutic’s efficacy is vital for the successful commercialisation of a rare disease-targeting CGT. The earlier any necessary alterations are made to a drug product of this kind, the better chance of it being commercially viable and available to the patients that need it.
Dr Richard Fagan, Director of BioPharm at UCL Business, believes that those in the rare disease space should focus on getting their therapy through clinical trials before looking forward: “For your rare disease-targeting therapeutic to get picked up by a larger pharmaceutical company, you’re going to have to push it further down the clinical pathway. Small patient datasets just aren’t enough anymore, so you’re going to have to go larger and spend more. Utilising a sound potency assay early on can push your therapeutic through early clinical trials quicker and may contribute to the successful commercialisation of your therapeutic.”
Overall, potency assays should be a primary consideration for everybody looking to commercialise a cell and gene therapy and companies should take active steps to develop a good one early in the drug’s development path.