To develop and commercialize them with maximum efficiency, the FDA, scientists and developers must innovate, according to panelists speaking during the Presidential Plenary on Commercialization at the International Society of Cell & Gene Therapy on May 26.
The U.S. cell and gene therapy market anticipates a wave of 10 to 20 approvals per year by 2025. To develop and commercialize them with maximum efficiency, the FDA, scientists and developers must innovate, according to panelists speaking during the Presidential Plenary on Commercialization at the International Society of Cell & Gene Therapy on May 26.
Addressing rare diseases is an important step as we move toward personalized medicine that “finds the right drug on the shelf,” and individualized medicine that “creates the right drug to treat the patient,” said Peter Marks, M.D., Ph.D., director of the Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration (FDA). “It’s a paradigm. If we can get it right for the very small diseases, we can get it right for the larger indications.”
The development of individual medicine, using products that are either customized or specifically developed for individual patients, creates a significant manufacturing challenge. To lower that burden, he advocates reuse whenever feasible.
“Non-clinical data and manufacturing information from one product may be able to be leveraged to another,” he suggested. “ln gene therapy, for example, imagine smaller groups of (individualized) products centered around the reuse of a vector backbone.” With this approach, “you’re not wasting time reinventing things and can bootstrap your way to diseases you can’t get to now.”
The main challenges to individualized medicine are manufacturing, machines, animal models and clinical issues, Marks said, while noting that the FDA is working with the National Institutes of Health and others to address these challenges.
“Current manufacturing platforms limit gene therapy production. The sweet spot is making 100 to 10,000 doses per year,” Marks said. “The set-up costs are as high for 20 doses as they are for 20,000,” so small numbers of doses aren’t economically viable. At the other end, the technology isn’t available yet to make large quantities of doses.
Likewise, he continued, “Today’s machines are stand-ins for what we’re hoping to do.”
Ultimately, Marks would like to see automation for downstream purification for adeno-associated vectors, and more standardized production occurring in closed systems to enable small-batch production.
Marks also called for new disease models.
“Testing on animals may be less than ideal,” he said, citing genome editing using CRISPR-Cas9, which uses a guide specific to a human DNA sequence. “One solution is to use humanized mice or organoids to facilitate safety testing.”
“We also need to rethink phased clinical development (in favor of) continuous clinical development.” As Marks explained, current trial designs are challenged by the need to document the natural history of the disease and to collect baseline data, as well as determining efficacy in very small patient populations. With Bayesian clinical trial designs, trials can be refined as data comes in.
In cell and gene threrapies, autologous therapies are the low-hanging fruit, said Arie Belldegrun, M.D., executive chairman and co-founder of Allogene Theraputics, founder of Kite Pharma, and co-founder and senior managing director of Vida Ventures.
Allogene was formed about three years ago on the premise of reducing costs, expanding access, innovating throughout development, and increasing speed and reliability. “It occurred to us that if a doctor wanted to infuse a patient with cells on Monday, we had to work the entire weekend – paying our technicians overtime – and fly the product to the physician,” Belldegrun recalled.
Those cost implications rarely are factored into development costs, but still need to be addressed. Autologous therapy, in which cells from a healthy volunteer have the potential to treat 100 or more patients from a single manufacturing run will reduce ancillary costs. “It’s the way to go,” he said.
Allogene also is working to optimize multiplex gene engineering and editing, enhance production speed, reduce product variability for an off-the-shelf autologous therapy. It also is testing the possibility of redosing patients, to expand therapeutic access.
“As an industry, we need to define best practices and align our industry to work together,” Belldegrun said. That includes defining critical quality attributes across disciplines, from chemistry, manufacturing, and controls (CMC), through translational and clinical development.
Among critical quality attributes, potency is a major consideration. “Companies need to think about it early on,” panel co-chair Bruce Levine, Ph.D., co-inventor of the first FDA-approved gene therapy (Kymriah), and founding director of the Clinical Cell and Vaccine Production Facility at the University of Pennsylvania, noted.
“Looking at potency late in the process isn’t working well,” Marks agreed. “People get far along in clinical trials only to learn that when they move production to a new manufacturing site (the product) seems to lose all of its activity.”
To reduce the risk of that happening, Marks said, “Pick a few things, measure them, and measure them the same way each time. Don’t let ‘perfect’ become the enemy of ‘good.’”
Once a product nears or gains FDA approval, modernizing production methods or equipment become another challenge. “We struggle with this at the FDA,” Marks admitted. It results in processes that are years behind those currently being used, often making the earlier products less competitive.
“Having critical quality attributes may be helpful in convincing us (of the need to modernize). To do that, developers need in vivo comparability studies. We’re actively thinking about what we need so folks aren’t disadvantaged, frozen in time, because the cost (of performing the studies needed to modernize manufacturing) is too high.”
Therapeutic development is only becoming more expensive. Defraying costs through development and manufacturing can deliver benefits throughout the entire drug development ecosystem but, as some pointed out, companies need to challenge the FDA to allow more innovations.
