By Jonathan D. Grinstein, PhD

Carlsbad, CA—The timing of the Cell & Gene Meeting on the Mesa appears to have been prearranged with the help of a crystal ball. Members of the cell and gene therapy field are anxiously awaiting the FDA’s review of three submissions before the end of 2023: two treatments for sickle cell disease—exa-cel (Vertex and CRISPR Therapeutics) and lovo-cel (Bluebird)—as well as Bristol Myers Squibb and 2Seventy Bio’s Abecma for earlier multiple myeloma.

The sector is at an inflection point. There’s a lot of excellent science and exciting clinical results. Still, it remains to be seen whether that will translate into commercial success—a major focus of this week’s Alliance for Regenerative Medicine (ARM) conference. 

Regulatory approval

All eyes, therefore, are on Nicole Verdun, MD, the new permanent director of the FDA’s Office of Therapeutic Products (OTC), which is within the Center for Biologics Evaluation and Research (CBER). Verdun’s plate has a healthy serving of cell and gene therapy clinical trials for rare and serious diseases, which typically do not fit the testing paradigm of a randomized clinical trial. According to Verdun, who will be working hand in hand with CBER director Peter Marks, MD, PhD, the key to the approval of cell and gene therapies for conditions with just a handful of patients is a mix of communication and regulatory flexibility.

“We have INDs open for diseases where there are 11 patients in the United States,” said Verdun. “There needs to be increased communication earlier on in the development process, and there has to be consideration for the disease, the benefit-risk for how rare it is, and we have to do what we can to partner to get more of these therapies to patients that need them.”

To get right at this, Verdun highlighted the “Support for clinical Trials Advancing Rare disease Therapeutics” (START) Pilot Program. Three chosen START participants must be sponsors of cell and gene therapies for rare diseases and serious conditions currently in clinical trials under an active Investigational New Drug Application (IND). These participants will be able to receive regular advice and ad hoc communication with FDA staff to talk about product-specific development issues, such as clinical study design, choice of the control group, and fine-tuning the choice of the patient population. START will begin accepting applications between January 2 and March 1, 2024. 

Manufacturing and commercialization

 As more cell and gene therapies begin to move into the clinic, there is growing attention on manufacturing, which may be the major bottleneck for creating commercialized products.

Automation and artificial intelligence (AI) will be major disruptors to the manufacturing and commercializing cell and gene therapy. The efforts made by Cellares with its Cell Shuttle to integrate batch processing and automation into the assembly process serve as evidence of this. But automation and AI will not be enough.

According to Ann Lee, PhD, chief technical officer at Prime Medicine, there are three key factors to developing commercial-grade manufacturing. The first is picking the right people, because getting a cell and gene therapy program into the clinic requires a breadth of expertise that will likely not be found in a single individual. The second is data infrastructure, because to generate data that will be submitted for an IND or BLA submission, processes need to be in place where it is retrievable, tracked, and analyzed. Third, Lee said that regardless of going the internal or external route, the process needs to be transparent because no cell or gene therapy will be approved if the manufacturing process is a black box.

Some key factors go into choosing to partner with an external CDMO for manufacturing or bringing it in-house, often touted as the best way to control one’s destiny. While many have approached the manufacturing of cell and gene therapies with the view to putting all their manufacturing capabilities into the hands of partner CDMOs, some have decided to take this on to various degrees to gain increased control of their medicine’s destiny.

For cell therapies, some of this may come down to whether a company’s approach uses allogeneic or autologous cells. Sumit Verma, senior vice president of Global Strategic Manufacturing at Iovance Biotherapeutics, said that, while there is a lot of allogeneic work being done and CAR T having that success rate, autologous cell therapy has its place as a potentially unrivaled personalized medicine but is incredibly challenging from a logistics side. “For the patient’s benefit, being able to manufacture [an autologous cell therapy] batch is a key concept that I think you’re going to see a lot more maturity next year,” said Verma.

With two autologous cell therapy, using patient-specific tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL), Iovance has taken an approach to investing in both their own manufacturing capabilities, as evidenced by their recent investment in establishing the Iovance Cell Therapy Center (iCTC)—a 136,000-square-foot facility in Philadelphia.

While Intellia Therapeutics will also be opening a new manufacturing facility in Waltham, Massachusetts, in 2024, chief business officer Derek Hicks said that in this market environment, he wouldn’t be surprised if there are more deals featuring a shared partnership between manufacturing and smaller biotechs.

“When you think about manufacturing, it’s not just that shared risk,” said Hicks. “It is how can you work with someone that actually helps you accelerate because we’re trying to get these products to patients. The research is moving very quickly, so how do you ensure that manufacturing doesn’t stop you from bringing things forward? These are the things that we all need to think about.”

Healthcare systems

Bob Smith, senior vice president of the Global Gene Therapy Business at Pfizer, said a lot of his concern for getting cell and gene therapies commercialized is related to the healthcare systems in the U.S. and abroad.

“A lot of healthcare systems have a negative innovation bias in the way that they evaluate and value the innovations that our sector is developing,” said Smith. “No individual company is going to be able to overcome this, and I think we need to think about how we communicate not just with the healthcare systems and how they evaluate not just the regulatory aspects, but now really the value of what we’re bringing to patients.”

For example, Smith points to some European markets where sometimes there isn’t a price approval for a year and a half after the regulatory approval.

“Think about the burden that is on small midsize companies that don’t have a balance sheet like [Pfizer does],” said Smith. “We can absorb that financial hit, but it’s going to put a tremendous financial strain on capital-intensive companies, and we need to really think through how we can change that paradigm to be much more efficient, principally for the benefit of patients but also, quite frankly, for the sustainability of the sector.”

Phil Cyr, senior vice president at Precision Value & Health, said that historically, a lot of payers and health technology organizations have been very focused on cost-effectiveness, but that they’ll also be looking at the budget impact and affordability, especially as cell and gene therapy begin to move into more prevalent diseases, which he believes will happen. Cyr thinks that the way to overcome this is by developing an evidence base to discourage people from thinking about sticker price and more towards long-term value.

“How do you go to a payer with a three to four-year window and make them understand that [gene therapy] will benefit them?” said Cyr. “I can think of one payer that actually built a model to figure out how long they needed to keep that member in their plan to recoup the money.”

For these reasons, organizations like Express Scripts and Cigna’s Embarc will play a key role in the future of gene therapies by helping protect customers from the high cost of gene therapy drugs and ensure access for those who need them.

 Expectations for 2024

Much is riding on the cell and gene therapy submissions that are due to be reviewed by the FDA before the end of this year. If they are successful, its possible that there will be a change in sentiment within the investor community—not to mention patients.

Next year, the Cell and Gene Therapy Meeting on the Mesa will move to Phoenix, Arizona, as the conference has maxed out its current capacity at the Park Hyatt Aviara Resort in northern San Diego. If the FDA approves these initial submissions, the new venue will likely be filled in 2024. But what if they’re not approved? All it takes is one bad batch that will reflect poorly on the entire industry.

As regulatory submissions and clinical data trickle in, there has to be a high standard. But standardization will not be achievable by a single business entity or the FDA alone. This new and evolving field will require organizations like ARM to unite different voices. That’s exactly what’s happening right now at the Cell and Gene Meeting on the Mesa.

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