“We’re in a place now where there’s a subtle change,” Marks observed.

The early onslaught of CAR-Ts was “incredible,” he said, comparing it to “one of those kids’ soccer pileups. Everyone was making CD19 CAR-T cells.”

Most of the products were in the autologous space (where the patient is his or her own donor) with a couple of allogeneic “outliers” (transplants come from a matched related or unrelated donor).

Sponsors are now increasingly comfortable moving into the allogeneic space and “branching out into other areas” from the initial research in core hematologic malignancies, like acute lymphoid leukemia and non-Hodgkin’s lymphoma to diseases like multiple myeloma, and “hopefully making a dent into solid tumors,” Marks said.

That has been made possible in part by the revolution in genome editing that came with the introduction of CRISPR. (Also see “The Gene Therapy Wave Is Here” – Pink Sheet, 24 Jul, 2023.)

As a result, “there’s a lot of activity here,” Marks said. Looking at the “pie chart” of development activities in cell-based gene therapies, the “greatest increase” is constructs beside the CD19 CAR-T cells “taking on an important role.”

Marks predicted a “pretty broad scope” of future cell-based gene therapies, specifically citing autoimmune, some infectious diseases, and a range of hematologic and solid tumors. Among the products in development include a CRISPR/Cas9 gene medicine from Lilly for metabolic syndrome and a therapy from Moderna, Inc. using CRISPR-edited lipid nanoparticle for chronic obstructive pulmonary disease.

CRISPR is “becoming an incredible tool that allows us to have an incredible power over editing the genome in multiple genes, or producing multiple cell types, basically cells from someone, each with a different gene altered or each with multiple different genes altered,” Marks said. “There is this desire to see can we, as fast as possible, come to some improvement in the current state of efficacy?”

‘Expedited Evolution’

Marks referenced the work of immunologist and oncologist Carl June, of the University of Pennsylvania, who was also on the agenda for the meeting.

“Dr. June’s work has indicated that if you have certain changes, you can get a better CAR-T cell,” Marks said. “The question is, can we figure out a way, as fast as possible, to essentially make certain genetic alterations so you have essentially the fittest of the CAR-T cells.”

“It’s almost expedited evolution, and for us, it’s a matter of balancing how many changes we can make, ensuring that we feel safe putting those changes into a human,” he added.

“We want to help facilitate innovation and help facilitate progress, but we need to balance that with making sure that we’re comfortable with the number of changes, or the number of different cells that go into a person, so that we are comfortable that there won’t be something untoward,” Marks continued.

He suggested the FDA’s development approach may evolve over time.

“One of the things that FDA does do well” is encourage step-wise development, Marks said. FDA starts by putting “our toe in the water. That’s the way I get into pool: very slowly. We get in slowly and then eventually we’re in the deep end.”

FDA Accepts ‘Some Level Of Uncertainty’ On Risks

CBER has already faced one safety issue with CAR-T cells: reports of secondary malignancies. Marks has previously said he is not overly concerned with the reports (22 cases out of 27,000 individuals treated in the U.S. by the end of 2023) and said that the safety issue should be balanced against the CAR-Ts “remarkable efficacy.”

The FDA later followed up with a boxed warning for six of the seven approved products. (Also see “CAR-Ts Getting Boxed Warning On Secondary Malignancies Despite Sponsor Causation Questions” – Pink Sheet, 23 Jan, 2024.)

Iwen Wu, director of the Office of Pharmacology’s Toxicology, Cell and Gene Therapy Products, said some uncertainty with gene therapy products should be accepted.

“Some of these questions about what the safety profile is or what the best edit will be probably won’t be answered until we bring these into the clinic,” she acknowledged. “It’s striking the right balance of doing what we can with the non-clinical tools available to really optimize these products … and then moving to the clinic when it is the right time.”

Centralized vs. Decentralized Manufacturing

Marks suggested two tracks for lowering manufacturing costs: centralized manufacturing for allogenic products and “fully automated production centers” for autologous products. He focused his comments mainly on strategies for manufacturing autologous products.

“We’re starting to see a wave of automation” among sponsors with “practically fully automated production centers” that can deliver a cell product within a week’s time, Marks said.

Decentralized production models also could allow for more innovation in addition to bringing the product closer to the patient, but consistency could suffer, he said.

“If you’re making a product that’s going to be used in a lot of different places, and you want it to be the same … you have the right quality controls in place” to ensure “you’re making the same thing every time, Marks said. “That can be a challenge, but it’s addressable.”

While there are “ardent” advocates for centralized and decentralized manufacturing, the FDA is decidedly “neutral,” he said.

“They are legitimate ways of going about this,” Marks added. “There are advantages potentially to decentralized manufacturing for certain products, particularly ones that are made fewer times, but we are there to support this process, as long as the ultimate product, whether centralized or decentralized, is at the same high quality.”