ASGCT2024: FDA’s Marks on Accelerated Approval, Gene Therapy Costs and More

Pictured: The FDA’s Peter Marks and Takeda’s Krist

Pictured: The FDA’s Peter Marks and Takeda’s Krist

In a fireside chat at the American Society of Gene & Cell Therapy conference, CBER Director Peter Marks spoke with Takeda’s Kristin Van Goor about how the regulator is approaching the exploding gene therapy space.

Pictured: The FDA’s Peter Marks and Takeda’s Kristin Van Goor sitting on stage at ASGCT/Photo by Jef Akst

“$4.25 million!!!”

That’s the email Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), said he received (give or take an exclamation point) from Commissioner Robert Califf when Orchard Therapeutics revealed the price tag of its newly approved Lenmeldy, a one-time gene therapy for metachromatic leukodystrophy.

While Marks clarified that the regulator does not consider cost when making individual approval decisions, he explained that part of his job is to consider the entire ecosystem of these therapies, and that such prices will ultimately prevent the field of gene therapy from being able to treat more common diseases on a global scale. He added that in this context, he and his colleagues must work to improve factors such as manufacturing to help make these novel therapies more widely accessible. “We do have to think about cost on this.”

That was but one topic of conversation between Marks and Kristin Van Goor, U.S. head of global regulatory policy and innovation at Takeda and chair of the ASGCT Regulatory Affairs Committee, in a fireside chat at the American Society of Gene & Cell Therapy’s 27th annual conference Wednesday morning. Marks and Van Goor also discussed at length the use of the accelerated approval pathway, ongoing staffing efforts at the FDA’s new Office of Therapeutic Products (OTP) and much more.

Accelerated Approval Considerations for Gene Therapies

“Accelerated approval has obviously been pretty controversial,” Marks said. Especially for diseases with big patient populations, there are “people who think we’re using it too much or too little.”

Confining his comments to accelerated approval for rare diseases, he emphasized that the regulatory pathway can help bring potentially life-saving therapies to market sooner. “[Being able to] use a biomarker or intermediate endpoint is a powerful way to get over the finish line initially,” he said—something that is particularly useful for neurologic diseases where it might take a few years to gather sufficient data on a traditional endpoint like function or survival. He added that this is especially valuable for smaller companies that don’t have an established revenue stream.

One consideration in the risk-benefit calculation for accelerated approval, Marks said, is whether there are other treatment options. He raised the example of hemophilia B, for which Pfizer earned traditional approval of its gene therapy Beqvez last month. “The gene therapies were developed in the background of multiple conventional therapies,” including protein-based therapies and bispecific monoclonal antibodies. “You had a large therapeutic landscape, which makes the risk-benefit calculus different than when you have a disorder for which there is just nothing out there.”

He also noted that if the FDA is going to err, he’d rather err on the side of bringing a potentially useful therapy to the patients who need it. “I would much rather take the chance that we’re occasionally going to make an error and give something an accelerated approval than have people so desperate that they’re going out and either going overseas to get unproven therapies, which happens, or using other pathways [where] the FDA doesn’t have much regulatory oversight.”

Van Goor pushed him on what that error rate might be, noting that Ellis Unger, a cardiologist who led the FDA’s Office of Drug Evaluation I, has previously thrown out the number 70%. Marks said 70% would be the lower bound of the interval. “Our goal is to get it right 90% of the time or more.” That said, he added, “we’re not keeping score.”

He added that the regulator would only choose to withdraw a gene therapy from market if “it’s pretty clear” that any benefits do not outweigh the risks. “Hopefully we won’t have to have that happen, but I think it’s important to know it’s an option.”

Moving Beyond AAVs: CRISPR Could Move the Needle on Gene Therapy

As has been a theme here at ASGCT, Marks brought up the issue of AAV manufacturing. He gushed over the idea of AAVs, which he said he just loves, but he was honest about the manufacturing challenges that threaten to limit the growth of gene therapies. “There are companies that have really mastered making AAV, but even they find it challenging to make this product really well.”

With CRISPR, on the other hand, manufacturing processes could theoretically be set up that apply across a range of treatments, Marks said. “Once you get it right [manufacturing], changing the guide isn’t going to change how it’s packaged.” He gave the example of CRISPR constructs targeting the liver for a range of conditions, which would be “99.9% identical.” That means, he said, you could create a platform that allows you to manufacture CRISPR-based therapies “in a much more facile way.”

This could also incentivize CDMOs to play a bigger role, he said, noting that it’s been hard to get these companies to make AAV-based gene therapies—harder, for example, than it was to get CDMOs to make monoclonal antibodies. “With CRISPR I think it’s going to be a different story.”

The other advantage of CRISPR-based therapies, Marks said, is that companies could make many different products that all target different mutations in the same gene, and the FDA could theoretically come up with regulatory processes to simplify the approvals for such groups of therapies. “There are a lot of nucleotides that can go wrong in the genome. I don’t think we can have 3 billion visits to the FDA a year,” he joked.

While noting that the details have yet to be worked out and that nothing is set “in stone yet,” Marks suggested that a company could present data on three different types of mutations—a missense, a nonsense and a deletion, for example—and then use those data to support the approval of additional gene therapies targeting other mutations in the same gene.

“It’s breathtaking how fast the developments in CRISPR technology are going,” Marks said.

Regulatory Changes Underway to Support the Growing Cell and Gene Therapy Space

When Van Goor asked Marks about his three- to five-year plan for OTP, he praised Nicole Verdun, who runs the new super office. He said that if she had been in his seat this morning, she would have said all the same things he was, only she would say it better. In other words, the two of them—along with the leadership team Verdun has brought on at OTP—are like-minded.

That said, he did admit that the agency is behind regarding OTP staffing. “No matter how much we play catchup, we’re always a little behind,” he said, estimating that there were probably 10 to 20 roles still open that they’d hoped to fill by now. Staffing up is critical, he added, so the existing staff doesn’t get overtaxed and leave.

In addition to the creation of the super office itself, the FDA is taking other steps to support companies in this space. Marks discussed a communications pilot project that he said was borne out of the COVID-19 pandemic when rapid vaccine development was of utmost importance. During that time, the FDA had constant communication with vaccine manufacturers, which Marks said contributed to a more than 25% reduction in time in bringing COVID vaccines to market.

The agency recently put out a notice in the Federal Register about the pilot, which will focus first on rare diseases that are imminently life threatening and neurologic diseases that have serious outcomes. Rather than facing a one- to two-month window for scheduling a meeting with the FDA, reviewers would be tasked with regularly checking email and then arranging phone calls or in-person meetings on short order—within days or a week.

Not only will this potentially benefit patients, Marks said, but “it might make the difference between a company having the cash on hand to go another quarter or two because they’re not burning that waiting for FDA.” He said the project will be formally announced soon and that the agency will be measuring the impact on development time and will consider broadening the program in the future.

More than anything, Marks emphasized that one of the mottos CBER follows is to be “transparent about what we’re doing. And that’s what we try to do.” It certainly showed in his candid comments this morning.

Jef Akst is Managing Editor at BioSpace. You can reach her at Follow her on X @JefAkst and on LinkedIn.

Jef Akst is managing editor of BioSpace. You can reach her at Follow her on LinkedIn and Twitter @JefAkst.