JPM: Four ways FDA is seeking to buoy gene therapy

Views & Analysis
FDA's Dr Peter Marks
Photo by Jonah Comstock

Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, speaks at the Informa Biotech Showcase during JP Morgan week.

One month ago, the FDA approved two gene therapies for sickle cell disease, including the first CRISPR drug to get the agency's nod. At the Informa Biotech Showcase on the outskirts of the JP Morgan Healthcare Conference today, Dr Peter Marks, director of the FDA Center for Biologics Evaluation and Research (CBER), told a packed house that the FDA wants to help get more gene therapies to that point in 2024.

In a short presentation, Marks shared four ways the agency is moving to help support gene therapy.

"I'll say from the outset, we don't have the answers for all the problems," Marks said. "We can't. On the other hand, we are going to try to do whatever we can here in the interest of patients."

1. Streamline the approval of platform technologies

The Omnibus Appropriations Act of 2023, which was finally signed into law by President Biden on the 29th December, contains provisions that should make it easier to get new gene therapies approved, Marks said.

"A lot of the gene therapies that we are thinking of have a certain difference from many of the other drug products and biologics that we use - because they have something in common, the vector backbone, that's the same between the products - and then you're swapping out inserts," he said. "And so, in the Omnibus of 2023, we provided input, and Congress passed a provision which allows manufacturers to reference prior manufacturing, toxicology information, et cetera, from prior applications, so that, hopefully, as we move forward in gene therapies, it will be easy to bootstrap your way from one to the other."

Going forwards, Marks said, the FDA wants to focus only on the disparate aspects of new gene therapies, which should streamline things for regulators and manufacturers alike.

"CRISPR Cas9 is the poster child for a platform therapy," he went on. "Since the initial CRISPR Cas9, which was just simple editing, we now have much more complex editors and base editors and prime editors. What you're dealing with is a molecule that's basically the same, with the exception of a guide. And so, that means that, even across different diseases, you're going to have something that's basically the same, where your focus, if you're a regulator, is basically on what's going to get you into problems. That is, anything that the guide can give you as an off target effect."

2. Encourage more gene therapies to seek accelerated approval

Marks said the FDA wants to continue to leverage its accelerated approval pathway for gene therapies as much as possible. They're good candidates, he said, because they tend to have a strong proxy measure for safety and efficacy. 

"When you have a gene therapy, you generally have an enzyme or a structural protein," he said. "Not always, but you generally have one that you can measure and you can see if you've reduced it, if you have too much, or you've filled it, if you had too little. And by doing so [...] you have something that's reasonably likely to predict that the product will have clinical benefit."

That can be done either with animal models or by referencing patients that have naturally low or high levels of the enzyme or protein because of a genetic condition, he explained.

"With accelerated approval, we want to get more things over the finish line," Marks said. "This is a way to do it. Will we always get it right? No. But if we get it right 90% to 95% of the time, we'll be in good shape. And, to that extent, we will not have kept back therapies from rare diseases where we could have helped somebody, where something could have made it there, and it didn't because we were just too conservative. Obviously, we have to have safety as first and foremost, but if we have to sort out some things for lack of efficacy, as long as it's not too high a rate, we can live with that."

3. Improve harmonisation with other regulators

Gene therapy, especially for rare diseases, is an area where working with other regulators around the world can be essential.

"If we have a population of 50 patients in the United States, the European Union has 75 patients, and Japan has a number of patients, the 50 patients in the United States don't tip the net present value calculation into the positive," Marks said. "If you aggregate everyone, you have a much higher chance of tipping that calculation into a place where it actually makes sense. And so, this unfortunate divergence of global regulatory requirements, which in this field of rare diseases, where it's affecting so few individuals, is actually something we have to do something about because we owe it to the patients globally."

So, the FDA is "gaining traction", in Marks' words, on working with other regulators on these approvals.

"I think the pandemic probably helped this somewhat, [because it helped] global regulators realise that what we do is more in common than divergent. In other words, what we do at FDA has a lot in common with what's done in EMA. There are some subtle differences. We do certain things they don't do, and vice versa. But if we can harmonise on our requirements and potentially even pull forces to review these products, we may be able to make it much more attractive for people to go into this rare disease area."

4. Support small companies in the rare disease space

And that's not the only pandemic-inspired lesson Marks mentioned. Finally, the FDA is launching a pilot, the Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot, to use similar methods to those employed by Project Warp Speed during the development of the COVID-19 vaccine to support small companies developing gene therapies for rare diseases.

"We're doing a pilot programme," Marks said. "We're accepting applications for three rare disease products in the clinic now, optimally in Phase 1, Phase 2, which are targeting rare paediatric genetic diseases. And when we select them, they'll get this kind of concierge service, and we'll see how fast we make milestones and we'll get feedback from the companies on how it works for them."

If the pilot is successful, it could become a permanent programme.

"So these are just a variety of ways that we are really trying to have things move, so that we have a breakout year this year. I was telling my team this morning, this is a great year to focus on gene therapy because I don't want to know what other stuff is going on," Marks joked. "I don't want to know it. I just want to focus on moving ahead."