FDA’s Marks Emphasizes Agency’s Support of Moving CGT Space Forward
While the cell and gene therapy (CGT) industry has shown remarkable progress, it still has some barriers to overcome. The FDA is taking numerous steps to help bring these products onto the market, asserted Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER), the unit that oversees biological products, including vaccines, allergenic products, blood and blood products, and cellular, tissue, and gene therapies, at a recent public appearance.
“I think the bottom line here for us is that we are very committed to helping move this field forward for populations of all sizes,” particularly for small populations, which is “one of the areas that is our highest medical need right now,” said Marks during a session in the CGT track at the Reuters Pharma USA conference, held March 28 and 29 in Philadelphia.
Indeed, a recent STAT article revealed that FDA reviewers were contemplating rejecting Sarepta Therapeutics, Inc.’s gene therapy for Duchenne muscular dystrophy, but Marks intervened twice, first clearing the way for submission of the agent’s application for accelerated approval last year and, more recently, “stepp[ing] in and direct[ing] staff to schedule a public hearing on the therapy on May 12.”
While the COVID-19 pandemic slowed down a bit the “continued growth” the CGT space has been experiencing, “the growth continues now, and I think we’ll probably see this year more…year-over-year growth, whether it be for investigational drug applications or amendments to those,” he said, adding that there are more than 2,500 active CGT investigational drug applications and 12 approved products, with five of those approvals happening in 2022 alone.
The chimeric antigen receptor T-cell (CAR-T) space is a big focus for manufacturers, as “success tends to breed success: Investors like success; product developers like success,” he stated. “This is an area where just this past year, we had just shy of 100 investigational new drug applications.”
So far, the approved CAR-Ts are all autologous products focused on hematologic malignancies, “but with some of the advancements in genetic technologies, particularly CRISPR-Cas9 — genome editing — we’re starting to see more and more allogeneic products and more and more solid tumor products, which are facilitated by the ability to make allogeneic products.” The quests for both allogeneic CAR-Ts and solid tumor-targeting CAR-Ts were common themes during the conference.
In the past, it’s been a challenge to make even one or two gene edits, he noted, but CRISPR-Cas9 allows “multiple gene edits.…The problem in solid tumors has been that you can’t find a single target on the cell surface that you can attack that doesn’t also attack other cells in the body. Here, one can have a requirement for multiple targets and can even program the cell so that” if it accidentally attacks a normal cell, “it shuts down the response. So this is, I think, an exciting time for this.”
The autologous CAR-Ts require harvesting a patient’s own immune cells, modifying them in a manufacturing facility and then infusing them back into the patient. But with allogeneic CAR-Ts, “the idea here is could you take a healthy donor, derive the cells, change them as necessary to make the product and then have an off-the-shelf product that you give to people in need,” explained Marks. “That obviously helps with product consistency; it allows you to have some off-the-shelf product, and you can give it to someone right away. And potentially, you could bring down the cost of these therapies, which is an issue right now. It’s actually limiting their use in earlier stages of disease. And so I think some of this field, it’s not a matter of getting to better manufacturing; it’s getting to more efficient manufacturing that can reduce the costs.”
Directly administered gene therapies “is an area where we think has tremendous promise, but it’s an area that is struggling a little bit. It’s struggling to kind of break out of manufacturing challenges, clinical development challenges, potentially reimbursement challenges.” But the area has seen “remarkable success,” he maintained, citing Novartis Gene Therapies, Inc.’s Zolgensma (onasemnogene abeparvovec-xioi), approved May 24, 2019, for the treatment of spinal muscular atrophy (SMA) in patients younger than 2 years old who have bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.
“This is a disease which takes children’s lives by the time they’re about 3 years old,” said Marks. “They become floppy; they can’t do the normal developmental milestones in their walk. They end up on a ventilator, and they die early in life.” However, one study found that 14 out of 15 children treated with Zolgensma in the first six months of life “develop normally.”
Marks acknowledged that “some uncertainties” exist. “We don’t know quite how long everything will be perfect, but from what we can tell right now, it seems to be a long-lasting result,” with patients reaching the ages of “8, 9, 10 years old, and they’re still OK.”
While SMA is “one of the more common neuromuscular inherited disorders, it’s still rare,” and other disorders “are even more rare. And they’re really important because we now have discovered that there are literally hundreds of thousands of them that are potentially approachable by gene therapy. And this becomes a real challenge for us because when you have these very small disease populations, our current development models aren’t all tuned for that.”
“It’s also important for us to get this right,” he contended. “Because as we think about the larger diseases and think about genetically addressing them through things like CRISPR-Cas9, they are reduced essentially into rare diseases, because the genetic abnormalities in different individuals may be different even though the overall disease, maybe congestive heart failure,” could have multiple different mutations. “So this is one of these issues that we’d like to try to get right.”
One challenge with developing more individualized products is the manufacturing process, explained Marks. Making 100 to 200 doses per year is the “sweet spot from the commercial perspective,” as this allows companies to make a profit. But the costs for producing products for 10 or 20 people is similar to the “costs for 100 to 200 people. And so…in terms of commercial viability, it’s a challenge.”
Another speedbump is posed by the fact that “innovation in this area often comes out of academic institutions…where people use different methods of making their gene therapy” for 10 or 20 people. But then when those institutions want to turn the product over “to someone who licenses for a technology,” such as a contract development and manufacturing organization (CDMO), “they often don’t transfer well, because they’re not done by some standard process, and scaling up” doesn’t work.
FDA Is Addressing Issues in Variety of Ways
The FDA is taking various steps to address potential commercialization barriers for these therapies. In October 2021, the FDA, the National Institutes of Health (NIH) and numerous public and private organizations formed the Bespoke Gene Therapy Consortium “to try to come up with a cookbook that sponsors can use — people who are developing gene therapy — so that they will be able to…more easily transfer these to CDMOs, reducing that cost of transfer because if you have to pay a half a million or million dollars to get someone to redo work so that they can transfer your manufacturing process, that takes a big dent out of the number of doses you can now produce.”
The consortium’s initial focus is on adeno-associated virus (AAV)-based gene therapy, focusing on preclinical development all the way through production. “The idea is at the end of the day, we’ll have a playbook, a way forward, that will hopefully help the industry feel like this process is derisked,” Marks said.
The FDA also has “reorganized our office that handles this area into a super office, which means we now have what went from being an operating division to essentially an operating company, which has its own divisions. And that is allowing us to focus more on the specific aspects of gene therapy, such as the chemistry, manufacturing and controls that are necessary.”
In addition, the agency is “leaning into the use of accelerated approval through the use of surrogate endpoints…because for some of these very rare diseases, if we don’t do that, using the best available science, we’re never going to get these products to people who are otherwise dying or severely disabled by a variety of diseases.”
Marks asserted that there is more than one way to get from “a commercially nonviable process to commercial viability.” One way, he said, is that “even if you don’t have enough patients in the U.S., we can make it easier for these products to be disseminated globally. Granted, we’ll have to deal with reimbursement issues globally. But you can imagine that in high-income countries, if you could have a way of having the EU, U.S., Japan, Canada, perhaps Switzerland, all have approvals close to the same time, that would give them a potential market that would be four or five times as large as just the U.S. for some of these disorders. It would take things that are not commercially viable and make them commercially viable. So we’re working towards global regulatory convergence.”
The FDA also is “trying to leverage what we’ve learned over the past three years” from the pandemic and Operation Warp Speed. “The biggest help during this operation was the amount of communication we had with those developing products. And so we will pilot a communications mechanism whereby we will essentially have constant contact with those developing certain rare disease products. It will be a pilot first, and we’ll see if it works. We may make it into a larger program.”
The 21st Century Cures Act implemented the Regenerative Medicine Advanced Therapy designation, which provides “the similar types of benefits that breakthrough designation has but is really tailored to cell and gene therapies, in particular, because if one gets this designation for accelerated approval, there is an expanded array of ways to fulfill the accelerated approval commitments to transition the product to…full approval. And that includes just taking the same patients from a study and following them for a longer period of time, which is something that is very natural to think about for gene therapies.”
The FDA also has published two “relevant regulatory [draft] guidances” focused on CAR-T agents and genome editing products, noted Marks. “Those drafts will find their way to final guidances and hopefully provide information for industry.”
Marks encouraged companies that are developing CGT products to interact with the FDA early in the process. One way is through INTERACT — or INitial Targeted Engagement for Regulatory Advice on CBER producTs — meetings. “These are early regulatory meetings, which are essentially very low risk, because nothing we say during them is binding,” he explained. “They are an opportunity for sponsors with a product that wanted to get information about preclinical, clinical development or, for that matter, even manufacturing,…[to] come in with a pretty simple package and [get] a response.”
Companies that do not have a specific product but have a platform, a gene therapy vector or manufacturing device also can meet with the FDA via “another type of meeting, where this is even a lower bar,” by which companies bring simply “a pitch deck…[and] a couple of questions, and we are able to have a conversation about our thoughts about that technology.”
This process, he asserted, “has proven incredibly useful bidirectionally because I think it helps sponsors get feedback about how our thinking is about what they’re developing and their platform, things that they might take into consideration. It also helps us tremendously because…sometimes sponsors bring in technologies that we were only peripherally aware of or thought were not as advanced, and it gives us the chance to see them. So that has been something exciting to have.”
He stressed that it’s important for companies in the pre-clinical phase to, “first of all, do your homework: Look at the field, and see who’s been really successful, who’s had issues. That may help you know the good paths to pursue.
“But then the important thing is come in and take advantage of interactions with the agency early on,” he continued. “And don’t be bashful about having a back-and-forth dialogue with the agency.…If we say something that you don’t understand, don’t try to interpret it. Come back and ask us, because what sometimes happens is that sponsors come in, they get a response from us, they’re not really sure what we said, probably because we weren’t totally clear with what we said. And if they come back, and we clarify it, then they’re in good shape. If they don’t, they can sometimes go off in the wrong direction. So don’t be bashful about engaging in a vigorous dialogue with the agency. That’s what we’re here for.”
“We are very committed towards advancing, developing, cell and gene therapies for populations of all sizes,” he maintained. “I think this is an incredibly exciting area. I think we have a unique role to play here where, if we do our job right, we can help keep this field moving forward, despite some of the challenges it’s had recently.”
Looking out into the future of the CGT space, “I’m hoping that we can help foster an environment where there is more and more commercial sustainability in this area. There are a bunch of nonprofits now trying to do gene therapy for each of their diseases. But as much as I applaud those nonprofits, the way we’re going to have the most equitable gene therapy for all of the different diseases that affect all sorts of different populations is to have a robust commercial enterprise where even for these very small populations, there is some commercial value there so that companies can make a living doing that, and then we will have the pursuit of these and have them available for the largest number of people in the country.”