Hi everyone, and welcome to episode three of our very special series for Cell & Gene the podcast called FDA Fridays. For this episode, I had the pleasure of speaking to one of the brightest minds in our space, Bambi Grilli, PhD. She's the professor of pediatrics and the director of clinical research and early product development for the Center of Cell and Gene Therapy at Baylor College of Medicine, and she's the chief regulatory officer for ISCT.
Dr. Grilli is a friend of Cell & Gene, and she's a leading expert in pediatric cell and gene therapy. And she brings a wealth of clinical insight and real-world perspective to our conversation, which you'll hear in just a second.
She discusses the multifaceted barriers that prevent children and families from accessing innovative treatments. And you'll hear her share details around the highly specialized expertise required for manufacturing and delivery, to the logistical, financial, and emotional burdens placed on families, especially those in rural or underserved areas. She and I explore regulatory hurdles unique to pediatric indications, including delayed approvals and insufficient trial data, and she shares powerful examples of treatments that work but remain stuck in perpetual limbo, unable to reach the children who need them most. So, this is a really important and informative episode, just as all three to date have been. The fourth, featuring Danielle Laragao, is coming up. Episode one features my conversation with Dr. K. Spratt, and episode two features my conversation with Monica Spetlea.
Please do yourself a favor and tune in to all three. And then, of course, Danielle is coming up for episode four. You will truly feel that it is time well spent. These are great conversations with experts in the space. So thanks for your time and attention during FDA Fridays. And for now, here is my conversation with Dr. Bambi Grilli. Enjoy.
Bambi, thanks for joining me on Cell & Gene the podcast for this special FDA Friday series. You're one of our best friends here at Cell & Gene, and so I'm really happy to have you back on the podcast and ready to hear all the great information you're going to share with us.
Glad to be here. Thank you for inviting me.
Absolutely. So, first I want to talk a little bit about access and equity. So from your perspective and based on your expertise, what are the most pressing barriers, would you say, preventing patients, especially the pediatric population, from accessing cell and gene therapies once they've been developed?
So I think that this is very multifactorial. I think that part of this is global to the field and part of this really does dig in very specifically to pediatric patients. But I want to start with kind of the high-level thing, which is the expertise that's required for the manufacture and delivery of these products, making it such that this isn't a product you can pick up at your Walgreens and take home with you and take in your house. This isn't a product that you can even go to your local hospital and receive in our current environment. This is a product that requires very specific manufacturing, usually by extremely professional experts in the field, and it requires very expert delivery. And so we're talking about patients, especially patients in rural areas, underserved communities, even states that don't have big academic medical centers, they have to travel to receive these treatments. And that's a big burden on people.
I have this, this is not entirely related, but it's similar, which is the UK was one of the early adopters of CAR T cells. They jumped in with both feet. They approved these products. They have a publication that from 16 approved CAR T cell centers, they think that 35% of the patient population has even talked to their providers about receiving those treatments. That's a low acceptance rate of a potentially curative therapy.
And the reason that most of the patients gave for why they did not want to receive these products was related to logistics. There's no... So let's say, and this is a big say, that your insurance company would pay for your product. They agree that they will pay what is in the US between $275,000 and $4 million for you to receive this product. Not counting, you know, if you get any kind of adverse effect, something happens and you're required to be hospitalized or in the ICU, God forbid. None of that is included in the cost I just mentioned. But let's just say that they've agreed that they're going to pay for this. And let's use the US as the example here, right? So, even in Texas, if you live in West Texas, there's not major academic medical centers in West Texas. You're going to be coming to Austin. You're going to be coming to Dallas. You're going to be coming to Houston. That is a long way. It's a big trip.
And especially in the pediatric world, what you see is a lot of people who have a child with a devastating disorder also have other children. So you're basically taking your family vacation to go someplace to stay in a hotel while your child is receiving care. And meanwhile, it's not like a vacation. You don't schedule it for June because that's convenient. It's happening while your children are trying to go to school. So there's the issue of who pays for the hotel, who pays for the airfare. And let's not even kind of get into the specifics of the fact that if your child is critically ill, the travel with them is extremely complicated. If they're in a wheelchair, if they require any kind of tube feedings, if, you know, God forbid, they're on a ventilator or receiving oxygen. All of these things are so hard to travel with. And so this whole process is so daunting for families. And then there's the issue of they leave their family behind. And again, not to be too pessimistic, but if your child has a bad outcome and they're in Houston, Texas, and their family, including their grandma and their grandpa, and your friends and family are all back in West Texas, sure, your husband's going to fly out. He's going to bring the other kids. Everybody will be there. But if your child dies in another city, you can't ever get over the fact that your safety net wasn't there. Their safety net wasn't there. All of the things they count on in their life aren't there. So that's a big thing that deters patients who know the issues from receiving these types of treatments.
Behind that is the fact that our healthcare system really isn't set up to accommodate this. So when the gene therapy for sickle cell disease, when those were approved late last year, Children's National published that they could probably treat 10 gene therapy patients a year. 10.
There's 10,000 sickle cell patients.
So, you know, we're talking about such a small percentage that they could take on, and that's going to be true at every academic medical center. And that compounded by the fact that they didn't say 10 sickle cell patients, they didn't say 10 of these types, right? So, you start taking that across the fact that as we get more and more approvals for more and more indications, if you still have the same number that can get treated, the number that can get treated per disease keeps getting smaller and smaller and smaller. And the last thing that I really want to push on is, in fact, the cost, because the cost is significant. And there hasn't been a huge uptick in insurance companies saying, yes, we will pay these amounts for these potentially curative therapies because there's so many issues around that, as far as the amount of money they put into it and what they might get back, especially in a world such as ours where insurance companies cover you based on where you're employed, right? So if an insurance company pays $4 million for my child to get gene therapy, but then I leave this company, two years from now, I leave this company and I go to some other company and some other insurance, then that's money that they don't actually see the benefit of having had that curative treatment. And I think that really at the bottom line, insurance companies are businesses and they look at it that way. And it is a big thing. And I know I'm taking a long time on this question, but these issues will keep coming back up.
There's the fact that in addition to, you know, how many products can you manufacture, how many of these high-acuity patients can a hospital take on, there's the incredible administrative burden that an institution takes on and the gap of money. So when you agree as a hospital that you are going to treat a patient with one of these products, you pay, right? The hospital pays and then they get reimbursed by the insurance company. Well, that's probably fine-ish when it's like a $100 antibiotic or $1,000 chemotherapy. But when you talk about a $4 million product, holding the basket there, holding the four million and hoping the insurance will actually pay, that's a huge risk the institution takes on. And you could see where they can't say, 'Oh, let's just do this. Let's get 400 million in the hole here.' Right. So, these issues become really large and play really large in our field. And I think it's really one of the reasons that there hasn't been a huge acceptance and uptick in the use of cell and gene therapy products overall, but it definitely plays out large in the pediatric world.
For sure. For sure. And really, thank you for that background because I think it's, you know, certainly the cost of the therapy, but all of the extras that are, you know, added on to that, you know, impacting family and caregivers that I don't think everyone always considers or thinks about, and certainly not the least of which is the family with, you know, a child suffering from a disease. So appreciate all that background information. Now, you know, we know that these products have promise in children, but, you know, as you've explained, one, there are very few approved, certainly for pediatric use. From a regulatory perspective, talk to us a little bit about the hurdles that are most responsible for any sort of gap in the regulatory landscape as they apply to pediatric use.
Yeah. So, I think that the biggest gap or the biggest hurdle is that frequently the FDA will push on a study on a product being shown to be safe and effective in adults before you can go back and prove that it's safe and effective in children. So, I think those of us in the field push pretty hard on this. And frequently when we're working on a product that we think will benefit children, we'll push on, you know, if we prove that a dose level is safe in adults, can we enroll the next patients at that dose level and they be pediatric? Depending on the risk profile of the product, the FDA's been agreeable to that sometimes, but that is something that slows us down. And if you just kind of project that into the future a little bit, you can picture that if an academic institution has done a complete phase one study with all adult patients and the number of patients who could potentially receive the product is, you know, going to be primarily adult, the incentive even in an academic institution to go back to do the PD study goes way down, right? It's like the product works, let's move it forward, let's get it out there, let's start the phase two, let's try to get approval. And definitely investors and things are really all about that, right? Like, where's the product? What data do you have? And so it becomes a little bit of a negative paradigm because you don't have the pediatric data. So then there's decreased interest in the pediatric data and these products move forward. But I don't actually think that that's the biggest thing. The second thing that could happen is fear of a child dying and how that would impact adult indications. Now, that's not going to be as much of a fear in an academic institution. Although, I will tell you that, you know, I work at Baylor. I work in the Center for Cell and Gene Therapy. The last thing we want is to be front page news for, you know, Center for Cell and Gene Therapy kills a five-year-old.
That is no good. So that is something that all of us do think about when we treat these children, especially if we pushed really hard to get the treatment to this child. But I have two stories about this that I think kind of illustrate the issues that we face. And the first one is the Don Cohen ADA-SCID story.
So, I'm sure you and your listeners know that SCID is a fatal disorder, an immune deficiency. Don Cohen and his team developed a treatment for this that they treated 70 children. They had a 100% response rate and 96% of those children remain basically free of their disease without further treatment. Right? So that cure rate, that is where we in the lay public at least would say it's a miracle, right? Like this is a fatal disease.
So 2015, they hand off the IP to a company called Orchard Therapeutics. Orchard Therapeutics never treats a child. So for four years, families knew there's a treatment that could cure my child, but I can't get access to it because there is not a trial. 2019, following intense pressure from Dr. Cohen and UCLA, the IP was given back to him, back to UCLA. And, you know, it's easy to think, yay, success story, right? He's got it back. He's going to be treating patients. But the truth is at this point, it's not really research, right? When you've treated 70 children and you have a 100% response rate, 96% what we would call a cure, there's no research question to be answered here anymore.
And so the problem is that you're not going to be able to receive grant funding from NIH or the California Institute for Regenerative Medicine or Texas CIRM because there's no research question. It's like you already know the answer. This stuff works.
Similarly, though, you're not going to be able to bill insurance. It's not an approved product, and the amount of money required to file a BLA is enormous. Right? So UCLA cannot take that on. That's why they hand it off to a company to begin with. I'm going to build on this story a little bit later because I know we're going to talk about innovative approaches. But Dr. Cohen and his team have been really, I think, innovative in how they're going to take next steps. And so he has been working. He has been treating patients, but it's not a sustainable thing. And those of us who work in institutional academic medicine, we call the status of his product currently a perpetual IND, right? He's not going to be able to market it. He knows it works. He knows he wants to give it to patients, and yet he's treating them on this perpetual product that's not in an approved status. So the perpetual IND thing is a big problem, and it's especially a big problem in pediatric indications when you cannot find a company to take it to market.
The other example I want to give is the discussion of CD22. So when CD19 CAR T cells got approved, you know, again, that it was miraculous. We all know the stories. We all love the product. But then we started to see breakthrough recurrence, relapse, patients who lost their response, right? So in response to that, an academic medical center developed CD22. They handed it off to a company. The company pursued adult indications for all of the financial reasons that we've talked about before. They did not pursue it in children, even though there was significant safety and efficacy data from the academic medical center about pediatric patients. And to this day, that's still the case. To this day, the product is still being studied in adults and not in children. So you have here two stories that really say we just can do better, and we have to change the modeling a little bit to get these products to pediatric patients.
Thank you for those two stories, and I know we will get to even more in depth in them when we get to the innovation part of our discussion. For now, you know, when it comes to rare pediatric diseases, patient numbers are often too low to meet traditional clinical trial thresholds, excuse me. So what would you say are the alternative trial designs or regulatory strategies that might enable more cell therapy products to reach children without sacrificing rigor?
I think this is an interesting question, and it's one that I've thought about a lot because I've met Theodore Ernoff twice now, and he is just a fascinating force of nature. I mean, he really is the biggest advocate for his patients. And when you talk to him, it's so obvious that we have the ability to really get in there and treat these ultra, ultra rare diseases and what we call N of one diseases, right? And whether it's an N of one or five or ten or even fifty, you and I both know that there's no statistical model that's going to get you to what would currently hit the bar of being an approved BLA, right?
So the problem is, how do we get past that? And I think one thing is people push very hard on regulatory harmonization. I don't know what they mean by that term, but to me that would mean that the FDA regulations look like the UK regulations look like Australian regulations. And I have to tell you, I don't see any possibility of that ever happening. There's just no way. You can't even get... I mean, you can look at the political climate right now and just say, okay, on any number of issues, we can't reach any sort of harmony about what it should look like. How in the world are we going to say that products should be there?
