Genetically Modifying Patients’ Skin Cells to Treat Rare Diseases

March 25, 2022

Recessive dystrophic epidermolysis bullosa is a rare, genetic, progressive condition caused by the deficiency of collagen type VII. People with severe cases of the condition suffer from blistering, vision loss, disfigurement, and other serious medical problems. Castle Creek Biosciences is developing a therapy that involves genetically modifying a patient’s own fibroblasts—the cells in the connective tissue—to get them to produce collagen VII. The modified cells are injected where needed and can be dosed repeatedly. We spoke to Matthew Gantz, president and CEO of Castle Creek, about the company’s experimental therapy for RDEB, how it works, and how the company is building out its pipeline through dealmaking.


Daniel Levine: Matt. Thanks for joining us.

Matthew Gantz: Great to be here, Danny.

Daniel Levine: We’re going to talk about Castle Creek, its approach to gene therapy, and some recent deals it’s made to expand its platform and pipeline. I thought we could start with your core gene therapy platform, though, which involves skin cells you take from a patient to genetically modify as treatments for rare connective tissue disorders. Walk me through the platform and how it works.

Matthew Gantz: Yeah, be delighted to. Our platform is based on what we call autologous fibroblast. So, we take biopsies from patients and we extract the fibroblasts that are in their skin cells. Then we transfect a healthy copy of the missing gene in question. For our lead indication, we’re targeting recessive dystrophic epidermolysis bullosa, RDEB for short. These patients are missing Collagen 7 and that’s important because Collagen 7 is responsible for ensuring that you have healthy anchoring fibers. It’s essentially the glue that holds your dermis and your epidermis together. Without it, any kind of trauma or friction causes blisters that fester into these chronic open wounds that are really debilitating and can lead to a whole host of complications, including sepsis infection, and then unfortunately, in some of the more severe forms of disease, to squamous cell carcinoma. These patients, unfortunately, die young. And what we’re really doing is replacing the missing gene in these patients using our autologous fibroblast approach and the combination of the lentiviral vector that we use, which has a high packaging capacity, because these are typically larger genes. We then transfect them into these fibroblasts. We grow them up, we’re able then to bank these cells so that we can dose repeatedly over time. So, it’s a single biopsy that allows us then to treat this terrible devastating disease. It’s really designed to be a chronic therapy.

Daniel Levine: As you mentioned, your lead indication is RDEB. For listeners not familiar with the condition, what is it, and how does it manifest itself and progress?

Matthew Gantz: It’s a monogenic disease. These patients are born missing Collagen 7, which is really a critical component for the development of these anchoring fibers. As I said, it’s the glue that holds your dermis and epidermis together. And without it, essentially these patients are missing skin or their skin’s very fragile. So, any kind of trauma or friction results in blisters that fester or these chronic open wounds that essentially never heal. You can imagine the amount of wound care, it’s 24/7. When you talk to patients and their families, they talk about it as if their skin’s on fire, as if a dog with sharp teeth is tearing at their flesh. So, it’s really a horrific disease, and it manifests itself in a variety of different ways. You have the repeated healing and scarring around the hands that leads to mitten hand syndrome, so these patients require surgeries to free up the use of their digits. It also affects the mucosa, so you get esophageal strictures. And so, there’s a requirement for surgery so that they can actually eat food and swallow properly. And many of these patients end up becoming wheel-bound because they lose functionality of their feet, it’s just too painful to walk. Ultimately, as I said, they succumb to infection and squamous cell carcinoma, which results in a lot of these patients dying young, unfortunately.

Daniel Levine: And what’s it like to live with this condition? What is daily life like for a patient who suffers from RDEB?

Matthew Gantz: It’s brutal. It’s probably one of the most horrific rare diseases I’ve ever come across. I’ve been in the biotech industry for most of my career and I have focused on the rare disease space particularly, and dystrophic EB is truly one of the most horrific diseases. It’s also known as Butterfly disease because the skin’s as fragile as butterfly wings, you know. These patients need to be bandaged every day and it can take hours to prepare the bandaging. They need to take bathes to clean the wounds—it’s basically 24/7. These patients are born missing skin, so the burden falls on parents and siblings, and other family members. And these families are really all in and they spend a lot of time undergoing surgical interventions, as well what we call digital dilation surgeries to free up the use of their hands. So, it truly is a devastating disease in terms of not only the cost and burden of care. And in some of the more advanced forms of disease, these patients can spend hundreds and thousands of dollars a year on advanced bandages and wound care, but that they also can succumb to infections, as I said, and the impact on their quality of life is horrendous.

Daniel Levine: Are there treatment options today?

Matthew Gantz: Yeah, right now, there are no treatment options available. It’s more palliative, maybe antibiotic ointment to ward off infections, advanced wound care, are really all that’s available right now.

Daniel Levine: Your lead product candidate is FCX-007. What is this and how is it delivered?

Matthew Gantz: Yeah, this is 007, otherwise known as D-Fi, our therapy that use utilizes our autologous fibroblast platform. So, this is an intradermal administration of D-Fi. We administer it around the wound and through the wound bed. It’s about a 15-minute procedure, and the combination of the lentiviral vector along with fibroblasts allow us to dose this once every 12 weeks, which really lines up very nicely with the current care paradigm of these patients. They typically come in every three to four months for their regular visits and we’re really able to design the therapy so that the treatments are in line with their typical visits.

Daniel Levine: And what’s known about the safety and efficacy of 007 to date?

Matthew Gantz: Right now, we’ve been able to demonstrate in our phase 1/2, we’ve treated up to 10 wounds across six patients. So again, this is an ultra-orphan condition. There are about 3,500 to 4,000 patients that suffer from RDEB in the United States so, an ultra-orphan condition. We treated, as I said, six patients, and up to 10 wounds in our phase 1/2 study. It was very well tolerated up to 52 weeks post-treatment. There were no drug related, serious adverse events reported. There was no replication-competent lentivirus detected, and there was no Collagen 7 antibody response. These are all things that we were looking for. So, the safety profile looked quite good in our phase 1/2. I think importantly, is the efficacy we demonstrated at a single dose over 12 weeks where we had 80 percent of the wounds that we had treated met the primary endpoint of complete wound closure.

Daniel Levine: What is the development path forward?

Matthew Gantz: Well, the development path forward is that we’ve taken the findings from our phase 1/2 and on the basis of our findings our interaction with the FDA we have embarked upon our phase 3 study. So we are evaluating our therapy in more patients. So, we’ve gone from six in our phase 1/2, and we’re enrolling at least 24 patients. We are also dosing them with an extra dose. So, we dose at baseline and at week 12. And then we are following these patients out for 24 weeks. And the primary endpoint is complete wound closure, 100 percent closure of the first wound pair, and that’s treated versus a matched control. So, we’re essentially using the other wounds on the patient that are not treated and we compare them to the wounds that we do treat.

Daniel Levine: You’ve got a number of other candidates in development for connective tissue disorders that use an ex vivo approach, but you’re also building a broader pipeline of gene therapies behind that. In January, you acquired Novavita Thera, which gave you an in vivo gene therapy platform and a pipeline of earlier stage candidates for metabolic and liver diseases. What was the thinking behind the acquisition?

Matthew Gantz: Yeah. I’ll tell you a little bit of the thinking and the story is actually quite really interesting. As we looked at how do we leverage our ex vivo platform, our expertise and knowledge and insight gained around the use of the lentiviral delivery approach, and I think very importantly, the manufacturing capability that we have here—we’re one of the first companies to have a cell therapy approved, and launched out of our Exton facility, which is about 30 miles outside of Philadelphia, which is a real center of excellence and hub for gene therapy development. So, on the basis of that, we entered into discussions with the Mayo Clinic, to expand into other collagen related skin and connective tissue disorders. And that resulted in a research collaboration that we announced back in September with the Mayo Clinic, broadening out into other collagen related skin and connective tissue disorders, such as osteogenesis imperfecta, which is otherwise known as brittle bone disease, and syndrome of vascular disorders called Ehlers Danlos syndrome that affect type 3 and type 5 collagen. And that was really exciting. Those are all  preclinical, we’re partnering with the Mayo. And they’re in the midst of doing some additional animal work as we look at bringing them forward. But in that conversation, we were introduced to a company that was spun out of the Mayo called Novavita Thera, and they had really interesting technology, utilizing an in vivo-based lentiviral approach, which we thought really complemented the work that we were doing at Castle Creek. And so, those conversations became quite formal late last year, and we were able to announce the acquisition of Novavita in early January.

Daniel Levine: You mentioned the collaboration with Mayo. When you announced that, the sense I got was that that was serving, in some regard, as a model for future deals you’re hoping to do. Can you expand on that?

Matthew Gantz: Yeah, we thought that this was really important. Obviously, the Mayo is one of the preeminent academic centers of excellence in the world and has some super dedicated researchers there. And so, we really thought that was a great opportunity for us to get closer to them and those conversations. I think they really liked our team, the approach that we were taking in the cell and gene therapies space, our vision for where we wanted to take the company, and the manufacturing capability that we had. They thought that it was a really great combination. Getting their trust and support there opened the possibilities that led to the Novavita transaction. So, for us that was important because with the Novavita transaction, we really now have evolved from what was really a search, develop, manufacture, and commercialize model. We now, with Novavita, we’ve now brought on some great talent, Joe Lillegard, who’s an MD/PhD, a leading expert in the gene therapy space and had a lab at the Mayo. He’s joined us as our chief scientific officer and his co-founder, Rob Kaiser has joined us as our VP of preclinical development. Both are on a host of papers and have done a lot of work in the space. And so we now have essentially built a research capability, with Joe and Rob and the Novavita team coming on board that has really taken us and allows us to become a much more fully integrated business.

Daniel Levine: A as you think about the Mayo collaboration, though, what does it do for Castle Creek and what might it say about similar collaborations with academic medical centers in the future?

Matthew Gantz: Yeah, I would say, obviously, it expands our pipeline into areas that we weren’t in. So, we essentially had two programs, one targeting recessive dystrophic EB, the other moderate to severe localized scleroderma, both building on this autologous fibroblast platform. The Mayo collaboration expands that significantly into a broader array of other skin and connective tissue disorders. That’s, I think, really important as step one, and it really ties us to one of the preeminent academic and research institutions in the world. So, I think that’s really important. This is really the tip of the iceberg in terms of the potential there on that front. And then through that relationship, being introduced to the Novavita team. We now have this in vivo lenti capability that takes us into a whole host of other areas that our ex vivo based approach maybe wasn’t optimal for. So, we now can go into other rare metabolic and liver diseases, and as opposed to this disease-modifying approach we would take with this ex vivo based approach, we can now apply more a curative approach, more, I think, of what people are more familiar with in terms of gene therapy, in terms of curing some of these diseases. And it really broadens out where we can go and allows us to rapidly expand our pipeline into these other disease areas. For me, this is important because we can really design and optimize therapies to treat a variety of different diseases. It really allows us to optimize the approach depending on the diseases that we’re targeting.

Daniel Levine: You joined Castle Creek as a CEO about a year ago. What attracted you to the company? What was the opportunity you saw?

Matthew Gantz: Yeah, several things. I was on the board of Life Sciences Pennsylvania, one of the industry associations here, and was very familiar with the kind of focus and the role that the greater Philadelphia area was playing in gene therapy with a lot of the great technology coming out of, UPenn and CHOP, Children’s Hospital Pennsylvania, and the whole revolution around gene therapy. So, I caught the bug. I’ve been in the rare disease space for most of my life, and I knew the main founder and the investor and founder that really helped build Castle Creek into what it is today, Paragon. I knew them and I was really captivated by the vision that they had in terms of where they could take the company. I thought that the background experience of having one of the first cell therapies approved and having a manufacturing capability was a huge strategic advantage for Castle Creek. And then, focusing on these rare diseases, which is really right up my alley and an area of great focus and interest for me. I thought that there was just a great foundation to build off the deep pockets commitment capability that Paragon brings the team that we had in place, backed by the manufacturing, the lead programs, and also the track record from a business development perspective in terms of acquiring and building companies really attracted me to Castle Creek.

Daniel Levine: You raised $75 million in 2020, you did get some non-dilutive funding to support your phase 3 study of 007 in the form of an FDA orphan product grant. How far will existing funding take you? And what’s the plan for funding the company from here?

Matthew Gantz: So, we’ve been very fortunate. We’ve got a great group of investors, led by Paragon, Fidelity, Valor, and a few other key individuals and family offices. And so, we have a lot of sight through most of this year. We are looking to raise additional funds to fund the company through our key inflection points in terms of top line data from our ongoing phase 3 in RDEB. And then also as we look at building out our in vivo lenti platform, we are looking to secure funding that will get us through the filing of our IND, which we’re a little over a year away from. So, the focus right now is building on these recent transactions, really focusing on executing on our lead program in RDEB, and getting the IND filed for our hereditary tyrosinemia program, which is a disease of inborn errors. These patients are missing a gene called FAH. And so, our in vivo program is addressing that as our lead opportunity. And what we’re really excited about is that it will then open the door for follow-on indications and other rare metabolic and liver diseases.

Daniel Levine: Matthew Gantz, president and CEO of Castle Creek. Matt, thanks so much for your time today.

Matthew Gantz: Thanks so much, Dan, appreciate it.

This transcript has been edited for clarity and readability.


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