Latest / BioSpace / From fragile skin to living medicine: Lessons from RDEB
Transcript
- BioSpace Marketing: Hi, my name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denatured. In this episode, you'll hear from Mark Lodeau, CSO and co-founder of Immune Bio, and Vishwas Sasadri, CEO and Director of Ebiona Therapeutics. We explore how recessive dystrophic epidomolysis billosa has become a defining case study for cell engine therapy and what this ultra-rare disease reveals about immune risk. manufacturing complexity, and the future scalability of advanced therapies. Hi Mark, thank you so much for joining this episode of Denatured. If you can please introduce yourselves, that would be great. I'm Mark Lodell. I'm the chief scientific officer of Inmune Bio, a card-carrying immunologist and cellular therapist since the 1980s and the inventor of the drug we're going to talk about today, which is to treat the pediatric recessive dystrophic epitomalysis pillosa or RDEB, as we prefer to call it. Thank you, Mark. Hi everyone. I'm Vish Sishadri. I'm the president and CEO and board director. At Abiona Therapeutics. ⁓ we're a selling gene therapy company and ⁓ our FDA approved ⁓ product in the disease space of RDEB, which is patients' own skin with ⁓ genetic modification to produce collagen seven. So ⁓ very excited to talk about the disease as well as the solutions we're trying to develop for that. Perfect. So that's a great introduction, gentlemen. So let's go ahead and start for our audience just to describe RDEB in the sense of what it is and what are its symptoms and How basically from my understanding, what a terrible disease it is. Yes. So as as Vish just said, it's due to a a selective mutation or loss of collagen seven A, which is one of the critical proteins anchoring the dermis and epidermis at the dermal epidermal junction. But it's a problem beyond the skin. It it's a systemic problem. So the the c the the symptoms they have in the skin, which is sloughing, the slightest ⁓ trauma causes the ⁓ the epidermis to slough from the dermis, they get blistering. But they get it up their nose, behind their eyes, down their esophagus. And so these children ⁓ suffer tremendous pain and distress through the dressings that they need for for skin. ⁓ but they also then have these problems of failure to thrive because their gut doesn't work. And a lot of them get strictures because of the formation of fibrosis. And some of these are esophageal strictures, so they may end up having to have esophageal dilatation procedures to every two or three weeks some of the children that that I've seen in London. So it's it is a a very, very debilitating disease. And the median survival for our dead patients, and our dead being the worst of the conditions that form epidemolis pelosa. But the median survival is mid twenties and many of these patients die of squamous cell carcinoma. So some problem major problems that that need skin ⁓ treatments and and some systemic treatments. But Vish knows more about this probably than I do. Well if I just to add maybe, you know, I think ⁓ you've summarized everything, Mark, about the how debilitating the disease is. ⁓ these large skin wounds sometimes have, especially in the extremities, they have they become chronic, which means they cannot self-heal. And once they become chronic, they have a high propensity for these squamous cell carcinomas that Mark mentioned. And oftentimes that can take the lives of patients and sometimes even infections that get into the body through these wounds. can also lead to sepsis and claim lives. And ⁓ because of this, if if you look at the cumulative risk of developing a squamous cell carcinoma for moderate and severe RDAP, by the age of 50, it's 95%. So that's how important it is to treat these wounds. And of course, it's a systemic disease because connective tissue is also beyond the skin. So the gut and ⁓ even cornea are dependent on collagen function. Okay. I mean this this definitely sets out a very unfortunately grim landscape for patients. But there's hope. That's what Azabiona has and also what you're developing, Mark. So we know that our deb care has almost been entirely about wound care and symptom control. But how do you both see genius therapy shifting the goal from managing symptoms to rewriting the biology of the disease itself? As Fish said, it's a progressive disease. And so getting these children early, ⁓ and being able to treat the these chronic conditions before they become ⁓ life changing i is very, very important. And the patients that we've treated, the pediatric patients we've treated, we've definitely seen ⁓ improvements in particularly in the children under the age of ten. So I think the the future is looking at at managing these children better with treatments. We don't have a curative ⁓ approach for for for collagen seven deficiency, but giving these child children the skin grafts that they need, giving them ⁓ something other than just a topical cream that allows them to to to stabilize these these wounds. When in a study was done by the FDA and and more recently ⁓ in Europe, looking at over eight hundred children and their carers, the issues that came up as the two most important issues were itch and pain. And it's difficult to understand quite how pain is is is so important to in in the in the distress that these children suffer. But the itch drives this sort of itch wound cycle. And as Vish said, infection is a major problem. So trying to improve their neutrophil function, ⁓ to deal with the these infections, trying to to deal with the skin lesions and trying to reduce the itch so that these children don't scratch. They don't make the wounds worse. I think I think are essential to to improving their their livelihood. And if I could just add, I think given the c complexity of the disease and how much it affects in the body, one therapy or one approach is not going to solve all the problems, we're gonna we're gonna need three, four, five different approaches acting in tandem to address these ⁓ problems. But since we have been focused on the skin side, which is more of the external barrier, and as one of the focus areas, as Mark alluded, we're following these patients for both patient reported endpoints like pain and itch, as well as investigator observed level of wound healing and things like that. And in terms of how are we trying to even bend the course of disease that you asked, Jennifer, it's it's more of can we give immediate relief but also think of changing the disease in its grassroots? When I say that, I'm not saying that you're gonna change the germline DNA makeup of these patients overnight, but can we at least give some kind of durable benefit with therapies that can supplement the gene in a way that y their own cells can be enabled as factories to start producing? the missing call seven protein. And that's really the approach that we've taken where we have recently presented data twelve years after a one time therapy where there's wound healing and ⁓ you know, pain control that's been ⁓ followed over the years. So that's encouraging, hopefully that's one step and then we we get more and more therapies into the market to address this in a you know holistic way. Yeah, that's actually such an interesting point. You think starting off over here with the skin grass. But as you mentioned, Mark, with it, there's there's all these other aspects to consider too with pain. So just going back to the skin grafts, I'm just wondering about how do you see the challenges of manufacturing and delivering these graphs, both as engineered products and living immunobiological interfaces with the patient. Yeah, I think ⁓ we the the process begins with the patient's own cells, right? So we need a sample of their skin biopsy and ⁓ it's the topmost layer of their ⁓ skin, which is epidermis made of keratinocytes. So we extract keratinocytes, grow them in culture and gene correct it, and then grow them further to make these sheets. And that's really what we supplied back to the centers where a plastic surgeon would apply these sheets like any skin graft. on the patient and that becomes part of the patient's skin over time. So that's ⁓ really the therapy. The process takes about twenty, twenty-five days to manufacture and supply these drafts to the patient. And ⁓ in a lot of the because patients have to travel to these treatment centers, it's not gonna be in their ⁓ you know, home clinic or very close by. But we ⁓ as a company are supporting those types of logistics just to make that process a tad easier for the patients as much as we can. And the clinical data have been quite impressive and promising. It's it's a ray of hope for these patients that if you can achieve long term wound healing and pain reduction for some of these menacing wounds, then that's seen as worthwhile going through this process or logistics of having to go to a center, give their skin sample and then wait for an operating room date. And basically configure their lives around that process for that period window that they have to plan around. Right. So that's that's how we are hearing from the patients and we're they have a very strong network. These patients are very well connected. They have their Facebook page. So one patient talks about their experience, and that's really how the ⁓ community depends on those experiences to learn and come forth for these types of therapies. The patient support groups are really central to this. And it's exactly what what Vish described. You know, the patients hear about treatments or clinical trials and it runs through the the the network very, very, very quickly. So yeah, it it's a it's a patient group that's easy to work with in terms of access, but difficult to work with because of the clinical condition that they've got. Okay. Understood. Are most of the patient populations, is it just inevitably going to be in the US or And Mark, where you're based out here, how is it in the UK? So so the prevalence of RDEB is pretty much flat across the world. And so we have upwards a about a hundred RDEB children under the age of sixteen in the UK. and we're fortunate from my perspective in that we have two national centers that are funded by ⁓ the healthcare system here. So nearly all of them go to the two national centres, which makes it relatively easy to to to treat them. and bring them into trials and bring them into early early treatment. But yes, if you look at the the the ⁓ the the population size ⁓ that's a hundred children in a population of sixty mil sixty million and if you just multiply it up by the p US population you get the the the US numbers and the European numbers as well. So I was speaking to R Deb in Germany, the the the Debra the charity in Germany and they they came back with very similar ⁓ prevalence. So so yes, it it it's a global disease and ⁓ the the talking to people recently ⁓ and trying to get drug into Russia, ⁓ into the into the Middle East. ⁓ yeah, it it's pretty much the prevalence is the same globally. Yeah, that that is ⁓ quite interesting. Now I'm just curious here when it comes to like a this entire cell therapy platform that we're looking at right now. So a decade ago, cell and gene therapy, maybe probably more than I said even a decade ago, was still very novel, especially for an ultra rare disease. But I'm wondering how has ⁓ real world experiences in RDB, both clinically, immun immunologically, changed the way you talk about risk, safety, and benefit with regulators, investors, or families. Well, Patricia's had more experience than that, so I'll I'll I'll defer to Vish in the first instance. But yeah, I think ⁓ when we talk about real world experience, right? I think ⁓ of course, since the launch of our product, it's very early days for us as well, because we have not yet commercially followed patients for years yet. But I would say that ⁓ when you you brought up this word risk, how is risk viewed by various stakeholders? I think let's start with the patients, which are the most important stakeholders. I think when we say what is the risk of treating patients with a cell therapy or a gene therapy or both, we always have to ask, what is the risk of not doing that? That is much bigger than the risk of trying something new. It's always gonna be the unknown, the uncertain. Will this technology work? Will it introduce a new risk? But then if you're reasonably satisfied that those risks are minimal compared to if you leave this untreated, patients are going to have a very poor quality of life and will also have very bad life expectancy. And I think that is the context that at least the regulators have viewed this as well, because our technology is introducing a gene and it's autologous. I think when we use autologous cells, it means the patient's own cells that can certainly minimize the immunological rejection. Factor, so you don't have a graft versus host kind of a problem there. But we are still using ⁓ vectors that introduce these genes and they're highly regulated. We have very regulated ways of seeing are we doing something unintended and how how have we taken care of that? Deborah is one of the organizations that's patient focused, the patient community there. They say the cost of doing nothing is humongous, right? That's that's really what the regulators also hear. And when we talk to the FDA, we also take these ⁓ representatives from the patient communities with us to explain that look at risk in relative terms of doing versus not doing. So that's one. I think you brought up the investors as well. I think there has been a lot of investor participation. If you look at RDB, the therapies right from the topical gel that was approved and then there is a bark extract that also sulcizes one such product. There's so many products that have come to market and that's testimony to how investors look at this unmet need and where there's an opportunity. So I think there is a positive change, I would say, overall, looking at how do we assess risk both both from a financial perspective, but most importantly from a patient care perspective, right? So that's my take. But ⁓ you know, Mark, please chime in. You have a different angle to view these. I think you're you you've hit the nail on the head actually, yeah. You're talking about risk and and so the gene therapy risk that everyone got worried about with the children preached in France in the late nineteen nineties. For severe combined immunodeficiency syndrome, another disease that is dreadful and kills children. Now, that was cured by gene therapy, an autologous gene therapy, and us two children developed acute mild leukemia because the virus, the the the LED virus or the retrovirus, chemoretrovirus integrated into the wrong site in the gene. Now I I knew the clinician treating those children. It shut down gene therapy for years, but in reality Well, it gave you took children with a fatal disease and you gave them a disease that could be treated. Because acute my leukemia in children is actually a very treatable disease. And both of those children were treated and were cured of the acute myodleukaemia. But it put back gene therapy for a long time and created this fear, ⁓ what about inappropriate integration next to a a a a hemodriver? Whatever. And that I think f our discussion with regulators, ⁓ obviously, ⁓ this particular therapy of mine is not gene modified, but I I'm a professor at University of College London and involved in all sorts of developments. We have discussion with regulators all the time and they reflect exactly what Vicius has said. They're much more comfortable with the risk that we take depending upon the treatment you're trying to deliver to the condition that you're doing. And it it has to be a a risk based approach where you actually you can take a bit more risk. You wouldn't be doing a gene therapy for dermatitis, for example, but gene therapy in this c scenario is entirely appropriate. particularly given the safety that we've developed over the l or understood in the last twenty five years. Yeah, I think it makes total sense what you're saying. You really have to look at the risk benefit profile here. We had a meeting with our our UK regulator a couple of weeks ago and one of the comments we got from one of the parents of the children who were in the the last trial that we ran, did they were asked you bought this child all the way and several hundred miles to come in to to be treated in London. And the parents said If I can improve the life of my child by one percent, that makes a actually a meaningful difference. And you think about when you're developing drugs of ten percent, twenty percent improvement, said one percent will get my child out of bed. And that's why we will do it and that's why we'll take this risk. And I think that speaks for it very well. We don't need to see huge change in this children to have a big clinical change. And and that's one of the problems one has when when assessing the the trials. You know, how how far do you what what do you really need to show? To have a meaningful clinical benefit. Yeah, that's it incredibly important. That's something I remember to covered in in the years past when when I was a journalist, is that sometimes a disconnect between clinical significance and statistical significance, ⁓ or between patients want to see and what regulators want to see is can be different. So I think I think just to sum it up here, gentlemen, if you had to pick one or two lessons from RDEP. Let's say coming from the cell engine therapy perspective and clinical perspective, and one from the immunobiology and the tr translational perspective, what would you say is the most important takeaway for how this avenue of therapy will expand into broader patient populations over, let's say, the next five to ten years? I would say some experience ⁓ with this product has definitely d taught us a lot, right? These are complex biologics. I think engineered cell therapy in itself is a new field relatively. And within that, to have something like engineered skin cells that are or sheets of skin cells, it's even more sophisticated. But I I think the experience of taking such innovations from academic institutions like Stanford, after having done a s a clinical study and where manufacturing was done in those institutions, and then we bring it up into industry. And we try to scale that. I think the most important thing is ⁓ staying close to patients and their needs and the community because how we build a product and the characteristics that we care for in the product has to be driven directly by what their lives look like and are we really solving their problems, right? That that interconnectedness is important. I've never in my career had an experience of having met after the trial is done 60% of our trial participants and Had dinner with them over some events like these. It's not something that ⁓ you will see in large indications like when you're working on lung cancer or something like that. It's a very special thing. And I think the best we can take from that is learning how can we best serve these communities, what are their needs, and building that into our product. I think whether it's cell engine therapy or any other modality, right? That's for me the biggest learning. And it's a continuing journey. I think once you go scale up and now go into the market. you're gonna only have more and more of that because you're implementing it in a commercial setting. That's a completely different ball game. So ⁓ yeah, that's where I would leave my thoughts. ⁓ Mark, we're ⁓ happy to hear yours. Yes, I so I've worked in hospitals and academic ⁓ units all of my career and th it's have been tissue engineering, immunotherapy products and and the take home method I have is one you've as Vish said ⁓ it w in their setting. You have to have a drug that can be delivered in the environment in which you're delivering it. Now they have specialist treatment centres, which works extremely well for a complex product. ⁓ we have engineered our product to be very friendly to hospital pharmacists so that it doesn't come in as a drug that's any different to any other drug, because hospital pharmacists get very nervous about cell and gene therapies. ⁓ so that's number one. Two, we've made it as friendly to the end user, to the clinician, so the clinician wants to use it. Dermatologists don't do cellin gene therapy. So you've got to get them on board and get them to understand that this is not crazy. So you you make it in a way that can be delivered. Bish has done it in a way that can be delivered by plastic surgeons and they get a a product that they're familiar with. So we deliver our product in a way that the f clinicians are used to it. ⁓ ours comes cryopreserve, so it comes with a a an automated cooling device and you press the button and it goes ping and tells you yes, now's the time to t to to give it to the patient. And then we've worked with the patients to say these are the the the technical difficulties. You're going to have to have an intravenous infusion, given all the problems that they have with venous access. But we've worked on needle sizes so that there's there's there's l less problem with that. So it's about, you know, making it fit in the real world with the environment in which you're going to work, ⁓ in which you're gonna work. So it it it's a great community and as we said, meeting these families, you do become really involved with them and they want to come back and they want to ⁓ to be treated. So I think Yes, it it's about working out how to make it work in the real world for the patients and the clinicians and the hospital environment you want to use in. Well, that has been a great introduction, so for audience who wasn't aware for RDEB. And I love that we're ending on a very positive note going forward here. So there's a lot to look forward to for the future and for patients. So thank you so much, Vish. Thank you so much, Mark. If you'd like to listen to more episodes of The Natured, please turn to biospace dot com. Thank you.