Hi, everyone. Thanks for joining. I just want to let you know that we'll get started in about 1 minute or so. Good afternoon, everyone, thank you for joining us. I'm David Moss, CEO of INmune Bio. Today, we're proud to share pivotal updates regarding our Mission EB phase III clinical trial and the impact of CORDStrom on recessive dystrophic epidermolysis bullosa, or RDEB, as you'll hear it in this presentation.
Today's event is being recorded and will be available on our YouTube channel later. As we begin, I remind everyone of our forward-looking statements, which is on the screen. Before we dive into the data, I want to introduce two individuals whose dedication has been instrumental in reaching this milestone. First, I'm pleased to introduce Dr. Mark Lowdell. Many of you know Mark.
He is the inventor of CORDStrom and a pioneer in the field of cellular therapy. With a distinguished background in developing advanced medicinal products, his vision for using pooled umbilical cord-derived mesenchymal stromal cells has paved the way for a potential new standard of care in treating systemic inflammation. I'm also thrilled to introduce Dr. Anna Martinez, the investigator of the Mission EB trial.
Dr. Martinez is the Clinical Lead at Great Ormond Street Hospital, or GOSH, in London, and a leading expert within the epidermolysis bullosa field, bringing years of clinical expertise in pediatric dermatology to this program. Dr. Anna Martinez is the specialty lead of the pediatric dermatology service at Great Ormond Street Hospital and honorary senior lecturer at the Institute of Child Health, University College London.
Anna trained at St. Bartholomew's Hospital and was appointed as Consultant in pediatric dermatology at GOSH Hospital in January of 2003. Since her appointment, Anna has led the National Commission Highly Specialized Service for epidermolysis bullosa, and is a world leader in management of skin fragility diseases. Anna runs the pediatric dermatology services at GOSH and manages children with many skin conditions. Most importantly, as the Chief Investigator who designed and led and was the key enzyme in this trial, she has been at the forefront of shifting the treatment paradigm for RDEB from simple wound management to systemic disease modification. At this time, I'll hand the call over to Dr. Mark Lowdell to discuss CORDStrom, how CORDStrom is addressing the critical window of opportunity for these patients before passing the webinar to Dr. Martinez. Mark, the floor is yours.
Thank you, David, and thank you and welcome to everybody who's joined the webinar. As David said, we're going to concentrate this evening on... or this afternoon, on CORDStrom, which now has an INN name, as you can see, and its first indication, which is in recessive dystrophic epidermolysis bullosa, or RDEB.
As you've seen, well, I hope we're going to demonstrate to you this evening, this really is a disease-modifying therapy for this horrible disease. I'm really excited that Anna is here to give you her observations from the trial and recount the clinical impact. What is CORDStrom, for those of you that might be new to this? It's a mesenchymal stromal cell product, but uniquely, it's a pooled product from four donor umbilical cords.
Its mechanisms of action are very well understood now, and I'll go through that in some detail towards the end of the webinar, after Anna. We know it can suppress inflammation in RDEB and other diseases. It can enhance wound healing in RDEB and other diseases, and in the right setting, it can suppress fibrosis.
We've got global IP, and we've already established large volume manufacture, which you'll see later on in the webinar. Anna, it's a delight to have you on, and thank you for fitting this into your busy clinical schedule. The floor is yours. Please go ahead and tell us, recount the trial and where you hope this to expect this to go. Thank you.
Brilliant. Thank you very much, Mark. When I say, "next slide," I'll let you move them, but thanks. I'm delighted to be here. Thank you for that lovely introduction. I'm Anna, and I'm going to talk to you about RDEB, recessive dystrophic EB. Next slide, please. Obviously, this is what it looks like from the outside, and this is what families and children have to live with every day. Actually, next slide, this is a multisystemic disease, and by that I mean that it affects most parts of the body, as you can see here. Importantly, next slide, please. It's a disease that gets worse and worse over time, and we published the natural history of this particular type of EB about three years ago. Next slide.
Why that's relevant is because the disease changes with time, and when babies are born, they often have absent skin, and this can take several months to heal, but it does heal. Generally, the first few months of life are relatively stable. Next slide. After that, from age 18 months onwards, we see this increased burden of disease, and although wounds open and close, they're not chronic.
We start to see first signs of internal involvement, this multisystemic disease. This inflammation starts boiling, the weight starts to fall, anemia starts, and we start to see esophageal strictures and scarring in the esophagus. Next slide. Why this is important is this is a really fantastic window of opportunity for anti-inflammatory therapies, which we can see.
Under the age of 10, we know that this has an opportunity that we will lose if we don't try and treat early. Next slide, please. From the age of 10 to 20, we see this increased skin involvement. Wounds start to become chronic. By that, I mean that they don't close within 21 days. We see bacterial colonization and what we call multiple comorbidities, many other complications aside the skin, and there's this dramatic reduction in the ability to heal. Next slide, please.
Now, also, because of this phenomenal levels of inflammation, which we know has been monitored, this inflammation affects how the body works in these major pathways in the body, leading to pubertal delay, growth failure, osteoporosis, fractures, anemia, and we know if we wait, the longer we wait, anti-inflammatory therapies, although they will help, they're likely to become a little less effective.
Next slide, please. From the age of 20 onwards, we see that the disease now just escalates. There's an exponential increase in inflammation. Wounds at this point, very rarely heal. Next slide. Tragically, these patients are at high risk of developing cancer, squamous cell carcinoma. This is a life-threatening complication of this type of EB. These tumors grow rapidly.
They're often on the extremities, where these children have had absent skin from birth and chronic inflammation and trauma, and the mean survival is just 2.4 years when the tumor develops. Most of these children, young people, will die in their late 30s or early 40s. Anti-inflammatory therapies, anti-fibrotic therapies, at this point, are likely to be less effective. The longer we wait, the harder it is to put out the fire. What do people living with EB right now actually want?
What are their priorities to get better? I was on the steering group of this prioritization survey of just under 900 members of the global community worldwide. For dystrophic, for this particular type of EB, what people living with recessive dystrophic EB want now is treatments to improve pain, itch, mental health, reduce inflammation, and to help their esophageal issues. They want anti-inflammatory therapies.
Next slide, please. What therapies do we actually have at the moment? We have two, and this one was called Filsuvez, which was approved in the U.K. a couple of years ago. It's a cream, in fact, it's quite... It's greasy. Most of it's sunflower oil, 10% is birch bark. It's meant to be anti-inflammatory, and it's for children over the age of six months. You're meant to put it on all wounds.
It's expensive, unfortunately, most of our patients don't want it. It's ineffective, they stop. The second treatment that we have available, but not in the U.K., is gene therapy, and this is called Vyjuvek, and it's a topically applied gel that is used that has a non-integrated herpes simplex virus, which carries the collagen VII to the skin.
The issues with this is you have to apply it under the age of three. You only can use 1 mL at a time, and so it really only covers about 1.75 of about less than two credit-sized wounds. Okay? You're only allowed to treat a very small area. When you're over the age of three, you're only allowed to use just under four credit card worth of body surface area to treat at a time.
You can imagine when you have a child with a back like this, then it's really not gonna go very far, and importantly, it's really not gonna have this systemic anti-inflammatory effect. It's just not going to do that. Next slide. The other thing about Vyjuvek is it's extremely expensive. It's approved in the States.
Actually, they've been using it now for 2.5 years, and it's approved in Europe last year. It's not approved in the U.K. The cost per patient per week is about GBP 25,000. The estimated global lifetime cost of this drug on its own is about $15 million per patient. Those are the two treatments that we have. There's an urgent need for early systemic anti-inflammatory therapy.
We knew this, in 2012, Cure EB, which is a charity, funded a study called EB-STEM, and this was an open-label study treating 10 children at Great Ormond Street with recessive dystrophic EB. These children received three infusions of bone marrow-derived stem cells, and we really saw very promising results.
Promising that we went to the NHS, and we said, "We want to start giving this treatment to our patients." On the back of that, they said, "No, you can't unless you run a double-blinded, placebo-controlled study." Next slide, please. That took us 11 years to finally open. I was awarded a big grant from NHS England, which stipulated we had to, unfortunately, give placebo intravenously to these children, which you imagine was very complicated.
We ran the study at Great Ormond Street and the other National EB Center for Children at Birmingham Children's Hospital. Next slide, please. The study was called Mission EB, and this is a lovely logo that Gabrielus, our first patient on the study, designed, and this is my core team. Next slide, please. This is the cartoon of the study. Essentially, patients were divided into two groups.
They either had stem cells, CORDStrom, to start, two doses, two weeks apart, and then a nine-month washout period, and then placebo, or they had the opposite. They would have to have two doses of intravenous infusions of placebo, a nine-month washout period, and then CORDStrom. Throughout the study, we collected a whole load of outcome measures.
The aim of the study was obviously to assess if they were safe, but also do they benefit our patients? Importantly, we really wanted to explore the views of the parents and families on the acceptability of the treatment, and we did this through blinded interviews. The first patient was treated, Gabrielus, the boy you saw there in 2021, and we completed the trial with no toxicity events throughout the study related to the drug. 37 children were recruited. This is the largest study yet to date, globally. Six withdrew, so we have results on 30, and we gave a total of 124 infusions. Thank you.
The results from 30 patients, 16 with intermediate type and 14 with the most severe type, 21 of our patients were under the age of 10, we saw a total itch reduction at three months of 21% and at six months of 26%. Remember, itch is actually the top two priorities of treatments that these families want globally. Next slide, please. We also saw benefits across all patients receiving CORDStrom for itch.
Under the age of 10, we saw an improvement not only in itch, though, but with their skin scores, so the improvement of wound healing. Their itch improved by 17%. The younger ones had an itch improvement of 17% and skin, 7%. The intermediate patients that had more severe disease also saw a pain reduction.
The average pain improved by 22% and the worst pain by 28%. When I'm talking about the most severe patients in this cohort, nine of the 30, they didn't see an improvement in their skin at three months, but they had this massive reduction in itch of 25%, even larger than the intermediate group.
If we look at the six-month data, remember, this is six months now after receiving treatment, the two infusions. Itch reduction is maintained even six months after the cells across all the cohort, and fascinating, the largest itch reduction was in the most severe patients, and their itch improved even further and was reduced by 27.5% at six months.
Importantly, we also saw in this cohort now, six months after the infusion, that not only was their itch reduced further, but we started to see a big improvement in their iScore-EB, the skin scores, the patient's report comes, and this, we didn't see at three months. The thought, most likely, is with this sustained improvement of itch, we start to see this real improvement in wound healing in these patients.
Thank you. Conclusions from the data is that cells, number one, are safe across the whole cohort. It was phenomenal. We saw no serious adverse events. Itch reductions maintained six months post two infusions. Imagine if we give them more frequently. The largest itch reduction was seen in the most severe cohort of these patients.
We also saw a big improvement in these scores, iScore-EB scores, in the most severe group, which we didn't detect at three months. This improvement that we saw and this sustained wound closure is likely to be, in my opinion, disease-modifying, improving pain and quality of life, and it should reduce their long-term risk of squamous cell carcinoma. We published this in the eClinicalMedicine toward the end of last year.
I'd really like to end a couple of minutes just talking about the qualitative data. These are interviews that parents and children had, blinded, after they had either the cells three months after cells or three months after placebo. The inter-person who was interviewing the children and adults didn't know what treatment order they had, and neither did the patient. These are the results.
There was clear evidence that people, adults, and children knew. 10 out of the 13 said they absolutely knew when they had CORDStrom as opposed to the placebo, because they simply felt better. In fact, all the intermediate patients and children, and one parent from the severe cohort, said that they had a large impact on the quality of life of their child. Many families talked about the difficulty of symptoms coming back when they could no longer have the cells. A quote from a parent said, "When she's been getting ill, she's just been recovering in the same way as her brother. Normally, illnesses affect her much more because it causes inflammation.
We've just been able to cope with everything so much better and have lots of energy, and I suppose life has just felt normal." Another family said, "I think it's been lovely to see him having energy and having an appetite. I suppose actually, that's one thing we've noticed. Well, she's put on weight." A child said, "It was less painful, and when I itch, it's painful, so obviously, that's not comfortable, but I had less pain. My skin was less itchy, my hands were less hot, and when they're hot, I itch, and that has not been happening so much." Another child: "Normally, it would hurt when I have a bath, but lately, it hasn't been hurting." These are quotes, genuinely, families expressing the quality of life improvements that they saw with this treatment.
The next stage is INmune Bio are going to support an open label study here at Great Ormond Street Hospital and Birmingham Children called Mission EB Deliver, and we're gonna treat all children that took part in the study, plus others that weren't able to, with a diagnosis of this type of EB. The study will be over 12 months, and each child will be offered two infusions every four months for 12 months, and we will be collecting, again, a lot of data. I wanted to end to say that CORDStrom has proven to be beneficial with no safety signals in all children with Recessive Dystrophic Epidermolysis Bullosa from the age of six months. The intermediate and younger patients over the age of 10 saw effects more quickly, with improvement in their pain and itch.
The most severe patients and older ones, although they didn't show skin changes at three months, by six months, their itch had continued to improve, and we also saw big improvements in their skin scores. Treatment with CORDStrom in recessive dystrophic EB patients is likely, in my opinion, to be disease-modifying, improving itch and quality of life, and it should reduce the risk of squamous cell carcinoma, the life-limiting complication of this disease. Thank you very much for listening.
Thank you, Anna. That was an excellent masterclass in RDEB. I know it was really painful to have a situation where patients had to be treated with placebo, but ultimately, it strengthens your data enormously. To have children and parents able to identify blindly in which order they were treated is really quite remarkable in this disease, in the absence of. You know, most of these studies are not done and double-blinded. I'm just going to give some details now about how the why CORDStrom works, how it works, and how we're going to deliver it coming as we move forward.
Those of you that have been familiar with mesenchymal stromal cell therapies and the difficulty in delivering them, it's largely been due to the heterogeneity, not just of where the source of the cells, whether they come from bone marrow or adipose tissue or, in our case, umbilical cords, but also within the individual donors.
There's donor heterogeneity, which gets worse as we get older, and also within a mesenchymal stromal cell product, there are multiple subsets of mesenchymal stromal cells. Many trials, I'd say 99.9% of trials of MSCs, have assumed that all MSCs are the same, and we knew that wasn't the case. We invented CORDStrom back in 2014, not within the company. It was an academic invention that we brought into the company.
I chose to use umbilical cord because it was an easy tissue, and they're much more homogeneous. We also decided that we would pool donors, and so that heterogeneity, if you make a product from a single donor, when you come back and make it from another single donor, it's inevitably different. By pooling donors, that heterogeneity of four donors is reflected in the next four donors, and so you end up with a much more homogeneous product, and that's proven to be the case, although I won't share today, we have a lot of data we've shared with regulatory agencies to confirm that. Most importantly, we can define our product on potency. I think that's the biggest difference between CORDStrom and all of the other MSC products.
We actually have a mechanism of action, which I'll share with you. We have potency assays to support that. These are some of the graphs behind the numbers that Anna just shared with you. If we look at CORDStrom versus placebo at three months and six months, and looking at improvement scores. These are going up as the patients improve. We can see significant improvements at three months in red and six months in green, in patients when they were treated with CORDStrom compared to the patients when they were treated with placebo.
If we look at the actual pain score, so a high number here is more severe pain, you can see that those on the placebo treatments remained stable in terms of pain, whereas those on CORDStrom, on average, in their pain score reduced over 12 weeks. So you heard that is the most important indication for these patients in terms of management of their disease. We think it's a key differentiation factor in terms of their quality of life. Itch is the second most important pathology as far as the children were concerned, and you know that there is this scratch or itch scratch and then skin wounding cycle, which just gets worse and worse and worse.
You can see some of these quotes from a study done by Deborah in the U.S. "I don't sleep, I can't wait for the sun to come up, so I can start being bandaged because of the damage I did while I was asleep." "And it's just a different form of pain." These children were assessed with an itch score called the Itch Man score, which has a zero to five. The patients in our trial were mostly level two and level three. In level two, sometimes this is described as sometimes interfering with activity, and children scored themselves. Level three, itches a lot, difficult to be still and concentrate. This is where the change, the quality of life starts to get really impacted.
If we look at these categorical scales and the percentage of patients in these groups, we can see that severity level two, mild itch, sometimes interfering with activity, 21% of the patients were at severity level two before treatment. A similar 21% of the CORDStrom-treated patients were at level three. If we look after treatment, those patients, 67% of those patients at level three, fell to level two, and this is this increase here. A 67% reduction in the children with level three, the severe form of itch. In placebo, the severity level, the patients in the severity level three, actually increased after or following placebo with no reduction in disease.
What that means in terms of other quality of life issues, we look at eating, and you saw that quote, "My daughter was able to eat." You can see here improvements in eating at three months and sustained at six months on CORDStrom and not with the placebo. Bowel performance, we have a high placebo effect here at three months. The story here is that CORDStrom showed effects at three months that were continued for six months.
If we look at other well-being scores, general well-being, sleep, and pathology, their ability to interact with their siblings and to go to school, in all aspects, CORDStrom at three months and at six months, outperforms the placebo treatment. If we look at skin scores, and, you know, obviously the picture here that everybody thinks of are those pictures that Anna showed you of topical wounds. Although those can be treated, they're still obviously a major issue for these children. Anything that can be done that can improve skin scores is important.
What you can see here is that looking at the number of patients describing, when we've analyzed the data and seen how these scores go, we've got 18% of patients who are on, under placebo getting worse, a small number, no change, and a small number improving. When they were treated with CORDStrom, a much lower number of patients got worse, a smaller number of patients got worse, and a significantly greater number of patients improved. That translates that these data on EBDASI are also seen using the iScore-EB skin score, where you can see a moderate, if any, improvement at three months on placebo, worsening. This is increasing skin score, is worsening disease, and worsening at six months.
Whereas at three months, patients treated with CORDStrom at three months, you can see, improvement in that skin score, which was maintained, and there was no worsening at six months. As I showed before, that's what translates into these improvements in well-being. One of the problems with using mesenchymal stromal cell therapies has been the inability to understand how they deliver the effects that we see. In fact, those of you who have been familiar with the length of time it took for remestemcel-L to be approved in the U.S. and in Europe, and that was most entirely due to their inability to convince the regulatory agencies that they understood the mechanism of action of the drug.
We know that CORDStrom and other MSCs secrete a number of cytokines. These are the cytokines that we have measured in CORDStrom. We know they're secreted. We can hypothesize how CORDStrom might be having these effects. Itch and pain are driven by release of interleukin 31 and TSLP from TH2 17 cells in the wound site and elsewhere in the body. We know that pro-inflammatory M1 macrophages are present at high numbers in the topical wounds, and we imagine elsewhere in pro-inflammatory sites throughout the body. We know that these M1 macrophages secrete IL-6 and drive this cell population. They also secrete IL-31 in their own right.
What we would want to do, we would hypothesize, is that the PGE2 secreted by CORDStrom would down-regulate this through down-regulating TNF-alpha, gamma and IL-6. PGE2 should also induce these M1 macrophages through the release of IL-13 to turn into an M2 macrophage. Similarly, the IDO secreted by CORDStrom should activate these M2 macrophages and induce them to migrate into the wounds, and these M2 cells will secrete these wound-healing cytokines, as well as immunosuppressive IL-10, which switches off the TH2/TH17 cells. CORDStrom can also secrete wound healing cytokines, TGF-beta, VEGF, and HGF, and we would expect these to go up in patients treated with CORDStrom. Interestingly, I spoke about this earlier on, the increase problem with wound infections as these children age.
The IL-8 secreted by CORDStrom activates neutrophils, and we would expect that to have a positive benefit on infection. This was our hypothesis, and we had to start trying to find out evidence to see if it was true. First off, we looked to see whether this PGE2 IDO access could induce this M1 to M2 transition, and that we could only do in vitro. What we did was use a cell line which can be differentiated in from arresting an undifferentiated M0 cell. By treating it with cytokines, we can drive it to an M1 phenotype, or we can drive it to an an M2 phenotype. Looking at these variety of surface antigens here, you can see the intensity of expression of these is different on M1 cells than it is on M2 cells.
What we did was we took the M1 macrophages that we generated, we treated them with supernatants from CORDStrom, and you can see that within three days, these cells change from the M1 macrophage to the anti-inflammatory M2 macrophage, with a reduction in CD80, the pro-inflammatory CD80, CD86 molecules. We demonstrated in vitro that this could happen, but plainly, we didn't have skin biopsies from the children to see if it would happen in vivo, but we could measure other aspects. What we did next was look to see whether these cytokines from M2 macrophages actually went up. You can see, if we look at the changes after treatment with placebo, compared to changes after treatment with CORDStrom, we can see that we increase this IL-13, which is indicative of M1 to M2 transition.
We increase the amount of IL-10 secreted, which is suggesting that these M2 cells in the patients are being activated and are secreting more IL-10. Interestingly, also, we saw a small uptick in IL-8, suggesting that they may well be having a systemic effect in IL-8. If we look at wound healing, and you saw that these children did show an improvement in skin integrity, we can see that TGF-beta, VEGF, TGF, all of these cytokines involved in wound healing are increased after CORDStrom, and in most of them, either reduced or are unchanged after placebo treatment. What was really interesting from our perspective was the change in TNF-alpha, this driver of inflammation. You know that as a company, we're interested in TNF-alpha for other reasons, we now know that.
We know from publications that TNF-alpha drives this IL-6 response and drives the inflammation, and we can see a significant reduction in TNF-alpha. These are all serum samples from patients pre- and post-treatment, either with CORDStrom or with placebo. Really uniquely, I think for this umbilical stromal cell product, we already know its mechanism of action, and we have evidence from the patient population that this mechanism of action is actually happening. It now means, of course, that we have ways of testing batches of CORDStrom so that we're able to have these as our release assays for the regulatory agencies, which tie in directly with our mechanism of action. They need to make this into a commercial product to be able to treat patients. We need to be able to make the product at scale.
We work with, as I've said, four umbilical cords. We select cords with specific characteristics, based upon that mechanism of action, to have the right cords for the right product. Indeed, we can select different cords for different products, and that's a different story. We take these into bioreactors, we produce master cell banks from the optimized cords, and those master cell banks then are stored down for expansion into working cell banks. These working cell banks give us the opportunity either to scale out with multiple three-liter bioreactors or, as we're doing at the moment, scaling up into 15 liters. Either scale up or scale out, we can end up in a single run, manufacturing around about 200 doses, which is enough to treat 30 patients for an annual run.
We already have the capacity to deliver these cells at the scale needed for commercialization. This is our path to market, which we're planning. As you, many of you know, we started this back in December 24th, we're now about 14 months into the process, where we got approval from the FDA for RPDD, and we got RPDD approval a month later. We've tech transferred into a commercial manufacturing space in the U.K., which we rent from a U.K. government facility called the Catapult. This is a very efficient and cost-efficient and staff-efficient way of doing this. We already have the engineering runs underway, and plan to have that license in place by the end of Q1 this year. We have a...
We've submitted the Paediatric Investigation Plan. The response from the MHRA will be on the 9th of March. They've promised us that. We have a face-to-face pre-MAA meeting with the MHRA already scheduled for the second week of May, which aligns almost very nicely with a pre-IND meeting for the open label trial that Anna described with the FDA. We can run that in the U.K., regulated by both re-regulators. That will lead to the Breakthrough designation submission at the end of Q2 this year. Then, either at the end of Q2 or very early in Q3, probably in July, we will submit marketing authorization to the MHRA, and they are fully aware of that timeline from this pre-meeting.
By the end of the year, when we've done a few more experiments that the FDA have asked us to do, we will be submitting our BLA to the FDA. This is where we are at the moment in terms of the alternatives. As you've heard, Vyjuvek and [Endovascine] are already out there and placebos as well. Vyjuvek is a topical skin cream from Krystal Biotech, and they have a $400 million turnover this year alone, and Anna identified some of the costs associated with that. The topical skin graft, I don't even know how many patients have been treated. None of these address the systemic nature of the disease, as Anna pointed out.
I believe that we have a great market opportunity to get into this disease and to provide the treatment of these children so desperately need. As I alluded to earlier on, we have a little bit of a way to go, but we believe this really is the first treatment that's beyond topical care. These IV infusions have already had multiple systemic effects in the children that you've seen in terms of EBDASI, iScore-EB, itch, pain, and quality of life. As Anna said, it's been a remarkable safety profile, even in these children with very severe disease.
Having an intravenous infusion is not an easy thing to deliver, and yet it was completely safely delivered and has been formulated for that. Commercial readiness, as you've seen, we're ready to scale up and scale out. We've organized and produced clinician-friendly packaging and a supply chain that fits in with hospital activities. The CMC is now locked down, and our potency assays, as you've seen, are simple and are validated. We've been engaging with regulators throughout, and that engagement is underway and is currently on time for that schedule that you saw. We are now moving from being a clinical development company to a commercial provider, which I'm extremely excited about, and we really look forward to being able to provide something for these children globally as soon as possible.
This, I think, is. This goes as a quote from Anna, from one of her parents, one of the parents in the trial. "We look at these changes, and you go, 'Oh, well, it was 27%, or it was 9%, or it was 7%.' That's not 90% or 100% improvements. What these children actually ask for is a 1% difference. A 1% difference, and the parents are happy to come into London with their child to be treated in a clinical trial. It's a lot for him. 1% less pain is 1% more real life." I think that's a tremendous quote, and in fact, it should be the company logo. With that, I'll hand this back to David, and very happy to take any questions, and I'm sure Anna will join in. Thank you very much indeed.
Thank you, Mark and Anna. It was great. If anyone has any questions, just type them in the chat. We have a few already. The first is: Do you believe that clear evidence of systemic wound improvement, i.e., measured by imaging, et cetera, would be required for approval?
We've not had that feedback from the MHRA, and indeed, it wasn't a comment that the FDA made in the Type B meeting that we had last year. These skin scores, and Anna's better position to answer this than I am, but these skin scores are internationally recognized. And they're One of the things that we measured in the upcoming trial is the total body area that's affected, which is a numerical value rather than imaging.
I can answer. It's extremely difficult to take photographs because it's very, very painful. You can't really do total body photographs. You have to do it sort of limb by limb, body by body area. Actually, it's been shown to be very unreliable because these wounds open and close. The pictures that we used from Mission EB with a company called Canfield, in fact, were not helpful. What was helpful were the quotes and the scoring systems that are validated, as Mark said. I wouldn't imagine that they would need that.
Yeah, let me just add, you know, Deborah did a panel with RDEB patients in 2018, it's recorded on YouTube with the FDA. Similar to what you mentioned, Anna, that the patients rank itch and pain far above their wounds anyhow. I think part of the history is, and maybe, Anna, you could add to this, is that a long time ago, they looked at RDEB as a topical disease because it presents itself with the external wounds, but it clearly is a systemic disease, right? With no systemic treatments on the market. All right. Question two: Can you elaborate on the few more experiments that the FDA has required you to do? This is the CMC part, Mark.
Yeah. Yes, and that's easy. When we went to the FDA, one of the things that I was interested in, currently, all of the batches of CORDStrom we've made have been made using umbilical cord donors from U.K. cord blood bank. These are cords from which the cord blood has been removed, and the discard tissues come to us for isolation of mesenchymal stromal cells. Now, I was interested to see whether the FDA would allow us to use U.K. donor cords to treat U.S. patients. The FDA came back and said, "Yes, but the cord donors will have to be tested for infectious diseases, disease markers in U.S. accredited laboratories." They wouldn't use European tests. That's not uncommon.
It's the same for umbilical cord blood. Now, this means that we have to go and get new cords, which we're doing all the time anyway, but we'll have to create a new master cell bank, and that new master cell bank will have to be from donors who've been tested both in the U.K. and in the U.S. Those are awaited. We're just sorting out the donors. It's simple things like, these ladies have given consent to have their blood tested in the U.K. for infectious diseases.
They haven't given consent for that to be done in the U.S. or for their data to go to the U.S. We had to change consent forms. We had to work with the umbilical cord blood bank to make that happen, and that's what we're waiting for. I was doing the audit yesterday at the cord blood bank. We are ready now to move forward with that. Once we get the new cords in, and we've selected those that are optimal for cords from an EB, and manufacture the net Master Cell Bank, then we'll have the data that we can take to the FDA. It's just a that slow process.
They're just additional CMC steps that the FDA has that are different from what the other regulatory agencies have.
Well, yes.
Next question.
They're just. Yeah. They're screening tests.
Yeah.
Yeah.
Exactly. Next question: Might CORDStrom have any applicability to other types of EB?
That I leave to Anna as the expert in EB.
Yeah, a brilliant question. I don't know who asked that. Yes, definitely. Junctional EB, which again, is systemic, very inflammatory, we would really. In fact, we have discussed on compassionate grounds, whether we can start treating the junctional children. That's another cohort. It's not such a large. It's a much smaller group. Yes, there are other types, which will be junctional type.
Great. Thank you, Anna. Next question: Can you talk about the increase in itch on placebo? It's not an increase in itch, it's just that they stayed on level two. Is that progression of the disease or just fluctuation without treatment to health? I'll let you answer that, Mark.
I think it, the initial numbers, I think it's fluctuation on, without treatment. Yeah.
Yeah. A second question: When thinking about labeling, we have seen cell therapies approved in patients as young as two months of age. Would you be seeking a similar age range, and does this position you to target pretty much the entire spectrum of RDEB?
I can answer that from a regulatory perspective, and Anna can answer it from a clinical perspective. The Mission EB trial was performed in children over the age of six months. There were good reasons for that, because not least because of the placebo treatment. Now, when one submits a Paediatric Investigation Plan in the U.S. or the U.K., you have to say what ages you're going to treat, and it's assumed that you will treat from birth.
We didn't have any data to support treating from birth, we have submitted our PIP on the basis of from six months. Anna, we discussed this on, only on Monday, about how we might deal with this in the open label. There are pros and cons for going below six months. Anna can talk about the technical difficulties. I have no problem in supplying this drug for children, less than six months. There are technical difficulties, which Anna will give details of.
Yeah, great. Thanks. I mean, I want to treat it as soon as possible from birth, we've said, four weeks. Because anyway, it takes a couple of weeks, sometimes that long, to get the diagnosis anyway, we'd need to confirm with a skin biopsy and genetics. As early as possible, when you saw the first phase with the keratinocytes in the absent skin, now that area is the risk for squamous cell carcinoma. The quicker we can heal that area, the better. The sooner we can give treatment, the better, is the answer.
Thank you. Have you noticed any increased interest or acceptance for cell therapies for rare pediatric diseases now that Mesoblast seems to be gaining traction for its therapy at gene therapy price levels?
I think the answer there is, certainly speaking to regulators, there's enthusiasm. In terms of funding, that's not an area that I can really speak to, apart from the fact we know that some very expensive therapies are already approved and are being used in the U.S. For rare pediatric diseases. Only today, I was talking to NHS England, and they were proposing that we go and speak to the National Institute for Clinical Effect, for NICE and clinical evaluation, rather, as early as possible. We will open those negotiations.
With the topical agents of Vyjuvek and Filsuvez, do you see CORDStrom as competitive or something that would be used in combination?
No. These are really good questions. You should come. It's combination therapy. Anti-inflammatory therapy is the most critical of all the therapies. There'll be other therapies that will be needed. Filsuvez, it does not work. Not that particular one. Vyjuvek, you have to apply weekly. There'll be better gene therapies that can last longer, hopefully permanently. There will also always be a need for systemic anti-inflammatory therapy for the older patients where you can't genetically correct. The treatment's gonna be individualized and combination therapies for EB, but with a key role of anti-inflammatory, in my opinion.
We also have to remember that the two licensed products, three licensed products, all three of them have itch as an a declared side effect. A solution to the itch problem is something that we would like to believe we can provide even for patients who are on alternative therapies.
Do you have a timeline in mind for including junctional EB patients?
Well, I can answer that because it's us that will have to make the sales. Globally, patients either get treated with a clinical trial product, an investigational medicine, or they get treated with a licensed medicine, or they get treated compassionately. In the U.K., drugs are actually manufactured under a different license for compassionate use, and we are waiting for that license to be awarded to the manufacturing facility where we're making CORDStrom. As soon as that happens, yes, if Anna has patients with junctional disease, she can prescribe it, and we can supply it. Yes, that's high up on our priority list.
What do you think is the optimal dosing regimen duration of CORDStrom? I'm gonna add to that. You know, we saw sustained durability over from three months to six months on the single course of therapy. What do you think, you know, the multiple course of therapy over a year would look like?
Anna can talk better to this than I can, but at least I will say that her design of giving the drug once every four months, or two doses two weeks apart, and then repeating it every four months, I think is extremely sensible given the data that she's already derived from Mission EB. There's been one small study in South Korea where a similar dose of umbilical cord MSCs, albeit from a single donor rather than a pool product, did have considerable effect on significant, statistically significant improvement in skin, excuse me, performance after three doses. This was three months apart. I think there's good evidence that the design that Anna's come up with, will be the one that's successful when we go forward with. Then it will just be consistent, constant treatment, throughout many, many years. Anna, what's your thought?
First of all, the logistics of doing it more frequently is not sustainable because, remember, it's really difficult to put cannula, cannulas in, drips in these children. We went for the balance between wanting to really have a sustained improvement globally in their health, but not too many interventions. If we made it six monthly, I didn't think that we would really get on top of the systemic inflammation that much. If we did it every three months, it's too many cannulas. I
imagine that the younger children, if we start early, we could space out the interval between the infusions somewhat, I would imagine, over time. The older children and over the age of 10, I suspect that they will need it roughly four-monthly. I think the beauty is that it's safe, and so we can adapt it over time if we need to. That's really the reason why we chose the four-monthly infusions.
I think we've also got an opportunity for some data which we didn't show. None of these patients, even though they've had multiple infusions, made any immune response to the product. Although this is a completely allogeneic product, we didn't see any T-cell immunity or antibody immunity to these products. I'm confident that we can give multiple infusions.
We only have a few more minutes left, unless I get more questions. The last one I have is: You mentioned that CORDStrom is likely disease-modifying therapy. Can you elaborate on the long-term potential to reduce the risk of squamous cell carcinoma, which currently has a median survival of only two and a half years for this EB subtype?
Yeah, sure. We know that we've published 25 years of data on cancer in these patients and where the cancers are, and they're predominantly in the extremities, in areas where they've had absent skin. We know that repeated trauma and open wounds, and there an itch which keeps opening the wounds, puts these areas at risk over time, increasing risk. The longer the skin is open and the longer wounds are chronic, the higher the risk that they will turn into squamous cell cancers.
If we can heal early, the dysplasia , so they don't have chronic wounds there, and make sure that the wounds, although they'll be there, they won't be chronic, it will for certain reduce, because they know the biology of these tumors. Obviously, we'll know that over time, that there is now very good evidence that the drive is trauma and chronic wound and inflammation in these cancers.
The very last question before I give the concluding remarks is: Can children with severe RDEB, who are not based in the U.K., participate in the upcoming study?
The current plan, and this is due to funding issues more than anything else, is that the trial will run solely in the U.K. But we'll be registered with the FDA as well, so the data from the U.K. trial will be usable in the submission for the BLA. No, at the moment, we have no plans to open clinical trial sites in the U.S.
Great. Thank you, Mark. I do want to note, you know, we put these children and parents first. We're doing all we can to accelerate this product, to get it to market. We really believe in what we're doing here, and we put the patient, their families first. As we conclude today's session, the data from the Mission EB trial reinforce our belief that early intervention with CORDStrom can fundamentally change the disease trajectory for these children living with RDEB. We've seen encouraging results, including a 26% reduction in itch at six months, and significant beneficial effects in patients under the age of 10. We're now moving aggressively toward making CORDStrom the first systemic disease-modifying treatment available for the RDEB community. Our regulatory roadmap is clear.
We've already submitted our pre-submission package to the U.K. MHRA. We intend to file a full marketing authorization application by mid-summer of this year. Following this, we're targeting regulatory submissions in Europe, at the EMA and the U.S. FDA in the fourth quarter of this year. As Mark highlighted earlier, the truly exciting aspects of our platform is the tunability nature of CORDStrom. This flexibility allows us to optimize the therapy's anti-inflammatory and regenerative medicine properties, specifically for unique challenges of this disease. We hope to leverage this capability to develop more advanced versions of CORDStrom RDEB, which we believe will allow us to expand the use across broader EB spectrums in the future.
By targeting this window of opportunity in early childhood, before the onset of life-threatening complications like squamous cell carcinoma, we aim to provide these families with more than just wound care. We aim to provide a better quality of life. I want to thank Dr. Lowdell for his groundbreaking invention, and Dr. Martinez, the entire clinical team, for their dedication to these patients. We remain relentlessly committed to delivering transformative solutions for these patients suffering from these devastating effects of RDEB. Our mission is to move beyond temporary relief and provide a systemic, disease-modifying therapy that fundamentally improves the lives of these children and their families. Thank you for your continued support of INmune Bio.