Good afternoon, and welcome to the VYNE Therapeutics Virtual R&D Day. At this time, a ll attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, t his call is being recorded, and a replay will be made available on the VYNE website following the conclusion of the event. Before we begin, please note that this presentation, including all verbal remarks, contains forward-looking statements, the accuracy of which depends on future events outside the company's control and therefore might cause actual results to differ materially from those forward-looking statements.
For a discussion of risks and uncertainties and other important factors, any of which could cause VYNE's actual results to differ from those contained in the forward-looking statements, see the section titled "Risk Factors" in VYNE's Annual Report on Form 10-K for the year ended December 31st, 2022, an d quarterly report on Form 10-Q for the period ended June 30th, 2023, as well as discussions of potential risks, uncertainties, and other important factors in VYNE's subsequent filings with the U.S. Securities and Exchange Commission. I'd now like to turn the call over to Dave Domzalski, Chief Executive Officer of VYNE Therapeutics. Please go ahead, Dave.
Okay, thank you, and good afternoon. Welcome to everybody. We're very excited to be hosting this event. Joining me today, we're very pleased to have Dr. Amit Pandya, who will provide a background of vitiligo and the treatment landscape. My colleague and Chief Scientific Officer, Dr. Iain Stuart, will take you through our recent data for our BET inhibitors, VYN201 and VYN202, as well as an outline of our development plans for these programs. Also have with us our Chief Financial Officer, Tyler Zeronda, who will provide a brief financial overview for the company. We'll then have a Q&A session. We have a lot to cover here, so we'll do our best to get to as many questions as we can. So next slide, please.
So the last two-plus years have been quite a journey for VYNE, as we have transformed this company from what was a spec pharma company with 505(b)(2) assets to what is now a biotech organization focused on developing our novel BET inhibitor platform for the treatment of immunoinflammatory diseases. We've kept our heads down during this period to get to this point where we now have very meaningful data for our BET inhibitors that we are excited to share with you today. The potential for multiple clinical catalysts over the next several quarters and a strong balance sheet off the heels of a very successful financing with a syndicate of some of the best healthcare funds in the world. Next slide. So current and previous development efforts by large pharma and large biotech with earlier-generation BET inhibitors have primarily been in the oncology arena.
BET inhibitors have been around for a little bit of time. The work in the oncology arena has been in both for the treatment of solid tumors as well as myelofibrosis and other hematological cancers. But we at VYNE are doing some of the first real work with our BET inhibitor platform in the autoimmune space. If you think about our platform, our platform has two verticals. On the right-hand side, you'll see VYN202. That is our oral BD2 selective BET inhibitor. We've spent the better part of the last two years on lead optimization for VYN202 and believe at this point we now have the most potent selective BET inhibitor in development. Iain will take you through some of our preclinical data as well as our clinical plans for this product. The other part of our platform is VYN201 on your left side.
This is our... what we, we refer to as our locally administered, tissue-specific pan-BD BET inhibitor. We've done work on multiple dosage forms for this product, including in inhaled and sterile injectable dosages. But for the purposes of this call, we are going to focus on our topical formulation, which is most advanced, and the exciting results from our recently completed phase I-B clinical trial in vitiligo. So why did we choose vitiligo? It really comes down to two primary reasons. One is we have, and we'll show this to you, very compelling preclinical data that drove us to take it into the clinic. And second, when we looked at the vitiligo marketplace, and Dr. Pandya will speak more to this, it's a very sizable market opportunity, significant unmet needs. Currently, there's only one prescription drug approved for the treatment of vitiligo.
In terms of other therapies in development, most of them are JAK inhibitors. So we, as a company, believe that the market is ripe for new therapies and certainly a unique mechanism of action, and we look forward to taking you through the data. So with that, if we move to the next slide, I'm very pleased to now introduce to you Dr. Amit Pandya. Dr. Pandya is a Board-Certified Dermatologist at the Palo Alto Foundation Medical Group. He's a clinical professor in the Department of Dermatology at the University of Texas Southwestern Medical Center, and he's also the former president of the Global Vitiligo Foundation. So with that, I'll turn it over to Dr. Pandya. Thank you.
Thank you very much, Dave. It's a pleasure for me to be here to speak to you on management of vitiligo. I am just going to share my screen and get started with my presentation. I'm going to try to briefly go through vitiligo and what it's all about, and then kind of talk about the challenges in terms of treatment of vitiligo and managing this condition. These are my disclosures of relationships with industry. Just to let you know that virtually all of these have to do with vitiligo products that are being developed for vitiligo and some for hyperpigmentation. Well, vitiligo is a common condition, and it's a progressive loss of pigmentation. It affects between 0.5% and 2% of the population worldwide. We think that there's 3-4 million people in the United States with vitiligo and about 70 million people worldwide.
Al l races are affected. It's just more noticeable in darker-skinned patients, and some have learned to embrace their vitiligo. It's thought that perhaps 20%-30% have learned to simply live with it, as you see this individual here, part of our video at the Global Vitiligo Foundation. And you'll see models, and you'll see people in the media who embrace their vitiligo. However, more than 70% have said in various studies that it, that it significantly affects their quality of life, and they want treatment. They want some type of treatment for their condition. Unfortunately, the disease course is unpredictable, and we have no biomarkers. We have no ways of following these individuals to predict the future, and this is something that they live in fear of waking up the next morning with a new lesion.
And studies have shown that this unpredictability and the spread of the disease has a big effect on quality of life. The peak age of onset, unfortunately, is young individuals. 50% get vitiligo by the time they're 20, and this is when people are going from childhood to adolescence to adulthood, very important years psychologically, and it can have a devastating effect on these individuals. There is an increased risk of autoimmune disease. About 25%-30% of patients with vitiligo will have other autoimmune diseases, particularly thyroid disease, but other autoimmune diseases can be present, from rheumatoid arthritis to alopecia areata to lupus, even psoriasis, atopic dermatitis can be present. There are several types of vitiligo. The non-segmental vitiligo is the type that occurs on both sides of the body.
90, about 85% of patients have non-segmental vitiligo. It can be mucosal, it can just on a mucous membrane, such as the lips, the eyelids, the genitals. It can be acrofacial, which means on the hands, feet, and the head. It can be lip tip, which is just the lips and the fingers, which is a rare form. It can be focal, where it's just one or two or three spots. Generalized is one of the more common presentations, and this is probably what you most commonly see in the public, is people who have it in many areas of their body. Universal is where it's almost completely involving, in the body, and that is not so common, but we certainly have some patients with that.
Fifteen percent of patients have segmental vitiligo, which is a little bit different because it only affects one half of the body, having to do with the embryonic planes as the skin is forming. Mixed vitiligo is where you have segmental plus non-segmental later on, and that's a more rare form of vitiligo. Here's an example of non-segmental vitiligo, where you see the lesions are on both sides and the patient has lost the color. You can see the normal skin on the bottom. This patient has an aggressive form of the disease that you can tell with this light brown area, telling us that it is advancing rapidly towards her neck. Here's generalized vitiligo, where the patient has it on both sides, but also has these small pinpoint lesions, which tell us that this is active vitiligo.
This is a patient who is getting lesions very quickly, and it's spreading quickly. And universal vitiligo, where it's all over the body and spreads fairly rapidly. Now, what causes vitiligo? Here you see a lesion of vitiligo here, but you see these small dots in what we call confetti-like depigmentation. This is a brand-new spot of vitiligo, and if we biopsy that, what we see are two things. Number one, we see T cells that are attacking the melanocytes, which are the cells that give us color, and the T cells are attacking the melanocytes right here. Here we see lack of melanocytes in the skin. There are no melanocytes here. This would be the little white circle that I showed you earlier. These are normal melanocytes here.
Now, the vast majority of treatments that we have nowadays, steroids, JAK inhibitors, tacrolimus, they work on this side of the screen. Very few things work on this side of the screen, which is stimulating the melanocytes to repopulate the skin. Phototherapy, there's a new product, afamelanotide, and perhaps even the BET inhibitor will be successful in repopulating the skin in this area. Everything else is really focused on removing the T cells, which we also have that evidence with the BET inhibitor in terms of getting rid of these T cells. So these two aspects need to be addressed when it comes to treatment of vitiligo. So in autoimmunity, interferon gamma is really the key in which vitiligo starts with the innate immune system.
Interferon gamma binds with the interferon gamma receptor, and through the JAK-STAT pathway, a chemokine called CXCL10 is produced. This binds with a receptor on these autoreactive T cells called CXCR3, and then that T cell goes to the melanocyte, secretes enzymes, and kills it. This is the pathogenesis of vitiligo. Again, anything that will reduce interferon gamma can improve vitiligo, and anything that blocks the JAK-STAT pathway can also improve vitiligo. Now, prognosis is really depending on several factors: younger patients, darker skin types, people with short duration of vitiligo, stable disease. In other words, it's not worsening in the last year. Face, ears, neck, axilla, hair-bearing areas with pigmented hairs, all of those do well, such as this young patient who's only had vitiligo for a couple of months, darker skin, has black hairs within that area.
This patient's gonna do well. On the other hand, we have m any, many patients that have a poor prognosis: older patients, lighter skin types, long duration of vitiligo, and rapidly spreading vitiligo, like those patients I just showed you earlier that have signs of activity... scalp, lips, elbows, wrists, hands, fingers, genitals, knees, shins, ankles, feet, toes, all of them have a poorer prognosis and are more difficult to treat. We need more agents for these areas. And then areas with white hairs, as you see on the right, this patient has a very poor prognosis because all the hairs are white, so there is no source of melanocytes from which we can repopulate the skin with color. We use dermoscopy to look at these hairs to see if they're white or black. Here's a forehead where these tiny hairs you can see are all black.
I know this patient has a better prognosis. If they're white, that's associated with the poorer prognosis. Here you see the markers of rapidly spreading vitiligo. Here you have trichrome vitiligo, where you have normal color, white skin, and in between, which is light brown skin. The melanocytes are completely gone here. It's just, it's happened so fast that the color still hasn't been shed from the epidermis. Another one called Koebner phenomenon, where you see a scratch leads to vitiligo. Then this one, confetti-like depigmentation, where you see these small confetti-like dots. 16 weeks later, without treatment, she is much worse, and unfortunately, at 31 weeks, she is much worse. This confetti-like depigmentation we described in 2015 as a very strong sign of active vitiligo.
These active patients, first, we have to overcome the activity of the disease, then and only then, will we be seeing repigmentation of the skin. To approach the management, one of the most important things is we have to listen to the patient's concerns and goals and really make our decisions based on shared decision-making. You'd be surprised that how some patients, even a small amount of vitiligo, is devastating, and they want to treat it, whereas others, large amounts of vitiligo in covered areas don't really bother them. They just want, for example, the face treated. We want to obtain our history of onset, triggers, progression, past treatments, review the effect of vitiligo on their quality of life. We examine the patient carefully using a Woods lamp to see better light-skinned patients.
We can see with the black light, we can see the lesions better. We determine the area of involvement, document the signs of activity, we provide prognosis and review treatment options, and we base it, again, on shared decision making. One of the most important things to remember for vitiligo treatment is that it's a long duration of therapy. You're looking at 6 months to get about 50% improvement at the most, but then you're looking at one year to two years to get maximum improvement. We have to set these expectations and tell the patient that you really know, I must have patience with me. And patients really want 80%-100% repigmentation is what they think is clinically meaningful repigmentation. Few patients achieve 100% repigmentation, and visible locations like the face and the hands are of most concern to patients.
I think pictures are super important, and this is one of the reasons why a lot of dermatologists and patients become pessimistic with the treatment because they cannot tell if there's 10% or 25% improvement, because they don't have pictures to compare from baseline to the time of the visit. So the three pillars of therapy is to reduce triggers by antioxidants, avoiding trauma, and reducing stress. We want to reduce that immune attack of skin, those T cells I showed you attacking the skin with... You can use corticosteroids, tacrolimus, pimecrolimus, and JAK inhibitors. And then we want to increase melanocytes and melanin production, and we do that with phototherapy, afamelanotide, which is a melanocyte-stimulating hormone analog, which is currently under investigation, skin grafting, and cellular grafting.
After about 3 or 4 months, phototherapy itself can reduce the immune attack of the skin. When you combine this, you can get effective treatment of vitiligo. However, it's very time-consuming, burdensome, and takes a long time. So the treatment options that we have for vitiligo is we have patients use camouflage, makeup, or a sunless tanning cream called dihydroxyacetone. I mentioned antioxidants, topicals, phototherapy, systemic steroids, systemic JAK inhibitors, the grafting, and depigmentation in some patients. So this is phototherapy. Phototherapy is difficult to do. Only about 10% of dermatologists in America even have a phototherapy booth to treat the whole body, and patients have to come in two or three times a week. I prefer three times a week, actually, for my patients.
But if you do it and you combine it with topical therapy and sometimes steroids, you can get about 25% improvement in 3 months, 50% improvement in 6 months, and 75% improvement in 9 months, after which it plateaus. So you can see it takes a long time, and this 75% is a mean improvement. They'll do better on the face, but not as well on the hands, feet, elbows, and knees. The mean improvement is 75%. So given this, standard treatment, now there have been JAK inhibitors that are being studied for vitiligo, and it makes sense, right? If you block JAK, you will reduce CXCL10, you will then not attract those CD8+ T cells to the skin, they'll disperse, and then you can stop the attack on the skin. Now, you likely know what JAK inhibitors do.
They're small molecules that are developed to treat immune-mediated diseases. JAK or Janus kinases are tyrosine kinases that are associated with cytokine receptors on cell surfaces as heterodimers. So you'll have one JAK here and another JAK here. So like JAK1, JAK3, for example. And when this cytokine binds with the receptor, then what happens is the JAK will cross-phosphorylate, and then through the STAT pathway, it'll translocate to the nucleus and affect transcription, and this is how it can work for a variety of immune-mediated diseases. And depending on which JAK is chosen to suppress, you can actually treat different diseases. Now, there are many adverse effects with oral JAK inhibitors, of course.
There's a small risk of increased cholesterol and cytopenias, but there is a higher risk of opportunistic infections, tuberculosis, herpes zoster, mostly in patients on concomitant immunosuppressants. And as you likely know, the current JAK inhibitors are used to treat diseases, serious diseases like myelofibrosis, rheumatoid arthritis, and these patients are often on other immunosuppressants and have a lot of other morbidities. But an oral surveillance study of tofacitinib versus TNF-alpha inhibitors for rheumatoid arthritis followed patients over 50 years of age with at least one cardiovascular risk factor, and there was a small but significantly higher rate of MI, stroke, thrombotic events, lymphoma, lung cancer, and death in the tofacitinib group.
Therefore, a black box warning was required by the FDA in September 2021, and now we see it for all JAK inhibitors, tofacitinib, upadacitinib, baricitinib, and we think probably for future ones that are approved. Currently, a lot of JAK inhibitors have been studied or are being studied. You can see the case series and case reports with oral and topical tofa, phase II studies that didn't pan out that you see there. Phase III studies, actually, that have started this year or will start this year with oral ritlecitinib, povorcitinib, upadacitinib, and then the only FDA-approved one, which is a topical ruxolitinib cream. So these are my treatment algorithms for vitiligo at the current... This is its current state. We, for localized vitiligo, topicals, antioxidants, phototherapy, skin transplant in some selected patients. Generalized vitiligo, again, topicals, antioxidants, phototherapy.
In this group, we can use systemic corticosteroids, and in very selected cases, we can use transplantation. But there are a lot of unmet needs. That we need more primary care physicians that are familiar with the diagnosis of vitiligo to prevent these delays in diagnosis. We need dermatologists that are knowledgeable about the treatment so that we can overcome this pessimism, and I think a lot of it has to do with the fact that dermatologists don't, just don't, haven't seen patients successfully repigment because of lack of photographs, lack of monitoring them carefully, and really treating them for 6, 12, 18 months. Better patient compliance, and we need less burdensome treatment. For example, once a day rather than twice a day application, I think, is really important.
Better treatment of areas with poor response, such as the hands, feet, elbows, knees, and a shorter duration of therapy. Rather than 6-12 months, why not have a treatment that works in 3-6 months? Topical and systemic agents that have a faster onset of action rather than, again, waiting for 3 months just to see a 25% improvement. Drugs that affect both aspects of vitiligo pathogenesis, the two pillars of treatment, remove the bad T cells that are actually attacking the skin and stimulate the good melanocytes to then repopulate the skin. A durable response so that when you stop treatment, it doesn't come back and you have a recurrence, so that we can have a lower recurrence rate, and we need more studies in children and with combination therapy.
That's kind of a whirlwind on this treatment of vitiligo and management. I just want to remind you, the Global Vitiligo Foundation, the vitiligo community is out there, and all patients really should be connected with us. We have an entire group of this community that are here to support people with vitiligo, and I will stop right there and thank you for your attention.
Thanks, Dr. Pandya. Before we turn it over to Iain to walk through the data, I just wanted to briefly, you know, set the stage on the vitiligo opportunity. You can move to the next slide. Thanks, Iain. As Dr. Pandya described from an epidemiological perspective, 0.5%-2% of adults have vitiligo. That translates to somewhere between 3-4 million individuals in the U.S., of which, as you can see on the slide, 1.9 million are diagnosed. But there's this large gap between those that are diagnosed and those that are actually seeking treatment, with only 10% or so actively seeking. And so that gap is, as Dr.
Pandya alluded to in his remarks is largely driven by the lack of approved and effective treatment options, and the burden to the patients that these treatment options have presented historically. So as we think about the market, with only one drug approved, Opzelura, and annual net sales of $10,000 per patient per year, this market is robust as it stands today, with the current number of patients seeking treatment, particularly for a differentiated therapy, which we believe VYN201 has the potential to be. You know, that being said, with so few patients actively seeking treatment, that patient activation portion certainly represents a large long-term growth opportunity for the category. You can see this illustrated on the right-hand side of the slide.
So on an annualized basis, the vitiligo indication for Opzelura has generated net sales of over $100 million within the first year of launch, as they penetrate that 200,000-patient number or so. You can see on the right, some of the longer-term analyst estimates, ranging from $500 million to $750 million, on what we would view as fairly conservative growth in those patients now coming back into the offices and seeking treatment. And so, you know, with this dynamic in play, both from that market penetration of the current patients that are coming into offices, as well as that longer-term category growth, perspective-...
We're very encouraged by the opportunity for new entries in the category. So with that as a backdrop, Iain, I'll turn it over to you to take us through the data.
Thanks, Tyler. Good afternoon, everyone. Let's move on to the next slide here. So let's start initially with our mode of action for BET inhibition and our impact it has on autoimmune diseases. We see obviously as a significantly differentiated treatment strategy. As Dr. Pandya presented in his opening remarks, the vast majority of drugs either in development or obviously approved are JAK inhibitors. So starting with BET inhibition. So what BET proteins are epigenetic regulators of transcription. They work primarily in the nucleus of a B or a T cell, and essentially as an epigenetic enabler, BET proteins recognize or read acetylated lysines that protrude out of the structure of chromatin and pick up signals that begin the process of transcription and ultimately translation of a protein.
This is very different from the JAK-STAT pathway, which everyone's familiar with. Dr. Pandya already talked about the JAK. The receptor itself begins phosphorylation and translocation of STAT itself into the nucleus to begin that as a core promoter for transcription. But what I would also say is the JAK-STAT pathway is also reliant on BET protein activity. To begin this process of remodeling chromatin, to allow RNA polymerase to come in and begin to code for the corresponding transcript, is ultimately then translated and becomes a fully formed protein. By inhibiting the BET protein, you essentially prevent this chromatin remodeling from occurring. You have transcriptional failure, and obviously, you do not get the corresponding translated protein, in this case, obviously a cytokine. So what I'd like to do is move to preclinical data specifically relevant to vitiligo.
As Professor Pandya has already talked about, CD8+ T-cells or tissue-resident T-cells are primed towards attacking, melanocytes and specifically causing detachment and loss of melanocytes, and ultimately, obviously, color and pigment, during a significant T-cell expansion. So what you're seeing here is the effect of VYN201 compared to ruxolitinib and actually preventing this expansion from in vitro tests, and we actually have a very significant, inhibitory effect on preventing CD8+ T-cells from expanding in these assays and actually slightly better or markedly better relative to ruxolitinib, the corresponding JAK1/2 inhibitor. Dr. Pandya also talked about interferon gamma T-cells.
CD8+ T-cells are sensitive to upregulated levels of interferon gamma that do drive the pathogenesis of disease, and similarly to what we see in respect to reducing CD8+ T-cell expansion, we also have quite a marked inhibitory effect on the expression of interferon gamma as well. So what you're seeing on the right-hand side is CD8+ T-cell viability. So the data here, the mechanism is not being driven by a direct cytotoxic effect. VYN201 is not killing CD8+ T-cells, very similarly to ruxolitinib, but has a more potent and more marked effect on preventing the expansion and preventing the expression of interferon gamma that drives the pathogenesis of disease.
Clearly, if, VYN 201 caused significant cytotoxic effect in the skin, that'd obviously give us some more concern in relation to long-term safety issues, for what is essentially a chronic disease. This is a model of a reconstituted human epithelium with cells. This is an in vitro test that we do to evaluate the topically applied VYN201 compared to ruxolitinib. So what, in this model, we actually take both skin of color and Caucasian skin cells, and we can actually reform an epidermis essentially in a Petri dish, and we can induce a phenomenon called melanocytolysis. Melanocytolysis is essentially the loss of pigment. We expose these cultures to both TNF-α and again, interferon gamma, and we can actually see the loss of melanin in real time.
What is being driven here, primarily, the loss of this is an upregulation of a matrix metalloproteinase called MMP-9. So MMP-9 has been implicated in causing and driving the detachment of melanocytes from the basal layer of the epidermis and through a mechanical shear, the loss of melanocytes through the skin, as Dr. Pandya talked about earlier. So patients who have certainly active vitiligo and in these stable disease, have a very much higher serum level of MMP-9. And the mechanism which MMP-9 works is it destabilizes a matrix adhesion molecule called E-cadherin. So E-cadherin binds melanocytes to keratinocytes, and the disturbance of this binding by MMP-9 causes the detachment of melanocytes and the loss of pigment. And on the right-hand side here, obviously, we can measure that specific loss of pigment.
So we are seeing here is MMP-9 secretion on the Y-axis, and we can apply, as I say, topical VYN201. We looked at 4 concentrations here. We actually compared it to ruxolitinib, RUX 1.5% here. You see a very nice dose response, where we prevent the continued secretion of MMP-9, despite the fact they've been stimulated with interferon gamma and TNF-α . Correspondingly, we see a reduction of what's called solubilized E-cadherin. So what happens through the action of MMP-9 as E-cadherin is converted into a soluble form, and as I said, subsequently absorbed into the body. This is something we're trying to prevent, and we want to keep E-cadherin in matrix. We do not want a soluble form, and again, you can see a nice dose-dependent reduction on the soluble form.
What that essentially means in relation to melanin content is on the right-hand side. Again, a very nice dose-dependent protection and the loss of melanin, again, over the concentration range that we observed in this study. This is what essentially looks like in pathology slides. So what you're looking at here is a vehicle-treated specimen that's also been stimulated with TNF-α interferon gamma. The green, the green areas here is called a TYR stain. So these are cells that produce melanin. TYR or tyrosinase is a key protein that is involved in melanogenesis or the production of melanin. So it's a very good way of marking where melanocytes are in a specimen. So the green dots here are melanin-containing cells. The blue dots are keratinocytes.
So in a normal situation, these, these, melanocytes should be bound very closely to the basal layer of the epidermis. You can see here, by stimulating with a cytokine cocktail, they're being detached and started to move up through the skin specimen and ultimately through mechanical shear, people scratching skin, et cetera, they are lost. What you're seeing here is exactly the same specimen, only this time pretreated with VYN201 at 1%, and the melanocytes are still very firmly bound to the epidermis. So it prevented this detachment despite the fact that the significant agonism from interferon gamma and TNF-α . We also looked at transcriptomic analysis of these specimens, looking at approximately 90 genes that are associated with melanogenesis, production of melanin, or melanocyte differentiation or the production of new melanocytes.
So what you're seeing here is, again, another stimulated specimen, but pretreated with VYN201. You see a significant downregulation of key type one cytokines that are involved, also involved in the pathogenesis of disease. TNF-α and interferon gamma are below the lower limit detection here, so we've managed to completely suppress the expression of these. But what we also found was an upregulation of a member of the WNT pathway. So the WNT pathway is, or the Wnt/β-catenin pathway, is significantly dysregulated in patients with vitiligo, and is a key pathway that drives both pathogenesis and melanocyte recovery. There is no JAK-STAT pathway is not involved in the agonism or the recovery of the WNT pathway.
So it's intriguing to suggest that not only does VYN201 downregulate some key cytokines that drive the pathogenesis of the disease, it could potentially upregulate a pathway that could potentially be beneficial to allow melanocytes to recover quicker and to produce more melanocytes, relative to the JAK-STAT pathway. RAB23 up here is involved in melanin exocytosis, which is the transfer of melanin to keratinocyte from melanocytes to keratinocytes, and again, is indicative of a more healthier function for melanocytes. So moving to the clinical phase I study. I will start here. We conducted a phase I-A study in healthy volunteers at the end of last year. Just to preface that, there was no safety concerns. We looked at five doses for up to two weeks of therapy.
There was no safety concerns, so we moved expeditiously into a phase I-B study, looking at active patients with vitiligo patients. This was for full face treatment for the face and a target lesion on the trunk. Again, with patients with active disease for once daily, up to 16 weeks. The trial enrolled up to 30 patients across three cohorts. These are the three concentrations that we evaluated for topically applied VYN201. Being a phase I-B study, safety is obviously the paramount objective. Obviously, exposure levels, VYN201, is designed as a soft drug, so it's designed to specifically metabolize rapidly or any drug that passes through the skin into the broader circulation in order to markedly shift the benefit-risk of BET inhibitors or pan-BD BET inhibitors.
Also, local skin tolerance is a key component with any topically applied medication. We're always cautious if patients are complaining of burning and stinging and itching, et cetera. We did exploratory efficacy as well, primarily around F-VASI. That's the Facial Vitiligo Area Scoring Index, biomarker we will not present today, and of course, photography. Key inclusion criteria, Professor Pandya has already laid out here. These patients had to have a clinical diagnosis of both non-segmental vitiligo but also have qualitative signs of activity on the face and on the body. Hyperchromic areas, confetti-like depigmentation, perilesional inflammation, and the Koebner phenomenon. They had to have an F-VASI score of at least 0.5. This is standard for studies of this type. Two contralateral lesions on the body, one is treated, one is not, primarily for biomarker purposes.
We control for leukotrichia or white hairs, that Doctor Pandya had already referred to earlier. They're difficult to treat. Safety, tolerability, and PK, obviously, the primary objective, but because we're treating patients with active disease, so have a very aggressive inflammatory component to their disease, we wanted to see, because we're only treating for 16 weeks, these studies tend to run for at least six months to many years, as Professor Pandya talked about, could we at least halt that continued progression of depigmentation? And then could we at least see some evidence of repigmentation over the course of the four months? Because we're looking at three doses, could we at least tease out some form of evidence of a dose response?
There's only one other study that we're aware of with Litfulo, which is Pfizer's oral JAK inhibitor, that enrolled exclusively active patients. It's currently in phase III. The other JAK inhibitors, whether it be approved Opzelura or povorcitinib, now moving into phase III or RINVOQ, included active and stable disease patients. Stable disease patients are expected to respond deeper and more significantly larger relative to the active patients, as Dr. Pandya talked about. Here's an example, again, of confetti-like depigmentation. Baseline characteristics of the trial, the age was roughly the early fifties, which is very similar to other studies of this type. Fitzpatrick's primarily came from patients with II, III, and IV. The vast majority of the patients, again, similar to other studies.
The F-VASI mean score was around one across all of the arms, again, similarly, but very different from the other studies, other than the Litfulo, as we included exclusively active patients. Here's the data. On the Y-axis is our change from baseline and the F-VASI score, and time across the X-axis. So the orange line at the top here is our lowest dose, 0.5%, and the mean reduction is approximately 78%. Remember, one of our key objectives here was to ensure that patients didn't get worse. So even with our lowest dose, you can obviously see some benefit on response here with respect to improvement in the F-VASI score.
But it wasn't until we really get to the 1%, you see a 30% improvement relative to baseline scores, and you see a significant and rapid onset of action, despite the fact that we're treating patients with progressive active disease. Once we get to the 2%, again, we see an additional, additional amount of efficacy here, accumulating around 39% improvement relative to baseline. This is a post-hoc analysis of a comparing of the data from our two higher doses relative to our lowest dose, and despite the fact that each cohort only had approximately 10 patients, we already had a statistically significant improvement relative to the low dose. On the right-hand side, we're looking at the categorical endpoints of F-VASI 25, or a 25% improvement relative to baseline 50 and 75%.
0.5% cohort, we had two patients around F-VASI 25%, so 25. But again, looking at our 1%, this is where we've had approximately a third of patients who had at least a 50% improvement relative to baseline, and again, looking at our 2%, similar numbers, but we actually had our very first F-VASI 75%, and one patient just slightly behind. So again, these are patients on active disease or have active disease, progressive disease, being treated for only 16 weeks, and yet already seeing meaningful responses to VYN201. This is the same data that I've shown earlier. This is a corresponding phase II-B data on the right-hand side, where the JAK inhibitors either developed or approved. Litfulo's data is here. You can see it tracks very similarly.
Again, this is the only other trial that included exclusively active patients, about 18%-19%. This group down here, obviously, this is systemic JAK, povorcitinib and RINVOQ. On top, Opzelura, had approximately 35%-38% improvement, but that's at 6 months. We get a similar number at 16 weeks, including exclusively active patients. All of these trials here had stable and active patients. So how do we compare conceptually across the JAK class? I think obviously we have a novel mode of action. We are a JAK class alternative. That is clear. These are all JAKs and different, specificities. But within the topical, space, we are a once daily therapy. As Dr. Pandya referred to, when you're dealing with chronic diseases, making it as easy as possible for patients to comply to therapy is critical.
So once daily is always more preferred relative to twice daily. I've already shown the rapid onset of action of just focusing on our F-VASI 50 rates at week 12. A third of patients, very similar to Opzelura, just a little bit further back, 20%-30%. VASI, but again, with active and stable disease patients, this is the only other trial with active patients, significantly further behind, and povorcitinib has a very similar response rate relative to Opzelura. I've already talked the potential of VYN201 to upregulate the WNT pathway, but as it has already been demonstrated that the JAK-STAT pathway and the WNT pathway are very important intracellular signaling pathways, but there's no crosstalk between them.
So a JAK inhibitor doesn't beneficially or negatively impact the WNT pathway, despite the fact that in patients with vitiligo, this is one of the key targets, and actually is a focus area for some preclinical projects that are occurring in Europe just now. Safety precautions. I think everyone's very familiar with the black box precautionary language for JAK inhibitors, whether it be topical or systemic. Povorcitinib is still in development, but as a JAK1 systemic agent, likely to be black box. I already talked about our VYN201 is a soft drug, and we expect it to have very low systemic exposure in order to minimize exposure any potential safety concerns from excessive exposure to the pan-BD BET inhibitor. So the data from Opzelura's label, the exposure is relatively high for topically applied medication. Moving to pictures, we'll show some examples from trial.
This patient was on our lowest cohort. She has a Fitzpatrick Skin Type V . She's an example of a very high F-VASI, almost a vitiligo universalis or natural skin color. You can see around her nose and on her cheek here, almost completely depigmented. And after 16 weeks of therapy, you can start to see islands of repigmentation above her brow, across her nose, tops of her lip, and either cheeks. Already, despite only treating for 16 weeks with significant disease, she's already starting to see some significant repigmentation. There's another patient who was on our top dose, 2%. She was a Fitzpatrick Skin Type II . Primarily, most of her depigmentation was on the midline up to the hairline, around the eyes, and around the mouth here as well. All this in the area at the top here is fresh repigmentation.
By week 16, we obviously see areas on her cheeks beginning to be repigmented, much larger islands of repigmentation around the mouth as well. So already, after 16 weeks, you're seeing significant response to therapy. These are examples of different forms of active vitiligo that we've talked about in the past. This is the confetti-like depigmentation. This gentleman is Fitzpatrick Skin Type VI , obviously darker skin. You can see there's white dots around here. So left untreated, this whole area would likely be completely depigmented within a few weeks to a few months. Not only have we prevented that from occurring, you can actually see the smaller areas have started to repigment, and the lesion on his nose is completely repigmented. These smaller areas of confetti-like depigmentation have disappeared. Inflamed vitiligo is another presentation.
You can see it looks quite red up on the hairline of this patient. Here we've actually, VYN201 has calmed down that significant inflammation, and already you're starting to see some significant repigmentation around here relative to what we see on the baseline case. Moving to safety. No serious adverse events were reported in the study. No treatment-related discontinuations. The most of the adverse events were mild in nature. There's certainly no signal that we're starting to see, despite the fact the study is a relatively small study, that give us any cause for concern. No dose or exposure-dependent increases in AEs, and I'll come back to labs in a second. As I talked about at the top of the call, we looked at local skin responses. We look at these six domains every visit.
Obviously, it's a patient report for burning, stinging, and itching or pruritus. The rest are assessed by the physician, and they're scored on four areas from basically zero, which is none, no local skin response or reaction, all the way up to severe. And you can see this is actually average data across the whole trial. But essentially, the average scores are somewhere between none and very mild. So the cutaneous tolerability of VYN201 for once daily treatment up to 16 weeks is certainly very supportive for its continued development. Moving to exposure. This is plasma concentrations of VYN201 on the y-axis. This is cohort 1 or 0.5%, 1%, and 2%. You can see we have very low systemic exposure.
This is the lower limit of the LLOQ for the assay here. It was 0.25 nanograms per mL. So again, the design thesis on maintaining low systemic exposure appears to be being played out with our clinical data. The red line up here is called the free C50 against the BD1 BRD4 binding domain. The two bromodomains are BD1 and BD2. The BD1 has been implicated as being responsible for more challenging dose-limiting toxicities from the early-generation BET inhibitors, primarily systemically administered. So clearly, if we started to see PK levels or exposure levels moving up to this line, we may start to see some more challenging dose-limiting toxicities. But the difference between these two lines is 724.
So there's plenty of space between these two areas. One of those adverse events of special interest is thrombocytopenia. Obviously, significantly blunted some of the early-generation BET inhibitors development and kept them essentially locked into oncology applications and really didn't have any applicability outside of this. So what you're seeing here is platelet counts. Across all the cohorts, we haven't seen any evidence of any low or lowering impact on platelets, which actually ticks and ties nicely with the very low systemic exposure we see for VYN201. So key takeaways from our trial is, clearly we see a very significant clinical dose response, very rapid onset of action.
We're always cautious of drawing, you know, definitive statements here, but the efficacy in patients with exclusively active disease suggests this may be a category leader as we start to expand beyond active disease into stable disease, who are expected to respond quicker and deeper. Clearly favorable results, again, looking at cross-trial comparison data. The safety profile appears good so far. Good, good tolerability in the skin, very low systemic exposure. And what's particularly exciting is that this is the first time that a BET inhibitor has been shown to give a clinical response in an autoimmune disease. So we're looking forward to move that to the next level of development. Speaking of which, this is an outline of the phase II-B study design we plan to take forward into the first half of next year.
There'll be a randomized, double-blind, vehicle-controlled phase II dose- phase II-B dose finder with an active extension phase. Again, looking at the efficacy, safety, and PK of VYN201 in non-segmental vitiligo. Trial size will be somewhere between 150 to 200 patients with a non-segmental vitiligo. We are looking at whether or not we can take three doses, sorry, two doses in placebo or three doses in placebo into the study. We will include active and stable disease. We anticipate the majority of patients will have stable disease if it corresponds similarly to Opzelura, Opzelura's phase III study. Again, roughly 50 patients per arm. Looking at, again, vehicle, low, mid, and high. There'll be a double blind portion of up to six weeks therapy and with an extension up to 52 weeks therapy. This is traditional for studies of this type.
The primary endpoint will be the proportion of subjects achieving F-VASI 50 at week 24. We're just following a similar endpoint here that Opzelura have followed for their phase II. However, we will be looking at F-VASI 25 and, of course, F-VASI 75 at both week 24 and 52. We'll be lo oking at the total VASI, F-VASI change of 50% at week 52, and of course, percent change from baseline of the F-VASI at both of these time points. Key safety assessments are very similar to what we evaluate in the phase I-B.
Iain, just before you head, move to the next slide, I think for the audience that may be listening in and not actually viewing the slides. Just for clarification, the phase II-B study, the randomized double-blind, of course, it actually be 6 months with an additional extension up to 52 weeks.
Okay.
Thanks.
Moving gears now to our VYN202, which is our BD2 selective BET inhibitor. Just moving over to this panel that Dave referred to at the top of the call. So we believe this to be a class-leading BD2 versus BD1 selective BET inhibitor. What we have found, not just us, but others have looked at the role of BD2 activity in relation to managing adaptive gene regulation, which is obviously hyperactivated in autoimmune and autoinflammatory disorders. Seems to be more relevant relative to the role of BD1 binding domain. BD1 binding domains appears to be more relevant in relation to managing homeostatic gene regulation and as managing regular cell processing, whereas BD2 seems to be more relevant with respect to managing, as I say, adaptive gene regulation.
Moving over to the table of BET inhibitors in development. Some are older generation up to the more modern times. What you're seeing here as potency against the BD2 binding domain and selectivity of BD2 versus the BD1 binding domain. Focusing on this column over here, some of the earlier generation BET inhibitors weren't specifically selected. We call them as pan-BD BET inhibitors, very similar to VYN201. As we go up the table, you can see the selectivity gets more and more improved. Nuvation just now are probably claiming the most potent and selective BET inhibitor in development just now. What I can say is that we are certainly more potent against BD2 binding domain, but we are markedly more selective relative to BD2 versus BD1 binding domain.
As Dave talked about at the start of the call, we spent two years really focusing on maximizing this selectivity in order to markedly shift the benefit of risk of inhibition and move it out of oncology into a broader applicability into other specialties, such as autoimmune and autoinflammatory disorders. We've already announced last week that we'll be taking VYN202 phase I-B studies in rheumatoid arthritis and psoriasis. We're all familiar with different strategies and different therapies that control the dysregulation of Th17 signaling, primarily starting at the point of differentiation between naive T-cells and the conversion into active and hyperactive Th17 cells. There's certainly several cytokines and targets here that are being targeted primarily around IL-12 and IL-23, such as ustekinumab, one of the older generations that really do...
That these monoclonals prevent this conversion and upregulation expansion of Th17 T-cells. Moving down specifically into cytokines themselves, obviously the first really targeted IL-17 was secukinumab, the monoclonal. We have others in recent terms, such as guselkumab, and in more modern deucravacitinib, these are small molecule inhibitors of IL-17. We have an older generation of TNF-alpha inhibitors, such as Humira. Moving down into the receptor itself, I actually worked on brodalumab, binding specifically to the receptor. Then as we move into the cell, probably the predominant mechanism is the JAK-STAT or the TYK2-STAT pathway. Plenty of drugs, obviously, in development and approved for these. And of course, deucravacitinib was the first TYK2 allosteric TYK2 inhibitor approved for psoriasis. So as I said earlier in the call, we don't work on the receptors themselves.
We work specifically in the nucleus to prevent this continued propagation of inflammatory signaling by preventing this activation and transcript forming and translation of corresponding cytokines. Really, what we want to do is really prevent and stall that transcript, depending on what signaling pathway is coming down. Most of it is driven through NF-κB signaling trans duction. The JAK-STAT pathway or STAT is translocated into here, but they all culminated here, and this is where we want to prevent this continued dysregulated transcriptional processing of inflammatory cytokines. So what does this convert to primarily into the biology on Th17-stimulated PBMCs? This is human data. Specifically looking at IL-17α, the IC50 of VYN202 against IL-17α is in the picomolar range, so very similar to monoclonal biologics.
Giving you an example here of Dice's data, it's a little bit further behind. So it's an exquisite anti-inflammatory inhibitory effect on the continuous secretion of IL-17 alpha in stimulated human PBMCs. Similarly, in autoimmune diseases, IL-22 is pathogenic, is upregulated in these disease states. We have a very similar response rate there, but one key question could be: How selective are BET inhibitors in relation to targeting these specific cytokines we know drive the pathogenesis of disease, but how do we prevent a broader immunosuppressive effect that clearly would have concerns through acute and chronic therapy in the clinic? So we use CXCL10 as a chemokine, a chemoattractant agent, that is a key component of the host defense mechanism. Obviously very important in protecting ourselves from viruses and bacterium.
VYN202 is not actually very potent against CXCL10, so specificity can be built in, in the inhibition process mechanism to really target the cytokines that we know drive the pathogenesis of disease and have minimal effect on other parts of the immune system that we know we rely on in order to protect ourselves from environmental insult. Moving to preclinical safety, this is from dog toxicology studies with VYN202. This is really where we focus most of our time to show the differential benefits of BD2 selectivity from a safety perspective as well as an efficacy perspective. What you're seeing here on the left-hand side is in a 14-day range-finding study, looking at supra pharmacological doses of VYN202. We get a very nice linear exposure into the window here. So this is our primary target, which is EC50 of BD2, BRD4.
As I already talked about, if we get very high levels, having an impact on BD1, we could potentially see some of these more challenging safety issues, so we can dose very nicely into the window. Single dose a day. The drug has a relatively long half-life, so we don't anticipate any need for multiple doses per day. But interestingly, despite the fact that we're dosing at supra pharmacological doses, we do not have any impact on platelet counts. So this is our vehicle group or zero group here. Looking across at the end of the first fourteen days of dosing, that we don't see any impact on platelet counts, and the dog is a very good predictive species for platelet count reductions for BET inhibition.
Another adverse event of special interest from the early generation of BET inhibitors is GI stem cell toxicities, primarily manifesting itself as significant gastrointestinal adverse events. Again, want to continue development. What you're seeing here is preclinical data from AbbVie with their pan-BD BET inhibitor that binds to both BD-1 and BD-2. You actually see a significant atrophy of the gastrointestinal villi. This is this area here, and goblet cells are our primary cells in our gastrointestinal tract that generate mucus, these small pink dots here. Significant depletion here, so a direct cytotoxic effect on goblet cells. What you're seeing here is the equivalent information from our toxicology study. This is a vehicle group here. The gastrointestinal villus have very normal morphology, and you can actually see the stain in these small goblet cells.
Despite dosing at very high levels of 10 mg per kg, we don't see any impact on the goblet cells. So a very different gastrointestinal tolerability profile relative to a pan-BD inhibitor. Moving to efficacy, primarily, let's start with psoriasis. So this is a psoriasis model in the mouse where we induce a psoriform-like plaque on the backs of mice. We expose them to a drug called imiquimod or Aldara. For 7 days, we induce a psoriform-like presentation, and then we treat them for a further 7 days, and we compare it with various competitors here. What you're seeing here on the gray line at the top here is our placebo group. So these animals are continually exposed to imiquimod. The y-axis here is the PASI score, so it's directly similar to the clinical PASI score.
These animals are continuing to get worse as expected. They're still being exposed to imiquimod. In this study, we actually compared VYN202 to deucravacitinib, the allosteric TYK2 inhibitor, and you can see here that the response relative between the treatment phases, that VYN202 does equally as well as improving the signs and symptoms of psoriasis as deucravacitinib, which was approved for psoriasis in the fall of last year. So it's culminating after about seven days of dosing of at least a PASI 90, despite also treating at exactly the same doses at 3 mg per kg. Moving it towards the end of the study, we looked at 1, 3, and 10 mg per kg doses of VYN202 when we had a very steep dose response. At the 1 mg per kg, we almost reach a PASI 90.
It's actually about a PASI 95, and very similar, we see that between 3, 10, and 30 mg per kg deucravacitinib. Relevant biomarkers in models such as IL-17, IL-23, and IL-22. See almost complete block across the three dose levels of the expression of IL-17 relative to control. A very similar number for IL-22 and IL-23, we know drives the Th17 differentiation, almost complete block here. Nice down-regulation on downstream IL-6, obviously TNF-α and interferon, and IL-1 beta. This is what it looks like on the animals from pictures, right at, just at the point before we start treatment. So this is when we've induced the disease state. So placebo group, this is 3 mg per kg VYN202 deucravacitinib. So again, very inflamed, indurated, flaking skin, and it's classic psoriasiform-like presentation.
This is the placebo group here, the continued thickening of the skin, significantly more erythema and flaking. You have almost complete clinical cure for VYN202 and deucravacitinib, both at 3 mg per kg. Moving now to rheumatoid arthritis. This is a rat model. The collagen-induced rat model is probably the most well-validated model with respect to translatability for response in arthritis. We essentially induce with a Freund's adjuvant challenge. Excuse me. Freund's adjuvant is an adjuvant injected into the animals at baseline, and then we re-challenge them around day 4, day 5, and we see a significant impact of signs and symptoms of arthritis in the animals' joints. The red line here is our placebo induced. The maximal score here is around 16. These animals actually reach 13, so have significant signs and symptoms of disease.
In this model, we actually compared VYN202 to GSK620. GSK have published on this molecule in the past. It is less potent and less selective than VYN202, so we decided to use this as a control molecule to see if the lower potency and selectivity of GSK620 or the higher potency of VYN202 translate into an improved clinical performance. And you can see here that at our top dose of 10 mg per kg, we had a 71% improvement in signs and symptoms and significantly better than GSK620. And that correlates nicely with swelling in the animals. We actually measure the volume of the paws.
The red line here actually shows, the animal's volume is, the size of the paws have doubled in size with significant inflammation, and again, at the 10 mg per kg, we have about 80% reduction in inflammation, relative to that control. We looked at pathology within the joints of the animals, at the end of the study. The maximum score here for the group size is 160. They had 155, so a really marked pathological presentation of arthritis in these animals. And you can see a nice dose-dependent reduction in the histology scores, culminating, with our 10 mg per kg dose. Three-quarters of the animals were completely histopathologically cured of arthritis, and only two had mild symptoms.
So quite a marked impact on improving the state of the joints and the limbs in these animals. We measured IgG1 as a global inflammatory marker of inflammation. You can see here, again, a nice dose response, 1, 3, and 10 mg per kg, culminating in 10 mg per kg, where we essentially have complete reduction of IgG1. Moving to the pathology here, this is a great example here of significant inflammatory infiltrate into the joint, significant granulation in the tissue, lots of marked bone resurfacing and eroded surfaces. You can kind of make that out here. Significant erosion and ulceration in the joint, and this is an animal that was exposed both to the CIA adjuvant and 10 mg per kg, and they're presenting with a normal joint.
So one question also is: Because we're targeting BD2 specifically, is there anything—do we lose anything as an anti-inflammatory agent by not binding to BD1? So we have actually conducted the psoriasis and arthritis models with VYN201, which is our pan-BD BET inhibitor, and VYN202, which is our BD2-selective BET inhibitor. So in the psoriasis model, VYN201 was applied topically. Obviously, 202 is intraperitoneal dosed. In arthritis model, VYN201 was injected intra-articularly, directly into the limb, and VYN202 was dosed orally. So the short answer is no. It does show that we get a very similar anti-inflammatory effect between the pan-BD BET inhibitor and the BD2-selective BET inhibitor, and we don't appear to lose any anti-inflammatory effect by not binding to BD1. What we, what we gain here is an improved tolerance, by not binding to BD1.
So it really does show the futility of targeting BD1 as a binding domain, by taking a BET inhibitor into an anti, anti-inflammatory disease, into a disease. So in summary, we clearly see VYN201 as a novel, highly differentiated mode of action, and we, we are targeting at the point of transcription within T cells. Clearly has a broad applicability, both in immuno and in fibroinflammatory diseases. We haven't touched on fibrosis in this presentation. The historical pan-BD BET inhibitors, we, we have built the entire inhibitor platform specifically to address these more concerning, clinical adverse events of special interest by hyper targeting towards the BD2 binding domain. Our preclinical evidence, I think, speaks for itself. We have a very powerful, set of data already and very good comparative data to other drugs that have been improved in this space.
And the thesis for both of these diseases, I think, are pretty clear as we move these into the clinic. So speaking of the clinic, our preliminary clinical development plans for VYN202 are presented here. So as a novel agent, we will start on healthy volunteers in a single ascending, multiple ascending dose study. We're looking at five strengths of VYN202 dosed orally. We'll also look at a food effect. Obviously, the recommended maximum starting dose will be based on our ongoing toxicology program, and then we will move into a multiple ascending dose cohort. We'll evaluate three strengths of VYN202 for once daily treatment, up to 14 days. Obviously, the doses will be set based on the data we get from our single ascending dose phase. We will be looking at specific biomarkers here.
The HEXIM1 gene is upregulated when BET proteins are inhibited, so we'll be able to determine some preliminary pharmacokinetic, pharmacodynamic modeling for target engagement. TGF-β1 is a critical component, a cytokine that drives both Th17 differentiation, but also the key marker for fibrosis that potentially can look at additional indications beyond psoriasis and RA on the right-hand side. Then we have IL-1 beta, IL-17, and TNF-α are all relevant to the right-hand side. So we will start with a psoriasis study in more moderate severe disease. That will be a multicenter, double-blind, placebo-controlled study. Roughly 40 patients, randomizing 3-to-1 randomization. We will look at low dose and a high dose versus placebo. We will look at a duration slightly longer than others. We will look at 12 weeks.
We want to see efficacy to develop longer than the traditional 4-week study that others have looked at. Obviously, we can generate a lot more safety information over that as well, and we'll include adult patients in this trial. Again, with a clinical diagnosis of moderate to severe plaque psoriasis, IGA 3, IGA 3 and 4, and a PASI greater than 12. Again, being a I-B, primary objective will be safety, tolerance, PK biomarkers, but there will be exploratory efficacy, such as the change from baseline in PASI report and, of course, the categorical endpoints or proportion of subjects that achieve a PASI 50, 75, and 90. The rheumatoid arthritis study, a very similar design to the psoriasis study.
Again, we will be treating up to 12 weeks, only these patients will also have a background of methotrexate, which is customary for studies of this type, particularly patients with active adult-onset rheumatoid arthritis. These are the key inclusion criteria for this population. Again, safety, tolerance, PK, biomarkers, where we will look at DAS28-CRP as the composite endpoint. We'll look at ACRs, which are the regulatory endpoints, such as 20, 50, and 70, and of course, % change from baseline in high sensitivity C-reactive protein, which is a serum biomarker for activity in the disease. These studies are looking to be started in the second half of 2024, and we anticipate to have top-line results in mid-2025.
But based on success in these trials, it clearly opens the door into other indications, such as the ones listed here, such as psoriatic arthritis, ankylosing spondylitis, and hidradenitis suppurativa. Tyler?
Thanks, Iain. Go to the next slide. As Dave mentioned at the top of the call, we had a successful raise of significant capital through a PIPE transaction at the end of last month with a premier syndicate of fundamental healthcare investors. So I just want to provide a brief update on our cash position and shares outstanding following the financing. We expect to report cash, cash equivalents, and restricted cash totaling $15.5 million as of September 30th in our upcoming 10-Q filing.
When reflecting the gross proceeds from the transaction of $88.2 million, our cash position totals $103.7 million on a pro forma basis, which, as you can imagine, provides significant financial stability for the organization moving forward, and really enables us to focus on executing against the plans that Iain just outlined. From a share perspective, we have pro forma fully diluted shares outstanding of approximately 42.8 million. That consists of 14 million common shares outstanding, including the 10.7 million shares issued as part of the transaction. And additionally, as part of the financing, we issued 28.6 million in pre-funded warrants with a nominal exercise price.
Moving forward, you should expect that these pre-funded warrants, that the $28.6 million, will be included in both our basic and diluted weighted average share count for purposes of calculating our loss per share. Next slide. So this is our last slide before we turn to Q&A, but we want to just take a moment to highlight or summarize the key milestones that we have ahead of us over the next 24 months or so. The pro forma cash of just under $104 million that I outlined provides runway through the end of 2025, and the multiple clinical catalysts that you can see here on this slide.
So just to reiterate those from what Iain took you through, for VYN201, we expect to initiate the phase II-B trial in vitiligo in the first half of next year, with the top-line readout, for the 24-week portion of the study, in mid-2025. And then for VYN202, as a next step, we plan to submit our IND by the end of this year. And upon FDA clearance, we will quickly initiate the phase I-A, SAD/MAD, in Q1. We expect those results to read out middle of 2024. And then as we move into the phase ones, for both moderate to severe plaque psoriasis, as well as moderate to severe RA, we'd anticipate that those trials will read out, in middle of 2025 as well.
So as it relates to the, the three clinical readouts in middle of, of 2025, those will likely come staggered over a six-month period or so. And we'll be able to provide further updates, as we gain concurrence from the FDA on the number of arms in the, the VYN201 phase II-B study in, in vitiligo, and then further into the phase Is for VYN202. So as we wrap up the prepared portion of the session, you know, I hope you, you see from, from what we've presented, that these are, are very exciting times for VYNE. We're certainly very encouraged by the data that we've generated to date across both programs, VYN201 and VYN202.
And we look forward to keeping you all updated on our progress as we execute against our strategy and look to deliver on these key value-creating milestones that you see here. So I think I'll leave it there. I think we have a few more minutes left for Q&A, so I'll turn it back to Dave.
Hey, thanks, Tyler, and thanks, Iain, as well as Dr. Pandya, for your thoughtful remarks in reviewing our data and your presentation. So, Dr. Pandya, if I can ask you to take your... unmute your microphone, and then we've got quite a few questions, so we're gonna try to get through them. We've got about 15 minutes or so. We'll do the best we can, and we're gonna try to cluster them together, for simplicity. So, first question we have is, how differently... This, I think, Dr. Pandya, will be for yourself. How do we think about the differences between patients with active disease and stable vitiligo, in terms of-
... how they would respond to therapy?
Well, patients with active disease have a barrier of activity that needs to be surmounted before one can start thinking about re--pigmentation. Whereas those with stable disease, you can start re-pigmenting immediately. And so there is a delay in seeing the improvement with patients with active disease. And that has to be kept in mind any time you're looking at data, anytime you're approaching a patient. And so that's why we tend to treat those patients with active disease more aggressively. We will give them systemic steroids to try to accelerate the process to overcome that barrier faster. But there is a difference.
Thanks, Dr. Pandya. Next question. Why do you think there are such a low percentage of vitiligo patients seeking treatment, presently? And do you anticipate that this will improve over the course of time with the approval of Opzelura as well as other eventually, or the potential availability of other agents like, like VYN201? So maybe Dr. Pandya, this is another one for you.
Yeah. You know, I've been a dermatologist for 30 years, and, up until recently, vitiligo was seen as a disease that in which one has minimal chance for re-pigmentation. And I think a lot of that has to do with the fact that dermatologists were just not satisfied with the treatments, mainly because of the duration and the burden of treatment, including the patients. But if you would hang in there and do the treatment and wait a year, you could see some improvement. So there were a few of us who actually did that, and we were seeing that improvement, but there was quite a burden associated with it. Now, with the approval of Opzelura, patients who had given up on treatment are coming into my office.
Patients who had not seen a dermatologist for years are saying, "I'm here because I heard there's something new, and I'd like to know, because I've tried everything in the past, and it either was too much for me or it didn't work." So I think more people will be coming in as the news comes out that there are new treatments for vitiligo. Right now, it's estimated that somewhere between 30% and 40% of people with vitiligo in America have not seen a dermatologist or have stopped seeing a dermatologist. So they're basically out there not getting any medi, any medical care.
Thanks, Dr. Pandya. And then one follow-up for you as well. It's just this question's been asked several times. Just your impressions of VYN201, our topical BET inhibitor, and thoughts on, you know, where it's potentially differentiated. Obviously, well, we're very excited about the results of study. It's early, it's phase I-B, but just your initial impressions and thoughts as this drug would move forward into the clinic, into a phase II-B and potentially beyond.
Yeah. I was expecting, you know, when you enroll patients with active disease, I thought that, if it, you know, a patient on placebo would actually get worse over 16 weeks. We would expect them to get 5% or 10% worse over those 16 weeks. So with the BET inhibitor, what I was hoping for was that the patients would not get worse. There would be a difference between those, you know, who would be on nothing versus those on the BET inhibitor. But I was pleasantly surprised when I saw not only did it not get worse, but they actually improved. So that because it's so different from the other studies I've been involved in, in which the majority of patients had stable disease, where I am expecting improvement.
So to see that improve, encouraging. To see the reversal of the confetti-like lesions that Iain showed was encouraging. And so, I think that the other aspect of the BET inhibitor that I like is that unlike a JAK inhibitor, it also will reduce E-cad, the E-cadherin, and so, therefore, the destruction of E-cadherin, so therefore, you don't have the melanocytes that'll detach. And we know that melanocyte detachment is part of the pathogenesis of vitiligo. We've never really had anything that works on inhibiting the detachment of melanocytes. And finally, the exciting thing that I liked was the fact that it does seem to stimulate through the WNT pathway, the melanocyte proliferation.
And if that's the case, that it does that part, then that might be something that we can use either instead of phototherapy or in conjunction with phototherapy to try to stimulate. So it's something new and exciting. Now, having said that, the numbers are very small. This is a proof of concept study. I'm waiting to make any type of, you know, statement or conclusion until we see the larger studies, but it's, it's hopeful.
Great. Thanks, Dr. Pandya. Next question: What are your mechanistic or hypothetical, at least reasons for some of the patients that were non-responders in the study? So maybe, Iain, you could take this one.
Yeah, I think it touched on what Dr. Pandya mentioned earlier is, you know, really controlling the inflammatory phase is key. It's almost impossible for patients to spontaneously re-pigment when you have uncontrolled CD8+ T cell expansion in the skin. Because these T cells are primed towards melanocytes so that they know where they go, they go to attack. So unless you get control of that, patients will re-pigment at their own rates. Maybe over the course of 16 weeks, they may have a moderate re-pigmentation rate, but it may take longer to fully re-pigment. Some patients, the opposite, they may re-pigment more vigorously to start with and may taper off. But it really, in both of those cases, you really do have to get control of the inflammation, and allow that to occur.
I think the patients who don't respond or have a weaker response within the first few couple of months doesn't necessarily mean they're a treatment failure. It may just take longer for them to repigment.
Yeah, I think I'll just echo some thoughts on this. When we were designing this study, and Dr. Pandya alluded to it, and we only had a short amount of time to try to see if we could have an effect. We thought we had something here with this drug. Once we saw our preclinical data, we were quite encouraged by that. But, you know, we just didn't have the time and the resources to run a you know, call it traditional six-month to a year-long study. And so our objective was to try to see, could we show some type of on-target effect in humans with the vitiligo? We had 16 weeks to work with, and as Dr. Pandya outlined, and we didn't know what we would get.
We were just hoping we could slow it down, maybe, maybe arrest it, from getting worse for patients that exclusively had, active disease. And if we saw anything, any green shoots, if you will, initial signs of re-pigmentation, that would be, you know, that much more encouraging to us. So I think one of the things that really jumps out is we only had one patient out of the 29 that actually, got worse from baseline, and that was by 3%. So that was one patient, obviously, with active disease, and they only, they only got worse by 3%. No one else got worse. So we were able to keep the vast, vast majority of these patients, at bay, if you will, and, and not get further loss, further loss of, of pigmentation.
We had 80% for both the 1% cohort and the 2%. 80% of the patients in those cohorts were responding, you know, positively, did see an improvement in their, in their EPASI scores, and so we, we were really thrilled with that. Okay, so next question. I'll stay with 201 for a few more, and then we'll go to 202. What doses do you intend to evaluate in the upcoming phase II-B trial in vitiligo? And do you envision the potential to go higher from the phase I data? So, Iain, you want to offer some initial thoughts?
Yeah. What I would say is we already have non-clinical data to support a higher dose. Clearly, it's intriguing to see, based on our data to date, could we potentially push the dose a little bit higher? Clearly, we need to analyze all the data. We've just got our top-line results relatively recently, but we do have that potential to increase the dose. But it's certainly something we have to look at in the broader totality of the data.
Yeah. No, I think we're certainly encouraged by what we've seen so far. We have some headroom. I think if there's the opportunity to do that, it's certainly going to be a strong consideration for us. Following up on the last one, I think on 201, just on the trial design, you know, this is probably for both Iain and Dr. Pandya, to get your thoughts. How do you expect the changes from the 1b to the phase II-B trial design of vitiligo? What would you anticipate to see from having a longer duration of study and introducing patients with stable disease? You know, would you anticipate to see anything different in terms of an impact on response rates? So, Dr.
Pandya, want to take initial thoughts, and then, Iain, you can follow up?
Sure. If it's like some of the other studies that we've seen with the other JAK inhibitors, where 25%-33% of the patients had active disease and, you know, 66%-75% had stable disease, I expect the re-pigmentation rate, specifically the F-VASI 50, the F-VASI 75, to be better than what we saw with this current study. It's very hard for me to predict whether it would be better than the studies that we've been seeing with the other JAK inhibitors, but I expect it to be better, and hopefully significantly better.
Great. Iain, any other thoughts?
I just follow on to that comment from Dr. Pandya. Obviously, we're dosing for an additional two months at a minimum. So as I said, if we can get control of the inflammation, allowing more time for patients' individual response rates and recovery rates to become deeper over time, irrespective of whether or not they have active or stable disease, I think all of that is positive in relation to contributing to the overall effect.
Yeah. One thing that we heard loud and clear as we've talked with you know thought leaders obviously such as Dr. Pandya and others and our advisors is we've heard a consistent theme as we look to move forward into phase II-B studies that obviously our objective is hopefully we've got data as Dr. Pandya outlined that is better than what we've seen in the I-B with a broader and more deepening effect. And from a competitive landscape perspective obviously our optimal goal ultimate goal is that it's better than what's currently available on the market. One thing we've heard loud and clear is that we in the end we don't have to be is that there's not a lot of currently available options.
There's only one approved product, which is obviously topical ruxolitinib, and the sentiment has been, we just need to be in the same general vicinity in terms of performance in the clinical trials. And the fact that we're a different mechanism of action, you know, we at least as we stand here today, you know, we've, we've had a, you know, very, very strong safety profile. Assuming that carries, we would then hopefully not have some of the, the warnings associated with other drugs that are on the market or in development.
The fact that we're a once-daily dose drug, again, if we see the same type of performance as we extend it to, you know, broader, longer-term studies, I think all of that that creates a lot of opportunity for, obviously, patients, providers, and for shareholders, in the company. So why don't we move, we've got a last few minutes, why don't we move to a couple of the questions on VYN202? So first question is, do you expect proof of concept for VYN202, 202, in psoriasis and RA could be helpful for other potentially, other potential indications? Any interest in pursuing other autoimmune indications? So, I don't know, Tyler, you want to offer some initial thoughts, and I'll turn it back over to Iain.
Yeah, sure. So, right at the forefront, as Iain kind of outlined, I think, you know, from a mechanism perspective, because, VYN202 acts at the point of gene transcription and has, you know, potential impact, broader impact on multiple pathways and cytokines. It does avail itself to opportunities beyond that. And so as we think about the proof of concept data in psoriasis and RA, you know, as a potential gateway into other strategically important and large market indications, I think Iain, you know, in the prepared remarks, mentioned a few of them, including psoriatic arthritis, where there's a natural linkage to both, as well as AS and HS.
Iain, any other thoughts?
Yes, I also mentioned, we haven't presented today, as we have some space, interesting data in fibrotic diseases as well. Some others have published the role of BET proteins as being key in the maturation of TGF-β1 , which is one of the key biomarkers that drives that, the pathogenesis of fibrotic diseases. So I think that's another area that the 202 could potentially go to downstream, but I think as right now, I mean, obviously, if we have positive data in psoriasis and RA, it does open up plenty of opportunities and sister indications, in the future.
Yeah. Well, we're obviously very, very enthusiastic about the level of interest that we've seen, you know, for the work that we're doing, with our novel BET inhibitor platform. Kinda rolls into, I think we've got time for one more question. So we've recently seen good results as well as sizable M&A transactions from other companies that have drugs in development in similar areas that you're considering for VYN202. How should we think about VYN202 in this context? So I mean, certainly, we've all seen, you know, some major M&A transactions, a lot of interest in the I&I space. We know that the initial target indications for psoriasis and RA, there are several players in this space.
But even with that being said, they all seem to have done quite well and offer meaningful alternatives for patients. So our objective for our platform from where we are today is our first objective was to show proof of principle for our BET inhibitor platform. We believe we've done that with VYN201 in phase I-B study in vitiligo. I think there's a bit of a read into what we can hope to see for our oral BET inhibitor, VYN202. We obviously are excited to get into the clinic. Our plans are to file the IND by the end of the year.
Everything's on track, and then hopefully get up and running with our SAD/MAD study early in the first quarter, and then with the readouts called middle of next year. So assuming all of that goes fine, we're eager to get into our proof of concept studies for VYN202 in both psoriasis and RA. We know these spaces well. You know, we think our initial thoughts of the study designs make a lot of sense, can generate a lot of meaningful data, both on the safety and efficacy side. And we envision, assuming we're successful, it's an opportunity for us to establish proof of concept, be the first time, assuming success, of meaningful results for a BET inhibitor, a systemic BET inhibitor in an autoimmune disease.
And assuming we do that, we think we'll have lots of optionality to consider, and we're obviously very excited about that. So I think that, that's it. I want to again thank Dr. Pandya, as well as my colleagues here, and I want to thank the audience for taking time out of your busy days to, to join us. For the other questions, just I haven't had a chance to get to, so we're happy, the team and I are happy to take those questions on a one-on-one basis, so don't hesitate to reach out. Thanks again. Thanks again to the LifeSci team , for organizing this, and we look forward to providing everyone on this call, updates as we continue to progress our business. Thank you very much and enjoy the holidays.