Okay, I think we're ready to get started. Welcome everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research Team. Very pleased to introduce from Crystal Biotech, Krish Krishnan, Chairman and Chief Executive Officer. Krish, thanks so much for joining. Maybe set the stage a little bit with Vajjvek, where we're at in the launch. We're kind of in like a little in between moment of the adoption curve. Thanks for having me, Josh. Yeah. I think, in The U. S, the launch has been going on for eighteen, twenty months, almost two years now, and a lot of patients who started on the drug in the 2023, are starting to heal, like the wounds are starting to heal, which is a big positive for us, in the long term because this is a chronic application and our expectation is the wounds heal, they feel good, they're able to do things they've never done before, and they get back on drug when the wounds start to blister, which they will because of their half life of collagen and the fact that skin cells turn over. So, it's a big positive. However, it makes it a bit difficult to think about launch in a linear manner, and it's much easier to think about the Vizureka launch experiencing some upward sloping waviness is the right way to think about it. So, there will be quarters where the number of patients getting on drug is a lot, and the number of patients pausing is not that high, and we could have a spectacular quarter, followed by a queue where demand is still good, but there are patients pausing. So, one of the things I tried to mention, which got taken to the extreme in the quarterly earnings, was to just remind people about this waviness. And hopefully, with a few quarters of experience with respect to the waviness, we will be able to inform how to think about it more predictably than we do right now. And is the drug holidays more of a DDEV phenomenon than RDEB, or do both? In terms of actual numbers, predominantly DDEB, but there are also some RDEB patients who started in the 2023 who are now starting to heal well. So, if you're a one of the hypotheses we have internally is if you're a severe RDEB patient, you should expect about eighteen months for all your wounds to heal. We're starting to believe more and more in that one paradigm because a lot of them who started early were severe, and as they start to heal, we're seeing that to be but, yeah, most of the pausing, because we go after DEB, is more so caused by dominant patients. So you did guide, at least in The U. S, that third quarter might be down sequentially quarter over quarter. How short kind of a plateau or decline effect you expect it to be? Are you confident you can drive growth then in fourth quarter? And if so, what gives you that confidence? Look, we're not looking at any significant drop in U. S. Revenue. Our objective in making that point was we had a really spectacular Q2, it was like $96,000,000 more than expected. We just didn't want people to draw a linear line towards Q3. That was the point of that message. So, we expect it to be a very reasonable quarter in The U. S. Without any big surprises. So maybe then you can talk about the efforts to get more DDEB patients. Actually, before I ask that, are you generally kind of saturated on RDEB? I'd imagine most patients with such a severe diagnosis would be on therapy, or if not, why not? Doctor. So we have, if you look at our reimbursement approvals as a proxy for patients, it is not exactly a proxy, but a close enough proxy. We're at a seventythirty split. We believe there are we believe very strongly there are 1,200 identified DEP patients to begin with. So even in RDEB, there is an opportunity. If you believe that 1,200 is split fifty-fifty between RDEB and DDEB, maybe there are 200 more RDEB patients to get. If you believe in the current split we have, which is seventy-thirty, maybe there are 300 or more RDEB patients to get, but we're definitely there are RDEB patients to get. And so, is the maybe you can describe some of the changes you've made to the sales force to find additional patients. Yeah. One of the things we observed in Q4 of last year, and it kind of showed up again in Q1 of this year, was it was taking longer for a rep to pull through a start form. We launched with 17 reps, on average, each rep covering about three states, and we started realizing that the patients are now further away, patients are moderate, physicians who treat these moderate patients are further away, takes a few iterations to get to them. We saw a slowdown in the number of prescriptions in Q4, Q1, so we said we made a conscious decision to increase the sales force, to where a rep manages two states instead of three, which is like a 24 target. We're well on our way to hiring more reps. We expect that it would take a couple of months for the reps to come up to speed, and so the full impact of the increased sales force should start to show starting early next year. So, where do you expect kind of that final sales personnel count to land? Right now, we're pretty well set on the 24, 25 number, and once we get past the 1,200, as we go into 3,000, it's maybe take even longer to get each patient pulled through. At that point, we'll think about if we need a higher but so we don't expect any big increase over the next year and a half or so. You also have a PDUFA date coming up for at home administration. Maybe talk a little bit about how those discussions are going, when the PDUFA date is, and as you're talking about some of the challenges with pull through, to what extent does sorry, not at home, care provider or even self administration, I guess, maybe for some patients? Yes. So, both in Europe and Japan, the label is broader, and patients, obviously with the physician's consent, have the opportunity to resort to self administration or caregiver administration, and one of the big changes in the label that we're working in The U. S. Is to effect that, bring that back to The U. S, where what we have seen, especially with adult patients, adult as an 18 or 20 older, who have moderate to mild symptoms, find it and this is the one big, if there's been an issue in the launch from a patient voice perspective, we see these adult patients do not want a nurse coming week after week and applying gel on the few wounds that they have. They feel it's simple enough that they can do it themselves. And so we believe that if we are successful in getting patient or caregiver administration, it would help the adult moderate to mild patients, it would provide an opportunity for patients to take the drug with them when they travel. You know, when we talk about summer holidays, one of the things people don't realize is, right now, the patient has to be at home to take the drug. Like, any visits to family or vacation is a compliance miss. So, we're hoping that changes. The PDUFA is September 13. Things are progressing in the right direction with the agency, but I do caution, look, we all know the agency is going through some changes internally. We haven't seen at Crystal any big impact of that, but I always say that, that in the current moment Do you assume There's a potential for delay. Yeah. I think we've seen enough of those to not necessarily be surprised if there are some temporary, hopefully, delays. When you get assuming you get that on the label, do you expect it to kind of clear out this bottleneck of kind of patients who you've had challenges pulling offering them just a very easy way to come on through? Does that drive kind of like a mini bolus before getting back to a steady state? Well, that's an interesting way to think about it. The way we've been thinking about is helping the current adult patients who are moderate and mild, who really are a little annoyed by waiting every week for a nurse to come in a window, we're thinking it would help with compliance on these patients. But I also I mean, that's an interesting point, I think. I don't know to what extent I mean, it's really an interesting point that maybe there has been some reluctance on prescriptions based on a nurse coming in, and we have to wait and watch, we're not. And how would self or caregiver administration work? Would they have to go to pick up the product from the pharmacy, like the nurse practitioner, or would you ship it to them? No, we ship it to the patient's home. Any logistical challenges for a patient to handle the product at home? Doctor. There are look, many training opportunities, opportunities with the nurses at the pharmacy. We have not we have, as in Crystal Health, we partner with, the nurses can provide training. We have plenty of videos on applying the drug at all different ages. We have our own nursing team internally who can advise a patient, CrystalConnect, on how easy it is to apply. And look, so we don't think application is a logistical challenge. The only challenge I can think about is, look, when a nurse comes to your home every week, we know what has happened. Now, we're a little bit it's up to the patient now to apply on a given week, and you're moving compliance from us to them to some extent. That's fair. Is the annual cap that we talked a lot about at rollout less relevant now because patients are moving to drug holidays, or is it still a pertinent factor? Not yet. We still see the patients who have been consistent on drug continue to be consistent on drug, so we don't expect any big I thought we did a remarkable job at CAP last year, and we're continuing on the same type of principle. The cap is reflected in the GTN, and our GTN has been very consistent in the 15% to 19% range, 18x of floats a little. So, we're not and we're also look, we're on the heels of 803 coming up through the channel. 803 is BVEC for the eye, eye lesions, and so, one of our objectives is to make sure payers understand the value proposition and keep that we have had excellent access to date, and we want to continue that going into 08/2003. Why don't we continue on ocular VIGEVAK? You've very well characterized the experience in one patient who's had really remarkable result. Is that the only clinical experience you've had? If so, is it a lot to extrapolate from that one patient into a pivotal trial? Look, this patient has been on drug for like eighteen, twenty, twenty four, I don't know, of eighteen months, consistently week after week, has had no safety issues. This patient was an extreme patient who was literally blind, or as they call it, hand motion, and now has pretty close to perfect vision of twentytwenty five consistently, right? We know that the vector transects epithelial cells pretty well. We know we have had no safety issues on Bijouac in the skin, not just here, but in patients in Japan who were on a clinical trial. Our PK data was very consistent. So, yes, you're right. Like, you cannot take one clinical experience and extrapolate as a valid point. However, if you take the collection of data and the time and the safety record, we feel very positive about the way the study has been designed and hopefully works out And well it's for the a placebo controlled crossover, so weekly drops for twelve weeks, both treated and then untreated, how do we think about the kind of the natural history of these abrasions in the untreated population, how quickly they appear and resolve? Doctor. So, in the natural history, saw, patients getting about six abrasions per month, was the average. The abrasions don't last that long. They turn over pretty quickly, so we think once a week is a pretty good way to administer the drug. We embarked on a classic blinded control study, so there's no ambiguity about whether the drug is working or not. But it was good to have patients in the natural history study, so you have an idea on if the dosing schedule is working well, and And is it both eyes or just one eye? Bilateral, both. And the primary endpoint is corneal abrasions or, like, how are you defining, because there's a symptom component and then there's a diagnostic? In this case, in the case of eight zero three, it's just a reduction in the frequency of symptoms. Symptoms. In the simplest way, yeah. And I think you provided a little granularity in terms of how you see the addressable market for the ocular indication. Maybe you can frame that for us. Yes. We expect it to be about fifty percent of the RDIP population and maybe ten percent to fifteen percent of the dominant population. From a pure financial perspective, look, any money, no matter what you believe the market opportunity is, it flows straight to the bottom line for us. We don't need to change much about in terms of even supply chain versus sales force and commercial, but the opportunity is about half the RDEV and 10 to 15 of DDEV. And without the drug holiday consideration, because this is now prophylactic. This is prophylactic and patient administered, meaning I mean, you could get the nurse who's coming in for your bandage change to drop in the eye drop, but it's pretty straightforward. So, we've got some ex U. S. Launches underway. Maybe we can run some of those numbers, Germany, France, Japan, number of patients in each country, kind of the mix of our ddeb of those diagnosed and pricing in each relative to The U. S? Yes. So, Germany, we've already I mean, our launch is underway in Germany. In France, we are treating patients under the Axis Precost program. There's a it's terminology thing. It goes from AP2 to AP1, and when you go to AP1, it's more closer to a commercial launch than when you are in AP2. We expect that to happen in Q4. And there's about 1,000 identified patients between Germany and France. France is a bit more concentrated, where a lot of patients are at centers of excellence. Germany, in terms of fragmentation, is between France and The U. S. We feel that the label affords like I mentioned before, there's an opportunity for caregiver self administration in Europe, you can treat from birth, So, we're pretty excited about launch in Europe and Germany, and our objective as a company is to launch in UK, Spain and Italy, assuming everything else works out as crystal, and then enter into distribution agreements for some of the other countries, Eastern Europe, Latin America, Israel, and then just to add a point, as you saw, we got approved in Japan, and we are expecting to launch in Japan in Q4. So, a lot of global launches happening in Q3 and Q4 at Crystal. And pricing relative to the net U. S. Price in each of these territories? That's a tough question. Typically, the Japan pricing ends up being in between The US and Europe pricing. In Europe, based on other drugs, we expect the German pricing to be about 50%, 60% of The U. S. Pricing, although in full disclosure, we're just starting to negotiate. The drug has a good value proposition. Enzyme replacement drugs have done well in Europe, and we will not know the answer till about a year from now, and then country by country, we make the case, But that gives you a general idea. So, you've done a great job building out the pipeline. And interestingly, the most recent entrant to the pipeline, think, is getting the most attention from investors, and maybe in part just because of how proximal it is, right? You've shown great data for ocular VIGEVEC. You've got a validated mechanism from Oxervate. So I think it's intuitive to kind of feel like this is well set up. And talk a little bit about neurotrophic keratitis and what the unmet need is that you're looking to address here. Yeah. So, neurotrophic keratitis is a disease of the front part of the eye, it's where the nerves that feed the cornea get damaged, resulting in issues with the corneal epithelium, all the way from punctated lesions to ulcers, a subset of them results in blindness, so it's a classic front of the eye corneal disease caused by a lack of a protein called NGF, which helps build the cornea. The prevalence of this drug, if you look at claims data, just over the last two years, has almost doubled as the awareness has increased. This is about sixty eight thousand patients in The U. S, and we did some claims data work and we feel really good that the market estimates are good, and the benefit is there is one approved drug for NK, which it's a private company, but if you do some back of the envelope type calculations, I think the opportunity in The U. S. Is north of $1,000,000,000 pretty easily. That drug has some limitations, and so we believe that the way KB-eight zero one puts a better value proposition to the patient. So, I guess, the most obvious limitation is oxalate dose six times a day, and I guess, what do you expect your dosing frequency to be? Doctor. Now, we're starting with a biweekly not so biweekly, twice a week administration, but we although the study's primary endpoint is at eight weeks, we are looking at four, six, eight, ten, and twelve weeks to see if our vector heals a bit faster than the oxybate endpoint. Second, besides the six days a week you know, six times a day is primarily because the patient has to sleep, so it's somewhat of a suboptimal dosing, in our opinion. The manufacturing, I've heard, is a 19 step process with Gold Chain, and so the whole margins we could be attractive on the margin side, and because it's a recombinant, we believe that pain has also been an issue with oxovate. Would you expect to see that with HSV gene therapy approach? Why or why not? Doctor. Look, I look at pain in this indication as, you know, the way I think about it is, any time nerves are growing back, there is an increased sensitization to pain, right? And I don't think we'll be any different than oxybate with respect to nerve growth. However, other reasons, because it's six times a day, you're constantly you are working the eye a lot more times with the recombinant product, so the frequency of dosing, plus the eye is being manipulated more than needed, and that adds more to the pain for oxybate. And finally, because it's recombinant, we've heard of deposits, some kind of phosphate based deposits, because it's recombinant, which we do not have. So, while we do expect the nerve growth pain to be not that different, I think we can alleviate on the other two components of pain in the eye. Do these lesions stay healed when they're healed, or do they recur? They recur. Do you have an idea how often? I think it varies by Maybe a few times a year. I guess the gist of the question is, I mean, if you've got a more convenient delivery option, does it make sense to continue to prophylax them as opposed to just treating an episode to heal? Doctor. That's an interesting question. We'll take it up under advisement. You've laid out some pretty ambitious timelines for the clinical program. Maybe kind of take us through them and what gives you the confidence that you can Oh. Enroll and generate data So, conservatively, we expect we are in the we've dosed the patient in the phase one study. We conservatively expect enrollment to complete before year end, but thankfully, it is an eight week study, so sometime in the first half, we should have Phase III data. And the expectation is, if that data is positive, because it's a classic blinded study with endpoints, we'll be very confident going into a pivotal study because the design will be no different and except maybe on the frequency of dosing, if at all, and just a broader population. Now, one of the good things about Crystal from a BLA filing perspective is our CMC is well established and well known, so a lot of BLAs get delayed, pushed out on the CMC side, less so on the clinical side, because on clinical, either P is less than 0.05 or not, like it's pretty straightforward given the AE profile. The CMC slows things down, and we thankfully, we got CMC behind us. So, our expectation is sometime towards the end of next year or early twenty twenty seven, we file the BLA, and if everything goes well, look for a launch in 2027. Like, that's at a high level, I'm not guiding. I don't want to get bogged down on these dates, but that's how we're internally thinking about. We've got a few minutes to try to cover at least some of the pipeline programs. We've been waiting for CF data for a while. It's close at hand, I which is think we're we've seen a lot of noise in the early stage CF trials, as there can be like patient to patient variability that ultimately balances out over a larger cohort. What is it you're looking for as early indicators of clear success? Yeah. So, in cohort three, which is the cohort we're in, it's the first cohort we get to bronch CF patients. We have six patients in cohort three, three of whom are prior modulators and three of whom are null patients. That's the setup. And I say that because if we seek good molecular data on the three null patients, we would be ecstatic in moving the drug forward. We do fully acknowledge and admit that FEV on such a small population, given we're bronching the patient, can be either it is very good and people will be skeptical, or it's not going like, we don't want to reach any type of decisions based on FEV at this stage. However, in and because we deliver full copies, two full copies of the CFTR gene, we also believe that expression will be super correlated to functionality. We're not trimming a gene, we're not if you believe that a gene, when expressed, will produce the required protein, if you believe that. And we will work on we're looking at ways to further cement functionality, but if you see good distribution. How are you thinking about announcing that data? Will you have a conference call to lay it out or Yes. Look, we're trying to we're waiting to get all three patients done, so you have we'll report on any progress in the study along the way. We're expecting to have a conference call, and then once we finish, hopefully, it's great, we'll go into a redosing paradigm, and that's important, right? People always ask me, what's the number at which you're happy that it's going to work? For us, the first any first number is like a beachhead. The lung gets clearer. We're expecting subsequent doses to have a bigger impact than the first dose as the mucus clears. That redosing is a big value add for us that's important for people to understand. For the AATD program, you've shown very good expression in BAL fluid. When do you think you'll have a sense of the regulatory path and what you'll need to show whether you'll need a CT scan study or not? So, we're in the AATD has gone faster. We're in the redosing paradigm. We're redosing patients in the AAT study. We will look again for LABAGE data like we did before. We're hoping to build on what we saw in the single dose study. At the end of this redosing study is a great point to have a conversation with the FDA on there are many ways to get the drug approved using molecular data, and we'll have that conversation at that point. Then another kind of timing The inhaled oncology HSV program, which is still moving forward, has shown some very good early clinical activity. When should we look for another update and a decision tree for what to do with that program? Yes. We issued a press release recently. We submitted the monotherapy data to the FDA to think about how to think about next steps. We have an end of Phase II coming up in October. As we said in the press release, we will know what the agency would like us to do with respect to the data following that. So stay tuned. And then one more timing question. Jun, been talking a lot about either strategic partner or spinning off that organization. When do you think you'll make that decision and based on what? We'd like to I mean, we have a management team in place at Zhijun now. The guiding principle is to get something done before finishing Phase II. We're in the thrones of starting Phase II on Declarte. So our expectation is over the next six to twelve months, we're trying to get investors to think of Shun as a separate company. All right. Well, we're out of time, but we covered a lot of ground. First, Thanks thanks so much everyone for tuning in.