Everyone for joining us. I'm Andrea Newkirk, one of the biotech analysts here at Goldman Sachs, and I'm super excited to be joined by the team from Krystal, Krish Krishnan, Chairman and CEO, and Suma Krishnan, President of R&D. Thank you guys both for joining us.
Thanks for having us, Andrea.
Maybe before we dig into the pipeline, which has been having some really exciting advancements, most recently on the back of ASCO and your upcoming data reads in CF and AAT. Krish, maybe we can start just on the Vyjuvek launch. What are you seeing right now in terms of where you stand in the transition from an induction to a maintenance phase? Where are we in the launch?
Yeah, when we, at the time of launch, 18 months ago, we had assumed we would be at a 50% compliance by now. We're ahead of that number. No matter how you calculate compliance, we're in the 83% ±5% range. We're ahead of that. That has to do a lot with the percentage of RDEB versus DDEB patients on the study. We're right now at 70/30. At some point when that ratio heads towards an equidistribution, we expect compliance to come down to 50%. I will say our conviction in the total market opportunity is just as strong, in fact, stronger than it's ever been. We realized that some of the low-hanging fruit has been captured by Vyjuvek.
As we go further into the community, we're proactively trying to figure out how to strengthen the commercial team in the U.S. to get those opportunities brought in a lot faster.
Maybe speak to what those efforts are. You've talked about expanding the sales force, but how does that logistically improve the operations?
Yeah, so we started with 17 reps across 52 states, which is about three reps per state. As you're done with the low-hanging fruit, just time-wise, it takes a rep longer to drive to a physician. As awareness is low, as you go into physicians further in the community, it may take a couple of cycles of visits before you help them understand a gene therapy that's herpes-based, that's dosed at home. One of the first things which a lot of rare disease companies do is to maybe have a rep focused on two states or one state per rep, which is another proxy for saying we're just increasing the effort required to pull a prescription through. Logistically, we're just trying to make it a little bit easier to get these prescriptions done faster for the patient.
On the idea that some of these physicians use multiple cycles, on average, what is the number of cycles or number of visits that they need to really start to understand the value proposition of Vyjuvek?
It all depends on the physician, the type of patients they have. Some of the community physicians have had exposure to KOLs for one indication or the other, and they come up to speed. There are some dermatologists in the community on whom we have to help understand that it's an epizoomal virus and doesn't integrate into your DNA. Realize that although it's herpes-based, it's not replicating, and some of the toxicities associated with herpes do not exist in the vector. In terms of cycles, Andrea, it's tough to say whether it's one or two or three, but it's definitely longer than talking to a KOL in one of these centers of excellence or close to a center of excellence and being able to pull a start form through.
That makes sense. How quickly do you think you could start to see the benefit of this expanded sales force?
My expectation is we're starting to see some benefit in Q2, a much higher benefit in Q3, and by Q4, it's stabilized. Definitely, we're looking for an impact in the Q3, Q4 timeframe starting now.
Okay. So you would look to reevaluate whether or not you needed to potentially even expand even further when you get into the back half of this year?
Yeah. The max we can get to is just to have one state per rep. Obviously, in a rare disease, that does not make too much sense, especially dealing with Alaska or Puerto Rico or Hawaii or some of those states. The answer is somewhere between 50% more versus 75% more, and we will definitely get to that point.
Got it. Let's talk about the nature of the pauses that you're seeing right now, because that is probably driving some of the dynamics we're seeing in terms of the maintenance and the utilization that you referenced. Speak to us about what you're hearing from the KOLs or from the patients as to how they're experiencing the benefits of Vyjuvek.
Yeah. First, I want to start with saying pauses are a really good thing for Vyjuvek. We try not to influence pauses in any way. Pauses is what leads to the drug having a long tail. What I mean by tail is this is a chronic application. We want patients to get their wounds healed, take a break, get back on drug when they see disruption or when new wounds appear. We want that cycle to continue for a very, very long time. That happens when patients pause. That's a big positive for us. A lot of patients get engaged in more physical activity. A lot of patients doing things they've never dreamt or haven't done before. The number one driver for pauses is complete wound healing. There are always a small percentage, and I would say like 90% or a very high percentage.
There's always mortality involved, or some of these patients go through some other serious condition that's above and beyond the skin, whether it's blood-related or blood transfusion-related. We can go on and on. In some cases, they have to leave the country for whatever reason. There are some adults with mild indications who probably don't like a nurse visiting them week after week and would rather apply Vyjuvek themselves, which Suma is working on trying to get the label modified for caregiver or self-administration, which is what we got in Europe. What we try and do is to make sure the patient experience on the drug is fantastic. Pauses, which are tough to predict because Q1 was the first time we saw a somewhat meaningful pause after patients have been on drug for 18 months and some of them in the OLE.
We thought that was great. We are already starting to see some of those patients get back on drug in Q2. We love this, and this is going to continue, right? Last night, in one of my... Describe this launch as kind of technically an upward-sloping sinusoidal curve. It is the easiest for me to comprehend how a launch looks like, which means if I am convinced of the market opportunity and I believe the patient experience, physician experience is good, I see no reason why we would not realize the opportunity to the first 1,200 and beyond in the U.S.
Perfect. How meaningful is that, Suma? Krish just talked about caregiver self-administration. You have that on the label in Europe. What activities are underway right now to bring that to the U.S., and how could that impact utilization?
I mean, we had to do some human factor studies, which we completed. Unfortunately, it was not within the time of the BLA. We did not want the BLA to get delayed to get that into the label. All those studies were completed to support getting that in the label in Europe and soon in Japan. We have provided that data to the FDA, and we are in the process of extending the label. The FDA is completely aware of this. This is something we already submitted the protocol, it is just the timing.
I would say on utilization, look, it obviously does not affect the young, severe patients in the study. Parents are pretty good about utilization. What will impact utilization is on 20-30-year-olds suffering from mild to moderate forms of the disease, which is predominantly dominant EB. We really think that getting that on the label is a tailwind to compliance. While on one hand, I am talking about compliance going from 83% to 50%, getting caregiver administration on the label could make that even longer if we get that in a timely fashion.
Got it. The path to getting to 50 just extends instead of dropping.
Yeah. Look, trying to get a patient, especially if you're an adult, and you see what a nurse does on dominant wounds, which is drop the gel and put a bandage, scheduling week after week is a bit of a chore if you're mild to moderate for them. It is a great way to start, and now that they're seeing benefits, I think trying to get this label change in a timely fashion, we're already halfway through the process right now. We are excited that we're timely in terms of making that label change and getting them back on drug with a higher utilization.
You mentioned that you're already starting to see some patients come back. If you could characterize for us what the extent of these pauses has been, do you see a variation between RDEB versus DDEB patients? Just logistically and mechanically, how easy is it for patients to restart Vyjuvek?
Correct. I do want to say that if you are a severe patient, you're not at the point of complete wound closure yet if you're 12, 18 months. Most of the pauses we see are predominantly on the mild to moderate side. We expect the wound to be healed for about 90 days based on science because the half-life of collagen is about 30 days. That's a median average expectation to come back. Not all wounds heal at the same time. While a patient achieves complete wound closure, there could have been a prior wound that has been closed already for 60 days. In terms of coming back, anywhere between 30-120 is fair game, depending on the severity, depending on when the wound closed. It's tough to put a final point on that number. Maybe over time, we'll get a better idea.
Right now, it's really in a month and four months is my best guess.
In aggregate, how many of your patients who have started Vyjuvek have paused?
You mean what percentage?
Yeah. Do you have a sense as to what percentage are taking a pause that's more than just a missed weekly dose, that maybe they're traveling, but have paused because their wounds are closed?
The reason they hesitate, we haven't shared that information. I wouldn't characterize it as a significant impact to the revenue line today. The problem with all these stats is they're so dynamic in nature that any number I say has no indication of what's going to happen in the future, including on pauses, right? For a long time in Q1, we thought about it should be estimate, so investors can have a good idea of how much is the demand versus how much is the pause. It is really difficult for us to, especially with patients coming back, pauses are not unidirectional, which is why I talked about this upward-sloping sinusoidal. I will say we haven't had a single instance, or at least to my knowledge, of somebody pausing or not being on drug either because of the safety or the efficacy of the drug.
Every reason I've heard is some kind of administrative annoyance on the nurses or some serious problem with their health. None of it is. Some obviously would like the one comment I've heard on Vyjuvek from the severe patients is, "Is there an opportunity to increase the weekly dose?" Outside of that, I have not heard any particular criticism on the safety or the efficacy of the drug, which tells me that this could be a franchise that extends for a long time.
You mentioned earlier that you continue to have confidence in what the addressable population is, the 1,200 patients. Just help us understand what work have you done to continue to have that confidence? You are almost two years into the launch. What is helping that?
Look, 81.2 is the ICP-10 code for claims data. It can be analyzed through multiple data sets, and you can actually pinpoint a unique claim to a patient. I would also advise that any investor interested in doing so can obtain their own ICP-10 data and do exactly the same analysis we're doing. We have been doing it every week, every month for the last 12-15 months. We are significantly convinced that the opportunity does exist. Yes, it is true that some of the patients, it takes a bit longer, but that does not reflect on the market opportunity. Actually, we can go as far as saying we also get claims hits on non-DEB specific, but symptomatic-related ICP claims, which is maybe 81.9.
If you analyze ICP-81.9, you will also align on that while there are 1,200 identified patients, there is a definite potential of another 1,800 that we can get over time. Obviously, it'll take a bit longer, but we feel very confident about the opportunity in the U.S. I will say when we see and when we speak with high confidence on the 1,000 identified patients between France and Germany or the 200-400 patients in Japan, it's inconceivable to believe that the U.S. market could be that much smaller.
That's a good segue to Europe. And your pre-launch activities, they're underway ahead of launching later this year. Where do you stand with preparations? When could Vyjuvek be commercially available there?
We're looking to launch in Q3. Most of the work we're doing right now is administrative or in terms of getting the labels and the cartons and the right language and the right shipping mechanisms in place, both in France and in Germany. In France, it's technically not called a commercial launch. It's under these ATU, which is kind of like an access/it's kind of like the access protocol you're in while you're negotiating a price with France. Given the broader label we have in Europe in terms of caregiver administration or self-administration, we believe compliance would take longer to get to 50% than in the U.S. Overall, we're very excited about the European launch. Based on the drug's profile, we actually believe we could get to a good price that we're comfortable with, at least in Germany and in France to begin with. The team is in place.
We look forward to a Q3 launch and then build upon that rest of the year and next year.
You've spoken in the past about some potential bottlenecks as it relates to just logistics of patients coming in, seeing their physicians, starting treatment. What is Krystal doing specifically to kind of work through those bottlenecks?
Yeah. Just to clarify, the hurdle is the first before the physician writes a prescription, they would like an in-office visit with the patient. We've been aware of this issue for a while, and we've been working very hard to figure out a way to allow a lot more patient visits. To give you an example, once we pinpoint the launch date in Germany, we would have the reps detailing the physicians and work with them to find a way to get patients into the office given that launch date. That effort will start to happen once we figure out whether the launch is on a particular day or a particular week. We're also working with the KOLs. One of the time-consuming parts of an appointment is the bandaging and unbandaging of the wound in a patient.
What we work in terms of additional nursing assistance to the extent we can under compliance, make sure that we make the life easy on the physician to see a patient and write a prescription. I know Laurent, who runs as General Manager in Europe, that if there is a hurdle with respect to the U.S. launch, it's getting the patient to come into the physician for the first time. Anything we can do to make that faster will significantly help with the launch dynamics.
If you think about potential other expansion opportunities for BVEC, most notably in the eye, maybe give us an update here on where that stands ahead of your phase III trial.
I mean, we should be dosing patients pretty soon, as we said. That has moved along. We have a natural history study. We have collected substantial data on patients from the natural history study. We have patients ready to go and launch. It is a decentralized study. This is one of the first, I think we are the first company to do decentralized studies, which is good and easy too because the drug can be taken by the Option Care nurse, and patients can administer at home, and they do not need to come to the clinician's office quite often. It is great that they will be compliant. We have the patients ready to go. It is just getting it up and running. We expect that to begin shortly.
You have spoken in the past about Vyjuvek in the skin being a $1 billion+ opportunity. When you think about the incremental opportunity afforded by expanding to patients with eye lesions, what does that represent?
You know, it's too early to talk about pricing on Vyjuvek in the eye. But the eye, look, you saw that New England Journal paper of a kid going from blindness to 20/20 vision. I'm not saying that all patients with lesions in the eye are blind to begin with, but the value proposition in the eye, as you can imagine, is far bigger. I wouldn't say far bigger. It's bigger than the value proposition in the skin when it comes to sight. Depending on the data and the phase III study, our objective is to make an the first thing I want to say is we hope to get a new label and a new NDC number for BVEC in the eye. And I think if the data supports it, we could have a value proposition to price at parity to the extent we can.
That would be the objective. Obviously, it affects about half the RDEB patients and 10%-15% of DDEB patients. So definitely, it would take the value proposition of the Vyjuvek franchise with the eye and the skin north of $1 billion. It remains to be seen what the impact is in other countries, in Europe and Japan. Right now, what we're focused on is getting the clinical study going and getting a good result by the end, close to the end of the year, and filing for approval.
Maybe we can focus on the pipeline here, Suma. There has been so much focus in 2025, even starting the end of 2024, on your inhaled delivery platform. Maybe just to level set for everyone here, what have you seen across these multiple data sets that gives you the conviction in your platform's ability to go into the lung?
I mean, as you know, we have three programs in the lung, and data from all of those three programs consisting that the message is very safe to administer the drug because there's a lot of safety concerns when you deliver vector into your lung. Does it cause pneumonitis or any kind of other lung complications? Clearly, we've demonstrated we've dosed over 50-55 patients or 60 across all our three programs, and we know it's safe. Across different, I mean, different concentrations or doses from all the way from E8- E10, we know it's safe. We have a good dose ranging, different doses that we can play around with depending on the kind of disease or the indication. It is certainly safe.
We've also seen preliminary data of basically mechanism because we know as we shared data on 408 end of last year where we did do bronchial biopsies and lavage, we clearly see expression of A1AT. And we also show that not only does it produce the protein, but it also does functionality. I mean, the main reason for AAT is to neutralize neutrophil elastase because that's the one that destroys your lung tissues and is the issue. We know that A1AT can be produced, is functional, is wild-type protein. It can bind to neutrophil elastase, and it can reduce neutrophil elastase in the lung. Mechanistically, we're very confident with a single dose and at a mid-dose level that we show, I mean, expression and functionality. That means it does transfuse and infect the lung cells even through mucous membrane, and it can produce the protein.
Hopefully, our next goal is in CF to demonstrate the same because we're going to start dosing patients, null patients, and hopefully, we intend to do bronchoscopy and validate that expression of the vector can transfuse the right cells. I mean, we already know that it transfuses the right cell based off our monkey cells. It transfuses the goblet cells, the ciliary cells, for example, in CF. That's the cell type that you need infection to produce the protein because in CF, it's a membrane-bound protein. We feel pretty confident based on our NHP model. We hope to validate that in our null patients. Of course, 40707 in the lung with oncology. Again, we have shown that obviously we're delivering IL-12, IL-2 directly to the lung.
We do see immune response, and we have seen early signals of efficacy by we see some partial responses, some stable disease. Very promising data, which we presented into ASCO, which we feel very confident now to move that program into the next step.
As you think about those three data sets, two we've seen, one is coming shortly. How do you think about prioritizing one, two, maybe all three of those programs across the respiratory portfolio?
I mean, that's a good question. I think the beauty is, I mean, the biggest obviously the clinical is a challenge. I mean, enrolling patients, getting the studies going. The biggest hurdle is CMC. CMC is the factoring, making the validation batches, the assays. As you can see, many of the companies in gene therapy stall with CMC because that causes them the delay. That causes them consternations with all of the assays and CRLs because of the issue. I mean, obviously, the vector is common across all our programs. I mean, our CMC is going to be a platform technology, which we are obviously going to take advantage of and file. I mean, as you know, our CMC has been audited not just by manufacturing, has been audited just by FDA, twice by the FDA, by EMA, by Japan, so globally.
We have come out globally well in all of the CMC. We are very confident in our CMC. Our CMC across all of these programs are very similar. We feel that that should not be an issue. We should be able to, and our assays are common across multiple of these programs. We need to execute on the clinical side for both CF, especially for CF in null patients. I mean, I had the opportunity to meet with the leadership team at the FDA, at the CEO meeting at Silver Spring. I was able to have discussions one-on-one and in a group forum. I feel like the new FDA leadership is very committed to specifically ultra-rare diseases.
I mean, so much to, I mean, I've heard them say that as long as you have a drug that shows mechanism, that if you have a gene that's missing and able to deliver protein and you can show expression of the protein and functionality of the protein, they're willing to approve the drug because they think these patients need them now. They are okay with no clinical studies proceeding based on that and then confirmatory trials, just like what they do in oncology. I think we have a very favorable leadership right now. I mean, there were concerns with Peter Marks leaving because we worked with him on Vyjuvek getting approved. I feel that we have a path forward.
We just need to get the data, and we'll have those discussions with the agency and figure out an accelerated path for some of these programs that have a real unmet need for these patients.
Maybe frame expectations for the CF read. What is the extent of data or how much can we understand from this initial tranche?
I mean, obviously, we are going to, our goal is to show mechanism. That means we will be bronching and biopsying these patients and looking for protein expression. That is the key. I think that is something that has not been demonstrated clearly, because we express, I know in the past with AAV and other companies, they have done expression of the protein, but in that case, the protein was the mini protein. In our case, it is going to be the wild-type protein that will show expression. At least there is no doubt that this is the real wild-type protein expression. Our intent is to show expression by biopsy by using immunofluorescence. Also, we look at transcript levels to show transcript levels of the wild-type protein.
I just want to add, I know we're dosing a combination of both null patients and patients already on modulators. Our primary focus is on showing a good level of expression in null patients. I don't want to get into what exactly is a good number because you have to remember that we're a redosing type mechanism. Similar to what we're doing with AlphaOne, once we see expression, we're going to move into a redosing paradigm. We're pretty excited about it. We're eagerly awaiting results of the CF program. It shouldn't be too far.
I mean, redosable is a real thing, right? Because if you look at skin, it's the most immunogenic organ. The fact that we can show that we can deliver BVEC in this highly immune, I mean, a region that's open wounds, full of immune cells that we can repeat administer and demonstrate functionality, we feel very confident about our redosability as Krishnan. Also with the levels of doses, we've learned so much from BVEC, which we can improve and use that further in our programs to make sure we get the dosing right, the frequency right. There's a lot of lessons learned that we can adapt to our new program.
What is the relative immunogenicity of the skin versus the lung?
I mean, skin is the most immunogenic organ because that's the first. If we can, I mean, I feel like in an open wound, I mean, lung, even it's not open. There's no, I mean, yes, in CF patients, they do have mucus and infections, and so is in skin. We are able to treat skin that has infection, has stuff. We feel like the mechanism is proven and we should be able to achieve the same in the lung.
How much will we be able to understand on FEV1 improvement? Is that too early?
It's too early because, again, we have to, I mean, it's in a single dose, you can't, I mean, FEV1 is, there's also logistical issues. It's spirometry. There are challenges with the patients. These patients are pretty sick. You can take an FEV1 six times within half an hour and get different readings with 10% variability. There are complexities around it in these sick patients. We need to see overall improvement with time. We have to repeat administer, and hopefully, we will collect that data with time. I think for these null patients, they have nothing at the moment. They have the challenges. Morbidity is another one of the biggest concerns for these patients because they're pretty sick. If we can show something that you're able to express with CFTR protein and they can tolerate the drug, I think we have a good path forward.
What does the path look like if you wanted to start redosing? Is it a one-month process?
No, it's pretty quick. I mean, we already, I mean, we finished this dose and we right away go into redosing. So it should not be, yeah.
Great.
I mean, it's just finishing up this and then amending the protocol and going.
I mean, we're doing that with AlphaOne right now.
The same patients.
I would not say overnight, but within a few weeks, we can get into a redosing paradigm.
Very quickly on AAT because you are going to have additional data this year. What should our expectations be for that disclosure?
Some of the repeat of what we completed in more patients, additional patients. I mean, obviously, this was our first study, and we learned some of the challenges because in AAT, it's a little more complicated. Unlike CF, you just bronch and you biopsy here after lavage. There's trickiness to lavaging. We have learned some of that. Because of that, we had patient samples that we were not able to get. Now we've gotten better at writing the lavage protocol. Hopefully, we can get additional patients with some more robust data, which you can reproduce some of the data that we announced last year.
Have you started dosing in the higher dose cohort?
We are working to redose first.
Okay. In the mid.
We are working to enroll patients in the high dose with 0.7 micromolars that we saw in the AlphaOne. We actually believe we have a good beachhead to redose. The safety profile was excellent, right? While we could potentially get a much higher number, the internal conviction is, look, with a couple of redosing paradigm and a clear safety profile, we should not ignore the mid-dose. I think just in terms of steps, while both are happening, we're trying to quickly get the protocol. We've already gotten the protocol modified and go into the redosing first while we continue to look for one or two patients just to see if the high dose is meaningfully different.
Maybe in the last couple of minutes here, I want to touch on NK since this is your. I think this is an exciting new program for you. Talk to us about what makes you so excited about the opportunity here.
We're super excited about NK because we already shown that we can deliver to the cornea, front of the eye with our BVEC program. Clearly, we see that in our animal studies. In our animal studies, which is a rich proxy for what's going to happen in the humans, we know with a single dose recombinant NGF protein, it's gone in minutes. If you give a single dose versus our vector, just topically applying to the eye, we see sustained expression for a week. We are super excited about that because I think it's a known mechanism, well proven, and we know exactly the number of patients you need to show statistical significance. Understanding based on what Oxervate has done, which is considering that they have to administer six times a day in these patients.
Speaking to a lot of the experts and physicians in this area, they are super excited about having a product where these patients, especially elderly patients, that you have to just put one dose, they can remember it. It's easy. They'll be compliant. They say Oxervate works, but the challenge is patients don't like it because they're not compliant. So it doesn't work the way it's supposed to. I think knowing the mechanism, knowing a pathway, knowing, I think it's just execution.
We're hoping to dose our first patient in the upcoming weeks. We'll definitely provide a pretty comprehensive review of the market opportunity, the number of patients across the U.S. and the rest of the world, and the study design that we're going into phase I/ II with. Suma will probably talk about next steps to get the drug approved during that call.
Great. Looking forward to it. I mean, sounds great. D-risk mechanism, known regulatory pathway. That's half of the battle probably.
And CMC.
Yeah. So we don't have to debate or depend on the FDA. If you know the endpoint and you know the design, it should be execution.
Great. Thank you guys both for joining in.
Thank you.
Thank you, everyone.
Appreciate it.