Okay, hi, good morning everybody. I'm Kristen Kluska at Cantor. Very happy to be hosting Neil McFarlane at Zevra Therapeutics. Thank you for being here today.
Thanks for having us.
This is our first fireside together since I launched coverage earlier in the year, so it's been a very exciting story to follow.
Thank you.
Cool. So to start, I'm going to ask you the typical boring question, which is just to give us a high-level overview of the company, and then we'll get right into some specifics.
Wonderful. And maybe before I get started, thank you for having us. I'm going to be making forward-looking statements, so please take a look at our most recent SEC filing for most up-to-date information. And with that, why don't I kick off who we are and what we're doing?
Please.
Zevra Therapeutics is a commercial-stage rare disease company. We have two commercial products today. One that is treating patients with Niemann-Pick disease type C, which is a rare lysosomal storage disorder of cholesterol buildup in the cell, and you have cell death, and then you have precipitating neurologic as well as visceral symptoms. Another commercial product that we have is in the market today in a more mature market for certain urea cycle disorders, where you have a number of enzymes that are in the urea cycle that process ammonia and nitrogen. And if you have a breakdown in one of those, you get buildup, and we have a nitrogen scavenger called OLPRUVA. It's in the market today.
We also have a late-stage rare disease development program called Vascular Ehlers-Danlos Syndrome, and that's a rare collagen deficiency that actually leads to stiffening of both vessel walls, arterial vessel walls, as well as hollow organs, and can lead to rupture and/or dissection or aneurysms and lead to death or severe challenges, and then we have a program that we out-licensed that is for ADHD, and we received royalties and milestones for that program today, and you put all that together with a balance sheet that's quite strong with about $217 million in cash today, so in a nutshell, that's where we are. I know we're going to get into some more of those, so thanks for the quick question.
Yeah, of course. Well, let's jump right in and talk about MIPLYFFA and NPC in particular. You mentioned it's a lysosomal storage disorder, but do you mind just giving a little bit more background? How severe is this disease? How many patients have it, et cetera?
Sure. So in the United States, there are about 900 patients from a prevalence perspective. In Europe, there's about 1,100 patients from a prevalence perspective. In the U.S., 300- 350 patients diagnosed. And as I mentioned, it's a rare neurodegenerative progressive disorder that leads to a multitude of varying symptoms. And in rare disease, if you know one patient, you know one patient. Not every patient manifests the same, but it has both visceral in the early stages of hepatosplenomegaly, failure to thrive in the infantile version, all the way to the later-stage patients who sometimes will be diagnosed with a psychotic break that is resistant to antipsychotics along with either gait or other cognitive functions. So the presentation of the disease can start, again, from infantile to later in life and a multitude of symptoms.
It's biology, from a biological perspective or a pathophysiology perspective. It is a cholesterol metabolism problem where NPC is an enzyme that brings cholesterol in and out of the cell, and when it doesn't work very well, you can get buildup of cholesterol in the cell and then leads to cell death. When those cells die in the neurons and the neurons die, you have more neurological problems, and obviously, in the spleen and the liver, you have hepatosplenomegaly.
Okay, so you got the approval late last year, but 2025 has been pretty critical because you've understood a lot more about the profile since. So maybe first, can you help us understand some of the new MOA data you've generated and why has this been an important part of your commercial discussions now?
Yeah, so absolutely. We just recently published some clarifying mechanism of action data around the upregulation of the CLEAR gene network and improvement of lysosomal function. So as I mentioned, with cholesterol buildup and cell death, the opportunity to process both this functional or not as fully functional NPC enzyme as well as building on the good ones, you get to process cholesterol faster out of the cell. So the CLEAR gene network and the pathway that's been recently published has been great for us in understanding it. What does this mean to the marketplace? We're talking about a disease-modifying agent. And our data shows disease modification into both our clinical trial data. At 12 months, we saw the halting of the progression of disease based on the NPCCSS scale, which is the clinical severity scale that shows disease progression.
And then subsequently, we've been able to actually publish our OLE data that has up to five years' worth of data in regards to its, again, on the NPCCSS score as halting the progression of the disease in combination with miglustat, which is what our label is. So when we talk about the mechanism of action, clarifying and learning more about it, along with the long-term OLE data, what we see both from a physician perspective that is looking for not just 12 months of data but looking for long-term data, we're able to satisfy it. But more importantly, on a payer perspective also, when you usually launch a product, you launch with a package insert. Today, we're launching with a package insert and five years' worth of OLE data that shows the halting of disease progression in those patients through five years.
Okay. And then another key priority for you this year has been working on the IP estate of the profile. Do you mind sharing with us the latest of where you are?
Yeah, that's a really good question and actually timely. Last week, the FDA actually provided some comment back to the patent office, and we're aware of the patent term extension filing that we did, and we're also aware of the data. We see this is under review and in process. I can't talk to you about what the patent term extension may look like, but we absolutely see the potential for patent term extension past our current orphan drug exclusivity, which is what today our regulatory protection is.
Right, the base case here.
Yeah.
Okay. Anything you can share about that just as we should be thinking about what are the next steps of this process?
Yeah, I can't give you much. It's in the review stage from the FDA going back to the patent office. Again, what I can say, though, is there's potential to be able to have patent term extension past the ODE, which is what we've guided to in terms of all of our public releases. ODE is where it is, and now we have the potential for more.
So it's essentially either past or not reviewed, essentially. Now that it's in the review stage, right, just theoretically, I know you can't talk about what the filing is, but what are the next steps? It's either accepted or it's.
Yeah, I'll give you very big highlights.
Yes, please.
Based on the information that is in the public domain in September, they will actually put it up for public review of 60 days, and at that point, the FDA, sorry, the patent office, will follow its guidance to being able to do its final review and let us know what our PTE is and the final dates.
Perfect. That's exactly what I was looking for. Thank you. That'll be exciting. So we're at a very unique time, right? Because actually, the great news is there have been two therapies approved in the U.S., and we're seeing real-time that everyone says they're complementary and that they're not competitive drugs by all means. But the good news that comes with that is also you have two companies that are proactively educating the market on this disease. So how do you think both of these collective efforts are going to influence future diagnoses?
I have to say you hit it on the money. What we heard prior to launch from our physicians that were in our expanded access program, as well as patients, is they would like to have access to as many mechanisms, varying mechanisms of action as possible to be able to halt and/or improve their disease progression. So we are a disease-modifying agent, as I mentioned. We have both organizations that are out there educating physicians, and as you mentioned, they in practice do see them as complementary. And for those patients who are appropriate, they're actually getting them on as many possible mechanisms as they can. So it's playing out the same way that we thought it would play out. And most importantly, I think we have seen the payers paying for our product, as evidenced by our pull-through rate and our Q2 revenue.
People will do the math, and they'll find out that we are actually quite good at the payers and getting them through the medical necessity process and then getting it paid for. The team's doing a wonderful job.
Okay, great. So now that you're at commercial stage, of course, your quarterly metrics are front and center for a lot of investors here. You've been kind enough to share with us several metrics along the way. So given where you are at the stage of the launch, are there some that are more important than others? And then this is an ultra-rare indication, so is lumpiness normal? How should we think about that?
Lumpiness is definitely normal. However, our success in converting 129 patients to prescription enrollment forms out of the 300- 350 patients that have been diagnosed in the United States is incredible. I think for those patients who have been waiting for disease-modifying therapy and our ability to be able to get them out and get out to the physicians and start to educate folks has been great. We have more work to do for certain, not just to get to the 300- 350 diagnosed patients, but to get closer to the prevalent number of 900 patients. The metrics that we are giving to date are important. One is we're giving prescription enrollment forms, which allows us to fill the top of the funnel for those folks who are looking on a quarter-over-quarter basis. It's important.
Knowing that we've gotten approximately 40% of all diagnosed patients in the first two full quarters of launch is pretty impressive. We're giving covered lives as another metric, and covered lives is those patients who are both on, or those payers, I should say, both on the commercial and the government side, how many of them have gone through and actually have it on formulary? It doesn't mean that you're preferred status or what have you, but are you covered? 52% covered lives is what we had at the end of our second quarter, and that is right on target with where we'd want to see as best practice for launch. Second quarter in a first full year, you're at about 52% coverage. If we can get ourselves to where we have for OLPRUVA today, 78%-79% covered lives, that's pretty much as high as you get.
So we're well on target, and I think we feel good about that. And then the last metric we give is revenue. We recognize revenue when product is shipped to a specialty pharmacy. We keep our target inventory levels the same every quarter, a day or two here or there, but same every quarter. So those metrics fill in the funnel. What does the coverage look like, and then what's the revenue on the bottom? We hope we'll provide the investment community with the metrics they need to show that we're continuing to exceed and excel in our launch.
Okay. So I know you don't have very specific guidance, but what's a win for thinking about the next couple of quarters in your eyes?
Yeah, it's the focus on those diagnosed patients who we haven't gotten to yet, as well as unlocking the undiagnosed patient population. In our current 129 patients, we do have some patients that are new to therapy. Some of the work we're doing, both in our physician education work as well as in the genetic testing work that we're doing, is actually paying off. We've had some new patient hits in the genetic testing program that are newly diagnosed that we're now getting into patient enrollment forms. In addition to that, we're doing the playbook of launch in rare disease. We've just recently launched a CME, well, not us, but we've supported a CME program that is both looking at patients who had more traditional neuro symptoms as well as those patients who have psych symptoms. The CME program is out there and launched last Friday.
We're doing a lot of on-the-ground work with our commercial and medical organization to be able to unlock those undiagnosed and then through a claims data and everything else going after the patients who have been diagnosed.
Okay, great. We're very much looking forward, but props to you to get a third of patients on the drug already this quickly. You don't see that too often. So maybe just helping us understand the life cycle management a little bit better. What's the timeline between a patient receiving their prescription enrollment form and then getting it fulfilled? And you do have a little bit of time under your belt now, so what are you seeing early on for refill rates?
Really early. So two things in that question. It's really early. You're sitting in your second quarter. So in regards to the timeframe of prescription form to payer to paying for it, it's shorter than when we started, but it is still too early because if you're government pay versus commercial pay that we actually have you on formulary already or versus an obscure plan in so-and-so that has never seen an NPC patient, it's going to take a little longer. So really pleased with shortening that window, but I can't give you an accurate timeframe because it's a small number and it's only our second quarter. In regards to refill rates, there are two things that I can tell you. One is that in our expanded access program, where patients were on therapy upwards of five years, and we haven't published our EAP data yet, but it's coming.
Our database closed at the end of Q1, and we're working hard to get that data published. Some of those patients are out seven years. We have an incredibly high adherence rate. Now, what we saw was patients stay on product, but there's a progressive disease and certain patients die. And that's all we saw for the most part of patients who stopped. They didn't stop taking the drug. A lot of times they passed away. The other stat you asked is on our commercial product, what's the refill rates look like? Right now, the refill rates look strong, but we're only in our second quarter.
I get it.
You need about six quarters to be able to have a 12-month persistence and adherence rate, but we're seeing the same kind of persistence and adherence that we saw in our EAP, and we're actually seeing that also in our European, what we call our global EAP program that is also accelerating.
Okay. So far, so good, but still early. So yeah, that's a great shift to Europe. Very, very unique experience with Europe because of the patient dynamics and what's on the market there. But just you mentioned the prevalence is a little bit larger in Europe right now, but maybe let's talk about the maturity and why is it easier to actually identify patients in Europe right now?
I don't know that I would use the word easy, but Europe has a head start.
Okay.
The miglustat has been approved in Europe for well over a decade, and a lot of the investment made in physician awareness, patient awareness, as well as diagnosis over the decade plus has been able to get that 1,100 prevalent, having a lot more diagnosed patients than in the U.S. I can't give you an exact number, but working with patient advocacy groups as well as country by country, we know that there's a much larger number of diagnosed patients in Europe. Now, easier, I don't know, but in Europe, for the most part, you've got reference centers that do the primary work and heavy lifting in rare disease. There are a number of them in France and Germany and in most developed countries in Europe, which is where most of the patients are actually diagnosed and treated.
Those patients and the majority of patients that are diagnosed in Europe are on miglustat because it's a standard of care if the patient can tolerate miglustat, so for us, we're in a very small number of patients, sorry, of markets in Europe with our EAP program, and what we've seen is that those centers of excellence have patients already diagnosed, and they want to be able to add an additional mechanism of action, and we've been able to do that through our EAP program. The other, I don't know if you asked this question or not, but one thing that was on my mind was we filed our MAA in the second half of July, end of July. We said the second half of 2025, so we were quite a bit early.
And that application has been filed, it has been validated, and we are in review right now, and I think that's an important component. There's been some confusion. Are you actually in review, or did you just file? We're filed, we're validated, and we are in review right now.
Thank you.
Oh, and one more thing.
Please go ahead.
The other part of Europe is that this time last year, we had about 70 patients or so in our European EAP program, and as at the end of Q2 this year, we had 89 patients, so we're continuing to enroll patients in Europe and getting physicians and patients to experience with MIPLYFFA in combination with miglustat, so through our review process, we'll be providing additional data like the EAP data I discussed. We actually also have pediatric data. The OLE data was already submitted, and the mechanism of action data, so we feel really strongly that our data package in Europe is much more robust, but it'll allow us also with the experience of the EAP patients as well.
Okay, so when we think about the cadence in Europe, like I said, U.S. very strong out of the gate, and you've identified ways to factor in adding more patients down the line, but this experience is quite unique. A lot of these patients are already on miglustat. They're maybe seeing their doctor perhaps a little bit more often because the doctor actually has a drug that they can give for them, right, so how does that kind of factor into cadence in Europe if you're approved?
Really, I don't know that I can talk about what that cadence looks like, but it's a much more mature market, and those patients, and we have the benefit of long-term data, so when I think about our data, it's miglustat by itself, which you saw progression of a few points over the 12 months versus adding MIPLYFFA and miglustat together, where you see the halting of progression through 12 months. Now you build on the long-term OLE data out five years, then you build on that with the EAP data that we've gotten out in abstract form, but the database closed, as I mentioned, at the end of Q2, and we'll be publishing that data too.
That will allow for folks to understand that you can have long-term disease halting and halting of the progression of the disease over time, which we hope will actually accelerate our European penetration because they're already on miglustat, standard of care. We see the delta in what you do in halting the progression versus progression with MIPLYFFA and miglustat together. The health technology assessments for Europe should look pretty good too because based on our data. So we're confident that we're going to be able to accelerate Europe probably faster than the US.
Okay. Yeah, that's very unique for a rare disease company.
Very much so.
So we're looking forward to it. Maybe I'll switch gears here, talk about UCDs with OLPRUVA. Can you talk about ideal patient population to target here and what factors go into patients switching, especially as the prescriptions tend to be longer here?
Yeah, OLPRUVA was our first launch product. We've been very open. It's been slower than we would have anticipated. We've actually pivoted at the end of Q3 last year to those more active patients who would like the clinical benefits that OLPRUVA brings in terms of palatability, portability, and the actual dosage that you have. We've now been able to go to physicians and patients to let them know that this product is an available product. There is also, though, a very high level of satisfaction with the current products that are in the market, and that's something that we've learned over time. It's a mature market. There are a number of products in the space. However, there are also dynamics changing where there are authorized generics coming to the market later today.
We believe that the product and OLPRUVA allows for patients to be able to have an experience that would allow them to get on the product, and we've now got a few commercial plans that have put us in a spot where we believe we can also win, so with that, that's where we've been focused our strategy on, and now we've got to see it execute.
Okay. And then your VEDS program, maybe you can walk us through this. I don't think people are as familiar. Just in general, what's the importance of collagen III across our organs?
Yeah. So the VEDS program is, just to back up a little bit, there are about 7,500 patients in the United States with VEDS. There are no approved treatments today for V ascular Ehlers-Danlos Syndrome. It's managed a lot of times by surgical intervention for dissection, or if you catch a rupture early on, then you can actually surgically intervene and patch the vessel. The stiffening of vessel walls as well as hollow organs that you see with VEDS is something that mechanical stress doesn't help. So celiprolol, which is available in Europe and is actually the standard of care in certain European countries, we have put together a program with the FDA under a SPA for 150 patients, two-to-one randomization for a decentralized study to actually study it in the U.S. and have for celiprolol to become the first approved product in the U.S.
Now, that trial has 39 patients enrolled after a hiatus of about a year prior to us acquiring the product. We've enrolled now quite a number of patients. We have invested into genetic centers who've got genetically validated COL3A1 positive patients, and we've put a lot of investment over the last six months into these centers that are now referring, let's call them more appropriate patients to our site to be able to come through the trial and then get dosed. Their investment is made. The next couple of quarters, we're going to have to find out if the investment is going to pay off. It started last quarter. We're hoping to be able to continue to see more in order to get this product across the FDA finish line.
Okay. I would say that you are in an enviable financial situation right now. Got a really strong balance sheet, got a new drug, so you're generating revenue there. So what's the perfect divide in your mind to focus on commercialization, but also maybe taking advantage of pipeline optionality here?
Yeah. We're in the second quarter of launch, and sometimes it's hard for me to fathom. 12 months ago, we didn't know if we had an approvable product with an AdCom. And 12 months from then, having a third of the diagnosed patient population already that is on therapy. I've been doing this a while. I've launched a bunch of rare disease products. I've never seen a successful product like this, a successful launch like this, not only in generating prescription enrollment forms, but also in the pull-through, which is a testament to this team and the investment that they've made in commercialization.
I would hope that, and our strategy is to be able to continue to execute on what is in front of us today so that way we can earn the right to go out and leverage the infrastructure we've built that does this really well in this metabolic space and in the rare genetic ultra-orphan disease space. For us today, let's have a couple more quarters under our belt of execution. We've just put in our MAA to expand our population to the much more mature marketplace in Europe. That's a big deal for us. We're not only filed it, but we're actually now validating and moving forward, as I mentioned. So we're in the crux of trying to expand the TAM with a higher prevalent population and more diagnosed patients. So ramping up for that's important for us as well.
And then getting our phase III trial in celiprolol ramped up because in order to have events, you've got to finalize and enroll all the patients. And that's kind of where we are today. Being in a financial position where we continue to say that our strategic plan and we have the resources we need outside of the capital markets to be able to execute on that, do we go at it alone? Do we go at it in partnership, or do we go at it at some type of a hybrid structure in Europe? That's not yet done, but we have the resources to do that. And we are fielding capabilities presentations and trying to make sure that we've got the right pricing core to data and obviously all the work that we need to be able to make a right decision there.
So we've got what we need, and now it's execution, and we're doing a pretty good job there so far.
Yeah. For that Europe opportunity, beyond just understanding the pricing dynamics, are there any other factors that you're going to consider, or would you kind of map out what the cost would be if you were to do it in-house, or what essentially work are you trying to do to understand what the true value is and which decision you ultimately make?
Yeah, absolutely. There are a number of big decision points. And by the way, we didn't start this yesterday. This has been going on for about since January. But the pricing and payer work is important as ever-changing dynamics in Europe in terms of at a country level around reimbursement. What sequencing we would do, how do we maximize the value, not just within the EU4 plus Europe, but I'm sorry, plus the U.K., but how do we look at this outside of that to make sure that we're impacting patients who can benefit from MIPLYFFA across the board, either we have a US label or a European label. So all of that work has been ongoing. The output of that work is also coming. Now, finalizing a label with our 128 comments will be important.
Once we get the mid-cycle, we'll really understand where we are, and we can start to make some real decisions. So getting all the data points in the right place for us to unlock the value is where we are. However, we're continuing to invest in the small number of countries in Europe to expand the EAP program. And as I mentioned, we've gone from approximately 70 patients last year this time to 89 patients at the end of Q2. So we'll continue to try and take care of patients in Europe as we're moving forward with the filing.
Okay, great. Anything that I missed that our audience should take away today?
Thank you.
All right. Well, thank you so much. Really appreciate it. It's been an exciting launch so far, and there's definitely a lot more legs to go. So thanks for your time, Neil.
Appreciate it.