Okay. Good morning, everybody. Thanks so much for being here, day 1 of the Cantor Fitzgerald Global Healthcare Conference. I'm Kristen Kluska. I'm joined by my colleague, Ayan Hussein, and we're very happy to be co-hosting the Zevra Therapeutics team. We have Neil McFarlane, the President and CEO, and Justin Renz, the CFO. Thank you both so much for being here today.
Good morning. Thanks for having us.
Okay, so in typical fashion, I'd like to start by asking you to provide us with a high-level overview of the company.
Great. Thank you. I will be making some forward-looking statements today, so please take a look at our most recent SEC filings for the most up-to-date information. Thank you for having us here right after Labor Day. It's a great way to kick off the fall. Zevra Therapeutics is a commercial-stage company that is really trying to find ways to redefine what's possible in bringing medicines to the rare disease community. We today have a commercial product in the U.S. for Niemann-Pick disease type C. We also have another product in the U.S. that we don't promote, called OLPRUVA, for urea cycle disorders. Then we have our European and global expansion opportunities that we're looking at for Niemann-Pick disease type C within a regulatory phase right now, along with geographic expansion to new markets to be able to take care of NPC patients.
We have a rare disease program in vascular Ehlers-Danlos syndrome. That is in phase III in the U.S. as well. All of that being said, we are well-capitalized to be able to execute on those three priorities, we call it the three legs on the stool, as we are moving forward, and looking forward to the rest of the conversation today. Tell you all about it.
Okay, great. Let us kick things off by asking some questions on MIPLYFFA. First, Neil, to take a step back, you joined the company as CEO roughly three years ago. At that time, we had no approved therapies in the U.S. for NPC. When you joined, again, three years ago, what was the vision of the market opportunity for NPC?
Yeah, it has been a really interesting ride. The opportunity to come to a company that was leaning in to becoming a commercial-stage rare disease company, with my track record, having done that a few times. The unmet need for patients in NPC in the U.S. versus Europe, and I will talk a little bit about that in a moment, not having an approved product in the U.S. versus having an approved product in Europe, a much more mature market in Europe versus the U.S., led me to believe that, number one, the clinical data was fantastic, both being clinically meaningful and statistical significance in bringing a product to market, but also the unmet need was huge.
The opportunity then for us to be able to take a look at this market and say, okay, there is about 900 patients from a prevalence perspective, but the 300 to 350 patients that we understand have been diagnosed through the ICD-9 and 10 codes and have a code is actually quite smaller than that of Europe, where you see about 1,100 patients in Europe from a prevalence perspective. But the majority of those patients, or a large majority of those patients, have been diagnosed, found, and on therapy because there was an approved therapy in the market in Europe for a decade plus. When we think about the unmet need, the clinical significance, and the opportunity to bring a product in, for me, three years ago, it was a dream.
How could we come in and penetrate the market and really do all the things that I hope we'll talk about some more today that we've been doing commercially to be able to identify patients early, to be able to offer a therapeutic product that has the potential to halt the progression of a devastating disease, and now based on long-term data that we've now published over the last few years, solidifying ourselves as a foundational therapy that we can then move and continue to penetrate the market.
Okay. So it sounds like three years ago, you were optimistic the market was probably larger than we estimated. If we fast-forward to today, fortunately, these patients do have options now. I'm curious if the vision has changed at all.
Yeah. Three years ago today, in our second year of launch, could I have imagined that of the 300 to 350 identified patients that we'd have as of the end of Q2, 184 patient enrollment forms and penetrated that percentage of the market? I would say no. I would say that would've been a dream. But today, what we've seen in our efforts around earlier diagnosis, what we've seen in our efforts to getting newly diagnosed patients added really is now allowing us to push the envelope to say, this market is somewhere between the 350 and 900 patients because it's early. We launched the product in the market in the end of November 2024. We're not even two years into the market and have really done a wonderful job of making the product available. I think there's also an element of this that we are learning as we're going.
We did not recognize the fact, and I don't think that anybody recognized the fact that there were so many adults. We're identifying patients in their 20s, 30s, 40s, 50s, even a 60-year-old that's a newly diagnosed patient. That is a market understanding that we didn't know. So we thought of this as a childhood disease, and now we see about 50% of our patients that are coming in are adults versus kids. So that learning, we continue to learn, and now we got to figure out how to be able to then take that learning and expand the market to get closer to the 900 and the 350.
Well, congrats on everything you've done in the almost two years to date. I know you're still hungry for more. Putting it all together, what would you view as a conservative, a base, and even a bull scenario when thinking about the total addressable market in the U.S.?
Yeah. As I mentioned, the learnings that we've had over the last two years, and we're learning every day. Every prescription enrollment form that comes in, we're actually trying to get as much of an understanding of the patient's journey, not just to therapy, but to diagnosis. That learning then allows us to be able to put into perspective what it is that we would like to be able to invest in to get more diagnosis. When I think about what we're learning, the wins that we're having off of what we're learning, I would tell you a minimum and maximum. I think the minimum today is that 350. I think the maximum is probably the 900. At this phase, the newly diagnosed patients and the adult patient expansion has given us belief that it's definitely more than the 350.
Okay. Do you mind just giving us an example or two of ways that Zevra has helped to identify new patients since the launch? How have these ultimately influenced the mix of patients you see today?
Yeah. In the rare disease space, we're talking about the potential for 900 patients in the United States. We are focusing the efforts, and I have to say that it's not just us. There are others in the NPC community that are also raising the voice of trying to get earlier diagnosis. There were some new guidelines that came out last quarter from a group of experts around the world stating the utilization of earlier genetic testing of combination therapy, which we have a product that's in the label with combination therapy, and use disease-modifying therapy. We're in that, and I think that that's also helping educate physicians and allowing us to be able to raise a voice for physicians to be able to think about NPC beforehand. It's all of the things that you do. It's the disease state education.
It's the genetic testing support that we provide. It is the pull-through of ensuring that if a physician has never had experience, we have an ExpertConnect program that allows for physicians with experience to get the opportunity to speak to physicians who don't have any experience to understand what that treatment pathway can look like. And then obviously, all the way through our patient services efforts that we do. I didn't give you a specific example, but what I'm telling you is that there's no secret sauce here. There's no one effort that is going to drive this market. It's everything that you've got to do to be able to get patients diagnosed early and then make sure you provide every support you can to keep them on therapy. So far, it's working.
Yeah, we do multiple disease awareness campaigns. We try to make ourselves available for everyone because as we were just talking about, just two years ago, there was no specifically approved therapy in the U.S., so the physician didn't have anything specifically to offer. This is really a new offering, and there's multiple therapies, and again, the guidelines state how we want to treat as early as often as we can, and we're happy to be a part of that and make people aware of that.
Okay. And thinking about the perspective of Europe, you talked about this earlier, but there has been an approved therapy there. Do we know over time if the introduction of miglustat led to more patients being identified over time, kind of as a way to predict what might happen here in the U.S., right?
Yeah, great question, and 100% accurate. We've seen this in almost every rare disease category that I've been in in my career. You don't have an approved product, physicians are less likely to think of that disease.
Right.
They're less likely to be able to. They can't offer anything to those patients, so they think about something else. You get a product approved, you start this educational campaign, the tide starts to lift. I'll give you an example. Last week or week before last, there was a meeting in Helsinki, a genetics meeting in Helsinki, and there were a number of physicians that were out there presenting data. One of the abstracts, I won't get into the data, but was from a German group. In that German group talked about patients that were on arimoclomol, not approved at that point in the game, but had been off and on the product and how the patients responded.
I will tell you that I wasn't there, but the feedback from the group was that the groundswell of other people now asking questions about patients who had autism that were misdiagnosed, patients who had MS that were misdiagnosed. All of a sudden, you start to have that education across the neurology community, the genetics community, that there's something there. All of that does rise the tide. In Europe, specifically, having a product and having socialized medicine also helps because you go to a reference center in a country to get taken care of for rare disease. We're aware of one site in Germany, for instance. They have 50 NPC patients.
Wow.
Because there are only certain centers you can go to within the German in-country to be able to be treated, likewise in France and other European countries.
Okay, thanks. I feel like during our conference, we always have a lot to talk about on IP. You received a recent Orange Book listing through 2041, and you're also currently waiting to hear on potential PTE. Collectively, how should we be thinking about the strength of the IP portfolio, and when you would now expect a potential generic could first come to the market?
Yeah, we are really pleased about the opportunity to continue to invest and drive awareness and get patients onto therapy with a longer runway. 2041 is providing us with a lot more runway. Additionally, the PTE will be within that range when it does get issued, and we will continue to invest in strengthening our intellectual property position so that way we can have the ability to continue to invest and drive patient awareness and get us closer to that 900 patient prevalence in the U.S.
Yeah.
So, really pleased with that. We are continuing to invest in that area, in IP, in additional IP as well, and we will drive to executing having that protection now in a much stronger way.
Maybe at the Cantor 2036 conference we can talk about how many patients are out there and look back at where we were thinking today.
Yeah, I think it is interesting because a lot of times when you start off in. This product had a long history. So for us, the opportunity to be able to extend that runway allows us to make more confident investments in the long term as well.
Okay. What can you tell us about the re-examination request in Europe, and what is going to be different this time around in terms of the people involved, the process, anything else?
Yeah. I probably will not be able to get into a lot of the depth
Sure.
in terms of the specifics, but-
Understood
The grounds for refusal that came through are specifically going to be addressed in the re-examination process. We have filed for what is known as an EAG meeting or an Expert Advisory Group meeting/SAG meeting, is another name for that, Scientific Advisory Group meeting. These are going to be experts that are called that will allow us to be able to raise the voice of the data that has been submitted. We cannot submit additional data. But we have been issued two new rapporteurs that will be able to take up the specific issues in the re-examination process, and we will be able to provide the data that we have. Again, the strength of our data, and from the clinical guidelines to the open-label extension to the expanded access program to our clinical trial that was statistically significant and clinically meaningful for patients.
This breadth of data we'll be able to bring alive to address the issues that they have. We still feel very confident in the strength of our data, and every day it gets better.
Okay, and then does the continued growth of the EAP factor into your confidence as well?
Well, we are really pleased to be able to support patients on a global level. As you recall, our global EAP is both Europe as well as other markets that we're expanding into outside of Europe. Some of them are named patient reimbursed, and some of them are compassionate use. But as of the end of Q2, we had 122 patients.
132.
132 patients that are continuing to grow. So the pull and the requests for compassionate use or expanded access is critical, I think, to also tell the story, which is we're not actively promoted, obviously you can't.
Right.
But the fact that we're getting inbounds from Europe, from major European markets that we're in, we're going to make it known.
Okay. Just in general, what's the number one misconception that you hear from investors or folks who are new to your story, and why don't you think that view is correct?
Great question. I don't know if there's misperception of what it is that we are or who we are, but there was, I think, a tendency to think that the market was not as large as we think it is.
Right.
We've been slowly chipping away at that, starting with our expanded access program that we converted in the U.S. really fast to then driving the quarter-over-quarter lumpiness that you see in enrollments. But overall, if you look on an annualized basis, we are doing a great job of driving this marketplace and getting access for patients to MIPLYFFA in the U.S. So it feels to me like we're building confidence in the investor community by executing, and that's what we'll continue to do.
Okay. And obviously, you ran clinical trials that were successful, but now that there have been patients on drug for a longer time, I'm curious if you've heard any anecdotes or any data points in particular that really go beyond what we could just see in a chart of looking at data.
Well, there are two things that I'm really pleased with and I think do bode well for long-term success as we see it. In our expanded access program, we had the opportunity to be able to see patients over a long period of time. We published data, recently shown four-year data. And the retention rate of patients in that expanded access program in the U.S. was really high. The discontinuation rates were really low. We're seeing a lot of those same characteristics now that we've been in the marketplace a few years, and we've transitioned those patients who were on drugs, some of them five years, continue to have that kind of durability.
That is probably one of the big takeaways for us that we have something that's meaningful to patients, and caregivers for that matter, because a lot of these kids need to have caregivers that give a product three times a day and so on and so forth. I feel that that's one of those takeaways that allows us to lean in. The other thing that we see is that our efforts are paying off, right? Our specific efforts in our disease state awareness. We can actually follow a click of a patient that asks for a physician, that we can help them get to a physician, and that physician puts a patient onto product. Those types of investments you can then say, okay, from disease state awareness to satisfying patients' needs by getting them on a product, those are efforts that you can double down on.
We're killing things that are not working, by the way. That is helping us tremendously in regards to refining where we invest to the further growth of the organization.
All right. Moving on to your VEDS program, which you have a BTD for. You've been guiding to engage with the FDA to explore paths to accelerated approval here, or sorry, accelerated development. What are the key goals, the asks, that you're going to present to the agency?
Yeah. So the VEDS program is moving along well. We had 66 patients as of the end of Q2 after restarting that trial. We did meet with the agency in the first half of this year to talk about ways to either accelerate the clinical program or accelerate the regulatory path forward, and we call that kind of advancing the clinical development of the program. We are on track now. They gave us some homework. I think it was informative and constructive meetings that we had. They gave us some homework, and we are on track in the second half of this year as we've guided to be able to have the next engagement for us to bring that homework forward and see what the path is for us. So a little early for us to talk about what those potential-
Yeah.
Areas are, but the homework is done, and now we're going to have an engagement here in the next half.
That's awesome. Maybe just to take a step back, could you just briefly talk about the event-driven design of the phase III study, and what are the biggest factors that are influencing event accrual and interim analysis?
Yeah. Let me take a step back. Vascular Ehlers-Danlos syndrome is a genetic disorder that affects the connective tissue of small to medium-sized vessels as well as hollow organs. An event is defined as a rupture aneurysm of one of those organs or vessels. The trial that was done previously was called the BBEST trial, and that study was done in Europe. The previous sponsor of the company we acquired had filed on that to try and get it approved. It had about a 78% reduction in events, defined as a dissection or aneurysm or whatever that was detected prior to. Moving forward, this is an event-driven trial. We have three events as of the end of Q2. We need 28 events to have an interim analysis, and then we need 46 events to be able to have a full analysis.
On that 28 events, we can have a non-alpha look and see what transpires, and that event rate being only three events so far is what really drove us to be able to go back to the FDA and to say, "Okay, guys. We're under a SPA. We have all this fancy regulatory support, but we really want to understand how we can get this product to patients quicker." Because don't forget, it is the standard of care in a lot of ex-U.S. markets. It's the standard of care in Europe. It's the standard of care in Japan. It's the standard of care everywhere for VEDS. Not everywhere, but standard of care in most markets that are mature markets. So we want to find a way to be able to get U.S. patients this product as fast as possible.
If the event rates are such that it's slowing, then it may become unethical to continue the trial, and we want to be able to get in there and execute on that. That's what we're doing with the agency right now.
Yeah. Thank you for that. Just in general here, how should we be thinking about the sales force and the marketing efforts over time? Do you think you're well-positioned now, or are there still ways to grow?
Specifically for VEDS or for our MIPLYFFA business?
I think for MIPLYFFA.
Yeah.
Yeah.
Today, we're focused heavily on the centers of excellence, and we believe that we're well-positioned to be able to explore these centers of excellence, about 40 of them in the United States, and we're doing a really good job as you see from our patient diagnostics and patient enrollment forms that we're getting. The flip side of this is that as we're getting smarter, I mean, I told you about this 50% of patients that we're seeing coming in are adults, we're also learning more. I give you just a really quick snapshot here. One of the things we've learned now with this 50% of the patients is there's a high overlap with adult diagnosed patients and cataplexy. It's one of the diagnostics that you see in the suspicion index, cataplexy.
If there's a large impact of cataplexy, then how do we think about making sure that we focus on patients who have cataplexy and some type of speech or swallow or other things that are with NPC to open that? If that shows us that there's an opportunity to be able to explore different areas to identify and diagnose patients, then we'll look at our sales force infrastructure. Today, it's doing really well. But as we learn, Justin has no problem in investing in ways for us to be able to identify new patients if there's a larger breadth of patients in a specific area.
That's great. Thank you for that. You are in a strong financial position currently. What are some of your goals to maximize this?
Yeah. No, thank you. Building on what Neil just wrapped up, we finished the second quarter with $260 million in cash. Even more perhaps impressively is how Neil and the team had us with a clean balance sheet. We actually have no debt. We've been able to actually generate more cash than spend, which is not necessarily the goal because we always are looking for places to invest thoughtfully. We're looking at the MIPLYFFA U.S. opportunity. What can we do to, again, reach as many patients as possible? Disease awareness is so important. We're, again, making investments in Europe, again, to do our best in the reassessment that we've discussed to make sure we're well-positioned and have all the options available to us for Europe and rest of the world.
I think MIPLYFFA is a tremendous drug, and the ability to offer it to as many patients globally as possible is on our initiatives. We talked about VEDS and celiprolol. We want to be well-prepared should we be so successful to, again, keep moving that forward, as Neil discussed, in the parallel processes between the phase III clinical study and working with the agency on how we can perhaps accelerate that regulatory process. We're, again, looking thoughtfully to see if there's anything tangential or modest that we can add because we really believe we have the team in place, the infrastructure in place to be a leading ultra-rare disease company. We have a strong base to build from, and again, in a position to invest thoughtfully as the opportunities present themselves.
Thank you. For these last few minutes, I'll just turn the floor over to you. What would you say is the most misunderstood or undervalued component of Zevra's valuation?
Yeah. I think that the growth story here for us and our hyper-focus is on the U.S. business. We are in a position where 184 prescription enrollment forms is a great start out of the gate, right? It is over 50% of the diagnosed patient population. That is huge. But the newly diagnosed patients, as we are seeing them come in, and we are seeing them come in at a faster clip now through our efforts and through the efforts of the broader investment that is going into NPC, we are now really confident that the marketplace is bigger than 350. Somewhere between that 350 and 900, but it is bigger than 350. I think as we are now learning, because in our initial forecast, we did not see 50%.
I can tell you this now. We did not see 50% of this market being adult patients. We just did not see it.
It has been characterized when I was in the clinic as childhood Alzheimer's, and today what we see is the adult patients that have been misdiagnosed. That gives us a lot of confidence that we have got a business to invest in that can be a driver of long-term growth for investors. When we think about the Europe and the global expansion, we are expanding into two other markets as we look today under our name patient basis program. We are investing into the re-examination process with a robust data package to be able to drive what we hope will be a positive outcome. But we are going to give it everything we have got. Then we have got this celiprolol program that we are trying to accelerate to move forward.
Underpinning all of the $260 million that we ended with last quarter, we have the resources now to hyper invest to be able to grow that U.S. business to get closer to the 900, to be able to execute Europe with positive, with success or failure with the EMA. We still have the opportunity to support those markets. Then if we are able to be able to accelerate the celiprolol program, we have got the opportunity to be able to invest in that and have a successful launch and take care of the patients in the U.S. Which about 7,500 patients in the U.S., it is not insignificant of a marketplace.
Yeah.
All in all, these three legs on the stool that we have from the U.S. business, the global business, as well as our pipeline, we feel like we are well capitalized. We have got a great team in place to be able to execute on it, and we will see what we can do to quell any of the misconceptions that might be out there.
With the strong intellectual property position that we are in too, we have years to execute.
Yeah.
Great. Thank you so much. It sounds like we do believe that there are a lot of reasons why investors should be looking at Zevra right now. We have covered a lot of ground. Is there anything else that you think we left out that should be
Not that I can think of, but we appreciate you guys.
Yes. Thank you for, Ayan, for your support.
Yeah.
Yeah. Absolutely. Thank you for being here.
Very good. Thank you.