Good morning, everyone. I'm Samanth Kulkarni, a senior biotechnology analyst here at Canaccord Genuity, and it's my pleasure to have Zevra Therapeutics with us here today. Zevra, as you might know, has a product that's approved and on the market already for an ultra rare disease called Neiman-Pick type C. The product is called MyPlypha, and it's been launched for some time now, and we've had some interesting things back and forth with Europe as well, the medicines agency there. so we have a bunch of questions for you guys and thanks for making it and for Zebra we have CEO Neil McFarlane and CFO Justin Renz and out there in the audience we have Nicole Oshner who knows everything about the company as well so so we'll keep this interactive we do have a mic going around so please feel free to raise your hands and we'll get the mic across to you in case you have any questions so with that I'll kick it off so Neil can you set the stage a little bit on exactly what's happening with MyPlyFAR the unmet need that that product serves the Neimanpick Type-C community and how it's received that and what you've done so far with the product.

Yeah, thank you, Suman. Thanks for having us. And we'll be making some forward-looking statements, so take a look at our most recent SEC filings for the most up-to-date information. Yes, we had our earnings last week, and we ended up announcing a very good quarter. And again, we are three prongs on a stool here. We have my play for in the U.S. that remains our core focus on driving value for patients in combination with Miglastat. We are also working through our geographic expansion strategy. We'll talk a little bit more about that in a moment, not only with our MAA process in Europe, which is going through a reexamination right now, but also in our market expansions that we're working on through named reimbursement and expanding access there. And then lastly, our solipolol program, where we are driving, you know, engaging with the FDA in the second half of this year after earlier this year engagement on how we can accelerate the development of this program for patients with vascular Euler's Danlos syndrome. So very proud of the execution in the first half of the year and looking forward to taking some questions and having a conversation today.

Thanks for that. So you mentioned prongs in the stool. I'm going to ask you to pick the highest priority prong right now. Is it my Ply-Fi in the U.S.? Is it the MePlypha pending application or the resubmission that you have into the EMA or something else entirely?

Yeah, I'm not sure. Clearly, our focus is on the U.S. MyPlypha business, but I don't know if there's one that's more important than the other today. All of them, I think, provide the opportunity for us to access meaningful therapeutics and potentially meaningful therapeutics to patients with rare diseases. So from a standpoint of how we see the evolution of our business and the growth of our business in the coming three to five years, these three prongs on the stool that I discussed about starts with executing in the U.S. for my play fund. The team has done a remarkable job so far. As you know, we had 184 prescription enrollment forms from launch to date in this marketplace where I think we're starting to generate not only patients who are currently diagnosed, but also continuing to unlock those newly diagnosed patients, which gives us that confidence that the market in just a short period of time is greater than the 300 to 350 patients that are currently diagnosed and more between that 350 and the 900 patients of a prevalent marketplace. So we're pleased with what we're doing, but we're not stopping here. We're going to continue to lean into the future.

So this is a bit of a question related to that. Now that MyPlyFi has been on the US market for some time, what can you say is working in your efforts on the commercial side versus where you think the company could do better? And has the Neimanpick type C market surprised you in any way?

Let me start with the last question, because I do think that the Neimanpick C market has surprised us in one way, and it's in a good way. You know, we for years have thought of Neiman-Pick disease type C as a childhood disease. We've always known that it had kind of four different phases from infantile to an adult version of the disease. I think the biggest surprise has been the number of adult patients that we're seeing in our enrollments as, you know, we've become more, getting more real-world data. Today, when we, actually, when we launched the product, our EAP was comprised of about 50% adults and 50% kids. Today, you know, we've surpassed that number by well over 100, and we're continuing to see this adult population and child population continue to remain about 50-50. That's a big surprise. Number one, it's a big surprise because as patients have been either misdiagnosed for a long period of time with something else, which we've seen. We talked about this on our earnings call. We've had some patients who had multiple sclerosis for many years who then, you know, continued to progress in symptomatology that was not necessarily defined in multiple sclerosis patients. And they have been genetically tested and then had NPC. We've had some patients who had autism spectrum disorder, but then progressed in other ways that you would normally not see in autism that they then got genetic testing and came on board. And just recently, actually, there was an article published last month, or actually, no, we're in August, June, and it talked about a case study around a patient who had Wilson's disease for many years who then had copper chelation and so on and so forth, but yet still progressed. They did genetic testing and came up with Neiman-Pick disease type C, an adult. So this learning is a big surprise for us in regards to what we're seeing in the marketplace. Additionally, last week, we got our expanded access data published, and that expanded access data had a very large cohort of adult patients for the first time, with some of them out to four years. So that's a big surprise, but that also then reinforces the market and the potential for expansion of the TAM between that 350 to 900. The other tactics that we're doing, I can't say there's one tactic that is the one thing that has been driving all the early enrollment, new enrollments, or one thing that has been really key to us educating physicians of patients that they have, it's really a multitude of factors. We're doing the disease state awareness. We're offering genetic testing. We are, we're driving our publication efforts to make sure that that's out there. The clinical guidelines have recently been published, which really gives a lot of strength to diagnosing early, utilizing combination therapy, and those things. So all of the pieces of the puzzle is really an integrated strategy that I think has been rising the tide and lifting the diagnosis and treatment of patients.

So patient endowment forms, this is a metric that investors are keenly focused on every quarter and maybe overly keenly. So what can you do there that might make those more predictable for you and for us in the sense that you might start giving us what to expect on that?

It is really challenging with the law of small numbers. I mean, we're talking about 900 patients in the United States from a prevalence perspective. I wish I had an answer that I could tell you that we're going to find, you know, X amount per quarter or per month. But in rare disease and in ultra-rare disease, once you know one patient, you know one patient. And I think the diagnostic odyssey that patients have, the journey that they have in their disease, everyone is different. So it's not something where I could say, if I do X, I'm going to see Y. We're doing a multitude of activities across the, I'd like to say, the rare disease playbook. We'll scale some up that are working and scale some down that may not be. But I think that the playbook of supporting patients and physicians for a new disease, we're starting to see those efforts pay off in the newly diagnosed patients and the expansion of the market.

So you mentioned roughly 180 or so cumulative enrollment forms. How representative is that of true patient share within 300 to 350 diagnosed and treated patients?

So 184 patients from levels to date, that represents the majority, the majority of that represents patients who were already diagnosed in that 300 to 350. However, as I mentioned last year, this time, we were starting to see newly diagnosed patients, kind of early in the launch, but newly diagnosed patients. We've seen newly diagnosed patients every quarter since then. So that's what's given us the confidence that the market and the TAM is expanding beyond the 300 to 350. And actually, that's something that we've had communicated back to us with those folks who've got access to claims data. They are also seeing it, even with the lagging claims data, they're seeing the marketplace rise based on the activity. So it's good. And now with guidelines and the efforts of our team and our medical team and everything else, it's really picking up.

So just to clarify, the 180 or so, it corresponds to one patient, new patient every time.

184 prescription enrollment forms comprises the majority of those comprised patients who were previously diagnosed, and a smaller part of that is the newly diagnosed patients. So the 300 to 350, the majority of our 184 prescription enrollment forms are in that 300 to 350 with the newly diagnosed patients coming.

Sure. So it's 184 distinct patients, though. It is 184. There's no refill component or anything like that to an enrollment form.

That is one prescription for one patient.

Okay. Got it. at what point would you be willing to share what fraction would be newly diagnosed patients in the patient enrollment form number that you have?

I think it's really too early for us to provide any guidance in that regard. And I think it's important also to note that we have a very small population of a very high impact product, but also a high value therapeutic that, you know, Me guiding you with one patient difference is a significant and meaningful change in our numbers. So it is really hard for me to give you that right now until we get to a steady state. And I don't know when that steady state is because our growth rate both in the U.S. on a quarter-over-quarter basis, as we were having this conversation last year this time, it was certain quarters were single-digit enrollments, certain quarters were double-digit enrollments, and very hard to navigate. But on a full year, we did about 52 enrollments last year. To date this year, although we had a single-digit enrollment, a double-digit enrollment, what we have now is 23 patients. So it's very challenging, I think, to go quarter by quarter. And the variability will continue as we continue to move forward. But the key here is the total market, addressable market. We're gaining confidence that it's bigger in our second year of launch.

Got it. So on that gaining confidence note, I'm going to press, but this is going to be a qualitative question. You can answer quantitatively if you'd like, but I think you won't, so I'll keep it qualitative.

So now that you know that you have a certain number of newly diagnosed patients within those patient enrollment forms, do you feel better about the number of years it might take you to expand that market from 350 to 900 prevalent patients, or are you the same or worse compared to where you were last quarter? um we are expanding that market now every newly enrolled patient above what was previously you know the running average of new enrollments which we are exceeding today uh on an annual basis uh year over year means we're expanding that market so we're expanding it now in terms of quantitatively i can't i can't answer that question i tried oh next time we should get chairs with cup holders

Yeah, yeah.

No, it's okay. It's okay.

So I guess you have these kind of green shoots that you see on newly diagnosed patients getting into the fold. What needs to happen from a larger or a wider viewpoint, I guess, to get more of those patients in? I know you have genetic testing going on. You have these AI models that you're using. Can you give us a flavor for what those might entail and what exactly needs to happen to get that to that number?

Well, like I said, it's an integrated strategy here, right? There's no home run. The opportunity to enroll patients earlier and get them diagnosed earlier and on treatment that allows for the halting and progression of this progressive and devastating disease, that's where we're focused on. So some of our efforts are to establishing the diagnostic earlier by educating the physicians and patient groups and everybody else. The other part of it is, as you mentioned, our bespoke AI model that we're utilizing EMR data along with claims data through the suspicion index of NPC to be able to hone in on our representatives who have got some of this data that now allows them to be more efficient. when they're in a call of a patient or of a doctor that they know has an NPC patient, can they start to expand in those areas? So that will then drive, you know, our goal is to drive additional patients who are not yet diagnosed and then have it on the back end lower the barrier for genetic testing for physicians to be able to then have a test available to them at no cost if they need to outside of their own health system. So I think it's through the journey, both the diagnostic journey and the journey of the patient with the disease, to us to be able to look at this more integrated approach upon all these things to help the rise of the tide. So I don't think that, yeah, like I said, I don't think there's one thing. But there is an element of this that is a playbook that we're following. And this is an important component. Miglostat was approved in Europe for NPC for well over a decade. and in Europe you have a prevalent number that's about 1,100 patients in Europe and you know they have more population than the US so you'd expect a little more. 900 in the US, 1,100 in Europe but the disease state, the education and the other things that have happened in Europe have led to a much more mature patient base that is closer to the prevalent number than where we are today in the US so we're utilizing that playbook to get our numbers closer to the prevalent number. And we're seeing that in the market today. We're seeing that in the numbers.

On that note, do you think your current spending is appropriate, current spending on the level of education and NPC in the U.S. is appropriate given what your plans might be for the longer term?

This may be a great opportunity for me to engage our CFO who's next to me here.

We have a regular push and pull with our Chief Commercial Officer, Josh, to find the best use of our treasure we take shareholder money very seriously so we have regular dialogue on sizing of the team efforts to invest we are in the growth stage so you know when we have 260 million dollars on our balance sheet as of June 30 with no debt and so we have the ability to invest but to your point we want to be very disciplined in that we try to demonstrate that in our quarterly results so it's a regular source of discussion we want to make sure that these investments that we're making in building out. Because again, we're still in the second year launch. So there's a lot of room to grow. And I think we're on the right track. We're always open-minded.

So you've given us the number of diagnosed and treated patients. You've given us what the prevalent population is in the U.S. At what point will you be in a position to maybe provide us peak sales potential for the product?

I think that goes back to your guidance question around can we kind of smooth the lumpiness of our quarterly enrollment. If we are able to get to a place where we could do that, I think it would be then behoove us to be able to provide that level of guidance. Today, I just can't. But I would go back to the peak opportunity for us in the U.S. goes back to the patient numbers, and that's that 350 to 900. A year ago, I didn't have as much confidence in where we were because we were one year into launch and we were doing well and exceeding expectations. Today, I can firmly say and confirm that in the numbers, and you can fact check this, that the growth of the market in the newly diagnosed patients is growing. That is what's giving us confidence that the peak opportunity is now between that 350 and 900. give us some more time and we'll let you know, we'll continue to execute on that. I just don't know how to answer that question in such a lumpy and myriad of approaches in such a law of small numbers in rare disease.

Right. The good news is the patients that come on MyPlypha stay on MyPlypha.

So you have a product here that targets clearly a really high unmet need in NPC. You mentioned to my first question that, or second question, I guess, you were pleasantly surprised about some of the older patients are coming into the fold now, diagnosed. Your product is, you know, it's a weight-based dosing. So for us financial types, what does that mean in terms of pricing on a weighted average, no pun intended basis?

Yeah, well, we provided some guidance on our initial call post-launch that of our expanded access program patients, which were about 83 patients at the time, the mix of those patients were 50% adults and 50% kids. And that guided us, even though we have multiple strengths and it's weight-based dosing, to be able to provide the $85,000 WAC per patient. That has remained you know plus or minus a few hundred dollars here there that has remained consistent when it comes to our current patient base which is again we've brought on board as many patients as many children as an adult so that that is consistent and I think until we see a significant switch between adults and children which we have not seen and I have to say we anticipated more children than adults at this point, then we will provide different guidance at that time.

So in the U.S., the label for MyPlyFa includes a combo therapy with Miglostat, which is the off-label standard of care. Are there any initiatives underway at the company to potentially use MyPlyFa as a monotherapy?

So the answer to your question is you are correct. The label is in combination with Miglostat. We are very happy with our label, and it's becoming more apparent that our label is part of the strength of the disease-modifying therapies that physicians had at their fingertips now. It became even more apparent with the clinical guidelines that came out last quarter, which basically state, you know, diagnose as early as possible, treat as early as possible, and use combination therapy and disease-modifying combination therapy. Well, in those guidelines, we are the only product that has combination therapy in the label with randomized clinical trial data that shows, you know, plus or minus myplifo with Miglistat. And that data along with, you know, what we're seeing in the real world where physicians have been embracing combination therapy. We think that the future of the Neiman-Pick disease treatment paradigm is going to follow the guidelines, which is treat with as many disease-modifying products as you can for the specific patients and utilize the different mechanisms of action to be able to clear cholesterol as best you can that gives people the best chance for lacking of, you know, progression of the disease. So that has played out pre-launch. It's played out now in the real world evidence we see, and now it's played out in the clinical guidelines. So we see the strength in our label actually that is in combination because that's where the future is and we're the only product that has randomized controlled data to show that.

So in the competitive landscape, it's you, there's combination use with Miglostat, and there's a product from private intrabio Acnursa. And then there's a couple of players who are either near approval or have phase three data that's coming. That's Barron and Rafael slash Cyclo. How do you expect this to play out? Do you expect to compete for payer dollars? Are all these complementary? How is the Neimanpick type C market going to play out from a competitive standpoint?

Well, one, as a company, I think as a company that's focused on patients and driving best impact for patients, the more therapies in the NPC space, the better. And as the guidelines state, utilizing multiple mechanisms, I think, is great. We've also seen that the investment that's come from these other players have also helped to rise the tide, right? More investment in disease state awareness, more investment in genetic testing, more investment in physician awareness. It's been great, and we hope that more products can come in. The other part of this is that our understanding with some of these that you mentioned are, they are actually going after a part of our label we don't have. It's the less than two years old, you know, and it would be wonderful if we could have patients who can have access to therapy earlier and hopefully halt or slow the progression of this disease and give those patients an opportunity to have multiple modalities like a MyPlypha and Miglostat in their later lives to help them move forward. So we see this as beneficial for patients. I think the guidelines have clearly stated that, you know, utilize multiple modalities and for the best outcomes.

Correct. So moving on to the application in Europe, you got the negative opinion from the European Medicines Agency. You've submitted a request for re-examination. You've had a recent case where a product for a rare disease, KDS trofenatide for Rett syndrome, there was a reversal of a vote. You know, clearly circumstances are different, but what gives you confidence that the EMA will reverse course on your pending application now?

Yeah, our confidence has remained consistent. It has to do with the unmet need and recognized unmet need, as well as the totality of the clinical evidence that we have. You know, I stressed on our earnings call, and thank you for the questions on the earnings call. I stressed on the earnings call, and I'll do it again here today what we have in our global eap patients and the continuous request for for my plifa and the majority of those eap patients are in europe continues to show the pull for an unmet need for a product that is that's not even registered right we're utilizing that in europe mostly compassionate use outside of france which has a specific program and that gives us a lot of confidence, right, that we are trying to fulfill a need. The clinical guidelines have also kind of reinforced that in Europe as well. The other part of this is that we have a clinically significant and statistically significant clinical trial. That's now been bolstered with both real-world evidence on the open-label extension data going out four years. Last week, the publication of our EAP data going out four years, the pediatric investigational plan data that's also now been published. So we feel like that robust totality all points in the same direction, which is halting the progression of this disease. So between those two, we're hopeful now as we go and have requested our re-examination, we will now have a higher emphasis on those specific areas of concern that the agency has come up with now that allows for the voices of experts in those areas to come to the table and to bring our story to life. And that's what we're doing here with the re-examination process. And as you also saw in that opinion, we've checked a lot of the boxes that were not checked in the previous application. So we've moved the needle. Now we have to continue to lean in on the totality of our evidence and demonstrate the unmet need.

Well, we have a couple of minutes here, so I'll be remiss if I don't ask you any questions on celiprolol. I've pointed that out as flying under the radar. I don't want to contribute to that myself. So celiprolol for vascular illness, Danlos syndrome. It's the only product in phase three that we know of. There's no product approved specifically for wedges in the U.S. How are you thinking about what you can do to get that product to patients sooner given the nature of that trial?

Well, we are doing everything. We have invested significantly in the acceleration of the enrollment. And just last month, we were at a regional meeting in Texas and driving through that as well. So we're investing in all of the clinical operations and trial enhancement activities you can think of. We also, though, took the opportunity in the first half of this year to go to the agency and to talk to them about the fact that we have lower event rates and the enrollment, it's not like the screening is not there, we're screening, but the enrollments and the conversion of that lower than we would like. But more importantly, how can we also work with them to find ways to accelerate the clinical development of the program through new regulatory mechanisms? So we had an informative discussion. We have now gone back out based on that and they They gave us some homework. We've been doing the homework, and we're on track to be able to re-engage with the agency in the second half of this year to be able to have further dialogue around those two areas, accelerating enrollment and or accelerating the development of the program.

And the last one, I'm going to squeeze this in for Justin. You're one of those rare biopharma companies that don't really need to raise capital, but you may want to. So given that luxury, how are you thinking about business development? What kinds of ultra-rare disease assets are there? What might fit?

What might not? those kinds of yeah great question we have really built the infrastructure around my point from the US and of course modest investments in Europe very targeted and specifically milestone driven so we very much with our business development team look for complementary assets so we'd look for ultra rare disease either late stage or commercial that could complement the my play for team because we have the infrastructure where we could truly add a product to our offerings at these centers of excellence calling on the same doctors and so we are very specific in our look it has to be the right price you know the right drug the right fit and so that is absolutely part of our you know inorganic growth strategy that we look to again we have the flexibility with our capital structure to look but again our focus is on my play from the US Europe and Celeprolol one two three with the inorganic growth strategy on top of that thank you and with all our time thank you everyone for coming and for tuning into the webcast as well thank you