Good morning, everyone. I'm Sumant Kulkarni, a Senior Biotechnology Analyst here at Canaccord Genuity, and I'm really pleased to have Zevra Therapeutics here today. It's a pivotal moment for the company. They recently had a positive advisory committee meeting on one of their pipeline products, arimoclomol, for Niemann-Pick disease type C. Also, another product called OLPRUVA, which is out on the market already for urea cycle disorders. It's a very exciting time for the company. Really happy to have you guys here. Thanks for making the time for us, and Neil McFarlane, the CEO, is here. We have Josh Schafer, the Chief Commercial Officer, probably the person in the hot seat, and then LaDuane Clifton, who writes all the checks. He's the CFO. So, thanks for making the time, and, Neil, if you could make a few brief opening remarks, and then we'll head straight into Q&A.
Great. Thank you, Sumant, and thanks for having us. It has been a very busy time for us over the last number of weeks, for sure, but also over the last number of years as the company has continued to transition to becoming a rare disease company. Part of that process with our pipeline now having one commercial product and a positive Advisory Committee meeting, two development programs that are going, one with an end-of-Phase 2 meeting coming, along with another one that's just restarted enrollment. It's a great time for us. I'm looking forward to spending some time with you today and talking about the exciting times ahead.
Oh, great. Thanks for that. So, yeah, I couldn't dial into the call yesterday, but I figured I'd ask questions here. So, this is as good a forum as any. Arimoclomol, you had a positive Advisory Committee meeting. I assume there is very little risk of an approval here from the FDA. Is that a correct characterization?
Well, the data so says that, and supports the fact that 97% of positive advisory committees go on to becoming positive PDUFA, and, and the FDA takes the advice of the committees in a positive way. I think our goal is to continue to make sure that we put forth everything we've got to making sure that we're taking care of what we can take care of, but we do feel very strongly that 97% is in our favor.
Got it. So, yeah, that's a good number. So, as you prepare to launch arimoclomol, you have OLPRUVA on the market already. You've seen that launch. It's taking off, and there was some, I guess, I don't know if a hiccup is the right way to characterize that, but, how would you balance what you need to do on OLPRUVA versus what you might need to do on arimoclomol, and can you manage that all at the same time?
Yeah. Thanks for the question, and I wouldn't characterize it as a hiccup. Rather, you know, the two markets are very different.
Right.
In the UCD market, all of the products work very similarly, and OLPRUVA came to market through a 505(b)(2) pathway, which meant that there was no clinical trial, very little patient experience. And our focus in the first six months has really been on building awareness of OLPRUVA and the clinical differentiation and why it's an alternative therapy for appropriate patients. And we've done a great job in getting in front of those physicians. We've been able to reach more than 90% of our target clinicians and prescribers and been working very closely with the managed care with the payers to ensure coverage. So, in many ways, we were able to work out some of the commercial kinks as we build our commercial organization, but I wouldn't say it was a hiccup.
I think, it has probably been a little bit slower of a launch than we anticipated, but that has more to do with the market dynamics than anything else. On the flip side of that, the NPC market is one where there are no approved therapies. Arimoclomol will be the first approved treatment for NPC, and the awareness is extremely high. We have patients who are already on our EAP program right now and receiving benefit, and these patients have seen, you know, anywhere from four to seven years of benefit from arimoclomol. So the awareness and the demand is much higher there. But it's the same team that is out there now promoting OLPRUVA, that will be in place to bring arimoclomol to patients.
Got it. So with this expanded access program, now that you are on the verge of approval, once you get it, how quickly can those patients transition on to reimbursed patients?
Yeah, no, that's a very good point. So of the 900 patients that from prevalence perspective in the United States, about 300-350 of those patients are currently diagnosed and being treated with routine care of some sort. Of those, approximately 70 are in our EAP program. As we move towards launch, we've been towards a successful PDUFA, I should say, and getting commercial drug in the channel, we've been working with the investigators in those programs to be able to anticipate a transition to commercial product once it's in the channel.
The other component of that is that as we are going into an end-of-the-year launch, as we go into the first part of the year, getting and making sure we've got the access taken care of, we've got all of the, you know, pre-approval work that Josh and his team have been working on in regards to the payers. The important part for us is that within 12 months, we're hopeful to be able to transition all of those patients. Some will transition quicker, some may take a little bit longer based on some of the dynamics in the specialty pharmacy space, but our goal is in 12 months, within the first 12 months, to transition out of the EAP program completely in the U.S.. Important because we wanna make this clear for everybody.
We also have an EAP program that's a global EAP program in Europe, and that program has about 70-80 patients as well. That program will continue to remain in place. There's been some confusion. We wanna make sure that the patient, patients and advocates that are out there know that we are transitioning with an approval in the U.S. We're gonna continue to remain with our EAP globally until we move forward, which we plan to move forward with a successful PDUFA in Europe.
Got it. How are you thinking about pricing of the product once it's approved, and what point do you expect to give us more info on that?
Yeah-
This is as good a time as any to do it, if you'd like to.
Sure. Thank you, Sumant. We might refrain on that one. However, you know, our goal is to be able to make the product available to as many patients as we can. I'll hand off to Josh to talk a little bit about some of the work that we've done and some of the flexibility from the payers that we've heard in the ability to bring a first, you know, product in, in the disease area to market in an ultra-orphan space. So, Josh?
Yeah, just to add on to that, we've done pretty extensive market research with payers, and we've presented the profile of arimoclomol to them. And I'd have to say that there is a real appreciation for the value that arimoclomol brings, the clinical value. And there's, you know, pretty wide range that the payers are, you know... I don't want to say there's price insensitivity up to a certain point, but they're open to a range of pricing, given the benefit that arimoclomol can provide these patients. The ultimate price decision is largely gonna be based on, you know, the label and how that plays out. But we feel that, you know, payers are very receptive to the profile and the benefits that arimoclomol will bring.
As Neil mentioned, our goal is to make sure that it's as available to as many patients as possible.
Understood. So you brought up label and how that might play out. Are there any labeling nuances we should be aware of that might have implications for how you might be able to commercialize the product, or is it fairly straightforward? Because this is a disease that has no approved products in the U.S..
Yeah. Really appreciate the question, and it's very timely. Yesterday, on our earnings call, we actually announced that late Friday, we received... They call it round one. We're not in a sparring match with the agency, just to be clear, but they call it round one. We received round one, which we are now processing internally. We're not gonna talk about the substance of that 'cause it is an ongoing evaluation by the agency. But I think it is fair to say that in every label negotiation with the agency, you get what you studied. And I think that's an important distinction for us. We studied arimoclomol vs placebo with underlying routine care.
Yeah.
That underlying routine care could include antiepileptics if the primary symptom was epilepsy, it could include substrate replacement, if you know, substrate reduction, I should say, in those patients. But routine care was balanced among both arms. So when we think about a label for arimoclomol, we think about getting what we studied, which is arimoclomol versus placebo with underlying routine care. That allows for, as Josh mentioned, that allowed for us to be able to test the actual impact of arimoclomol with baseline. So this impact you see in the data that we've shared with the over 1% point change over 12 months is clinically meaningful for patients.
And we heard that time and time again at the advisory committee as well, that a one-point change, the difference between somebody who's able to ambulate in a wheelchair, that's a meaningful change. Somebody who can swallow without or with dysphagia. So I think that this element of the label for us should be running the, you know, straight down the middle of the fairway, if you will, but you usually get what you study. So we're in that discussion now. We're hopeful to continue our rounds of discussion and end up with what our Phase 3 study delivered.
Got it. So clearly, there's a baseline level of care associated with-
Mm-hmm
... Niemann-Pick type C right now, which is off-label miglustat, right? So in that case, once you have an approved product, how do you expect the payer dynamics and things to work out? How is it currently being paid for, given there is no real specific approval for Niemann-Pick type C?
Correct. So you mentioned that there is off-label utilization of miglustat for these patients who need substrate reduction and can tolerate miglustat. In our study, we specifically stratified patients to both arms based on miglustat use, one way or another. We saw about 20% of the patient population, in our study, was not on miglustat at the time. Josh, I'll hand off to Josh in a moment to talk a little bit about the fact that we've tested that as well. That's considered part of routine care for those patients who need it, or those patients who can tolerate it. And the outputs of our payer work lends to what Josh talked about before.
Yeah, and our research suggests that payers are receptive to allowing patients to stay on whatever that routine care is and add arimoclomol to that. And we believe that arimoclomol will really become the foundation of therapy as we go forward. Some of the other patients who are not on miglustat are on treatments for other symptoms related to epilepsy or other things that, you know, those would likely continue as well. So payers understand that these patients are taking a lot of medications. There's a lot of comorbidities that are associated with Niemann-Pick, and they are receptive to, you know, an understanding of the fact that there will be additional therapies that are added to arimoclomol, but that will become... You know, we believe it'll become foundational therapy.
Got it. So if you look at the 900 or so Niemann-Pick type C patients in the U.S. and 300 diagnosed, what are you gonna try to do to close that gap between the 900 to 300?
That is exactly what we've already started. Maybe I'll ask Josh to start a little bit on the commercial side of what we're doing, and in the absence of our CMO, I'll take on some of the medical affairs things that we're doing.
Sure. As I just mentioned, many of these patients have other comorbidities and are oftentimes misdiagnosed for up to-
... five years or longer before they are definitively diagnosed through a genetic test with Niemann-Pick. Helping physicians understand what some of those early presentations might be, what some of the other misdiagnosis might be through claims databases and that sort of research, case study work. So helping to really educate some of the, those who are not experts in NPC, so that they can earlier identify these patients, because we also know that the earlier you treat these patients, the better you're able to manage their disease. So that certainly is one of the things that we're already engaging with, and again, working with the experts to really educate the prescribing community as to the impact of this disease and the need to diagnose and treat early. Right.
Well, a couple of the things that most folks that have been in the rare disease space have experienced is when there is no treatment available for a certain disease, it's challenging to have a physician diagnose that disease, knowing that they don't have something they can actually treat a patient with. So when it comes to some of these areas, as you think about, you know, newborn screening, you think about genetic testing, some of the other LSD panels that are multi-disease panels that allow you to be able to diagnose.
The awareness level that our medical affairs group is doing with working with some of the states. There are two states and two groups in Texas, as well as in New York today, that are actually doing some of the specificity and sensitivity testing around newborn screening, and how can we elevate the opportunity for kids or newborns to be identified earlier before they're symptomatic, maybe? I think that kind of work is gonna take some time to be able to move it forward. But our, but our ability to educate physicians in the heterogeneity of how this disease, Niemann-Pick C, presents, and that if you see somebody with Parkinsonian-type movements and ataxia, you can think NPC, in addition to some of the other things in your differential. The opportunity for us to educate those physicians, we're out there doing that today.
As an example, at the SIMD meeting in May, June, around there, time's flying, we had a medical affairs booth which covered both OLPRUVA and our arimoclomol too, to show some of those synergies that we're able to get. But in that booth, our medical affairs organization had about 100 information requests. 50 of them were on Niemann-Pick C, 50 of them were on OLPRUVA. Those 50 physicians that we can now go back out to and start to educate about the disease course, about the potential products that are in development and some of the data, and so on and so forth, I think will go a long way to bridging that gap.
Mm-hmm. I guess, how could prenatal testing impact the incidence of Niemann-Pick type C, if at all?
It has the potential to increase that.
So moving on, like you're kind of on the verge of winning the battle on behalf of patients in the U.S. Ex-U.S., how are you thinking about European approval for your product? Because miglustat is already approved there, and what are the next steps that you might be able to take with the EMA or the European Medicines Agency?
So with a positive PDUFA, it is our immediate next-day goal to have conversations. We're already in conversations and continuing to drive forward with the European Agency along with our EAP program. We have this ATU program in France that is continuing to move forward.
A lot of what the CHMP opinions were and the challenges that took place prior to the U.S. filing, actually. Actually, let me back up a bit. The program was originally filed in Europe before it was filed in the U.S.
Yep.
So just to give a little historical perspective. So there were some comments made in the original European filing, around length of data, you know, the more robust safety profile, so on and so forth, that were things that it was so long ago that we didn't have the ability to, to answer, robustly.
Now, in the last couple of years since the CRL, and what we've done both on the confirmatory evidence component, also on revalidation of the tool, along with how the methodology and our statistics and providing statistically significant randomized controlled trial, no matter how you sliced it, as you saw at the advisory panel, we plan to take this robust package now, and actually go and address most, if not all, of the questions that came up previously from the CHMP and European regulators. So we plan to take that back to them now, with the backdrop of actually change in legislation or change in some regulations when it comes to European rare disease therapeutics, getting through the regulatory process there.
And then we plan to understand how we can then package this, have the dialogue, and support those European patients. So it is day two. Day one, approval; day two, how do we make sure we make this product available as possible for those patients in Europe?
All right, cool. Day three is approval?
No, no, day one is approval.
Day one. Okay. U.S.
So US approval.
Yeah, U.S. approval. Yeah. Right. So going back to the, the package that you have now, my understanding is that it was specific to addressing what the FDA had brought up as issues with the Complete Response Letter here. But if you look at what happened with the European Medicines Agency, how specifically have you addressed those concerns in the package that you have currently?
Yeah, not to get into specifics of each and every one of the concerns, but what you saw in our U.S. filing was a robust resubmission. Our resubmission had over 500,000 pages in it, and included additional data from our OLE program, additional data from our expanded access program, about three and a half years, our OLE program, about three and a half years. A safety database that had over 600 patients in it. Our natural history comparison with the NIH natural history data, which again we weren't able to do previously, we were able to do with that matched paired analysis with the EAP patient data.
You saw as we reported on this and were in our briefing books, that this robustness of clinical data in such an ultra-rare disease doesn't come along very often. But the time from the original submission four years ago to today, we've been able to really build on this. So we feel really strong that the clinical data and the package is impacting patients and, you know, the positive Advisory Committee panel vote clearly supports that.
Got it. So with the European regulators, would this be a months-long process, years long? How should we think about the time frame for a potential approval in Europe?
I think we need to go through step one, U.S. FDA approval, and then have step two, and I'll give you those timelines after step two.
Okay, got it. All right. Expanded access protocol in France, we have the product being sold. It's as far as I know, the only country in the world where you can sell the product with the... You're nodding your head, so you can correct me soon. But France is the place where you have revenue from the product already. That gives you an implied price for the product. When you have approval in the U.S., you'll have a price out here in the U.S. How are you thinking about pricing in Europe? Because that can be a very different ballgame.
Let me start with just making sure we're clear. We have. We are under the NATU program, which is a nominative ATU program in France that provides pre-commercial revenue as you take care of those patients. Approximately 30 of our 70-80 patients in our global EAP in France, and as you mentioned, we generate approximately $2 million net a quarter. It's been very consistent. Those patients have actually now also been part of this data generation that we've been able to generate because they've been on the product for some time. As a matter of fact, it's weight-based dosing, so as patients stay on longer and they do better, they gain weight.
Huge for this patient population, and as they do that, then you know you may see some variation in the revenue. The other part of the question that you asked in regards to... Can we-
Price. So it was pricing related.
Oh, pricing. Oh, yeah, yeah, yeah.
Right.
Sorry. Thank you. So it's an interesting perspective because in France, if you overprice and they reimburse you, and then your price comes in lower, you owe them the money back. So it's a conservative approach that we've taken-
Mm-hmm.
With our pricing in France to ensure that we never have anybody asking us for our money back. And when we think about normal, and then normal's not a good word, I tell my kids not to use it all the time, so I should probably not use it. But, when we think about more traditional ultra-orphan drug launches in the U.S., that you start with a product, and then you bring it to Europe with an approved product, on average, you probably see a 30% decrease in price for these types of, you know, thousand-patient populations. So we would expect that once we price the U.S., that we would follow very similar patterns to other comps in the ultra-rare space around that 30% differential.
As you do your pre-commercial work, do you have any specific examples in Europe or in France specifically, where you've gone from this payment program to a commercial product and what the differential in price has been?
Yes, there are. I won't name the product names, but I actually happen to have been part of some of those in my previous life as well. Yeah, no, there is, there's absolutely precedent to being able to price your product above the current ATU price in France, that you would negotiate.
Ex-U.S., do you plan to do this yourselves, given it is an ultra-rare disease and-
So today, it's too early to tell you that. We need to reestablish the, I would say we need to actually continue our process with the EMA to understand what that is. But we're also undergoing our strategic planning review. We talked about this in Q1, on our Q1 call. Coming into the organization in October, there's a plethora of assets. We needed to focus on doing a few things really well, so that way, we could actually demonstrate as an organization we can execute and as a team. But part of this evaluation since January, when we kicked off our strategic planning, is to understand all and discover all of the value in the organization and what makes sense in our hands and what makes sense in other hands, in other folks' hands.
Part of that process is our pipeline evaluation. Part of that process is global expansion.
Got it. So we have a minute or so left. I'll ask you a pipeline question. You'll have to wear your CMO hat again. So celiprolol Phase 3 for vascular Ehlers-Danlos syndrome, how do you expect that to evolve, given there's nothing approved for that indication as well?
So, thank you for that question. And maybe in the last 30 seconds, we can talk about the excitement around 1077 as well as we go into our end-of-Phase 2 meeting. Celiprolol, as you mentioned, for vascular Ehlers-Danlos syndrome, was being enrolled previously under a SPA, as well as a decentralized trial under the previous sponsor before we acquired Acer. They had enrolled 17 patients, and then had some resource challenges and were unable to continue the trial. As part of our early review of our portfolio after the acquisition, we heard a cry from the patient organizations that they really wanted to get into the trial.
And as part of our initial evaluation, and I would call it preliminary evaluation, we felt like there was value in this program with nothing else and an incredibly unmet need in the U.S. About 7,500 patients in the U.S., with COL3A1. I'm messing that up. See, I didn't have my CMO hat on. The genetic challenges with VEDS. And what we also saw was the opportunity to be able to engage and reengage the agency to start the trial and see. Well, we talked about it on our call yesterday. It exceeded everybody in this organization's expectation, the outpouring of desire to try and get into the trial.
So, for us, that is a data point that we'll now take into our assessment, and then understand how that looks moving us forward.
Got it. 1077, yeah, you-
Yeah, 1077, very quickly, as we mentioned, on our call yesterday, we've submitted our briefing book to the agency after our Phase 2 data and then, having the time with our advisory boards as well as with patient advisory boards, to understand how to be able to differentiate the product and have a clinical differentiated profile. That's it. We'll have a meeting, by the end of Q3, and it'll inform how we move forward with our Phase 3 program, in idiopathic hypersomnia.
Got it. We don't have music to kick us off, so I'll squeeze one last one in. So, you're a rare disease company now. You have assets. Like, clearly, you have one approved asset, one that is on the verge of approval. How are you thinking about business development to add more products to the bag from a commercial perspective?
Yeah, I think we have three things to focus on: getting arimoclomol approved, building the synergies with OLPRUVA to be able to have two products in the marketplace so we can take care of patients, and then our 1077 program and understand what that Phase 3 looks like. If we can continue to execute on those, it'll give us the opportunity, and I think we'd have earned the right to go out and find ways to leverage our infrastructure, but we have some things to do first.