RARE Daily

A Rare Disease Drug Developer Tries to Earn Its Stripes

June 13, 2024

Zevra Therapeutics, formerly KemPharm, rebranded itself in early 2023 following the acquisition of the experimental therapy arimoclomol for the rare lysosomal storage disorder Niemann Pick disease type C. Zevra is Greek for “zebra,” a symbol of rare disease. The company subsequently built out its rare disease pipeline through the acquisition of Acer Therapeutics in November 2023. An FDA decision on arimoclomol is due by the end of September. We spoke to Neil McFarlane, president and CEO of Zevra Therapeutics, about Niemann Pick disease type C, the FDA’s upcoming decision on whether to approve the drug, and its broader efforts to build itself into a rare disease therapeutics company.

Daniel Levine: Neil, thanks for joining us.

Neil McFarlane: Thanks for having me, Danny.

Daniel Levine: We’re going to talk about the ultra-rare lysosomal storage disorder, Niemann Pick disease type C, Zevra’s experimental therapy, which is approaching a decision with the FDA, and its broader efforts to build a pipeline of rare disease therapies. I’d like to start with a little history. Zevra had been Kempharm, which had been developing a treatment for ADHD and had drug delivery technology. That treatment known as Azstarys is now on the market. What was the thinking in renaming the company and how big a strategic shift did this represent?

Neil McFarlane: So, the company made a strategic pivot a few years ago from the prodrug technology company into the rare disease business. about a year ago, Back in February 2023, it changed the name from Kempharm to Zevra to really provide an additional level of focus. The zevra is Zebra in Greek, which is the symbol of rare diseases in the industry. And then in November of 2023, the company actually transacted another acquisition of a company named Acer Therapeutics, which was developing and had a commercial product in the ultra-rare disease area, which really cemented our business from a development to commercial stage organization. And we’ll talk a little bit more about our next products in the pipeline in the future.

Daniel Levine: You joined the company in 2023 as CEO. You brought with you a background in rare diseases. Having served at Retrofit and Genzyme before that, what attracted you to Zevra? What did you see as the opportunity?

Neil McFarlane: Yeah, it’s been an exciting six months as I joined the company in 2023. This is a critical stage of growth for Zevra. I believe in the products and the pipeline, and most importantly, the people, the purpose of the company. Having this deep focus on patients is very much aligned with what I enjoy doing and what I’ve been able to do in some of the companies you discussed a moment ago. But I also believe that that background allows me to be able to help drive towards long-term success. And it’s really not that often in our industry that you have the opportunity to get in at a pivotal stage of transition and help to build a leading rare disease company, which is our mission.

Daniel Levine: The company’s lead therapeutic candidate is pending approval at the FDA. This is a treatment for Neimann-Pick type C. Can you explain what the condition is?

Neil McFarlane: Sure. Neimann-Pick C is an ultra-rare progressive neurodegenerative disorder. It is a lysosomal storage disorder, and it’s really characterized by the inability of the body to transport cholesterol, which then leads to accumulation of cholesterol and other tissues in the body, primarily in the brain, and eventually other organ damages as well. But it can be fatal, actually, it’s more likely fatal. And these lysosomes, which are really the recycling bin of the cell, break down large molecules such as proteins and carbohydrates and fats. And sometimes when you have defects in the transport proteins, and, in this case Neimann-Pick C is the NPC1 and NPC2 genes, this breakdown leads to the accumulation, and eventually leading to death. Prevalence is about 1800 patients estimated in the U.S. and Europe, of which about 900 patients are estimated in the U.S. of which, let’s call it 300 to 350 of those patients are diagnosed and or treated today.

Daniel Levine: How does the condition manifest itself and progress?

Neil McFarlane: So, as I mentioned, you get this mutation, either the NPC1 or NPC2 genes, which are responsible for making these lysosomal proteins. And it’s highly variable. The heterogeneity of the disease allows it to present with specific symptoms that vary from one person to another, and actually even sometimes with multiple family members that are impacted with the disease, they can also present differently. Both children and adults can be affected by a Neimann-Pick C and usually you get these physical and cognitive limitations that come and they can present as speech challenges. They can present as cognition, the inability to swallow, having challenges with ambulation and walking as well as fine motor skills, having some dystonia, dissymmetry, and those areas that allow for patients to really lose independence. The important thing to notice is this disease progression is irreversible and it can be fatal. The average age of patients, or mean age I should say, of death is 13 years old. So, it is a very severe disease and something that we’re really working hard to try and bring treatments to.

Daniel Levine: Are there treatment options that exist at all, and what’s the prognosis for someone diagnosed with the condition today?

Neil McFarlane: So, there are no approved treatments for Neimann-Pick C in the United States. The current approaches involve both supportive therapies as well as specific symptom therapies. Today in other parts of the world, there is a product that is approved for Neimann-Pick C, but we would be the first product with one of our programs, which is arimoclomol that is in the development phase today for Neimann-Pick C in the U.S.

Daniel Levine: What is the therapy that you’ve been developing? This was acquired through Orphazyme, is that correct?

Neil McFarlane: It was, that’s correct. So arimoclomol is an oral investigational product today, and we’ll talk a little bit more about it, but as I mentioned, cholesterol builds up in the cell and the work that we’ve done to date and previously with Orphazyme really shows that it may enhance cholesterol metabolism and thus improve the lysosomal function and clear these cholesterol, so the cholesterol doesn’t build up in the cells and provide the severity of the clinical symptoms that I talked about before. The evidence to date states that arimoclomol can really act on multiple fronts to help to reduce this lipid buildup in the cells. And some of that science we’ve actually built on since the acquisition of the product and have now resubmitted that to the agency and have a PDUFA date later this summer of September 21st.

Daniel Levine: When Orphazyme had originally sought approval for it, it got a complete response letter. What exactly were the issues that the FDA was concerned about?

Neil McFarlane: Yeah, so there were three real main areas that have been discussed publicly. One was the sufficiency of and validation of the Neimann-Pick C Clinical Severity scale, or better known as the NPCCSS, which you shouldn’t say too many times fast. The other one is really the appropriateness of how to handle some of the missing data and certain methods on how to evaluate the primary endpoint. So let’s call that statistical approaches to handling the data. And then the last one was really around the robustness of the confirmatory evidence to support a single efficacy study, which in the ultra-rare disease space is an area that you can have a single study that allows you to demonstrate the safety and efficacy of the product. We have been able to work with the agency with multiple meetings over the last few years to sufficiently address these questions by re-scoring of the swallow domain, going to a revised four point NPCCSS, which takes out the cognition domain, working through both the preferred statistical analysis as well as the original analysis that we completed as part of the phase 3 program, and then really providing a very clear story of the nonclinical and the clinical work, the natural history work, as well as our expanded access program, and then tying that directly to the clinical trial results. So, we feel like we’ve really done a robust job in developing the responses to the CRL, and as I mentioned before, the agency also, I think, has agreed that we’ve answered them sufficiently to provide us with a PDUFA date, which is September 21st, 2024.

Daniel Levine: So, if all goes well, when might the drug become available?

Neil McFarlane: Yeah, post the PDUFA date. With a successful PDUFA date, we plan to be able to move forward with commercializing the product as soon as it is approved. That’s one of the areas that I think is really important. With the Acer acquisition I spoke about earlier on, we were able to develop and pull forward the commercial infrastructure that we needed to execute on this ultra-rare disorder with the centers of excellence across the United States. And that’s allowing us to make this pivot from development to commercial in a way that we can work out the bugs and get our professionals out there in the space to raise the awareness of not only Zevra, but then also of the products when they’re approved, and supporting the community.

Daniel Levine: This is a small market. Is the expectation your existing commercial team will market the drug, or do you need to add a team in preparation of its availability?

Neil McFarlane: No, we’ve pulled the investment forward by commercializing Olpruva, which is our therapy for certain urea cycle disorders, which is another rare, potentially fatal genetic condition that really reduces the body’s ability to process nitrogen and that results in toxic ammonia being developed in the bloodstream, and these hyperammonemia crises can be very challenging. So Olpruva, which is approved, is a commercial product that we acquired through the transaction with Acer Therapeutics. This has really allowed us to get boots on the ground working with the KOL community, working with the metabolic centers of excellence and getting Zevra and Olpruva to patients where it can be beneficial for them, and then also allowing us to be able to leverage this infrastructure with the potential approval of arimoclomol in those same centers and accelerate the commercialization of arimoclomol to patients in the U.S.

Daniel Levine: How are you thinking about building a pipeline beyond this?

Neil McFarlane: We’ve spent a lot of time talking about arimoclomol, which is our lead development program that’s in the agency today with this PDUFA on September 21st. We have other products in development as well. We have a program called KP1077, which very recently, just a few weeks ago, delivered top line data in idiopathic hypersomnia, which is a rare sleep disorder. We will plan to get the full data set out at an upcoming sleep conference, an academic upcoming sleep conference called Sleep 2024 in the June timeframe, and we believe that this could be a promising treatment for patients suffering from IH. That’s our phase 2 program. We also have a phase 3 program that was part of the Acer acquisition in vascular Ehlers-Danlos syndrome. We actually did a preliminary portfolio review as we brought these companies together, and we felt this was a program that was important to continue progressing in its phase 3 program. So that program is also ongoing.

Daniel Levine: Is there something though that thematically links these programs or are these just opportunistic as you pursue what’s available?

Neil McFarlane: Yeah. No, they fit exactly the Zevra mantra, right, which is our mission is to deliver products to patients that are meaningful in the rare disease space, but it’s also part of our greater mission to be able to become a leading rare disease company. All these products that we talked about before have the potential to deliver in a highly unmet area like rare disease benefits to those patients.

Daniel Levine: The FDA granted arimoclomol rare pediatric disease designation. The company could be eligible for a priority review voucher, which could then be sold. Those have been selling for around one hundred million dollars. This program though, is set to expire this year if no action is taken to extend it. What does the program mean to a company like yours?

Neil McFarlane: Yes. This is something that we’re all watching very closely. This is a government program that provides an accelerated review voucher. If you develop a program in the pediatric arena, we would be eligible. We will be grandfathered in the event that the program does go away. We believe, and I believe that I speak on behalf of the rare disease community here, that this is an important component of allowing for non-dilutive financing for companies that are small companies working in the ultra-rare disease area to help them move towards building medicines for patients who are otherwise overlooked. We also think that the value of these, just based on economic principles of supply and demand, if the program goes away, the value may increase for these programs. We’ve seen this in the past. Todays, I think you mentioned, that they’re approximately a hundred million dollars in terms of the value today. We would see that value increasing if the supply went down. So we’re hopeful that Congress will be able to act and authorize the pediatric review vouchers, but we’re also prepared, and then we’ll be grandfathered in the event that we get arimoclomol approval to be able to monetize that for non-diluted financing for us to continue our journey of bringing rare disease therapies to patients.

Daniel Levine: Zevra in April announced a refinance of existing debt and up to a hundred million committed in a new credit facility. How far will existing cash take you and what’s the plan for raising additional capital?

Neil McFarlane: So, we are really happy that we partnered with some of the highest quality investors in this space to be able to provide this debt facility. As you discussed, over a hundred million dollars. That puts us into 2026 in terms of runway. As we’ve mentioned in our last press release, this forecast includes sales from Olpruva and reimbursements from our French EAP program, but it does not include revenue from the sales of arimoclomol or the sale of a priority review voucher, which would clearly add to our cash balance as we move forward. So we feel like we’re adequately capitalized to be able to execute on the near term drivers for our business today. And with success, we’ll be more than adequately capitalized, I think, to be able to execute on our mission to bring rare disease therapies to patients in need.

Daniel Levine: Neil McFarland, president and CEO of Zevra Therapeutics. Neil, thanks so much for your time today.

Neil McFarlane: Thank you, Danny.


This transcript has been edited for clarity and readability.


The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.


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