All right. Good afternoon, everyone. It's David Amsellem, again, from the Piper Sandler Biopharma team, and welcome again to our virtual CNS Symposium. We're delighted to have Harmony with us. Lots to talk about. We have COO Peter Anastasiou, and we have Chief Medical Officer, Dr. Kumar Budur.
Thanks so much to both of you for joining us. Maybe what I'll do as a quick starting point is turn it over to Peter and Kumar for some brief introductory remarks, and then we can go right into questions. Peter, I'll turn it over to you. Thanks again.
Yeah. Thank you. David, thanks for having us, and thanks to the Piper team. Just wanted to say a couple introductory comments. Obviously, we just had our earnings last quarter, and there were really two key, last week, our quarterly earnings. There were two key themes. First is the record quarter we had in terms of performance for WAKIX, and I think that's really important for a few reasons.
One, clearly shows the important role that WAKIX has in the marketplace and will continue to have in the marketplace, and that it's growing this much in the seventh year on the market. Clearly, it's got an important role in the treatment of narcolepsy, but also, I think, speaks to the commercial execution and the capabilities of our team. Importantly, it pays for our pipeline.
That really strong performance allows us to bring forward products like BP-205, which was the other area of focus for our earnings call last week and the emerging data, the first clinical data that we have with BP-205, and I know Kumar will cover some of that. But it's certainly that WAKIX performance is an enabler for us to pay for that product, but also other products in the pipeline and also enables us to be able to do business development transactions, which is a high priority for us.
Yeah. Thank you, Peter. Hey, David. Good afternoon, and thank you for having us. Let me start with that 205. We have been getting a lot of questions, especially in the light of the preclinical data that we presented last year, especially, more importantly, the clinical data, the initial clinical data that we presented at the earnings call last week. So I'll provide a comprehensive overview of 205, and that will hopefully answer a lot of questions.
Let me start with the chemical scaffolding, the chemical structure itself. BP-205 has a novel chemical scaffold that gives it some unique attributes, like high potency, and avoids some of the molecular structure-related AEs, like hepatotoxicity or cardiotoxicity. Then it also gave us very high potency in the range of 0.015 nM. This continues to be the most potent orexin two receptor agonist in the clinical development.
Beyond that, it also has excellent selectivity. The preclinical data, the safety pharmacology and toxicology studies were clean, and the preclinical data showed that it could potentially be dosed once a day. This data was shared at the sleep meeting last year and also at the World Sleep Congress last year. Now, fast-forward, we are in the clinic now. We shared single ascending dose study last week at our quarterly earnings call.
Just an overview on the study design itself. It is a standard single ascending dose study, double-blind, randomized, placebo-controlled study, men and women, healthy volunteers. 72 subjects participated in this study. We studied dose range from 0.2 mg all the way to 6 mg, so about 30 folds. What we saw in the single ascending dose study is it reinforced our belief that BP-205 has the potential to be the best-in-class orexin two receptor agonist.
Starting with the Tmax, we saw very short Tmax, 30- 75 minutes, which points to rapid onset of efficacy. We saw Cmax and AUC that were dose proportional from 0.2 mg all the way to 6 milligram. We saw a long half-life of 25 hours, which will potentially lend itself to once-a-day dosing, help with wakefulness in the later in the afternoon, early evenings, and especially the combination of the high potency and longer half-life is very well suited for indications outside of NT1, where there is no orexin deficiency, where we depend on the higher cascade mechanism of action of BP-205 for the downstream effects on histamine, norepinephrine, dopamine, and serotonin. Apart from that, safety tolerability. We did not see any cardiovascular, hepatic, or visual disturbances.
The AEs of note were headache, fatigue, and diarrhea in about 10%, 4%, and 3% of the patient population respectively, or healthy volunteers respectively. In terms of next step, we have completed dosing in the MAD study.
We did disclose some safety tolerability profile from the MAD study. We did see some target engagement AEs in our MAD study, like insomnia and polyuria. But the insomnia was neither severe nor sustained. We will disclose the full data set in the fourth quarter. The PK analysis is still ongoing. Finally, we have opened our IND in U.S. We will be commencing sleep-deprived healthy volunteer study, and the top-line data will be available in early 2027, and we are on course to initiate multiple phase II studies in product CNS indications.
Great. Well, that's a great overview and leads me to a number of follow-up questions, Kumar. First, on the MAD study, just to clarify, you didn't mention visual AES. I'm assuming that you did not see visual AES in your MAD data set thus far?
That is correct, David.
Okay. Looking more broadly at the category, you mentioned once-daily dosing. On this topic, we're seeing a number of orexin two receptor agonists being evaluated in sleep-wake narcolepsy and IH as split dosing.
I guess with that in mind, how important, in your view, is once-daily dosing in narcolepsy and IH? I have a bunch of other questions about your development in narcolepsy and IH, but I'm particularly interested in your thought process regarding once-daily dosing and sleep-wake.
Look, if there is an ability to dose once a day, that is always preferable from a patient's perspective, convenience, compliance. Pitolisant, for example, has a half-life of 20 hours. It's dosed once a day in the morning upon awakening, and patients love it, and prescribers like it.
Okay. Taking a step back, you are going to have MAD data in sleep-deprived healthy volunteers sometime next year. You have also talked about a broad phase II program in indications beyond sleep-wake. Can you give us a sense, general sense, obviously, I know you are not going to tell us exactly what you are going to be doing, but a general sense of how you are thinking about it?
We know that mood has been talked about by your competitors, cognition, attention. Alkermes is doing an ADHD program. Fatigue comes up. There is a lot here to look at, a lot of white space. But just give us a general sense of how you are thinking about these potential indications. I know we will know more next year, but it certainly cannot hurt to ask now.
Yeah. I will actually address that.
Yeah
Certainly Kumar can chime in. Our desire is to aggressively develop BP-205 and, in fact, to have what I would consider a broad orexin strategy. We would love to have a portfolio of orexin agonists to take full advantage of both the narcolepsy and IH, but also the broad areas outside. Certainly, that is something that we are working on with our partner, Bioprojet, both in the development of BP-205 and the potential identification of follow-on compounds.
But specifically, with BP-205, all those great features and benefits that Kumar talked about in terms of the potency, in terms of the potential for once-daily dosing the novel scaffold, all of those are really relevant, certainly within narcolepsy and IH, but are also particularly relevant in those broader indications.
While we haven't been specific and won't till we get closer to the startup of those phase II studies, those areas that you mentioned, cognition, attention, mood, fatigue, are many of the areas that we, along with our partner, Bioprojet, are looking closely at and are intending to start multiple phase II studies in mid-2027.
Yeah. I'm glad you mentioned the Bioprojet partnership. We know that Alkermes has multiple orexins. Lilly, with their acquisition of [Suntha, they have multiple ones. It looks like you're taking a similar approach. Just a couple of questions here. How quickly do you think these additional orexins could enter human development, SAD, MAD work, et cetera?
That's number one. Then are you going to take an approach similar to, say, Alkermes, where one molecule is focused on, say, sleep-wake, and then another molecule might focus on a larger indication like mood or attention? Is that a good way to think about how you may approach your orexin program?
Yeah. I'll actually start with that first or that second question.
Kumar can certainly chime in on the first. Again, we won't get into the specifics, but yes, there are practical reasons that it would be challenging to have one asset focused on both narcolepsy and IH, given that it's a rare disorder, a higher price point, oftentimes requires specialty distribution, a lot of support, versus those broader markets that are in the millions of patients versus in the tens of thousands of patients, and have a different price point, different payer pressures, different demands. So yes, that's why I say that our desire would be to have a portfolio of orexin agonists. Again, that's something that we are aiming to achieve.
Yeah.
Right, David, in terms of the backup compounds. Those kind of things, like any responsible R&D organization, whenever you have a lead compound. You automatically start working on the backup compounds, try and see if there is anything to optimize, and also to build some redundancy, right? All of those efforts are ongoing. In terms of timelines, we are just not ready to provide those timelines yet until we get closer.
Okay. Let's turn to EPX-100 or clemizole. Just a high-level question there. Just help us contextualize the nature of the unmet need in Dravet and Lennox-Gastaut. These are polypharmacy-heavy markets. You have an agent mechanistically that has some overlap with others, so I am just trying to better understand how you are envisioning the potential role of the agent in these two clinical settings.
I can give a perspective on the unmet need and some of the differentiation, and then Kumar can maybe speak to some of the specific features, and even some of the open-label data that we've seen. Yes, there are a number of treatments out there for Dravet and Lennox-Gastaut, and as you point out, most of these patients don't usually get satisfied by one of those treatments, so it's ultimately a polypharmacy market.
There's a great deal of still remaining dissatisfaction, both on the efficacy front, but also on the safety fronts. As example, FINTEPLA has a requirement to do echocardiograms. Also, EPIDIOLEX has known issues with GI side effects, but also with requirement for LFTs to be done regularly. Also, dosing is an issue. There are products in development and on the market that have three times a day dosing. As we talked about earlier with our orexin agonist, less frequent dosing certainly is better for compliance for patients.
Clemizole, EPX-100, being twice a day certainly is valuable relative to those three times a day agents. Despite the fact that there are a number of treatments out there, we believe that it can occupy a place where there's currently unmet need.
Yeah. The unmet need, as Peter mentioned, is both on the efficacy side and also on the safety and tolerability side, right? With clemizole hydrochloride, David, you're right, the mechanism of action overlaps with some of the other mechanism of actions that are currently in development. It's a 5-HT2 serotonergic mechanism of action very well established.
In our clinical trials, both the phase II, phase III studies, one in Dravet syndrome and one in Lennox-Gastaut, they're ongoing, top line 2027 with anticipated approval in 2028. We did disclose the data from the open label extension part of the Dravet syndrome last year at the AES meeting. In patients who have been exposed for at least six months to clemizole hydrochloride, we saw a median reduction of 50% in countable motor seizures over 28 days. This is considered clinically meaningful.
Yeah.
In addition, we also saw 50% reduction in seizure frequency in 50% of the patients. One thing to note is these patients were already on at least four anti-seizure medications, so this was used as adjunctive therapy, and this speaks to the unmet need in this particular patient population. More importantly, as Peter alluded to, in terms of safety and tolerability, clemizole doesn't require echocardiogram monitoring.
It does not require any liver function test monitoring because we haven't seen any of those abnormalities. Also in terms of tolerability, one of the common issues with many of the anti-seizure medications is nausea, vomiting, abdominal cramps, diarrhea, or appetite suppression. In the data that we presented, the only AE of note was diarrhea in about 2% of the patient population.
That was the last cut we presented at the AES meeting last year in December, and we are going to present another data cut at the AES meeting towards the end of this year.
I wanted to dive more deeply into clemizole relative to bexicaserin, which Longboard, before it got acquired, called it a 5-HT super agonist. We know a lot about bexicaserin in particular. I just wanted to get your thoughts on this idea of their 5-HT2C selectivity. You've talked about your own safety profile. As you look at bexicaserin in particular, how do you see clemizole stacking up from a cardiovascular safety perspective?
Yeah. 5-HT2 super agonist is the stated mechanism.
Yeah
Of bexicaserin.
Sure.
Based on the publicly available data, they're pursuing DEE and Dravet syndrome in two phase III studies. We decided to take a much more puristic approach and went with DS and LGS in two phase III studies.
Sure.
In terms of differentiation, there is some positivity of data, right, to control, to compare and contrast. The only thing I can say is, look, when it comes to dosing frequency, clemizole is administered twice a day.
bexicaserin is administered three times a day, which is definitely an advantage from a patient and from a caregiver perspective. We just need to wait and see what the data looks like in terms of efficacy, safety, and tolerability.
Yeah. Okay. You mentioned FINTEPLA. FINTEPLA does have a REMS in place. You have also talked to not incorporating monitoring, Echo monitoring in your phase III. I am just trying to get a sense of how confident you are you could avoid the same kind of REMS that is associated with FINTEPLA.
Right, David, great question. That is data-driven.
Yeah.
Clemastine hydrochloride was in the market for two decades as a first-generation antihistamine in the 60s and 70s, and it was sunsetted with the arrival of the second-generation antihistamines, not because of any safety or tolerability issues. That is the historical information. FDA asked us to develop clemizole hydrochloride as a new chemical entity. We went back and did all the tox studies, six months, nine-month tox in dogs, and specifically we looked at cardiovascular tox in beagle dogs.
We have healthy volunteer data. Based on the totality of the safety and tolerability data, there was nothing to suggest that it requires any kind of additional cardiac monitoring. Two studies, they are being conducted in U.S.
Europe, India, and China. All the regulatory authorities have seen our investigator brochure, all the tox data from the pre-clinical studies and safety tolerability study and data thus far, and there has been no signal that warrants any additional monitoring.
Let's switch gears to pitolisant and lifecycle management there. You've got an April 27 PDUFA for pitolisant GR. I wanted to get your thoughts on how you think about the value proposition of pitolisant GR relative to WAKIX and what your commercial strategy is going to be for GR.
Yeah, I can comment on that. Yes, obviously the file has been submitted and accepted. We have the PDUFA date. In terms of the value proposition, it starts with the pre-existing condition of narcolepsy and that there is significant GI symptoms that co-travel with narcolepsy. 80%-90% of patients that have narcolepsy also have GI symptoms, not necessarily even tied to their therapy, just as part of their disease.
They've always been a bit more sensitive to GI side effects. The GR, as the moniker implies, is gastro-resistant coating that has been applied. That's one of the potential benefits, has helped to address or minimize the GI side effects that can happen with narcolepsy patients. The other piece is that there's the potential of being able to start at a therapeutic dose.
Currently with WAKIX, as great of a product as WAKIX is, and we talked earlier about the continued strong performance and the great place it occupies and the unmet needs it fills, there are ways to potentially take a very good product and make it even better. One of the ways is because currently patients start at a subtherapeutic dose on WAKIX and then go to the therapeutic dose. There's a little bit of titration.
With this gastro-resistant formulation, there's the potential that patients could start on 17.8 mg, which is a therapeutic dose, straight away. Those are some of the benefits that the therapy brings. In terms of commercial infrastructure and commercial approach, clearly this is going to be a big part of our focus when hopefully it gets approved on April 1 next year. Also because this is not a retail distributed product, besides the sales force and marketing and all the typical activities, we also have a closed distribution network with specialty pharmacies in the hub, and that's going to be another lever that we're going to be able to utilize in the commercialization of WAKIX GR.
Lastly, and importantly, we have utility patents that are filed. One of the other great benefits that it has is it has LOE and exclusivity into the 2040s. That's also another important feature of the product from a business perspective.
Yeah. Let's switch gears to pitolisant HD. As you look at HD, can you talk to dosing relative to WAKIX that you are evaluating? How much higher of a dose relative to WAKIX are you evaluating in the phase III?
Right. pitolisant HD, the key value driver. In phase III studies, two phase III studies, one in IH and one in narcolepsy, top-line data anticipated in 2027 and anticipated PDUFA in 2028, well before the loss of exclusivity of WAKIX. To add, iterative patents have been filed for this compound as well, all the way into 2040.
In terms of pitolisant HD, David, it is an optimized formulation of pitolisant. So milligram to milligram, it is not the same as WAKIX formulation. It also has a GR coating, and we are going up to 60 mg, of pitolisant hydrochloride there. This is based on the data to show linearity, exposure, response with pitolisant, and also based on the safety and tolerability data.
In addition to the usual endpoints that we study in narcolepsy and IH, with pitolisant HD in narcolepsy, we are also targeting fatigue, and in idiopathic hypersomnia, we are also targeting sleep inertia.
Right
Just one comment.
Yeah.
While we are looking for additional labeling in IH, I just want to point out that IH is not an indication that WAKIX has today, as a reminder. That would be a brand-new indication in addition to potential additional labeling that can help differentiate it in the marketplace.
One more question from me on this. Once HD enters the market, where does that leave GR, I guess is my question. Is there a space, is there a lane for GR? Is that sort of your, quote, "lower dose product?" Just help us understand where these two ultimately fit. My understanding, my view, my bias is that HD is going to be driving much of your business over time, but maybe that's not the right view. Help me better understand how you are thinking about it.
Yeah. As a leader in the space, we want to give options to the clinicians and also to patients. In the future world where both of those are on the market, clearly, WAKIX at its current dosing is very effective for patients, and clearly tolerable and meets an unmet need. Having the GR formulation and the ability to skip the subtherapeutic dose will be valuable for some patients. For other patients, they may require higher dose.
Some patients can be refractory or not getting full response, and only getting partial response, so there's the ability to have the GR coded higher dose formulation. Additionally, currently, WAKIX, as we said, is not indicated for IH, so there's a whole other patient population that we are currently not able to serve with WAKIX that we hope to be able to serve with HD.
Terrific. Well, wish we had more time, but I will leave it there. Thanks so much, Peter. Thanks so much, Kumar, and thanks everyone listening in, and we will
Yeah. Thanks to you, David.
talk to you soon. All right.
Thank you, David.