Try and keep running out schedule here. Good afternoon, everybody. Thanks for joining us for a session with Barbarus. My name is John Wallovan, senior analyst here at Citizens Life Sciences at our twenty twenty five conference. We have Pong Lu and Wim Sovian.
Good. Good enough.
Head of head of, medical and head of commercial. So it's a perfect time to to jump in that hereditary angioedema. Cat's out of the bag, but tell us what you guys are working with because you guys have a little bit of different spin on the space and what you're targeting. You're blazing a path forward with the mechanism and I'd love to learn more about how you guys are thinking about the differentiation. So I'm not sure who would like to jump off, but maybe talk to us about ducrictovant and how you guys are different in the space.
Yeah. Actually, maybe I will start since you mentioned the mechanism part, then we will start from the science and medical part, then we will go to the commercial part. So as maybe everyone knows that HE is definitely a highly competitive field even though it's a rare disease here. And so far that compared to all available treatment or currently that are ongoing treatment that all these, you know, that the new new treatment here is target on the Kallikrein pathway no matter for factor 12 inhibition or pre Kallikrein or Kallikrein there. And compare all these upper stream that target or upper stream, you know, that are products there.
And the ducritiban actually is a b two receptor antagonism. It's sort of like the molecule, you know, that the compound maybe someone of, you know, iCatibinder. It's a oral treatment and the target to the b two receptor is more downstream. Therefore, that are currently from the science part, we consider that a one molecule and have two different formulation, and the one is called immediate release formulation. It can reach the the the plasma exposure level really within the fifteen minutes.
It will be great for the rapid onset and the treat the oral treatment. And then the other is that extended release formulation, and we can cover that the twenty four hours exposure range with once daily treatment. Then that based on this, we will have the one molecule, two different formulation covers that, you know, the oral that are two efficacy, safety, and the convenience that all three part based on these two data. That's from that the current available set of phase two results here. In addition, I want to also highlight because we are more downstream compared to others, we have broader patient coverage of broad indication because we are not only treated type one, type two HE patients highly dependent on plasma Kallikrein pathway, but also potentially type three patients is some that the genetic mutation is plasma kallikrein independent pathway there.
Therefore, the nucleotide in addition to the three part we just mentioned also can have broad patient population and can provide the, you know, the new treatment for patients we still, you know, have a high medical need there.
You talk about the differentiation from the plasma kallikrein inhibitors, which we have a lot of today. I think just mechanistically thinking about the efficacy it makes sense, but we also get questions about long term safety and I think that might just be a function of a new mechanism and probably people who like the other stories more are saying wait until something happens. But talk about what's giving you more confidence in the long term safety of bradykinin antagonism today versus what we knew five years ago.
Oh, that's excellent question, Jonathan. That's because that as as mentioned, that I tadband as the only, right, b two receptor, you know, that the antagonist molecule there is only on demand treatment. Therefore, as you mentioned, people always ask, how about the long term propy use, right, Block this receptor there. So compared to the five years ago, as mentioned, that icataban first that have been used over ten years have a lot of really that the clinical practice there to show that this mechanism is well tolerated and safe even for certain that the different patient population there. The second that we have to see for the ducritibon here that even for our phase two result, for example, the chapter one result that we've already accumulate the safety and the tolerability data up to two years now.
And the deuquitabine is very well tolerated, and that's direct evidence to show even though we agree still small sample size, but as up to two years, deuquitabine was very well tolerated and no any treatment related signal was observed.
Can you talk about your preclinical tox package and where you guys are in that development?
Yes. So far that we've already complete, almost complete all the tox package no matter to support on demand or profit that are filing later on.
Alright. So that should give everybody a lot more confidence in in long term safety. And we cover a few companies and no one else has both an acute and a prophylactic. So Wim, you got the heavy lifting and talk about the evolution of those two different markets and the interplay between the both. Can you tell us, you know, how has this changed and how could you guys fit in?
I think the beauty is that, as you said, we have one product that one drug that can work in the two settings. So we're indifferent in how this market really evolves. What we do see from the market and what we see from the guidance from the academic and the scientific community is that no patient should suffer no attack. The only way to do that is through prevention. So we know that today already in terms of number of patients, sixty two percent of the market in The US is prophylactic.
Value is even more than that. We anticipate that to grow. We anticipate that is it 70%, seventy five %, eighty %, who knows? Well, we don't think that that will retract. Whatever is happening in the market, there is big expectation of orals in on demand, but I don't think that will fundamentally change the dynamic, which is to go to more prevention.
I think then in each setting, it's really important to to offer a value proposition, to offer a profile that really can set out. And I would say there has been tremendous progress in AG, particularly on the prevention side in the last ten years. But for me, good is the enemy of great. And when you look at the market today, whether it's on demand or prophy, patients have to make a choice. They have to make a trade off.
Either they say, I absolutely wanna have efficacy. And if you want that, you have to go for an injectable. If you don't want us if you're willing to give up on that and you say, I prefer the the convenience of an oral, I don't wanna stick myself with a needle, then you have an oral option. But you have no product that offers injectable like FSC, stable tolerable profile in convenient daily oral dosing. And that's I think where we make a difference both on lemadenopathy and prophy where we have a package, if we confirm that obviously in our Phase III, which is critical, that really stand out and that will entice a lot of patients to make that choice.
And we hear very often people saying, well, it's a sticky market. Patients will reality is not. I mean we know even in this market where there is not much change, five percent of patients every quarter are switching therapies. That will increase if there are more entries. If you have alternatives in front of you, you can make that choice.
So I think I'm very confident. We're very optimistic about if we can repeat the data from the Phase II and the Phase III that this will be a very competitive profile.
I agree that we see a willingness to switch and adopt new therapies, but also we do see some stickiness to like CINRIZE and the HIGAR, some of the older drugs. What's going on there? And why aren't those going the way of the dodo?
It's frankly, quote, unquote, a dying race, but Calviton is the same. Mhmm. These are patients that have been in Calviton for ten years, fifteen years, and they just don't wanna get off. They don't wanna change anything. And so but we'll see that that's going down on the It's a minority.
Exactly. That's good. Yes.
Maybe we we should dial in on acute first. Can you talk about the phase two data you guys generated and and, you know, what you saw that gets you so excited?
Yeah. We definitely have very exciting that the phase two on demand that the treatment data there, and we show that the overall data with even though it's oral molecule as mentioned because of fast absorption there, we show that the time to onset of the treatment relief that is about one hour, one point one hour there. Even before that, I have to see some data which is released for end of progression. The first sign patient feel the drug being effective is only around twenty five minutes. Then go beyond the aduclideband also show dramatic good that sustained effect.
That means that it's a with only single that the treatment there, we show the time to substantial symptom relief is around two to two point six hour there. And there's a resolution, complete resolution, it shows that within twelve hours. All these, we also that the people think is only the the order. Right? I tag vendor.
To be honest, we agree that it's provide convenience and show know, that are great. That, you know, that the treatment option for patients. But meanwhile, from efficacy side compared to iCAD band data, we also say it's maybe not only just the oral one, but it's a better one.
And you guys have given us a lot of data, and sometimes it's hard to parse through what's important. Then there's, you know, time to symptom relief, time to stopping progression initially. Like, what's the important thing that people should look at when they're thinking about the acute data?
I think what's really important for me
Well, maybe from a clinical trial perspective, and then what do patients care about in the real world or do physicians care about if those aren't the same thing?
Well, I think I think they are aligned. But I think ultimately what matters for the community is the area under the sinking curve. You know from our corporate deck, we have this picture of an attack, and it happens when you treat, how we then see end of progression, and it goes to complete resolution. It's not enough to be very quick in the plasma and have a first popping an attack in early onset of symptom. You have to go the whole way.
And I think that holistic package of making sure that this area under the curve of symptoms, that that's minimized to the maximum extent, that's really what the value is that patients and doctors are looking for. And that's why this why they will put out the comparison with injectables because whether we like it or not, C1 inhibitor and icataban, they're pretty good. So what Pong was describing is the date of the data we had, these are indirect treatment comparisons. We can see that you can really have an impact, not just in the beginning, but over the whole course of an attack.
And how important is it treating early? And do injectables work slowly or less slowly just because they are used later in an attack?
So working quickly is absolutely important. The benefit of an oral is I can sit here next to you, I feel an attack coming, and I pop a pill. So it's super fast. You need to have your pill with you, but if you have that, it's super fast. Most patients on injectables don't have the medication with them.
Mhmm.
So that is the first burden. The second burden is you need to find a place to inject yourself.
Do you mean like a location or a body part?
Body part is probably they kinda know that. Yeah. The location. We heard a story. We had a patient actually going to our office talking about she's on an IV.
And she says from the moment that she's in the car she's she's in the event. She has an attack. She has to find her car. From the moment she's in the car, she has her kit. It takes an hour to infuse the drug.
So that's a massive time that you lose compared to your now for a trial perspective, I think it was really critical at Pong did in terms of qualifying ATT because we really demonstrated that the drug works in ATT and In real life, it's completely different story. I % align with Calvista, builds early onset treat right away.
Mhmm. One more thing I would like to add is also for injectable is because that especially with the most popular injectables that is very painful. Mhmm. They inject side pain is a big factor, actually prevents the patient's eating treat acute attack. Patient eating evaluate which one is more painful.
Is it my sweating or my attack here? Interesting. Or is it really the injectable pain from the treatment here. Right? That's another layer of the treatment burden Mhmm.
For patient to overcome. That's exactly with our treatment here. This burden is much less or zero here. That's why hopefully it can benefit, you know, most patients here.
And then remind us of your phase three trial that's ongoing, the design, how things are enrolling, endpoints, timing of data, all the good stuff.
That's a big question. But indeed, I have to say that our pay tool trial that for for on demand is that a rapid d three study went very well. We've already made announcements that we complete. That is a targeted enrollment, and we expect the top line readout to the first half of the two thousand twenty six. Currently, team is closely monitored that is the the attack because it's time to event.
Right? Mhmm. That really the attack assessment there. So we maybe update more that, you know, give more update regarding the the readout soon. But the team still that evaluate that all the the study here.
And our as mentioned, that are from that the primary readout that for study is onset of symptom relief. But meanwhile, we have a serious secondary endpoint just as we mentioned, it's not only onset, but it's a greedy area of curve under the tag. We will definitely show that even that of repeat, the symptom relief resolution, single dose use, all these are very important factor to evaluate.
And how the studies were run ten years ago versus today are different. How should we think about what you need to show to get people excited? I think the expectation should be that the trial is going to be successful versus placebo, but it's going to be, you know, how meaningful is that result. So how do you think about what's what's good data in this readout?
I think that we can say if the phase three data is as good as our phase two, I think it's definitely a very, you know, it's exciting news for patient.
Mhmm.
And compared to the past, all the patient have to drive to the center
Mhmm.
To get a treatment to evaluate. For our phase three study right now, it's really home setting.
Mhmm.
The patient just take a medication, qualified attack with by the call with the physician and get a treatment. It's more like a real world setting there. That in addition, we have our rapid use at open label extension. Mhmm. It's completely like that, you know, that the real world evidence generations at the settings.
Mhmm. So all these data put together, we think we will provide a very good picture there.
What goes into adjudicating an attack? Is it just calling and talking about the symptoms or is there a specific criteria that are required to treat?
We do. We have specific criteria. Just mention the patient do have to demonstrate that they have swelling there. It's not like a prodrome of the attack, for example, headache or some prodrome there. The patient will release a talk with doctor to say that they have either peripheral swelling or abdominal pain or maybe some patient have a laryngeal attack there Mhmm.
Then confirm that that the patient that the physician confirms that's an attack, then they will treat.
And when we think about the on demand acute opportunity, what does that look like? Because it was, you know, a fairly large market when Firazir was a branded drug, a genericization, and then more prophylactic drugs coming? What's kind of the evolution there? And what do you think the opportunity is?
If you look at data at the moment, I think these are data from Q4 'twenty four, About sixty two percent of the patients are on prophy. The complement is on demand, so it's a smaller portion of the market. But the value is even lower. It's 21% of the value comes from on demand. So it's definitely not the biggest segment that is out there.
We anticipate, as I mentioned before, that the prophylactic will still grow. Small, fast, we'll see. But with new entries of products coming in as well, I think there will be some push behind that. We won't I don't anticipate a move back to on demand. Now that said, we also believe there is opportunity in on demand.
And the reason is, to what Peng was describing earlier, between thirty and forty percent of the attacks are not treated. Mhmm. The patient has left hand swell and they're right handed, and they know what it takes to inject themselves with a catheter and say, you know what? I'm not treating. If you have a capsule, why would you not treat yourself?
Mhmm. And there's a lot of impetus from the physician community on this as well. And it's very telling at the patient meeting, I was talking to a doctor and he told me that it's I'm really frustrated because I thought patients I thought I was clear to patients that they should treat all the types, but they don't. And so that's kind of it's a joint effort from the whole community to really drive that further. And that will be enabled by effective oral therapies.
Do you think there's going to be pricing pressure then because of the lower prices there?
Sorry, in terms of
In an acute setting with generic icanumab available, does that kind of limit the opportunity? Or does the value proposition still stick?
So we we actually did a payer advert last year with, like, two hundred two hundred thirty million lives covered for the payers that were there. And when they saw the data, they were, wow. This is if you can repeat this, this is a big deal. And their anticipation so there is indeed generic in The U. S.
Market, but it's not a real hurdle for uptake for better medicines. But you got to, obviously, if you have not the same efficacy, it's a different story. I think if you look at the holistic package that we bring and being oral, there's a lot of advantages associated with that. And payers are not payers will probably on an individual basis, sometimes there is abuse. I mean, I heard from one of the KOLs saying, I limit my prescriptions to two months because I had a patient who was taking ketamine every two days.
Mhmm. That's abuse. So besides that payers are relatively standoffish in terms of managing HAE at this stage.
Okay. And then I want to pivot to prophylaxis. Can you talk about the data you guys generate in Phase II? You mentioned injectable like efficacy. What is that?
Yeah. In our phase two study with a placebo controlled settings that did your equipment showed that compared to placebo, there are 85% attack reduction for all the attacks. And meanwhile, for moderate or severe attack, this reduction up to over ninety two percent and also over ninety two percent attack reductions at attacks who need that on demand treatment. That's in our placebo controlled trial. And with open label extension study, there's that up to almost two years, the equipment showed a 93% attack reduction for the overall baseline attack.
Therefore, that they're really compared to the, you know, injectable like efficacy that demonstrated in other treatments. We do have strong belief that even though it's oral treatment, it can reach injectable like efficacy as the data tell us.
And can you talk about your phase three design for prophylaxis?
Actually for prophylaxis, all the study designs that is quite comparable, it will be six months treatment placebo controlled and we targeted to enroll around 80 patients there, 81 patients. Try to encourage the enrollment. Our active placebo ratio will be two to one. Mhmm. Therefore, that the patient have a higher chance, right, to to get the active treatment.
And when do you think you could have data from that trial?
Currently, we expect the February.
And I was thinking about this either today or yesterday. Have we ever seen a phase three prophylactic study fail? Don't think so.
I can see You
know they have type one, type two.
Yeah, don't think so. Yeah. So this trial should work and again it becomes how does this look comparative, right? So again, do you just want to see what you did in phase two? Is there an opportunity to enrich the population, show better efficacy?
Do you expect, you know, a migration? What do we see when we go from phase two to phase three typically?
I think you mentioned a very good point, Jonathan, that the translation from the phase two to phase three is really high for HAA trials as I mentioned, and also the study design is similar that from the phase two to phase three. For us that I think one thing we really want to highlight for our phase three study, we would use extended release tablet, our two p market formulation in phase three. And then compare the formulation we use of phase two. Actually, this formulation even further optimized that is a p two to trough ratio, and it provide even more that twenty four hour that exposure coverage there. Therefore, that if it gives a buffer, that is some maybe if we get to the questions of variability, right, for phase three trial will be higher compared to phase two, but we said really that are very, you know, sufficient or even better or high that the c 12, the exposure coverage there, we expect the efficacy from phase three study at least comparable, even better.
I think that's a really good point, and I'd recommend people take a look at your corporate deck showing those PK curves, because usually you go to phase two, three, don't change anything. But the change you guys made actually gives you better drug coverage for a longer period of time. So I think that's a really important point to keep in mind. So I'm glad you mentioned And then when we think about the prophylactic opportunity, we have Teixyra, the market leader that's doing very well. Orlodayo keeps taking share and selling well despite efficacy not on par with injectables.
So how do you guys think about that dynamic for you guys? Because you're going to be in oral, and it seems like you have a wide window where there could be success.
Yes, absolutely. So we were very pleased when we saw the update from BiCryst this week. I think it's testament to the need of having an oral in the prophylactic setting. And so that's really reflected in their forecast. I think it was very interesting that they showed how the patients today have a higher preference for an oral when you ask them than a couple of years ago.
It went from thirty five percent to like seventy percent of the patients all want to have an oral intervention. So I think that bodes extremely well for us because what we can bring if we confirm our data in the Phase III is on top of that, we have the injection at a different level, meaning at the level of Ataxayo and then Heygarda. And so I think that's really offers us a great opportunity. And it also means that we anticipate that in the equilibrium in the HE prophylactic market, orals will be dominant. Is that 55%, sixty %?
Who knows? I mean, crystal ball. But we think it will be dominant. And I think we have great cards to really be the dominant leader in the oral segments in that respect. And so new patients, they should go on to XR because if you can start on a drug, why would you go into an injection if you can get the same efficacy with an oral?
There are a lot of patients that tried Ornodale. By the time we launched, around 1,000 people have done that and left A big pool of patients. Even those patients on Oradayo today, they still have breakthrough attacks. And that's each time that's an opportunity for us to step in and say, you know what, Switch.
Why do you think that there was that increased preference for an oral? Because, you know, what changed? You think either I prefer it and I always prefer it, or is there something that I
think there's maybe some psychology. Because I remember my grandmother when she when injection was given, oh, that must work. That's that's a serious a pill was like, oh, yeah. It's like an addict.
Oh, you're doing something more Yeah.
Harder. And I think that's maybe a perception that has been in people's heads. But now they see, you know what? Actually, so many and there's a lot of peer to peer interaction. HEE is a really great community.
So the patient meeting in Baltimore in the July will bring together 1,200 patients. So they talk. They exchange. And so building that confidence, some people want to take that first step, other people say, yeah, we're to wait a little bit. And so that's probably behind that preference change.
We covered a lot of ground. And maybe just to put a button on everything, can you talk about your current cash position and then remind us just of the timing of your readouts just to give some context for investors.
So from a cash perspective, December '24, we had €280,000,000 in the bank, which is important today. And for the readouts?
For the readout for our on demand, as mentioned, our pivotal readout will be q one two thousand twenty six. For prophylaxis, it will be February. Meanwhile, we also want to mention and highlight that we also will initiate acquired angioedema pivotal study by the end of this year. Therefore, ducritibat, as we mentioned earlier, our target population is not only HE. We target a bradykinin needed angioedema.
That's including HE type one, type two even type three HE and also acquired angioedema.
Which is differentiated again.
Absolutely.
Well, Wim Pong, thanks so much for getting us over here on Farberus. And we look forward to tracking the progress. It's going be an exciting time coming soon.
Thanks so much.