Okay. Well, good afternoon, everybody, and thank you once again for joining us for the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the TD Cowen Biotech team, and it's a great pleasure to have with us today, Marino, CEO and President of Dianthus. Marino, good to see you. Appreciate it.
Good to see you, and thank you for having me.
I think the first thing we need to discuss is how you feel about Real Madrid. Gonna keep on asking that all season now that you're not doing all that well.
Yeah. I'm focused on the World Cup now.
You're conceding the season, I like it.
I'm not conceding anything. I'm just focused on the World Cup.
Yeah. We're talking about the La Liga in Spain. Well, in all seriousness, let's. You have a lot going on this year with pasitelefusp, and maybe just give us a little bit of the overview for you. What are you focusing on this year?
Again, thank you for the opportunity to join you here today. For claseprubart, you know, we had really great data at MG in September, phase II data, which I think most investors would agree, surprise to the upside. It gave us a lot of confidence around the potency of this drug at 300 mg, 2 milliliter, one shot every 2 weeks, and the safety profile. You know, that felt like a very important de-risking moment. I feel now we're on the cusp of another big moment. If not so much maybe de-risking, a more of a confirmation moment, that we really do have a potentially, you know, a blockbuster neuromuscular, you know, therapeutic here with claseprubart. The team is just executing phenomenally.
We're continuing to just stay focused on executing to try and meet or beat expectations. The next big moment is the interim responder analysis announcement for CIDP. Our one single pivotal trial, phase III trial, in CIDP, where 2-part trial, where we test 300 mg, 2 milliliter, one shot every 2 weeks in part A. We allow patients who are standard care, or IVIG stable, standard care IVIG, refractory or naive, all CIDP patients. We switch them. It's a truly a switch study. Literally within 7 days, they're switched off IVIG and onto claseprubart.
What we're looking for is not to continue to be stable, but for additional response above and beyond the standard care or IVIG that the patients are on by at least one point on the MGC score, because only those that respond above and beyond what they were on before will then get randomized into part B, where you continue to get drug or you get placebo, and it's about showing a separation in terms of relapse rates over a year. It's a very exciting moment on multiple levels. I'm sure you probably have some questions around it. No surprise it's a big focus for patients. We're also executing on our phase 2 MMN trial.
There, we're looking to provide top-line results in the second half of this year, and there again, we have a nice precedent with empasiprubart, the C2 inhibitor from Argenx. We're looking to see similar efficacy data as they did in their phase II, then proceed into a phase III. Those are near-term sort of milestones from claseprubart. We have others with our two and two, our bifunctional fusion protein second program we can get into later if we have time. There are some important external catalysts as well. The phase 3 data from empasiprubart and MMN will be a big one for claseprubart later this year.
Excellent. By the way, for the audience, if there's any questions, by all means, don't be shy and happy to take them. Maybe, first of all, on Maverick. Just remind us that I think we're expecting data in Q2 or an announcement of part A, there's a few things that you're gonna be looking at. There's, it's a 300 mg dose. There's a question about what you see in part A. You're not gonna be able to show us the data 'cause it's part of a pivotal, just like with ADHERE from VYVGART. They weren't able to show us the data either. In part B, you're supposed to randomize the 300 or 600 against placebo. Depending on what happens to part A, you might make a decision.
There's gonna be maybe a decision whether you resize the study, depending on what you see. I think the bar, you've mentioned is kind of 40% to 50% response rate in part A, to take into part B, just given the historical claseprubart data and your powering of the study. Any thoughts as to anything new as to what we should be expecting?
No, I mean, I think you summarized it. you know, we're gonna be very limited in terms of data we can share. Look, we went into this trial designing it for success. It was to be able to compete for patients, the open label coming in only every two weeks, part A. That's really helpful for us in terms of recruitment. That's why we're accelerating our timelines versus other studies are being delayed. It's very patient-friendly. Yeah, there's three things I'm telling investors to look for. Are we keeping the dose at 300 milligrams every two weeks in part A? If that's the case, that means we're seeing the efficacy we hope to see, at least similar to claseprubart's phase II data. Do we get rid of the 600 mg arm in part B?
If we do that's a huge confidence signal. We don't need the higher dose. If we get rid of the 600 arm in Part B, we've just cut the size of this trial by a third. Again, we're accelerating recruitment. We're cutting down the time that claseprubart has ahead of us to market. If we can cut the size of this trial by a third, we've just made this a real race. If we cut the 600 mg, that should be another strong signal. Hey, they're seeing really good, robust data. They're feeling really good about 300 mg every 2 weeks, at least being similar to riliprubart. Now, there's one other element.
Right now, if you go to ClinicalTrials.gov, you'll see that we need 192 patients in part B. For that, we're saying we need a conservatively 480 patients in part A. If you do the math, 192 divided by 480, you get a 40% ratio. What does that mean? You know, we're expecting somewhere close to 50% efficacy responders, much like riliprubart did in patients who are refractory to IVIG or stable on IVIG. You know, you always set that ratio to be a little more conservative. It's okay to over-enroll. You can always end the trial early, but you don't want to reach your N in part A and not have your part B enrolled. You always want to be a little more conservative. We put it at 40%.
If that ratio stays the same, everybody should understand that that means we are seeing efficacy. That's exactly what we'd hoped to see from the beginning when we designed this trial. If we cut 600 arm in part B, we just made part B 128 patients. If we cut part A by a third, we will go from 480 to 320 in part A. Again, 128 divided by 320 is 40%. If that's what we end up with going forward, that should be a very nice, strong signal that, hey, we are seeing what we hoped to see when we started this trial. In other words, at least similar efficacy to riliprubart. There is an upside scenario.
If somehow we're seeing significantly better responder rates than riliprubart's on their phase II, because we're a more potent antibody, or we're just a different chemical entity, whatever it is, if somehow we're seeing much better responder rates, and we're seeing that spread across different geographies, if we're seeing it, you know, of course, being driven by the refractory or stable IVIG patients, not naive. If 15% of our baseline patients coming into part A are naive, very similar to riliprubart, but we're seeing really robust efficacy numbers that are clearly showing us that this is materially better than expected, materially better than what we saw in phase II for riliprubart, then we would go ahead and make that ratio a 50%, meaning part A doesn't become 320, it becomes 256.
We just signal to the market that we are seeing really good efficacy numbers that seem to be better than riliprubart, not equal, but better. I think that would be a very strong signal. The question here is, by being more potent, by being a different chemical entity, are we going to be able to extract more efficacy in CIDP patients than riliprubart? We don't know the answer to that. That interim and responder analysis will partly answer that question.
Got it. Okay. The timing is Q2.
That is what we've guided to, yes.
Okay. Any sense what are you hearing on enrollment for really riliprubart?
We're hearing what they said. We've been hearing it for, you know, a couple of years that they're having trouble recruiting. Look, when we, when we were designing this trial, after we saw, of course, A rgenx was successful with efgartigimod with a highly enriched trial. There are some very important differences between our trial and that here, which we probably should get into. When we saw that they were successful, that wasn't ever a question in my mind. It was, what does the FDA do with them, with this data? When they got an indication for all adults with CIDP, no restrictions. I mean, think about that. They didn't even allow refractory patients in their trials. No FcRn is gonna study refractory to IVIG patients. If you're refractory to IVIG, there's very little chance FcRn is gonna work.
FcRns don't work as well as IVIG. Yet all adults with CIDP, no restrictions. When I saw that, I said, "Okay, we need to do this trial." When we talked to investigators, the first reaction they had is not another CIDP trial. Where the heck are we gonna find all these patients for all these trials going on? When we said, "Well, here's what we're thinking," they said, "Okay, if you do this, you're gonna get patients." Because why? The number one group of patients that go into these trials are patients who are on IVIG and stable. They're highly motivated to go into these trials. Why? Because they may be stable, they may be doing, quote-unquote, fine, but they really don't wanna be on IVIG. If you go into the IVIG head-to-head trial for riliprubart, you're blinded from the start.
You got a third chance of getting placebo. That's not great. A third chance of getting IVIG. Well, that's not great. Your whole point of coming into a trial is you wanna get the new drug. Maybe you'll get riliprubart or empasiprubart in the other trial, but you don't know if you're gonna respond to it. With riliprubart, you gotta come in every week to the clinical site, and you gotta get two shots. With us, it's open label. You only have to come in every 2 weeks. There's no guesswork. We're gonna switch you, and we're gonna try you on this new drug. By the way, you have a really good chance of either staying stable and therefore being on a much friendlier, you know, dosing administration.
More importantly, it looks like 50% of patients or more get better on this mechanism than they do on IVIG or standard care. I mean, it's open label. That's it. You come in half the times, you get one quarter the number of injections, and there's no guesswork. Only if you respond and get better than you were doing before, then you get randomized. Then, yeah, you have a chance of getting placebo, but guess what? If you relapse by that 1 point you improved in part A, it means you get back to how you were doing before. You get rescued right away. Guess what drug you get put on if you want? The drug you know you responded to in part A, then you can continue on that drug for 2 years. Think about if you're a CIDP patient.
Which trial would you wanna go into? Wherever we're competing for patients, it's a no-brainer. Try this trial. It's so much more patient-friendly. We've heard they've had, we've been hearing they've been having recruitment problems for a long time now, so I wasn't surprised with their delays announced last fall. What was interesting to me is, of course, I got a lot of questions from investors. "Are you also gonna be delayed?" When we had our MG data, we presented that not just to MG physicians to show them what their trial, the trial they participated in and what it accomplished. We also showed it to our CIDP investigators. Say, "Hey, you should see this. It's a neuromuscular condition.
It's the first blinded, randomized, you know, placebo-controlled trial in a neuromuscular condition for an active C1s inhibitor. They were really impressed. What we saw, what we heard anecdotally is they said, "Okay, I'm definitely now putting more patients in this trial." What I saw going into the fall is literally the curve start to turn like a hockey stick. By the time we got out to our Q3 earnings, that's when we felt very confident to move up our interim responder analysis from second half to second quarter. That is because we're seeing an acceleration in our in our recruitment, but essentially this, the opposite of what Sanofi is seeing. I think there's a question.
In part A of the CID... Wait.
No, go ahead and I'll.
In part A of the CID-CIDP trial, someone is IVIg stable. They go on the plus separate part, they don't improve by at least a point. How do you communicate that either to investors or to the FDA? They wouldn't be classified as a responder, and yet if they're stable, they're responding to IVIG. They are also-
Doing well.
Doing well and technically.
Yeah, I know.
...A responder.
This is. Let me repeat it. The question is, you're only randomizing patients who get better after... if they're stable and on IVIG after you switch them. What about patients who are switched but continue to do all right? Isn't that a success, essentially? What do you do with that? It's a frustration by some investigators, to be honest. 'Cause they're like, "Hey, this is actually really good news," but at the end of the 13 weeks, if they didn't get better, they have to leave the trial. That's the way the trial's designed. Only responders above and beyond where they were when they came into the trial can go into Part B.
I don't know if it's entered into your sphere of awareness. Corcept got a CRL letter. One of the things that since it's published the FDA cited was a lack enthusiasm for randomized withdrawal studies, which I haven't seen before, but I've seen-
Yeah. The question is around Corcept and having gotten a CRL, around randomized withdrawal studies. Look, well, all I know is we had this in-depth conversation with the FDA and regulatory bodies around the world, and nobody said no way. Nobody said no. They said, "Yeah, of course," it depends on... It's an sBLA, assuming the data is good, we will, you know, consider it for an approval. I can only go by what the FDA has told us and precedent set with Argenx.
Yeah. Maybe to your point, so you're doing a modified ADHERE study, essentially.
Yes.
EMPA is now in the second phase, I'm sorry, in the first study, and I think INVIGORATE is doing head-to-head against IVIG.
Yep.
Then the second study that they're doing is a modified ADHERE, including the naives.
Mm-hmm
...And the refractory.
Mm-hmm.
All comers, essentially. I guess the question to you, does it make sense to maybe do also a head-to-head against IVIG around-?
Yeah, look, I think, I'm really highly encouraged by Sanofi and Argenx seeing the potential for complement inhibition to be at a minimum, you know, equal to IVIG in efficacy, but potentially superior. Again, I look at Argenx, and they have a drug on the market that if it could do as well in CIDP as it's doing in MG, would not be a $4 billion blockbuster, it would be an $8 billion blockbuster. They're not doing a head-to-head versus IVIG with FcRn. No FcRn's gonna do that. They are doing it with their C2 inhibitor. I think that speaks to the confidence about complement inhibition being a paradigm shift in CIDP and potentially being a better treatment, more efficacious treatment than IVIG, which has been considered the gold standard for CIDP for a long time.
Look, if Sanofi and empasiprubart come out with positive studies in their head-to-head versus IVIG, it's a no-brainer for us to do something to show that we have just as good or better data. We don't need it for regulatory approval. Why take the risk? Let them show us the data, and then we'll move very quickly to do something that gives the market confidence that, yeah, we're at least equal, if not better. That, if those two show that they're better than IVIG, it's lights out. I mean, we know we have a more potent antibody, so whatever they can show, we should be able to show at least equal data.
You know, the interim responder analysis for CIDP is gonna tell us something, it'll tell us by being a more potent classical pathway inhibitor, do you show are you gonna show similar efficacy rates to riliprubart or better? If it's similar, then we know that we both shut down the classical pathway just enough, that it's, they're both potent enough. There's no need for more potency. If we show that we're better, I mean, that's a, that's another paradigm shift, that somehow, unlike MG, by being, you know, much more potent in shutting down the classical pathway, you might extract better efficacy in CIDP. We're not seeing that in MG.
In MG, with some disarray from Regeneron, a C5 inhibitor, that put out a press release in August, we saw that 75% inhibition was enough. They showed a very nice robust change from placebo in the MG-ADL at 26 weeks, and they said they only got 75% inhibition. This target we've had of 90%, IC90, it goes out the window.
Mm.
That's evidence that you don't need that level of inhibition. In CIDP, we don't know that. We don't know if being way up there like we are is going to provide better FC or equal FC to less potent classical pathway inhibitors.
Any more questions on CIDP?
Yeah. I get calls from investors on concerns about potential lupus-
Mm-hmm.
Could you address that?
Sure. There's this theoretical risk of autoimmune activation, more specifically with upstream inhibitors, and more specifically, DILS, drug-induced lupus-like symptoms. What is that? Pull up any label for any anti-TNF, whatever your favorite anti-TNF is, HUMIRA, Enbrel, whatever. Look at it. In the warnings it says, "There's a risk of patients having drug-induced lupus-like symptoms or DILS." All it is that the patient has some kind of reaction that looks like lupus, but all you do is you stop the drug, and the symptoms go away. Let's be clear. We are not talking about inducing lupus. That's not what people are talking about. This is about DILS. If anybody says lupus, there's a chance they're probably shorting the stock. It's DILS.
It has never happened with sotrovimab, it has never happened with riliprubart, and it has never happened with us. It happened with a C1q inhibitor. Both C1s and C1q are part of the C1 complex, but C1q is a very different molecule. It even looks different. It looks like an octopus, right? It holds two C1rs, two C1ss, so it's like this pentamer. C1q, though, if you inhibit C1q chronically, you should expect to see DILS. You should expect to see drug-induced lupus-like symptoms. Why? Because C1q has a very clear dual function C1s does not. C1s is just part of the complement cascade, part of the classical pathway. C1q is, yes, obviously the initial step in the classical pathway, the complement system, but C1q also works as an opsonin that clears the body of dead debris of apoptotic cells.
If you chronically suppress, inhibit C1q, you are also preventing its ability to clear the body of this dead debris. That accumulation of that dead debris is what's theorized causes a reaction that looks like lupus. All you have to do is stop the drug, and the symptoms go away. That's it. There's no black box warning, there's no risk of death, there's no risk of lupus for life. That's not what we're talking about. The evidence of that is in January 2022, Annexon with their C1q inhibitor in a Huntington's trial, phase II, reported that a patient had a case of DILS. They were very clear. They stopped the drug, the symptoms went away.
C1q comes back, and it starts clearing the body of the dead debris, and everything goes back to normal. That has never happened with a C1s inhibitor. I will point out, sotrovimab in its clinical development program, they tested 6,500-7,500 milligrams by IV every 2 weeks. I think it's the highest dose antibody there is. It wipes out all C1s. It literally mimics someone who has no C1s in their body. They had no cases of DILS in their entire program. The riliprubart in us, we only inhibit the activated form of C1s, which is less than 10% of all the C1s in your body. If you were to take someone's plasma who was on one of our drugs, riliprubart or claseprubart, you're gonna see plenty of C1s.
It's just activated C1s if they're, you know, if they're suffering from a complement-mediated disease that's wiped out. C1s, 90% of all C1s is still floating around like normal. We're actually really not concerned, but of course, in our first in-human study in phase II UM-G, the FDA wants you to just do something to look for it. We test for ANAs. We did. We didn't see anything, just like riliprubart didn't see anything, just like sotrovimab didn't see anything. We fully expect that we'll be able to stop monitoring it on a routine basis, like we did in phase II. You do it once in a study with patients, you show the data to the FDA, then you stop doing it moving forward. That's exactly what happened with the other two C1s inhibitors.
Is it known from a pathology standpoint? Complement will become activated when you've got antibody deposition, and you get both complement-mediated destruction and then antibody-mediated cytotoxicity. You're blocking one channel. Do you know the balance of the two that's implicated in some of these inappropriate antibody deposition symptoms?
No, I don't think so. I think that's something that we need to look more into. Yeah. Are you concerned about any side effects or?
I just think.
Yeah. Yeah, no.
Much more knowledge than we know.
Yeah. No. We're looking to fund more and more investigator and independent studies looking at all sorts of interesting questions like that, but we don't know that yet.
Let's maybe shift over to MMN. You're gonna have your phase II MoMeNtum data, 36 patients at 17 weeks, in the second half. The data from Empassion, that's the EMPA or Argenx phase III, will come out at the same time. They changed their endpoint to grip function now, and that's based on the data and the durability and continuing improvement on grip strength versus IVIG. You know, head to head, time to relapse on moving away from IVIGs, moving to a secondary endpoint. Your study, obviously, it's a phase II, so the primary endpoint is safety, and then you have the same sort of secondary endpoints. What's a win in that study for you, and what would be the next step?
It's a very similar trial to ARDA.
A consistent safety profile to everything we've seen to date, and, you know, prevention of relapse or need for IVIG rescue that's in the ballpark of what EMPA showed in their phase II, so anywhere from 80, 100%, let's say. So we can move quickly into phase III. That's it. I mean, they've already provided a proof of concept. We know we have a much more prone classical pathway inhibitor. We know MMN is a classical pathway-driven disease. We just need to get to market as soon as possible because in the end, what you'll have is at worst, we'll have similar efficacy. They'll have a box warning very likely 'cause they shut down both the classical and lectin pathway, the two main ways to trigger the complement system if you have Encapsulated bacteria.
They're an IV.
Mm-hmm.
I don't know their dose. They haven't revealed that. I don't know their full safety tolerability profile. They've never presented that. I know for a fact that at least we're gonna have a safety and a dosing administration advantage. The question MMN, just like CIDP, is by being a more prone classical pathway inhibitor, can you get more efficacy? We'll only really be able to answer that, I think, at the end of the phase III program.
Yeah. In ARDA, they had this IVIG dependency period and IVIG monitoring period.
We're doing that too.
You're doing that.
Yeah.
It's the same protocol.
Yeah.
You basically.
We did exactly the same. We just, you know, we made it a week longer, I think.
Mm-hmm.
Slightly different ends, but we replicated their phase two.
Your study is a little smaller than theirs.
Yeah.
There was 54, you're 36.
Yeah.
What's the reason for that?
Wanted to move more quickly.
Yeah.
It's a safety study.
Right. They did like two-
I think that's gonna be enough.
... 2:1 randomization.
Right. Yeah.
With two doses.
Right.
You're doing one to one.
Yes. Yeah.
Well, I guess you have proof of concept already, which they needed to provide.
Yeah, exactly.
That makes sense.
I'm not concerned about MMN efficacy. I think it's more like I'd love to know more about their safety and tolerability, and I'd love to know more about what exact dose are they testing. Once I know that, then I can tell you what our complete differentiation will be aside from IV to subcutaneous auto-injector and box warning or not.
Okay.
I'm assuming they would only have one box warning, and that would be for the risk of meningococcal infections. We'll see.
Okay.
If I can... You know what?
Yeah.
I back to the CAPTIVATE study. That's our CIDP study.
Mm-hmm.
I wanna make sure people understand there are very important differences between ADHERE, the trial that got efgartigimod, the indication for CIDP, and our CAPTIVATE study. They look similar, they're very different. The first difference is we do allow refractory patients into our trial. If you look at the riliprubart data, their phase II, they show equal response rates, whether refractory or stable on standard care or IVIG. No FcRn studies their patients in IVIG refractory patients. They're sorry. They're not gonna test their FcRn in refractory to IVIG patients. If IVIG did not work, FcRn is very unlikely to work. FcRns are less effective than IVIG. They're just a much more patient-friendly, much better tolerated version of IVIG. The second difference, we do not make patients wash out of IVIG or standard care and relapse. Okay?
They said they did that to confirm diagnosis. There's no need to do that anymore. That's a relic of the past. No studies are doing that anymore in the future, evidenced by the fact that with their complement inhibitor, they do immediate switch. They're not doing any washout and making people relapse. That's not what we're doing. We're switching within 7 days, whether refractory or stable on IVIG. Finally, when they say they had a 67% responder rate in part A, please understand that 67% of patients who relapsed were able to get back to feeling the level of function they were when they were made to wash out of IVIG. That means a full third never got back to baseline, period. That is about as clear a signal as you need that it is not as effective as IVIG.
With riliprubart, what we fully expect to see as well with claseprubart, you switch right away. I expect to see 50% or greater patients get better than they were doing on IVIG. That's a very different number. When we say 50% responder rates, that's above and beyond how they were doing on IVIG, whether refractory or stable. efgartigimod, 67% of patients who relapsed were able to get back to baseline. One third were not. Very different numbers. We cannot compare those percentages across in part A. Riliprubart's data very clearly shows that there is a signal there that it could be superior to IVIG. That's why you have two companies, Argenx included, doing head-to-head studies versus IVIG with their complement inhibitors. Nobody's doing a head-to-head study versus IVIG with their FcRn.
Mm-hmm. What do you expect for the naive population?
At least similar to what riliprubart. They showed that three-quarters of the patient... That's gonna be the smallest group in any study, right? Though, you know, if you're diagnosed with CIDP, you get on very likely on IVIG really fast because you've got to stop the progression. Any damage done to the nerve is irreparable. It's not, it's irreversible. We expect anywhere less than 20%, probably 10%-15% of patients in our trial would be naive. We'll disclose that with our interim responder. We'll tell you that this efficacy we're seeing is not driven by naive patients, that we have the representation of naive patients for our trial is similar to riliprubart. They did see 75% of patients get better. That's a very nice, robust number.
Yeah. Well, terrific, Marino.