Great. Welcome back everyone. We have CEO Marino Garcia of Dianthus Therapeutics here joining us for a fireside chat. Now, I'm gonna kick it over to Marino to give a brief overview of Dianthus, and then we'll jump into a Q&A. Marino, over to you.
Thank you, Alex, and thank you to you and Stifel for this opportunity to present a little bit on Dianthus, so background, Dianthus was founded back in two thousand and nineteen with the idea of developing next generation complement therapeutics, and our lead program in the clinic, DNTH103, is a perfect example of what we mean by next generation. It's a very potent monoclonal antibody that inhibits the activated form of C1s, and therefore only inhibits the classical pathway, leaving the lectin and alternative pathway intact, and the whole idea was to develop an effective, potentially safer, option in the complement space for conditions like myasthenia gravis, and deliver it in a low volume, self-administered, infrequent auto-injector.
Something that could be, you know, very convenient for patients, like a Dupixent-like profile, like the GLP-1s are delivered to so many patients. Last year we went public, and we revealed our phase one data, which confirmed that we do have a very potent classical pathway inhibitor, with a very nice, healthy, long half-life, partly due to the YTE half-life extension, modification we made to the antibody, and we could potentially have that differentiated safety profile. We are now in two phase two programs. First one started Q1 of this year in the MaGic trial in MG patients, and we expect data for that in the second half of next year. We started our second phase two program in MMN, multifocal motor neuropathy, the MoMentum trial.
For that, we expect data in the second half of 2026. And later this year we'll be announcing our CIDP program and revealing the design of that program, the approach we're taking with that third indication. You know, the really good news, at least in the last year, is that we've had some major developments from a competitor standpoint that have allowed to de-risk at least two of those three programs, where previously there wasn't a lot of data for classical pathway inhibition being effective.
And it's in MMN, where we had argenx and empasiprubart show very good data, especially as recent as their R&D day in July, with their C2 inhibitor, and showing how classical pathway inhibition can lead to very positive results in MMN. And then we also had a significant de-risking external catalyst, if you like, from Sanofi with their active C1s inhibitor in CIDP, showing very, very robust efficacy in three different CIDP patient groups. Patients who are stable on IVIG and switched to their active C1s inhibitor, patients who were refractory to IVIG and switched to their active C1s inhibitor, and in patients who were biologics naive and started on their active C1s inhibitor. So really, really very impressive efficacy across those three categories.
That's, you know, been a really important milestones for us as a company, which partly led to the $230 million PIPE we raised earlier this year, which gives us a cash runway out to the second half of 2027, which will allow us to read out data from all three indications.
Great. Great overview, and we'll definitely dive into all these aspects. But I did wanna kick things off by thinking about the complement pathway, and specifically why the classical pathway as one of those three arms of activation is attractive for targeting broader autoantibody-driven diseases.
Sure. Well, I mean, I think for MG, it's the science is pretty clear. It's actually quite often referred to as a classical pathway-driven disease. It's all about and I'm talking of course, with patients who are AChR positive, where they have the antigen-antibody complex, triggering the complement cascade. The lectin and alternative pathways are really there to help it fight against the risks of infection from encapsulated bacteria. So the idea of being a blunt instrument and being a terminal pathway inhibitor and shutting down the entire complement system, that is obviously proven to be very effective in myasthenia gravis, as we've seen with Soliris, Ultomiris. But, and most recently, the most recent C5 inhibitor approved, Zilbrysk, or zilucoplan from UCB.
The issue, though, is again, you're also blunting the effects of the lectin and alternative pathway, which are there to fight against those risks of infection. So you have those very significant, you know, box warnings and risks outlined in their labels. So Enjaymo is a first-generation C1s inhibitor. It's not specific for the activated form of C1s. That is out on the market, approved for cold agglutinin disease, and if you look at the label, there is no box warning against any safety issue, but it's shown tremendous efficacy in cold agglutinin disease, a disease where there's never been no previously approved biologic.
That was the proof of concept for if you just target the classical pathway, in those diseases where we know the classical pathway is what's driving regulation, the dysfunction, and leave the lectin alternative pathway alone. At least the FDA agrees, and the precedent's been set, that you will have a lower risk of deadly infections like meningitis.
Yeah, and I guess from Enjaymo then to riliprubart, what's the rationale for targeting active C1s versus total C1s, and what does that get you in terms of just a more feasibly druggable target?
Sure. So if you look at the label for Enjaymo, we love the safety and tolerability profile. We love to have that as part of our label for DNTH103. The burden there is around dosing. Because it binds to not just activated form, but pro-form of C1s, there's a lot of drug that needs to be delivered that's just binding to inert proteins that don't provide any benefit. Proform of C1s is not really implicated in the complement cascade that eventually leads to the formation of the MAC. So if you look at the Enjaymo label, it's IV every two weeks, delivering 6,500-7,500 milligrams of antibody every two weeks. That's a huge amount of drug.
By going after only activated form of C1s, which is much less prevalent, we can give only 300 milligrams every 2 weeks, and with our 150 per mL formulation, that means we could get 300 milligrams into one 2-mL auto-injector. Auto-injectors that are out there already approved and widely used, that can take up to 2 mL or so antibody. It doesn't really make sense to go after pro-form of C1s, certainly not in the indication we're going after.
Yeah, and then, you know, you mentioned it as well, the C2 inhibitor empasiprubart from argenx is additional validation here. Where does C2 fit into the classical pathway story, and how does that provide additional validation for efficacy and safety here?
Sure. I think, argenx has very clearly stated that the C2 inhibitor blocks the classical and the lectin pathway. Their efficacy they're seeing in MMN is purely driven by the classical pathway inhibition. The lectin pathway is not adding any benefit. So, and it is, at least, previously has been dosed as an IV every week or every two weeks. We believe that, by inhibiting the lectin pathway, you're not just not adding any benefit, but you're potentially adding higher risk of infection or other side effects. So you may be adding some safety, baggage there.
So there's really no need. We believe in a more targeted approach for MMN. We know it's a classical pathway- driven disease. They've pretty much confirmed that as well, and just inhibit the classical pathway. We don't touch the lectin alternative pathway. We leave that to be, to do whatever it's supposed to do for you.
So there's the dosing convenience, of course, dosing administration convenience. I don't know how potent they are as a classical pathway inhibitor, so I'm not sure how we compare, but we know we have a very potent classical pathway inhibitor, so I'm gonna assume a very similar efficacy, and certainly, I think we will likely have some safety advantages as well.
Yeah, and I wanted to talk about the specific design elements of 103 , and I guess most comparably to riliprubart as the, you know, active C1s antibody that's out there now in phase three. So can you talk about... You alluded to the YTE component. Can you talk about the potency and some other, the physical properties of the molecule, that make this differentiated at this point?
Yeah, so let me start with what, how we're somewhat similar. We're both inhibiting the active form of C1s, both being delivered subcutaneously. We both have long half-lives. We have about a sixty-day half-life. They have actually a slightly longer half-life, about seventy-four days, I believe, half-life. So on those fronts, we're very similar. Where are we different? Is really at its core, it's on potency, and we've shown that in our corporate deck. There are multiple assays we've conducted head-to-head to show how, you know, almost in any way you want to look at it, from an in vitro head-to-head experiment standpoint, we do have a more potent antibody. And what does that mean?
It means that we can, you know, inhibit the classical pathway in a very powerful way, in a very strong way, with much lower amounts of drug. And so if you look at what that means, what's the so what for patients? Their phase 2 study in CIDP was conducted after a high IV loading dose. It's 600 milligrams every week. They have a 150 mg/mL formulation as well, so that's 4 milliliters. So if you were to put that into an auto-injector, for example, 2-milliliter auto-injectors are approved today, that would be 2 self-administered auto-injectors every week.
We know we get above the IC90, the 90% inhibition of the classical pathway, very strong inhibition, with one 300 2-milliliter shot every 2 weeks. So at the end of the month, that increased potency translates into two shots a month for us versus eight shots a month, potentially, for riliprubart.
So I think it's gonna come down to just a. I think we'll see what the data reads out at the end of the programs, but I think it's gonna come down to just being a much more convenient, patient-friendly administration.
Yeah, and I did want to talk about your phase one data, too. Some of the key things coming out of that, specifically your confidence around dose selection moving into phase two. What do we know about how much you need to inhibit this pathway in order to achieve the efficacious result based on Enjaymo and the data from riliprubart so far?
Sure. So, we know that using a CH50 hemolytic assay, getting above the IC90 or 90% of that levels of inhibition of the classical pathway, it's very strong inhibition, and that you're likely to max out your efficacy at those levels. We, there, there's only one dose-ranging study that we know of with complement, that looked at two different levels of inhibition using the CH50, and that's the zilucoplan in their phase 2, Zilbrysk in their phase 2 publication. One dose inhibited the classical pathway 88%, another 97%, and at the end of the study, the MG-ADL scores are pretty much identical.
It seems to suggest that once you get to around 90% and above, you're maxing out on efficacy. We know from our phase one publication that in humans, the PK levels we need to achieve to inhibit the classical pathway by at least 90% is about 87 micrograms per mL. Those numbers have remained pretty consistent throughout the phase one study, from the very beginning to the end of that study. Very consistent with the in vitro experiments we've conducted as well. We know also from that phase one that if we dose DNTH103 every two weeks, one shot, one 2-milliliter, 300-milligram shot every two weeks, once we get a short loading dose and get patients to steady state, that our steady state will hover between about 115 and 125 trough-to-peak level.
So on average, about 120 micrograms per ml. That's a good, almost about 40% above the target level. So we know we're getting way up there above IC90, with just 300 every two weeks, and that's partly because of the long half-life and accumulation by dosing every two weeks. So that gives us a lot of confidence that whatever efficacy an active C1s inhibitor can have in these three indications that we're going after, that we will get it with that 300 milligram shot every two weeks. But you'll notice that in our MG trial and our MMN trial, we also added a higher dose.
And that we doubled the dose because we wanted to answer the question we sometimes get, and we want to answer it for ourselves: What happens if you use an active C1s inhibitor, an upstream inhibitor, a classical pathway-only inhibitor, and you get levels to way above the IC 95? We know our IC 95 from the phase 1 is about 149 micrograms per mL, and because of our linear PK with 103, we know that dosing double will basically get us to about 240.
So somewhere between 200 and 250, let's say, micrograms per mL. So again, way above where we need to get to to achieve the IC 95. And it's just to answer the question, is there any potential other benefit or efficacy that you can extract at higher dose, and it's to just reassure investors that we're not leaving any efficacy on the table.
Yeah.
Frankly, we don't believe there's gonna be an efficacy difference. I think what we're gonna see is that 600 and 300 are gonna be about the same. But we're doing it just in case, in our phase 2, to make sure we're fully informed before going into phase 3.
Yeah, and I guess moving towards phase two and thinking about MG as the lead indication, I think when, you know, I talk to people about Dianthus in the context of the data we have today, some people are a little bit surprised that MG is your lead indication, just given the data from CIDP and also from MMN. You know, why, why did MG come out as your first indication?
When we came out of our stealth mode just over two years ago, MG was the first indication because you know, after having conducted quite an analysis, looking at the landscape of all potential indications we could go into, it had the most attractive commercial opportunity. It's a multi-billion dollar blockbuster market that keeps growing where we could have a highly differentiated, best-in-class complement therapy. Remember, MG, there really are only two targeted class of biologics. It's FcRn and complement. If we can be by far the best choice in one of those, if you look at the complement therapies in MG, in both approved and in development, they're all C5 inhibitors.
There's nothing like a classical pathway inhibitor like ours, and also with the very patient-friendly profile that we potentially could have. So, it became very clear that that was the biggest commercial opportunity. Also, it's also the most de-risked. It's, you know, MG is very well known as a classical pathway disease-driven disease. We know what the clinical development pathway looks like. We know what the regulatory pathway looks like. So it's all. Like, we just need to execute against what's already a very well-defined path to an approval, and it's where the biggest commercial opportunity sits.
I also want to remind people, until a year ago, when argenx first revealed their MMN data with empasiprubart, and until Sanofi revealed their CIDP data in November, there was no real, you know clear evidence that classical pathway inhibition could work, that the science made sense. It made sense that it would work, and that's why we added those two indications, early, or toward the middle of last year.
Yeah.
MG just was further advanced. It's where the biggest opportunity, I believe, sits. Certainly, MMN and CIDP, the level of excitement and the de-risking that's occurred over the last year has been incredibly helpful to us, and as I said, it was part of the reason we were able to execute on this raise earlier this year to give us a long runway.
With MG as your lead indication, you have your phase 2 reading out next year. Can you- you talked about two dose arms. Can you talk a little bit about the design, how that compares to what's out there in the field, and what the bar for success really looks like to, you know, get to that product profile you alluded to?
Sure. So, essentially, we just took what's already been done before. So I mentioned zilucoplan earlier. It's exactly the same program. We have a brief loading dose by IV. That's just for ease of execution of clinical trial and just to get patients up to steady state levels as quickly as possible, because it's a short 12-week trial. We are targeting about 20 patients in each arm, the 300 mg, 600 mg every two weeks, as well as placebo. That's a fairly robust number for MG, phase 2 programs. And, as I mentioned, we expect data in the second half of next year. Our bar for success is we're looking for efficacy that's similar to what was seen with the C5s, for example, and FcRn.
So I think if anywhere north of 1.5 difference on the MG-ADL from placebo, anywhere north of that to us, that looks like it's a go. It's an efficacious MG program. I just wanna remind people, though, it is a phase 2 program with a small n. Although relatively big compared to other trials, it is only 20 patients, so its primary endpoint is really around safety and tolerability. It is a phase 2. But in the past, you know, we've seen that if you get you know, into the high 1, you know, 1.5-2, for example, difference from placebo, that results in a positive P value. So fully expect that that might be the case as well with 103.
Yep, and then you've started your MMN study as well. How does that design compare to the empasiprubart study, and, and what do you view as a positive outcome there?
It's a little longer, but instead of running the dose ranging sequentially, it's in parallel, but it's pretty similar. We, again, are not looking to add risk or reinvent the wheel. It's clearly something the FDA is comfortable with. And so we pretty much replicated the, you know, the trial as close as we could.
Yeah.
So, but, you know, hopefully because we're running the dose ranging in parallel as opposed to sequentially as they did, you know, we'll be able to execute the trial a little quicker.
Yep. CIDP, you're gonna announce the trial design, you know, later this year. I guess the context here is that, you know, there's slightly different trial- or not slightly, quite different trial designs that were run by both Sanofi with riliprubart and then argenx with ADHERE. You know, some elements are interesting, some elements may be more challenging for a biotech like yourselves. I guess maybe I'll ask you, you know, what are good elements of the, of each trial that you think are, you know, maybe something that you would wanna include, or maybe just punt that for later this year?
Nice try, Alex. No, look, let me just say this: we love the open label portion of the, you know, part, aspect of the phase two trial that Sanofi conducted and how we're able to, you know, see data within the different patient groups. We especially were pleased to see the label argenx was able to get in June with their enriched withdrawal program. You know, that's a program where, I mean, I don't know how you can have a higher probability of success at the end of the day. And the fact that the FDA took that and gave them a label, a very broad label, for all adults suffering from CIDP, we took that as a very good news for us as well.
Yeah.
We are in the midst of these interactions with the FDA, and our goal or what we're planning for is before the end of this year, once we have an IND cleared, like we did with MG, like we did with MMN. Once we have an IND cleared, is to then reveal for investors our approach to the CIDP program.
Have you said whether you think this is gonna be or could be a pivotal study, or would it be more of a proof of concept study?
Stay tuned.
Okay, sounds good. And I guess what.
Alex, I'm not trying to be cute.
I know.
You know, you just remember with the FDA. I know what we aligned with with the FDA, but until I see a cleared IND with no, you know, with what comments, whatever the comments they have for our program, I don't wanna get ahead of them.
That's good.
I'm eager to get the information out, but until I get that green light from the FDA, I prefer to just hold off.
That's always a good policy, and you know, moving on with classical pathway inhibition, obviously there are a lot of potential indications you could go after. You know, argenx is looking at other indications like dermatomyositis, you know, Hansa 's looking at AMR. Any other indications jumping out at you at this point that look exciting from both a mechanistic or commercial perspective?
Yeah, look, t he reason we picked these three is because they came up as far and above as the most attractive from a commercial standpoint, and where the probability of success or the biological risk, if you like, was, you know, high probability of success, low biological risk. We are looking at other indications. There's two bars I wanna make sure we get over before we announce any more indications. A, again, on the biology, is there a proof of concept out there? Is there something we're certain we will be successful in with 103 ?
And secondly, that it can deliver, you know, on its strengths, on its differentiated profile, that can very clearly address an unmet need, where there's significant value that could be created for patients, for obviously shareholders, et cetera. So, you know, I'm trying to keep that bar high, to make sure that we're not, distracted from, you know, the big opportunities we do have in front of us. So at this point, there's no indications we're ready to announce, but it's something the team's actively looking at.
Yep. Yeah, and obviously, folks are continuing to develop here. You know, one reality this year I think folks are focused on too is the oral C1s readout in cold agglutinin disease. I'm curious, you know, what are you gonna be looking for in that readout to understand if this is a competitive molecule to riliprubart or riliprubart and yours?
Yeah. So, it's kind of what I was hoping to see from argenx with empasiprubart at their R&D day, but didn't. And I understand why, for competitive reasons, maybe they didn't wanna reveal more information. But there's two things I would be looking for, is, one, what can they show to provide confidence around what levels of inhibition they're achieving of classical pathway? Are they getting really significant? Are they really shutting it down? Are they getting above that 90% IC90, as measured by CH50 hemolytic assay or whatever other assay they wanna use?
I think that I just need to understand how a an oral BID drug every day can, you know, can get up there, can get levels high enough that you know it's shutting down the classical pathway in a significant way. So any PD/PK data will be helpful, of course, and then, of course, safety and side effect profile. I mean, there's, you know, an oral, it's a fairly large dose. I don't know what kind of off-target side effects it might have, what kind of GI issues, et cetera.
I think, you know, I've had a long history in this industry, and I know the challenges with BID drugs in terms of compliance and hassle for patients. I don't know how that will compare eventually at the end of the year to a Dupixent-like, you know, auto-injector. You see how GLP-1s have done incredibly well. We'll see how the GLP-1s do in the future. So it's gonna be an interesting time. But those are the two bits of data that I wanna see is, tell me.
You know, show me in a convincing way what kind of levels of inhibition are you achieving of the classical pathway, to give you confidence you can work in other conditions outside of CAD, if it does work in CAD. And then secondly, like I said, the safety and tolerability.
Yep, totally makes sense. And, you mentioned your cash runway, I'm just curious if you could lay out, you know, what's included in those assumptions?
Because it goes out to the second half of 2027, we've indicated that we'll obviously be able to read out the MG data next year, the MMN data in 2026, and we will provide a little more clarity as to what data we'll be able to read out with CIDP, and by when, but we will be able to get data out from that trial within that timeframe as well.
Great. Marino, always fun to chat. Appreciate you joining us today.