Great. Hi, everyone. I'm Matt Vandenbosch. I'm on the healthcare investment banking team at Goldman Sachs. I'm joined here today by Marino Garcia, the CEO of Dianthus Therapeutics. Marino, thank you for making the time.
Thank you for the opportunity to update everyone on what's going on at Dianthus. I appreciate it.
Excellent. So I guess for those a little less familiar, can you just provide a brief background on Dianthus?
Sure. So, Dianthus Therapeutics, we are building a really exciting autoimmune company focused on rare diseases. Our first program is a very potent classical pathway inhibitor, an active C1S inhibitor called classiprobar, where we are taking it into building a nice sort of neurology neuromuscular franchise with it. We've already had two very strong callus or proof-of-concept moments in myasthenia gravis. the first indication with our Phase II data back in September of last year, where we raised $288 million. And then earlier this year, with an interim responder analysis, it was actually an early $1.2 billion in cash, which will take us as a runway into 2030. It will allow us to read out multiple catalysts for clasipibabard, including the Phase III for our MG trial, which we're starting imminently. and we'll provide further guidance on when we expect the phase three results in CIDP. And the third indication we're going after with class hyperbar is MMN, multifocal motor neuropathy, and for that we have our phase two results which we'll read out in the fourth quarter of this year. And we're on track and everything there from a blinded perspective is looking really good in terms of the safety and tolerability, very consistent with everything we've seen in the two other indications with Clos-Hyperbart. And the whole idea here with this pipeline and product, Clos-Hyperbart, is that we are going to deliver really great efficacy in the three neuromuscular conditions and as a complement inhibitor do it in a safer manner where we can avoid a box warning for the risk of infections from meningococcal infection from encapsulated bacteria like meningitis. and do it with an auto-injector, a 2-milliliter auto-injector, actually the exact same one Dupixen uses, where patients could self-administer it every two or four. Very convenient form for patients to be able to live their lives independently of infusions or having to go through very long, sort of self-administered subcutaneous injections, like, for example, with scartigamon. So that's our first program. Our second program we licensed in from Leeds Biolabs in China. It's a bifunctional fusion protein, again, pipeline of product potential, potential best-in-class or best-in-disease potential there, and that is targeting both BDCA2 or looking to reduce type 1 interferon on one side and on the other, Bafapril. And the idea here is to bring about, you know, two mechanisms that we know work in certain conditions, like the first three indications we've announced, like SLE, Sjogren's, and dermatomyositis, where there's very strong evidence for both mechanisms, put that into one therapeutic and hopefully to bring about better efficacy than any one mechanism can provide. And so we are in the clinic. We're in a phase one trial with healthy volunteer patients, and we are healthy volunteers, and we're looking to read that out in the second half of this year. And we're very excited about that as our next program at Diantis.
Very positive data readouts for Clisipervar over the last year. Can you just go a little deeper, summarize the success that you saw in Myasthenia Gravis and in CIDP?
So Myasthenia Gravis in September was a very important moment because it was the first time we had actual patient data. And it was a small phase two, but despite only having just over 20 patients in each arm. We tested 300 milligrams, our target dose, and then a high dose, 600 milligrams. We didn't see any efficacy difference. We knew there wouldn't be. The 600 milligram dose was really just there to reassure that we weren't going to leave any efficacy on the table. And despite the fact that there was just over only 20 patients, and it was primarily a safety study, all the efficacy endpoints were secondary endpoints, really strong, robust, statistically significant data, whether you looked at the MGADL or the QMG or, you know, multiple other efficacy measures. I mean, we had efficacy, like, within the first week and all the way through the 13 weeks, and very, very robust, despite the fact that placebo patients had an outsized response. The placebo response was actually higher than we would have liked to have seen, and the lesson learned there is we had an MGADL. MGADL is a very simple eight question self-administered patient questionnaire. But we didn't have a QMG. The QMG is in criteria because we were a young company. It was our first trial. We wanted to encourage people to put patients in our trial. And we thought this would make it too burdensome. But what we saw is that our placebo response was a little bit higher than we had hoped. And I think it was because some patients being moderate to severe when maybe they weren't. And so, of course, when they got placebo, they had an outsized response. We did a post hoc analysis, and we said, well, what if we had had a QMG screening criteria like other complement inhibitors had? And we saw that a placebo response would have been closer to a two. And then, you know, the separation from placebo would have been much more dramatic. Statistically significant data, the safety looked really great, and it confirmed that 300 milligrams every two weeks was absolutely the target dose. What really excited us, though, after when we did some of the post-hoc analysis and looked at some of the open-label data is it seemed to indicate when we took patients who were on placebo and put them into the open-label portion of the trial, we didn't give them a loading dose. We started injecting them only every two weeks. and as their PK levels crept up to the target PK level of what we achieve with 300 milligrams every two weeks, we saw that patients were having a really robust response on top of the already robust response they had in the blinded portion. And what that told us is that at PK levels, half of what we achieve at steady state with every two-week dosing, we see a very strong response. That's the PK level we achieve at every four weeks. So like I told you before, we always thought we were overdosing, that we don't need to achieve the high levels, the PK levels that we achieve with dosing every two weeks, that what we could achieve with every four-week dosing will be enough. And then there was this independent data from Regeneron. They have a C3 inhibitor, some DisRAM, pretty nice robust response versus placebo. And what's interesting, we don't know a lot about the drug, but what they did reveal at that point is that they only achieved 75% inhibition of the classical pathway. we get above 90% inhibition with every two weeks. Every four weeks, we get above 75% inhibition. So what they proved is as a complement inhibitor, if you're just somewhere in the high double digits, above 75%, you're maxing out efficacy. So our every four-week dosing should have a pretty good shot at being the same as every two-week dosing. So we're taking both those doses into... But that was a big moment, obviously, and it reassured folks that, yes, active C1S inhibition works, very well tolerated. We had the CIDP data. I think most people expected it would work in CIDP. So we had this interim responder analysis. We said after 40 patients, complete Part A, just to reassure people and let them know it's working. The reason people felt that it should work is because Rilipibart, which is an active C1S inhibitor in Sanofi's pipeline, I think they're only pursuing CIDP. There's some other indications they might be doing some earlier studies in. But CIDP looks like to be the only indication. they had a really strong proof of concept phase two study that showed you know somewhere around 50 percent of patients when switched off standard of care for cidp would risk had additional benefit on really i think most people and like we expected we would have similar data despite the fact that we're about seven times more potent our open label cidp data is that we were seeing significantly better response rates than what Rulipibar had demonstrated, meaning that our difference in potency in a CH-50 hemolytic assay, we weren't sure would that mean better efficacy. It definitely seemed to result in better efficacy, at least in CIDP. So what that meant is that we got to our target of number of responders in the open label Part A much sooner than expected, so we were able to make the announcement sooner than expected. And that, of course, you know, really turned from my perspective. Where I stand now with Clasipibart is this antibody, in my mind, is de-risked. It works in neuromuscular conditions. We know in MNN it's going to work. Empasipibart, the C2 inhibitor from Argenix, has shown proof of concept. They'll have phase 3 data later this year. We are seven times more potent than Relipibart, and we showed better efficacy in CIDP. and the assay that Orgenix used to demonstrate potency as a classical replicate their assay. And whatever efficacy data they show, we will at least be able to show that. Will we be better in MMN? We don't know. In CIDP, the answer seems to be yes, potency matters. We're not sure in MMN. We'll have to see the data. So from my perspective, from an efficacy standpoint, safety tolerability, again, we're not done with all the trials, but it's looking really, really good. My focus with the team now is execution. as fast as possible. Get to market as fast as possible. Why? Because in MG, the market is evolving. Still less than 20% of U.S. patients that are eligible for biologics, ACHR-positive patients are on biologics, less than 20%. That market is evolving. And the sooner we can get out there, the more we can do with this. CIDP, at one point, relipobard had a three-year advantage. now it's looking like it's less than two years they'll have another update later this year every time they have an update they delay their phase 3 data we'll see what they say later this year we'll have an update later this year on how our CIDP trial is going too I'd like to get that advantage down to as small a kind of advantage as possible because every quarter, every few months that we can cut in their advantage just means more market share for us so that'll be, that's why it's so important And with MMM, of course, it's really just us and M-Pacipabar, making sure we understand what's the optimal dose, you know, in terms of risk-benefit or, you know, in terms of tolerability. And the PDs, we're looking to maximize the impact on type 1 and interferon as well as on the B-cell side with the Baph-April side of 212. And so, you know, now our focus is on making sure we get that right and kick off the clinical programs in SLE, Sjogren's, and dermatomyositis as quickly as possible as well.
For MMN in particular, the data coming, the two data coming later this year. Can you just talk a little bit more about what we should look for in the data and why investors should be excited about that as a commercial opportunity?
Yeah, and look, MMN has been always a little bit underappreciated and living in the shadow of MG and CIDP. Now that we have those two big pivotal moments behind us, more attention is being paid to MN, which I'm happy about. And it really helps that Argenix is also talking about MN a lot more now. And we really, like Argenix, believe this is a blockbuster opportunity. This is a, you know, 70% to 80% of physicians, if you talk to them, neurologists that treat MN in the U.S. will tell you, nothing really works that well. IVIG is not that as it is in CIDP, for example. And partly because of that, it's severely underdiagnosed. They agree, you know, 80%, I think, of the physicians, it is definitely underdiagnosed. It's smaller than the other two, but nothing really works. And there's only one other competitor. It's really only two biologics, two classical pathway inhibitors with dianthus and argenics. I think this market is a multibillion-dollar opportunity. I think in our slides we have at least a $5 billion market in the U.S. in biologics by 2035. and well first off we know we have a much more potent classical pathway inhibitor so they're a C2 inhibitor they block both the lectin and classical pathway they finally published using the Cadell microvCH50 what their potency looks like at the IC50 they didn't give the IC90 so we said okay that's their assay of choice that's where they talk about their potency so we used the exact same assay we did a head-to-head at the IC50 we got very similar numbers for them so we know we're doing this right uh it's very consistent results at that at the ic50 we're about six times more potent but i think what you want to do is maximize your inhibition of the classical pathway to really make sure you're maximizing efficacy in any disease especially one like mmn where we know you know classical pathway inhibition works at the ic90 we're 38 times more potent i mean that's really dramatic i want to remind you versus relipobar we're seven times more potent at the IC90, and we saw better efficacy in CIDP. We're 38 times more potent at the IC90. We'll have to see what the data looks like. But we have a much more potent antibody. We don't touch lectin-alternate pathway. Enzymo, cetimumab, is out there and approved for cold agglutin disease, and it has no box warning, no REMS. I believe if you block the lectin pathway, you're going to inhibit the complement system's ability. You're likely going to end up with a box warning, Just like alternate pathways inhibitors have it, C3 inhibitors, C5 inhibitors, et cetera. Very likely they'll have a box warning and we won't. And then finally, they're an IV. I don't know what dose every month, but it's a dose they did not, I don't think, test in phase three. They had 10 and 30 milligrams per kg once a week, once every two weeks in phase two. But they're testing a once a month IV, and I don't think they've disclosed what dose in their phase three for MMS. So we'll obviously have a more convenient option because we're testing 300 milligram, 2 milliliter. If we have similar efficacy, we'll see. Safety, I think we'll have an advantage on box warning. And then certainly on convenience, we will have a better option for it. I think this is definitely a multibillion-dollar market opportunity that we will layer on top of CIDP and on top of MG, all with one target, neuromuscular, you know, in the market. We have this data coming later this year to expect from our data. There's only 12 patients per arm. We're testing 300, 600, and placebo. Early safety, I can tell you from a... It's looking very consistent with what we saw with MG and CID. Endpoints, like grip strength and so on, and secondary endpoints. But this study is far from being powered for STAT-SIG. And I know I said that for MG, but, you know, MG was almost twice the size of this trial per arm. So really trying to manage expectations. All we're looking is for signals and trends that look right in efficacy. We really want to move to phase three as fast as possible. And pacifibrat has shown that classical pathway inhibition works, and we hope that they'll have really good data when they report out their phase three in the fourth quarter. There will be the inevitable temptation to compare our phase two to their phase two a couple of years ago. I'll caution again. There's a couple of reasons for other than the obvious reasons. One is it's a smaller trial. We have a much smaller trial. But secondly, you know, they really focused on as much IVIG rescue as placebo patients. I think for IVIG rescue, that endpoint is now irrelevant. The primary endpoint in phase three is GripStra. But the reason you can't compare whatever we're going to show in terms of percentage of patients who required IVIG rescue is because Mpacipabart, if you deteriorated by at least two points on the MRC-10 or 30% on GRIB strength, a clinical deterioration, you would get IVIG. But they also had another element. If a patient just asked for it, we have the MRC, we have the GRIB clinical deterioration, the IVIG, that was not enough to give it to them. So obviously they had some patients on, you know, not an insignificant number of patients on placebo that asked for IVIG even though they weren't showing clinical deterioration, and we won't have that. So you're not going to be able to compare percentages. So I just cautioned previously, MG, CIDP, and what we're seeing currently in CIDP, yes, perfect, and then are we seeing some trends, some signals on the efficacy that we expected? And really the job for the team is going to be to get to a phase.
A little bit about CIDP, competitive landscape, and second about competitive landscape for complement approaches in CIDP.
Look, I think a lot of investors are very excited about CIDP, and it makes sense. There is a treatment paradigm change coming in CIDP, and frankly, it still is. It's still seen as more of the most effective treatment for CIDP. Efgar Tigmod is a very nice, novel innovation for CIDP patients, but it's inferior to IVIG on efficacy. It's just a much better tolerated, much easier to use version of IVIG, but not as effective. So I think that's why, for example, you didn't see, I think, any companies studying any refractory patients to IVIG, because if IVIG didn't work, it's very unlikely an F-Cartigamide or any FCRN will work. But IVIG is still the most effective treatment, and now we have a nice option for patients who may be naive. Try F-Cartigamide first, because if they respond, fantastic. It's much better tolerated and easier to take than IVIG, so that's great. Maybe if a patient couldn't tolerate IVIG at all, you try F-Cartigamide. But if a patient doesn't respond to IVIG or they respond really well to it and can tolerate it, there's really no other option. With Relipobard in their phase 2, and we're seeing in our open-label phase 3, portion of our phase three trial is that it would be more efficacious than IVIG. Patients who are on IVIG or standard care and stable or refractory to IVIG or standard care switched immediately to relipibart, you saw about a 50% improvement, switched immediately within seven days to claspibart. And we're seeing, again, I spoke to the potency differences earlier, it seems to be translating to better efficacy so far. We'll see at the end of the trial if those numbers hold up, but it's looking very promising. So when I look at, you know, the CIDP market in the future, what I think we're going to see is that classical path of inhibition is seen as the most potent, effective way to treat CIDP, then IVIG, and then which one will be used first, second, what will be the, you know, how will physicians tackle CIDP patients? We'll see, But I think if you have a clearly more effective treatment that's much better tolerated and safer than IVIG and certainly a lot more convenient, I don't see how classical pathogen inhibition won't be the first line. And like I said, up to this point, the efficacy we're seeing looks superior to Rulipobart, to the other active C1S inhibitor, and I think it's because of that potency difference. So it may be that the most effective treatment will be clacipibart, then ralipibart, then IVIG, below that. And you'll see some data at some point and see IVP, but certainly in terms of its potency around classic patho inhibition, it's the least potent of the three complement inhibitors, ralipibart, S, and pacipibart. It's the least potent. So I don't know what that will mean in efficacy, but right now it looks like the more potent you are, the more efficacy you have.
myasthenia gravis, can you talk a little bit more about the phase three design and some of the enhancements that you made based on what you saw in the phase two? Yeah, I kind of hinted at
it earlier. So the first thing is we are going to have a QMG screening criteria. We're going to try to keep that placebo response down to what we've seen historically around a two-point improvement so we can let the antibody really do, you know, show what it can do. We're testing, of course, 300 milligrams every two weeks, one shot every two weeks, like a Dupixent, exactly the same dosing administration as Dupixent.
And then we're testing it once every four weeks.
So we are making the trial larger, but we think it's worth to test that every four-week dose because, again, as I mentioned, the open-label data, the SEMDISRAN data, forinigeneron, everything is telling us that just north of 75% inhibition, PK levels that are half of our steady state at 300 milligrams every two weeks seem to, you know, look like it could be just as efficacious. So, and that trial we said would start mid-year. Everything's on track to get that. The part that I'm most excited about is we had a regulatory IPP announcement where we agreed with the FDA that looking at ANAs, testing for ANAs, screening out for high ANAs or even double-striined DNA is irrelevant. That was just something to look at in phase two, but we should not bother with it anymore. It doesn't mean anything. Our number one reason for screen failures in MG and the reason we weren't able to report out our data even earlier, MG patients just have high ANAs. And so we had a huge amount of patients that basically couldn't come into our trial. Very frustrating for the investigators, for the patients, for us. We couldn't put them in our trial because we agreed we don't need to track it, we don't need to screen for it. It's irrelevant. There's from our phase two results from MG. the IDP results, because it's open label, so everybody, you know, they're talking to each other. It's a small community, the neuromuscular specialists. I think, you know, we have a really good chance. Everything's on, everything's going really on the job. But hold, what's your perspective? Oh, for sure, it's the most, the most crowded of the three indications we're going after, but I want to point out a few things, and Argenix is saying this as well, which I'm really happy to hear. Less than 20 percent of patients who should be on biologics in the U.S. with MG, this market could easily be two to three times larger so it's not just about uh competing for market share it's about growing this market and what does the market need to grow well if you look at autoimmune markets and historically what got them to 40 50 penetration biologics you got to make it really easy an auto injector no box warning just really simple good efficacy that's what clasibibar offers we'll see if anybody else can offer the same combination of those three things efficacy safety and the convenience of an auto injector itself um the other thing is so please not just launched from amgen i mean that like it takes months for that to kick in and really show any efficacy if it does show efficacy it's you know it's got its side effects and its issues the the big advantage is simple is it's once every six month iv that's really nice it's very convenient patients don't get these drugs if you have mg for convenience they're not they're looking for efficacy so despite its less than ideal profile, I think it's beating expectations. And I think it's because, again, even with it's being used second line, by the way, mostly, even with the FCRNs out there, even with the underpenetration biologics, there are a lot of patients out there who are just looking for more options. And that just proves it. So for me, the MG market, people feel like, oh my God, that's it. It's over. FCRNs own it. Not really. There's a huge potential for growth, and there's still a lot of patients out there that are not satisfied with what's offered. Even in the worst-case scenarios where you assume Klasipibar is a second-line option to FCRNs, which I do not believe is going to be the case at all, I think we're going to have a very nice first-line position in MG. It's still a multi-billion-dollar blockbuster. And then just add on top of that CIDP and MMM, and, well, I mean, the numbers, it doesn't take much to get to a multi-billion-dollar peak. I think with MG, it's about continuing to grow the penetration of biologics, continue to educate physicians on why we should be treating those patients earlier, faster with biologics, and then just having more options that are very convenient, safe.
You mentioned the in-licensing, how it came into Dianthus, and the prioritized indications. Maybe just touch a little bit on clinical development plan and how you're thinking about pursuing.
Yeah, we're very excited. I mean, it looks like, you know, it looks at least similar or better in terms of PDC depletion and type 1 interferon reduction to lidofilumab on one side. On the BAF-April side, the Ig reductions look like, you know, the NIDIR is like deeper and longer than POVY, so could have a nice infrequent biologic in our hands here with that best-in-class, both that BAF-April and PDCA2 inhibitor. So right now the goal is to figure out what's the right dose. We're taking two mechanisms, putting them together into one bifunctional fusion protein. It's about figuring out how do we maximize the PDPK while also making sure that we manage for any potential tolerability or safety signals. So that work is ongoing with healthy volunteers. We plan to report out what we found and, you know, what doses we think we plan to take into Part B of our Phase I trial, which is SLE patients, and potentially into MAD or Phase II studies as quickly as possible. That's really the next step. We're very excited. We're working with Lise, our partner in China. The Phase I study is being done in China. And, yeah, I mean, I'm very excited about the potential here for 212. If we can get to that optimal PD profile and dosing profile without any, you know, significant new safety or tolerability signals that kind of, you know, change the risk-benefit profile, then this drug could be really, really, it'll be a nice foundation.
Question here, just all funded. You talked about a billion, too. Can you just talk about your focus areas for this year and just general aspirations for the company?
Yeah, look, from the very beginning, this has been about building a very exciting, independent, self-sustaining biotech, autoimmune company, folks in rare diseases for now over the long term. And pipeline has always been a priority. And so I'm very, very pleased with where we are today. There's more to do. And stay tuned for any future developments there. But the immediate focus, like I said, Klasa, we're right about execution, both. And it's to be able to get this option to patients as quickly as possible in the market and therefore be able to be part of that, you know, solution to growing the penetration of biologics in MG and change the treatment paradigm in CIDP and potentially in MMM. And with 2.1.2, again, it's just making sure we zero in on MAD phase 2 portion and get moving as fast as possible. And now that we have the cash, potentially, you know, try to do as many of these, as many of the pivotal trials in parallel with the team and build a really nice rheumatology franchise there to complement our, no pun intended, our complement inhibitor in the neuromuscular space. The team is growing. We're doing really, really well. I'm just really, really eager to see how the company develops in the next couple of years. But it's been a fantastic five years and the way we've grown every year. And I expect that we're going to be getting to the time. Thank you, Matt. Really appreciate it.