Great. Thanks everyone for being here. My name is Yanan Zhu, and I'm one of the biotech analysts here at Wells Fargo. We're privileged to have the management team of Ionis Pharmaceuticals with us today for a fireside chat. With me here are Beth Haugen, CFO, and Onaiza Cadoret-Manier, Chief Global Product Strategy and Operations Officer. Thanks, Beth, and thanks, Onaiza, for being here.
Yeah. Thank you.
You know, a lot to talk about. I hope, I was wondering if we can dive right in into the eplontersen polyneuropathy U.S., approval and launch. I have a set of questions here. So how is the BLA going? Is it past the mid-cycle review? Any issues emerging from the review?
So, let maybe I'll just start really quickly with, thank you for having us, first of all. And it is a great time to be at Ionis. We've got a whole host of commercial opportunities advancing towards the market right now. Eplontersen is our most advanced drug. It'll be, hopefully, we'll have our PDUFA date, and an approval in December, with our PDUFA date on December 22. And then, of course, we're making excellent progress on preparing to launch that shortly after approval. But maybe if I can just take a second to sort of set a framework for the company. There's just so much that's going on at Ionis right now.
Obviously, eplontersen is a huge area of focus for us, but we're also really excited about olezarsen and donidalorsen, two phase III assets that are moving towards the market. With eplontersen being a co-commercialization with AstraZeneca, olezarsen and donidalorsen will both be commercialized by Ionis in two indications with olezarsen and then in HAE for donidalorsen. So a lot of excitement around those two assets, as well as all of the commercial prep that we're doing. The phase III pipeline is advancing and expanding. We now have eight drugs in development under ten indications in phase III. We continue to make progress. Spinraza is a global market leader, continues to show resilience in the face of competition and potentially will return to growth.
And then, of course, recently we had Qalsody approved, which is the first medicine approved for a genetic form of ALS, and we were really excited about that. It actually is our second approval for a neurodegenerative disease, and we're really excited to have Qalsody alongside Spinraza. And of course, lots of progress on the technology as well. So lots of things happening at the company and, and with eplontersen and the exciting phase III data we've seen. Maybe I can ask Onaiza to sort of fill in on the data and where we are on the approval process.
Mm-hmm. Yeah, I'd be happy to. Thanks for the question. So we're very excited about our first co-commercialization launch that's coming up with polyneuropathy. The PDUFA is December 22. We're getting all prepared for label negotiations. Everything's on track, so really no surprises. And the team is preparing, right? Most importantly, we're making sure that supply chain is ready, that there'll be enough product to get into channel post-approval, and then obviously all the other commercial launch readiness aspects are moving along well. We have had field medical in place for the last two years, approximately, so that's going well, and they're testing out kind of, you know, our data streams right now. We've had 35-week interim data, the 66-week data, the 85-week kind of long-term data, so we're getting a lot of great read on that from advisors.
It's looking very strong from an efficacy perspective and a safety perspective. Our KOLs are really enjoying kind of the sustained and durable kind of reduction in TTRs, very nice, tight, tight, tight kind of, you know, stability of TTR knockdown over time, which really bodes well for our dosing regimen, for once monthly, self-admin. And then halting of disease progression, as well as obviously improvement in quality of life and a substantial number of patients improving from the therapy, which was kind of really unexpected in this disease course, because it's a very declining and progressive disease. So that's boding really well. Sales teams are pretty much all hired. AZ's leading the sales effort. Our nurse case managers are almost all hired as well, right? We've got...
So we're really in that phase in the last quarter to get people in for kind of training, compliance training, disease training, and eplontersen training as well. All the readiness measures are actually in place to go, and looking forward to that December 22 date.
Great.
Yeah.
So you mentioned AZ hired almost all the sales team. Is this going to be a neurology-focused sales team? And how is AZ going to leverage its cardiology sales
Yeah
... present sales force for this?
Good question. So as you know, and I don't know if everybody else in the audience knows that polyneuropathy is about 40,000 patients worldwide, mixed phenotype. It's about 3/4 of that, and 10,000 is pure polyneuropathy. So when the 25%, pretty much the patients are gonna present in a neurologist office, the other three-quarters are gonna be ubiquitously kind of across the system... they could be hand surgeons, GI, cardiologist office as well. So we're really kind of trying to branch out with the sales team to the other places that they will present. So they will be calling on a variety of different physicians, neurology, cardiologists, as well as a couple of others to where we've seen good uptake and identification of patients, and that will, you know, change and grow over time.
Initially, most of the treatments in centers of excellence, but we're also seeing treatment move out into the community as well. AZ's done a nice job. It's a mix of teams. They've hired people from outside the company as well for this launch. This is a Tier one launch for AstraZeneca, and people with amyloidosis experience. We're bringing kind of the rare disease amyloidosis experience to the table. We think that's really important for this launch, and not just cardiologists as well. So it's gonna be really a mix, mix of the two. For the cardiomyopathy indication, which will come after, I think you'll see a lot more effort from their current Farxiga sales force at this point in time. We're focused really on the PN piece and leading into the systemic launch here.
Got it. Got it. For this launch, how should we think about it in terms of the competitive dynamics with Onpattro's existing silencers? Do you think this is mainly a newly diagnosed patient opportunity, or could this be also a switch opportunity?
Yeah, so I think there's, like, there are two parts to the marketplace, right? And it's mostly a silencer play for polyneuropathy. It's a systemic disease. As you get to cardiomyopathy, you have the two stabilizer silencer mechanism going on. Versus Amvuttra, I would really think about this as a market growth. This is a growth opportunity for all players in the marketplace. As I said, 40,000 patients for polyneuropathy, including mixed phenotype, less than 20% are on treatment, right? So lots of headroom to grow over here. If you take a look at where Amvuttra sales are coming from right now, more than half are really coming from switching first generation Onpattro to Amvuttra.
So even they are then really have a lot of work to do to get to newly patients, new patients who are newly diagnosed as well, right? So they're gonna churn through that business first, and I think, you know, by the time we're on, we're all gonna be looking for new patients really to get on treatment. There will be some switch that will still be remaining, but, you know, most of the growth will come from new patient diagnoses.
Got it. Got it. Do you think you have an edge or differentiation between you and AstraZeneca to acquire, or, encourage, new patients getting treated?
Yeah, yeah. I think we have a very strong product profile. I'm very encouraged by a couple of things that are coming out in the testing. One is this really tight kind of TTR reduction over time. Physicians seem to really like that. They feel that that knockdown and sustainability is gonna give them better clinical effect in the long term. So that's really playing out well. Halting of disease progression, improvement in the symptoms of Norfolk Quality of Life. And then our self-administration profile is also a nice advantage, particularly well, actually, both physicians and patients really like it for different reasons. The self-administration for patients gives them empowerment over their disease, the ability to take it with them where they are. It's a portable with them.
It's self-administered, so if they're at home, they're on vacation, the ability to travel with it is a really great degree of flexibility. And then for physicians and patients, it reduces the hassle factor of trying to go into the office for an injection, right? You don't have to go in, you don't need the appointment, and as I said, a lot of the treatment still is in centers of excellence. It's actually hard to get an appointment, and they're really far away. Some of them are living here in rural areas that are not close to a center of excellence. So it's not like it's an easy drive to your doctor's office as well. So we think all of those will bear into place: efficacy, safety, and administration.
Got it. In terms of pricing strategy, should we think about parity or some other strategies? What is the progress with your payer discussions, and how soon do you think reimbursement will be in place?
Yeah. You know, I mean, listen, we'll price appropriately, as we always say, to ensure best access for patients. And you know, price will be priced when we actually launch the product. You'll get a chance to see it. No surprises there, I think. You know, I wouldn't say anything like really meaningfully different. I think that the uptake by payers has been pretty responsive to the rare disease. They're pretty quick to do formulary evaluations. This is a Part D drug, not a Part B, so we will have to go through P&T and formulary committees. That's usually depending on the payer, and the plan can happen in the first few months of the product lifecycle as well. So, they get the ability to prescribe it right away too.
They just need to get, like, a temporary code and get it through, but then the full formulary evaluations happens in the first six months, usually, of a life cycle. Mm-hmm.
Got it. That leads to the next question in terms of the milestones once you—you know, A, after approval, how soon is the launch? And then, B, after the launch, what might be the first sales and first appearance on the income statement?
Yes, so I mean, most companies have like, you know, as soon as you get the label done, you want to launch as quickly as possible, so it usually happens in the few weeks past approval. You would expect the same thing from us. We have a pretty big milestone attached to the U.S. approval of $50 million at Ionis. So that will be the first of many. We have a total in the deal of about $500 million of milestones coming up. This is the first of that, so $50 of that. And then there are outside of the regulatory R&D milestones, there are also sales milestones that also range between $500 million-$6 billion, and so we would get payout for that.
AZ will be booking the sales on the top line. We will be recording it in terms of, you know, a royalty stream that comes to us in the U.S., which is around the mid-20%. And then outside of the U.S., we have a different structure-
Right.
-which is in the mid to high teens.
Got it. Got it. And in terms-
Anything to add, Beth?
No, you covered it.
She's got all the financials down. I want to make sure I'm checking with my CFO here.
Yeah. Yeah, I think it's important to point out the U.S. royalty is not a tier structure.
No.
It is mid-twenties-
Mid-twenties
Out of the gate.
Yeah.
Got it.
Yeah.
And in terms of what you have to put out, 'cause you have some responsibilities for certain cost of the launch, right? So what is your the thing that you need to do and pay for this launch?
Sure. So we're, as Onaiza said, we're gonna be responsible for some of the medical affairs. All that is already in the field. We're working collaboratively with AstraZeneca on that. We'll be responsible for the patient services part of this, which is really important because, as Onaiza said, we have the expertise in rare diseases. We have the expertise in the disease. We know these KOLs. Alongside that, we'll be responsible for the publication and presentation plans for the drug. But I think really what's important to remember is that this is truly a co-co relationship. This is a true partnership. You know, AstraZeneca will be taking the lead in the field with a lot of those commercial and medical affairs activities, but we sit jointly with them on a joint product team.
We work together on the product strategies, the brand strategies, the market access strategies on a global basis, not just in the U.S. And I think that's a really important differentiator for us in this co-co, and it's helping us to get ready for the subsequent launches.
Yes
... olezarsen and Donidalorsen as those come down the path. Economically, what that means for Ionis is that that we incur about 45% of the global phase three development costs. AstraZeneca has 55% of those. And then for, pardon me, the U.S. related commercial and medical affairs expenses, AstraZeneca has a much larger percent of those. We have a small minority piece. And then outside the U.S., we have no responsibilities for cost. That's all sits on AstraZeneca's responsibility and on their P&L. So I think it nicely mirrors a a co-co structure without necessarily having that profit share complexity.
Got it. Okay. That's great color on the polyneuropathy franchise. But Eplontersen has a much bigger opportunity in cardiomyopathy, and the phase III study is ongoing. Potentially data first half 2025. So just want to get your thoughts on the recent data presentation by BridgeBio for their acoramidis phase III ATTRibute study. What might be the read-throughs to your CARDIO-TTRansform study for in terms of future competitive dynamics in this you know cardiomyopathy space?
Yeah. So, acoramidis was, I think it's really good for patients. I'll just start off with the headline there, right? It's really good to have another option as another stabilizer for patients that will be coming onto the marketplace. From our perspective, it's not the same mechanism, right? We are a silencer mechanism or stabilizer mechanism. They do different things, for patients. And, as most KOLs will say, the order of entry for these drugs didn't work out the way that the biology works, right? The first is you want to turn the faucet off and reduce the production of the TTR, which is what a silencer does. And the stabilizer takes the amyloid fibrils at the end and stabilizes them.
So there's a part for both of them to play, for a patient here, and they will compete more directly with tafamidis. From our perspective, we were really looking to see, like, you know, everybody sized and powered their trials based on tafamidis' ATTR-ACT study. We know the market's changed quite a bit. Patients are getting diagnosed earlier in their disease. Diagnostic tools have changed, like scintigraphy, and we wanted to see kind of the demographics of their trial. And it was nice to see that they are much more like a contemporaneous study, having milder patients in their study, which is kind of, you know, what our expectation is of our TTR cardiomyopathy trial as well. And we're encouraged to see that.
We're encouraged to see that they had, you know, a good effect, albeit they missed all-cause mortality, but it gives us really strong consideration that we have double the size of any actually cardiomyopathy trial right now. So we're really looking forward to getting the best data of any CM trial. Thought leaders are looking at us as a landmark study because we will have data on lots of subgroups that are really important for them to know how to treat a mild patient versus a moderate or severe, and we will have a nice proportion of those three.
We'll have hereditary patients and wild-type patients, and then we'll have patients who are naive to tafamidis and on top of tafamidis, and all being able to give you and give the market and the physician some data sense of what's the cardiovascular risk reduction that you can benefit from, from an Eplontersen treatment. That's gonna go a long way for getting these 500,000 wild-type patients diagnosed and treated. Yeah.
Got it. Also, we have another event in a space that is the upcoming advisory committee for Onpattro, essentially for discussion for the six-minute walk endpoint as a approval endpoint here. You know, I was curious about your thoughts on what how that will come out, and also in the event of a FDA approval, how should we think about potential impact to eplontersen's opportunity?
Yeah, it's an interesting one to watch. I think the FDA is gonna be looking pretty much at a functional endpoint in a market that already has a cardiovascular kind of hard endpoint from tafamidis. But, you know, it's the first silencer with a functional endpoint in cardiomyopathy, so it's interesting for us to watch. I do think, you know, I think the biggest question really, as you probably all know, is: Is that functional improvement in the 10-15-meter kind of walk improvement clinically meaningful, and is that gonna be really important from another product that will help patients in this area? Will the physicians find it clinically meaningful to be actually used in their practice? I think that's the biggest question.
If they do get approval and they do get on market, you know, then, then they have, they have some really commercial kind of headwinds, I think, that are facing them. If I were looking at it, if they've got the... I didn't do the study for a cardiovascular endpoint. It's a functional endpoint, and then, you know, there's also the, will the payers actually reimburse them as the way a tafamidis is reimbursed? And then there's just the practicalities of an IV infusion, right, in the office, pre-steroid treatment for Onpattro. That will always be part of their product profile that, you know, when you have another product or choice with potentially a cardiovascular, you know, harder endpoint, you know, what will they actually choose?
So we don't really see it as a relevant direct competitor to us, but, you know, interesting to watch how FDA will make decisions on it.
Got it. Got it. Perhaps we could pivot to olezarsen, the other drug with phase, you know, in phase III with upcoming data. There's also going to be data on severe hypertriglyceridemia next year. So we have both near term and a bit of midterm data from this same drug. So let's talk about FCS, the near-term data. What is the bar for success from this phase III study called BALANCE? How much triglyceride lowering is necessary for success here? And also, what do you expect in terms of safety, such as platelet count and liver enzyme readout?
Do you want to take this one? Yeah, sure. Okay. You're on a roll. Okay. Yeah. So olezarsen, I think for me, my personal favorite in the Ionis' solid pipeline here, it's gonna be our first independent launch, so it's a very exciting one. As Beth really nicely expressed, everything we're doing for the co-co for eplontersen is getting us ready for our independent launch, and this is the way this was designed in these types of sequences. It's exciting on multiple counts. So first of all, you know, we have the first indication, FCS. It's a rare disease, as you said. Where, what's the bar for success? I'll get to that, but it is followed then by a larger indication for severe hypertriglyceridemias over 500, with a patient population that's addressable in the U.S., you know, at around 3 million.
There is a huge unmet need across both of those indications. FCS, there's really nothing on the market right now. These patients are. You know, if you followed kind of a day in the life of one of these patients, you'd really get to see how difficult it is to live with this disease. It is, requires a patient to be virtually on a no-fat diet. Literally, they cannot take more than two spoonfuls of olive oil in a day. That means, just think about that, like, every single day of your life. That's, that's like no alcohol, no going out to restaurants, restrictive diet every day on what you face, and if you go off of that, you know, you're feeling it in, cognitive function, you're feeling it in abdominal pain, and you're certainly at that long-term high risk of acute pancreatitis, right?
So those are the types of things these patients live for. I think the bar is get them an appropriate, effective treatment that gets them out of risk of AP, acute pancreatitis, and allows them to live somewhat normal daily life. Of course, you'll see triglyceride reductions. I just don't view it as, like, a bar for what these patients actually really need, right? Like, it's more important to think about the totality of what you need to do for them to bring that in. We have had very strong triglyceride reductions, two studies that we did, which were in lower triglyceride level patients. If you recall, that was around 60% reduction. These patients have higher TG levels. We could see, you know, bigger drops because they're starting at a higher baseline. But again, I don't think that's the bar for FCS.
The bar for FCS is to get them an appropriate treatment that gets them out of harm's way for AP, gets rid of symptoms, and allows them to get back into a normal way of life that they don't currently have.
Does that translate to a threshold level of TG, that the target level? Or-
No, not for FCS. No. I think for SHTG, the medical guidelines, so this is the non-genetically confirmed, severely elevated over 500. The medical guidelines are very clear about getting patients out of harm's way. Both the ACC guidelines and the endocrine guidelines really talk about it in two ways. There's a threshold of 880. If the patients have 880 triglyceride levels, you want to get them certainly below that because that's when the chylomicrons increase in their biologically, and those are leading to... And they transport triglycerides that could lead to higher acute pancreatitis risk.
And then, the guidelines will also say, "Try to get them below the 500 threshold," because there is also additional risk of remnant cholesterol floating around in their body that can lead to additional, ASCVD as well. So you're trying to manage these two risks for this patient population, so we've set these thresholds of triglycerides for severe hypertriglycerides very well. Yeah.
That is for the SHTG indication, but for FCS, it's just any reduction for those patients will be beneficial because they started off so high.
So high.
Yeah.
You're trying to get them out of the abdominal pain, the cognitive, and of course, reducing their risk for acute pancreatitis, right? And that happens by also reducing their TGs, but there isn't a threshold that... They're starting with very elevated levels, but they have other things going on in their body.
Got it. Very helpful. I think the BALANCE study also has a higher dose than previously studied. It's some 80 mg dose. You know, you mentioned some data point for the 50%, 50%, like, 60% reduction in people with lower triglycerides. Is it the expectation 80 mg could give you greater reduction?
You know what? We'll see how this plays out. You know, we added in the 80 mg dose because the FDA asked us to. They want to usually see dose ranging across two different doses, so we think I think it's a really good, good, good addition, actually, to our clinical trials. And I, I think, you know, you have to always keep in mind, so there is a linear association that's been shown in some data modeling, right? For the higher the trigs and the higher the dose, the better the drop, as you're saying. But, you know, I always get surprised by biology because there's biology that plays, the disease that plays into fact, and, you know, There are a lot of other things that are going on with these patients as well.
So we'll let the data bear out, but, you know, we're expecting to see data on both doses and, you know, of course, the company and the FDA will make the right decision based on where the data comes out on those two doses.
Got it. And, you know, at the BALANCE study, data readout time, how do we think about safety, in terms of platelet count and liver enzyme? You know, what to watch out for and what's your expectation for a successful drug? What kind of profile is necessary in this patient population?
Yeah. So, you know, I'll just step back, and I think there. One of the benefits of being part of a platform is that you could see actually kind of like good, nice, read-through from all of our LICA medicines into the other LICA medicines. So we already had the eplontersen phase 3 readout. It was very clean in terms of safety. We have over 8,000 patient exposure for these ligand-conjugated antisense molecules going on in the clinic, also looking really good from a safety perspective. So I don't expect anything different for olezarsen here. Yeah.
Got it. In terms of comparing data set between antisense and siRNA, you know, I think we do have some data from Arrowhead also on the severe SHTG. Anything that we need to take into consideration when looking across the two data sets?
Yeah. So that's a really good point. So a couple of things I may have missed in the, in your first question. So, we have a first-mover advantage with olezarsen, so we're well ahead of Arrowhead. On their SHTG trials, they did a phase II, but it was in the more severe patient population, right? It was in the 500+. Our phase II are in a more moderate population of 150-500. All right? So you can't compare across those two different baseline characterization of, of patients. You actually have to compare it in the same. We also had different doses. We, as we just talked about, we had the 50 mg there, and we have a higher 50 and 80 going on in the higher one. So it's, I, I really would encourage us not to compare those.
You should never do cross-trial comparisons, but here you actually study different patient populations as well. We are well, as you've said, into our phase IIIs, with 2024 looking at, you know, enrollment completion here. Arrowhead has not started their phase III yet. And as we, we've got advice back from the regulators when we were designing ours a couple of years ago, is that you need to study 1,500 patients. You need 1,500 patients worth of patient exposure. So we've got the two pivotals, plus we have a CORE 1 and CORE 2, but we have an ESSENCE trial to gather the safety exposure as well. So collectively, we'll have 1,500 patients.
So as you're looking at the phase 3 studies for all other players in the space, I really encourage you to see whether they're actually sized appropriately to what the FDA guidelines have been for us, because it's gonna be the same across the board.
Got it. Yeah, obviously, SHTG is a market with more than 2 million,
Mm-hmm
eligible patients for treatment, and that's appropriate.
Yeah
from the trial side.
For prevalent diseases, you need the ICH guidelines, where it require to characterize safety.
Right
in those large populations in a meaningful way.
Right.
You got it.
Yeah. So I was wondering, you know, do you plan to launch in... Obviously, you will launch in FCS on your own.
Yes.
But for severe SHTG, a much larger population, what's your thoughts there?
Yeah, we're planning. There's a lot of work going on for the launch of both indications for olezarsen. That's why I say it's one of my most exciting, exciting areas. Because, you know, you have to think about going from a rare disease to a more prevalent. And we've also have these 3 million patients that are being treated by two very different physician types: the cardiologist and the endocrinologist. So we're doing a lot of segmentation work to see, you know, where these patients are going to be treated as early adopters, which will take, you know, more time. What's kind of this aggressive treatment mentality do we have? And we're seeing a lot and understanding a lot about the different physician segments for SHTG. So it's gonna be a handful of cardiologists and a lot of endocrinologists.
Preventive cardiologists are really eager to have a treatment option over here, lipidologists as well as endocrinologists. Once we've understood kind of the, you know, the go-to-market kind of approach to where the uptake will be, we will size our field force accordingly, as well. Yeah.
Got it. Got it. Maybe, you know, in the time left, I wanted to touch on some broader pipeline programs. I, you know, given the time, I think, let's talk about Angelman Syndrome. You, you're going to report data, or you and your partner, Biogen, are going to report data in mid-2024. Can you talk about in terms of, number of patients, what endpoint? And also in general, how do you feel about, you know, the data Ultragenyx has produced so far? You know, in your assessment, is that, kind of a improvement, sets up the bar, or do you think there's still room to further improve?
Yeah. So Angelman's is one of 12 neurodegenerative disease drugs we have in development today, in clinical development in patients. So we're, you know, I think we obviously have a leading pipeline in neurology. It's a focus for the company. The study is a phase I, II study, so it's in patients. It's about 44 patients, ages 2 to 50, so a broad patient population. We're assessing safety, obviously, since it's a first in man clinical study. But we're also looking at various different doses with the dose escalation study. We're looking at PK/PD, target engagement. We'll be looking at biomarkers. We'll also be looking at potential endpoints that we could use for the phase III study.
And all of that data is gonna be very informative as we and Biogen look forward, hopefully, to bringing that drug into phase III development. As you said, we'll have the data from the study in mid-2024. Exactly what that data package is gonna look like, we haven't, you know, worked that out yet with Biogen. But I know that this is a program they're excited about, and we're looking forward to sharing the data.
Got it. Beth, I wonder if you we can end with a discussion about, about the financials. You have many phase III studies ongoing. You will launch your wholly owned drugs, olezarsen, donidalorsen, in the coming years. How should investors think about R&D and SG&A expenses going forward?
Sure. So we have a healthy balance sheet today, and that puts us in a very unique position. We also have a very substantial sustainable base of revenues from Spinraza royalties, as well as from our currently partnered programs. All of that helps us fund the investment period that we find ourselves in today. We're sort of at the top tier of our R&D expenses as these big phase III studies are fully enrolled or are nearing full enrollment. So we would anticipate that will, you know, start to level off over the next coming years or so. SG&A expenses, however, are gonna grow, as they should, in order to be able to drive the top-line revenue growth that's so important for the company and frankly, for bringing these drugs to patients.
So you can anticipate that that will grow, and that should grow at least ahead of revenues. But once we get on the market with these drugs, it should grow, you know, in relation to the revenue growth that we would anticipate. So look for us to be investing for growth over the next, you know, next little while, but with a healthy balance sheet to support that.
Got it. That, that's very helpful.
Okay.
With that, I think we're out of time, and really appreciate Beth and Onaiza for being here and providing these updates.
Thank you.
Thank you.
Thanks for having us.
... I guess so. Yeah, yeah, we're just gonna go through it. All right, everyone, I think we'll get started with our next presenter here. Again, my name is Derek Archilla. I'm one of the senior biotech analysts here at Wells. Very excited to have our next presenter, MoonLake Immunotherapeutics. From the company, we have Jorge Santos da Silva, the CEO. Jorge, thanks for joining us.
Thank you.
Awesome. So if anyone has any questions in the audience, I always kind of forget to ask, you know, you can raise your hand and we can lob them in, but maybe just to start, Jorge, maybe you can just kind of give a little bit of background about your company, and you guys have had a lot of interesting things going on in the last couple of months, so maybe you can just kind of highlight some of that before we dig into some of the questions.
Absolutely. Again, thank you. Thank you for having me and us here in the beginning. So very briefly, MoonLake Immunotherapeutics was founded in 2021, based on a license agreement with Merck, the German Merck, to license nanobody technology, which we think is sort of the next wave of biologics to treat several diseases, namely inflammatory diseases. And that license agreement is really focused on the worldwide rights of a drug called sonelokimab. That's an IL-17A and IL-17F inhibiting nanobody. And as I said, the company was founded in 2021 around that license agreement. A year later, in 2022, in April, so probably among the darkest days we've lived over the last dark 2 years or 3, we went public at Nasdaq.
About a year later, so in June 2023, we read out our big phase IIb trial in a big inflammatory disease, hidradenitis suppurativa. On the back of that, we made a relatively large raise. We raised about $500 million to continue our programs and go into phase III. The company, when it was founded, we were just finalizing the data around phase IIb in severe psoriasis. Very large trial as well. So about 300 patients. HS is about 230 patients, and we're also running a phase II in psoriatic arthritis, another, yet another inflammatory disease that's another 200 or so patients.
So a pretty big, robust package that we've been building as we have built the company the way, the way that I just described. Why are we so excited about this asset? Not only because it's showing phenomenal data, I'm sure you will ask questions about that.
Sure.
But also because, as we said, I mean, IL-17 is a pathway that has proven to be the leading pathway in many indications. Even when there was a lot of excitement about other pathways, like IL-23, time showed that after all, IL-17 continues to be the MOA that allows you to treat the majority of diseases in the INI space, those where IL-17 or neutrophils are involved. And the exciting part about our molecule is that we're only one of two molecules that is able to inhibit all the pro-inflammatory cytokines that drive the IL-17 path, and that's IL-17A and IL-17F. There's only two. It's only us, and bimekizumab can do that.
The Nanobody also has an additional advantage versus monoclonal antibodies, in that it's much smaller and is able to bind albumin, which is enriched in inflammatory sites. So as you can imagine, winning MOA, small size allowing you to go into very different tissues and very deep tissues, and we've shown that that's indeed what happens with our molecules. So really bringing the best of both worlds to create what I think so far is proving to be a very unique molecule in dealing with all these inflammatory disease.
Perfect. So maybe just to drill down on the MIRA trial, I mean, you guys reported out, you know, the 12-week data for sonelokimab and in HS. So just maybe you can kind of just review that data set, and I guess what, what's most apparent? Obviously, you used kind of a more stringent endpoint than some of the other trials, but also, what do we kind of see from, like, a dose-response perspective in that trial?
All right, so there's, there's a few things there.
Yeah.
So let's maybe unpack the results first. As you mentioned, Derek, we were the first to use a higher endpoint called HS75. For those of you not familiar, in immunology, you have some letters, right, which describe a score and then a number that describe how well you improve that score, forever. Hidradenitis suppurativa, the target was to have a 50% improvement. We were the first company to ever use a 75% improvement as a primary endpoint, and even reporting a secondary 90% improvements. And you're absolutely right.
There, we showed a delta to placebo in the order of 30%, which is much higher than any of the molecules that had ever reported HS75 as a secondary, but also in the primary endpoints that other molecules have used as their primary endpoint, HS50. We have performed well above those molecules. Give you an example, Cosentyx, I'm sure you heard about this, about this, this product recently approved and launched in Europe for HS, I guess, soon here in the US, they had a delta on HiSCR50, so 50% improvement of 11 points. We had an improvement in that same score of 38 points.
So you would need to treat 4 x more patients with Cosentyx to reach our level, and that gives you a sense of how impactful the data was. For a young, small-cap biotech, we also went much further than that. We showed several scores, patient-reported outcomes. The whole totality of evidence shows you a molecule that performs better than every other molecule out there, and with real impact in patients' lives, especially, and I would call attention to this, Derek. Investors and analysts really like to talk about HiSCR because that's kind of the standard score, but that score doesn't really cover the most important lesion that these patients suffer from, which is, we call the tunnels.
Tunnels are essentially real lumens that form inside your body, get filled with neutrophils, form pus, and this just oozes out of your body every day, all day, right? It's a horrific disease. And we were the first company to show a real morphological improvement of these structures inside the body. These patients are really acting very deep, as I said, the nanobodies would. And about over 40% of our patients stopped releasing pus within 12 weeks. So it used to take 8 years, or it takes 8 years for you to get diagnosed, and you suffer in isolation, and then in 3 months, we give you a over 40% chance of not oozing pus anymore. I think that's obviously a phenomenal result.
So very, very, very interesting scores, well above what has been reported before, and we're comparable, doing better than the other drugs. The phase II is designed as a pivotal trial. We'll essentially replicate the same protocol for phase III. So we expect these results to be actually quite significant, and to be reproducible quite easily in phase III. As you mentioned, in this phase IIb, we tested two doses. We tested the 120 mg dose, which was the dose that proved to be the best for psoriasis. And we also tested doubled that, so 240 mg, because traditionally, people have always doubled their doses.
The big monoclonal antibodies cannot get deep into the skin, so typically you give double the- double that amount, that's where you get the better results. What we saw with our doses was that the 240 and the 120 performed quite similarly to each other, but actually the 120 tends to be numerically better in different scores versus the 240. They're not statistically significant in terms of difference, but the 120 seems to be the better dose, which is supported by PK data and therefore will be the dose that we carry forward for phase III.
Gotcha. Okay. And just in terms of the safety, so again, you know, hitting both the IL-17, I guess, isoforms or, you know, looking at that, is, is that, again, in terms of safety, more like Bim in term, or is it more like, I guess, Cosentyx in terms of, like, the safety profile that's kind of emerging for us sonelokimab?
I think all the IL-17s are actually quite similar to each other.
Right.
There is one difference. Obviously, bimekizumab is also tends to perform quite a bit better in terms of efficacy-
Yes.
By the way, right? So again, for those of you that don't know, IL-17 A and IL-17 F, these form dimers, right? And there are three dimers that drive inflammation, two A's, two F's, and one A, and one F, right? That's how inflammation is driven. bimekizumab hits all three, like we do. Cosentyx or Taltz, that's another good example, hit AA and a little bit of AF. They leave- they cannot do anything with FF. The efficacy of bimekizumab is typically better than Cosentyx and Taltz. The difference on the safety is that there is a little bit of transient Candida when you also hit F with bimekizumab, right? That's typically a low percentage in disease like HS, very manageable.
Sure.
That's the least of your concern: you have three days of thrush, but that's really the only difference. We, in psoriasis, tended to have less Candida than bimekizumab. I think in HS, we're also seeing... We also saw the same trend in the first 12 weeks. We have to remember that in certain diseases like HS, there is a big baseline of Candida. The patients typically already have this as a comorbidity. What we expect to see, Derek, and we'll talk more about it in our 24-week-
Yeah
-readout in October, is that, the percentages are as expected, and these are really not very serious cases. Majority of patients resolve very quickly, and importantly, there's no dropouts related to this. Just to finish off, 'cause I never like to talk about safety and Candida without putting things into perspective, right?
Sure.
We're going against molecules like the TNFs or the JAKs, or even the IL-23s, right? So we're talking about oral thrush versus death-
Yeah
... and malignancy and all other complicated matters. So from a safety perspective, we're... And that's what we hear from the KOLs. We're in a very, very good place.
Gotcha. Then maybe let's just talk about that 24-week data and what we should be expecting. And I guess, you know, what do you think is going to be noteworthy? I mean, you're switching some patients off placebo to, you know, receive drug. You're switching people off the initial Humira, you know, control arm or active control arm onto sonelokimab. So I guess, how should we kind of—like, what are the most important data points to take from that readout?
If you wanna hear more, you should join our Capital Markets Day on Monday next week. You're all very welcome. There, there's a few things that I think will be more-