Great. Hello, everyone, and welcome back to H.C. Wainwright's twenty-sixth Annual Global Investment Conference. My name is Patrick Trucchio. I'm a senior healthcare analyst at H.C. Wainwright. It's my pleasure to introduce our next speakers, Rhonda Hellams, CFO, and Curtis Rambaran, CMO, Head of Clinical Science of Silence Therapeutics, a leader in the discovery, development, delivery of novel siRNA therapeutics for treatment of disease with significant unmet medical need. So maybe we can just start with some of the background on Silence. This has been such a critical time for the company, a big year in terms of data readouts, getting these lead compounds moving forward into middle and late-stage development. So maybe kind of tell us a little bit more about the Silence platform, how it's differentiated, and how you've gotten these lead compounds to where they are today.
Sure, and thank you for inviting us here, Patrick. So yeah, Silence has been around for quite a while. We have some extensive know-how in this siRNA space, so we are silencing genetic diseases. I will say probably in the last seven to eight years, we've been primarily focused in the liver. So today, our proprietary clinical platform is largely focused in the liver. So we have a program that just finished phase two, that's in cardiovascular disease, so it's for lowering Lp(a). And then we have just completed a phase one with our divesiran program, which is targeting polycythemia vera, and that, of course, it targets the TMPRSS6.
So, we have, you know, advanced, as you said. We've been very productive, I would say, and we've been executing quite a bit in the last year and really moving these programs forward.
Right. Great. And then the lead program is zerlasiran. This was formerly SLN-360. It targets Lp(a). Maybe you can start first with what is Lp(a), and why is this protein problematic?
Okay, so lipoprotein(a), sometimes referred to as Lp(a), it's a unique protein, actually. It's a combination of one molecule of an LDL-like particle containing ApoB-100 and a large glycoprotein, ApoA, in combination. So potentially, from a biology perspective, you're at risk of the deleterious effects of LDL, be it proatherogenic, pro-inflammatory, also the deleterious effects of ApoA, which is proatherogenic and potentially prothrombotic, all-in-one. It's... we know that one in five of the global population have elevated levels. We know it's genetically determined. It's coded for by the LPA gene, and it's not affected by diet or exercise, and to date, there's no approved therapies.
So it's a common risk factor, it's causal, based on Mendelian randomization, we have no approved therapies, and this is really a major public health issue.
Can you talk about just the awareness of Lp as a key cardiovascular risk factor and how you would expect that to evolve in the years ahead?
Since we published our single-dose data in April of 2022 at ACC, we have seen, I would say, like a groundswell of enthusiasm, of awareness in the field across patients, physicians, advocates. Definitely the testing has improved. We are not at the level we want to get yet, but we anticipate with all the groundwork that's being done and all the other trials out there, that it will continue to improve. A lot of work is being done, even by us also, trying to help, particularly around testing.
Maybe you can frame this around sort of the cholesterol-lowering market, where I think most folks have some familiarity. How do you see the Lp market kind of developing relative to that market?
So we see, we definitely see similar similarities. This is a chronic disease, as I mentioned, one in five of the global population, so a huge market potential, multiple players. As you know, even with our cholesterol-lowering, the first wasn't naturally the best, the third or fourth. So we think there's a lot of room for multiple players. And as we test more patients, I think, you know, the targeted population treatment certainly will increase. But this is a huge, multi-billion-dollar global potential market.
Do we know what level of knockdown is necessary with Lp to show... demonstrate efficacy in cardiovascular disease?
So I think we don't at present. The trials will help us-
Right.
coming, so we'll learn more as we go along. But we know that there's a continuous relationship with risk. So as your Lp levels increase, so does your overall risk.
In June, we had the latest data from the phase 2 trial. I believe it was through 48 weeks.
Yeah.
In ALPACAR-360. Can you give us the key takeaways from that data?
Yeah, so that showed one, a highly significant reduction in Lp levels from baseline versus placebo out to week 48. We also saw a quite potent efficacy, so we had a maximal median knockdown of 90% and greater in both of the doses that we used, the 300 milligrams, 450. In addition, the drug was very safe and well-tolerated, so in the phase 2, we had no participants, say, default from the trial because of any issues related to the drug. So well-tolerated and very promising profile, and I think we look forward to planning the future development.
Can you tell us, you know, the 90% knockdown, was this sort of consistent over the time frame? Was it, you know, how soon until the drug has the effect that you're looking for, and what is the durability, and how should we think about dosing going forward?
It's a great question, so as we saw in the phase 1, when we dosed after a single dose, we had almost 98% knockdown at four weeks. That is the sort of the deal. You saw a similar pattern in the phase 2, and when we say a maximum median knockdown, you know, at least 50% of the subjects would have at least 90% knockdown for the duration of the trial, and we in the phase 2 will, you'll see more of this when we present the data later this year. We use the time average as analysis, which is a very good index of efficacy over time because it factors in the, the peaks and troughs, so rather than taking an efficacy at, say, a specific time point, we have looked at overall efficacy over 48 and then 60 weeks.
Are you seeing an impact on any other lipids? Are you seeing, like, LDL-C?
So we have seen, as in the phase 1, in the phase 2, we have seen an effect on LDL-C and also ApoB. In the phase 1, we had about a 20-25% maximum knockdown of LDL, and that was dose-dependent. That's very encouraging because these are cardiovascular disease patients, well-managed on current standard of care, including PCSK9s. So this is a further LDL lowering on top of standard of care.
What have you seen from a safety and tolerability perspective?
As in keeping with the siRNA modality, it's been very safe to date. As I mentioned, we didn't lose any of the subjects in the phase 2. No one defaulted from the trial. We have had some injection site reactions that were very mild, self-limiting, very much in keeping with the siRNA modality when you inject subcutaneously. In terms of durability, we tested our different dosing regimens in the phase 2, and we anticipate that going forward, we will have at a minimum a three-monthly dosing regimen.
When is the next data readout from ALPACAR-360?
We presented the 36-week to 40th-week data. The next will be 60 weeks. That was the duration of the trial, so we follow these subjects out to week 60. In an upcoming medical conference, we'll be presenting the further durability, safety, and efficacy out to, from baseline out to week 60.
How should we think about clinical development pathway at that point, once you have this next data set? You know, will we move into a cardiovascular outcomes trial?
Yeah, so that's the next logical step. We are doing all the groundwork at present, leading up to the phase III. So there's, as you know, you have to do a lot of preparation on many different fronts. We are doing that. We have not stopped. We are doing some additional work that would feed into the phase III. Yes, we'll need a cardiovascular outcome trial. We'll be having our key regulatory discussions later this year, and then we are continuing to plan for the phase III.
How do you see zerlasiran positioning in the market where, you know, as we're looking ahead, right now there's no treatments approved, but we look ahead, we see that there are three pivotal CVOTs underway. How does zerlasiran compare to some of those mechanisms? How might you be able to position, you know, as you approach. If you maybe can take some of those learnings from those trials, maybe from those launches, how do you see your, you know, where do you see your product profile?
So absolutely, I think, you know, we have an opportunity as the, as the market is being built, as the field, we continue to learn more. So we are furthest ahead is the pelacarsen. That's an antisense oligonucleotide that's dosed every month, and that is expected to read out in maybe the middle of next year. And then we have another siRNA in development. We know from the modality this is a potent therapy, long duration of action, so we think the infrequent dosing will be very, very attractive. We have a quite a renowned steering committee made up of, you know, the good and the great in cardiovascular trials and LPA biology. They're helping us define the trial, and we are working on a differentiated program that will be looking at different elements, including the target patient population.
But we think, you know, this is a big opportunity, very much like, as you mentioned, the statin and the cholesterol field.
So the ASO data, I think, is you mentioned expected next year.
Yeah.
How much of a read-through will that CVOT provide through to zerlasiran?
So that will be the first program that will provide data showing reducing LPA translates to benefit. So it will be quite, quite important for the field. But again, that's, they are targeting a specific LPA level, a specific patient population. We are looking at ways of differentiating, but I think that will, as the first in the field, that will certainly build confidence, in the wider community, that lowering LPA is beneficial.
Right. Are there any additional questions from the audience on zerlasiran? So I think then we'll move on to divasiran. So this was formerly SLN-124.
So I think first, just here as well, maybe talk about TMPRSS6. Why is this, you know, what is this target, and, you know, what is the mechanism of this drug?
Yeah. You know, I can start by saying that TMPRSS6 is a negative regulator of hepcidin, so what it does is that it reduces our hepcidin levels. Why that's important is that hepcidin is a sort of master regulator of iron flux, so it determines the iron availability to the bone marrow and the iron that actually gets into the systemic circulation or the plasma. So if, as TMPRSS6 is a negative modulator, if you inhibit TMPRSS6, you elevate hepcidin levels, and then you have better control of iron distribution in the systemic circulation, so divasiran is specifically designed as an siRNA to knock down on TMPRSS6.
Great, and then, now the program is focused on polycythemia vera.
Yeah.
So, maybe talk a little bit more about PV.
Right
A nd the shift over to this indication, and why, you know, why PV?
So PV is a sort of a natural target for several reasons. So this is a mild proliferative disorder due to excessive production of red blood cells. To produce red blood cells, you need iron. So the concept is by inhibiting TMPRSS6, you reduce iron availability to the bone marrow, and you redistribute it into other areas where it's not gonna have any deleterious effects. PV. So what we are trying to do in PV is to reduce the production of red blood cells. This is important because it's a rare disorder, about one hundred and fifty thousand patients approximately in the U.S., three and a half million globally, when you have increased red blood cells, you're prone to thrombotic effects and cardiovascular events, and the first objective is to reduce what we call your hematocrit.
Your hematocrit is an index of red blood cell mass. So, most guidelines recommend you reduce your hematocrit to below 45%. The first thing you get, or first treatment you're offered when you're diagnosed is phlebotomies, is the equivalent of having blood taken off like you're delivering blood. The issue is that, some patients don't tolerate it very well. These patients are iron deficient at baseline because they're using so much iron to produce red blood cells, and phlebotomy also, reduces your iron even further. So we think that having a therapy that could potentially modulate red blood cells and potentially reduce phlebotomies would be very attractive to these patients.
So you have the phase I, II trial, SANRECO, that's underway.
Yeah.
You've shown some initial data there. Were you able to-- I guess, in that data, are you seeing what you wanted to see? Yeah.
Absolutely. So I think we did a press release earlier this year. We showed that in the world. So as a phase I, we looked at a range of hematocrit levels. So to get into the trial, you had to have at least three blood phlebotomies over the last six months, or five over the last year. Sorry, it's an open-label study. We treated these patients across three dose levels, dosed infrequently at every six-week intervals, and what we saw is that the drug eliminated phlebotomies in the well-controlled hematocrit group and maintained that in a infrequent dosing down to levels that are recommended by the guidelines of less than forty-five. And it was quite sustained.
In all dosing groups, we had a sustained reduction in hematocrit over the treatment period, and also, we also saw positive effects in other indices of iron metabolism. Equally important, we showed that we elevated hepcidin in this population. As I mentioned, hepcidin is the sort of important marker. We elevated it and also maintained it in the physiological levels for the duration. We certainly showed in the phase I we engaged the mechanism, and we did that in a very safe fashion. The drug was very safe, well-tolerated, again, exhibiting the platform of siRNAs that we have seems to be very well-tolerated and safe in the clinic to date.
So I guess when we look at the phase II portion of this program, you know, we'll get some additional data, I presume, on hematocrit-
Yeah
And phlebotomies. I'm wondering also if you can talk a little bit about the importance of improving symptoms and 'cause it's something just that has come up that we've heard.
Yeah
Is important. So maybe talk a little bit about that, and as well, what do you need to see in that data to give confidence to move it forward?
We are planning to start the phase II later this year. Again, we are doing all the groundwork. We have some of those patients from the phase I would be able to roll into the phase II. Even in the phase I, you mentioned an important point with symptoms. That's very important for these patients, so we are collecting data. We're using some symptom scores. We'd also do that in the phase II, which will be a larger number of subjects. In the phase II, as you would do in all phase II trials, we'll take the opportunity to look at potentially even different dosing regimes.
So I think if we can absolutely show a benefit longer term on symptoms, that will be a good additional benefit in combination with having a drug that's safe, that can be dosed quite infrequently, because these patients are on other, you know. They have lots of comorbidities, so they tend to be on lots of other drugs at the same time.
What, what is the bar from the FDA to get approval? What would you need to demonstrate? Do we know?
So we'll have the discussions coming in the near future. We know that guidance recommend a hematocrit less than 45, so that-
Okay
W ill be our target, and we have seen already in the phase I, the drug can easily get patients, in a sustained fashion, below that sort of, cutoff. But we'll have the.