All right, good afternoon, everyone. Thanks for joining Jefferies Healthcare conference in London. My name is Clara Dong. I'm one of the biotech analysts here at Jefferies. Sitting next to me, we have Steven Romano, Chief R&D Officer from Silence Therapeutics. Welcome.
Thank you very much.
Steven, maybe why don't you start off giving us a quick introduction of Silence Therapeutics and your technology platform?
Sure, no, happy to. Silence has been around for about 20 years. We're a global clinical stage biopharmaceutical company, and we have a proprietary small interfering RNA technology platform. We refer to that as GOLD, meaning GalNAc Oligonucleotide Discovery platform, because we utilize currently in our clinical portfolio GalNAc-directed ligands to target hepatocytes. Conditions where the proteins, the imbalance in disease-associated proteins are based on production in the liver, we can target those very effectively. Our technology is, like many other companies in this space, we have proprietary components to each of the technology elements of our platform. For instance, with our sequences, we have a machine learning algorithm that's a proprietary algorithm to help us identify what we believe are the most specific and effective sequences, because obviously we're targeting messenger RNA to quiet down or to silence the production of disease-associated proteins.
We also have algorithms that allow us to ensure that we minimize any off-target pharmacology. Besides that, we have a host of different chemistries, proprietary chemistries that we apply to our compounds to ensure that they're stable, durable, and potent. We refer to that as our chemistry toolbox. We've got a long history in oligonucleotide chemistry, and we have a very robust IP library based on the technology we have. We're always looking for opportunities to optimize the technology.
Maybe just also give us a quick snapshot of, based on the technology, what programs are you running right now?
Yeah, so we're very excited about several programs we have. We have three programs in the clinic. The lead compound is targeting Lp(a); that is, SLN360. That is currently phase III ready. We've announced that we're not going to move forward into the cardiovascular outcome trial that is required, a single CVOT trial for registration purposes, until we have a partnership. We've been working on that. We are phase III ready in every way possible. We have a terrific phase III protocol that we believe really does differentiate the product from the other ongoing phase III trials. We have had great feedback from the agencies, in particular FDA, EMA, and PMDA. We completed a Japanese phase I trial earlier this year so that when we move forward into phase III, we can also include Japanese patients, which is important to partners and certainly to us.
We're very excited about that. Lp(a), by the way, is an independent cardiovascular risk factor. It's not unlike LDL or hypertension. It's not modifiable by exercise or diet. You really need a potent, specific, and directed therapy. This is genetically defined, and at least 90%-95% of the contribution to the level of Lp(a) that you have is genetically defined. We're very excited about that opportunity, but that's sitting, waiting for a partnership. The next program we have is SLN124. SLN124 is a very interesting compound. It targets TMPRSS6. The lead indication for us with SLN124 is polycythemia vera. I don't know how much people know about polycythemia vera, but it essentially leads to an overproduction of red blood cells. You have a very high red blood cell mass. That leads to viscosity of the blood.
The consequences of that are thromboembolic events or bleeding. A good portion of those patients, perhaps 10% over the first 10 years, can progress to myelofibrosis. A smaller percentage, but an important one, about 3%, can actually advance to acute leukemia. It is a relatively chronic condition that people have to live with, but you have to manage the risk. One way you do that is by reducing the amount of iron that is available to the bone marrow so that you are not fueling these clonal progenitor cells, and you reduce the amount of RBCs being produced. We are very excited about that. That is in phase II, and I know we are going to be talking more about that. We have a third program in the clinic, but that is with our AstraZeneca partnership. That is up.
We develop the compound in the discovery space, discovery and non-clinical development, then we pass it to them for the clinical development. That is in the clinic as well. Three of our compounds are in the clinic off of our current platform.
Maybe let's focus on the polycythemia vera product first. Maybe just talk about the MOA here, because you are targeting kind of the upstream in signaling cascade. What could be the benefit of that?
Just to take a step backwards, polycythemia is, as I mentioned, driven by overproduction of RBCs. TMPRSS6, which we target with SLN124, is a negative regulator of the hepcidin pathway. Hepcidin, of course, is the major modulator of iron in the body. What we are looking to do by targeting TMPRSS6 at the top of the signaling pathway, really, essentially, is to really potently block that. We increase the amount of hepcidin. Hepcidin leads to restriction of iron to the bone marrow, which then, of course, leads to a decrease in the production of RBCs and, of course, consequently, a reduction in hematocrit and hemoglobin that should allow patients to be managed at the target levels of 45% or below for hematocrit. That is the way the product works.
Maybe talk about the polycythemia vera market overall. There are several products here. What's really the unmet need and how might your program fit in this grand landscape there?
Yeah, so I should say we are very excited about this compound. It's a first-in-class siRNA targeting polycythemia vera. We have terrific data, which I hope we'll get into with regards to our phase I data, and we're already into phase II. Very excited about that. If you look at polycythemia vera, the patients typically initially need to be controlled by phlebotomies. That's sort of the first step in the management of these patients. They're overproducing RBCs, they have elevated hematocrit, and of course, the guidelines by the WHO organization is to keep patients at hematocrits below 45%. We know that excursions above 45% are associated with about a fourfold increase in cardiovascular outcomes, whether they're thromboembolic events or bleeding. The goal is to keep their hematocrit under 45%. Most of the current treatments, including phlebotomy, patients have many excursions above 45%.
You try to attempt to maintain hematocrit below 45%, but bottom line is it could require many or more frequent phlebotomies to manage their condition. By the way, these patients are almost always iron deficient at presentation. Phlebotomy is effective at reducing hematocrit, at least for short periods of time, but that also contributes to their iron deficient status. Some of the symptoms that are part and parcel of the condition are fatigue, brain fog, et cetera. They can all be complicated by actually continuing to utilize phlebotomies where you remove 250-500, maybe 600 cc of blood. You are exacerbating their iron deficient status, even though you are getting their hematocrit below 45%. Many of the patients also are on low-dose aspirin to limit the concern around coagulation and thrombotic events.
If they're not well controlled, if their hematocrit is not well controlled, you can add cytoreductive agents. They typically can help to some extent, particularly if they have other cell lines that are elevated, like WBCs and platelets. They may need a hydroxyurea or a combination with interferon or even a JAK compound to target the allele burden that they have.
Maybe based on your market research, how large is the PV market overall?
Yeah, I mean, it's an orphan condition, and we have orphan status and fast-track designation in the U.S. and orphan status in the E.U. as well. It's not a very rare condition. We have about 150,000 patients in the U.S. with polycythemia vera. That's the prevalence. In Europe, major four markets plus the U.K. probably have about the same, probably about 3.5 million worldwide. It's a reasonably sized orphan condition that the need of these patients has not necessarily been met well by the currently available therapy. There's a large opportunity to actually enhance the management of these patients.
Great. As you mentioned the phase I data, let's make sure we talk about that. What are the key highlights from the phase I data there?
Yeah, we have really terrific phase I data. We completed that study earlier this year and initiated a phase II. Our phase I study looked at three different doses of our drug, 3 mg/ kg, 6 mg/ kg, and 9 mg/ kg. We gave the drug at Q6 week intervals for four doses and then followed them out an additional 16 weeks. Essentially, they had their first dose at week zero, second at week six, third at 12, and the last at 18. We followed them all the way out to the end of 34 weeks. What we saw across the board, and by the way, I should say a little bit more about the types of patients we included, we included PV patients regardless of their baseline hematocrit.
Whether they were well controlled, meaning 45% or below, or whether they were above that, we allowed all those patients into the study to immediately start treatment with our drug. We also allowed patients regardless of their risk status. Typically, you bifurcate the patients with PV into risk categories based on age. If they are over 60, they are in a high-risk group automatically, or any age if they have a history of thromboembolic events. We allowed both high-risk and low-risk patients. We also allowed patients who were on background therapy. Whether they were on cytoreductive agents or interferon or even JAK compound, we allowed all those patients in the study as well, as long as they were stabilized on their background therapy. We added this to their standard of care.
The other important qualifier is that they all had to be what we refer to as phlebotomy dependent. These are patients that require at a minimum three phlebotomies in the previous six months or five phlebotomies in the previous year to get into the study, because you want to be able to show that you can demonstrate a reduction in the need for phlebotomy while maintaining hematocrit at 45% or below. That's the key outcome for these trials. The data we saw was very robust. About 0.5 of the 21 patients, this is a phase I open label, 21 patients, half of the patients were well controlled. Every well-controlled patient that entered the trial actually sustained hematocrit below 45% and did not require phlebotomy. We essentially removed the need for phlebotomy in that well-controlled population over the course of the treatment period.
For those patients who came in at higher hematocrits, and we had patients as high as 59, we saw a very nice reduction down to 45 in the groups by the end of the treatment period, which, as I mentioned, were those four treatment doses that they received. Very robust effect. We also saw, obviously, was hemoglobin came down. You maintained low levels of systemic iron. That is important because you want to restrict iron to the bone marrow, so you're not fueling these clonal cell lines. We saw, very interestingly, an improvement in ferritin. Although these patients are iron deficient, you want to see, and you want to keep their iron level low, you also want to see a rebalancing of the body's iron stores. What we saw was a very nice elevation of ferritin, which reflects the intracellular iron that's available.
You get improvement in your iron status, which could actually translate into improved symptomatic management for these patients as well. We were very excited about that data. The other thing I want to highlight is after that treatment period, we followed them for an additional 16 weeks. We maintained the elevation of hepcidin. That's the biomarker, obviously, that you want to look for to demonstrate robust engagement in the target. We saw elevations of hepcidin in the first few weeks that were maintained throughout the 34-week period. That's important because in our phase II, which we've started, we're now looking not at just confirming the Q6 week dosing strategy, but we're looking at a quarterly dosing strategy as well, because we have very good evidence that the impact of elevation of hepcidin persists well beyond the last dose.
With that very promising phase I data, how do you expect those results to translate into the phase II trial you just mentioned? You were looking at kind of different dosing intervals. Yeah.
You know, obviously, we feel very confident about the Q6 week interval. I think, again, because we saw very consistent and persistent elevations of hepcidin in these patients. By the way, the elevation of hepcidin off the baseline levels were 20-40 fold. These patients come in at very low hepcidin levels, but you're getting a very robust elevation, which is exactly what you want to do. You want to demonstrate that you've engaged the pathway in a robust enough way to have an impact on outcomes. What we also saw was, no, I think I'll stop there. That was the most important thing. Looking at phase II, excuse me. Looking at phase II, we feel very confident we're going to replicate the Q6 week data. It's hard to imagine we wouldn't.
We also feel confident that we have a good shot at demonstrating quarterly dosing because of the persistence of hepcidin in phase I. We also anecdotally had several patients that might have missed a dose in what we saw. You are always learning from your phase I. It is exploratory. We saw with even those patients who skipped a dose, they maintained their hepcidin level and obviously maintained their hematocrit below 45%. These are all suggestions and indication that we can feel comfortable studying a quarterly dosing strategy, which we are doing. We are very excited about that.
The phase II, we know is on track for the third quarter of 2026.
That's right. It's a 36-week study. We follow these patients for nine months. We did a really nice job. This is a complicated, as I mentioned, it's an orphan condition. It's always difficult to execute programs in orphan conditions. You need to sort of spread the net quite widely with regards to the amount of study sites that you include and the countries that you include. We were able actually to beat our what we thought was going to be a very tough guideline, which was completing the enrollment of the study within a year. We were able to complete it actually almost a full quarter early. That puts these study results into the early third quarter of next year. We're very excited about that.
As you mentioned, the dosing intervals. When we think about the competitive landscape, there is another company developing a weekly injected program.
That's right.
Yeah. How does that, how does your program differentiate in terms of the convenience, the potential for disease modification as well?
Yeah. So Rusfertide, I think you were referring to, is a mimetic. It is a little different, but it is targeting the same pathway, the hepcidin pathway. They are doing it by providing an exogenous synthetic hormone, which is given on a weekly basis, which is perfectly reasonable. We like the fact that they actually demonstrated a robust effect because it is the first program that advanced with targeting the hepcidin pathway and demonstrated a robust effect. That is terrific. That is a weekly dosing, and it is an exogenously administered hormone. Ours is targeting the underlying physiology. We are targeting TMPRSS6, which I mentioned the background and the importance of that. We can give the drug on a much less frequent basis. Certainly on a Q6 week basis, that is a terrific advancement. If we can get to quarterly, that would even be better.
Either way, I think that suits the needs of patients with regards to convenience, but also for the confidence, the durability of the effect of our drug. That is part and parcel of the siRNA platform. This platform is very durable, always produces effects that are likely to be months, if not longer. The bottom line is it can convince the physician and the patient that they can confidently maintain their levels of hematocrit below 45% with minimal excursions above. That actually should give the patients and the physician confidence that you can control this very well. Because even on phlebotomies, as I mentioned, you're going to get excursions above 45%, and that contributes to a higher risk of cardiovascular outcomes.
Great. We are looking forward to the phase II data next year.
Yes, we very much are.
I also want to touch on the other program you talked about, Lp(a). I know you mentioned it's phase III ready and waiting for a partnership. Given there's also some relevant key events in the Lp(a) space, I do want to make sure we discuss this as well. How do you think your program is differentiated from other players in this space? What's the opportunity there?
Yeah. I think, as I mentioned, Lp(a) is a genetically determined cardiovascular risk factor. It contributes independently to risk in patients. It's not modifiable by current medicines or by diet or exercise. Clearly, patients at high risk who also have elevated Lp(a) are going to have a substantial residual risk that is contributing to their potential outcomes over a lifetime. The bottom line is it's very important to develop these potent compounds that can reduce Lp(a) and, of course, translate into a reduction in risk associated with this lifelong elevation of risk. The bottom line is we have a program that we've gotten through phase II. What we've demonstrated is very robust suppression of Lp(a). We've demonstrated that you can get to 90%+ .
In fact, at our higher doses, 300, 450, we demonstrated at maximum suppression up to 98% or 99% suppression of Lp(a). We know we can have a very robust effect and potent and durable effect. We've also shown that in the trials that in the multiple dose portion of our phase I and in our phase II trial, we demonstrated that you can give the drug. We evaluated the drug at Q4, Q8, Q16, and Q24 weeks. We put all that into an updated PKPD modeling. It clearly shows that we have a very competitive profile with substantial reduction and persistence of that effect, for instance, at quarterly dosed or a bit less frequently.
The bottom line is our phase III program, we feel we have a competitive profile, but we feel the way to really differentiate is in the type of phase III program we're going to develop. The current phase III programs that are ongoing really are looking at the highest component of patients with elevated Lp(a), really targeting around the top decile. We know that since those studies were started four, five, six years ago, that there's a lot of additional evidence that suggests levels even lower than that are actually contributing in patients with otherwise high background risk of cardiovascular disease.
The way we want to differentiate is broaden the population of high-risk vascular patients that we bring into the study, but also look to lower the entry criteria, because a lot of patients who may benefit from the drug or from a potent reduction of Lp(a) were not included in the current studies that are ongoing. We have worked with a terrific group of world-renowned cardiologists, lipidologists, and trialists to design our trial, our phase III trial. We have had great feedback from the agencies, as I mentioned earlier, including the FDA. We feel there is an opportunity to differentiate not just on the fact that we have a robust and potent compound that can be given infrequently, but on the design of our phase III, because if that is positive, that can read into the label and obviously read into the marketing of your drug.
Broader population of patients at high risk, but at lower levels, still elevated, but at lower levels that deserve to be reduced and to have the benefit of a potent Lp(a) lowering drug.
This is FDA-aligned trial design for phase III.
Absolutely. FDA, EMA, and PMDA as well.
Do you think in the future, if you have a partnership for this program, do you need to re-engage with the regulatory agency in terms of the trial design?
No, not if the trial is going to go as designed. No, there would be no reason. Obviously, if you're going to tinker with the design of the study, and that's always an opportunity for any third party, it all depends on the extent of the tinkering. In our discussions, we've had ongoing discussions with potential partners. I think we've gotten very good feedback from them as well around the design and the opportunity to differentiate.
Great. I also want to touch on your partnership with AstraZeneca. Maybe give us an update on, give us an overview of this partnership and any recent update we should be expecting.
Yeah. The partnership allows us to work in a collaborative fashion with AZ and to advance as many as 10 potential programs. We have the first one in the clinic now. It is in phase I. We do the discovery work. Obviously, after agreeing on the target, we do the discovery work, the nonclinical development, prepare the IND, SCTA, and then we pass it to AZ to move forward. Like many of these collaborations, we receive milestone payments based on development, regulatory, and eventually sales and sales targets. Right now, it is in phase I. We cannot say what that target is. That is up to AZ to describe. We know that they are in phase I. We are hoping that they will advance to phase II, which would allow us to receive the next milestone.
Lastly, maybe just lay out the upcoming milestones for the company and what should investors be looking forward to?
Yeah. I think, first of all, obviously, since we've just completed the enrollment of our program ahead of time, that is critical. The completion of that trial and the results of that trial in the third quarter of next year will be very important. With regards to the Lp(a) activity, there's a lot of activity in the field. In fact, there's a big milestone that's hopefully coming up in 2026, hopefully in the first half of 2026, which is the Novartis cardiovascular outcome trial for the antisense oligonucleotide. That's going to be followed a short time later, hopefully by the Amgen compound, which is an siRNA like ours. That will be the first time that we've been able to, the field has been able to, demonstrate that, in fact, robust lowering of Lp(a) will, in fact, translate into benefit on cardiovascular outcome.
The assumption is it's going to be at a minimum 15%-20% relative risk reduction. The current trials are powered appropriately to demonstrate that. I think that is going to be a very important point for us as well as the field. The other things that we're doing that we didn't mention were we've got other compounds that we're working on in the preclinical space. We haven't divulged the details there. We're also looking at extrahepatic opportunities. As you know, there's a lot of opportunity by targeting the liver, the hepatocytes. There is also a great deal of unmet need, medically speaking, on conditions if you can target the siRNA technology to other cell types and tissue types. We have been working on that as other companies have as well.
We have generated some very promising data in multiple cell types. We hope to be able to share that data sometime in the future, perhaps next year as well. I think those are the key events in the next 12 months or so.
Lastly, remind us your cash position and rolling.
Yeah. At the end of September, September 30, we had roughly $102 million. That allows us to move our current portfolio of activities into 2028.
Great. Thank you so much, Steven, for sharing your time with us. Thank you to the audience for joining us. Enjoy the rest of the conference. Thank you, everyone.
Thank you very much.