Silence Therapeutics plc (SLN) Earnings Call Transcript & Summary

Thank you, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Goltz, one of the biotech analysts here. It's my pleasure to introduce Steven Romano, head of R&D from Silence Therapeutics. Just as a quick reminder, the format for today is a fireside chat, but if anyone in the audience has a question, please raise your hand to make sure we address it in our discussion. But before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. And with that, Steve, thanks for joining us today. And maybe to kick things off, I'll just hand it over to you to make some introductory comments, and then we can go into the Q&A.

Thank you, Mike. It's nice to be here. So, just maybe a few words on Silence. So we are a global biopharmaceutical company, clinical stage, that focuses on the development of small interfering RNA compounds. And we've been fortunate. We have what we refer to as our Gold platform, which means GalNac oligonucleotide delivery platform, and we target the liver using GalNac as the ligand. But we have a range of technologies that we apply to our compounds. That's for us with the IP we have, a very robust IP library. And that includes the sequences, the manner in which we choose our sequences, the chemical or chemistry modifications that we apply to our sequences to ensure that they're durable, potent, and safe, as well as IP around the linkers that we use to attach our sequences to the GalNac and direct it to the hepatocytes. So the bottom line is we've been successful over the last few years. We've really transferred, shifting from a research company into a clinical stage company, and we've had three products in the market. Our lead compound now that we're really focused on, obviously, is Divesiran.

Great. Thanks for that introduction, Steve. And maybe we can focus on the lead program, Divesiran, in development for polycythemia vera. You recently shared some very promising Phase 2 data, but before we dig into some of that, maybe you can just give us a brief background on the disease, what patients experience, and what.

What the unmet need is? Yes, sure. So, polycythemia vera is a rare myeloproliferative neoplasm. It's associated in almost all patients with a JAK mutation. It's a driver mutation. And it leads to an overproduction of red blood cells. You can also have an overproduction of other blood cell lines. The issue is that when you have an overproduction of RBCs, red blood cells, your hematocrit, which is the portion of your blood, the volume of your blood that is associated with the RBCs, grows and it causes viscosity of the blood, and that can induce thromboembolic events and other severe cardiovascular outcomes. So in these patients, what you try to do is to reduce the hematocrit and retain hematocrit below 45%, which is considered a more safe range for these patients. And there was a very nice study that was done and published in The New England Journal of Medicine back in 2012 or so, 2013, that demonstrated that even if you maintain patients in the range of 46% to 50%, the former have four times elevation of cardiovascular death and cardiovascular events such as thromboembolism and bleeding. So that is the target of treatment, maintaining these patients below 45%. Most of these patients are older patients, although we see patients as young as their 30s. About 85% of the patients are over 40, and a good portion of the patients present older than 60. And we typically divide the population into high-risk or low-risk. The high-risk population is based on being over 60 because that places you at a higher risk just based on age, or any age patient that also has had a history of a thromboembolism. So we really aim our treatment at reducing the likelihood of having thromboembolisms or other cardiovascular events. And we do that by giving them phlebotomies, which is really the first-line treatment, which is simply removing blood from the patient with some regularity. That can work, but actually can complicate their symptomatic presentation and the burden of the symptoms, because these patients tend to be iron-deficient even at baseline, because their bone marrows are chewing up iron to create and make the RBCs, overproduce RBCs, and you add to that by removing blood in order to help them. So you're complicating their iron-deficient status and contributing to the symptom burden. So if we can do anything to reduce the need for phlebotomy, that would be tremendous. And by the way, I just want to add one more point about that is only about 75% to 80%, no more than 25% or 30% of patients maintain their hematocrit below 45% on a regular basis. So there's a huge issue here and a gap in treatment that we think Divesiran may be able to serve.

Yes, makes sense. I guess, how should we think about the market opportunity there and where you might fit into the current market? I know there's other agents out there.

There as well? Yes, it's a good question. So, bottom line is there are a number of other different therapies out there besides phlebotomy. We often use cytoreductive agents such as hydroxyurea. There are newer compounds like the pegylated interferons like Besremi, or for instance the JAK compounds, which are used second or third line, but they are available for patients as well. And then very recently, the first hepcidin-directed therapy, which is a mimetic, was approved. And I think that's very exciting. The opportunity for us is probably in the range of $1 billion to $2 billion for our compound. The space, I think, is going to be growing with the entry of a new class of medicines that is largely well-tolerated, safe, but very effective. And then what's really interesting, and I'll just reflect on this for a moment, is the label for Ruspertide, which is the mimetic, actually has an indication that's quite broad. So it's for erythrocytosis, even though we all are studying patients that are phlebotomy-dependent and meet certain criteria to get involved in the trials. The indication that was given to them is actually very encouraging because we think this is a great pathway to exploit for helping patients to manage their condition much better. And I think that's a good indication of potential size of the market even expanding.

Makes a lot of sense. Maybe you can talk about your mechanism of action, you know, kind of how it relates to Ruspertide.

Yes. So, Ruspertide, we're all targeting, or these new class of medicines are targeting the hepcidin pathway. So, hepcidin is the major modulator of iron in the body. These patients often have low levels of hepcidin. So what our compound does is target TMPRSS6. TMPRSS6 is a negative regulator of the hepcidin pathway. So if you block TMPRSS6, you elevate hepcidin. Hepcidin will reduce the amount of iron that's available for the bone marrow. So it essentially restricts iron to the bone marrow and therefore will starve the bone marrow of iron that's necessary, and therefore you see a nice drop in hematocrit. The mimetic that was just approved is actually an exogenously administered hormone, and that is a peptide, a synthetic peptide, and that is given on a weekly basis by injection. The way our compound works is to increase the endogenous production of hepcidin. So it's targeting the same pathway but in a different manner.

What are the advantages of getting endogenous hepcidin versus exogenous?

Well, I think it's a couple items. First of all, with the technology we have, siRNAs are very durable. So you can give them very infrequently. But the reason why that's important is it means that they are elevating hepcidin, so the biomarker that we're targeting, they're elevating hepcidin in a durable fashion. So you have a consistent elevation of hepcidin, a smooth increase and maintenance of hepcidin levels that clearly is associated with the benefit of the drug versus giving an exogenously administered hormone, which does work, obviously, but has to be given on a regular basis.

Understood. Maybe now we can, with that background, maybe we shift into some of the data you shared. Phase 2 results from your SanRaco study. We thought they were best-in-class, but maybe you can highlight your thoughts on the data and high level some of the key takeaways there.

Yes. So I think the results really were terrific. We were very satisfied with that. We got a response rate of close to 90%, so about 88%. And that compared with a placebo response of about 19%, so the placebo-adjusted response was just under 70%. That's a very robust effect. And actually, that is looking at patients, the response criteria was patients who were able to maintain a hematocrit below 45% throughout the period from week 18 to 36, so it was a 36-week study. Patients adjust to their assigned treatment in the first 18 weeks, drug or placebo, and then from 18 weeks to 36 weeks, you evaluate the response. So that 90% response refers to, or nearly 90% response, refers to the percent of patients that were able to maintain their hematocrit below 45% without the need for a phlebotomy. Very, very robust. The interesting thing about this trial is that we looked at two different dose strategies on the active drug. So besides placebo, which a third of the patients received, two-thirds received the drug. But they received the drug at either Q6-week intervals, which was essentially replicating or confirming one of the dose arms that we had in our Phase 1, or they received it at a Q12-week interval. And all patients received 6 mgs per kg, which was the dose we decided was most reasonable to bring forward into Phase 3. So what we did show was that either Q6 weeks or Q12 weeks was actually very effective, similarly so, in achieving that very high level. So very excited about that. And we'll move forward with that 12, you know, every 12-week arm into our Phase 3 program.

You just put that dosing interval into perspective, Q12 weeks, you mentioned durability versus kind of what maybe is the competitors out there.

Yes, so the hepcidin mimetic, of course, is given on a weekly basis, and that's injected subcutaneously. The ASO, which is being developed, [ salibursin ], is given on a monthly basis. That's very typical of the requirements for an antisense oligonucleotide. They tend to be a bit less potent and durable, but [ salibursin ] has already sort of shared their Phase 2 data in a once-a-month injection, a Q4-week injection. Ours, of course, is a Q12-week injection, again, sub-Q. There are compounds behind us, for instance, DISC has a monoclonal antibody that's targeting the same pathway, targeting TMPRSS6, and they are looking, I believe, at both Q2 and Q4-week, and we just heard something about their Q2-week data, and perhaps we'll hear about their Q4 and we can take it at ASH. So we are really sitting in a very enviable position where we have a durable compound that confidently suppresses hematocrit to below 45% and can be given on a quarterly basis, which by the way fits kind of nicely into the way these patients are managed because these patients are seen on a regular basis because in order to maintain, you have to keep a close eye on these patients. So a quarterly dosing strategy would really fit into kind of the routine dosing strategy, manner in which these patients are treated.

Yes, makes sense. Maybe just back to the Phase 2 data you shared and maybe talk a little bit about the placebo response, what you saw there, and sort of how it compares to your expectations.

Yes, so when we powered the study, when we were starting the Phase 2 study, we assumed about a 20% placebo response rate, but we didn't really have a lot to hang our hats on, and we didn't have the Ruspertide Phase 3 data yet, but we also suggested that we would have a very robust effect above that, somewhere in the 40% to 50% range. So I think we were very good at our expectations. This placebo came in around 19%. The effect was higher than we had initially anticipated, but you always plan for a comfortable margin to be sure that the trial is powered appropriately for a good positive outcome. So that was really what we did. Now, Ruspertide showed about a 77% response rate and about a 33% placebo response rate, but naturally that was in a larger population. So when you move from smaller populations, we had 48 patients in our Phase 2 to 200 patients studied, for instance, and I think they enrolled closer to 300. It's not surprising that you get more variability, but they still showed a robust effect. That 44% placebo-adjusted rate obviously was robust and the drug is now approved. Again, we have a close to, you know, a close to 70% placebo-adjusted effect, 69%. So we hope that carries through into Phase 3.

Makes sense. I know this is a top-line release, but maybe you could just talk about some of the secondary endpoints, kind of hematocrit control, iron.

Markers, PROs, things like that, just kind of what you're seeing there. Yes, well, we expect to, we've submitted an abstract to ASH, so hopefully we'll get that accepted, perhaps an oral, which would be great, and we'll be able to go into the details of all the indices of iron indices as well as all the blood indices also show the curves for hemoglobin and hematocrit. We didn't share that in the top-line results, but as anticipated, very similar to what we saw in Phase 1, you see a relatively rapid reduction in hematocrit in the first two to three weeks even, and then that persists in a durable fashion. You see the same thing with hemoglobin, as you would expect. And with hepcidin, which is the biomarker of import, you see an elevation of that hepcidin with a general maintenance of that as well. So all that laboratory, you know, effect that we saw in the Phase 1 that sort of parallels the effectiveness on the clinical side, we're seeing that mirrored in Phase 2. So you'll see more of that. Other secondary outcome measures, as you mentioned, are evaluating symptoms, and we did include a symptom score that's typically used in this disease state and other similar myeloproliferative conditions. And we also have the PROMIS, which is specifically evaluating fatigue. So we'll have that data. We haven't shared any of that, but we'll share that data. Another secondary outcome measure was the rate because in the U.S., the FDA is agreed to a response criteria, as I mentioned. But in the EMA in Europe, they really want to look at a reduction in the rate of phlebotomy. So we showed a very effective and statistically significant effect on that as well, but we'll share all that information in full at the meeting, including the symptom management.

Great. And maybe you can comment just on what you saw for the safety profile. Yeah. You know, maybe provide a little color on anemia, thrombocytopenia. Yeah. Site reactions.

The profile of the drug was very similar to what we saw in Phase 1. We had an independent safety review committee that reviewed the data on a regular basis from the Phase 1 study as well as in the Phase 2. And by the way, the protocol was a combined Phase 1, Phase 2, so we have that view of the safety throughout both of those programs. Yes, you do see an elevation of platelets. This is very typical of restriction of iron to the bone marrow. You get a sort of bias towards the production or a higher production of the megakaryocyte line, which is a platelet line. So you do see an elevation of platelets. It happens relatively quickly over the first few weeks, but then it plateaus. And we saw an increase in the 30% percentage range, not different from the Phase 1, and I think very similar to the profile that you saw with Ruspertide. So again, that same mechanism, very predictably inducing a reactive thrombocytosis. We're not seeing patients' platelet counts go to dangerously high levels, and keep in mind that many of these patients, based on their disease state, will have elevated platelets when they come in. So I think it was simply demonstrating that the drug's mechanism is very similar to what we've seen and produces a similar effect. Naturally, many of these patients have indices in the anemic range when they enter the study because they're heavily phlebotomized and some patients come in with relatively that are generally, obviously all below 45%, but some of them are quite much below that, so you have to be cautious about that. But we only had two adverse events reported as anemia, and these are well-honed investigators, they're hematologists, they understand the condition, and they only reported two that they considered to be clinically significant. We'll review all the data and the laboratory data in time as well. But generally speaking, the tolerability was very good. The concerns around injection that you have with any compound that you inject subcutaneously or intramuscularly, in this case sub-Q. We saw actually very few injection site reactions, actually much fewer than we saw in Phase 1. So I think we feel very confident about the tolerability of the drug. But generally safe and tolerated as it was in Phase 1 with no new safety issues or signals.

This is a top-line sort of release, but any feedback or you shared the data with some physicians and what kind of feedback.

Yes, well naturally we with some of our experts that are advising us, and these are folks that are very familiar with the entire portfolio of products available in development. But yes, we got very encouraging feedback. So, yes, we're very excited. I think people do believe it's potentially a best-in-class compound based on the efficacy we're seeing. I was cautious as a drug developer. You have to wait till you confirm those results in a Phase 3, this is Phase 2, but I think everything's pointing in the direction of having a very, I think, valuable profile for patients and for physicians who manage these patients.

Understood. I guess maybe just back to Ruspertide and kind of when you think about comparing your data to theirs, I know it's, you know, sort of Phase 2 to a Phase 3, so there's, you know, you've got to be cautious there, but just, you know, key points of differentiation that you think have come out so far you approved.

Yes, again, I want to be very careful. They have an effective product that's been approved, so that's great, since the first hepcidin-directed that's approved that makes it a little easier for us, for instance, because we know that a drug targeting this mechanism, with this mechanism targeting this pathway, is likely to move in the same direction. And we're very confident also because the types of patients that they enrolled are very, very similar to the patients we enrolled in Phase 1 and Phase 2. So we feel very confident about that. I think obviously that one of the distinctions is convenience, and now convenience is not going to carry the day, efficacy is going to carry the day, but convenience is important because convenience actually can translate into greater compliance in the marketplace. So when you need to have an injection on a weekly basis or any more frequently than we have, there's an opportunity, unfortunately, to miss doses and obviously the control of your symptoms and your condition is going to be affected. I'm really affected by that. With a durable compound, with a mechanism like ours, if confirmed in Phase 3, that's a real advantage. I think the value proposition is not around the infrequent dosing, but the fact that you can confidently, with infrequent dosing, maintain a hematocrit below 45%. And as I mentioned earlier, that's the goal of these patients, their hematocrit below 45% to reduce the likelihood of cardiovascular outcomes.

I also just wanted to ask about your response definition versus theirs. They used a little bit more of a stringent approach.