Hello everyone. Good afternoon and welcome back to H.C. Wainwright's 28th Annual Global Investment Conference. I'm Patrick Trucchio, a Senior Health Analyst at H.C. Wainwright, and it's my pleasure to welcome our next speaker, Steve Romano, EVP of Research and Development at Silence Therapeutics. This is an HCW top pick in second half 2026. Silence is a clinical stage company. It's advancing and growing a pipeline of siRNA therapeutics targeting areas of high unmet need across rare and cardiometabolic diseases led by divesiran and polycythemia vera, or PV, which met its primary endpoint in the phase II SANRECO trial in August and is advancing to a Q12 dosing interval toward a phase III registrational trial in the first half of next year. With that, Steve, welcome.
Thank you.
Great to have you with us. So just maybe first, before we get into the pipeline, if you can just give us some background on Silence, on the platform,
Sure
And what's differentiating about this platform.
Yeah. Silence has been around for a while, about 20 years. Our focus is obviously small interfering RNA. We have a proprietary technology, like many other companies in the space. What's special is, like other companies, we have specific chemistry modifications that we apply to our sequences. We have a proprietary algorithm to choose what we believe are the most potent and specific sequences to target for silencing of gene products, disease-associated proteins. And we have also algorithms that ensure that we choose the safest compounds. So not only are they durable and specific, but they're safe, and we have always updating our algorithms there. We also have IP around our linkers, and of course we use GalNAc technology, which is specific to the hepatocyte center in the liver. That is very similar to the other companies, but the other pieces of it is really our proprietary technology.
Like I said, we've been in the space for a long time. We transitioned from really a research-focused company to a clinical stage company over the last five to six years with now three products that have entered the market, and I think that just underscores the safety and the confidence we have in our technology.
Divesiran targets TMPRSS6 in PV. Can you explain the mechanism and why inducing a controlled iron restriction is the right way to manage a myeloproliferative disease?
Well, it's the right way to manage polycythemia vera. Some of the other conditions may not necessarily be targeted with a suppression of TMPRSS6. But the patients with polycythemia, as you probably know, have a JAK mutation. That causes an increase in the number of RBCs, the red blood cells, so their hematocrit goes high. When you have a high hematocrit, you can have viscous blood essentially, and it sets you up for thromboembolic events. These could be as serious as cardiovascular death or, of course, thromboembolic events that are non-fatal as well as bleeds. We know that one of the major needs in patients with polycythemia vera is controlling the hematocrit and the red blood cell count. Our compound targets TMPRSS6. TMPRSS6 is a negative regulator of hepcidin production. Hepcidin is the major regulator of iron in the body.
By blocking TMPRSS6 in the hepatocytes, you take off the brake and you increase the amount of hepcidin that is available. Hepcidin will then restrict iron to the bone marrow and therefore essentially starve the bone marrow of the iron needed to continue to overproduce RBCs. That's really the technology. It's very elegant and rather simple, to be honest with you. Fits very nicely with the underlying pathophysiology.
Great. In August you reported top line 36-week results from SANRECO, that's the phase II trial, 88% of divesiran treated patients maintain hematocrit below 45%.
Yeah.
Without phlebotomy versus 19% on placebo. Maybe you could just walk us through this trial and the program and what stood out most to you.
Yeah. So maybe just a quick description of the trial. This was a continuation of a combined phase I, phase II protocol. We had reported our phase I results at ASH and then additional data at EHA last year and the year prior. We were very confident in what we were seeing there. We saw very robust effects, increase in hepcidin that was associated with a decrease in systemic iron availability and an ability to maintain hematocrit below 45%, which is really the target in these folks, while essentially eliminating the need for phlebotomy in well-controlled patients. The phase II study took one of those doses, the 6 mg/ kg dose. We had weight-based dosing both in phase I and phase II. We looked at 3 mgs, 6 mgs, and 9 mgs.
We decided to take the 6 mgs forward into the phase II, but rather than give it in the Q6-week regimen that everyone got in phase I, we decided based on the results of phase I and the durability that we were seeing in our phase I patients, that we could actually evaluate a longer duration interval. We are looking at both Q6, which would essentially replicate and confirm one of the doses that we had and the results we had in phase I, but also look at a quarterly dosing schedule, which was Q12. As you mentioned, in the phase II study, we enrolled the same population of patients that we did in phase I.
All of these patients is what we refer to as phlebotomy-dependent, meaning regardless of whether they are high risk, low risk patients, by definition over 60 or with a history of thromboembolic events, or whether they were well controlled, well, actually they were all well controlled, but whether they were on background cytoreductive therapy or not, perhaps just on phlebotomy or phlebotomy plus additional treatments like hydroxyurea or Jakafi, which is a JAK compound, or BESREMi, which is a pegylated interferon, all those patients were allowed into the trial. And what we demonstrated is we replicated the Q6-week arm of the phase I study, but we also demonstrated a very robust effect in the quarterly arm.
That's the bottom line is the results of that study were that both Q6 weeks and Q12 weeks were robustly effective, reduced the need for phlebotomy, and maintained hematocrit below 45 in upwards of 90% of patients, and that was well above the placebo rate of about 19%. Very excited about that. We're showing a durable effect, we're showing a robust effect in the Q12-week arm, which we want to take forward into phase III. The safety and tolerability were clearly established. No new issues from the phase I study. We feel very, very happy about those results.
Yeah, that's interesting. Can you talk a little bit more about the dosing and the decision to bring the once quarterly dose forward?
Yeah. Again, if we looked at the data from phase I, which again was Q6-week, we gave everybody four doses at Q6-week intervals, that's the first 18 weeks, zero, six, 12, and 18, and then followed them all out to week 34. Followed everybody 16 additional weeks. If you look at the results of that study, the patients had a rapid elevation of hepcidin as quickly as the first two or three weeks, and then it plateaus, and it plateaus well beyond the last dose. The bottom line is we got a lot of confidence that these patients, because you're really looking at that biomarker. That's the biomarker that's going to drive the efficacy of the compound in the patient population. You see a persistence of that elevated hepcidin without any attenuation in a large number of patients.
That gave us the confidence to look beyond Q6 weeks. We wanted to replicate that, as I said, but we also wanted to look at a quarterly dosing. A quarterly dosing, I think, fits into the management of these patients as well. If you can confidently suppress hematocrit to below 45 without excursions above that over a certain period of time, like a quarterly interval, I think that would be very helpful to managing these patients and keeping them in a safe level of hematocrit.
Can you talk about the safety profile and what you've seen from safety and tolerability?
Yeah. The safety profile is as you would expect. Keep in mind that you're giving to patients who require many phlebotomies, so they're very often suppressed with regards to their blood levels, so they're iron deficient, et cetera. What you want to do is maintain hematocrit below that. I'm sorry, I lost my train of thought. Your specific?
Just on the safety profile.
On the safety profile.
Tolerability.
Yes. Sorry.
Yeah.
The bottom line is you want to make sure that you can safely suppress hematocrit. You do not want patients to get too suppressed. You want to do it to a safe level and be able to see that durably. We saw that without major issues. No major safety issues at all. Everything that we saw in phase I with regards to ISRs, it is an injectable drug, of course, you want it to be well-tolerated by patients. Was very well managed. Any of their other indices were as expected. In patients that you elevate hepcidin in, you are going to get a reactive thrombocytosis, which is an elevation of the platelets. We saw that as we did in phase I, and as other folks in this space have seen with their products as well.
A reactive thrombocytosis that plateaus off and does not increase into areas of real concern, which would be well above 1 million, say 1.2, even 1.5 million. Bottom line, very well tolerated. In our phase II study, the ISRs were very low, so patients were very accommodative to the injections.
You have submitted an abstract to ASH in December just to confirm that. What would we expect from this full data set beyond the top line, particularly on symptoms?
Yeah
Baseline characteristics, and extension durability?
Yeah, that is exactly right. You are going to see all the data on the demographics of these patients. You are going to see all the details on the blood indices, so the other blood lines, et cetera, the hematocrit and hemoglobin. We will show the curves for both of those, obviously, over time. We are examining the individual patient data at a regular basis so that we have a full clarification of those curves and the persistence of the effect.
You will see the results from the symptom scores, the quality of life scores. We had a multi-item score that looked at a number of different symptoms associated with the condition. We also looked specifically at fatigue, which can be a very debilitating symptom in these patients, and often exacerbated by the need for multiple phlebotomies. We are looking at all of that. Yeah, and we will show all the iron indices as well.
The end of phase II meeting, I think is planned with the FDA by the end of this year. Is that on track? What are you looking to learn?
Yeah.
What would be a favorable outcome from that?
Yeah. So, as is typical with an end of phase II, you want to make sure you have confirmation for the dose that you're choosing to take to phase III, the interval that you're going to evaluate in phase III. The size of the study, that's very critical because the other companies that are ahead of us, there's a couple companies that have either completed phase III, the Protagonist compound now with Takeda, and sapablursen, which was Ionis, now with Ono. They've just started a phase III. In each case, they marked 250 patients as the target. If you look at the efficacy of our compound, we absolutely do not require as many patients to confirm the efficacy on the primary outcome measure. The response criteria, which is keeping patients below 45 on hematocrit without the need for phlebotomy.
But what we do want to understand is what is the size of the trial we need to get some very key secondary outcome measures, including symptoms, into potentially the label. Because we know rusfertide, which was recently approved, did get fatigue in the label, and I think that's very important. So we're evaluating that right now. Remember, we have phase II data, and that will help us decide and determine the power assumptions for phase III, both on the primary outcome measure, but also on some of the symptom measures.
Right. That's interesting. Can you give us a sense of the number of patients, the design of the study, and u ltimately, what we'd be looking to prove in phase III, would we look to recapitulate phase II? Yeah.
Yeah. That's exactly right. Remember, phase III is a confirmatory phase. For an orphan condition, you typically need only one confirmatory trial. Your phase II trial, if done well, as ours was, will be supportive evidence for the evaluation of the overall submission. We have considered 250 going into the discussion, but we are now looking at the power calculations that would get us a leaner, more efficient study. Now I say that, I believe the other two companies ahead of us that chose 250 patients probably were guided to some degree on the minimum safety database that you need for an orphan condition. You hate to overpower a study just for purposes of safety, but that is going to be a key point that we'll discuss with the agency.
What is the most efficient trial design, and what is a reasonable safety database, exposure database, that would allow them to have a robust review of our data? But we feel very confident about the safety, and we would like to get a study done as rapidly as we can, of course.
Are there additional indications where divesiran could be relevant?
Yeah. We have done a fair amount of preclinical work, looking at different conditions that are associated with low hepcidin levels or iron loading. We have about a half a dozen or more conditions that we have reviewed and discussed with our key opinion leaders and experts in each of the conditions. We have prioritized the opportunity in HH, so that is hereditary hemochromatosis. But also looking at a very interesting model of essentially giving the drug preconditioning patients with MDS that require a hematopoietic stem cell transplant. The preclinical model really showed a robust improvement in engraftment and a reduction in mortality and morbidity. That is a very different paradigm for the use of a drug like ours, but I think it's a very interesting one. It could, of course, if positive, you could look at broader populations of patients undergoing transplant.
Right. Just back into PV, with these other compounds that are already in phase III,
Yeah
How do we think about sort of the differentiation of divesiran? Is it dosed less frequently? Is it improved efficacy, better tolerability profile? How do we think about this?
Yeah. Well, what I would say is, clearly, we'll have a more convenient dosing schedule if we replicate the results in the quarterly. But that's not really enough. What's important is managing patients well. So if we can manage patients with less frequent dosing, that would be terrific. But I think one of the value sort of propositions for us to establish in a phase III is the ability to maintain hematocrit below 45 for a majority of patients over a reasonable timeframe. We know from previous studies, and there was a study in The New England Journal of Medicine back in 2013, there was an Italian researcher that oversaw it, that patients maintained between 46 and 50 hematocrit versus under 45 had a 4x increase in cardiovascular death and thromboembolic events. So we know it's very important to reduce the excursions above 45.
I think with a longer acting drug like ours, with the confidence that you are maintaining durable suppression, that could be a real advantage. That's the real value driver for us.
Right. That's interesting. Then maybe when we look across the early cardiometabolic pipeline SLN312, I think global rights were returned after the phase I trial.
Yes.
SLN365 and SLN098. I think both targeting INDs in the second half of next year. Can you maybe talk us through each of these compounds? What is the priority among them?
Well, first, the priority for us right now, and we just raised just over $200 million a few weeks ago on the back of these good phase II results, so we are confident that we can cover the phase III costs. Now we are looking to prioritize the rest of the portfolio because small company, obviously in biotech, you have to be careful and prioritize your investments. I love all of these programs, of course, as you would imagine, somebody from R&D. But I think we have to determine. So I will tell you one I am really excited about is the GPR146, and that is 365. So that is targeting a novel non-LDL receptor target that would reduce the production of very low density lipoproteins and can contribute to a reduction, obviously, in circulating atherogenic lipids.
That could focus on a rare condition, which is really in our wheelhouse, if you will, and that would be homozygous FH. Now, the interesting thing about that is the compound 312 that you mentioned is AngPTL3. That is a compound that is being returned to us from AstraZeneca, not because the data were great, because the data were very good and they have been presenting that at multiple lipid meetings over the past couple of months or so, and will continue to do it through the year, but for strategic purposes. But there is very interesting preclinical evidence that the combination of an AngPTL3, which is another non-LDL receptor targeted means of reducing circulating atherogenic lipids, in combination with GPR146, might actually work even better.
When you think of patients with homozygous FH, they often require multiple treatments in order to improve their lipid profile and reduce cholesterol, LDL to levels that are reasonable or targeted. They often cannot meet that target. There is a real need here. Those are very important to me. The other is inhibin βE, and I think everybody's familiar with inhibin βE. It's a very interesting compound, but that compound is one that we wouldn't necessarily bring forward ourselves, because there you have to do very large studies. Again, as a biotech company focused more on the rare orphan side of things, we would look to outsource it or collaborate. That's targeting a very interesting target. The genetic evidence is very strong for targeting that particular inhibin βE.
At first, everybody thought it would simply be for weight loss, but in fact, it improves the composition of weight in the body. It's not likely to be alone a means of controlling obesity. But in patients who are overweight and have other metabolic disturbances, inhibin βE, with or without an incretin, could be a very interesting way of managing patients' weight, but also the improved distribution of weight, so reduced visceral fat, reduced liver fat, maintenance of lean muscle mass, which is really critical because that's a big problem in obesity treatments these days, is that you don't lose just fat, you lose fat and you lose lean muscle mass, which is a real problem because when you gain weight, which many of these patients unfortunately do or go off their medicine, they gain more percentage-wise in fat. You don't just all of a sudden bulk up.
Sure.
There are challenges there that inhibin βE might be able to target.
I did want to ask about zerlasiran. This is the cardiovascular program in Lp(a).
Yes.
This is a phase III-ready program. I am just curious where you stand with this program and any read-through from the Novartis program.
Yeah. Lp(a), it is a very interesting target, and we are very excited about that. I will tell you, we have set aside zerlasiran. It is phase III-ready, to your point, but we have not invested in it because we were waiting for a collaborator, a partner. Unfortunately, the Novartis program, the Lp(a)HORIZON study, did not demonstrate an effect, but we have not seen all the data. That was just a very short note that came out on a Friday before a holiday. Bottom line is we are really going to want to dig into that data. That is an ASO, so it is not an siRNA, so you do not typically get as robust an effect with regards to reduction. But there are so many unanswered questions, but we will certainly be looking forward to kind of really evaluating that data set.
Right. Maybe just as a last question, what do you believe is the most misunderstood part of the Silence story?
I think it is just that we have gone under the radar, if you will. We are sort of silent. Bottom line is we are in the clinic now with three great compounds. We have demonstrated our capabilities both on the chemistry and the discovery side, as well as being able to transition into the clinical stage. Now that we have good data that we are progressing into full development beyond phase II into phase III, I think our profile is going to dramatically increase. I hope you will see us for quite some time.
Right. Terrific. Okay. Steve, thank you so much. Thanks to Silence for attending. Thanks for everyone for being with us. Have a great rest of your day in conference.
Yeah. Thank you.