Good morning, everyone. Welcome to day one of Cantor's Global Healthcare Conference. My name is Prakhar Agrawal. I am a biotech analyst at Cantor, and for the next session, we have the pleasure of hosting the team of Silence Therapeutics. Representing Silence, we have Rhonda Hellums, Chief Financial Officer, and Steven Romano, Chief R&D Officer. Silence management team, thank you for joining us.
Thank you for having us.
For having us.
Maybe we can start with a quick overview of the company and the pipeline and the key priorities over the next one to two years.
Sure. Yeah. Silence is an siRNA company. We have been developing our technology for over 20 years. In the last seven to eight years, we have been focused primarily in the liver, so working on the GalNAc, and therefore we call it our GOLD platform. In the last, I would say five to six years, we have been able to pull three of our programs forward into clinical development. Our lead asset, which is divesiran, just completed phase II, and Steve will, I am sure, walk through all the results from that phase II blinded placebo-controlled study, which was great. We also have a program that is phase III-ready, zerlasiran in cardiovascular. We did have a phase I that just completed ANGPTL3, that also had data results this year. We are focused right now primarily moving this divesiran program forward into phase III as quick as possible.
I think we will walk through those results, and you will see. We just raised $200 million, so that allows us to advance this program quickly.
Great. Thanks for that overview. Maybe first question on the chemistry. There is a lot going on in the siRNA space. How is Silence's chemistry different from the many competitors out there?
Yeah. We are an siRNA technology, so we have proprietary algorithms that help us choose the right sequences, so that is critical obviously. We want to choose sequences that are both potent and durable. Then we have a range of chemistries, what we refer to as our toolbox, that we apply in different and unique ways. Every company has a similar range of chemistries that they apply to their compounds, but you can do that in many different ways, and this underscores our very robust IP positioning is our chemistries. We also obviously have proprietary linkers, and then the manner in which our linkers are connected to GalNAc is also part of our proprietary portfolio, IP-wise.
Okay. Moving to divesiran, which is your TMPRSS6-
Yep
mechanism. You had some data recently. Why don't we start with the overview of the mechanism-
Sure
and what unmet need are you trying to solve in polycythemia vera?
Yeah. Our lead indication is polycythemia vera. Polycythemia vera is associated with an overproduction of RBCs, also some other blood cell lineages, but elevations of hematocrit lead to greater viscosity of the blood. That leads to the risk of cardiovascular outcomes. That can be as severe, obviously, as fatal outcomes, but also bleeds and thromboembolic events. The challenges in PV and managing PV is that many patients cannot manage their hematocrits, even if they're aggressively managed with phlebotomies and even cytoreductive agents that are added as well, depending on the individual case requirements, cannot manage their hematocrits in a steady way, convincingly and durably keeping their hematocrit below 45. We know there's a four-fold increase in cardiovascular death and thromboembolic events, even in patients who are maintained between 46 and 50.
There's a great need in PV patients, particularly those that are phlebotomy-dependent, to enhance or improve their ability to maintain hematocrits below 45. We target TMPRSS6. TMPRSS6 is a negative regulator of hepcidin. Hepcidin is the body's major modulator of iron. Blocking TMPRSS6 actually will increase the production of hepcidin. Increase in hepcidin will lead to restriction of iron to the bone marrow. Essentially, you're starving the bone marrow of the iron needed to continue to churn out RBCs. That's really how it works, and we have demonstrated that it works very robustly. This pathway has already been sort of precedented because you just have a new product. It's a different type of product than ours, but it's a hepcidin mimetic that's been approved, and so the pathway has been de-risked completely.
It's just a matter of us moving now forward into phase III and completing a confirmatory trial. Our phase II results were terrific.
Yep. You mentioned rusfertide, which got approval recently. I guess from your perspective, what are your thoughts on the label and the indication?
Yeah. I do not want to say too much about another company's product, but I will say the indication is terrific. They got an indication that is broad. It was for erythrocytosis. We are targeting the exact same population. I think what has been precedented in the space for the hepcidin-directed therapies has been to target phlebotomy-dependent patients, whether or not they are on background therapy, whether they are not considered high risk or low risk, but that they are phlebotomy-dependent. But the indication they received was for erythrocytosis, so that is a good indication that following that same pathway, we should have that similar indication, and we would be pursuing that as well.
Okay. Both drugs, divesiran and rusfertide, target the same pathway, but mechanistically, are there differences? Why an endogenous way of modulating hepcidin versus a synthetic approach?
Well, look, I think we target an endogenous improvement or increase in hepcidin by blocking TMPRSS6. We can do that based on our technology, which is very durable. As you know, the siRNAs you can give very infrequently, you get a very durable effect. The pharmacodynamic effect is very distinct from the PK effect in the case of siRNAs. The product is out of the systemic system within 24 - 36 hours, but the PD effect persists for weeks, if not months. The benefit there is that consistent increase in hepcidin that is sustained durably over time. The mimetic, of course, is a synthetic hormone that is given exogenously, and it gets removed from the system very quickly, so you have to give the drug frequently. Of course, with the newer medicine, you have to give it injections on a weekly basis to maintain that.
I think that is a very important differentiator is the fact that we are elevating hepcidin in a durable manner with an siRNA technology.
You presented phase II PV data recently.
Yes.
Before we go into specifics, any highlights from your perspective from that data set and the feedback that you got from the physician community?
Oh, I think it's been very well-received. Obviously, we demonstrated a very robust effect, so about 90% response, 88% response, and a placebo-adjusted effect that's just under 70%. That was the case for both intervals that we studied. Just to remind you of the study design, it is a randomized controlled trial, but we looked at both 6 mgs given on a Q6-week basis, but also given on a Q12-week basis. The study was powered for the combination of those two arms against placebo, and we showed a very robust effect. We feel that we potentially have certainly we're a first-in-class siRNA, but we potentially, if we are able to confirm this in a phase III, may have a best-in-class profile of the drug. Both doses were robustly positive.
Yep. I feel like your every six weeks dose looked pretty good as well, like 90%+ response.
Yep.
You could have gone with either doses.
Well, the
the 6 weeks probably had a little bit better efficacy as well.
I think, well, the bottom line is our view of this, remember, it was powered for the combination. With the two arms, you are essentially just looking qualitatively at the effect. It looks very, very similar. And of course, you have the advantage of a less frequent dosing with a quarterly dosing schedule. The 6 mg given Q6 was a confirmatory dose arm from the phase I, because we had already demonstrated that doses between 3, 6, and 9, or I should say each 3, 6, and 9, demonstrated robust effect when given on a Q6-week basis. But we saw enough evidence of persistent elevation of hepcidin following the last dose in the phase I that suggested we could move to a longer interval. We chose the 6 mg dose to take forward, but we looked at both 6 and 12.
In the study, both 6 and 12 looked to be very similar in their effect. Robustly the benefit over placebo was tremendous.
Okay. I know heading into this phase II data set, we were talking about the placebo response.
Yep.
It was pretty low at 19% in the phase II. Even when we compare to 30%+ response on the placebo arm for rusfertide in phase III. What drove the low placebo response? Are there differences in endpoint definition or the population that could be?
No, I think, in a smaller study, you can hover over investigators, you can control things very nicely. Our physicians and our team was really on top of it to make sure there were no misses with regards to following the protocol to the point. I do believe that when you move from a phase II into phase III, and you have some greater variability in your population and a wider population of patients overall, then naturally you may have a bit more elevation in placebo rate. But what I feel very confident about is the likelihood of demonstrating the same robust effect on drug, and that is because the effect we saw in phase II is very, very consistent with the effect we saw in phase I.
Perhaps you may, in a larger study across a larger geography of sites, get a little bit of an elevation on the placebo response. We feel confident we will maintain a very robust effect with the drug. So your placebo-adjusted effect will still be great.
Yeah, if you compare the placebo-adjusted effect size versus rusfertide and the combination of data from your phase II and the phase I as well, seems like you have an efficacy differentiation as well versus rusfertide. Would you agree with that?
Well, I am very careful about making cross-study comparisons. This is the phase II. Rusfertide was a phase III. They did a very good study. Clearly, they have a drug that works very well. But I do feel very confident that we are likely to demonstrate a similar degree of benefit in our phase III as we did in phase II. So I feel very confident about that.
Okay. Maybe we can talk about the safety side as well.
Yep.
Anemia rate in phase II, can you talk about that and how was anemia managed in those patients?
What we've described in our top-line result was the investigator-determined adverse events, and there were two of those, two anemia events. They were both on the Q6, by chance, the Q6-week dosing strategy. The bottom line is we have not yet discussed in full all of the laboratory data, which we will at ASH. We'll share more of that information. But that is based on the CTCAE convention of grading and reporting on adverse events. It was very consistent with that grading system.
Got it. The investigator-assessed anemia rate versus CTCAE-
Yep
What would be the difference and
Well, that was how it was reported.
Okay.
These are hematologists who report events based on their sense of whether it's new from baseline data through the course of the study, and then they judge severity based on typical components of clinical severity. They reported two adverse events of anemia. I do want to be very clear that the laboratory data we will report in full at ASH, because many of these patients come in with anemia, so their baseline indices are low. These are heavily phlebotomized patients, and in many cases, they've had phlebotomies very soon prior to entry, and that obviously lowers their hematocrit. We have a potent drug on top of that, so certainly you're going to see a reduction of hematocrit as the mechanism. That's how the mechanism works. All of these hepcidin-directed mechanisms work. A lot of it depends on the baselines.
Okay. At the ASH presentation, will we get the clarification around when patients are anemic at baseline? How did that
We'll have a more robust and fulsome presentation of all the data, including the blood indices on entry and then over the course of therapy. Again, this is very typical of the mechanism.
Yep. How long does the anemia last for these patients given the long durability of divesiran?
These patients are very well managed during the study. No patient had a grade 3 anemia. There was no reason for transfusion or any other intervention. These were asymptomatic. Most of our laboratory data were associated with asymptomatic patients. It's not a concern. It's just as we saw in phase I, and we had an independent safety review board that managed and reviewed all the data throughout the phase II. Similarly, they suggested there was no new safety issues. So it's a very similar profile than what we've reported on in phase I.
Got it. Injection site reactions was another-
Yeah
safety event that a lot of investors were focusing on. How did that compare to phase I, and do you think that could be differentiated versus rusfertide because I think it has a-
We had a very low rate of injection site reactions in phase II, actually lower than in phase I. I think that is a very good sign of the tolerability of this particular mechanism and product, but also of our portfolio. The siRNAs appear to be very well tolerated.
Okay. What is the grading of the injection reactions like all-
They were almost all grade 1, meaning that they resolved on their own.
Okay. What did you see on the platelet count changes in phase II versus phase I?
Yeah. Again, keep in mind with hepcidin-directed therapies, when you elevate hepcidin and restrict iron to the bone marrow, you are going to have what is generally referred to as a reactive thrombocytosis. So you do get an elevation of platelets over baseline. Many of these patients, remember, come in at elevated levels of platelets as part of their overall disease. But the bottom line is you see that very early on it plateaus, and then you do not see a continued elevation. So you are not seeing a concerning signal here. What you are seeing is very typical from what you would expect with a hepcidin-directed therapy and what the other programs have shown as well. Very similar to our phase I.
Okay, similar to phase I. Is the trend going to be similar to rusfertide as well?
I think in general, very similar. Again, when you restrict iron to the bone marrow, this is a very typical and expected effect, is this reactive thrombocytosis.
Okay. When you present the full data set at ASH, anything else that investors should focus on from an efficacy standpoint or from a safety standpoint as well?
Well, we will have an opportunity to show the symptom scores as well, because this is a phase II remember, but we were evaluating the effect of the improvement on hematocrit control and phlebotomy as well as symptom management and quality of life measures. We will have that data that we will share as well. The data that we shared from the phase I was exploratory, using the similar outcome measures, and showed a directionally very positive effect. We anticipate that we will be able to share more of those details from the phase II at ASH as well.
Okay. Regarding the next steps, when do you plan to have the end of phase II meeting and expected phase III design? Any major differences versus-
Yeah
what rusfertide has shown in phase III?
Well, I think the general design of these programs is precedented now. So you have rusfertide completed a phase III. You have sapablursen that is in clinicaltrials.gov, has described their study. We already had discussions with the agency around our phase II design, and that was to anticipate the questions that might come up for a phase III. So we resolved many of those issues in those discussions. I don't think there's going to be any surprises. As is typical in end of phase II, you really want to agree on the dose and the interval that you're going to bring forward into phase III. So we'll have that discussion, and I think very importantly, we need to resolve the issue around the size of the study.
If you look again, and I'm just suggesting it's precedented, you look at what rusfertide did and what sapablursen is doing, they both seem to have designed trials of about 250 patients. Rusfertide over-enrolled. Sapablursen is targeting 250. I think given our consistent effect and our effect size, I don't think we need that study to confirm the effect, but it may be that the agency will require a certain minimum exposure for safety purposes, even in an orphan condition. So we'll have those discussions. But what I would hope for is a discussion of what is the most efficient design of a phase III so that we can execute that trial and get to market as soon as possible, because we do believe we have a superior product.
Right. And how much is a typical safety database needed for a rare disease like this?
Well, generally the guidelines are roughly about 300 at six months and 100 at a year, and that seems to be probably what the others have targeted. But we have a very safe technology now. This is the third compound in the clinic. I think we can leverage that experience and obviously with the consistency of the effect, make some arguments that the drug effect is pretty well in the bag, if you will. I think we will be able to demonstrate that in phase III as well. Do we really need to power the study to cover safety, or are there other ways of more efficiently gathering safety data? These are some of the questions that we will have to discuss with the agency.
Given the profile of the drug, rusfertide is approved. How are you thinking about enrollment timelines?
Yeah.
Maybe if you use rusfertide's phase III enrollment as an analog, it took a little bit of time to enroll. What are your expectations?
Well, first of all, there is a lot of interest in the hepcidin-directed therapies, obviously, so that will help. There is an expansion of the consideration of these opportunities for patients, so that will help as well. Not everybody is going to transition on to the first hepcidin-directed drug in the period of time that we will be enrolling. We do know that that obviously is an issue we have to consider. But we have considered that. We will consider that based on the geographies that we utilize to enroll our phase III and the sites we utilize. But yes, we anticipate, obviously, sapablursen is doing their phase III as well, so we need to prepare for that. But we feel very confident. We were able to execute a phase II study very rapidly. We enrolled 48 patients.
Of course, that's a smaller study, but we did it in a full quarter shy of what we had anticipated, so about eight or nine months. And we're using the same geographies and a lot of the same influencers or experts, so we're just expanding that. We did that for the phase I. We had four continents involved. And in phase II, we've just expanded that footprint. We'll do the same here. But we feel very confident we can still meet very aggressive enrollment targets.
Okay. So it could be faster than rusfertide? Could be faster than rusfertide?
I don't want to keep on comparing ourselves to rusfertide, but no, we'll do the best job we can.
Okay
to get the trial done as rapidly as possible.
Got it. Maybe if you can talk about the divesiran form factor as well.
Yeah.
Will this be an at-home injector or physician-administered?
Yeah.
What is the doses?
Yeah. Let me tell you what we've done to date. To date, we have had a weight-based dosing regimen, and it's a vial and syringe. Moving into phase III, we are going to move to a flat dosing, so we've increased the concentration of the drug. We will utilize a flat dosing that will minimize the number of injections required. That also allows us, in parallel, to develop a prefilled syringe. The question is, at launch, is that prefilled syringe best utilized by the healthcare provider in the office or at home? We will have the option for either at the time. We've got, obviously, commercial assessments we need to make, but we will assume that we're going to have a prefilled syringe that could be used in the office or at home.
Prefilled syringe. Okay. Physician-administered could have advantages with the Part B versus Part D mechanisms as well.
Yeah, we're going to have to take a good look at the commercial sort of-
Okay
issues there. But our plan is to have a prefilled syringe ready for launch that could be administered either by the healthcare provider or at home.
Right. What's the typical number of injection frequency at a time for-
Yeah. For the newer flat dosing and the higher concentration, it will be two injections.
Okay.
The plan in phase III is to move to a Q12-week interval, so it really minimizes the-
Okay
requirement.
People are still figuring out the PV market after rusfertide's approval as well. Takeda is saying $1 billion-$2 billion in peak sales. Jakafi is already a blockbuster in PV in a niche indication. How do you see the PV market evolving with rusfertide's approval and divesiran, obviously, in a few years?
Yeah. Look, they're going to build this market. I think there's still some work to be done there, but I think the $1 billion -$ 2 billion that they have guided to is in line with our market research as well. We'll be lucky to have them out ahead of us, and then they will build that market, so by the time we get out.
I also just want to add to what Rhonda said is, there are opportunities to progress a franchise where you target other conditions where low hepcidin or iron loading is associated with the condition, and potentially targeting TMPRSS6 could be a benefit. So we are looking at other opportunities for other indications as well, and that could obviously increase the market.
Okay. Maybe on the PV, we saw the Takeda Protagonist deal for rusfertide after a positive phase II. So what could be attractive for you strategically and from a partnership perspective for divesiran? Because we know the mechanism works. You have great data. So how do you maximize the value of this asset?
As you can imagine, there is a lot of interest with the data that we've presented to date. So I think, look, we can move forward. We're going to move this forward as rapidly as possible with the phase III. There's a possibility for commercial partnerships. I think the Protagonist Takeda deal, of course, sets a precedent for us. Of course, economics are going to be a key driver for us as well. Everything is time and place, but again, we'll continue to move that Phase III forward and then continue to look if there's a good partnering opportunity for us.
Got it. Maybe in terms of other PV competitors as well, there are ASOs, as you mentioned. There is an antibody as well from Disc Medicine that has read out. Argo's probably has an up to 24 weeks siRNA. I guess amongst all these different modalities, how do you maintain the differentiation?
Well, I think the most important thing for us to do is focus on trimming the time behind sapablursen, which has started their phase III. That is what we are really critically focused on, is executing as rapidly a phase III program as we can. Obviously, yes, there is growing interest in this space. We feel, obviously, the siRNA technology is a superlative one. We can get to very infrequent dosing. Here, we are looking at quarterly dosing for phase III. We have shown robust effects, so I feel that that is incredibly important as we move forward.
We also have a first-in-class siRNA, and we want to maintain that status, so that is critical. That being said, targeting TMPRSS6 with a monoclonal antibody is absolutely reasonable. Even if you engineer your monoclonal antibody to extend the half-life, you can only get so far typically. You always have concerns about immunogenicity.
I am sure the companies are evaluating that carefully. The other siRNA from Argo's, as you mentioned, is like our drug with regards to the type of technology it is, but that is behind us. They have not yet generated any patient data. They have anticipated starting a phase II study soon, but we just need to stay ahead. I think in general, this is a good sign that there is interest in this space, that there is a lot of excitement around the hepcidin-directed therapies, and we are very happy, as Rhonda said, that rusfertide will be out there building the market for us, and that we will follow as quickly as we can behind it.
Okay. Maybe as we think about all these mechanisms and drugs that will ultimately get approved, if you have similar efficacy as rusfertide based on your research and talking to physicians, is dosing convenience enough of a differentiator?
Well, I think dosing convenience is a very important one. I think if you think about compliance, I do not want to speak to rusfertide per se, but if you think about any other condition where there's a need for a weekly injection, for instance, compliance can be an issue. We will minimize that concern by a quarterly dosing, particularly if it is given by the physician. These patients are seen on a regular basis to have their hematocrit checked, so there is no question that they will be seen. So you can ensure compliance. So that will be an opportunity and a convenience one as well. I still think that manipulating the condition through an endogenous mechanism is a valuable one, but we will have to see the data. Again, I think it is very exciting that these compounds are getting to the market.
It is great that there is one ahead of us to build the market, but we are looking forward to moving forward as quickly as possible.
Okay. Maybe going back to the Takeda Protagonist deal structure, they had a sort of a co-commercialization deal with a possible opt-in longer term. Does that structure make sense? Is that attractive to you or something else in terms of letting a partner maximize the value of this asset globally?
We would definitely want to maximize this product, of course. I think we are open to any structure, of course, depending on the economics. But commercialization will be key for us, especially building that globally.
Okay. What other indications could make sense for divesiran?
Well, we have done a fair amount of preclinical work in different models of conditions of low hepcidin or iron loading. There are a couple that we are more interested in than the others, and hereditary hemochromatosis, I think, is an opportunity to evaluate. We are also, very interestingly, we generated some data looking at patients, excuse me, preclinical data, looking at the effect of the benefit, potentially, with a hematopoietic stem cell transplant and improving engraftment. We have some interested parties in both Europe, experts in both Europe and the U.S. that are interested in that. Improve engraftment and actually morbidity and mortality as well. That could be a very interesting area. You could start with MDS patients who require hematopoietic stem cell transplants, and if that data is positive, that could potentially expand to other patients undergoing transplant for other purposes.
Those are two areas that we have drafted protocols for proof of concept. Depending on the funding availability and what we prioritize, those are two of the options that we have.
When could we hear more about these other indications and your plans to go forward?
Yeah. We are focused right now on the phase III. Once we have our end of phase II meeting and move that phase III protocol forward, we will evaluate the resources we have. We have other programs as well that we're looking at, and we'll continue to pull what resources we have and how we would prioritize this. We have extrahepatic that we are expanding into as well, outside the liver. In our technology platform, we have a GPR146 program that's in preclinical stage as well. Then, of course, these that'll expand the divesiran franchise.
Okay. Disc Medicine is testing TMPRSS6 for sickle cell. What do you think about that indication?
Well, I wish them good luck. That's a tough condition to manage, and if there's any potential benefit to targeting TMPRSS6 in those patients, I'd love to see that. We have not ranked that high in our list of opportunities because there's so many opportunities where we might feel a bit more confident about the potential effect based on targeting TMPRSS6.
But if that indication or if that data set is positive, any reason you wouldn't go after that?
No, again, we'd have to prioritize. As I mentioned, we have looked at a range of about half a dozen conditions, including sickle cell, and we have prioritized a couple others.
Okay. Got it. And in terms of early-stage pipeline, especially the extrahepatic targets that you mentioned, any specific asset that we'll hear more about in the next, let's say, 12 - 18 months?
On the extrahepatic?
Yeah.
Well, we're targeting a number of different cell types. We haven't shared that data yet, but we've been able to get our siRNAs into a number of different cell types and demonstrate functional impact. So that's critical, but we'll share more of those details in the future.
Okay. You raised $ 200 million recently, so what does it cover?
Yeah, that $ 200 million plus the $ 72 million we had at the end of Q2 definitely gets us through the phase III, and then again, will depend on the phase III study size, and then we'll determine which ones we move forward. But yeah, two and a half to three years gets us there.
Okay. Got it. Well, that's all the time we have today. Thank you so much, Rhonda and Steve, for joining us.
Thank you very much. Thank you.