Silence Therapeutics plc (SLN) Earnings Call Transcript & Summary

Good morning. I would like to welcome you to the Silence Therapeutics conference call to discuss top-line results from the Phase II SANRECO study. [Operator Instructions] I would now like to turn the call over to Gem Hopkins, Vice President and Head of Investor Relations and Corporate Communications.

Thank you, Heidi, and thanks, everyone, for joining us. With me today are Iain Ross, our Chairman and Interim Principal Executive Officer, who will provide some opening comments; and Steve Romano, our Chief R&D Officer, who will review the SANRECO study and top-line results. We will then open the call to your questions. Rhonda Helmes, our Chief Financial Officer, is also joining us on the line and available for questions. Today's press release and presentation are available on our corporate website at silence-therapeutics.com/events. Before we begin, I would like to remind you that this call will contain remarks concerning Silence's future expectations, clinical development plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Our actual results may differ from those contemplated by these forward-looking statements. Factors that could cause these results to differ materially are described in today's press release as well as our filings with the SEC. Any forward-looking statements that we make on this call are based on assumptions as of today, and we undertake no obligation to update these statements as a result of new information or future events. With that, I'd like to turn the call over to Iain. Iain?

Thank you, Gem, and good morning and good afternoon, everyone. Earlier this morning, we issued a press release announcing positive top-line results for our Phase II SANRECO trial evaluating divesiran, a first-in-class siRNA therapy in patients with polycythemia vera or PV. Let me be clear, this is the big win scenario. We are absolutely thrilled with these results and what they could mean for patients, physicians, families and the broader PV community. This is also an important milestone for Silence. Turning to Slide 4. Silence is a platform company that has pioneered siRNA research for over 2 decades. The PV results we are sharing today highlight the key strengths of the siRNA approach; high potency, durable effect, specificity, favorable tolerability and the potential for infrequent dosing. We now have completed clinical data across multiple programs in hundreds of patients with rare and cardiometabolic diseases, reinforcing the strength and productivity of our GOLD platform. We see a significant franchise opportunity for divesiran, our first-in-class siRNA therapy for PV, a rare hematologic disease with substantial unmet need. Of the roughly 150,000 patients in the U.S. and an estimated 3.5 million globally, most still rely on regular phlebotomy. Based on its emerging profile, we believe divesiran could offer a differentiated best-in-class treatment option for PV patients. Beyond PV, encouraging preclinical data in several other hematologic conditions support the potential for divesiran to become a broader hematology franchise asset. Slide 5. This shows why PV is our first indication and why it represents a compelling commercial opportunity. First, the unmet need remains significant. Many patients still rely on phlebotomy, underscoring inadequate durable disease control and a large addressable market. Second, today's treatments have meaningful limitations. Physicians continue to navigate trade-offs in efficacy, safety, and tolerability, and the treatment burden. At the same time, Jakafi approximately $1 billion in annual PV sales demonstrates the strong commercial potential. We believe divesiran has the potential to raise the bar with a differentiated profile that combines a robust efficacy results, favorable safety profile, infrequent dosing, and an improved patient experience. Overall, we see a large underserved population, a validated market, and an opportunity for a best-in-class therapy with significant long-term value. Turning to Slide 6. Today, I'm very pleased to say the SANRECO top line results delivered on all fronts. Let me repeat that, it delivered in all fronts. The study met its primary endpoint with strong response rates observed at both the every-6-week and every-12-week dosing intervals. Divesiran was well tolerated with no major safety concerns. The results Steve is about to walk you through clearly support infrequent dosing and a potentially best-in-class product for the treatment of PV. With that, I will turn the call over to Steve to discuss the San Rico program and the divesiran PV data in greater detail. Steve?

Thank you, Iain. We're very excited to share the top-line results of our SANRECO Phase II trial. So let's jump right in. As a reminder, PV is a rare myeloproliferative neoplasm. It's associated with a JAK mutation in nearly all patients and leads to clonal expansion of red blood cells. This presents in patients as elevations in hematocrit levels. The primary objective of treatment is to reduce hematocrit and maintain it less than 45%. This is most often achieved through periodic therapeutic phlebotomy, the removal of blood from the patient. Today, we will be reporting on the SANRECO Phase II results in 48 patients. But as a reminder, we previously conducted a healthy volunteer study in 24 patients, and of course, the Phase I portion of the ongoing SANRECO study in 21 patients. You're likely very familiar with the terrific results reported from that portion of the trial. This slide highlights the global Phase II trial locations. We conducted the trial in 9 countries across 4 continents, the U.S., Europe, Southeast Asia, and Australia. The Phase II trial has 3 components. The first is a 36-week double-blind, randomized portion leading to the primary outcomes we will discuss shortly. The second component is a blinded extension period where those patients randomized to placebo in the previous period have been blindly randomized in a 1:1 fashion to 6 mg per kg, either Q6 weeks or Q12 weeks. All other patients remained on their initially randomized dose interval. The plan is to transition all patients to the dose interval chosen for Phase III and follow patients out to 144 weeks for further safety and efficacy evaluation. I'd like to briefly go over a bit more detail on the Phase II design prior to delivering the top-line results. All patients met the World Health Organization criteria for PV and were considered phlebotomy-dependent. This was defined as having a minimum of 3 phlebotomies in the previous 6 months or 5 in the previous year. This is very similar to other trials ongoing in this condition. We allowed patients to be maintained on other standard-of-care cytoreductive treatment if their regimens were stable for a minimum of 12 weeks. Importantly, all patients entered with hematocrit well controlled, meaning less than 45% -- patients were randomized to drug or placebo in a 1:1:1 manner with all patients receiving divesiran 6 mg per kg, but either on a Q6 or Q12-week interval. The primary endpoint was the proportion of patients maintaining hematocrit less than 45% without the need for phlebotomy during weeks 18 to 36. There were a number of secondary outcomes, which included safety, tolerability, PK, and quality of life measures. Now we can turn to the results, which are quite exciting. As you can see, 88% of divesiran-treated patients met the criteria for response versus 18% of those patients on placebo. This gives us a nearly 70% placebo-adjusted difference between divesiran and placebo. We were delighted to see this robust effect, but we knew based on our Phase I results that we had a potent compound. This was very highly significant with a p-value of less than 0.0001. Remember that the study was a Phase II in an orphan condition, so the power was actually based on the combined arms, active arms versus placebo, and I just reviewed that data. But we can also, of course, evaluate the effect of each active dose arm. Here, we see once again a very robust effect in both the Q12-week and the Q6-week arm with response rates over 80% and 90% in the respective arms. And these can essentially be considered similarly large response rates over 60% and 70% placebo-adjusted differences, and we will plan to move forward into Phase III with the less frequent quarterly dose interval. You may recall that the SANRECO trial was designed as a combined Phase I/II trial and that patients from Phase I were eligible to enroll in Phase II. Our assumption was that the time frame between completion of the Phase I trial, which was 16 weeks beyond a patient's last dose, and the initiation of Phase II would greatly minimize any potential carryover effects of earlier treatment exposure. But to be more confident in that assumption, we conducted a sensitivity analysis on those patients entering Phase II who met the same stringent criteria of Phase I, in particular, the need to have had a minimum of 3 phlebotomies in the previous 6 months or 5 in the previous year. As you can see, that included 40 patients, and the response rate in this population of patients, excuse me, was nearly 90% with a very low placebo response rate. Now as a reminder, the study was powered actually based on 10 patients per arm, and we, in fact, enrolled 48 overall. A key secondary endpoint was the phlebotomy rate. This is of interest as it's an outcome of greatest concern to the EMA. As shown here, the mean number of phlebotomies over week 0 to 36 was 0.2 in the divesiran combined arm versus 2.1 in the placebo arm with again, a highly statistical p-value. The difference is perhaps more clearly captured in the bar graph showing the percent of patients who did not require any phlebotomies over the same time frame, over 90% of divesiran-treated patients versus just 12.5% of placebo-treated patients. Divesiran groups also showed improvements in a number of other secondary outcomes, including hematocrit control, markers of iron metabolism, including ferritin and patient-reported quality-of-life outcome. More detailed presentations of this and other data will be shared at upcoming research conferences. Summarizing safety and tolerability, as previously seen in Phase I, divesiran was well tolerated and no new safety issues were observed. ISRs were relatively infrequent and all self-limiting. As is expected, many PV patients will have laboratory results that are reflective of anemia, given these patients are receiving frequent phlebotomies often in addition to other cytoreductive. Given that background, there were only 2 investigator-reported adverse events of anemia, both Grade 1. With regard to next steps, we have submitted an abstract to ASH, which will be held in New Orleans in December, and we will plan on having an end of Phase II meeting with the FDA by year-end. And given the robust top-line data I've shared with you, we will work to initiate the Phase III registration trial in the first half of '27. Summarizing, we feel the emerging data represent a potentially best-in-class profile for our first-in-class siRNA in phlebotomy-dependent PV patients. I hope you'll agree we demonstrate terrific efficacy with a nearly 90% response rate in divesiran-treated patients, generally well-tolerated safety profile and now have the opportunity to pursue a quarterly dose in our Phase III trial. With that, I'll pass it back to Iain.

Thank you, Steve. We hope you share our enthusiasm for these impressive data today and the potential that divesiran represents. We're now happy to take your questions.

[Operator Instructions] We will take our first question and the question comes from the line of Andrew Tsai from Jefferies.

Congratulations on these stellar results. So with this data set on hand, can you give us a teaser of what your Phase III design could look like at this juncture with the quarterly dosing interval? How big of a study are you thinking? How quickly could it enroll? And how quickly could we generate the data? And then secondly, can we expect you to file a Breakthrough Designation over the coming weeks?

Yes. Thank you for the question. Yes, we're going to be planning our Phase III study. I can't really talk to the details of that trial. I will say it is very likely, obviously, to be a one-to-one randomization in a parallel-group study design, not different from many of the other studies that have been done in the space. But with regards to numbers, we certainly feel very confident that we have a very robust effect size, and that would suggest that we don't necessarily need large numbers of patients to confirm that. But keep in mind, we have to have discussions with the FDA regarding the minimum requirements for a safety database. So that will be critical. But I can assure you, we will look to manage the most efficiently designed trial and execute that as efficiently as possible as well. I also can't really comment to the length of the trial. But typically, as you can imagine, it's got to be a study of 32 to 36 weeks in duration, if it's several -- if it's 200 to 250 patients like the others. And again, as I mentioned, we'll look to see if we can't make that a bit more efficient. But the bottom line, we would assume a time frame of enrollment of somewhere in the 12- to 18-month range. So I should leave it at that. And yes, we'll pursue the quarterly dosing. With regard to Breakthrough, that's something we're considering very carefully right now.

And then as a quick follow-up, bigger picture, there are several PV treatments available or soon to be available. So can you remind us the ultimate market positioning of divesiran and how its addressable market might be different actually? And so maybe said in another way, what would be the hypothetical use case if this were to make it to the market?

Well, just remember, it's going to be based on the population of patients that we'll study. And as you know, we are studying a broader group of patients with PV, but they all need to be or have been in the trials considered phlebotomy-dependent. Now they could have been on other cytoreductive therapy. So, that expands the opportunity as long as those medicines are stable. And we're showing that there doesn't appear to be any difference between those patients who are only on phlebotomy and those patients that are treated with cytoreductives as background as well. So, the population would be really anybody who requires phlebotomy at a minimum level to maintain their hematocrit, regardless of their background therapy and regardless of their status, for instance, low or high-risk profile.

Your next question comes from the line of Mike Ulz from Morgan Stanley.

Congratulations on the very robust data as well. Maybe just a follow-up quickly on the Phase III, just your decision to move forward with the Q12-week dose versus maybe moving both doses forward, if you can give us a little color there.

Yes, Mike. Well, typically, obviously, in an orphan condition, you want to minimize the active treatment arms based on the size of the study to keep the size of the study reasonable and be able to execute it in a reasonable time frame. So we will carefully look at all the data. And of course, as we've suggested, it looks as though the Q12-week dose will be the right dose to move forward with, and it would be much more sensible to keep that on a 1:1 randomization with placebo. But more to come when we have discussions with the agency and confirm the design of the trial.

The next question comes from Rich Law from Goldman Sachs. [Operator Instructions] Your next question comes from the line of Prakhar Agrawal from Cantor.

Congrats on the strong data. Maybe just first -- I had a couple. So first question on the baseline, if you can compare and contrast the baseline in this population versus maybe what has been seen with rusfertide in Phase I and Phase III? And then I had a follow-up.

Phase I. So again, as I mentioned, these are patients that are phlebotomy dependent. They could be on background therapy. They could be only maintained on phlebotomies, but -- and they could either be high- or low-risk with regards to their profile. And of course, that depends on age and the history of thromboembolic events. So I would suggest it's a rather typical population as have been enrolled in other trials, including the rusfertide trial. But the bottom line is we'll reveal those details in an upcoming research meeting. I will tell you, as is typical, you have a predominance of males, and the age of the patients roughly are in the 50s on average. So, a very typical population of patients with polycythemia vera.

Got it. And maybe on the safety profile, you said 2 cases of grade 1 anemia. If you can elaborate on what doses were these patients on and maybe the nature of the anemia events? And if you can just elaborate on the broader safety profile as well because that's something that we have gotten a lot of questions on, injection reactions, the rate versus Phase I, as well as thrombocytosis or platelet count increases versus Phase I. Even qualitative comments would be very helpful.

Yes. So I'll give some general comments on this, and we're going to share more of those details as we mentioned in our research presentation. But the bottom line is we did see a modest elevation in platelets as would be expected. Remember, that is typical of hepcidin-directed therapy where you're restricting iron to the bone marrow. You'll have a reactive thrombocytosis. It's not unlike what we reported in Phase I, and I believe it's similar to what has been reported in other studies. So that's very typical. That was not considered a concern. With regard to WBCs, which is another thing you keep a good eye on, there was no change there. And again, that was very similar to our Phase I data. With regard to ISRs, or low rate of ISRs, we haven't shared the exact figure, but low rate, all of them self-limiting and Grade 1. So very manageable. And again, very similar to what we experienced in Phase I. With regard to the anemias, and keep in mind, patients who -- excuse me, the physicians who are treating patients with polycythemia vera, particularly those patients who are phlebotomy-dependent are used to seeing out-of-range values at baseline. So very frequently, these patients come in already with out-of-range values with regard to hemoglobin, for instance. So the physicians are very comfortable managing that. And I think that might contribute to the fact that we only had 2 cases. None of them -- neither of them were symptomatic and both were Grade 1. They happen to be in the Q6 arm. So I think that's what I can generally say is the safety and tolerability very similar to what we've highlighted and shared from the Phase I study. And we'll share more of that data, as I mentioned, in research presentations coming up.

We will take our next question and the question comes from the line of Patrick Trucchio from H.C. Wainwright & Co.

Congrats on the data. My first question is just in terms of the onset. I was wondering how quickly divesiran separated from placebo. And then as it relates to the secondary endpoints, specifically on symptoms, can you give us a little bit more detail on the improvement in symptoms and just the importance of improvement on symptoms in this indication?