Silence Therapeutics - Earnings Call - Q4 2024

Executive Summary

• Silence Therapeutics reported FY 2024 financials alongside its Q4 2024 update and extended cash runway guidance into 2027 after deciding to initiate zerlasiran’s Phase 3 CV outcomes trial only with a partner in place, prioritizing divesiran in PV and rare disease programs.
• FY 2024 collaboration revenue rose to $43.3M, net loss narrowed to $45.3M, and year-end liquidity reached $147.3M (cash, cash equivalents, and short-term investments), underpinning the runway extension and program prioritization.
• Clinical execution remained strong: zerlasiran Phase 2 ALPACAR-360 showed >80% mean time-averaged Lp(a) reduction with durability and good tolerability; divesiran Phase 1 in PV reduced phlebotomy frequency and lowered hematocrit with favorable safety, with Phase 2 enrollment underway and full enrollment anticipated by YE 2025.
• Key catalyst and stock narrative driver: partnership timing/terms for zerlasiran Phase 3 and continued PV data flow; management emphasized active partnering dialogue and cash discipline while maintaining confidence in zerlasiran’s competitive profile.

What Went Well and What Went Wrong

What Went Well

• Divesiran Phase 1 in PV demonstrated elimination of phlebotomy in well-controlled patients, reductions in hematocrit across cohorts, physiologic hepcidin increases, and favorable safety; Phase 2 dosing initiated and enrollment expected to complete in 2025 (“we anticipate full enrollment … by the end of this year”).
• Zerlasiran Phase 2 ALPACAR-360 produced >80% mean time-averaged Lp(a) reductions over 36 weeks, >90% maximum reductions, with effects persisting at 60 weeks and good tolerability (“no safety concerns emerged with infrequent dosing”).
• FY 2024 revenue growth and narrowed net loss versus FY 2023, supported by cumulative catch-up under collaborations and disciplined cash management; year-end cash and short-term investments of $147.3M.

What Went Wrong

• Decision to defer zerlasiran Phase 3 initiation until a partner is secured delays the program timeline versus earlier expectations; Phase 3 start now explicitly “dependent on partnership”.
• Quarterly collaboration revenue variability persisted; Q3 2024 revenue declined to £1.1M from £2.8M YoY with cost of sales exceeding revenue in the quarter (timing of milestones and project progression).
• Hansoh opted not to pursue further development under the collaboration, eliminating expected future Hansoh revenue streams; SLN retains rights and is evaluating next steps.

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the Silence Therapeutics fourth quarter and full year 2024 conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Jim Hopkins, Head of Investor Relations and Corporate Communications. Please go ahead.

Gem Hopkins (VP of Investor Relations and Corporate Communications)

Good morning and good afternoon, everyone. Thank you for joining us today. My name is Jim Hopkins, Vice President of Investor Relations and Corporate Communications at Silence. Joining me on today's call are Craig Tooman, our President and CEO, who will provide an update on the business; Rhonda Helms, our Chief Financial Officer, who will review our financial performance; and Steven Romano, our Chief R&D Officer, who will provide a clinical update. For those of you participating via conference call, the accompanying slides can be accessed by going to the investor section of our corporate website at www.silence-therapeutics.com.

I'd like to remind you that during today's call, management will make projections or other forward-looking statements regarding anticipated future events or the future financial performance of the company, including clinical development, timing and objectives, the therapeutic potential of our product candidates, our operational plans and strategies, anticipated milestone payments, anticipated operating and capital expenditures, business prospects, and projected cash runway. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC and any future filings. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Craig. Craig.

Craig Tooman (President and CEO)

Thank you, Jim, and thanks to everyone for joining today's webcast. I'm pleased to be with you today to discuss our 2024 full year performance and share some color on what's ahead for the company. I'll start by quickly touching on a few key highlights about our full year performance. Starting with zerlasiran, our siRNA for high Lp(a); the ALPACAR-360 Phase II study of zerlasiran in ASCVD patients with high Lp(a) delivered positive results that were featured in a Late Breaker at AHA and published in JAMA. The study showed Lp(a) reductions exceeded 90%, effects were durable, and zerlasiran was observed to be well tolerated. These data support a competitive profile that we believe can be further defined in phase III. The Silence team, supported by top cardiologists, have done an outstanding job designing what we are confident is a highly differentiated phase III program for zerlasiran.

We recently met with global regulatory agencies on the design and received very positive feedback across the board. The Silence team has also been successfully executing on core readiness activities for phase III development, including manufacturing readiness. Turning to divasteron, our first-in-class siRNA for polycythemia vera. The SANRECO Phase I study of divasteron delivered positive results that exceeded our expectations. Data were highlighted at ASH and showed divasteron completely eliminated the need for phlebotomy in all well-controlled patients. The safety and tolerability profile continues to look very favorable. In addition, we started dosing patients in the SANRECO Phase II study, and the European Commission granted divasteron orphan drug designation for PV. As a reminder, divasteron also has FDA fast track and orphan drug designations for PV.

In terms of other pipeline advancements, we are pleased to have our third siRNA from our mRNAi GOLD platform enter the clinic in 2024 under our AstraZeneca collaboration. We value this partnership very much and are proud of the program we were able to advance together. We look forward to its further progress and the potential to earn additional milestones. We also progressed several preclinical siRNA candidates for hepatic targets. Turning to slide five and what's next for our company. This morning, we announced that in 2025, we are prioritizing investment in programs targeting rare conditions where we believe we can deliver on clear unmet needs with first-in-class and/or best-in-class siRNAs. Divesiran is a great example of that. We remain confident in our zerlasiran program for high Lp(a) and believe we have very differentiated design for our phase III program.

However, today, we are making clear that we will only initiate the Phase III outcome study once a partner is secured. This strengthens our cash position into 2027 and gives us flexibility to invest in our innovative pipeline while we continue partnering discussions for zerlasiran. We have listened very carefully to our shareholders and made this decision with our collective feedback in mind. I want to reiterate that we continue to believe strongly in zerlasiran's potential. There are very few cardiovascular assets in development that aim to treat an unmet medical condition as large as the Lp(a) opportunity. We are hopeful we will secure the right partner to bring this very promising program forward. Until a partner is secured, we do not plan to provide any further updates.

Turning now to Divasteron, we announced this morning that we completed follow-up in the phase I portion of San Rico this month and look forward to presenting more data from that study at medical meetings this year. The outstanding data from the San Rico Phase I study have generated a lot of excitement from the medical community and patients who want to be involved with the program. In fact, we also announced this morning that we anticipate full enrollment in the San Rico Phase II study by the end of this year. While we are currently focused on the PV indication for Divasteron, we continue to believe it has broader therapeutic potential. Given the outstanding PV results we have seen in phase I, we are planning an investor event later this year and look forward to discussing the program in more detail then.

In addition to Divasteron, we were pleased to announce today that we plan to start a phase I study of SLN548, our wholly owned siRNA targeting complement factor B, in the second half of this year. Steve will go into a bit more detail on this in a few minutes. In terms of what's next for our mRNAi GOLD platform, we have multiple undisclosed programs that have generated encouraging preclinical data. This includes the three targets that we've retained global rights to following the conclusion of the Hansoh Pharma collaboration we announced this morning. We are evaluating these programs as part of our broader portfolio and will determine which ones we want to bring forward ourselves or potentially partner. As I mentioned, we will be prioritizing targets in rare conditions where we believe we can deliver valuable competitive profiles to address patient needs.

In addition, we plan to invest selectively in our extrahepatic work, where we are seeing promising early data for programs targeting multiple cell types. We look forward to sharing more as we move ahead and these data mature. With that, I will now turn the call over to Rhonda to review our 2024 financial performance and guidance for 2025. Rhonda.

Rhonda Hellums (CFO)

Thank you, Craig. First, I would like to point out that effective January 1 of 2025, Silence has transitioned from a foreign private issuer to a U.S. domestic issuer, which requires us to comply with the U.S. domestic reporting requirements under the Exchange Act. We are now required to file periodic reports and registration statements on U.S. domestic issuer forms with the SEC in accordance with U.S. GAAP as opposed to IFRS and in U.S. dollars versus British pounds. Now let me turn to the financials. For the year ended December 31, 2024, the company recorded $43.3 million in revenues versus $31.6 million in 2023. The increase of $11.7 million is largely due to the collaboration arrangements we have entered for development of candidates utilizing our mRNAi GOLD platform.

As Craig mentioned, our AstraZeneca collaboration continues to advance nicely, and we are hopeful that this program will continue to move forward and allow us to receive additional milestones. Turning to the Hansoh Pharma collaboration, we announced this morning that Hansoh opted not to pursue further development under our collaboration. As a reminder, this was a collaboration to develop siRNAs using our Gold platform for three undisclosed preclinical liver targets. Hansoh formerly had options to license China region rights on two of the targets and global rights on the third target. As a reminder, we record revenue from our collaborations based on percentage of contract completion. Therefore, in 2024, we recognized $24.6 million resulting from a cumulative catch-up following the completion of all required obligations to Hansoh under the collaboration. Finally, during 2024, we recorded the remaining royalty revenue from an Alnylam of approximately $144,000.

The expenses related to our partner programs, including the portion of our employees' time dedicated to these programs, are recorded as cost of sales as they are attributable to the revenues. These expenses were $11.8 million in 2024 compared to $12.9 million in 2023. As expected, R&D costs rose in 2024 to $67.9 million versus $56.9 million in 2023. This increase was primarily due to advancing our proprietary zerlasiran and divesiran programs, which Craig previously mentioned. We also strategically invested in further development of our platform and identifying new targets to further expand our proprietary pipeline. General and administrative costs were $26.9 million in 2024 versus $26.2 million in 2023. The increase was primarily as a result of additional legal and accounting expenses required to transition to filing as a U.S. domestic issuer, including our transition to U.S. GAAP.

The company's net operating loss for the full year of 2024 was approximately $63.3 million versus $64.4 million in 2023. The decrease in our net loss is due to the increase in revenue, partially offset by the increase in R&D costs as a result of advancing our programs in clinical development. We reported other income of approximately $4.5 million, which largely represents the accretion of our U.S. Treasury bills compared to $1.8 million in 2023. We also reported approximately $13.7 million from the benefit of our R&D tax credit in the U.K. compared to $11.9 million in 2023. The company's net loss for the full year of 2024 was approximately $45.3 million versus $54.2 million in 2023. The company's cash, cash equivalents, and short-term investments were $147.3 million at the end of December of 2024. This includes cash and cash equivalents of $121.3 million and short-term investments of $26 million.

Turning to slide eight and the 2025 cash guidance. As Craig mentioned, we have made the decision only to initiate the zerlasiran Phase III outcome study once we have secured a partner. This allows us to extend our projected runway into 2027. I'll echo Craig's comments that we are prioritizing programs targeting rare conditions where we see the opportunity to deliver on clear unmet needs with innovative siRNA therapies. This includes divesiran for PV, which remains a top priority. In addition, we look forward to advancing additional programs in our pipeline, including our extrahepatic work. With that, I'll turn the call over to Steve for a clinical update. Steve?

Steven Romano (Chief R&D Officer)

Thanks, Rhonda. As Craig mentioned, we made great progress advancing divasteron, a first-in-class siRNA for PV in 2024. The San Rico phase I results were impressive and have garnered enthusiasm for the program. The phase II study is enrolling very nicely, and as Craig mentioned, we anticipate full enrollment by the end of this year. As a reminder, PV is a rare myeloproliferative neoplasm, a type of blood cancer, that is associated with erythrocytosis or an increase in the production of red blood cells. Other blood cell types, including WBCs and platelets, may also be increased. The increase in RBC mass corresponding to a substantial elevation of hematocrit leads to a higher incidence of thrombotic or clotting events and an increase in adverse CV outcomes.

PV is associated with a range of burdensome symptoms, including fatigue, cognitive disturbance, and pruritus, and additionally, longer term can transform to myelofibrosis and acute myeloid leukemia. PV impacts around 150,000 individuals in the U.S. and 3.5 million worldwide. The aim of the treatment is to maintain hematocrit less than 45%, a level that is associated with a reduced incidence of thrombosis and CV-associated death. Treatment usually requires routine phlebotomy along with a low-dose aspirin. Many patients, regardless of risk level, require the addition of cytoreductive agents to ensure achievement of treatment goals. Phlebotomy, while helpful, is time-consuming, may not maintain patients at safer hematocrit levels consistently, and can contribute to iron deficiency and overall symptom burden. At the bottom of this slide, we have a quote from Nona, who is living with PV.

She says, "The PV aspect means that you have to have phlebotomies regularly, and I think the most crippling thing about that is the fatigue." We are hopeful, based on the San Rico phase I data, that Divasteron has the potential to greatly reduce and even eliminate the need for phlebotomy. Turning to slide 12 in Divasteron, a first-in-class siRNA for PV, I'll quickly review how Divasteron works for those less familiar. TMPRSS6 is a negative regulator of hepcidin, the body's master regulator of iron metabolism, including its absorption, distribution, and storage. The therapeutic hypothesis for the use of Divasteron in PV patients is the following. By silencing TMPRSS6, hepcidin production and release by liver hepatocytes will increase, leading to the restriction of iron to the bone marrow and thus reducing the excessive production of red blood cells, a process dependent on availability of iron.

Turning to the San Rico phase I study, the design was open label with three cohorts and enrolled 21 PV patients. We tested doses of 3, 6, and 9 milligrams per kilogram, consisting of 6, 8, and 7 patients, respectively. All patients were scheduled to receive four doses at six-week intervals and then were followed for 16 additional weeks for a combined total of 34 weeks of treatment and follow-up. Key inclusion criteria for the trial subjects included a diagnosis of PV based on WHO criteria and a history of requiring a minimum of three phlebotomies in the previous six months or five phlebotomies in the previous 12 months. Patients on stable doses of cytoreductive agents were allowed, and given the exploratory nature of the phase I study, both well-controlled patients, that is, those with hematocrits 45% or less, and those less well-controlled with hematocrits greater than 45% were included.

As Craig mentioned, all patients completed the follow-up period this month, and the phase I study is now complete. The data slides I'm about to show you are from the ASH presentation in December and include 19 PV patients with a combined history of 79 phlebotomies in the six months prior to enrollment. You can see historic phlebotomy details are in orange shades to the left of center and capture all events up to day one, the time of the first dose administration. To the right of center, in blue shades, are any phlebotomies recorded during the trial, both the treatment period as well as the follow-up period. No patients entering the trial with well-controlled hematocrit levels required a phlebotomy. In other words, 100% of this group maintained adequate control of hematocrit as per treatment guidelines. Only five phlebotomies occurred during the treatment period.

All were in patients who entered the study with high baseline hematocrit levels, those over 45%. Two phlebotomies occurred in the 16-week follow-up period following the last administered dose. In fact, no patient with a hematocrit less than 50 at baseline required a phlebotomy during the treatment period. These data are very promising. Given the fact that we included a range of patients in this trial, regardless of baseline hematocrit, it's important to evaluate the effect of Divasteron on both well-controlled patients, again, those with hematocrit levels less than or equal to 45%, as well as those with high baseline hematocrit levels. You can see here that Divasteron reduced hematocrit levels in all patients, regardless of baseline levels. Divasteron also demonstrated robust target engagement. You can see here we observed early and sustained hepcidin elevations. Importantly, these elevations are within the physiologic range of hepcidin levels.

Importantly, Divasteron was safe, well-tolerated at all doses tested. The majority of treatment emergent adverse events were mild, none over grade 2. There were no treatment-related serious adverse events or TEAEs leading to discontinuation. In summary, the phase I data showed that Divasteron eliminated the need for phlebotomy in all well-controlled patients, lowered hematocrit levels in all patients regardless of baseline levels, and the safety tolerability profile continues to look very favorable. We look forward to presenting additional phase I data at medical congresses this year. Here's a high-level look at the design for the ongoing phase II portion of San Rico. This is a randomized double-blind study evaluating Divasteron in up to 40 PV patients. Unlike the phase I, where we allowed patients to enter with a range of baseline hematocrit levels, all patients entering the phase II will have hematocrit level below 45%.

The study is 36 weeks, and we are assessing two different dose levels and regimens. The primary endpoint is the % of patients with hematocrit at or below 45% without the need for phlebotomies. We will also be assessing the effect of Divasteron in improving PV-related symptoms. As we mentioned, the study is enrolling nicely, and we anticipate full enrollment by the end of this year. Turning now to SLN548, our wholly owned siRNA targeting complement factor B. The complement system is a critical component of the innate immune system and is made up of several dozen liver-derived proteins and protein fragments. It complements the ability of antibodies and phagocytic cells to rid the body of foreign microbes as well as help clear cellular debris, including damaged cells. It plays an important role in inflammation.

There are three distinct biochemical pathways that can lead to activation of the complement cascade and include the classical, alternative, and lectin pathways. Importantly, both deficiencies and overactivation of the complement system play a role in a broad range of conditions with immune components. Given the complexity of the complement system pathways and large number of proteins involved, there are a plethora of potential targets for therapeutic intervention. SLN548 is an siRNA targeting complement factor B and could potentially play a therapeutic role in conditions associated with overactivation of this pathway, including complement-mediated renal diseases, among others. The long-acting profile of our mRNAi GOLD platform compounds could allow for the development of an infrequently dosed therapeutic option. We're excited to advance this compound into a first-in-human study in healthy volunteers later this year. This slide is a brief summary of the phase I study design.

It is a randomized double-blind, placebo-controlled, single-ascending dose study that plans to enroll up to 32 healthy volunteers across four dose cohorts. The primary objective is to evaluate the safety and tolerability of SLN548 in healthy subjects, as well as the pharmacokinetic and pharmacodynamic profile. It incorporates sentinel dosing, and all patients will be vaccinated and receive prophylactic antibiotics as appropriate. We look forward to sharing more details about this program, including our development strategy at a future time. As Craig mentioned, we anticipate starting the study in the second half of this year. With that, I'll turn the call back over to Craig.

Craig Tooman (President and CEO)

Thanks, Steve. In summary, our decision to only initiate the phase III outcome study of zerlasiran once we've secured a partner extends our projected cash runway into 2027. This gives us flexibility to invest in our innovative pipeline while we continue partnering discussions. We remain confident in zerlasiran and will provide an update when there is one. On this slide, you can see our anticipated clinical milestones for 2025. For divesiran, we completed follow-up in the phase I San Rico study this month and will present additional data at the medical meetings this year. We anticipate full enrollment in the phase II San Rico PV study by year-end. We are also planning to host a divesiran-focused event later this year, so stay tuned for more information on that. For SLN548, we are planning to start the phase I study in healthy volunteers in the second half of this year.

We're also looking forward to progressing our extrahepatic work and sharing these data at the appropriate time. The Silence team remains very, very focused on executing to deliver life-changing siRNA therapies to patients in need. With that, I'll pass back over to the operator for your questions.

Operator (participant)

Thank you. At this time, we'll conduct the question-and-answer session. As a reminder to ask a question, you'll need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Mike Wilson on Morgan Stanley. Your line is now open.

Kostas Biliouris (Analyst)

Good morning, and thanks for taking the question. Maybe just one focused on zerlasiran. I guess to the extent you can, if you could provide some color on partnership discussions, and then just how important is the Horizon data to those discussions, which we're expecting, I guess, first half of next year now, and then maybe secondly, just talk about some of the types of partnership structures you're considering. Thanks.

Craig Tooman (President and CEO)

Thanks, Mike. We're not going to comment specifically on ongoing partnership discussions today, but it is interesting to note that since the recent shift in the timing of the Horizon readout, companies, including Novartis, have pledged more funding for Lp(a) studies. Interesting phenomenon. Look, we're not a one-product company. We've got a portfolio of assets with great potential, and as you know, Divasteron is a great example of that. It is a fine balance to kind of manage the resources amongst the products, and we want to make sure we get the best returns. Thus are our announcements today. Silence has really done an excellent job. I'd give us all, the team, all full credit for getting Zerlasiran to this point, which is designing this highly differentiated phase III program.

We continue to believe in its high-value potential, very competitive profile, substantial market potential that we've talked about on multiple occasions. We are actively engaged, so I will say that. We remain actively engaged in partnering discussions and hopefully will be able to secure the right partner to bring this very promising program forward, both in development and commercially. I won't say more on that, but we will update you if there's something to update you on regarding a partner.

Kostas Biliouris (Analyst)

Great. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Kostas Biliouris of BMO Capital Markets. Your line is now open.

Kostas Biliouris (Analyst)

Hello, everyone. Good morning. Thanks for taking our questions. Maybe one question on zerlasiran and one on divesiran from us. How ready are you for the phase III trial? Specifically, from the time you secure a partner, how fast do you think you can start the phase III? Will the partner be able to potentially make changes to the phase III design, or do you think the phase III design is set and the partner needs to kind of agree to that? The second question on divesiran is, would you consider evaluating divesiran in hereditary hemochromatosis given the relevance of the target there? Thank you.

Craig Tooman (President and CEO)

We are in a logistical phase. We're wrapping up phase III readiness activities, which are on track to complete by mid-year. We're in a little bit of a period where we can make some fine-tuning if we needed to do that with a partner, but we've advanced very, very nicely across the team in order to be prepared, including, as I mentioned, manufacturing preparedness, which is very important. There is some time, a bit of time, before the track that we had outlined before really gets more fixed, if you will. In terms of HH, Steve, do you want to comment on HH?

Steven Romano (Chief R&D Officer)

Yeah, sure, Kostas. Yes, we're certainly obviously focused on the PV program and executing that, but we do know because of our mechanism that it applies actually across a fairly broad range of conditions where hepcidin may play a role or manipulating the hepcidin pathway may play a role therapeutically. We're looking at that. HH is one of those, of course. We haven't declared any additional work specifically with regards to trial work, but we're examining the opportunity to expand our program.

Kostas Biliouris (Analyst)

Thanks very much.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Richard Law of Goldman Sachs. Your line is now open.

Kostas Biliouris (Analyst)

Thanks. Good morning, everyone. A couple of questions for me. What is the goal for Divasteron regarding differentiation? Can you differentiate clinically from Rusfertide besides dosing frequency? Also, what are the biggest hurdles that you see for partnering zerlasiran? Thanks.

Craig Tooman (President and CEO)

Steve, do you want to take differentiation, Divasteron?

Steven Romano (Chief R&D Officer)

Yeah. First of all, we want to be the first siRNA to the market for PV, so we're very excited about that opportunity. Clearly, and I wouldn't minimize it, one of the major differentiations, of course, is going to be the infrequency of dosing. In fact, as I mentioned, as we move forward into completion of the phase II, we may have an idea of an even less frequently dosed regimen versus what we evaluated in phase I. The other things we'll look for, obviously, are symptomatic improvement, etc. We'll look across the range of important dimensions to measure outcome in this disease. Until that work is done, it's hard to say what point of differentiation or points of differentiation will be available.

The bottom line is the convenience factor is going to be a very important one, and we hope that that long-term effect could have an impact on the likelihood that patients maintain hematocrit at levels that are safe and below 45% consistently. More to come on that as the profile of the drug is known.

Craig Tooman (President and CEO)

In terms of partnering and hurdles, really no single item for the parties. It's different for every one that we've had dialogue with. The dialogues do tend to be a little bit around the notion of business strategy and recognition and intrigue in the very large market opportunity. We remain very confident in the program as we've discussed. The dialogues continue, and we will pursue that. As you know, partnerships often don't really happen on a clock. It involves coincidence and needs and timing amongst the parties, but we are very active, I can tell you that. Thank you for the question.

Kostas Biliouris (Analyst)

Yeah, thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Keay Nakae of Chardan. Your line is now open.

Keay Nakae (Director of Research and a Senior Research Analyst)

Yeah, thanks. Question about the candidates being developed for Hansoh. Is there anything there worth continuing to pursue on your own, or how do we view the status of that?

Craig Tooman (President and CEO)

Yes, thank you. We're very interested in the programs that we have been developing in that productive partnership. We have seen and continue to see encouraging preclinical data in each of the programs. Now we will actually retrieve those programs and have the opportunity either to develop them ourselves or potentially partner or license. It actually gives us the control to determine what we want to do with those, but obviously in a context of having good data. I don't know, Rhonda, if you want to reiterate a little bit of the financials on that because it's not abundantly clear, perhaps.

Rhonda Hellums (CFO)

Yeah, sure. As I mentioned, the revenue did show the cumulative catch-up. Because we have no further obligations in our collaboration, all the original upfront milestones are basically recognized at the end of the year. We do not anticipate further from Hansoh. However, we will continue to have revenue from AstraZeneca as that program continues. All the other additional new targets from the AstraZeneca collaboration could potentially add some revenue to that as well.

Keay Nakae (Director of Research and a Senior Research Analyst)

Okay, thank you.

Operator (participant)

Thank you. One moment for our next question. Again, as a reminder to ask a question, you'll need to press star one one on your telephone. Our next question comes from the line of Myles Minter of William Blair. Your line is now open.

Myles Minter (Biotech Equity Research Analyst)

Hi, everyone. Thanks for taking the questions. First one on zerlasiran. Just in your regulatory discussions, did you actually propose a dose to take forward into that phase III? I know you said 300 milligrams previously, but you have not associated a frequency with that. That's the first one. Second is I take a lot of questions about how a 5-10 sort of nanomole per liter increase in hepcidin that you get with divesiran actually confers the efficacy you're seeing when Rusfertide theoretically gets much higher than that. Maybe you can talk about the difference between the endogenous trigger that you're getting with TMPRSS6 inhibition and maybe the safety ramifications between that and giving a hepcidin mimetic in PV. That would be helpful. Thanks very much.

Craig Tooman (President and CEO)

Steve, both of those for you.

Steven Romano (Chief R&D Officer)

Yeah, yeah. The question is with regards to the differences in a way of intervening on the pathway, the hepcidin pathway. Yes, obviously, Rusfertide is an exogenously administered hormone. Naturally, it's not a surprise that you typically get larger exposures based on that. Ours is manipulating the pathophysiology, the underlying physiology, and increasing the internal production of hepcidin. It's less important, the level, as we've already learned in phase I, than the correlation with that increase on clinical benefit.

What we see very clearly, as we've shown you, is with that increase in hepcidin within the physiological range, which, by the way, is 20-40-fold higher than the baseline of these patients who come in in our phase I study with very low levels of hepcidin, is corresponding, it appears, or correlating with robust outcome, which is a reduction in the need for phlebotomy and the maintenance of hematocrit. That is very, very clear that we're getting the intended effect clinically, which is, in fact, the registrable endpoints for this program and other programs. We're doing that by increasing hepcidin within levels of the physiological range, but much above the baselines. I think that's very important.

Craig Tooman (President and CEO)

In terms of the dose frequency and the agency deliberations.

Steven Romano (Chief R&D Officer)

Yeah, but I should also add that the safety, because you asked about safety, and you cannot really comment comparatively on safety until you actually conduct your program. Even then, it's going to be cross-program comparisons. We want to be very careful about that. Clearly, our compound is very safe. What we're seeing in phase I and what we're beginning to see in phase II is a very safe profile. Okay. With regards to the interactions with the agency around, I think the question was around zerlasiran, and we have talked to the agency naturally about what we believe is the reasonable dose, or I should say the optimal dose and frequency. This is a very competitive space, so we're not sharing that information at this point.

Obviously, when you talk to regulators about a phase III program, you need to be pretty confident about the decisions you're making. I'll leave it at that.

Craig Tooman (President and CEO)

It also further advised, obviously, our phase III planning and design. Thank you.

Myles Minter (Biotech Equity Research Analyst)

Makes sense.

Steven Romano (Chief R&D Officer)

Thanks for the questions.

Myles Minter (Biotech Equity Research Analyst)

Thank you.

Operator (participant)

Thank you. Thank you. I'm showing no further questions at this time. I'll now like to turn it back to Craig Tooman for closing remarks.

Craig Tooman (President and CEO)

Just want to thank you all for joining us on today's call. We really look forward to keeping you updated on our progress. Very excited about the opportunities in front of us, and have a great day.

Operator (participant)

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.