Apellis Pharmaceuticals, Inc. (APLS) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Apellis Pharmaceuticals Fourth Quarter and Full Year 2024 Earnings Conference Call. [Operator Instructions]. After the speaker's presentation, there will be a question-and-answer session. [Operator Instructions]. Please be advised that today's conference is being recorded. I would now like to turn the call over to Meredith Kaya, Senior Vice President, Investor Relations and Strategic Finance. Please go ahead.

Good morning, and thank you for joining us to discuss the Apellis Fourth Quarter and Full Year 2024 Financial Results. With me on the call are Co-Founder and Chief Executive Officer, Dr. Cedric Francois; Executive Vice President of Commercial, David Acheson; Chief Medical Officer, Dr. Caroline Baumal; and Chief Financial Officer, Tim Sullivan. Before we begin, let me point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. Now I'll turn the call over to Cedric.

Thank you, Meredith, and thank you all for joining us this morning. As we close out another year, I would like to recognize the progress our team has made. We achieved important milestones in 2024, strengthening our business while navigating some headwinds along the way. SYFOVRE generated over 120% year-over-year U.S. net revenue growth. We presented positive Phase III VALIANT data with EMPAVELI in C3G and IC-MPGN. We advanced our earlier-stage pipeline and we fortified our financial position. Looking ahead, our strategy is focused on 3 key pillars: first, to transform the treatment of geographic atrophy with SYFOVRE. Second, to maximize EMPAVELI's impact in rare diseases. And third, to advance our innovative pipeline, leveraging our expertise in complement science. Starting with pillar #1, SYFOVRE is the market-leading treatment for geographic atrophy in the U.S. with more than 510,000 injections administered through December. Recent regulatory developments within the competitive landscape confirm our view that SYFOVRE is the leading treatment for GA. SYFOVRE's unmatched prescribing label, which includes increasing effects over time and flexible dosing will enable us to further strengthen SYFOVRE's market leadership over time. SYFOVRE has generated nearly $900 million in sales in less than 2 years, making this one of the most successful launches in recent history. With only 2 approved treatment options available and no new competitors on the horizon, we are in a strong position. Our 2 key priorities heading into the rest of 2025 are to secure SYFOVRE's leadership and to grow the overall GA market. We are still in the early phases of growth and estimate that only half of diagnosed GA patients are seen by an eye care professional. Of those less than 10% are receiving treatment. Building a new market takes time, but we have the right products, strategy and team to execute. The U.S. is our primary commercial focus for SYFOVRE, but we will continue to explore select international markets. We were pleased to receive approval from the Therapeutic Goods Administration in Australia last month and our regulatory review in Switzerland is ongoing. As we continue to focus our efforts on the SYFOVRE launch, we are also working to develop the next-generation treatment for GA. To do this, we are combining SYFOVRE and APL-3007, our siRNA. This approach is designed to comprehensively block complement activity in the retina as well as the choroid through local and systemic C3 inhibition. We plan to initiate a Phase II trial in the second quarter. Shifting gears then to our second pillar. Maximizing the impact of EMPAVELI in rare diseases. EMPAVELI continues to elevate the standard of care in PNH. We also look forward to becoming a theater in nephrology starting with the anticipated launch of EMPAVELI in C3G and primary IC-MPGN. We recently filed the supplemental NDA for EMPAVELI based on the positive Phase III VALIANT data. These results hit the trifecta with unprecedented reductions in proteinuria, significant clearance of C3 deposits and stabilization of eGFR. Even more compelling was that these results were consistent regardless of disease types, transplant status or age. If approved, we expect to launch in the second half of 2025. Our partner, Sobi recently received validation of its application, putting them one step closer to making this life-changing treatment available to patients in the EU. The second half of 2025, we are also planning to initiate Phase III trials for EMPAVELI in 2 new nephrology indications, focal segment to glomerulosclerosis and delayed graft function. Lastly, our third pillar, our innovative pipeline. We are excited to be advancing the first-ever gene editing approach, targeting the neonatal Fc gamma receptor with our partner Beam Therapeutics. We look forward to sharing more about this program and our broader emerging pipeline with all of you soon. We are excited about the future of Apellis. We have 2 potential blockbuster products with SYFOVRE and EMPAVELI, a robust development pipeline of clinical and preclinical programs and a clear path to profitability. I will now turn the call over to David Acheson, our new Executive Vice President of Commercial. I'm sure many of you are familiar with David from previous earnings calls at the investor events, and we are thrilled that he is now leading our commercial organization. David?

Thank you, Cedric, and good morning, everyone. Let me start with SYFOVRE. With over 510,000 injections administered and nearly $900 million in net sales, SYFOVRE has had a remarkable launch. Our focus going forward is to both strengthen our leadership position and grow the overall market. The recent regulatory update from our competitor provides us more confidence than ever in the strength of SYFOVRE's differentiated profile. Three things that now are very clear. SYFOVRE has consistently demonstrated robust and increasing effects over time. SYFOVRE is the only GA product approved for as few as 6 doses per year and SYFOVRE is the only product in a preferred position with many payers. In the fourth quarter, SYFOVRE maintained its market leadership with approximately 94,000 doses delivered to physician offices, including 89,000 commercial doses and 4,600 samples. Total market share remained stable at over 60% and new patient share trended positively, ending the year approaching 50%. As of December, there are more than 2,300 sites of care that have ordered SYFOVRE. SYFOVRE's fundamentals remained strong. In the first 2 months of 2025, we are seeing continued growth in the number of SYFOVRE injections administered which is the true measurement of demand. There are, however, a few temporary factors expected to affect orders of commercial vials and net revenue in the first quarter. First, the overall GA market growth in the quarter has been tempered due to typical Q1 dynamics like Medicare reverifications and winter storms affecting distribution and patient visits. And second, we have also seen a spike in sample usage over the past 2 months. We believe retina specialists are using more samples because of a reported funding gap at non-for-profit co-pay assistant organizations. We estimate there could be 5,000 or more incremental samples used in this quarter as compared to the average quarterly sample volume in 2024. The momentum we are seeing in injection demand to date sets the stage for continued growth in 2025 and beyond. Maximizing the GA opportunity will require a long-term and strategic approach. We need to make sure each patient has access to a retina specialist who can treat them. We need higher utilization from those physicians who are already treating patients with SYFOVRE as well as adoption by retina specialists who may have initially been hesitant to utilize GA treatments. And we must continue to further strengthen our formulary positions, being the only GA products with preferred status provides a significant competitive advantage. We're executing across key initiatives to achieve these goals, including broadening our reach to the eye care community, amplifying real-world data through key forums, educating payers on SYFOVRE's differentiated value proposition and connecting with patients through our DTC campaign. We recently launched Phase 2 of our DTC campaign featuring Henry Winkler. This campaign focuses on increasing awareness of GA and SYFOVRE and ensuring GA patients are able to connect to a retina specialist who can treat them. Now let me shift to EMPAVELI. The commercial and medical teams are ramping up their efforts in anticipation of EMPAVELI's potential label expansion into C3G and IC-MPGN later this year. We are in the process of hiring our field-based team which will allow us to hit the ground running and make a significant impact in the early phases of the launch. Ahead of approval, we are executing several prelaunch activities focusing on disease state awareness. These include participation in key nephrology conferences, building relationships with key physician accounts, KOL and payer engagement and patient education. These activities maximize the likelihood of a successful launch in C3G and IC-MPGN. They also reinforce our commitment to rare nephrology with our programs in DGF and FSGS. The commercial opportunity is significant with an estimated 5,000 C3G and IC-MPGN patients in the U.S. EMPAVELI is the only drug to be studied in a broad patient population. Given the strength of the Phase III data, we believe EMPAVELI will be used across all patient groups and disease severity. Physician feedback has been consistent that treatment choice will be based on efficacy over the route of administration given the severity of C3G and IC-MPGN. Many patients, even those with mild to moderate disease will eventually suffer kidney failure. In PNH, EMPAVELI generated approximately $23 million in U.S. net product revenue in the fourth quarter. Compliance rates remained high at 97%, and the safety profile remains consistent with our previous updates. We expect continued competitive pressure in 2025, but this should be more than offset by initial revenue generated from C3G and IC-MPGN. With that, I will now turn the call over to Caroline.

Thanks, David, and good morning, everyone. I'll start with SYFOVRE. We continue to see evidence supporting SYFOVRE strong efficacy and consistent benefit to GA patients over long periods of time. Earlier this month, we presented 48-month data from our GALE extension study that reinforce SYFOVRE's increasing effects over time. These data demonstrated that early treatment with SYFOVRE leads to preservation of retina tissue at magnitude of approximately 1.5 disc areas on average at 48 months in non-subfoveal GA patients dosed monthly. For context, 1.5 disc areas is the size of approximately 2 foveal areas, which is considered highly meaningful by retinal specialists. We are also beginning to see real-world evidence of the benefits of SYFOVRE treatment, an independent analysis of real-world data concluded that by month 9 of treatment, SYFOVRE reduced the annualized growth rate of GA by over 40%. Separately, another analysis of real-world data following SYFOVRE treatment showed stable visual acuity over multiple injections. While there are always limitations to independent analyses, these results add to the extensive clinical data set for SYFOVRE and strengthen confidence in its treatment benefit. As Cedric mentioned, we are also developing a next-generation treatment for GA. We believe combining SYFOVRE and our siRNA, APL-3007, may provide comprehensive complement blockade in the retina and in the choroid. Specifically, SYFOVRE inhibits complement in the retina and APL-3007 is intended to target systemic complement activity in the eye. With less C3 present in the eye following administration of APL-3007, there may be an even higher degree of efficacy contribution from SYFOVRE. Last month, we shared Phase I data with APL-3007 in healthy volunteers showing greater than 90% knockdown of C3 products as measured by the remaining levels of protein in the blood. We expect to initiate a Phase II study with SYFOVRE and APL-3007 in GA patients in the second quarter. Shifting to EMPAVELI. The Phase III VALIANT results provided further confidence in EMPAVELI's ability to control complement and provide a meaningful difference to patients with rare kidney diseases. Based on these data and the strong rationale for complement inhibition, we plan to initiate 2 pivotal studies with EMPAVELI in the second half of this year, one in primary focal segmental glomerulosclerosis or FSGS and one in delayed graft function, or DGF. The complement pathway plays a significant role in both diseases, and there are currently no FDA-approved therapies. FSGS is a rare kidney disease that causes scarring of the glomeruli. Similar to C3G and IC-MPGN, FSGS results in end-stage kidney disease within 5 to 10 years for approximately half of patients. There are an estimated 13,000 primary FSGS patients in the United States. DGF is a complication in kidney transplantation, where the transplanted kidney fails to function and typically requires dialysis within the first week of transplant. This negatively affects the long-term survival of the kidney and overall patient outcomes. In 2023, there were an estimated 21,000 transplants in the U.S. using deceased donor kidneys. DGF occurred in 30% to 35% of these transplants. FSGS and DGF were chosen due to their high unmet need, significant complement involvement and our ability to move directly into pivotal programs with potential approvals by 2030. Given our leadership and expertise and complement we are uniquely positioned to bring treatments to patients with these devastating diseases. I will now turn the call over to Tim for a review of the financials. Tim?

Thank you, Caroline. I will now provide an overview of our financials. Additional details are available in the press release that we issued earlier this morning. Total revenue for the fourth quarter of 2024 was approximately $213 million including $168 million in SYFOVRE and $23 million in EMPAVELI U.S. net product revenue. Total revenue for the full year 2024 was $781 million, a nearly 100% increase as compared to 2023. Turning to the rest of the P&L. For the fourth quarter, cost of sales was $40.9 million. R&D expenses were $76.4 million. SG&A expenses were $121.5 million, and we reported a net loss of $36.4 million. Regarding SYFOVRE, gross to net remained stable relative to the third quarter. We anticipate gross to net to be in the low to mid-20% range through 2025. We took a 1% price increase on January 1 that is intended to help offset some of the ASP erosion while managing customer reimbursement. We continue to execute against our strategy while maintaining financial discipline. We made strong progress from a financial perspective in 2024. As you can see on Slide 17, our total revenue in 2024 nearly matches our non-GAAP expenditure. With $411 million in cash and cash equivalents at the end of 2024, we remain confident in our financial position. We anticipate operating expenses in 2025 to be relatively stable compared to 2024. We expect our existing cash, combined with our future product sales to be sufficient to fund our core business to profitability. Now I hand the call back over to Cedric for closing remarks.

Thanks, Tim. We have started 2025 from a position of strength and are focused on building on the success of SYFOVRE preparing for our second commercial launch with EMPAVELI in C3G and IC-MPGN, progressing our pipeline and solidifying our financial position. By doing this, we remain confident in our ability to create significant value for patients and shareholders over the coming years.

[Operator Instructions] And our first question will be coming from Jon Miller of Evercore ISI.

Congrats on all the progress. One on EMPAVELI and the kidney indications, I guess, and then a quick follow-up on that. Obviously, your primary endpoint showed really great results with the spot test in uACR but the competitor had a 24-hour endpoint. I know you said in the past that you looked at 24 hours, but we haven't seen it yet. Do you plan on presenting that publicly? I assume it was included in the submission to the FDA. Do you have a sense of which metric the FDA is most focused on? Some commentary on that would be great.

Jon, thank you so much for that question. So look, we're very excited about the submission with EMPAVELI, of course, and looking forward to feedback in short order. The 24 hours was consistent with what we saw with the spots, but the endpoint, of course, was the spot. I think what is really important here is not just the proteinuria, right, but the consistency that we had across all the phenotypes of this disease and across all of 3 important metrics that exist. There is, of course, the proteinuria which has such a highly clinically meaningful reduction but we also had to eGFR stabilization. And in addition to that, and I cannot overemphasize that the impressive results on the histopathology, right? I mean, so when you look at these kidneys, you see the C3 deposits go away, melting like snow in the sun, quite frankly, over the course of a couple of months. And after 6 months as much as 70% of patients have no more detectable C3 deposits. So that's something really important to bear in mind, we're excited about the submission about what we can do for patients and the submission for the publication will come out soon as well.

Maybe just as a quick follow-up. Given recent news coming out of the agency, I'd love to get a sense of your confidence level that you'll be able to launch in second half of '25 that the agency will be able to meet its PDUFA requirements and you'll get a timely review.

Of course, we have no control over macro, but at the current point in time, there is no indication at all, that there is any type of delay.

Our next question will be coming from Tazeen Ahmad of Bank of America Securities.

Great. I have a couple of questions regarding SYFOVRE. So just based on the metrics that you've cited or really trends in the first quarter, how should we be thinking about results in the first quarter relative to 4Q? Could it be that sales would be lower this quarter for the reasons that you mentioned. And then regarding the beneficial status in Medicare Advantage, do you think that that's going to have an early and noticeable impact on new patient share in the year? Or do you think that's something that would happen more gradually? And then I have a follow-up.

I'm going to hand it over to David.

It's David. So like we talked about in the call, some of the things that we're seeing in Q1 are transient impact to what we think will impact net revenue. And while they are anticipated to be temporary, we do think that Q1 will be lower than Q4 as a result. And we're not going to guide on anything for Q1 beyond that, but that's where we are currently, at least with what we've seen so far. And the other thing to note, too, by the way, is one of the things that is really positive for us is that the good news, we're seeing injections, which we talked about in the call as well, grow in Q1 versus Q4 which is very positive for us. And we expect -- once we get some of these temporary impacts against the Q1 numbers out of the way, we should see and continue to see and expect to see 2025 to have growth.

Okay. And then my follow-up is about the label change that was made for the competing product. How important is it that the label for Izervay will say, monthly injection relative to every other month because it does seem, based on our doc checks that up until now, docs seem to have adopted every other month. Do you think that practice will change?

Yes. So look, I think it's a little bit early here, right? In regard to the label change, I think there's still some things here that folks are still trying to figure out. I will tell you myself and Caroline, which I'll hand to in a second for some comment. We were at the Macula Society when this came out, which is a prestigious meeting that was held in Florida. And the general talk and discussion was around SYFOVRE and the every other month dosing. And I think the more important part was the follow-on to that, which is we had a lot of robust data that was presented at that meeting. That really helped us to solidify even further that SYFOVRE's consistent increase effects over time is going to have impact. And is it have an impact -- that was a lot of the discussion. Plus, we're the only product that can be treated, and is in the label for as few as 6 doses a year, and we're the only product that has preferred positions with payers. That was the conversation at Macula Society. So I'll hand it over to Caroline for additional comment.

Thank you. Tazeen, What I hear from my colleagues and what I know from being a physician, is that efficacy and convenience are really important driving factors for patients, physicians and payers. And we have consistently demonstrated efficacy with every other month dosing. This has not been demonstrated with Izervay in a clinical trial and the FDA did not approve them for every other month dosing. So our label includes all of our benefits, our efficacy, increasing effect over time in a flexible dosing regimen that includes monthly and every other month dosing.

Our next question will be coming from Anupam Rama of JPMorgan.

This is actually Malcolm Kuno on for Anupam. So with the Izervay headwinds over the last several months and the updated label. What are you hearing from payers on the potential for preferred tiering for SYFOVRE?

Yes, Malcolm, thank you. It's David. Thanks for the question. So we're really fortunate to have a number of payers and sizable plans that have us in a preferred position. I think it's a little hard to forecast what that looks like. But I will tell you, when we look at and have conversations with the payers, it really comes down to every other month dosing and the fact that we have it in the label with the efficacy that matches up to that. So those are the things to keep in mind. And we'll see what happens in the future, but I can't really predict what will happen moving forward with the payers, at least at this point in time.

Our next question will be coming from Salveen Richter of Goldman Sachs.

Could you give us a little bit more color on how we should think about the cadence of the SYFOVRE launch here in 2025, just given the commentary on 1Q being lower than 4Q, but there's growth in 2025. And also in the context of a potential label update for Izervay and the formulary status and expansion ex U.S.

Thank you, Salveen. So I think, first of all, really important to bear in mind, injections continue to grow, right? And that is a reflection of the unmet need in this disease. Remember, fewer than 10% of patients which geographic atrophy has been treated. And only about half of patients are currently being seen by accurate professionals. So the opportunity there to do good for patients and to generate revenue is enormous as it has always been. So that is as far as the overall market is concerned. Competitively, quite frankly, I think we are in an enviable position right now. Last year, of course, we went through several motions. But at the end of the day, I think it's important to bear in mind that the CRL for our competitor, beyond whether it's resolved or not now, really called out the shortcomings that our competitor has. Most notably, the fact that there is -- that there was a 12-month limitation initially, which a lot of physicians did not know and then, of course, also the lack of data for every other month dosing. So I think it was important to kind of level set the knowledge around 2 products so that physicians can take the right decisions. So we're very excited about where 2025 is heading and beyond as well.

Our next question will be coming from Yigal Nochomovitz of Citigroup.

I had a question on the combo trial with APL-3007 and SYFOVRE. How are you thinking about the phasing of the dosing there given the intravitreal and the systemic? Are you going to interweave them? Or can you just talk more about the strategy for that combo dosing? And then will this Phase II have any comparison arm? Or is it just going to be a single arm study?

Thank you so much, Yigal. So we're super excited about our 3007 program, and you are asking, as usual, an excellent question, which is we thought carefully through how to implement this in a physician setting, right? So the idea there is that with a subcutaneous injection, you lower the systemic levels of C3. So turning off the faucet, if you want, and you give a [ stoichiometric ] advantage, so dosing advantage to SYFOVRE for, which should still need [ NDA ] to control the enzymatic activity of the complement cascade. We will synchronize those injections to every 2 months and every 3-month administrations, both of which to the intravitreal and the subcutaneous, both of which would happen in the physician's office. So I think that's something really important. There will be a dosing component to this as per usual so that we can explore those 2 separate pathologies. But in the broader strategic context, I mean, we're looking forward to this year to growing the market in GA, truly establishing ourselves as we are the market leader, but growing that share that we have. And then also to what we subjectively, of course, but I believe will be one of the, if not the most exciting developmental program in geographic atrophy by the end of this year and into 2026.

And maybe one for Tim. Just on EMPAVELI. Obviously, you have a ton of really interesting larger indications coming down the pipe, as you've alluded to, the C3G, IC-MPGN, FSGS, potentially DGF. So as far as the patent looks like, do you have any comments on how you might extend that even further given the potential for very significant revenues on these follow-on indications?

Yes, sure. If I heard you correctly, you asked if there was a way to kind of extend our exclusivity. Is that -- did I understand that from a patent perspective?

Yes.

So look, we have composition of matter through kind of 20 33-ish, 2035 with customary extensions. So that's still a pretty reasonable runway for the indications that we discussed and we discussed that those are both chosen because we believe that we would have the ability to launch those with a significant amount of patent life left. There are other things that we have in mind. We also have, as Cedric mentioned, some combination product work ongoing that could really change our -- the profile of our systemic administration of pegcetacoplan. So we're looking at life cycle management initiatives as well. But from a composition of matter perspective, 2035 is really where that runs out.

Our next question will be coming from Colleen Kusy of Baird.

Congrats on the progress. So you've had some strong momentum on the payer front last year. Can you put into context what percent of the market you have preferred positioning in? And how much more growth on the payer front do you expect to achieve in 2025?

Thank you, Colleen. And good to have you back. So I'm going to hand it over to David.

Colleen, good to hear from you, and thank you for the question. So we've got some big plans like Aetna is a great example that as of January 1 has us in a preferred position and a patient has to start with SYFOVRE before they could move to the competitive product. So there's some big plans that are out there. I think percentage-wise, it's a little bit hard to talk through that because there are so many intricacies in the plans on how they actually look at this. And the downstream accounts, in particular, to the PBMs can make their own decisions on what they want to do with that. So -- but I will tell you, we have a number of sizable plans in 2 major PBMs that have us in a preferred policy position for their downstream accounts to make those decisions on.

Great. That's helpful. And then for C3G and IC-MPGN, have European regulators and U.S. regulators historically approached that review similarly since we've seen some positive momentum on the European opinion front. Just wondering how that decision might have read through to the U.S. review.

Yes. So thank you so much for that question, Colleen. So our partner, Sobi and Apellis have been in lockstep through all of this. And we're very excited about the global deployment of EMPAVELI in the U.S. and Aspaveli ex U.S., of course. I think what's -- and again, kind of highlighting what we've mentioned many times, in the U.S., for example, we estimate there are approximately 5,000 patients. We estimate and we believe that we will only be competing with the only other product should it be approved and maybe on the market by the time we get there for about 1,000 out of those 5,000. So it's a really special opportunity for us, and the numbers in Europe are quite a bit higher than 5,000, really unique opportunity that deserves the prioritization that it gets within Apellis as well as with our partner, Sobi.

Congrats.

Our next question will be coming from Phil Nadeau of TD Cowen.

First, a follow-up and another question. The follow-up is on your comments you made about the sampling. Can you go into a little bit more detail on the dynamics of why there's a funding shortage? And what gives you confidence that this is just a Q1 issue and it won't persist later in the year?

Sure. Thank you so much, Phil. So look, the sampling are a reflection of a couple of factors, but one that stands out is what we spoke about before, which are these organizations that provide support to physicians to help with the co-pay of the product. That is not just for SYFOVRE, but for all intravitreal injections. And it's important to note that we do not have real visibility on how this is managed. This is by design that is it should be appropriately -- these are independent organizations that determine how they manage their fundings. So we contribute, others contribute. We typically contribute at the beginning of the year, but it can happen throughout the year from other organizations and it has happened before that they run out. So what then typically happens is that physicians will go towards sampling to be able to still take care of those patients, right? So I would say that the increase in samples is a reflection of the fact that these patients are in need. There is a, hopefully, by all expectations, temporary funding gap. The physicians compensate for that with sampling.

Got it. That is helpful. And then a broader question on EMPAVELI and C3G and IC-MPGN. In the slide deck, you outlined 4 buckets of patients with that disease. Can you talk about how you're going to focus your marketing? For example, will you focus on post-transplant patients where you're likely to be the only option or are there other elements or physicians that you think are our highest priority?

Yes. Well, thank you so much, Phil. So again, I think you point on something that we're particularly proud of, which is that when we study these diseases we went very broad, right, we said we're going to study C3G as well as IC-MPGN, which are split about 50-50 in the population that we are targeting. We looked at pre transplant, but also post transplant, which is a segment that often gets neglected. We studied pediatric patients as well as adults. And we studied what happens in this disease is sometimes C3 is depleted, sometimes it's not. We studied everything. And everywhere we saw a consistent response as far as the impact on the disease was concerned. So what that means moving forward because I think what you're asking is where is kind of the -- where are the initial demographics. I think the post-transplant segment is a particularly interesting one. I think it's also worth noting that within this small community of transplant nephrologists, EMPAVELI is taking on quite a pristine reputation, not just because of the data that we had in VALIANT, but also because all of the recent xenotransplant, you may have seen in the news, the kidney transplants that are happening from genetically modified pigs are transplants that were either rescues with EMPAVELI or are now in all cases, as far as we know, proactively being protected with EMPAVELI. So the -- I'd say the reputation of EMPAVELI to be able to control complement within the kidney is growing steadily and something that, of course, bodes well for our launch later in this year.

Our next question comes from Akash Tewari of Jefferies.

So this is Kathy on for our Akash. So on Astellas earnings call, they stated that docs were essentially warehousing patients and pausing their Izervay doses until the 24-month label update rather than slipping them to SYFOVRE? And then as such, they were expecting a bolus in March once dosing resumes. So given the Izervay's label got updated a couple of weeks before the PDUFA with the 2-year data on the label, but without every other month dosing, what are you seeing in terms of SYFOVRE versus Izervay uses within the past few weeks? And then what should we expect regarding dynamics on SYFOVRE versus Izervay going forward? And then what do you think your team needs to do to change doctors' perception?

Yes. So I think I will answer the first part, and then I will hand it over to Caroline to talk about doctor perception, which of course is very important. But I think, look, there may have been some warehousing with certain physicians with certain patients to take home very clearly here is that we are a definitive market leader and we are growing that leadership. That is very clear from all of the intelligence that we have internally at Apellis and something that is rooted in the data that we have, right? So I think that is the key message for us. And I'll hand over to Caroline to talk about how physicians currently view the products.

Thank you, Cedric. Well, we hear a lot from our physician colleagues. We just attended 3 major meetings, most recently the Macula Society. And physicians are very enthusiastic about our differentiated efficacy data. And our long-term data, I mean, we presented tissue saved and how much tissue that was over 1.5 disc of retina tissue that's saved with SYFOVRE use, and we presented long-term data, patients who've been treated with SYFOVRE for 48 months. So this is really unprecedented and this is the key driver amongst physicians. I think that in the end that physicians really speak to the scientific data and it's very meaningful for them.

Okay. Understood. And then just like a super quick follow-up. It seems like -- could you provide some more color on inventory in Q4 because it seems like quarter-over-quarter sales growth was about 10% versus vol growth was about 5%, but you mentioned that you had stable gross to net dynamics.

Yes. Yes. This is David. So thank you for the question. coming out in Q4. And usually, you'll see in any given quarter, at the end of the quarter, some move in regard to orders that will move inventory a little bit. We saw a little bit, of course, coming out of Q4 and sometimes you'll see a little bit more around the holidays. But it did not put us in a situation that we were out of a typical 2- to 3-week range that we have. And we may see a little bit of drawdown in the front of Q1, but for the most part, it was not a significant number that we would be concerned about in any way.

Our next question will be coming from Ellie Merle of UBS.

In terms of GA, I guess, what's the latest that you're seeing in terms of patient adherence and what you're seeing in terms of any discontinuations, I guess sort of how we should be thinking about long term, what the discontinuation rate or compliance on therapy might be? And then just a second question, in terms of your expectations for the number of samples beyond 1Q, I guess, what do you expect in terms of dynamic in 2Q on the rest of the year. You mentioned this is a temporary funding gap in the patient-assisted organizations. But just curious what you expect over the course of the year in terms of the number of samples.

Yes. Thank you so much, Ellie. So first of all, as it relates to the adherence, we actually see adherence levels for SYFOVRE will be similar to what we have or what you find with anti-VEGF which is a very positive trend, considering that anti-VEGF is kind of more viewed as an acute treatment with an immediate benefit, whereas with SYFOVRE as we all know, you make an investment in the future protection and this large amount of tissue that you can preserve if you are fatal to the product. So that is something that we have no concerns around. As it relates to the samples, I will have David answer that.

Yes. So I think a couple of things. And just remember, upfront, I think it's important to remember that samples being requested and put into a patient for treatment is a sign of demand, which is very positive for us. And we're seeing the injections increase in Q1 versus Q4. So we feel good about that. I think a couple of things. First of all, we believe this is temporary, and we anticipate that these issues that we're working on that the samples are being used in place that the commercial product will be fixed over time. We don't know what that looks like as far as timing and the funding gap and when all those things kind of come together, that Cedric mentioned, it's really -- it's in the control of the groups that manage this with patients and with physicians. So we really don't have an answer to that. But we will continue to supply samples if needed and put patients in a place where they can be treated.

Our next question comes from Annabel Samimy of Stifel.

So I'm just trying to understand the competitive dynamics a little bit better for SYFOVRE. Can you help us square away comments about leadership position of greater than 60% share. But then new patients is more like 50-50 and then we've got competitive headwinds coming from the label expansion, but then you talk about positive trends in injection growth, preferred formulary status and positive feedback that you're getting from the community around efficacy and flexibility of SYFOVRE. So I guess maybe you can help us really understand what that competitive headwind is that is pushing the new patient share to 50-50 because it looks like everything is sort of lining up well for SYFOVRE, but I'm not sort of able to square away why it's still 50-50 for the new patient share.

Yes. Thank you, Annabel. I think look, -- we'll see where it ultimately will end up, of course, right? I mean we -- the direction is positive for us, right? So -- but I think most importantly, even a couple of months ago, I think we were in a competitive situation where the data or the knowledge around our competitor was, I would say, weak in the retina community. As far as it relates to what does this drug actually do? What does it do in the long run? A lot of physicians, as I mentioned, didn't know that this drug was only approved initially for a 1-year period. So that was a [indiscernible] not a surprise. So I think that there -- we are now playing in a level playing field and the level playing field, the differentiation on efficacy is incredibly robust, right, and that is being recognized by retina doctors. And that's not just on a magnitude basis, it is also on the longitudinal data. And I would say that it's a real turning point for us that we're looking forward to working from. I don't know, Caroline, if you want to add something?

Well, I think one of the things that really differentiates us with physicians is that every other month dosing. And we use clinical studies to guide us. And the robust data we have a heterogeneous broad patients that were studied all shows to demonstrate the efficacy into year 4 with every other month dosing, which will just increase the convenience and help patients stay compliant. So I mean, physicians continually come up to me, grateful for what we're presenting and show that this long term and every other month dosing, it speaks to their patient population.

Okay. Great. And if I could just ask a question on C3G, MPGN launch. What are your expectations there? You're not -- [ SYFOVRE ] is clearly going to come out a little bit earlier, but you did mention that; physicians were a little bit more focused on -- are a lot more focused on efficacy. But I'm curious the level of urgency patients have to get on treatment. And so what can we expect for, I guess, an early launch trajectory for that product?

Yes. Thank you, Annabel. I think the key thing is that we see the demand in the request that we already get for compassionate use and expanded use access, right? So demand is very important. Remember, these are younger patients, about half of whom over a 10-year period, which is not a lot when you're 20 or 30, 50% is the chance of losing their kidneys. So the need is incredibly high. And again, I want to emphasize that based on the data that we have, we will probably be competing probably only for about 20% of that overall bucket of patients. So a really important opportunity for us and for patients.

Our next question will be coming from Douglas Tsao of H.C. Wainwright.

First question I had was in terms of the siRNA plus SYFOVRE product, Cedric. I know in the past, spoken about SYFOVRE having a very powerful effect on preservation of photoreceptors and less so on RPE cells. And so I'm just curious, with this approach, is this sort of what you're specifically targeting by going after the choroid, which isn't -- which is sort of adjacent to the RPE as well?

Well, Doug, I'm very impressed with that question, but you are correct. This is -- so the impact that SYFOVRE has on the photoreceptors is near perfect right about 100%. When you look in the first 6 months, I mean it's an incredibly robust impact on those photoreceptors. The RPE cells are the ones that continue today, of course, meaningfully slow down. And then the question that we're trying to answer here is since if we -- on the choroid side, right, on the back of the eye, if we can lower C3 levels, will we be able to impact the RPE cells in a way that is similar to the photoreceptors. So excellent question, and the answer is yes.

Okay. Great. And just a quick follow-up on for David. Just I'm curious to the extent that you anticipate seeing an impact on the Medicare redesign for this year or if you can sort of quantify it at this point?

Thank you for the question. I think quantifying that is challenging for us, and I would hate to take a guess at it. So it's something we're looking at. We've got a whole team, of course, that manages all the things that we do with payers and especially in our space with CMS. But I don't think I can quantify that at least at this time.

Our next question will be coming from Joseph Stringer of Needham & Company.

Two from us. Just wanted to get your updated commentary on any -- on the switching dynamics between SYFOVRE and Izervay. And secondly, I know prior question asked about adherence rates, but just curious what about compliance rates for SYFOVRE, for example, patients missing or skipping injection. How does that look? Or how has that changed over time?

So this is David. Thank you for the question. A couple of things. I think Cedric and Caroline touched on already some of the compliance where we fall with SYFOVRE and it's about in the same range as anti-VEGF. So -- and actually, I feel good about that because for us to be in the GA treatment area with something that's that compliant, I think is very positive because it is a disease that goes definitely slower than wet AMD. As far as the question on the dynamics of switching, so we look at this on a regular basis. I will tell you that we've had a number of weeks, especially during the CRL period that they had for the competitive product that we saw a number of switches. And I still think we're seeing that today in the first part of the front end of Q1. And the good thing is, and I think what's driving my thinking around that is the fact that we are seeing an increase in injections in Q1 versus Q4. And I think that we're in a good place to see growth overall in 2025.

Our next question will be coming from Lachlan Hanbury-Brown of William Blair.

I wanted to ask more about the efforts that you've made to get doctors off the sideline. You said that the sort of shift towards the efficacy-focused messaging is resonating well with physicians. But I'm wondering if you can sort of translate that into any changes of actual prescribing behaviors or new prescribers?

Yes. So that is what we are seeing, and thank you for that question. I think what is gratifying after 2 years of launch now is that the data becomes very clear, right? We have the extension study, the data becomes much more concise to communicate. And the main message at Macula Society, which is one that I think really resonates the most is that if you are on 4 years of treatment with SYFOVRE, you can have up to 3 square millimeters of retina preserved, right? And 3 square millimeters of retina is 1.5 disc areas. It's a huge amount of [ real estate ] in the back of the eye. That is -- when you tell physicians that it resonates incredibly well. That is the reality of this drug and one that we can now really use moving forward. The safety situation is very stable and efficacy is becoming the prime focus.

Got it. And a follow-up, if I may, sort of following up on Yigal's earlier question on patent life for EMPAVELI. Curious if you can give any color on what you had assumed for IRA price negotiations when you were doing the sort of business cases for FSGS and DGF, I realize there's probably still more questions and answers there, but just would be great to get your thoughts on sort of what you'd assumed.

Yes. Thank you so much. So these are -- look, we did a thorough analysis after the readout of VALIANT [ in the kidney ] based on the premise that we have clearly exquisite target engagements in the kidney glomerulus. And we did the usual work that you do in that situation, the competitive analysis, the biology, what can we do with the patent lab of the drug, and that is where these 2 the [ diseases ] emerge. So much more will follow, but we're excited about these indications and when we get the full [indiscernible].

Our next question will be coming from Ryan Deschner of Raymond James.

Have your expectations for gross to net in 2025 and a steady state evolved at all in the last few months? And can you give us any more detail on what you're expecting to see in terms of timing and duration of the impact of the new DTC campaign on sales in 2025 and beyond based on what you saw in the prior campaign.

Thank you very much for the question. I'll take the gross to net piece and then hand it over to David for the impact of the DTC. So the simple answer is no. Our view on gross to net hasn't changed at all. At the end of the third quarter, we did guide to low to mid-20s throughout the course of 2025, and that remains the same. And David?

Yes. Thank you, Tim. So I appreciate the question on DTC. It's a little early. We started running that commercial on television with Henry Winkler in mid-January. But I can give you one piece of information that happens that will give you an indicator of some of the early impact that we can see. We did have the commercial run during the Saturday Night Live 50th anniversary special. We had about 15 million views on the commercial, which was attributed to driving about 3,000 visits on our website, at that time. So we can see things like that early. It's going to take time for us to see the total impact throughout the next several months.

And we do have time for one more question. And our last question will be coming from Derek Archila of Wells Fargo.

Maybe just 2 for Tim. I guess, how should we think about OpEx growth in 2025 relative to '24? Is there going to be a lot of growth coming from some of the R&D initiatives that you guys talked about. And just based on some of the seasonal factors in 1Q and the sampling, I guess how should we be thinking about gross margin trends to '25?

Sure. So from the perspective of OpEx versus 2024, as we said in our prepared remarks that we expect those to be more or less the same. I think that's probably the case when you think about what we've -- some cost savings from our European infrastructure some of which we scaled down. That will be offset by some R&D expenditure that gets increased. And then from the gross margin perspective, we don't guide on that. There's a lot that goes into gross margin that sort of moves around. But from a sampling perspective, I think we gave you everything we could from the perspective of color on how we project that. We really don't have any visibility. But we do know what we did talk about is that we see an approximately 5000 vial estimated increase of samples in this quarter. And so doing the math on that, you can kind of get to a reasonable idea of what our revenue is per vial. You can understand what that would be. And frankly, that's the piece that we can right now kind of get into our gross margin impact in the first quarter, at least as an estimate. Beyond that, we really have no visibility, unfortunately.

And I would now like to turn the call back to Cedric Francois for closing remarks.

Thank you so much, and thank you, everyone, for joining us this morning. If you have any follow-up questions, please feel free to reach out to Meredith. Thank you so much.

And this concludes today's conference call. Thank you for participating. You may now disconnect.