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spk15: Good afternoon. My name is Valerie, and I will be your conference operator today. At this time, I would like to welcome everyone to the Appellus Pharmaceuticals' fourth quarter and full year 2020 fiscal results conference call. Today's call is being recorded, and a replay will be available at appellus.com. I would now like to turn the call over to Tracy Venise, Vice President of Communications at Appellus.
spk01: Thank you, Valerie. Good afternoon, and thank you for joining us today to discuss Appellus' fourth quarter and full year 2020 financial results. With me on the call are co-founder and chief executive officer, Dr. Cedric Francois, chief medical officer, Dr. Federico Grossi, chief commercial officer, Adam Townsend, and chief financial officer, Timothy Sullivan. Before we begin, I would like to 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 our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. Now, I'm pleased to turn the call over to Cedric.
spk02: Thank you, Tracy, and good afternoon to everyone joining us today for our first quarterly conference call. 2020 was a defining year for atletes, marked by the positive Phase III Pegasus data in paroxysmal nocturnal hemoglobinuria, or PNH. The Pegasus results highlighted the potential of Pexetacoplan to elevate the standard of care in PNH and the broad platform potential of targeting C3 for complement-driven diseases. In 2021, we look forward to a transformational year for ATHLEES as we further build on our global leadership in complement across a broad range of diseases with high unmet need. As you can see on this slide, our corporate strategy is based on three strategic objectives, and we expect to make significant progress against each of these this year. Our first objective is to establish systemic Pexetacoplan, a targeted C3 therapy, as a disruptive treatment across rare, complement-driven diseases. We have a PDUFA date of May 14th for the potential U.S. approval of Pexetacoplan in PNH, and our Chief Commercial Officer, Adam Townsend, will discuss our work to prepare for a successful commercial launch. We also expect to advance four additional registrational programs of Pexita Copeland with our partner, Swedish Orphan Biovitrum, or SOVI, as we work to maximize the broad potential of targeting C3. The second objective for our company is to be number one in treating retinal diseases. In what will be a seminal event for Apedis, we expect top-line results from our phase three clinical studies of Plexeta Copeland in geographic atrophy, or GA, in the third quarter of this year. GA is a relentless and disabling disease that affects approximately five million people around the world, and we have a unique and exciting opportunity to advance what could become the first drug for people living with GA. Our third objective is to develop new technologies to control complement. Our research team has been very active on a number of fronts, and we look forward to advancing three new product candidates into clinical development by the end of next year. As you can see, we have an ambitious strategy and several key milestones in 2021 to advance our global leadership in the treatment of complement-driven diseases. Now, let's dive deeper into our first objectives. establishing systemic pexetacoplan as a disruptive therapy for rare diseases. I will now turn the call over to our Chief Medical Officer, Dr. Federico Grossi, to review our recent data on pexetacoplan in PNH. Federico?
spk04: Thank you, Cedric. I'd like to begin by reminding everyone why we believe that pexetacoplan has the potential to elevate the standard of care for people living with PNH. PNH is characterized by the destruction of oxygen carrying reptile cells through both extravascular and intravascular hemolysis caused by uncontrolled complement activation. Current treatments inhibit the complement cascade downstream at C5, controlling intravascular but not extravascular hemolysis. As a result, while C5 inhibitors offer improvement patient survival, they do not address many debilitating symptoms from which people living with PNH continue to suffer. Only Pexetacoplin targets complement centrally at C3, controlling both intra- and extravascular hemolysis. As a result, Pexetacoplin met the primary endpoint in the Phase III Pegasus study and became the first and only investigational therapy to demonstrate superiority compared to Solaris or Echolizumab. with an improvement in adjusted means of 3.8 grams per deciliter of hemoglobin at week 16, as well as sustained improvements in other key clinical measures. The safety profile of Pexetacoplan was comparable to Solaris and Distell. Based on these results, we received priority review from the FDA for Pexetacoplan in PNH with a PDUFA date of May 14. Additionally, in December, we announced top-line data at week 48 from the PEGASUS study. These long-term results show that pexetacopalin has the potential to help PNH patients gain and maintain more complete control of the disease. At week 48, hemoglobin increases were sustained with pexetacopalin-treated patients with a mini-improvement from baseline equal to the increase seen at week 16 in pexetocoplan-treated patients. Importantly, as you can see in the graph, Solaris-treated patients who switched to pexetocoplan during the open-label period also experienced sustained improvement in hemoglobin and other key clinical measures, similar to patients treated with pexetocoplan immunotherapy during the randomized control period. Sustained improvements in transfusion avoidance, critical site count, lactate dehydrogenase, or LDH levels, and functional assessment of chronic illness therapy, or facet fatigue scores, were also observed in patients treated with Pexetacoplan. At week 48, the safety profile of Pexetacoplan was consistent with previously reported data, and no new safety signals were identified. Also in December, at ASH, we presented a matching-adjusted indirect comparison, or MAIC, analysis across the pivotal studies for Pexetacoplin and Ultramiris or Ravulizumab, a longer C5 inhibitor. In the absence of clinical head-to-head study, MAIC is a valid and accepted method for comparative effectiveness research used by health technology assessment bodies across the world. The MAIC showed that on pexetocoplan, 76% more patients achieved hemoglobin stabilization compared to patients on ultramarines. Also, 64 more patients in pexetocoplan achieved LDH normalization. This is remarkable because LDH is the biomarker of intravascular hemolysis. The type of hemolysis that C5 inhibitor like ultramarine control well. Additionally, on major important to patients' quality of life, 71% more patients treated with pexetacoplan were transfusion-free. And there was a nine-point difference on the facet fatigue score of pexetacoplan over ultramarine. These results reinforce the potential of dexatoclopram to elevate the standard of care by targeting C3. As with other MAIC analyses, matching may not adjust for confounding factors due to difference inherent in the study design and entry criteria. I'd like now to move to our ongoing Phase III print stage. But we believe pexetacopran has the potential to receive broad label based on the results from Pegasus. The PRINCE study evaluates pexetacopran in patients that are more representative of the overall treatment-naive population. On this slide, you can see the PRINCE study design. 53 treatment-naive PNH patients were enrolled. The two primary endpoints evaluated after 26 weeks are hemoglobin stabilization in the absence of transfusions and reductions in LDH levels. As noted in the slide, patients in the control group have the option to escape to pexetacopalin if their hemoglobin levels drop by two or more grams per deciliter below their baseline. I'd like to discuss a couple of key points about this study. BRAINS used the standard regulatory endpoint for PNH studies that were designed for C5 inhibitors, and therefore focused on intravascular analysis. As we all know, PNH is characterized by both intra- and extravascular analysis, so we believe that some of the secondary endpoints, such as hemoglobin levels, transfusions, and facet topic score, are equally as important since they truly reflect the impact this disease has on patients. Additionally, even on measures of hemolysis, we have set a higher bias vertex as a coupling. Patients' imprints are considered to have unstable hemoglobin levels if they lose only one gram per deciliter in hemoglobin levels. Historically, in studies with C5 inhibitors, patients were allowed to drop by two grams per deciliter before being considered unstable. We have been fortunate to be minimally impacted by COVID-19 across our PNH clinical studies. However, the timing of spring stop-line data will not be at the end of May or beginning of June, in line with the public guidance, but later than initially expected. This is due to COVID-19-related delays in local regulatory approvals of the extension study, which have precluded us from transitioning all patients in two countries and delayed our database lock. We are very excited to see the impact of texretacoprin on treatment-native patients and look forward to sharing these results later next quarter. I'll now hand the call over to our Chief Commercial Officer, Adam Townsend, to provide an update on our P&H launch preparations. Adam?
spk03: Thank you, Fede. The positive Phase III Pegasus results showed the potential of Pegsetter Copeland to elevate the standard of care in P&H, and we are working hard to prepare for its successful U.S. launch in anticipation of our May PDUFA date. As you can see on this slide, people with PNH continue to suffer from significant unmet need despite their current treatment with C5 inhibitors like Celiris and Altamiris. Clinical data and our own market research have shown that about a third of patients on C5 inhibitors continue to require transfusions to address their falling hemoglobin levels. Another third of these patients continue to be severely anemic and experience other symptoms like severe fatigue. This has a huge impact on these patients. The final third of patients have closer to normal hemoglobin levels, but only achieve that at the expense of maximum output of red blood cells from their bone marrow. As these data show, there is an urgent need for new treatments within PNH. Over the last two years, we have built a robust commercial organization in preparation for our first launch of PECS at Copland within P&H. Our integrated team is focused on ensuring that we are ready to effectively address the needs of patients at launch, and our progress is highlighted on this slide. Our value and access team is fully staffed and engaging with high priority payers representing more than 80% of all US P&H patients. Our discussions with those payers have yielded positive feedback on the clinical profile of pexetocoplin. APELIS is also in the late stages of finalizing our distribution model and patient support resources and programs. We will aim to provide patients with a consistent positive experience, both at the time of treatment initiation with pexetocoplin, as well as long-term assistance as and when needed. As an example, we have established Appellus Assist, a patient-focused program designed to ensure a high-quality patient treatment experience, including the recruitment of our care educator team, which will interact directly with patients through product and drug administration education. In parallel with our commercial activities, our medical team has also been preparing for launch. As shown on this slide, our medical affairs colleagues have been actively engaging with the top treating physicians via our virtual presence at medical meetings and in-person engagements when appropriate. They have also initiated an early access program for Pegcetacoplin in the U.S. and already established multiple sites to treat PNH patients who are experiencing ongoing disease activity despite treatment with Soliris or Altamiris. On marketing efforts, early activities with healthcare professionals, or HCPs, have been really strong and positive, showing high engagement above industry benchmarks. Almost 90% of targeted US P&H HCPs have accessed our content focused on the unmet need in P&H, examples of which can be seen on the left-hand side of this slide. Separately, over 2,000 patients, caregivers, advocates, and other P&H community members have opted in to communicate with APELIS via our community outreach and patient marketing efforts, which can be seen on the right-hand side of this slide. Patients and caregivers are also spending considerable time on our website, which tells us they are interested in our information, particularly around the existing unmet need. Finally, our focused and experienced sales team will be deployed to cover the top 1,000 to 2,000 HCPs, including more than 90 key treatment centers. We are excited about the commercial team we are building and honored to have the opportunity, pending approval, to bring PEGSET to Copland to P&H patients this year. As well as preparing to elevate the standard of care for P&H patients, we are quietly preparing for the future potential approvals in new indications. The commercial organization is excited to see our GA results later in the year. I will now turn the call back over to our Chief Medical Officer, Dr. Federico Grossi, to review the additional systemic program indications, as well as geographic atrophy.
spk04: Fede? Thank you, Adam. Beyond PNH, we're advancing four registrational programs of systemic pexotocopin in rare diseases with high and med need with our partner, SOVI. As seen on this slide, in the second half of the year, a patient expects to initiate a phase three study to further a registrational program in immune complex membranoproliferative glomerulonephritis, or ICMPGN, and G3 glomerulopathy, or C3G. plan to start registration of problems in collaglutinin disease, TAD, and hematopoietic stem cell transplantation associated thrombotic microangiopathy, or HSCT-DMA. Also in the second half of this year, APELIS expects to complete enrollment for our potentially registrational Phase II meridian study in amyotrophic lateral sclerosis, or ALS. In parallel to our work in systemic Pex-Zeta Copeland, we continue to execute our phase three studies of intravitreal Pex-Zeta Copeland in GA with top line results expected in the third quarter. We believe that our GA program represents a unique opportunity to make a difference in the life of five million people at risk for blindness with no treatment options available and few opportunities in the horizon. Results from the largest retrospective study in G8 secondary to age-related macular degeneration, or AMD, were presented as a late breaker at the American Academy of Stemology meeting. The study, which was conducted in partnership with Verona Health, highlighted the disabling impact this disease has on quality of life. also reiterated that WebMD is an expected occurrence in GA patients and showed that it is observed more frequently if WebMD is present in the fellow eye, with 22% of GA eyes developing WebMD over 24 months. These results echo feedback received on our recent GA webcast, which feature a panel of leading vet specialists and further underscore the need for new treatments. I encourage you to listen to the archival recording of this event on our website and the event presentations in the investor section. Now to our Pivotal Phase III GA studies. Debian Oaks are two large world control studies that compare the efficacy and safety of monthly and every other month in traditional Pex-Zeta Copeland with sham treatment in more than 1,200 patients. The primary endpoint of both studies is the reduction in growth of GA lesion at month 12. The studies will continue for a total of 24 months, and safety and efficacy will be assessed again at that time. In Philly, we saw the treatment effect of pexotocoplin increase from month 6 to month 12. and we look forward to seeing the results of longer treatment with Pexetacoplan in our Phase III study. Full study design details can be seen in this slide. We're excited to see the top-line results from Derby and Oaks in Q3, and we'd like to take this opportunity to reiterate why we believe these studies will be successful. First, Derby and Oaks have the same study population and core study design as Phoebe. which demonstrated robust and statistically significant results that have been confirmed through multiple sensitivity analysis. Second, DERI and OX include more frequent assessment that will provide an even more complete evaluation of the primary endpoint. Third, cases of oxidation required confirmation by the reading sector, which reduces the potential for bias in the diagnosis. In addition, patients experiencing exudations can receive anti-BGF treatments while continuing on pexetacoplan, which we expect to reduce the number of study treatment discontinuations. Finally, the studies are sufficiently powered to meet the primary endpoint given the current rate of misinjections in this space. For all of these reasons, we believe DERBI and OX will be successful. and we are excited to see the results later this year. Success here will position us as the leader in the treatment of retinal disease. The last component of our strategy is the addition to apartment of several new technologies defined to control complement. We plan to advance three new product candidates into clinical development at the end of next year. The first area of focus is on less frequent dosing while maintaining the strong clinical benefit seen in multiple studies with Pexetacopla. The second focus is to expand our MD offerings to treat all forms of MD and potentially avoid the onset of advanced MD altogether. And finally, we believe that C3 play a critical role in many neurodegenerative conditions and are pursuing new technologies focused on neurology. We look forward to sharing more about these programs in the months to come. I will now turn the call over to our Chief Financial Officer, Tim Sullivan, for a review of the financial results. Tim?
spk16: Thank you, Fede. Since we issued a press release earlier today with the full financial results, I will just focus on the highlights for the full year 2020. As of December 31, 2020, Appellates had $877.6 million in cash, cash equivalents, and short-term marketable securities, compared to $352 million in cash and cash equivalents as of December 31, 2019. This increase primarily reflects the addition of cash from our follow-on offering for gross proceeds of $404 million in January 2020, our convertible offering for gross proceeds of $329 million in May of 2020, and also the receipt of $250 million in the upfront proceeds for the SOBE transaction in October 2020, less our cash used in operations. Research and development expenses were $325 million for the full year ending 2020, compared to $221 million for the same period in 2019. The increase in R&D expense for the full year 2020 was primarily attributable to an increase in manufacturing expenses for our Phase III clinical trials and potential commercial launch, costs associated with ongoing and planned clinical trials, compensation and related personnel costs primarily due to the hiring of additional personnel in 2020, among others. General and administrative expenses were $139.4 million for the full year ending 2020 compared to $67 million for the same period in 2019. The increase in general and administrative expenses for the full year 2020 was primarily attributable to an increase in professional and consulting fees employee-related costs due to the hiring of additional personnel and director's stock compensation expense, among others. For the full year ending December 31, 2020, the PELS reported a net loss of $344.8 million compared to a net loss of $304.7 million for the same period in 2019. We remain well capitalized to execute on the potential launch of Pegceta-Coplin and PNH and to continue to advance our robust clinical development plan. Our cash runway is expected to fund operations into the second half of 2022. I will now turn the call back over to Cedric for closing remarks.
spk02: Thank you, Tim. As you heard today, we have a transformational year ahead, and the key commercial, clinical, and regulatory milestones are shown on this slide. As you can see, we have a busy 2021 as we work to deliver on the full potential of targeting C3 across a broad range of complement-driven diseases. Before we move to Q&A, I would like to thank the patients, investigators, and caregivers who have participated in our clinical trials, and our employees and investors who have helped advance APEDIS through this difficult year. We look forward to keeping you updated on our upcoming milestones. And now, operator, please open the call for questions.
spk15: Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star then 1 on your telephone. One moment, please. Our first question comes from Anupam Rama of JPMorgan. Your line is open.
spk06: Hi, guys. Thanks so much for taking the question. One of the most common questions we've gotten recently is in Derby and Oaks, how do you think about the potential impact of sort of missed injections? and how that impacts the study, the stats plan, how we should be thinking about this. Is the Philly every-other-month arm maybe a reasonable proxy for how we should be thinking about the potential effect of APL2 with missed doses? Thanks so much.
spk02: Thank you so much, Anup. Great hearing you, and thank you to everyone for joining this call. The brief answer to this question is that the studies, Derby and Oaks, continue to be well-powered to show what we intend to show in these studies in spite of the missed injections that we have seen so far. Obviously, we did have missed injections, and the study was impacted by COVID, but we have a way of looking back, as you alluded to, to the Philly trial and compare the frequency of missed injections, how these missed injections occurred, and based on that, make an assessment of the quality of the Phase III clinical trials. And it is those assessments that make us highly confident that we are in a good place to measure the primary endpoint with good quality.
spk04: Great. Thanks so much for taking our questions.
spk02: Thank you, Anupam.
spk15: Thank you. Our next question comes from Umar Rafa of Evercore. Your line is open.
spk13: Hi. Thanks so much for taking my question. Cedric, what percentage of the patients had wet AMD at baseline in the fellow eye. I'd be very curious. And also, sort of separately, for the primary endpoint, can you remind us how the autofluorescence was done in phase two and how it's being done in phase three? I guess what I'm really asking is, are you using CSLO, the scanning laser, or using the standard fundus camera? Thank you.
spk02: Thank you so much, Imre, for that question. So I'm going to start with the second part of your question. which is that we measure autofluorescence in exactly the same way in the Phase 3 as we did in the Phase 2 clinical trial. And then I have to ask you to repeat the first part because the line was breaking up a little bit.
spk13: Oh, no problem. What percentage of these 600 patients in each trial had wet AMD in the fellow eye? Because I recall one of the discussions with FDA was whether they should or should not be included, and FDA encouraged you guys to put them in. but presumably that will impact the conversion rate. So I'm curious what percentage have it at baseline?
spk02: Yeah, no, thank you so much. So in the Philly trial, as you may recall, at baseline we had 38% of patients who had geographic atrophy in the study eye and wet AMD in the contralateral eye. That compares to a normal natural frequency of that demographic of approximately 25%. So we had many more patients that came into our phase two clinical trial having that phenotype present. The reason for that is that back then, there were two large phase three clinical trials that were enrolling with lampalizumab, which excluded those patients from their studies. In the phase three clinical trials, you know, we are not commenting, of course, yet on, you know, the baseline characteristics. That will come in due time. But everyone should expect, I think, a lower present and naturally lower occurrence of patients coming into the study with that particular phenotype. The reason simply being that we do not compete anymore with these other studies and that I think we will be closer to that 25% normal demographic spread.
spk13: Thank you very much.
spk02: Thank you.
spk15: Thank you. Our next question comes from Steve Seedhouse of Raymond James. Your line is open.
spk09: Yeah, thank you. the COVID data that's coming up. I'm just curious if you have a hurdle that you set to determine next steps. That asset in that indication, I think Alexian has talked about a 20% mortality delta or having statistical confidence at a 20% reduction in mortality at their interim analysis, which ultimately they didn't meet. I'm wondering if you have something similar established that'll determine if you advance that to phase three or not. Thanks.
spk02: Yeah, thank you so much, Steve, for that question as well. So as we have previously publicly reported, I should say, in December, at the end of December towards Christmas, we completed the enrollment in this study. So we are now getting close to the point in time where the Data Safety Monitoring Board will make an assessment. That should be expected in the near future. And then the top line results will be after the full data analysis has been completed.
spk15: Thank you. Our next question comes from Derek Archilla of Siebel. Your line is open. Great.
spk11: Hi, guys, and thanks for taking the questions. Maybe one on P&H. I mean, Cedric, can you just provide some color how you think about the competitive landscape shaping up in that indication, particularly with the orals that are in development? And then maybe I'll just throw in one more in terms of some of the new programs you might be launching, you know, from now to 2022. is there an oral complement inhibitor in the mix there? Thanks.
spk02: Yeah, thank you so much, Eric, for that question. So as we have commented many times, you know, we are excited about the development of new complement inhibitors by others and ourselves. I think we're really just at the beginning of what complement control can do in a wide range of indications. Of course, the launch in PNH being the first one now, where very importantly for patients, I believe, and we all believe, that the control of extravascular hemolysis will elevate the standard of care in these patients. In a couple of years, particularly in PNH, we may be looking forward to the introduction of oral products that can control the alternative pathway of complement in these patients and thereby address extravascular hemolysis. And while on the surface it may seem much more appealing to have an oral product compared to a twice-a-week subcutaneous product, It's important to bear in mind that in a disease like PNH, there is no room for error. What I mean by that is that when you are reliant on a pill that you need to take twice per day, for example, forgetting to take a pill could have important consequences. That is a liability that many patients are not very comfortable with, neither are physicians. In line with that also is the fact that we still need to find out if the majority of patients respond well to these products and whether the control of PNH is durable in the long run. So we look forward to the phase three readouts. But beyond that, I want to end this on a positive note. I am personally very excited about the development of oral products. In PNH, not so much, but I think in other indications where kind of the exquisite control of complement is less important, it will provide a lot of opportunities. As it relates to our own internal programs, we are not yet ready to comment on that, but we look forward and are excited about sharing more in the months to come.
spk15: Great. Thanks. Thank you.
spk02: Thank you.
spk15: Our next question comes from Justin Kim of Oppenheimer and Company. Your line is open.
spk07: Hi. Thanks for taking the question. Just maybe on print, as we prepare for that readout, Could you walk us through maybe perhaps what unique insights we may see from this naive to complement treatment population? And particularly maybe where the geographies where APL2 is being used here may differ from like a standard of care perspective.
spk02: Thank you so much for that question, Justin. I'm going to hand that one over to our Chief Medical Officer, Dr. Gross.
spk04: Thank you, Sadiq, and thank you, Justin, for that. Really looking forward to the outcome of that study and sharing with you the results. So the study, as you point out, is looking at a PNH population that is naive to complement inhibitors. And the primary endpoint is hemoglobin sterilization, which is a typical endpoint for PNH studies. And in addition to that, we're looking at quality of life and transfusion dependency. So that the population, this population does not differ from the, you know, treatment naive population that you see on regions where ecolizumab is available. We had to do the studies in regions where ecolizumab is not available in order to do it, but the population does not differ. Okay, got it.
spk07: Maybe just a follow-up to the previous question. and maybe ask maybe slightly differently, when you think about pan-AMD sort of therapies, is it a fair assumption that we may see sort of modalities outside of intravitreal injection if we're looking at, you know, populations who maybe have less severe disease?
spk04: So, can you repeat the question on AMD?
spk07: Just wondering, you know, as we think about sort of new agents in a pan-AMD sort of therapeutic, does that suggest a non-injection-based therapy potentially?
spk04: Well, when you look at this is outside of AMD, you know, for diseases into the eye, the, you know, the level of systemic exposure that you will get from treatments that are not injected into the eye may be too high. So they'll have to be, you know, a therapy that administer systemically you can, you know, achieve good levels in the eye at exposing the patients to, you know, to moderate the drug and having safety concerns from a systemic perspective. Got it. Thank you.
spk15: Thank you. Our next question. comes from Althea Young of Kansas, Australia. Line is open.
spk10: Hey, guys. Thanks for taking my questions, and I look forward to a very exciting year ahead of you guys. One, just for me, is on, I mean, obviously, you know, Alexion, you know, kind of is going to be acquired, and sometimes there's disruption which can occur, you know, and I just wanted to get your perspectives on whether, you know, from a human resources standpoint or even a commercial standpoint, that you're sensing any sort of opportunity that you might be able to take advantage of, even though your data is already quite robust. And then the second question I have is just, you know, on the four programs that are kind of moving toward registrational, you know, ALS is always interesting and a little bit challenging. I mean, do you perceive that as being a higher risk, higher reward program, or should we think about them all kind of a little bit more in equivalence? Thanks.
spk02: No, thank you so much. Well, starting with the first question, our primary goal is to elevate the standard of care in PNH. You know, the competitive landscape has changed, but at the end of the day, We believe that the important unmet need that exists in PNH is going to be the main driver of sales, and we look forward to addressing that. Then as it relates to the other indications which are currently in registrational development, of which there are four, so C3 glomerulopathy with ICMPGN, ALS, colic glutenin disease, and HSCT-associated thrombotic microangiopathy, The ALS trial has a special place. It has a special place as the first neurological indication that we are targeting. It has a special place as, of course, an indication with an incredible unmet need that we hope to address. And also has a place where we believe that C3 offers advantages over other places in the complement cascade where this disease can be controlled. So for us, again, the primary motivation for us was to bring the science together with the molecular entity that we have and our belief that we can address the unmet need. Is this a high-risk program? Of course it is. Any trial in ALS is, with a high reward associated. But one that we do truly believe fits very well into kind of the plethora of indications that we are pursuing with systemic vaccine tackle planning.
spk06: Thank you. Thank you.
spk15: Our next question comes from Laura Christensen of Cowan. Your line is open.
spk14: Good afternoon. Hi, guys. So my question is actually about the allergic reaction to PEG that have been sporadically seen in people who have received the Pfizer and Moderna vaccines. I believe the CDC recommends that anyone who experiences an immediate allergic reaction to PEG should not receive the booster. So I was just wondering what gives you confidence that patients aren't being sensitized to PEG and, you know, I assume that is your belief, but if it's not, you know, why that's also the case?
spk02: Yeah, thank you, Laura, for that question. So, you know, as you correctly mentioned, there are a couple of isolated cases of anaphylaxis that have been associated with tech sensitization. This is something that is well known, you know, that can sometimes occur. It's important, therefore, that when you introduce products like ours, especially in the beginning, to make sure that there is a good follow-up. What is important to note here, however, as well, is that with the introduction of the vaccines with, you know, the pegylated element in them, there does not seem to be an extra sensitization because the booster vaccines do not seem to be associated with any type of additional immune reactions. So we feel very comfortable with where we stand right now. Will we in the future in these rare diseases, right? I mean, once in a while see an anaphylactoid reaction. That is possible. Thus far, that has not been the case.
spk14: Perfect. That's helpful. Thank you.
spk02: Thank you.
spk14: Thank you.
spk15: Our next question comes from Matthew Lucini of BMO Capital. Your line is open.
spk12: Hi, good afternoon. Thanks for taking the questions. So first, on PNH, commercially, I guess I'd love to get a little sense as to what your internal market research is telling you about the initial launch. And what I'm really looking for is a little bit more of the color around things like, are your doctors telling you that the patients are asking for the drug? Are they planning to call patients in versus waiting for the next visit? any kind of color there that could help sort of set our expectations around what the initial launch is going to look like. And then secondly, just kind of a housekeeping question, it looks like R&D saw a pretty decent sequential step down in 4Q, and I'm just wondering if that's something that we should think about as sort of the new baseline going forward or how we should think about that as we think forward into this year and beyond. Thank you.
spk02: Thank you, Matthew. I will hand the first question over to our chief commercial officer, Adam Townsend, and then Tim will take your second question.
spk03: Thank you, Cedric, and thank you, Matthew, for the question. So we've spent a lot of time with the P&H community, patients, caregivers, and everything that surrounds the patient. And we do believe that we expect some patients to have a conversation with their physician about the potential to elevate the standard of care with pexetocoplin. We've got various patient-focused marketing activities out there, and we're getting a great response from them as they interact with our content. They truly understand the unmet need that exists within the market. So, whilst this is very much an efficacy-driven story for us, we think that at launch that physicians will have identified the patients with the highest unmet need. And you've seen from our presentation and our previous discussions, we look at the market of C5 treated in thirds. We expect to transition from the patients that have the highest unmet need to the broader patient and unmet need population as we work through. A core piece of that will be when patients go in to have a conversation with their physicians and we also expect some physicians to have already identified the patients and actually potentially call them in. Still a rare disease, it will be a very thoughtful approach to launch and obviously this is a an important conversation for patients and physicians to have around the potential of texas.
spk16: Sure. And thanks, Matthew, for the question. I'll take the R&D question. So what you're seeing in terms of the 4Q step down in R&D is actually more of an accounting and SOBI-related concept. SOBE, as you know, from the structure of the deal, will reimburse Appellus for $80 million worth of R&D expenses over the course of the next four years. The way those are accounted for and when those began started in the fourth quarter, primarily, of 2020. And so that is actually counted as a contra account. And so from a GAAP perspective, those amounts were deducted from R&D. And that just brings the number down. Ultimately, the reimbursement for that $80 million will come over time over the next four years. So I would look at the true R&D expenses much closer to the third quarter, flat to a little bit up, and probably it will steadily, although not dramatically, rise over the next year. Great. Thank you. Very helpful.
spk15: Thank you. Again, if you'd like to ask a question, please press star then 1 on your touch-tone telephone. Our next question comes from . Your line is open.
spk05: Hi, great. Thanks for taking the question. I had one on Derby and Oaks. So, as you know, Cedric, in Philly, the difference in the absolute lesion growth area between the sham and the monthly was .66 meters squared. And that was obviously deeply . Now, presumably the bar is lower in Derby and Oaks given a higher power. So could you comment at all on the hurdle that you need to hit for the difference in the GA lesion growth area for Derby and Oaks to be successful? Thank you.
spk02: Thank you so much, Yigal. So the Phase III clinical trials are more than 95% powered to show the same effect that we saw in the Phase II clinical trial. for the monthly-dosed individuals, and somewhere between 80 and 90% for every other month-dosed individuals. This is, of course, on a presumption of similar variability, and accounts for a p-value of 0.05. So, you know, again, for us to kind of protect the p-value that we got in the Phase II clinical trial, we made sure to have as few changes as possible. We are studying the same exact patient population. We analyze and read the findings in the same way. You know, all of that was maintained between phase two and phase three.
spk15: Okay.
spk07: Thank you.
spk02: Thank you.
spk15: Thank you. Our next question comes from Laura Chico of WebWish.
spk08: Hey, thanks very much for taking the question. I just wanted to circle back on one with respect to wet AMD. Cedric, I think you indicated the normal frequency is around 25%. I'm wondering if you could just comment then around maybe what is an acceptable rate of new onset exudation that we should be thinking about in Derby and Oaks, A, from a regulatory perspective, and B, from a commercial perspective. Just kind of curious if patients do have a lower baseline frequency there, how might that change the expectation? And then a quick follow-up, just with respect to P and H, Could you just remind us or talk a little bit about your expectation of whether APL2 labeling would also extend to include Altamira's treated patients? I think you had a slide there comparing that with Altamira's. So what type of data or guidance might you be able to provide for patients thinking about a transition? Thank you.
spk02: Thank you so much. So starting with the first part of your question, the – the wet AMD occurrences that we had in the phase two clinical trial are important to contextualize, right? These were small exudates, which did not lead to significant vision loss. And that is why in the phase three clinical trial, we are studying the exact same patient population as we did in the phase two. So if your question is what is acceptable from a physician perspective or from a regulatory perspective in terms of exudation, it is the exudation rate that we saw in the phase two clinical trial. And that exudation rate was arguably artificially higher than what you should expect in the phase three because we had so many patients in the study that had already wet in the contralateral eye when they came into the study. And also because in the phase two, with the benefit of hindsight, we had some investigator bias that may have contributed to an increased frequency of treatment with anti-VEGF as well. All of that will be corrected in the phase three clinical trial. But I think the most important take-home message here is that our phase three clinical trial, you know, if it hadn't been for, um, COVID, if it hadn't been for the kind of the, um, the IMPDs that we had to wait for in Europe, uh, would have been rolled probably in nine months. I mean, and that gives you a sense of the unmet need that exists and the willingness and desire of physicians to treat these patients. So we are, um, you know, we start with a, with what I believe is a very strong baseline and, uh, we will see what the, what we see in the phase three clinical trial, but importantly, um, Exudations in patients with geographic atrophy are a normal phenomenon, and I would encourage listeners that haven't done that to look at our presentation at the American Academy of Ophthalmology. It was a late-breaking abstract where we looked retrospectively at 69,000 patients with geographic atrophy. It's the largest study of its kind ever done, and the purpose was to find out how frequent it is for patients with geographic atrophy to develop wet AMD. And on a base case, The number to bear in mind is that patients with pure geographic atrophy, meaning no exudations yet anywhere, develop wet AMD based on claims-based data in 8% of cases over two years. If you start off with wet AMD in one eye and GA in the contralateral eye, then that GAI has a 22% odds of developing wet AMD over the course of two years. So not at all unusual. And again, it comes down to what is the nature of these exudations that are observed. Then to get back to your second question as it relates to the labels. So we are not yet commenting on labeling. We believe that we will have a broad label when we get our approval, a broad label. Label would mean including treatment-naive patients. And in that particular case would, of course, be applicable and usable in patients that are on baseline ultramarines as well.
spk08: Thanks very much.
spk02: Thank you.
spk15: Thank you. I'm showing no further questions at this time. I'm going to turn the call back over to Cedric Francois for any closing remarks.
spk02: Thank you so much. And thank you, everyone, for joining us on our inaugural financial results conference call. We are excited about the transformational year ahead for us. I would like to close by reiterating our corporate strategy for leadership in complement. We aim to establish systemic Pexita co-plan, as a disruptive therapy across rare complement-driven diseases. We plan to become number one in the retina with the first treatment for geographic atrophy, and we continue to advance innovative technologies to control complement with a focus on complement factor C3. Thank you again for joining us today.
spk15: Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may all disconnect. Have a great day.
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