管理層發言
Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Earlier today, we announced that the license and collaboration agreement with Sarepta Therapeutics is closed. Arrowhead expects to receive a $500 million upfront payment in the next 10 days and has already received $325 million through the purchase by Sarepta of Arrowhead common stock priced at $27.25 per share. Arrowhead will also receive $250 million to be paid in annual installments of $50 million over five years and has the potential to receive an additional $300 million in near-term payments associated with the continued enrollment of a Phase I/II study of ARO-DM1, which we are on track to achieve during the next 12 months. Taken together, this adds up to $1.375 billion in cash payments. We are also eligible to receive development milestone payments of between $110 million and $410 million per program and sales milestone payments between $500 million and $700 million per program.
The total potential value of this deal, including upfront payments, equity investments, and potential milestone payments, exceeds $11 billion. On top of that, we are also eligible to receive tiered royalties on commercial sales. This was clearly a big deal and a critical step for Arrowhead to bring balance back to our business model, which in part relies on partnering noncore assets to provide capital for us to develop and commercialize our own wholly owned assets. In addition to the substantial immediate capital infusion, the deal also accomplishes a few equally important goals. One, brings in a partner with extensive development, regulatory and commercial expertise for development of drugs they have in-licensed. Two, increases Arrowhead's focus in the cardiometabolic space. Three, reduces the forward growth in our R&D expenses as Sarepta assumes clinical development responsibilities for multiple programs.
And four, provides the potential for substantial downstream nondilutive capital as milestones and ultimately royalties earned. We are now funded into 2028 and potentially through multiple commercial launches by Arrowhead and our partners. We believe we are now well-positioned for growth in 2025 and beyond. We see three primary value drivers fueling this growth from our internal development activities in the near term. These are plozasiran, obesity, and CNS. Let's begin with plozasiran. We expect our first commercial launch of plozasiran to drive substantial growth. Pending positive FDA review and approval, launch could take place late this year. We see the value proposition of plozasiran in FCS as quite clear and a substantial differentiation from any other available therapy. We think the magnitude and consistency of triglyceride lowering, the potential ability to get patients to triglyceride goal, convenient quarterly dosing schedule, and well-tolerated safety profile simply make plozasiran a very difficult drug candidate to compete against.
But this is just the first step. We are also confident that our current Phase III studies, SHASTA-3, 4 and 5 have the potential to show similar differentiation and value in the much larger severe hypertriglyceridemia or SHTG population and we believe this represents an attractive and underappreciated commercial opportunity. We are now on pace to complete enrollment for the registration of SHASTA-3, SHASTA-4 and MUIR 3 studies this year which would enable study completion in 2026 and a subsequent sNDA filing. That would substantially broaden the reach of plozasiran and provide a large opportunity for growth. As we have said in the past, we believe plozasiran has the potential to be a $2 billion to $3 billion per year drug in the SHTG market alone. Turning to obesity. We believe our two early-stage programs, ARO-IoN-HPE and ARO-ALK7 represent high-value opportunities with near and midterm data readouts that can provide more clarity on where they may fit in the obesity and metabolic treatment paradigm.
James will talk about the status of the programs in a moment, but we see the targets and pathways as very promising. Both programs are supported by published human genetic studies and the preclinical data have demonstrated dramatic results with the potential to fill gaps in the current standard of care. The possibility of long-acting agents that spare muscle mass and enable visceral fat loss without dependence on caloric restriction is exciting indeed. It appears that Arrowhead is the first company to start clinical studies against the INHBE target may currently be the only company able to address the ALK7 target, which utilizes a new version of our TRiM platform capable of delivering to adipocytes. The third area that we see driving near-term growth is our emerging CNS pipeline including the new TRiM platform, which in animal models appears capable of delivering sRNA across the blood-brain barrier, including deep brain distribution using subcutaneous injection.
Near-term clinical proof-of-concept would truly be disruptive, and we think would open the door to treating many millions of patients without adequate options. Our initial efforts with this platform address Huntington's, Alzheimer's and Parkinson's disease, all devastating conditions that lack good treatment options. We believe that HTT, MAPT and alpha-synuclein are the most validated targets in Huntington's, Alzheimer's and Parkinson's, respectively. And these are the targets we are addressing with ARO HTT, ARO MAPT and ARO SNCA, respectively. Our preclinical data in nonhuman primates have been very compelling, and we are now focused on completing IND/CTA enabling studies and GMP manufacturing to support early clinical trials. We anticipate having CTAs for ARO HTT and ARO MAPT toward the end of this year and for ARO SNCA in early 2026. Sarepta has the right to take HTT forward, and we are currently focused on keeping MAPT wholly owned.
We have not made a decision yet on partnering versus retaining ARO SNCA. As I mentioned, we believe the triumvirate of plozasiran, obesity and CNS will be our primary near-term value drivers. It is also the way investors should think about our focus. We are building a growing cardiometabolic pipeline, which includes obesity, and we will see where the new CNS platform takes us as clinical data come in. In addition to plozasiran, ARO-ALK7 and ARO-INHBE our cardiometabolic franchise includes zodasiran, our ANGPTL3 targeting drug candidate. We expect to begin a Phase III study in HoFH next quarter with zodasiran. We have a large amount of clinical data with this candidate and feel confident that it could be an effective medicine with an attractive dosing schedule in this population. This would be a relatively simple addition to our FCS and SHTG sales representatives' bags. So the incremental commercial costs associated with this additional potential product are expected to be minimal.
The Phase III study will be small, and this is a good use of fairly modest resources for us. Where else can we go in cardiometabolic? As I mentioned, ARO-ALK7 is important not only because of the compelling targeted treatment for obesity but also as a proof-of-concept that we can address the adipocytes. Adipose is the largest endocrine organ in the body, and as such, is expected to be a rich environment for cardiometabolic and obesity targets. We expect to build this out. Similarly, we believe the initial candidates built on our new CNS platform are important because of the neurological targets they address, representing some of the most challenging poorly treated public health crises remaining and also because they offer the possibility of disruptive clinical proof-of-concept. We also see important opportunities to develop additional obesity candidates based on new CNS targets. Remember that RNAi is a rifle shot and as our understanding of obesity increases, we see a role for highly specific intervention that could only be practical with systemic delivery.
We believe that this has the possibility to treat difficult diseases with reduced risk of safety and tolerability challenges that have led to so much disappointment in the CNS drug development space. This year, we also plan to expand our cardiometabolic presence with a CTA for our first dimer. It is designed to silence expression of both APOC3 and PCSK9 and we hope it will combine the triglyceride lowering qualities of plozasiran with the LDL-C lowering properties of other PCSK9 inhibitors. With this focus on cardiometabolic and a wait-and-see with CNS, we have a number of programs that are noncore. These are potential partnering opportunities and could bring additional immediate and long-term capital. Janssen generated compelling clinical data with ARO PNPLA3 and addressing a genetically defined mash population that could number in the 10 million persons range in the major pharmaceutical markets could be attractive to the right company.
This is a program for which we will seek a partner. We have learned much about our pulmonary platform through the various clinical programs. It appears to be well tolerated and quite effective at delivering to the deep lung. It is our intention to find a good partner to help identify new deep lung targets and develop a suite of candidates. Similarly, we have been very impressed with knockdown data coming out of the ARO-RAGE clinical studies. But given the complexity and expense associated with developing this as an asthma and/or COPD drug, we will seek a partner for Phase II and beyond. Clinical data from both ARO C3 and ARO CFB have been quite good and both candidates appear to do what they are designed to do. There are clear markets one or both could address, including C3 glomerulopathy, IgA nephropathy and certain lupus populations. We would like to find the right partners to develop these candidates.
This is where we are now and what we see as key growth drivers for the future. Let's review how we got here and a few key accomplishments from the quarter and since our last earnings call. First and more importantly, the U.S. FDA accepted the new drug application for investigational plozasiran for the treatment of familial chylomicronemia syndrome. This is our first NDA filing, which is a key milestone for Arrowhead, and we are pleased that it was accepted for filing. The FDA provided a PDUFA action date of November 18, 2025 and indicated it is not currently planning to hold an advisory committee meeting. We now know the potential launch date pending FDA review and approval, so we continue our work to be ready for an efficient launch on day one. Andy will talk about the work in a moment. Sticking with plozasiran, in November, we announced new results from the Phase III PALISADE study and the open-label extension from our Phase II MUIR and SHASTA-2 studies.
These data were presented in two oral presentations at the American Heart Association Scientific Sessions 2024 and PALISADE data were simultaneously published in the AHA Journal circulation. The data continued to be promising across studies, across the spectrum of triglyceride disorders and after short and long-term follow-up. In addition, plozasiran has been overall generally well tolerated to date. During the quarter, we also initiated a Phase I/II clinical trial of our first obesity candidate, ARO-INHBE, and recently received regulatory clearance in New Zealand to initiate the clinical study of our second obesity candidate, ARO-ALK7. As I mentioned, these programs represent potential drivers for growth for Arrowhead, so we are excited to get both moving into and through early clinical studies. Lastly, we presented interim healthy volunteer results from a Phase I/II clinical study of ARO CFB for the treatment of complement-mediated diseases. Data have been compelling so far, and we anticipate additional data readouts later this year. With that overview, I'd now like to turn the call over to Dr. Bruce Given. Bruce?
Thank you, Chris. Good afternoon, everyone. As Chris mentioned, the big highlight for the clinical and regulatory teams was the submission and subsequent acceptance of our first new drug application or NDA by the U.S. FDA for investigational plozasiran for the treatment of familial chylomicronemia syndrome, or FCS. The FDA provided a PDUFA action date of November 18, 2025, and indicated it is not currently planning to hold an advisory committee meeting. We also expect to submit approval applications to additional global regulatory authorities in coming months, for plozasiran for the treatment of patients with FCS. FCS is a severe and rare disease that often is caused by various monogenic mutations that lead to extremely high triglyceride levels. The normal level is triglycerides below 150 milligrams per deciliter, but patients with FCS typically have triglycerides in the thousands. Such severe elevations can lead to various serious signs and symptoms including acute and potentially fatal pancreatitis, chronic abdominal pain, which can be as frequently as daily, diabetes and cognitive issues.
The clinical basis of the NDA submission is comprised of the findings in the Phase III PALISADE study, which were positive with supportive confirmatory evidence from the Phase II clinical studies of the SUMMIT program. PALISADE successfully met its primary endpoint in all multiplicity-controlled secondary endpoints, including statistically significant reductions in triglycerides, APOC3 and the incidence of acute pancreatitis. In PALISADE, plozasiran achieved deep and durable reductions in triglycerides with median changes from baseline of approximately 80% in the plozasiran 25-milligram group and a statistically significant 83% reduction in the risk of developing acute pancreatitis compared to placebo in the pooled plozasiran 25-milligram and 50-milligram group. Overall, plozasiran has been generally well tolerated to date. In the PALISADE study, the most frequently reported treatment emergent adverse events for the 25-milligram dose that is proposed for marketing approval were abdominal pain, COVID-19, nasopharyngitis and nausea.
In addition to FCS, we are making good progress on the other Phase III studies in the SUMMIT program. These are SHASTA-3, SHASTA-4 in patients with severe hypertriglyceridemia, or SHTG, and MUIR 3 in patients with mixed hyperlipidemia. The SHASTA studies are designed to assess safety and efficacy and the MIRROR study is to provide additional safety data needed for the expected SHTG supplement to our plozasiran NDA. The SHASTA studies are global, randomized, double-blind, placebo-controlled Phase III studies to evaluate the efficacy and safety of plozasiran in adult patients with SHTG and prior documented evidence of fasting triglyceride levels greater than 500 milligrams per deciliter. Eligible subjects will be randomized to receive either plozasiran at 25 milligrams or placebo. The double-blind treatment period duration will be one year where subjects received a total of four quarterly doses.
After month 12, eligible subjects will be offered an opportunity to continue in an optional open-label extension. SHASTA-3 and 4 and MUIR 3 are all enrolling well, and we are on schedule to reach full planned enrollment this year, which would enable study completion in 2026 and subsequent sNDA filing. We are also working towards initiating SHASTA 5, a Phase III study in patients with SHTG that are at high risk of acute pancreatitis. We intend to initiate that study this year. In addition to the Phase III program for plozasiran, we are actively working on a study design and preparation for a Phase III study of zodaseran, our investigational RNAi therapeutic candidate designed to reduce production of angiopoietin-like protein 3 or ANGPTL3 which is a liver synthesized inhibitor of lipoprotein lipase and endothelial lipase, in patients with homozygous familial hypercholesterolemia or HoFH. Following a successful Phase II study called Gateway, we will provide more details on that study when it is initiated later this year.
This is another program that makes sense as it is potentially complementary to the medical affairs and commercial organizations we are building to support a plozasiran launch, and there is significant overlap in types of physicians who treat FCS and HoFH, both rare and lipid disorders. I'll now turn the call over to Andy Davis. Andy?
Thank you, Bruce. The recent acceptance of our first NDA by the U.S. FDA for investigational plozasiran is incredibly energizing for the FCS community. The frequent feedback we received from both physicians and patient societies who have read about plozasiran in last year's publication continues to be very encouraging. They cite several potential differentiating attributes of plozasiran that I will discuss briefly. First, the reduction in triglycerides is both deep and durable. As Bruce mentioned in his remarks, in PALISADE, plozasiran reduced triglycerides from baseline by an unprecedented approximately minus 80% as early as month one and maintain this reduction with a minimal variation throughout the full 12-month treatment period. Second, people living with FCS for the first time have real hope of achieving triglyceride levels below guideline-directed risk threshold associated with acute pancreatitis, such as 880 and even 500 milligrams per deciliter.
At least half of the patients at the 25-milligram dose in PALISADE saw TGs below 500 milligrams per deciliter with approximately 75% achieving levels below 880 milligrams per deciliter. To support physician education on guideline-directed risk thresholds, we previously announced the launch of our disease awareness campaign. A key focus of our messaging is to educate the community about expert guidelines which recommend maintaining triglyceride levels below 500 milligrams per deciliter to reduce the risk of acute pancreatitis. Third, the triglyceride reductions from baseline were consistent in patients with genetically confirmed and clinically diagnosed FCS. Results from PALISADE published in the journal Circulation showed that plozasiran at the 25-milligram dose, induced rapid, deep and sustained reductions from baseline in APOCIII of greater than minus 90% and in triglycerides of approximately minus 80%, independent of gene variants causing FCS.
We believe this supports the potential value of plozasiran in patients with clinically diagnosed disease regardless of genetic status. Fourth, plozasiran is the first and only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS. This is truly the outcome of most importance for physicians, patients and payers. And lastly, plozasiran demonstrated generally favorable safety and tolerability with low rates of discontinuation for adverse events and is conveniently dosed every three months, potentially reducing the treatment burden on both physicians and patients. As we prepare for the potential launch of plozasiran at the end of this year, we have built highly experienced market access and marketing organizations and our clinical development colleagues have established a fully operational medical affairs function.
Medical science liaisons from medical affairs are in the field conducting scientific exchange, our market access colleagues are presently engaging with payers to communicate clinical and economic evidence, and our National Sales Director will be executing our final field force hiring plans in the coming months. We are on track, and we're incredibly excited about the possibility of bringing investigational plozasiran to FCS patients and their families. I'll now turn the call over to Dr. James Hamilton.
Thank you, Andy. First, I want to give a quick review and update on two of the programs that are part of the Sarepta collaboration, ARO-DUX4 and ARO-DM1. These are both muscle targeted programs in Phase I/II studies, which Arrowhead will continue to run until study completion, at which time, Sarepta will assume responsibility for clinical development, and ultimately commercialization. We are currently conducting a Phase I/IIa double-blinded, placebo-controlled dose escalating study to evaluate single and multiple ascending doses of ARO-DM1 in up to 48 subjects with myotonic dystrophy. We're in the dose escalation stage of the study, and we are enrolling patients at a good pace. We expect to reach the enrollment targets in the Sarepta agreement, which would trigger an additional $300 million in payments and potentially have first data to report this year, pending discussions with Sarepta and agreement on disclosure timing.
Moving on to the second Sarepta partnered muscle-targeted program, ARO-DUX4. This is also in a Phase I/IIa dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO DUX4 in adult patients with FSHD type 1. The study is designed to enroll up to 52 subjects. Like ARO-DM1, we are in the dose escalation stage and should have first data available to report this year also pending discussion and agreement with Sarepta. These are both very interesting programs for muscle diseases with no adequate treatments available. Our preclinical data have been very compelling, and we believe the programs have the potential to be best-in-class. Our colleagues at Sarepta had extensive neuromuscular development, regulatory and commercial expertise. So their input at this time is helpful and their strategic direction and involvement in the future clinical development and commercialization will be critical.
We have a high degree of confidence that the Sarepta team can help accelerate the programs and maximize the chances for clinical commercial success. I also wanted to give a quick update on our obesity programs, ARO-INHBE and ARO-ALK7. These programs are both designed to intervene in a biological pathway regulating fat storage which in an environment of nutrient excess can become dysfunctional and overactive. ARO-INHBE is designed to reduce expression of Activin E, which is a ligand for adipose ALK7, while ARO-ALK7 is designed to reduce expression of the ALK7 receptor itself. In preclinical models, both programs demonstrated substantial reductions in fat mass versus control while simultaneously preserving lean mass. Additionally, both targets are supported by human genetics where loss of function carriers have favorable body composition and metabolic characteristics compared to noncarriers.
We always prefer genetically validated targets because we think they reduce biology risk and give important insight into predictive safety and tolerability. For ARO-INHBE, in December, we began dosing in a Phase I/IIa dose-escalating study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ARO-INHBE in up to 78 adult volunteers with obesity. In part one of the study is designed to assess single and multiple doses of ARO-INHBE monotherapy and Part 2 of the study is designed to assess ARO-INHBE in combination with tirzepatide, a subcutaneously administered GLP-1 GIP receptor coagonist. We see the potential to have initial data from part one of the study later this year. For ARO-ALK7, we recently received regulatory clearance in New Zealand to initiate a Phase I/IIa first-in-human dose escalating study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ARO-ALK7 in up to 90 adult volunteers with obesity.
We are completing manufacturing of drug supply as we speak and anticipate dosing to initiate in the middle of the year. During the last quarter, we also presented interim clinical data from a Phase I/IIa clinical study of ARO CFB, which targets complement factor B and is being developed as a potential treatment for various complement-mediated diseases. The data were presented at the eighth Complement-based Drug Development Summit. Complement Factor B plays an important regulatory role in amplifying complement alternative pathway activation and has been identified as a promising therapeutic target for complement-mediated kidney disease such as IgA nephropathy, which is the most common glomerular disease worldwide that carries a high lifetime risk of progression to end-stage renal disease. In the Phase 1/2a study, circulating levels of CFB protein were reduced by a mean of up to 90% to date with the duration of response greater than three months.
Additional data from the higher dose levels in multi-dose cohorts are pending and will be presented at an appropriate medical conference. ARO CFB has been generally well tolerated to date with safety data supportive of further clinical development. Treatment-emergent adverse events have been mostly mild in severity, with none leading to study drug discontinuation. We look forward to completing part 1 of the study over the coming months and subsequently look ahead to part 2 of the study in patients with IgA nephropathy. I will now turn the call over to Ken Myszkowski.
Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended December 31, 2024, was $173.1 million or $1.39 per share based on 124.8 million fully diluted weighted average shares outstanding. This compares with a net loss of $132.9 million or $1.24 per share based on $107.4 million fully diluted weighted average shares outstanding for the quarter ended December 31, 2023. Revenue for the quarter ended December 31, 2024, was $2.5 million compared to $3.6 million for the quarter ended December 31, 2023. Revenue in the current period relates to our collaboration agreements with GSK; revenue in the prior period primarily related to the recognition of revenue from our license and collaboration agreements with Takeda and GSK. Revenue recognition related to the Sarepta license and collaboration agreement will begin during the quarter ending March 31, 2025.
Revenue will be recognized over a period during which we are providing key performance obligations. This is primarily related to our responsibilities to manage certain clinical trials for the clinical candidates to which we granted Sarepta an exclusive license agreement. Total operating expenses for the quarter ended December 31, 2024, were $163.9 million compared to $140.1 million for the quarter ended December 31, 2023. The key drivers of this change were increased candidate costs and salaries as the company's pipeline of clinical candidates has both increased and advanced into later stages of development. Net cash used by operating activities during the quarter ended December 31, 2024, was $146.3 million compared to $117.8 million for the quarter ended December 31, 2023. The increase in cash used by operating activities is driven primarily by higher research and development expenses. Turning to our balance sheet.
Our cash and investments totaled $552.9 million at December 31, 2024. Including the $825 million in upfront payments from the Sarepta agreements, our pro forma cash and investments would be $1.4 billion at December 31, 2024. Based on our expected cash inflows from the Sarepta agreement debt repayments as well as other cash burn, we expect our cash and investments balance to be approximately $1 billion at the end of calendar 2025, and we expect to have cash runway into 2028. Our common shares outstanding at December 31, 2024, were $125.6 million. With that brief overview, I will now turn the call back to Chris.
Thanks, Ken. Not only do we see several growth drivers over the coming years, we have a robust potential catalyst calendar in 2025. Throughout the year, we expect multiple events that we believe are important. For plozasiran, we expect the following key events: initiate SHASTA-5 in patients at high risk of acute pancreatitis, fully enroll SHASTA-3, SHASTA-4, and MUIR-3, make additional global regulatory submissions, commercial launch in FCS in the U.S. and potentially the EU pending review and approval. For the obesity programs, we expect to initiate dosing in the Phase I/II study of ARO-ALK7 and potentially have the first data for Part 1 of the Phase I/II study of ARO-INHBE. For plozasiran, our investigational RNAi candidate partner Takeda and being developed to treat the liver disease associated with alpha-1 antitrypsin deficiency, we have the potential to reach full enrollment of the Phase III REDWOOD study.
For ARO-DUX4, ARO-DM1 and ARO-MMP7, we have the potential for initial data in the Phase I/II studies and the potential to achieve $300 million milestone payments from Sarepta. For both complement programs, ARO-CFB and ARO-C3, we have potential data readouts. And lastly, for the emerging CNS pipeline, we anticipate filing CTAs for our first systemically delivered and subcutaneously administered programs. As always, there's a lot going on at Arrowhead to be excited about. Thank you for joining us today. And I would now like to open the call to your questions. Operator?
分析師問答
Thank you. Our first question will come from Luca Issi of RBC Capital. Your line is open.
Great. Thanks so much for taking my question and congrats on closing the deal with Sarepta. Maybe, James, on obesity, can you just talk a little bit more about INHBE. I know you're testing both, but is this fundamentally a monotherapy play in your head or this is more like an add-on therapy to GLP-1 or whatever is next for this category? And maybe related, can you just talk about what will the downside case for the data later this year and maybe an upside case for the data later this year, what's the bogey here? So any color there? Much appreciate it. And then maybe, Bruce, super quickly, we've obviously seen Novartis is pushing out their data to next year for Lp(a). Just wondering what was your reaction to that news? And what does this mean for the broader category, including all pass around. Again, any color there, much appreciated. Thanks very much.
Sure. Thanks, Luca. I can take a shot at the first question. Like you said, we are studying ARO-INHBE in monotherapy as well as in combination with tirzepatide. And we'll have to wait and see how the data look. We haven't really made a call on what the future path development path looks like for that molecule. And similarly, I think we'll just have to wait and see. We don't have really a specific bogey to hit; I think we'll see how the data evolves on both the monotherapy side and in the combination arms.
And just to be clear, look, obesity is not a one-size-fits-all condition. And I don't think people who are in it are thinking of it that way. This is a huge number of patients with a variety of different needs. And so, we are developing over time, a suite of drug candidates against that could be used in combination with each other, in combination with others, in combination with existing therapies, in combination with new therapies. We are really excited about these two pathways, and we think they're a great step forward. And it's just not clear how the world is going to use these or, frankly, any other obesity drugs that are coming online.
And finally, your question about Lp(a). I don't have a lot of insight here. We're not on the inside of certainly the Novartis program. We're not on the inside of the Amgen program. So we really don't know. I mean, I think in general, I would say that I'm more excited about Olpasiran just because I think it's a more effective agent with respect to knocking down Lp(a). It's certainly more convenient than an antisense approach and probably better tolerated as well. So I'm generally more excited about Olpasiran from a cardiovascular disease perspective. But what's going on with Novartis's compound and frankly, even what's going on with Amgen's compound, I don't have an inside track on that information.
Got it. Thanks so much, guys.
Thank you. One moment for the next question please. And our next question will be coming from the line of David Lebowitz of Citi. Your line is open.
Thank you very much for taking my question. I'm curious in the early days from what you've seen talk to your doctors regarding APOC3 and current commercial launches. Is there any feedback you're getting from doctors on what they're seeing.
Yes, I'm just happy to comment on the feedback that we continue to receive with respect to plozasiran, which, as I mentioned, they view as highly differentiating based on the attributes I spoke to on the call. So I would say, despite the fact that there is an option available, physicians and patient societies continue to remain really enthusiastic about plozasiran.
Thanks for taking my question.
Thank you. And one moment please for the next question. Our next question will come from the line of Ellie Merle of UBS. Your line is open.
Hi. This is Jasmine on for Ellie. Thanks for taking our questions and congratulations on the announcement today. I just wanted to follow up on an earlier question. So for INHBE and ALK7, will we see weight loss data or anything on body composition from the Phase I/IIa trial. And if at this early time point, we won't see that yet. What are you looking for to see from the PK/PD results to give you confidence to move forward? Thanks.
Yes. I think regarding the first part of the study, the monotherapy arms, we will evaluate body composition using full body MRI in addition to monitoring weight loss. We will also consider the standard Phase I metrics, focusing on safety and plasma pharmacokinetics, which will likely resemble those of other GalNAc SiRNAs. Additionally, we can assess the active biomarker in the blood, which serves as a direct indicator of gene target knockdown.
Great. Thank you.
Thank you. And one moment for the next question. Our next question will come from the line of Maury Raycroft of Jefferies. Your line is open.
Hi. Congrats on the progress and thank for taking my question. Just going to ask about the SHASTA-5 study. I know you plan to start the study in the second quarter, and you've mentioned it could include 140 patients and the purpose is mostly for payers. For this study, do you have estimates on what the timeline to data could look like? And can you talk more about the strategy here? I guess, could the totality of acute pancreatitis stated derisk and outcomes study or potentially even replace the need to run a CVOT study?
So Mary, it's hard to predict. No one's ever attempted a trial like this before; it will be the first ever outcome study focused on pancreatitis as the primary endpoint. It will be enrolling patients that are a clear risk for pancreatitis. So the enrollment timeline is sort of to be determined, you might say. And in addition to that, as with the CVOT for instance, it is an outcome study. So we will go until we get the required number of events. So it's not a fixed duration after enrollment is complete. But in fact, it will keep going until the required number of events are seen. So a couple of levels of uncertainty there. We feel good about it. We think it will be well received by clinicians. But in reality, it's hard to really predict exactly when it will happen. We think it will be a very important study though, and we think it will especially be a very important study to payers and to health assessment organizations, especially outside the U.S., where places like the U.K. and Germany, these health assessment organizations are very, very important health technology assessment organizations.
They're very important. They really determine whether or not patients are going to have access to a new drug. So we think this is going to be a revolutionary study, first of its kind practice-changing. And it will impact the U.S. as well, but we anticipate less so than it will in Europe. The second part of your question, I didn't quite understand if you were asking whether it would limit the need for CVOT. I don't really think so just because I think that the question of atherosclerotic risk related to triglycerides is really separate from the question of pancreatitis risk. So I think there are two very important risks, but they're really independent questions and especially for patients with milder forms of hypertriglyceridemia where the pancreatitis risk is quite low, but the atherosclerosis risk is still very important. And we think based on genetic data represents an area of really unmet medical need and persistent residual risk of atherosclerotic cardiovascular disease.
We think we're the first drug that's really in a position to truly assess that risk and assess the opportunity for a drug that quite effectively reduces triglycerides to impact that cardiovascular risk.
Got it. Its all helpful perspective. Thanks for taking my question.
Thank you. One moment for the next question. And our next question will be coming from the line of Edward Tenthoff of Piper Sandler. Your line is open.
Great. Thanks for all the updates and for everybody as well out there. Question with respect to Europe, overseas with plozasiran. Now that we've gotten the U.S. situation sort of laid out, what are plans for Europe? And would you be partnering overseas? Are there certain thresholds we're waiting for would there have to be additional studies? Just maybe you can update us on sort of what's taking is overseas, both for FCS, but also longer term for severe hypertriglyceridemia. Thanks.
Yes, thank you for the call. This is Andy. We are actively preparing for commercialization in European markets with a commercial partner. More details will be available in the future. We are very excited about the potential of the large European markets and the opportunity to introduce plozasiran to patients there as well.
Okay. Thank you.
Thank you. One moment for the next question. And our next question will be coming from the line of Patrick Trucchio of H.C. Wainwright. Please go ahead.
Thanks. Good afternoon and congratulations on the progress here. I have a couple of follow-up questions. First, can you discuss how you see plozasiran's competitive positioning compared to olozarsen in FCS and also in the broader severe high triglyceride population? How do you anticipate these product profiles will compare in real-world settings, especially with the upcoming launch of plozasiran? Additionally, you mentioned the adipose tissue targeting platform. What targets or disease areas do you find appealing as you work on this part of the pipeline? When can we expect an update on this development?
Thank you for the question. This is Andy. I'll address the first part of your question related to differentiation. I'll speak primarily to the plozasiran data, but I would encourage you to do your own comparison between the balance and PALISADE studies to the extent you want to understand the key differences yourself. I think one of the primary differentiators that we see is around the reduction in triglycerides. As we've talked about from PALISADE, we see a triglyceride reduction from baseline, which is largely unprecedented, approximately minus 80% from baseline, and we see that as early as month one and then continued throughout that full 12-month treatment period. So, I think that's the first point of differentiation one would focus on. I think the second point of differentiation is what that means for FCS patients as far as achieving guideline-directed risk thresholds. So many of these society guidelines point to less than 500 milligrams per deciliter as the goal to which they want to get FCS patients below in order to reduce the risk of acute pancreatitis.
So obviously, the larger the TG reduction from baseline, the greater the proportion of FCS patients who are likely to achieve that guideline-directed goal. So we think that's a key area of differentiation as well. And third, in comparison to those studies, you'd have an appreciation for the fact that PALISADE study both genetically confirmed and clinically diagnosed patients. And what we saw was that plozasiran was the first and only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in that population. So again, an important point of differentiation we spoke to acute pancreatitis as an important outcome for payers and patients and physicians. And so, seen a statistically significant difference in PALISADE is an important differentiator. And then lastly, the safety profile has been generally very tolerable with low rates of discontinuation for adverse events.
And importantly, we see in every three-month dosing with plozasiran, and that's different from the alternative. That's only four injections a year and what patients tell us is they prefer fewer injections and what physicians tell us is that helps with compliance and adherence. And so, they're quite excited about in every three-month dosing regimen. So that would be, I think, the final point of differentiation I might point you towards. So those are just a handful of differentiating attributes of plozasiran that we recognize as a team.
So let me add my thoughts. This is Bruce Given again. I believe it’s a bit easier to compare the BALANCE study with PALISADE than to directly compare SHASTA-2 and the existing data for SHTG with olezarsen because the BALANCE study included both mixed hyperlipidemia and a limited number of patients related to SHTG. This makes it more challenging to predict what olezarsen will demonstrate in SHTG. We have a clearer idea of the expected outcomes for plozasiran, as I think SHASTA-2 gives us a solid indication of what we might observe there. Generally, I believe both for FCS and SHTG, this market represents an educational opportunity for the industry, including us and Ionis. We are opening up a market that has been virtually untreatable, significantly underserved with available treatments that have existed for years, mostly generic and not widely promoted. While the market often views this in terms of head-to-head competition, I see it more as an opportunity for expansion.
Having multiple players will actually facilitate that. We appreciate the direct comparisons that Andy mentioned, but I believe the greatest benefit to patients will come from multiple voices ensuring physicians are well-informed about these markets and aware that effective treatments are now available. It seems more about how both of us can grow the overall market rather than competing for a limited share. I’d like to emphasize that from a medical standpoint.
Then on the obesity question, the adipose question, Patrick, this is James. So the indications that we're looking at, of course, include things like obesity, type 2 diabetes, lipodystrophy is also on the list. And we have a lot of targets that are of interest in the adipocyte. Of course, we're not going to share these targets publicly at this time. I think we're evaluating those targets preclinically and you'll learn about the individual targets as they reach the clinic.
Great. Thank you so much.
Thank you. One moment for the next question. And our next question is coming from the line of Mayank Mamtani of B. Riley Securities. Your line is open.
Yes. Good afternoon. Thank for taking our questions and congrats on the Sarepta deal close. So on that Sarepta partnership. Maybe a couple of quick questions. On ARO-DM1, you have cohorts 4 and 5 exploring 12 mg per kg quarterly and semiannual dosing. Just to clarify, when you have day 180 biopsy data from both cohorts 4 and 5, is that part of disclosure within this year? Or is that sort of a follow-up to initial sort of SAD early MAD update you have this year? And then similarly for ARO DUX4, which I understand is a larger study, how further would you be along in the MAD when you and your partner plan to put out an initial update this year.
Hi, Mike. So our job here is to continue these programs moving forward as quickly as we can. We think these are important drugs. We look forward to handing them over to Sarepta once we finish the current studies. We really can't give you any guidance on data readouts because that's entirely up to Sarepta. We will be generating data all year when they decide to present data when data are interruptible and such, we'll be really up to them. So…
Okay. Okay. Understood. And just a quick one on zodasiran and HoFH. Maybe if you could contrast the Phase III target patient population with that of another existing therapy and could patients theoretically get both antibodies to have optimal outcomes. Thanks again for taking my question.
Yes. I don't think that they'll be used together. And I think the target population is basically very much the same as the other existing therapy, of course, is an intravenous infusion. It has the same liability as all the monoclonal antibodies have for patients that occasionally develop severe allergic reactions, which doesn't tend to characterize the siRNAs. And of course, we would be quarterly dosing as opposed to monthly dosing. But I think the patient population itself, which is essentially patients that are still have high LDL cholesterol despite high-dose statins and PCSK9 inhibitors, that's basically the patient population. There's a nuance there you also pick up some patients that are intolerant to statins. But essentially, the biggest part of the population of patients that despite high-dose statins and PCSK9s are still not at goal, which is basically the treatment population as well.
Got it. Thank you.
Thank you. One moment for the next question. And the next question is coming from the line of Andrea Newkirk of Goldman Sachs. Your line is open.
Good afternoon. Thank you so much for taking our question. Maybe a follow-up to the prior one. Could you just speak a little bit more on this decision to restart efforts with zodasiran? And maybe quantify for us the magnitude of the commercial opportunity that you do see in HoFH to justify the incremental investment that you expect to see on both the R&D as well as the commercial side. Thank so much.
The Sarepta deal provided us with the capital to consider the opportunity, which we viewed as a clear decision in this industry. The clinical program data has been positive so far, and we were simply waiting for the capital to allocate to it, which we now have. The Phase III program is not very costly, and it will involve a relatively small study. The market is not huge, but the additional commercial costs will be low since we plan to address this market with plozasiran anyway. As I mentioned in my earlier remarks, we are effectively adding this to our existing sales representatives, meaning the Phase III will not significantly increase our costs, and the added commercial expenses are minimal. We see this as a market where we can gain market share, and our intention is to move forward with it.
Thank you. One moment for the next question. And the next question is coming from the line of Mani Foroohar of Leerink. Your line is open.
Hi, guys. Thanks for taking the question. A couple of quick ones to clarify. When you talked about your pro forma cash balance, et cetera, $1 billion, you said that was one of the things that into account was debt service, and you described as debt repayment. Are we to assume that you're going to be putting capital to paying down the 15% debt that you took out? Or should we just assume that, that is debt service in the form of interest? And then I have a follow-up.
So we do need to make certain payments when we bring capital in from milestone payments and such. So that is included in the cash balance that I referred to earlier. And to the extent there are further milestones down the road, certain percentage of those would be considered debt repayments. But we wouldn't be making anything beyond that.
Okay. That's helpful. And then I just want to clarify your views on how you should think about the CVOT. How do we think about potential gating to restart that, timing to pursue of CVOT and how to think about your own view on what are getting events to begin such a study and the capital that you put into place and how that might affect your willingness to partner other assets to continue to keep the balance sheet for running given that, that adds meaningful OpEx?
Yes, that's a great question. I don't have a concrete answer other than that we would like to conduct the CVOT, and the reasoning for that is clear. I'll let Bruce elaborate on that shortly. We want to proceed, but we're waiting for additional capital. We're not ready to start until we have a clearer outlook on funding. Although we currently have a decent amount of capital, we will need a significant influx of additional funds before we can consider starting that initiative. I mentioned some of the current programs where we are interested in potential partnerships, such as Arrow rage, discovery partnerships in pulmonary, and collaborations with C3, Factor B, and PNPLA3. These are not core to our business, and we're open to letting them go. We'll see what kind of capital might come in with those. However, some programs are currently off-limits. We believe ALK7 and INHBE hold too much value in the near to mid-term to consider partnering them.
We'll also hold onto MAPT for now and evaluate its progress. We're open to a discovery partnership in CNS with a limited number of targets, and if the right capital comes in from that type of partnership, we could consider a partnership in that area. Although it's not a major priority now, it's something we are willing to explore. As for adipocytes, there are numerous new targets we plan to pursue ourselves while keeping them wholly owned to strengthen our cardiometabolic franchise. However, there are likely enough opportunities to bring in partners for new targets as well. Cardiomyocytes is an emerging area; we aren't currently involved in clinical trials for them, but we have promising technology that may be ready soon. This could also be an area for potential partnerships. There's a lot of possibilities, and we'll assess how things develop and what kind of capital is available before making decisions on the CVOT. Bruce, would you like to add anything?
No. For those who may not be up to date on the case with CVOT, there is a growing amount of information from Mendelian randomization studies. These studies indicate that a significant portion of the unmet need and residual risk persists despite our ability to reduce LDL levels significantly. This risk appears to be largely attributable to elevated triglyceride-rich lipoproteins. We believe plozasiran is the most effective drug we've seen for lowering these levels. Based on the Mendelian randomization data, we expect it could be very effective for patients with mixed hyperlipidemia and severe hypertriglyceridemia, particularly in the range of 500 to 800 milligrams per deciliter. We anticipate that CVOT would likely demonstrate a meaningful reduction in residual risk even with well-controlled LDL. We are eager to pursue this study as we consider it crucial for answering this question. Scientifically, it would be very significant for cardiologists, similar to the current interest in Lp(a). We are keen to proceed, but we need to ensure we have the proper funding to do so.
And also to be clear that the SHTG market alone, which, of course, would not require the CVOT, we have ongoing Phase IIIs now. We said we're going to be fully enrolled this year, we believe, and we think those studies will be finished in 2026. Those enable addressing a market that we think makes plozasiran a $2 billion to $3 billion per year drug alone. So yes, we do like the idea of continuing to expand the reach of plozasiran. But even with what we're doing right now, we think that makes plozasiran a large drug.
I'm sorry. I just want to clarify. So what I'm taking away from this is that, you've given us some updated clarity on your cash position that net of sort of contractually agreed upon payments for debt service, but not including additional voluntary paydown of principal beyond that? Do you expect to have cash pro forma near the end of this year about $1 billion. Despite that, given your existing OpEx and CapEx you expect for your platform, you still need more capital to be able to feel comfortable moving forward into the CVOT. Is that a correct interpretation of what you just said?
Yes, that is a correct interpretation of what I said. Additionally, we have other initiatives in obesity and CNS, as well as the current SHTG studies, which we believe will also create value. These will require capital, which is why we will need to secure additional funding to proceed with a CVOT.
Thank you. One moment for the next question. And our next question will be coming from the line of Brendan Smith of TD Cowen. Your line is open.
Hi, thank you for addressing my questions. I have a quick inquiry about zodateran. I understand that you mentioned a Phase III trial for HoFH starting next quarter. Considering the development cost synergies with plozasiran and reviewing the entire balance sheet along with the cardiometabolic pipeline, do you have any plans to potentially explore heterozygous FH with zodateran, perhaps if it proves effective in HoFH or even simultaneously? I'm curious if that's an option you’re considering, or if you've decided to focus solely on HoFH and pursue other indications with different drugs. Thank you.
Yes, we have examined this issue closely. We believe that for patients who receive the right doses of statins and also undergo PCSK9 inhibition, there remains a significant unmet medical need among those who can't reach their targets in the HeFH market. Unfortunately, there is no regulatory pathway available to address these patients outside of pursuing a full development program for HoFH, which would likely require a commitment to a cardiovascular outcomes trial. We don't believe that this effort is justified in this case. If there were a way to create a tailored program that specifically targets the remaining unmet needs after adding PCSK9 to statins, that would be worth exploring. However, we've looked into this and found no clear regulatory path. So, to answer your question, we are not pursuing HoFH for that reason.
Got you. Okay. Thanks very much guys.
Thank you. One moment for the next question. And the next question is coming from the line of Jason Gerberry of Bank of America. Your line is open.
Hi, guys. Thanks for squeezing me in. For me, I'm just kind of curious how you guys are thinking about this two to three year window where you launch plozasiran for FCS. And if you think that's enough time for revenues to be meaningful. And as you think about the challenge really of taking this largely undiagnosed patient group and getting them into what sounds like if you talk to clinicians, who are already prescribing the existing therapy, a small number of specialist centers to prescribe the script or if you look at it more as sort of an educational launch, and it's really all about SHTG. Just kind of curious to get your perspective there.
Yes. Thanks, Jason. This is Andy. So as I mentioned in my remarks, we're incredibly enthusiastic about plozasiran specifically for FCS patients. We do think there is a community of FCS patients who for a long time have been have not had great options for them with respect to pharmacotherapy. And so, plozasiran being available, we think will truly be a game changer for many of these FCS patients. That's what they've told us. And so we do believe in the return on investment over the next two to three years for plozasiran and FCS specifically. And we're heavily focused on bringing those patients a treatment option that didn't exist previously. I would just say, as it relates to any future markets, there is a high degree of overlap, as you would know, between those physicians that will be interested in treating for SHTG versus those that will be focused on patients who have familial chylomicronemia syndrome. So any medical and commercial-related activities conducted over the next two to three years focused on FCS. No doubt, there'll be an overlap of those physicians that will be interested in understanding that therapy for patients who have SHTG as well.
Thanks, everyone, for joining us today, and we look forward to seeing you next quarter.
This does conclude today's conference call. Thank you for joining. You may now disconnect.