Earnings call: Arrowhead Pharmaceuticals focuses on cardiometabolic drugs

Arrowhead Pharmaceuticals Inc. (NASDAQ:ARWR) discussed their fiscal 2024 second-quarter results, emphasizing their strategic focus on the cardiometabolic space and progress in their drug pipeline. The company highlighted their late-stage drug candidates, plozasiran and zodasiran, which are moving towards regulatory submissions. Arrowhead reported a net loss for the quarter and outlined their financial position, including recent equity financing and milestone payments.

Key Takeaways

• Arrowhead Pharmaceuticals is concentrating efforts on the cardiometabolic space with two promising late-stage drug candidates.
• The plozasiran PALISADE Phase 3 study is complete, with top-line data expected in June and an NDA submission planned by year-end.
• The company is also preparing for a Phase 3 study of zodasiran for HOFH and is awaiting FDA feedback.
• Arrowhead has initiated dosing in clinical programs for complement-mediated and skeletal muscle diseases.
• The company plans to host R&D webinars and present at medical and scientific meetings to showcase their pipeline.
• Financially, Arrowhead has strengthened their balance sheet through equity financing and milestone payments from Royalty Pharma.

Company Outlook

• Arrowhead plans to advance 18 clinical programs across various indications throughout the year.
• Upcoming R&D webinars and presentations at medical meetings are scheduled to highlight the company's work.
• The company is eligible for up to $485 million in additional milestone payments from Amgen (NASDAQ:AMGN) and Royalty Pharma.

Bearish Highlights

• Arrowhead reported a net loss of $125.3 million for the quarter, with no revenue recorded compared to the same period last year.
• Total operating expenses increased to $126.2 million from $98.1 million year-over-year.

Bullish Highlights

• The Phase 2b study of plozasiran showed promising results in reducing triglyceride levels.
• The company's cash and investments totaled $523.1 million as of March 31, 2024.
• Arrowhead is actively discussing potential licensing or commercialization partnerships.

Misses

• The placebo effect in the SHASTA-2 study was challenging, but the company has strategies to manage it in future trials.

Q&A Highlights

• The company discussed the efficacy and tolerability of their drugs in various patient populations and the rationale behind dose selection for their SHTG program.
• Arrowhead is focusing on data-driven decisions for the advancement of their complement programs, with initial data expected by year-end.

Arrowhead Pharmaceuticals is clearly making strides in the cardiometabolic disease area, with several late-stage drug candidates and a robust pipeline. Despite the financial loss this quarter, the company's strategic partnerships and financing efforts seem to be laying a foundation for future growth. The upcoming months will be critical for Arrowhead as they await top-line data and progress with regulatory submissions.

InvestingPro Insights

Arrowhead Pharmaceuticals Inc. (ARWR) has been a company of interest for analysts and investors alike, particularly given its strategic initiatives in the cardiometabolic space. Here are some insights based on real-time data from InvestingPro and InvestingPro Tips that may provide additional context to the company's current financial health and market position:

InvestingPro Data:

• Market Cap (Adjusted): $3.06 billion

• Price / Book (as of Q2 2024): 6.33

• Revenue Growth (as of Q2 2024): -87.0%

InvestingPro Tips:

• Analysts have revised their earnings upwards for the upcoming period, indicating a potential positive shift in the company's financial trajectory.

• Despite the anticipation of a sales decline and a drop in net income for the current year, Arrowhead operates with a moderate level of debt, which may provide some financial flexibility as it continues to develop its late-stage drug candidates.

For readers looking to delve deeper into Arrowhead Pharmaceuticals' financials and market predictions, there are 8 additional InvestingPro Tips available, which can be accessed by visiting https://www.investing.com/pro/ARWR. Remember to use the coupon code PRONEWS24 to get an additional 10% off a yearly or biyearly Pro and Pro+ subscription. These tips could offer valuable insights for making informed investment decisions, especially in light of the company's recent net loss and the critical upcoming period for its drug pipeline.

Full transcript - Arrowhead Research Corp (ARWR) Q2 2024:

Operator: Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference Call. Throughout today's recorded presentation, all participants will be in a listen-only. After the presentation, there will be an opportunity to ask questions. [Operator Instructions] I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

Vince Anzalone: Thank you. Good afternoon, everyone and thank you for joining us today to discuss Arrowhead's results for its fiscal 2024 second quarter ended March 31, 2024. With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter. Dr. Bruce Given, our Interim Chief Medical Scientist who will provide an update on our cardiometabolic pipeline. Dr. James Hamilton, our Chief of Discovery (NASDAQ:WBD) & Translational Medicine, will provide an update on our earlier stage programs. And Ken Myszkowski, our Chief Financial Officer, will give a review of the financials. Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q. I'd now like to turn the call over to Chris Anzalone, President and CEO of the company. Chris?

Chris Anzalone: Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. As we discussed in our last conference call, Arrowhead has reached a point where our business requires a greater degree of focus. We are in the process of building out our expertise within the cardiometabolic space and focusing more of our spend in that area. These are wholly appropriate actions because our cardiometabolic programs represent a substantial amount of potential near, mid, and long-term value. We need to ensure that they are properly resourced, both from a financial and human capital standpoint, and that they are at the center of investor analysis of our business. This is a good thing for Arrowhead. We have two late-stage drug candidates with data across diverse populations, from ultra-rare to highly prevalent, spanning over 1,000 human subjects. We see a train of potential value creation with plozasiran and zodasiran and expect to file NDAs or supplements to expand those labels almost every year over the next five to six years. This is a pipeline within just two drugs, and I believe we will start unlocking value in the very near term. Further, we expect to expand our cardiometabolic reach into obesity and metabolic disease with two additional drug candidates reaching the clinic this year. The plozasiran PALISADE Phase 3 study in patients with familial chylomicronemia syndrome or FCS, is clinically complete. The last patient's last visit occurred last week. The database should be locked over the next two weeks, and I expect to disclose top-line data at our cardiometabolic webinar in June with a fuller dataset hopefully presented this year at an appropriate medical conference. We believe that plozasiran will become our first commercial product, and we are preparing for an NDA submission for use in FCS patients by the end of the year with a potential launch in 2025. To this end, our commercial preparations are well underway. We have begun building our commercial team including people with deep expertise in cardiometabolic marketing, commercial operations and market access. We're also in the later stages of solidifying a specialty pharmacy and patient hub system that will be ready to help ensure FCS patients get plozasiran soon after its anticipated approval. Beyond our commercial infrastructure, we have begun building out our medical affairs team with a focus on field support to help clinicians better understand APOC3 inhibition. Additionally, we have begun helping physicians who request early access to plozasiran to do so for appropriate FCS patients prior to approval. We are also studying plozasiran in the broader severe hypertriglyceridemia or SHTG population. Toward that end, we have begun screening patients in two Phase 3 studies, SHASTA-3 and SHASTA-4, and are preparing a third Phase 3 in SHASTA-5. Of course, it is early, but our aggressive goal is to complete enrollment of those studies in 2025. SHASTA-3 and SHASTA-4 are 52-week studies, and SHASTA-5 is an acute pancreatitis study that will follow patients until a set number of pancreatitis events is reached. Turning to the zodasiran, we submitted briefing documents including Phase 3 study designs for patients with homozygous familial hypercholesterolemia or HOFH, to the FDA and expect an end of Phase 2 meeting this month. We hope to initiate Phase 3 soon after we receive regulatory feedback. We have also completed our analysis of how to move forward in the large mixed dyslipidemia population with a cardiovascular outcomes trial or CVOT. We have submitted our proposal to the FDA and expect feedback over the next month, and then will seek input from the EMA and other regulatory authorities. We will provide detailed information about our plans, expected timing and costs once we know we have regulatory alignment on design. Plozasiran and zodasiran are important candidates for us because they offer new and expanding commercial opportunities over the next several years, and because clinical data have suggested that they have a high probability of success. Bruce will talk more specifically about results, but a lot of data have been presented recently, and we have been encouraged by the safety and tolerability, target engagement, and downstream changes in lipids and lipoproteins across multiple patient populations. As I mentioned, over 1,000 people have enrolled in a plozasiran and zodasiran clinical studies. Safety and tolerability data have given us confidence that these could be appropriate therapeutics not only for small and medium-sized populations, but also importantly, broad mixed dyslipidemia populations. Target (NYSE:TGT) engagement measured by circulating protein knockdown of APOC3for plozasiran and ANGPTL3 for zodasiran have been impressive and consistent. The exact numbers will vary a bit depending on the study population, duration of treatment, dose level, and measurement time point. However, we are consistently seeing mean max knockdown exceeding 75% to 90% with a long duration of effect that supports a quarterly dosing interval for plozasiran and zodasiran. This is what we designed the programs to achieve, so we are very encouraged to see clinical results consistent with our expectations. The downstream change in various lipids and lipoproteins have been favorable and consistent with published genetic data in APOC3 and ANGPTL3 deficient humans and consistent with experimental data in animals receiving APOC3 and ANGPTL3 inhibitors. Similar to target engagement, the exact changes varied a bit between different study populations, but generally speaking, subjects treated with plozasiran and or zodasiran showed improvements in multiple atherogenic lipid and lipoprotein levels, including remnant cholesterol, which is increasingly viewed as an important target for new therapies to address atherosclerotic cardiovascular disease, or ASCVD. Numerous epidemiologic studies have shown an association between higher triglyceride-rich lipoproteins or TRLs, and an increased risk of ASCVD. Despite potent LDL cholesterol-lowering therapies, residual ASCVD risk persists due in part to high levels of atherogenic TRLs. Remnant cholesterol is also believed to be a major contributor to the residual risk of atherosclerotic cardiovascular disease after LDL is well controlled. We believe plozasiran and zodasiran represent significant opportunities to help a lot of patients. For all the reasons I mentioned, we are moving as quickly as possible toward treatments in FCS, HOFH, SHTG, and the very large population of patients with ASCVD due to mixed dyslipidemia. We believe we can help a large number of patients and create a substantial amount of value with plozasiran and zodasiran alone. However, it makes sense to leverage our growing cardiometabolic capabilities by expanding the vertical. We expect to introduce two new candidates into the clinic in the fourth quarter aimed at obesity and metabolic disease. These are ARO-INHBE, a liver-directed candidate targeting inhibin βE, and an undisclosed candidate targeting adipose directly. We will discuss those in more depth during a focused webinar in the summer. We continue to make progress beyond the cardiometabolic vertical as well. Within pulmonary, the ARO-MMP7 and ARO-MUC5AC Phase 1 studies continue to enroll patients, and the ARO-RAGE Phase 1 study is enrolling high FeNO patients with moderate to severe asthma. The FeNO cohorts have been slow to enroll because the high baseline FeNO required of the study has led to a high screen fail rate. We believe in the candidate, and the target engagement data has been what we had hoped for, so we are not going to wait for that to read out before progressing to a Phase 2 study. We have designed a Phase 2 study in asthma patients and are moving toward launching that in the fourth quarter. ARO-RAGE tolerability has been good in the Phase 1 study. We have seen clear evidence of substantial target engagement in the Phase 1, and data in animal models were very encouraging. The RAGE pathway has also generated a good amount of KOL interest, so we are excited to move forward as quickly as we can. Moving toward new programs, during the last quarter we began dosing in two new clinical programs, AROCFB for the treatment of diseases associated with activation of the complement pathway, and ARO-DM1 for the treatment of type 1 myotonic dystrophy or DM1. These programs split well with ARO-C3 and ARO-DUX4 respectively. The former is enrolling the patient portion of a Phase 1/2 study, and together with AROCFB, provides a focused portfolio in complement-mediated diseases. ARO-DUX4 is enrolling FSHD patients in a Phase 1/2 study, and together with ARO-DM1, creates a focused skeletal muscle portfolio. We now have 14 clinical stage programs, 10 of which are wholly owned. I expect we could have 18 clinical programs by the end of the year. This is a lot, and they certainly can be difficult to track and properly value by investors. We think of our wholly owned assets in a series of verticals. As we have discussed, the cardiometabolic vertical is our primary focus. But beyond that, we have a pulmonary vertical, a complement vertical, a muscular disease vertical, and by the end of the year, a CNS vertical. We expect to partner within these four verticals in order to limit our spend and bring in capital to properly fund our cardiometabolic vertical and our other research programs. But we believe this is the way investors should look at our pipeline. Understanding and properly valuing these assets can still be difficult, so we recently announced the upcoming 2024 Summer Series of R&D webinars to highlight some of our work. Starting this month and continuing each month through September, we will host five webcast events. Each event will feature presentations by Arrowhead team members and external key opinion leaders who will discuss disease areas and treatment landscapes. We will talk about Arrowhead's candidates, the biological rationale and preclinical data supporting each candidate, and our clinical development strategy for each pipeline program. The series is designed to highlight important value drivers in a focused way. The Summer Series schedule is as follows. May 23 is Muscle Vertical Day, where we will cover ARO-DM1 and ARODUX4. June 25 is Cardiometabolic Day, where we will give an overview of both plozasiran and zodasiran data to date, including Phase 3 PALISADE FCS data, and talk about the future of the programs and the diseases we aim to treat. July 16 is Pulmonary Day, which includes ARO-RAGE,ARO-MUC5AC, and ARO-MMP7. August 15 is Obesity and Metabolic Disease Day, where we will talk about ARO-INHBE and the undisclosed adipose candidate; and September 25 is CNS Day, where we will highlight our central nervous system programs, including updates on the platform and on a specific undisclosed candidate planned to enter clinical development later this year. In addition to the Summer Series, we also recently announced a busy month of presentations at medical and scientific meetings. These include presentations at TIDES USA, the American Thoracic Society 2024 International Conference, the International Conference on Antiviral Research, European Atherosclerosis Society Congress, and the National Lipid Association Scientific Sessions. These are all planned for May. In addition, we plan to present on many of our programs at several medical meetings throughout the year. We have a lot going on, including a lot of exciting results to talk about. During the last few months, we also strengthened our balance sheet with two inflows. The first was done in January when we announced an equity financing with gross proceeds of $450 million. The second was just announced last week. That was a $50 million milestone payment that we received from Royalty Pharma following the completion of enrollment of the Phase 3 OCEAN(a) Outcomes Trial of olpasiran, being conducted by Amgen. We originally licensed olpasiran, previously called AROLPA, to Amgen in 2016 and then monetized our future royalty stream in a transaction with Royalty Pharma in 2022. Arrowhead is further eligible to receive up to an additional $375 million from Amgen and $110 million from Royalty Pharma in aggregate development, regulatory, and sales milestone payments associated with olpasiran. This is a good example of how we use partnering and creative financing structures as important parts of our long-term financing strategy. We are always working on potential future deals and now is no exception. We are confident that we can complete additional transactions this year to further strengthen our balance sheet to support future clinical development and commercialization of our wholly owned programs. With that overview, I'd now like to turn the call over to Bruce. Bruce?

Bruce Given: Thank you, Chris. Good afternoon everyone. As Chris discussed plozasiran and zodasiran at a high level, but I want to spend some time going over a few specific things: First, the data on the SHASTA-2 study of plozasiran that we presented at ACC and simultaneously published in JAMA Cardiology. Second, the design and status of SHASTA-3, 4, and 5. Third, expectations for our upcoming EAS and NLA presentations; and lastly, a review of the soon to report PALISADE study of plozasiran in familial chylomicronemia syndrome or FCS. Let's jump right in with the SHASTA-2 study of plozasiran. To review, plozasiran is designed to reduce production of apolipoprotein C-III, or APOC3, a component of triglyceride rich lipoproteins, or TRLs, and a key regulator of triglyceride metabolism. APOC3 increases plasma TG levels by inhibiting breakdown of TRLs by lipoprotein lipase. It also inhibits uptake of remnant cholesterols, derived from TRLs, by hepatic receptors in the liver. The SHASTA-2 study was a double-blind, placebo-controlled Phase 2b study in adults with severe hypertriglyceridemia, or SHTG. Three dose levels of plozasiran 10 mg, 25 mg and 50 mg were evaluated against placebo in 229 participants with fasting triglycerides of greater than or equal to 500 mg/dL at screening. Each participant received subcutaneous injections on day 1 and week 12 with subjects then followed all the way out to week 48. The primary objective of the study was to evaluate the safety and efficacy of plozasiran in adults with SHTG and to select a dosing regimen for later stage clinical studies in this patient population. SHTG is characterized by triglycerides levels greater than 500 mg/dL and is known to significantly increase the risk of ASCVD and acute pancreatitis, often with recurrent attacks requiring repeat hospital admissions and worsening outcomes. Pancreatitis risk is proportional to the number, characteristics, and concentrations of TRLs and increases as triglycerides increase. Currently available drug therapies generally don't sustainably reduce triglycerides below the pancreatitis risk threshold. In addition to SHASTA-2, there is also an open label extension study that is ongoing. So final data from the double-blind treatment period of SHASTA-2 were presented at ACC and published in JAMA Cardiology. These were exciting data, which received a lot of attention and were well-received at ACC and in subsequent discussions with physicians. With respect to pharmacologic activity, treatment with plozasiran led to dose-dependent placebo-adjusted reductions in triglycerides at 24 weeks, which was the primary endpoint. The reductions observed were minus 49%, minus 53%, and minus 57% for the 10, 25, and 50 milligram doses respectively. For perspective, currently available drugs usually would be expected to produce reductions of maybe 20% or so. As expected, these triglyceride reductions were driven by corresponding placebo-adjusted reductions in APOC3 of minus 68%, minus 72%, minus 70% at week 24. All these measures were highly statistically significant. Week 24 measurements represent the point of minimal efficacy, referred to as trough measurements, just prior to the next planned quarterly dose. Mean maximum non-placebo-adjusted reductions from baseline in triglycerides in APOC3 were up to 86% and 90% respectively, and typically occurred around week 16 or week 20. Importantly, we also looked at the percentage of patients who met the goal of reducing triglyceride levels below 500 milligrams per deciliter, a level above which the risk of acute pancreatitis meaningfully increases. Among subjects treated with plozasiran at the week 24 trough time point, greater than 90% receiving the 25 or 50 milligram doses, achieved a triglyceride level less than 500 milligrams per deciliter. In addition, around half of the subjects at these doses achieved normal triglyceride levels of less than 150 milligrams per deciliter at week 24, which is surprising given the mean starting levels of almost 900 milligrams per deciliter. In addition to reductions in triglycerides, subjects treated with plozasiran also showed improvements in multiple atherogenic lipid and lipoprotein levels, including remnant cholesterol, HDL cholesterol, and non-HDL cholesterol. Plozasiran demonstrated a favorable safety profile in SHASTA-2. Observed adverse events generally reflected the comorbidities, and underlying conditions of the study population. The adverse event and serious adverse event profiles, were generally similar across treatment groups, although worsening of diabetes did appear more frequently in the 50 milligram dose. All serious treatment emergent adverse effects, were deemed not related to plozasiran. Overall, then, the deep, consistent, and sustained reductions in APOC3 and triglycerides and improvement in multiple atherogenic lipoprotein levels, gives us a level of confidence as we initiate Phase 3 studies in patients with SHTG. These 3 Phase 3studies are called SHASTA-3, SHASTA-4, and SHASTA-5. I will start with descriptions of SHASTA-3 and 4 since they are very similar to each other, and are being initiated now. Both studies are global, randomized, double-blind, placebo-controlled Phase 3 studies to evaluate the efficacy and safety of plozasiran in adult subjects with SHTG. 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 receive a total of four quarterly doses. After month 12, eligible subjects will be referred, I'm sorry, will be offered an opportunity, to continue in an optional open-label extension. The primary endpoint for the studies is placebo-adjusted percent change in fasting triglyceride levels at month 12. SHASTA-3 is planned to include approximately 400 subjects, and SHASTA-4 is planned to include approximately 300 subjects. We've begun activating sites for these studies and will activate others as quickly as possible. There are already patients in screening, so we expect to have the first patient's dose soon. This has moved very rapidly, and I'm proud of the work done, by all of the Arrowhead teams involved, our CRO, and the investigators and institutions that are participating in the studies. I also want to give a quick update on SHASTA-5. We are still finalizing some details about the study, but it is currently planned as a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate plozasiran versus placebo in approximately 140 adult subjects with SHTG at high risk of pancreatitis. Subjects must have triglyceride levels greater than 880 milligrams per deciliter and a history of acute pancreatitis events. It will be randomized in a one-to-one ratio to receive either plozasiran 25 milligrams or placebo dosed quarterly. The primary endpoint of the study is incidence of adjudicated acute pancreatitis events, compared with placebo. Now that SHASTA-3 and SHASTA-4 have been initiated, the plozasiran clinical development team is finalizing the SHASTA-5 design and working to initiate the study as soon as possible. We think performing a dedicated study in this high-risk population, if successful, will be useful for payers on a global basis. Next, I want to highlight some upcoming presentations on plozasiran and zodasiran. At the European Atherosclerosis Society, or EAS, on May 28 and 29, we will be presenting final results from the MUIR study of plozasiran and the ARCHES-2 study of zodasiran. Both of these studies are in mixed hyperlipidemia populations recruited with identical enrollment criteria. For clarity, this field is moving away from the term mixed dyslipidemia, to the term mixed hyperlipidemia. So, expect to see and hear the two terms used synonymously in the short-term, but in the longer term, expect to hear mixed hyperlipidemia used more frequently. I already described plozasiran mechanistically, but to review, zodasiran is designed to reduce production of angiopoietin-like protein 3, or ANGPTL3, which, like APOC3, is a hepatocyte-expressed regulator of triglyceride metabolism. However, ANGPTL3, while similar to APOC3 in having an effect on lipoprotein lipase, also impacts endothelial lipase and non-LDL receptor-mediated uptake of LDL. As such, by reducing ANGPTL3, zodasiran causes some downstream changes in atherogenic lipids and lipoproteins that are different than those produced by plozasiran. These include additional reductions in LDL-C and apolipoprotein B, while also driving similar reductions in triglycerides, remnant cholesterol, and non-HDL cholesterol as those seen with plozasiran. This is why we are taking a very close look at the various options for Phase 3 clinical development in an ASCVD population with mixed hyperlipidemia, a population of patients estimated to be around 20 million in the U.S. alone. We have engaged with external advisors and have completed an exhaustive analysis of the potential designs and studies. We have recently completed a submission to the FDA on a potential study design, and will have additional interactions on the specifics over the coming 30 to 60 days. We will talk more about our plans after we receive feedback from FDA, and other key agencies. Upstream of that, the coming EAS presentations will be a good way, for folks outside the company to see some of the data that have gone into our thinking. We and our KOL advisors believe that there really is not a bad choice between the two. As you will see, results from both MUIR and ARCHES-2 look compelling. Now moving to the PALISADE study of plozasiran in patients with FCS. PALISADE included FCS patients who were genetically confirmed, and somewhere around half who were clinically diagnosed. FCS is a severe and ultra-rare genetic condition, often caused by various monogenic mutations. FCS leads to extremely high triglyceride levels, which can lead to various serious signs and symptoms, most notably including acute and potentially fatal pancreatitis. Currently, the available therapeutic options leave most FCS patients persistently vulnerable to pancreatitis. The PALISADE study is a Phase 3 placebo-controlled study to evaluate the efficacy and safety of plozasiran in adults with FCS. The primary endpoint of the study is percent change from baseline in fasting to triglycerides at month 10. A total of 75 subjects were randomized to receive 25 milligrams of plozasiran, 50 milligrams of plozasiran, or matching placebo once every 3 months. Participants who completed the randomized period, are eligible to continue in a two-part extension period where all participants are receiving plozasiran. The last study visit for the last patient enrolled in PALISADE occurred about a week ago. This will be Arrowhead's first completed Phase 3 study and represents a significant milestone for the company. Importantly, it brings plozasiran potentially closer to the FCS patients that may benefit. Our goal now is to work efficiently to generate initial study results and provide a top-line data readout as soon as our Cardiometabolic Webinar next month, and subsequently present a fuller data set at an appropriate medical meeting. This is an exciting time at Arrowhead as we eagerly await these results. I'll now turn the call over to James.

James Hamilton: Thank you, Bruce. The discovery and early development teams made some notable progress over the last quarter, and we also have a busy several months ahead with the Summer Series of R&D webinars that Chris mentioned earlier. We do an enormous amount of work in seeking to innovate new medicines that is, often only recognized once there is a clinical candidate. So I wanted to talk for a moment, about how we see our priorities and the goals of the team. Number one, is to push the TRiMTM platform to new cell types and continually seek to optimize the safety, and activity of each construct. Number two, is to develop new candidates against attractive gene targets where using RNA interference, is the only or best method to inhibit the target. Number three, is to conduct IND-enabling non-clinical studies and first in human clinical studies in the most efficient manner possible, to get meaningful readouts that accelerate mid and late stage development. And number four, is to develop assets which can be readily partnered and support business development activities which remains a key strategic focus as our pipeline has continued to grow. I think, we've made good strides in these areas recently, so let's talk about a few examples. We've continued to expand the reach of the TRiMTM platform. We now have clinical programs and three different tissue types including liver, lung and muscle. We also expect in the very near future, to have clinical programs and two additional tissues specifically CNS and adipose. Each one of these expands the universe of diseases we can address and the number of patients that we can potentially help. During the CNS R&D webinar scheduled for September, we plan on giving an update on a specific candidate that is currently undisclosed and highlight the significant progress we're making on a subcutaneously administered construct designed to deliver siRNA across the blood-brain barrier to the CNS without the need for intrathecal administration. This is a much more patient-friendly mode of administration and may be able to access tissues in the deep brain that, have been difficult to access with IT injections. This is potentially a big step forward for us, and the field overall and we are excited about the progress. During the obesity and Metabolic R&D Webinar currently scheduled for August, we will also talk about platform advancements and pipeline expansion. The pipeline is expanding by two programs and we will talk about the addition of adipocytes as a new cell type we can access with the TRiMTM platform. As you all know the obesity space has recently gained a lot of attention with the success of GLP-1 agents. However, we see a clear areas that remain underserved. We have not disclosed much publicly about the development of our two obesity programs. So this event will be a good opportunity to get people up to speed on where we are and where we see the clinical development programs going. Moving on to current clinical development programs, during the last quarter we brought two new agents into the clinic. First, AROCFB is designed to reduce hepatic expression of complement factor B which plays an important regulatory role, in amplifying complement alternative pathway activation, and has been identified as a promising therapeutic target. AROCFB is being developed as a potential treatment, for complement mediated kidney diseases such as IgA nephropathy which is the most common glomerular disease worldwide, and carries a high lifetime risk, of progression to end-stage renal disease. Additionally, AROCFB may have clinical applications in non-renal diseases, involving complement activation. Last month, we announced that we had dosed the first subjects in a Phase 1, 2a clinical trial of AROCFB designed to enroll up to 66 healthy volunteers, and patients with complement-mediated kidney disease. A second new clinical program, ARO-DM1, is designed to reduce expression of the dystrophia myotonica protein kinase or DMPK gene in the muscle as a potential treatment for patients with type 1 myotonic dystrophy or DM1. Pathogenesis of DM1 is driven by abnormal DMPK transcripts that, cause misregulated splicing, known as splicopathy, for certain messenger RNAs, which are directly linked to the clinical manifestations of DM1. In March, we announced that we had initiated and dosed the first subjects in a Phase 1, 2a double-blinded placebo-controlled dose escalating study, to evaluate single and multiple ascending doses of ARO-DM1 in up to 48 subjects with DM1. Moving on to our clinical stage pulmonary programs, ARO-RAGE, ARO-MUC5AC and ARO-MMP7. We continue to enroll patients across all three programs, and are confident that we will have multiple opportunities for clinical readouts this year. The first of these will occur at ATS later this month. We are scheduled to present a poster on ARO-RAGE which will include data from mild-to-moderate asthma patient cohorts that, we have not reported on previously. To review, ARO-RAGE is designed to reduce expression of the receptor for Advanced Glycation End products or RAGE as a potential treatment for inflammatory pulmonary diseases. We are currently enrolling asthma patients with high baseline levels of fractional exhaled nitric oxide or FeNO, which is a biomarker of IL-13 driven type 2 inflammation in the lung. We are expecting to have high FeNO cohorts enrolled and dosed late this year. The next programs are ARO-MUC5AC, which is designed to reduce production of Mucin 5AC or MUC5AC as a potential treatment for muco-obstructive pulmonary diseases, and ARO-MMP7, which is designed to reduce the expression of matrix metalloproteinase 7 or MMP7 as a potential treatment for idiopathic pulmonary fibrosis or IPF. Both ARO-MUC5AC and ARO-MMP7 have already enrolled and dosed healthy volunteers, and we anticipate the patient cohorts will be enrolled and dosed in time to enable initial clinical readouts in the second half of this year. Our pulmonary R&D Webinar scheduled for July will review these programs in more detail. I will now turn the call over to Ken.

Ken Myszkowski: Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended March 31, 2024, was $125.3 million or $1.02 per share based on $123.3 million fully diluted weighted average shares outstanding. This compares with net income of $48.7 million or $0.45 per share based on $108.1 million fully diluted weighted average shares outstanding, for the quarter ended March 31, 2023. No revenue was recorded in the quarter and the quarter ended March 31, 2024. Revenue of $146.3 million, was recorded in the quarter ended March 31, 2023. Revenue is recognized as we complete our performance obligations, or key developmental milestones are reached. Revenue in the prior period primarily related to the recognition of payments received, from our license and collaboration agreements with Takeda and GSK (LON:GSK). Total operating expenses for the quarter ended March 31, 2024 were $126.2 million, compared to $98.1 million for the quarter ended March 31, 2023. The key drivers of this change were increased research and development costs, primarily compensation costs, and candidate costs as the company's pipeline of clinical candidates, has increased and advanced into later stages of development. Net cash used in operating activities during the quarter ended March 31, 2024 was $92.4 million, compared with $31.7 million during the quarter ended March 31, 2023. The increase in cash used in operating activities is primarily driven by higher R&D expenses as well as the prior period including $40 million cash receipt of revenue milestones. Construction of our Verona facility is effectively complete. We are currently undertaking commissioning and qualification activities which puts us on track for manufacturing drug material to support our clinical trials later this year. We expect final payments to be made over the next several months totaling $50 million after which we expect capital expenditures to be nominal. Turning to our balance sheet, our cash and investments totaled $523.1 million at March 31, 2024, compared to $403.6 million at September 30, 2023. The increase in our cash and cash and excuse me the increase in our cash and investments was primarily related to the $450 million equity issuance, partially offset by our ongoing cash burn. Our common shares outstanding at March 31, 2024 were $124.1 million. With that brief overview I will now turn the call back to Chris.

Chris Anzalone: Thanks Ken. This has been another quarter of solid execution for Arrowhead. Our Phase 3 PALISADE study of plozasiran is clinically complete, which sets us up to take the next step in growth for Arrowhead, as we make the transition into a commercial organization provided we receive regulatory approval. We also initiated that the SHASTA-3 and 4 Phase 3 studies of plozasiran in patients with SHTG and are finalizing the design and preparations to initiate SHASTA-5 in patients with SHTG at high risk of acute pancreatitis. We are waiting for FDA feedback on a Phase 3 program to address ASCVD, which we will discuss after we reach regulatory alignment. In addition to progress in cardiometabolic, we have been very productive in platform development and pipeline expansion. Our TRiMTM platform can now deliver to CNS and adipose tissue, and we will soon have new clinical programs targeting those tissues. We also initiated clinical studies during the quarter for two new candidates ARO-DM1 and AROCFB. Thank you for joining us today and I would now like to open the call to your questions. Operator.

Operator: Thank you. [Operator Instructions] Our first question comes from the line of Luca Issi from RBC Capital. Your line is now open.

Luca Issi: Great, thanks so much for taking my question. Congrats on the progress. Maybe on FeNO, sounds like the high FeNO cohort for RAGE has been slow to enroll. Can you maybe just expand on it? When is the earliest we can actually see that data, and maybe what are the bogies in term of FeNO reduction that are below, on par or above your expectations? And then maybe second on LPLA, what was your reaction to Lilly starting a cardiovascular outcome trial that is way bigger than your trial than Novartis (LON:0QLR) (SIX:NOVN)' trial? I think Novartis has a 7,000 patients' trial, you have an 8,000 patients' trial versus Lilly starting a 13,000 patients' trial here for LPLA. Does that mean that your trial is underpowered? Any thoughts there? Much appreciated. Thanks so much.

Chris Anzalone: Thanks Luca. So I can address the FeNO question. You know it's look, it's just been slow to enroll, because we are requiring high FeNO in these patients with moderate-to-severe asthma. So I don't have good visibility on when that could be complete. I think our take-home message there was that we were sick of waiting around. We think this is a good drug and we want to move expeditiously into a Phase 2 and so we're going. We've got a Phase 2 designed and we are moving towards that. I think we'll start that in the fourth quarter. And so, we are looking forward to seeing the FeNO data, of course, but it's not rate limiting. I think the drug is too important to wait for that. Bruce, do you have anything to add about the LPLA?

Bruce Given: I don't think there's a problem with the Novartis or the Amgen studies being underpowered. I don't really, know what's driving that very large study size for Eli Lilly (NYSE:LLY). The devil may be in the details there. But I don't worry about the power of either the Novartis or the Amgen studies.

Luca Issi: Guys, thanks so much.

Chris Anzalone: Thank you.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of Edward Tenthoff of Piper Sandler. Your line is now open.

Edward Tenthoff: Great. Thank you very much. So many things going on tough to the side where to start. But with the Phase 3 policy data coming up, top line data, just for cardiovascular event. Again, what kind of expectations should we look for in the trig lowering, especially with data already out from the earlier study? And how will this really compare? Do you think with the Ionis program, which is a little bit ahead of you guys, how do you expect to compete for the small patient population? Thanks.

Bruce Given: Well, as far as expectations go, that's you're asking me for a crystal ball. I think that, our indication so far is that plozasiran very powerful drug, when it comes to knocking down APOC3 and APOC3 seems to be very important for this patient population. And but that said, I mean, I don't have any insight into, at this point what - the PALISADE data will show. So hopes are hopes, but in reality, you got to see the data. That said, I don't have any reason to believe that we won't expect a good outcome, but these trials are - it's a 75 patient trial. So we'll have to see - how the trial goes, how the placebo group has performed, because that oftentimes has a lot to do what happens in these trials. So I can't really give you a forecast on that, Ted. I mean, we're excited to see that.

Edward Tenthoff: Just to kind of clarify, Bruce, I'm sorry to touch it off, but just to clarify…

Bruce Given: Yes, go ahead.

Edward Tenthoff: With kind of the reductions that you've seen with the prior trig reductions in other studies, and severe hypercholesterolemia patients, et cetera or a hypertriglyceridemia patients, where do you think, how do you think that will play in these FCS patients? Sorry, that was more my question?

Bruce Given: Yes, I guess what I can say is, we've had a smattering of FCS patients in the SHTG, study. We've had a few patients in Phase 1. So far in that small number of patients, we've seen essentially similar results from the perspective of percent reductions in triglycerides between the FCS patients and for instance, what we saw in the regular SHTG patients. If that holds in this larger patient population, we should be in good shape. But as I said, each clinical study is its own clinical study. But we don't have reason from what we've seen so far to go in expecting a different result, but we'll have a much larger patient population here to look at.

Edward Tenthoff: And again, how do you guys expect that helpful? How do you guys expect to compete with Ionis who's a little further ahead? Thank you.

Chris Anzalone: Yes, so, of course, that's going to depend on our data. Here's what I believe. I believe that we will have an advantage in dosing intervals. I think we'll be dosing once a quarter rather than once a month. And then, as Bruce says, we'll see if the data holds with what we've seen in the past. My hope is that we continue to have a more powerful drug that is better tolerated, but we'll have to wait to see what these data look like in this relatively small study. I'll also say one more thing. You mentioned a very small population of FCS, Ted, and of course, genetic FCS is not a very large population. But the population that we studied was genetic FCS and phenotypic FCS, if you will. So those patients with, with trig above 880 in the history of pancreatitis, and in turn, that would be about half and half in our study. And so, we'll see what makes it to the label. But that's the population that we studied, and that is a substantially larger population than simply genetic FCS.

Edward Tenthoff: Yes fair point. Appreciate it.

Chris Anzalone: Sure.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of Ellie Merle of UBS. Your line is now open.

Unidentified Analyst: Hi, this is Jasmine on for Ellie. Thanks so much for taking our question. So when we get updates from patient cohorts from MUC5AC and MMP7 later in the year, can you give any color on the number of patients that we might see and anything on specifically what endpoints we'll get? Thank you.

Chris Anzalone: Yes, sure. So the number of patients, it depends on enrollment we're doing about, we're doing seven per cohort in the IPF patient cohort. So a single-digit number of patients, call it less than 10, assuming we report maybe the first dose of IPF patients. And then the endpoint for that would be MUC5AC, MMP7 levels in the valve that we're measuring in all IPF patients. And then for MUC5AC, we probably have a little bit more, in terms of the number of patients, 20 or so that we have available to report on. And that would be MUC5AC protein levels from sputum. That's the primary biomarker that we're looking at.

Unidentified Analyst: Okay, great. And just a quick follow-up, if I could. At ATS on RAGE, can you give any specifics on what we can expect there? Any data?

Chris Anzalone: Yes, sure. So we'll be presenting the healthy volunteer RAGE data. And then the RAGE, the serum RAGE knockdown data in the patient cohorts that we have available.

Unidentified Analyst: Great, thank you.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of Jason Gerberry of Bank of America (NYSE:BAC). Your line is now open.

Unidentified Analyst: Hi, good evening. This is [Dina Ahn] for Jason. Congrats on the progress this quarter. And thank you so much for taking our question. I just had a quick one on plozasiran, just in terms of thinking about the PALISADE data. I believe your data will include FCS patients and high TG patients with functional LPL activity. And just curious how you see the inclusion of the patients with the LPL activity enriching your data set. And do you plan to break out clinical activity of these two subgroups to maybe inform comparisons with Ionis' plazazarin? Thank you.

Bruce Given: Well, as Chris said, I mean the patients that are not genetically proven FCS at the point they enroll are phenotypically FCS patients. They're not just high triglyceride patients. They're patients that really look and feel like FCS, but they just have not had the genetics done at the time of enrollment. And as Chris said, that's a fairly large population. And they tend to be, some of them are undiagnosed FCS patients. But oftentimes they're compound heterozygous, which may or may not include LPL, but then have other genetic abnormalities as well. And the compound effect winds up having them phenotypically look like they have FCS. So it's a heterogeneous group. And at this point, again, when we haven't seen the data, everything's blinded, can't really say how that might play into the results. That's going to be one of the really interesting things to see. In the data is, do the genetic FCS patients look and behave the same? We'll see. We'll know more once we have all the data in our hands.

Unidentified Analyst: Thank you. And I just had a quick follow-up. Apologies, I missed this in your prepared remarks, but to the ARO-RAGE Phase 2 asthma trial that you're planning to initiate later this year, is that an all-comer population or is that going to be in just the eosinophilic high-type 2 patients? Thank you.

Chris Anzalone: Yes, we're still waiting on feedback from regulatory agencies. So we'll talk more about the design later once it's cleared to us.

Unidentified Analyst: Got it. Thank you so much.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of Maury Raycroft of Jefferies. Your line is now open.

Maury Raycroft: Hi. Congrats on the progress and thanks for taking my question. I was going to ask one on FCS to follow-up some of the others. Assuming the genetic and clinical patients perform the same in the PALISADE FCS study, and that study's successful. What are your expectations for a label, what the label would look like, and how could that play into the commercial opportunity? And then as follow-up, can you comment on baseline pancreatitis in this study and what do you expect to see on that measure?

Chris Anzalone: Okay. Well, let me take the pancreatitis question first. There was a significant history of pancreatitis in the patient population, and we have had some events. There's still a few events to be adjudicated that are, I think, are being adjudicated maybe this week or next. So I don't know what the total number of pancreatitis events in the study will be in the end, but it's a number. It's enough that you will be able to hopefully see something, but we don't know at this point. So that's on pancreatitis. With respect to labeling, of course, we don't make that decision, the agency does, but the decision to look at either genetic FCS patients or if you will phenotypic FCS patients is something that the agency bought into. Certainly historically, when there's been agreement between the agency and a company, historically the agency tends to give you labeling that reflects the population that you studied. Obviously, any individual situation can vary, but our certainly expectation going in would be that labeling would reflect the patient population we studied. That would have an impact, obviously, with respect to potentially a different, there could be a differential label between us and plozasiran. We won't know until we get there, but we could see a distinction.

Maury Raycroft: Got it. That's really helpful. Maybe one last follow-up for a number of patients out there that would be clinically defined with FCS. Do you guys have any bookends on that? What that could look like?

Chris Anzalone: So, we've gone at that from a number of ways. It's in the thousands. We haven't set on it. On an exact number, but it feels like it's in the thousands. Beyond that, it's hard to tell at this point.

Maury Raycroft: Okay. Okay. Understood. Thanks for taking my question.

Operator: Thank you so much. Our next question, please stand by. Our next question comes from the line of Mayank Mamtani from B. Riley. Your line is now open.

Unidentified Analyst: Hello. This is Kevin for Mayank from B. Riley. Thanks for taking our question. I have a question about the future strategy in terms of you have those potent drugs, plozasiran and zodasiran. Can you elaborate on how you would go carve the target population given that there are specific distinctions in terms of mechanism and more clinical effects by these two compounds? Thanks.

James Hamilton: So Kevin, the way I tend to think of it, if you think of sort of lipid and lipoproteins as a bit of a continuum and on one end you have familial hypercholesterolemia, a very LDL dominated sort of disease if you will, which then comes down into HEFH and patients that for other reasons just have very high cholesterol, but maybe normal triglycerides. And then you come into the middle where you have a mix what used to be called mixed dyslipidemia, now called mixed hyperlipidemia, that in an untreated state patients are maybe a combination of LDL and triglycerides often with a lot of metabolic syndrome, obesity, diabetes, etc. about 20 million patients in the U.S. and a lot of those patients are already on statins and already have some level of control of their LDL. So from what's left untreated it's largely in this triglyceride rich lipoprotein/remnant sort of phenotype if you will. And then going further up that side you get into the severe hypertriglyceridemia's and at the outer end of that one you have FCS. So if you think of it that way, I almost think of it like a U shape where one end of the U is familial hypercholesterolemia and the other end of the U is FCS and you come down and in the middle you have this 20 million patients with mixed hyperlipidemia. So on the one end that's cholesterol that's a very healthy place for Angptl3. And we've already seen that to an extent for instance with Regeneron (NASDAQ:REGN)'s multiple antibody works well on that side of the spectrum. And then on the far side of the other spectrum with FCS and SHTG and the phenotypic FCS you have plozasiran. So the real question is in the middle where you've got a mix of LDL and triglycerides in the phenotype and both drugs look to be very interesting drugs in that mixed dyslipidemia or mixed hyperlipidemia population. So what it means to us is that on the two ends of the spectrum the drugs have target markets that make a lot of sense and in the middle both drugs look like they could be a major improvement over what's been available to practicing physicians for the last 30 years. So that's kind of how we see it. I hope Kevin that that makes some sense to you.

Unidentified Analyst: Yes, thank you so much.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of Brendan Smith of TD Cowen. Your line is now open.

Brendan Smith: Great thanks very much for taking the question. Maybe just another quick one on pulmonary and then I have a broader follow-up. So first I actually just wanted to see if there's anything else specifically that you're seeing in the asthma patient data that's giving you more confidence and movement to Phase 2. Maybe more to the point if you've seen any of the high FeNO patient data yet like if you're seeing good FeNO knockdown or anything like that. And then more broadly I just wanted to check and see if there's any update on potential licensing or commercialization partnerships or maybe when we might get an update there and what that's looking like? Thanks very much.

Bruce Given: Sure. I think the biggest driver in moving in not waiting and moving you know towards that Phase 2 is the safety and tolerability that we've seen so far and the and the target engagement we're seeing good rage knockdown. We've seen we've seen a lot of excitement from KOLs for the rage pathway and so it just makes sense just makes sense. So we're moving as quickly as we can there. On the on the partnering side we have we are we are always or virtually always in discussions as you can imagine. We have no control over timing and so I have nothing to report at this point other than the fact that this is an important part of our business and we do expect to execute additional transactions.

Brendan Smith: Okay. Thanks very much.

Bruce Given: You're welcome.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of [indiscernible]. Your line is now open.

Unidentified Analyst: Thank you. First question. Is there a rationale for the different sample sizes between SHASTA-3 and 4 as one deliberately over sampled?

Bruce Given: Not really. The so the design of the SHTG program was in many ways a result of our discussions with FDA about their overall expectations for what they wanted to see in efficacy, database safety, database, et cetera. And it just turned out that it could have been 350 in both. In the end, practically, it made sense to have one be 401, 300, but it was really largely just driven by practicalities to get the patient population that the agency was requesting. So it really is accidental, you might say, that they're different size.

Unidentified Analyst: Okay. And then in terms of the…

Bruce Given: Yes, they're both way overpowered for efficacy. If you saw the results from SHASTA-2, they're both way overpowered for efficacy.

Unidentified Analyst: Okay, well, that's great to hear. Just in terms of the mix CVOT, since you have a design you're ready to submit for review, have you selected one of the two? And then based on the feedback, you still, I guess, have the option to switch or how should we think about where you're at with this?

Bruce Given: Yes. So until we get. Until we have feedback in alignment with regulators, it makes sense for us just to stand pat on this. We'll give you, of course, all the information that we can, once we have confirmation from the regulators that we are all aligned on what this study looks like. So stay tuned on that. We're still working.

Unidentified Analyst: Okay thanks.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of William Pickering of Bernstein. Your line is now open.

William Pickering: Hi good evening congrats on the progress and thank you for taking my question. On SHTG, in SHASTA-2, you had a fairly sizable placebo effect of 17% at 24 weeks. Could you comment on whether you think that's a reasonable proxy for what to expect in the pivotal and if there are any strategies to potentially limit that?

Bruce Given: Yes. Well, it's kind of interesting because if you actually look at the data, placebo was essentially plugging along at, right around zero change. And then, at week 20, it was like zero. And then at week 24, it dips down to, whatever, you know, minus 17, I guess. And then it was halfway back, up to zero, you know, four weeks later. And then eight weeks later, it was right back to where it had been for the first 20 weeks. So it's just one of those weird deals that, this is what makes it hard to do placebo-controlled studies. Placebo just behaves strangely at unpredictable times. And all of us, you know, just have to put up with that. We did things in the trial to try to minimize placebo, changes in placebo. But, but in the end, it's always difficult to, to really manage that.

William Pickering: And if I could just squeeze in a very quick follow-up, you know, what led you to pick the 25 milligram instead of the 50? And do you think that you'll be able to demonstrate a more compelling efficacy profile versus plozasiran at that dose?

Bruce Given: Yes, well, 50 and 25 were very similar with respect to, with respect to activity, with respect to efficacy. And that was not only in SHASTA-2, but that was also in MUIR. They just looked really close. And yet there was a difference in tolerability. And so, it really was a benefit-risk decision in the parlance of, the regulatory parlance, but in our parlance as well. You look for, you know, we put up with side effects in this business, when we have to. But if, in fact, there's a dose available that essentially gives you full efficacy and has, better safety and tolerability, you take that one. I mean, our overall assessment of the 25 milligram dose in both of those two large Phase 2s in which it was in is that it's, kind of indistinguishable from placebo. The difference between active and placebo is so small as to be, not convincingly different at the 25 milligram dose. In terms of safety? In terms of safety and tolerability, right. And that mattered a lot, when the efficacy looked basically the same. And 50 milligrams looked a little different from placebo. So we took advantage of the fact that we were at the top of the dose response curve for efficacy and we had, a better safety and tolerability profile.

William Pickering: Makes sense. Thank you very much.

Bruce Given: You bet.

Operator: Thank you for your question. Please stand by for our next question. Our next question comes from the line of William Pickering. I'm sorry. Our next question comes from the line of Patrick Trucchio of H.C. Wainwright & Company. Your line is now open.

Patrick Trucchio: Thanks. Good evening. Just a couple of follow-up questions on the complement programs. Just first, I appreciate that dosing in the Phase 1 2a trial began last month. I'm wondering, though, if you can talk about potential timing of initial data in this trial evaluating AROCFB and kind of what you'd be looking for in that initial data and later data give confidence in advancing this program. And then secondly, if you can talk more broadly about the potential advantages of CFB relative to existing treatments for various complement media disease, and how you envision CFB fitting in these, the different treatment paradigms. And then lastly, how should we think about this complement program relative to AROC3? And can you talk in more detail how these programs may progress in parallel?

Chris Anzalone: Yes, sure. Maybe I'll take the last one first. Thanks for the question. So I think we will make a data-driven decision for C3 versus CFB. We think there are maybe some indications where C3 might work better, something like C3 glomerulopathy where the disease is really driven by the accumulation of, excessive C3, and then others where CFB might work better. But I think that'll be really data-driven. And then in terms of advantages over some of the other therapeutics out there, I mean, I think the dosing advantage is really significant that we would have for both of these in terms of duration of effect for AROC3, we're getting 88% knockdown that can be essentially maintained for three to four months after a single dose. So I think if you're, again, looking at dosing quarterly versus other therapies that require either, daily oral dosing or frequent subcutaneous dosing, I think there's a big advantage there. We'll see what the dosing regimen looks like for AROCFB, but based on preclinical data, that's a very potent molecule. And so, I'd expect something similar in terms of duration of effect. And then data timing, the CFB study just got started. It's a healthy volunteer study. And so, the biomarker knockdown of circulating plasma CFB, that's the main efficacy or activity biomarker of interest. And we could potentially have something by year end for that.

Patrick Trucchio: Great. Thanks so much.

Operator: Thank you for your question. This does conclude our question-and-answer session. I would now like to turn the call back over to Chris Anzalone for some closing remarks.

Chris Anzalone: Thanks, everyone, for joining today, and we look forward to seeing you at the Summer Series starting later this month.

Operator: This does conclude today's conference. You may now disconnect.

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