Earnings Call Transcript
Arrowhead Pharmaceuticals, Inc. (ARWR)
Earnings Call Transcript - ARWR Q3 2025
Vince Anzalone, Vice President of Investor Relations
Thank you. Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2025 third quarter ended June 30, 2025. With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview; Dr. Bruce Given, Interim Chief Medical Scientist, who will provide an update on late clinical and regulatory; Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise, who will provide an update on commercialization activities; Dr. James Hamilton, Chief Medical Officer and Head of R&D, who will discuss our earlier stage development programs; and Dan Apel, Chief Financial Officer, who will give a review of the financials. Following management's prepared remarks, we will open the call to questions. 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?
Christopher R. Anzalone, President and CEO
Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Before discussing the progress we've made over the past quarter, I'd like to address questions surrounding our partnership with Sarepta Therapeutics. Sarepta has recently experienced high-profile setbacks in products and programs that are unrelated to those licensed from Arrowhead. Nevertheless, the situation has negatively affected our stock price. So, I'd like to talk about what we think is important from an Arrowhead shareholder perspective. Sarepta recently announced a strategic restructuring plan that includes cost-cutting measures and a pipeline review that prioritizes funding, development, and commercialization of the programs the company in-licensed from Arrowhead. Sarepta management has clearly stated that it believes this represents the future of the company, and this gives us confidence that Sarepta will continue to meet its financial, development, and commercial obligations under the agreement. The collaboration is continuing to operate as expected, which is, of course, a good thing for Arrowhead. It represents a source of capital to fund internal programs, platforms, and commercial build-out while ensuring that assets licensed to Sarepta are developed and commercialized. Should Sarepta fail to meet its obligations, the agreement has clear termination provisions that, in our view, would cause potentially valuable assets and associated intellectual property to be returned to Arrowhead without Arrowhead having to repay any of the capital we have received from Sarepta. That would also be an acceptable outcome. Let's now move on to our progress in the recent period. The biotech market has been challenging over the past several years, but we have no control over the broader sentiments. What we can control is our drive to serve patients and create shareholder value. We view these broadly as three interrelated mandates: to create value – to create novel medicines capable of real impacts on human health; to generate the capital to fund development of them; and to build an engine to drive the growth of both. We made important progress in all these areas during the recent period. Let's begin with development. This is clearly led by plozasiran. We continued to have productive interactions with regulators in the U.S. and Europe about our market authorization applications for the treatment of FCS, and we look forward to our November 18 U.S. PDUFA date. We are also on track with commercial build-out, and our complete team is nearly assembled to support an FCS launch. Further, we achieved full enrollment in SHASTA-3, SHASTA-4, and MUIR-3, Arrowhead's Phase III studies designed to support regulatory submissions for plozasiran in the treatment of severe hypertriglyceridemia, or SHTG. These studies enrolled approximately 2,200 patients in 24 countries in a very short period of time. The primary endpoint is focused on triglyceride reduction at 12 months. So, with full enrollment reached in June 2025, we are on track for study completion by mid-2026. Zodasiran, Arrowhead's candidate designed to reduce expression of ANGPTL3, is being developed as a potential treatment for homozygous familial hypercholesterolemia, or HoFH, a rare genetic condition that leads to severely elevated LDL-cholesterol and early onset cardiovascular disease. We initiated the YOSEMITE Phase III study and enrolled the first patient in July. Approximately 60 subjects over the age of 12 will be randomized to receive four quarterly doses of 200 milligrams zodasiran or placebo. The primary endpoint of YOSEMITE is the percent change in fasting LDL-cholesterol from baseline to month 12. We think that given our Phase II data, this feels like a relatively low-risk Phase III, potentially enabling a commercial opportunity that overlays well with the team we are building for plozasiran. Therefore, with a relatively small investment in a one-year, 60-subject Phase III study, we see an opportunity to extract more value from the commercial infrastructure we are already building. Beyond plozasiran and zodasiran, there are two additional investigational RNAi-based candidates developed by Arrowhead that are currently in late-stage pivotal studies. Fazirsiran, being developed for Alpha-1 Antitrypsin Liver Disease, is partnered with Takeda. Arrowhead retains a 50-50 profit share in the U.S., 20% to 25% royalties outside the U.S., and up to $527.5 million of remaining regulatory and commercial milestones. Takeda has guided that its Phase III study could be fully enrolled this year, and the study has a primary endpoint at 2 years. Olpasiran, being developed for ASCVD, is licensed to Amgen, which announced that its Phase III cardiovascular outcomes trial was fully enrolled in the first half of 2024. We are eligible for up to $485 million of remaining milestones related to this program. I highlight these four late-stage drug candidates because we expect them to be substantial value drivers in the near to mid-term. They also set up the possibility of multiple launches between November 2025 and the end of 2028. As we've discussed in the past, plozasiran and our other late-stage drug candidates together form the basis of our near-term value proposition. But these are enhanced by several programs underneath them, all of which made good progress in the recent period. Broadening out the cardiometabolic franchise are our first two obesity candidates: ARO-INHBE and ARO-ALK7. ARO-INHBE began a Phase I/II study early in the year, and we recently announced that we dosed the first subjects in a Phase I/II clinical trial of ARO-ALK7, which we believe is the first investigational RNAi therapeutic to enter clinical studies targeting adipose tissue. We expect to have initial, early datasets for both candidates at the end of the year. Expanding the cardiometabolic franchise, we expect to reach the clinic this year for what we believe will be the first RNAi dimer in clinical studies. It is designed to reduce expression of both PCSK9 and APOC3 and could be a powerful agent in the treatment of ASCVD in patients with mixed hyperlipidemia. There is substantial unmet medical need in this large patient population, and we should have a good idea how well this drug candidate lowers LDL-c and triglycerides in 2026. We continue to make good progress in manufacturing, toxicology studies, and clinical trial planning, and we are on track to file a CTA in the coming months. Our burgeoning systemically delivered CNS franchise is also a potential near to mid-term value driver. Should this platform translate from primates to humans, we think it would represent a transformational leap forward in CNS therapies. Importantly, later this year, we expect to file a CTA for ARO-MAPT, our wholly-owned candidate against Alzheimer's disease and various Tauopathies. We are hopeful that we can achieve initial proof of concept with this platform and candidate as early as late 2026. Beyond these, we have a wealth of other clinical-stage programs to drive longer-term value and serve as sources of capital through business development. In fact, we are on track to meet our '20 in 25' initiative whereby we would have 20 individual drug candidates in clinical studies or at market by the end of 2025. Nine of these are partnered. The 11 wholly-owned clinical candidates serve as potential partnering targets and provide value redundancy for our other programs, and we expect several data readouts through the end of the year. Together, these give us a tremendous amount of ammunition to create value. This brings us to the second important component of building durable value: an adequate source of financing independent of the capital markets. We currently have a strong balance sheet relative to our needs over the next few years. In addition, we have made important progress sourcing new capital in the recent period. We recently announced that our Visirna Therapeutics majority-owned subsidiary signed an asset purchase agreement whereby Sanofi will acquire rights to develop and commercialize plozasiran as a potential treatment for FCS and SHTG in Greater China. Visirna will receive an upfront payment of $130 million and be eligible to receive milestone payments of up to $265 million upon approval of plozasiran in FCS and SHTG in Mainland China. Arrowhead is further eligible to receive royalties on net commercial product sales in Greater China as part of the Arrowhead-Visirna license, which was assigned in part to Sanofi. When we co-founded Visirna in 2022, we saw Greater China as an important but undervalued potential future market for multiple programs in Arrowhead's pipeline. We licensed Chinese rights for plozasiran, zodasiran, and ARO-HSD to Visirna, which received outside funding to support development. Sanofi has a strong presence in China and is well-positioned to assume commercialization of plozasiran should it be approved by Chinese regulatory authorities. We did not use any Arrowhead funds to advance China-specific development or regulatory activities. And upon closing, we will own approximately 56% of Visirna. There are tax considerations and other costs, but we ultimately expect to realize a sizable amount from this deal. We hope that over time, we may monetize Chinese rights to zodasiran and ARO-HSD in a similar fashion. The next key capital-building event I want to mention is reaching the first of two pre-specified enrollment targets in a Phase I/II clinical study of ARO-DM1 for the treatment of type 1 myotonic dystrophy, which is partnered with Sarepta. Reaching this milestone triggered a $100 million payment, which is due from Sarepta within 60 days of when it was earned. We believe we are on track to meet the second enrollment target at the end of the year, which would trigger an additional $200 million payment. Our large pipeline and expectations that we have cash into fiscal 2028 suggest that we have the first two categories of value creation under control. This leads us to the third priority: creating an engine to drive the growth of both. I think it is rather clear that we have built this as well. We are now able to address gene targets in five different areas: hepatocytes, pulmonary, adipose, skeletal muscle, and CNS. We also believe we are capable of silencing two genes with a single molecular entity using our dimer technology. This gives us broad reach to go where disease is. And coupled with our expectation of introducing three to four new drug candidates into clinical studies every year, we expect to continue to grow our ability to impact human health very rapidly. This also aligns with our ability to continue to access significant capital through business development before and after achieving substantial product revenue. Ultimately, we are doing all of this to bring important medicines to the patients who need them, and this does not happen without careful preparation. We are building a right-sized commercial organization staffed with what we think are the top people in the field with extensive experience in cardiometabolic and rare disease. We've made strong progress in market access, analytics, operations, marketing, and building a commercial sales team. U.S. launch preparations are now in full swing for plozasiran in FCS, and we intend to be launch ready even before our PDUFA date on November 18. With that overview, I'd now like to turn the call over to Bruce Given. Bruce?
Bruce D. Given, Chief Medical Scientist
Thanks, Chris, and good afternoon, everyone. Since we last spoke, we've continued the forward momentum in our development of plozasiran to treat FCS and severe hypertriglyceridemia. Our U.S. NDA to support FCS treatment was submitted last year, and our PDUFA date is November 18, 2025. Filings in Europe, Australia, and Canada are all progressing as well. We are reassured that the cadence of our interactions with U.S. and global regulators has not changed, nor have any expectations of adhering to established timelines. Two months ago, we completed enrollment in our SHASTA severe hypertriglyceridemia development program well ahead of expectations. The SHASTA program comprises SHASTA-3 and SHASTA-4, two adequate and well-controlled trials designed to meet the statutory requirement of substantial evidence for effectiveness, along with the supportive MUIR-3 trial in mixed hyperlipidemia, which provides additional safety data in a relevant patient population to satisfy regulatory requirements for a complete file. The sizing of the Phase III SHASTA-3 and 4 studies was informed by the needs of regulatory authorities to demonstrate safety while confirming the efficacy suggested by the Phase II SHASTA-2 trial where the primary endpoint of difference in triglycerides at week 24 compared to baseline for the 25 milligram dose was minus 53% with a p-value less than 0.0001, which was accompanied by a numerical decrease in adjudicated events of acute pancreatitis. The two SHASTA Phase III trials are similarly designed, totaling around 700 patients and are very highly powered to demonstrate statistically significant improvement in triglycerides with 25 milligrams of plozasiran compared with placebo over 12 months of treatment. After accounting for randomization allocation in the SHASTA studies, the placebo-controlled double-blind MUIR-3 study was designed to demonstrate statistically significant improvement in triglycerides with 25 milligrams of plozasiran compared with placebo over 12 months of treatment and is also expected to achieve a high level of significance while primarily serving to enhance the safety database for the SHTG filing. Assuming positive data, these three separate Phase III studies should support our planned sNDA filing for SHTG in the fourth quarter of 2026. Although SHASTA-3 and 4 were not prospectively designed to be outcomes studies, given the sizing of the combined studies and the observed event rates in the SHASTA-2 study, we hope to observe at least a favorable trend in plozasiran's impact on documented acute pancreatitis within the studies. However, the SHTG program also features a unique outcomes study named SHASTA-5 designed to directly assess the ability of plozasiran to reduce the time-to-first event of positively adjudicated acute pancreatitis in high-risk SHTG patients. While it is possible that this trial will be submitted to regulatory agencies for possible inclusion in labeling, the primary audience and impetus for this study is actually national health technology assessment organizations. On the basis of observational data demonstrating the causal link between elevated triglycerides and risk of pancreatitis and observed effects of plozasiran in SHTG patients, it is expected that less than 150 patients will be recruited to accrue sufficient events in this outcomes study. We look forward to presenting more details on the design and rationale of this study at an upcoming major medical meeting. The broader cross-functional cardiometabolic clinical team has been present at key medical congresses this past quarter, including ENDO, National Lipid Association, and the American Society of Preventive Cardiology. We continue to share new data to demonstrate the value of plozasiran, and the reception from the scientific and clinical communities has been engaged and enthusiastic. Turning our attention to zodasiran, another genetically validated RNAi drug designed to reduce expression of angiopoietin protein like 3 or ANGPTL3 is now in development for the treatment of homozygous familial hypercholesterolemia, a rare genetic disorder characterized by exceptionally high LDL cholesterol levels due to very low or absent LDL receptor function. The results of GATEWAY, our open-label Phase II study in this population were presented this year at the European Atherosclerosis Society and showed robust and durable reductions in LDL-C and other atherogenic lipoproteins. The efficacy results were similar to those of evinacumab, a monoclonal antibody against ANGPTL3 that requires monthly infusions. But with plozasiran, the dosing is convenient quarterly subcutaneous dosing. We are pleased to report that YOSEMITE, the Phase III study of zodasiran in HoFH, began earlier this year and the first patient was randomized last month. Assuming successful demonstration of safety and efficacy, data from YOSEMITE could support regulatory filings for zodasiran as early as 2028 or 2029.
Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise
Thank you, Bruce. The FDA PDUFA date for plozasiran, set for November 18, is now less than four months away, and I'm pleased to report that our commercialization preparations are fully on track. When I last updated you in May, we were in the midst of building out our commercial sales organization. I'm proud to share that as of this month, our national sales leader, full team of regional sales leaders and fit-for-purpose field force of rare disease specialists are now onboard and undergoing training. By the end of this month, this team will begin engaging with key healthcare professionals, advancing FCS disease education in preparation for launch. Our market access team continues to execute exceptionally well against our Pre-Approval Information Exchange strategy. To date, we've connected with payers representing over 85% of U.S. covered lives, delivering compelling data on the clinical value and anticipated profile of plozasiran. We remain highly encouraged by payer interest, particularly in plozasiran's potential to deeply lower triglycerides, support achievement of guideline-directed goals, namely less than 500 milligrams per deciliter and significantly reduce the risk of acute pancreatitis. We're also seeing positive developments in the FCS landscape, which reinforce our confidence heading into launch. The significant unmet need in the FCS community is clear and acknowledged by both payers and providers. On the payer front, dynamics appear to be favorable, with access being granted to both genetically confirmed patients and those patients satisfying the diagnostic scoring tools designed to discriminate patients with SHTG from those whose signs, symptoms, and medical history mimic genetic FCS. This is especially motivating given that plozasiran is currently the only APOC3 inhibitor to demonstrate clinical results in both genetic and clinical FCS in a Phase III registrational study. And from a provider perspective, the specialty mix we're observing, preventative cardiologists, endocrinologists, and lipidologists is exactly what we anticipated and aligns well with our launch targeting strategy. In summary, we remain on schedule and energized by the opportunity to bring investigational plozasiran to individuals living with FCS and their families. We are excited for what plozasiran, a potential first-in-class siRNA therapy, could mean to those suffering from this difficult disease.
James C. Hamilton, Chief Medical Officer and Head of R&D
Thank you, Andy. I'd like to provide an overview and updates on several of our early stage clinical and translational development programs. In obesity, our ARO-INHBE and ARO-ALK7 programs, both targeting the Activin pathway, are currently being investigated as treatments for obesity in Phase I studies. The INHBE study is currently enrolling multi-dose cohorts using ARO-INHBE in combination with tirzepatide. The ARO-ALK7 study is in the single dose escalation phase, with multi-dose and combination cohorts opening soon. We anticipate sharing data from both the ALK7 and INHBE studies at the end of the year. Regarding our muscle clinical programs partnered with Sarepta, the ARO-DM1 Phase I/IIa study has completed the single dose cohorts and is now enrolling multi-dose cohorts of patients with myotonic dystrophy. Similarly, the ARO-DUX4 Phase I/IIa study has nearly completed enrollment of single-dose cohorts and the first year-long multi-dose cohort is open for enrollment. Consistent with previous guidance, we are on track for data availability by year-end. However, final timing on data release is determined by Sarepta. Our wholly-owned ARO-MAPT program is on track for submission of a CTA by year-end. As a reminder, ARO-MAPT uses subcutaneous administration of a novel siRNA delivery platform designed to deliver a siRNA targeting CNS Tau protein expression across the blood-brain barrier. Tau aggregated into neurofibrillary tangles is believed to be one of the causative factors of Alzheimer's disease and is also causative of various other Tauopathies. Non-clinical evaluations in monkeys with subcutaneous administration of ARO-MAPT using clinically translatable doses have shown better than 75% knockdown of tissue-level MAPT mRNA in the CNS. Importantly, monkey tissue level knockdown has translated into CSF tau protein reductions of better than 75%, with duration of effect supportive of either monthly or potentially quarterly subcutaneous dose regimens. The monkey CSF tau protein knockdown data are an important translational step as we move this program towards the clinic. Full pre-clinical data will be presented at an upcoming scientific conference.
Daniel J. Apel, Chief Financial Officer
Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended June 30, 2025 was $175.2 million, or a loss of $1.26 per share based on 139 million fully diluted weighted average shares outstanding. This compares with a net loss of $170.8 million, or a loss of $1.38 per share for the prior year quarter ended June 30, 2024, based on 124.2 million fully diluted weighted average shares outstanding in the prior year quarter. Revenue for the quarter ended June 30, 2025 was $27.8 million, driven almost entirely by the recognition of revenue related to our license and collaboration agreement with Sarepta. Of the $27.8 million, roughly $20 million related to the ongoing recognition of initial Sarepta consideration and $7 million related to reimbursement of collaboration-related costs. After the end of our third fiscal quarter, we announced two important events, each of which will have a positive impact on our financial position. First, there is a $100 million DM1 milestone payment from Sarepta, which Chris mentioned earlier on the call. As this event occurred after June 30, revenue associated with this milestone will be recognized in our fiscal fourth quarter financial results. We anticipate achieving the second DM1 development milestone valued at $200 million by the end of the calendar year. Second, on August 1, we announced that Sanofi signed an agreement to acquire exclusive rights to develop and commercialize investigational plozasiran in Greater China from Visirna Therapeutics, Arrowhead's majority-owned subsidiary. Visirna will receive $130 million upfront upon closing. Additionally, Visirna will receive up to $265 million in potential future regulatory milestone payments and potential royalties associated with the sales of plozasiran in Greater China. We expect to record revenue of $130 million in the fourth quarter associated with the upfront payment only. Turning to expenses. Total operating expenses for the quarter ended June 30, 2025, were $193.3 million compared to $176.1 million in the prior year quarter, or an increase of $17.2 million. The year-over-year increase was driven by, amongst other things, roughly $10 million of higher R&D costs, primarily as a result of our Phase III registrational trials for plozasiran in SHTG, as well as higher costs related to active candidates in the preclinical stage. It's worth bearing in mind that year-to-date, approximately 70% of our clinical trial spend can be attributed to the Phase III registrational trials for plozasiran in SHTG. As Bruce mentioned, these studies are now fully enrolled, and we expect data to read out next year. Additionally, as planned, our SG&A costs have increased by $7 million year-over-year, driven primarily by our preparations for commercialization in advance of the FDA's upcoming PDUFA action date later this year on November 18. Turning to cash. Net cash used in operating activities during fiscal quarter 3 2025 was $154.7 million compared with net cash used in operating activities of $115.4 million in the prior year quarter. The increase in cash used in operating activities is driven by several factors, including the aforementioned higher operating expenses and timing of clinical trial payments. Turning to the balance sheet. Our cash and investments totaled $900.4 million as of June 30, 2025. Our common shares outstanding as of the end of this quarter were 138.1 million. And with that, I will now turn the call back over to Chris.
Christopher R. Anzalone, President and CEO
Thanks, Dan. Arrowhead continues to achieve strong execution in discovery, clinical, regulatory, and business development. Our pipeline has become increasingly mature with four Arrowhead discovered candidates currently in pivotal Phase III studies. In addition, our commercial build-out is designed to make us launch-ready very quickly should plozasiran receive regulatory approval on the November 18, 2025 PDUFA date. And lastly, we have a strong balance sheet that we think gives us the financial resources to continue to move multiple innovative new medicines through the clinical and regulatory process and ultimately get them to the patients who need them. Thank you for joining us today. And I would now like to open the call to your questions.
Operator, Operator
Our first question comes from Maury Raycroft of Jefferies.
Farzin Haque, Analyst
This is Farzin on for Maury. When thinking about your own SHTG pivotals with ongoing SHASTA-3 and 4, how are you thinking about the prospects of competitor, Ionis' programs reading out in September from the core studies, especially with respect to the triglyceride reduction as well as signals in the acute pancreatitis?
Christopher R. Anzalone, President and CEO
I'll take that question, and Bruce, feel free to add anything if needed. We don't have control over other companies' studies, making it challenging to compare drugs across different studies. Our focus remains on our own research, where we've seen strong results in our Phase II studies and positive data from our Phase III study in FCS. We believe we have a leading triglyceride reducer. We're eager to see the results from the SHTG studies, but that's our expectation moving forward. Bruce, do you want to add anything?
Bruce D. Given, Chief Medical Scientist
Not really. As you said, it's hard to compare across studies. I will say that what they have relayed about their patient population looks quite similar to our patient population at the time of enrollment. So, I think it will be interesting for us to see what their data actually shows when they report it out in September and then probably in more detail at a later academic presentation. So we'll follow with interest, but how much bearing it has is always hard to tell.
Christopher R. Anzalone, President and CEO
And one of the keys here in the studies and then once we are at market are two primary things, I think. One is how deeply can you reduce triglycerides from baseline, and second is how many patients can get to goal, whether that's goal is defined as triglycerides below 880 or below 500. I think those are the key points here, and we would expect physicians to look at that. We expect patients to look at that.
Operator, Operator
Our next question comes from Jason Gerberry of Bank of America.
Jason Matthew Gerberry, Analyst
So, another question on the SHTG program. If I heard you right, so it sounds like what you're confirming is your baseline demographics of your two Phase III studies look similar to the published baseline demographics that Ionis had published for its core studies. I guess that would be in terms of the two key subgroups, which is ultra-high triglyceride levels and past history of AP. And I'm curious your thoughts. Ionis indicated that they are seeing events on a blinded basis, at least 13 with like a SKU of like 700 drug, 300 placebo, something like that. So, I'm just kind of curious, as you absorb that because like the event rate is the big unknown here. So, I'm just kind of curious, has your thoughts changed at all around the probability of showing at least a strong numerical trend by pooling the SHASTA-4 and 5 studies?
Christopher R. Anzalone, President and CEO
Bruce?
Bruce D. Given, Chief Medical Scientist
It's difficult to answer that question, Jason. The reason is that we count only the true adjudicated cases of pancreatitis, while the Ionis approach includes both pancreatitis and abdominal pain. Abdominal pain can be non-specific, and although they try to determine whether it is related to factors like alcohol or gallstones, comparing actual pancreatitis cases to abdominal pain events is challenging. It’s hard to predict what their results will indicate regarding pancreatitis, which I see as the most significant measure. Abdominal pain is relevant in SHTG and high triglycerides; it can severely impact patients and be troublesome, but it isn't as critical as pancreatitis, which can cause organ damage and potentially be fatal. Thus, it poses a different challenge for physicians and payers. This aspect is more difficult to evaluate, and I doubt we will get detailed information on it when they release their results in September. So, it's hard to say anything definitive at this time. We will also monitor abdominal pain, but our primary focus is on acute pancreatitis, as that is the real severe disease.
Jason Matthew Gerberry, Analyst
And will you guys be publishing your baseline demographics, I don't know, in the next six to nine months or so?
Bruce D. Given, Chief Medical Scientist
Yes, I think we will. We'll be submitting that for a future medical conference for sure.
Operator, Operator
Our next question comes from David Lebowitz of Citi.
Unidentified Analyst, Analyst
This is Mary Kate on for David today. Thanks so much for your overview of the anticipated FCS launch. I guess how does this treatment address the clinical unmet need in this space? And maybe what feedback are you receiving from physicians ahead of this potential launch?
Christopher R. Anzalone, President and CEO
Andy, you take that and Bruce add anything that you think should be adding.
Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise
Yes, happy to take that. So, thank you for the question, Mary Kate, related to clinical unmet need. We know with respect to familial chylomicronemia syndrome patients that they suffer from physical symptoms, including abdominal pain and of course, as Bruce mentioned, acute pancreatitis, which can lead to recurrent pancreatitis, necrotizing pancreatitis and in some instances, fatality. And so one of the big things that we believe plozasiran addresses as far as meeting the unmet need, first and foremost, is a deep reduction of triglycerides to a level that has never been seen before with existing therapies in this space. We've talked about an 80% reduction from baseline seen in the PALISADE study. Moreover, the outcome of interest, of course, is reduction in acute pancreatitis risk. And plozasiran is the only agent in a registrational Phase III study that has demonstrated a statistically significant reduction in acute pancreatitis risk in PALISADE. So, those are two of the primary unmet needs that we believe plozasiran can address in FCS. I would say, moreover, just from a patient convenience and tolerability perspective, plozasiran does continue to have a very desirable profile with only quarterly dosing, so four injections a year, which is very different than the current treatment regimens that are available for these patients presently. So hopefully, that addresses your question around why we believe plozasiran fills some important unmet clinical needs.
Operator, Operator
Our next question comes from Patrick Trucchio with H.C. Wainwright & Co.
Patrick Ralph Trucchio, Analyst
Congrats on all the progress. I'm just wondering, as payer access appears favorable for both genetically confirmed and clinically defined FCS, is there any differentiation in the coverage path for high-risk severe high triglyceride patients, particularly those that don't have a pancreatitis history? And I guess I'm just wondering if you can speak to your expectations for pricing between FCS and severe high triglyceride indications, particularly just given the different population size of medical cost burden.
Christopher R. Anzalone, President and CEO
So regarding pricing, we're not prepared to opine too much on a potential SHTG price. We are still looking into that. We certainly would expect that to be a lower-priced drug than FCS. But beyond that, we're still working on that question.
Operator, Operator
Our next question comes from Prakhar Agrawal from Cantor.
Prakhar Agrawal, Analyst
Congrats on the quarter. So maybe on the Sarepta situation, I think Sarepta also owns 10 million-plus shares of Arrowhead stock. So, what could be a practical solution here to solve for this if Sarepta intends to sell their shares? And secondly, on SHTG, maybe a question for Andy. What sort of commercial activities are you doing to educate the community about how SHTG is different from the lipid market? It seems that the Street has been anchored to lipid pricing and the uptake there for the drugs? Any color there would be helpful.
Christopher R. Anzalone, President and CEO
Sure. Yes, Sarepta does own some Arrowhead shares. Their lockup period is still in effect right now. I can't tell you what their plan is for those shares. I can tell you that we have had inbound interest in acquiring shares. And so I'm not so worried that if they decide to sell those that they can find a buyer; they certainly could. But I don't know what the longer-term plans are in terms of holding on to those shares for how long. Andy, do you want to address the…
Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise
Yes. Thanks, Prakhar. As it relates to education, of course, we have active medical education in the form of our medical science liaisons who are conducting scientific exchange. Moreover, there is independent medical education, continuing medical education that's ongoing related to individuals with extremely high triglycerides, the unmet medical need, burden of disease, and education around clinical study results, certainly in the case of PALISADE. I would say a lot of the education that's happening now in the community is related to education around the disease burden, around goal attainment, namely an education around the guideline-directed risk threshold of 500 milligrams per deciliter, and then, of course, a focus on the outcome of interest, which is acute pancreatitis events. And so that largely is the focus of our education. And as our commercial field team gets out into the field towards the end of this month, of course, they will be highly focused on a similar disease education as well. So, I think that answers your question.
Christopher R. Anzalone, President and CEO
And your question is an astute one. Yes, triglycerides can be found on the standard lipid panel. But when people think about lipid drugs, they generally think about them in the context of ASCVD. This is not what this drug is. Plozasiran is not an ASCVD drug. Plozasiran is a pancreatitis drug, and I think should be thought of as such and priced as such, to be honest. So yes, this is a lipid parameter, but this is not an ASCVD drug. This is a pancreatitis drug. And there are populations that are at substantial risk of pancreatitis, acute pancreatitis with the high levels of triglycerides. And so I think that's the way you need to look at it.
Operator, Operator
Our next question comes from Eliana Merle of UBS.
Jasmine Alexandra Fels, Analyst
This is Jasmine on for Ellie. Congrats on initiating the YOSEMITE trial for zodasiran. I'm wondering if you can talk about your latest on your estimations of the size of the HoFH addressable patient population.
Christopher R. Anzalone, President and CEO
Andy?
Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise
You're experts on that. Why don't you take that one?
Bruce D. Given, Chief Medical Scientist
Yes. So the literature would suggest that the prevalence for HoFH is anywhere from roughly 1 in 500,000 to 1 in 1 million persons. And so there's been quite a lot of evidence produced in the HoFH space over the years as new therapies have become available. So, we see the accessible population for HoFH being similar to those estimates.
Operator, Operator
Our next question comes from Edward Tenthoff of Piper Sandler.
Edward Andrew Tenthoff, Analyst
Actually, a little housekeeping question, if I may. Congrats on the Visirna deal. So does that cash go to Arrowhead? And is it able for you guys to invest that?
Christopher R. Anzalone, President and CEO
The cash will go into Visirna, and a significant portion of that will be distributed to Visirna's shareholders. As I noted earlier, we will have about 56% ownership of Visirna at closing. Not all of the funds will be distributed, as there will be some tax liabilities, and we need to retain some cash in the company to support ongoing studies related to plozasiran, even though Sanofi will be overseeing that. There are also studies for zodasiran and ongoing ARO-HSD studies. While the associated costs are not significant, they do exist. Ultimately, our goal is to monetize the China rights for zodasiran and ARO-HSD similarly to how we handled plozasiran. In summary, we expect to bring back a significant amount of that capital, but not all of it.
Edward Andrew Tenthoff, Analyst
Great. That's helpful. And then when it comes to the R&D, the annual R&D from Sarepta, is that paid all at once on the annual anniversary?
Christopher R. Anzalone, President and CEO
Yes. So, they will pay us $50 million a year for five years, and that payment is due in the first quarter of every year. So, I believe it's February. Is that right, Dan? It's February. And so we have $100 million due now for the first DM1 milestone, $200 million that we think we will trigger at the end of the year, and then a further $50 million due for the annual payment in February.
Operator, Operator
Our next question comes from Luca Issi of RBC Capital Markets.
Shelby Hill, Analyst
This is Shelby on for Luca. Can you just talk about the initial presentation for plozasiran? Our understanding is that initial approval will be for pre-filled syringes. So, is that correct? And if so, what is the path to have this in the form of an auto-injector? And how should we think about that timeline?
Christopher R. Anzalone, President and CEO
Sure. Andy, you want to discuss that? And then Bruce can talk about more of the granularity of the auto-injector.
Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise
Yes, that's right, Shelby. So our initial presentation for plozasiran in the FCS space will be a prefilled syringe. And there is development underway for an auto-injector in the SHTG space. Bruce, if you want to comment any more on that?
Bruce D. Given, Chief Medical Scientist
Yes. I would just say that the auto-injector will be either available at the time of launch for the SHTG indication or soon thereafter. That's our current expectation.
Operator, Operator
Our next question comes from Mani Foroohar of Leerink.
Ryan Thomas Mcelroy, Analyst
You have Ryan on for Mani. Congrats on the quarter. Maybe shifting over to the INHBE readout later this year. Can you just share a little detail around which cohorts we should expect to see data from, whether that's the SAD/MAD combo? And then internally, what are you guys really hoping to see here relative to the other data sets from muscle-sparing agents that we've seen so far?
Christopher R. Anzalone, President and CEO
Yes, sure. I can take that. We'll have data from all of those cohorts that you mentioned, SAD/MAD as well as the combination cohorts. And we'll be measuring a handful of different biomarkers, including PD biomarkers like measurable active in the blood. Of course, we can look at body composition based on MRI and weight loss changes in body weight. Then of course, we've got a whole host of lipid parameters and glycemic control parameters that we'll look at.
Operator, Operator
Our next question comes from Mike Ulz of Morgan Stanley.
Michael Eric Ulz, Analyst
Maybe just a follow-up on the last question related to the obesity updates later this year. Just curious if you see what you want to see there, what would be some of the scenarios around next steps for those programs?
Christopher R. Anzalone, President and CEO
Yes, those are difficult questions. We don’t enter most studies with a specific plan for how to proceed based on the outcomes. We are focused on finding the truth. We conduct the study, analyze the data, and determine our next steps from there. I don’t intend to avoid your question; we simply do not approach these studies with any preconceived notions about what the results might indicate until we have the data.
Bruce D. Given, Chief Medical Scientist
Yes. I would just sort of add to that that we need to keep in mind that these are novel mechanisms. These are not just another GLP-1 agonist sort of drug. We're looking at different behaviors and really looking for white space opportunities here. And it's very hard to predict those. It's much easier to answer a question like that if you're coming in with the 10th GLP-1 agonist. But it's quite hard to answer that question when you're dealing with a completely novel mechanism that has not been in humans before.
Operator, Operator
Our next question comes from Joseph Thome of TD Cowen.
Joseph John-Charles Thome, Analyst
Maybe on the MUIR-3 study, I guess, given that these patients will likely have a lower mean fasting triglyceride level, is there an increased risk that potentially this patient subset would be more at risk to self-adherence of or self-levelization of diet or maybe a little bit less adherence to background with the bone therapy than what you might see in SHASTA-3, SHASTA-4? And I guess, could that create some variability in the AE profile or endpoints, I guess, why or why not? And then when you think about the readouts for these three trials, would these all come at the same time, and it would be one top-line release? Or would these be discrete events?
Bruce D. Given, Chief Medical Scientist
In response to your first question, we strive to encourage participants in our clinical trials to adhere to the protocol by providing them with regular dieting advice and reminders. It's difficult to predict if their behavior will significantly differ from the SHTG population. We conducted two trials for mixed hyperlipidemia recently, one involving plozasiran and the other zodasiran. The adherence observed in those trials was comparable to what we experienced in SHASTA-2 and PALISADE. We tend to focus meticulously on executing our clinical trials, which likely contributes to our low dropout rates and high adherence levels. Therefore, I’m not overly concerned about this aspect. Additionally, we utilize placebos in these trials, and we anticipate that the behavior of the placebo group will closely mirror that of the active treatment group, so any discrepancies should balance out relative to the placebo. Overall, we do not expect any significant differences.
Joseph John-Charles Thome, Analyst
Great. And then the last one was, are these going to read out at the same time in the top line? Or will these be three separate releases?
Bruce D. Given, Chief Medical Scientist
I don't think we've really come to a determination on that. In theory, we'll have the data from these three trials fairly close together, but I don't think they will all show up on the same day. So I'll leave it to Chris if he wants to predict how we'll make that decision a year from now.
Christopher R. Anzalone, President and CEO
My first thought on that is that, yes, they are three separate studies, but they're part of one grander study. And so it would seem to make sense to release them all on, but I'll be honest with you, we haven't really discussed that.
Operator, Operator
Our next question comes from William Pickering of Bernstein.
William Pickering, Analyst
Congrats on the progress. Just about your DM1 program. At your muscle R&D Day last year, you indicated you were planning to dose up to 12 MPK in that initial study. My understanding is the highest dose under the current protocol is 6 MPK and that's unchanged from when Sarepta licensed the product last November. Is my understanding correct? And if so, what was the rationale for reducing that max dose versus the prior plan for having a lower max dose than the FSHD study?
Christopher R. Anzalone, President and CEO
Sure. So we still can go up to 12 mg per kg in the current study, the DM1 study.
Operator, Operator
Our next question comes from Madison El-Saadi of B. Riley.
Madison Britt Wynne El-Saadi, Analyst
On the quarter. I guess maybe going back to obesity. Given the n size, the sample size, I guess, is it your assumption that any statistical conclusions are achievable? Or is that kind of precluded here? And just assuming a competitive muscle-sparing weight loss is achieved, where do you think you need to land on frequency of dosing to be competitive given there are other muscle-sparing candidates being developed, including other siRNA candidates?
Christopher R. Anzalone, President and CEO
Sure. So this Phase I study is really hypothesis generating. There's not a powering necessarily that goes into cohort size. I think the effect size that we would see from this study would be used to power a subsequent study down the road. And then in terms of frequency, we're looking at the most frequent probably quarterly dose administration. So, I'm not sure if there's anything out there that can match that frequency to date and certainly not the GLP-1s, at least not that I've seen and some of the muscle-sparing molecules are probably more frequent than that. So, we're looking at quarterly to every six months. Beyond that, I don't really see any benefit to even less frequent dosing. So, I think we're in a pretty good place in terms of frequency of dose administration at quarterly dosing.
Operator, Operator
Our next question comes from Morgan Lamberti of Goldman Sachs.
Morgan Jane Lamberti, Analyst
This is Morgan on for Andrea Newkirk. Kind of going back to obesity and specifically ARO-ALK7, can you speak more to how you are delivering siRNA to adipocytes? And then recognizing that it has not been explored in humans, what gives you confidence in the safety profile? What potential risks could you see in this targeting? And is there good loss of function data out there for us to see?
Christopher R. Anzalone, President and CEO
Sure. Let’s address those questions possibly in reverse order. Regarding our data on loss of function ALK7 carriers, we know there are some homozygous individuals who appear to have no health issues. Additionally, there are many heterozygous ALK7 loss of function carriers who seem to be phenotypically normal. They may have protection against conditions like type 2 diabetes and show improved body composition, including a better BMI-adjusted waist-to-hip ratio. The molecule utilizes a ligand-targeted approach that is specific to adipose tissue and adipocytes, allowing for a ligand-driven mechanism that enhances the uptake of the siRNA into the cells. Beyond the human genetic data, our confidence in the safety to initiate the study is supported by numerous non-GLP and GLP-tox studies conducted in non-human primates and rodent species. In these studies, we tested doses significantly higher than those we plan to use in the clinical trial, all of which were completed without any dose-limiting toxicity. Therefore, we feel well-positioned regarding safety as we enter this Phase I study.
Operator, Operator
This concludes the question-and-answer session. I would now like to turn it to Chris Anzalone, CEO, for closing remarks.
Christopher R. Anzalone, President and CEO
Thank you all for joining us today, and I wish you all a good end of the summer, and we will see you next quarter.
Operator, Operator
Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.