Arrowhead Pharmaceuticals - Q4 2023
November 29, 2023
Transcript
Operator (participant)
Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode. After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.
Vince Anzalone (VP of Investor Relations)
Thank you, Justin. Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its fiscal fourth quarter and year ended September 30, 2023. With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter, Dr. Javier San Martin, our Chief Medical Officer, who will provide an update on our mid and later-stage clinical pipeline, Dr. James Hamilton, our Chief of Discovery and Translational Medicine, who will provide an update on our earlier-stage programs, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, Tracie Oliver, our Chief Commercial Officer, and Patrick O'Brien, our Chief Operating Officer and General Counsel, will be available during the Q&A portion of the call.
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 10-K filed today 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 (President and CEO)
Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Arrowhead made significant progress toward reaching our 20 in 25 goal to grow our pipeline of RNAi therapeutics to a total of 20 clinical stage or marketed products by the year 2025. With yesterday's announcement of a CTA filing for ARO-DM1, our newest skeletal muscle-targeted program being evaluated as a treatment for Type I myotonic dystrophy, we now have 15 clinical stage programs. Ten are wholly owned, and five are being developed with partners. We expect these 15 clinical programs to go to 16 over the next month, with the addition of one more CTA this year. This will complete an extraordinarily productive year on the development front. In 2023, we will have nominated nine new potential clinical candidates using our TRiM platform across four different tissues: liver, pulmonary, CNS, and skeletal muscle.
In addition, we will have filed four CTAs for new clinical candidates during the calendar year. We believe this type of productivity is simply unmatched in our field and is particularly impressive given the size and market capitalization of our company. Even so, we expect more in 2024. To understand these 15 clinical programs now, the 20 we will shortly have, the new targets we are planning to address, and the new cell types we will target over the years, is to understand the magnitude of patients we expect to treat and the value we can create over the long term. Of course, there is too much there to discuss in this setting, so today we will focus on some of the accomplishments, events, and considerations that may drive and unlock value in the near term. I see three primary areas.
First, we are de-risking our pulmonary platform with knockdown and safety data in our clinical trials and toxicity data from our chronic tox studies. These enable us to move toward mid-stage studies addressing three main categories of chronic lung disease: inflammation, mucus obstruction, and interstitial lung disease, each of which have unmet treatment needs. Second, we are making good progress toward becoming a commercial company. We expect our initial commercial product to be Plozasiran, formerly ARO-APOC3, in the treatment of familial chylomicronemia syndrome, for which we will complete a phase III study in Q2 2024, followed by our anticipated second indication for treating patients with severe hypertriglyceridemia, or sHTG, and a later potential indication for treating the broad population of patients with mixed dyslipidemia and atherosclerotic cardiovascular disease. And lastly, we have directional guidance towards strengthening our balance sheet in a shareholder-friendly way. Let's start with the pulmonary platform.
We believe that Arrowhead is the first and only company to show clinically that RNAi can be harnessed to silence the gene expression in the human lung. This is important and marks the accomplishment of a key long-term goal we set for ourselves several years ago. We've always thought that once we have human safety and activity proof of concept with one candidate, it will unlock value in the entire platform and provide confidence that other programs could work similarly, much like our current expectations for new liver programs. So let's talk about important de-risking steps. First, we think we have confirmation that we have adequately addressed the chronic GLP toxicology issues of our first-generation ARO-ENaC candidate. In that program, we saw findings of local lung inflammation in chronic rat and monkey toxicology studies.
We determined that this result was consistent with macrophage overload syndrome, and thus, we needed to make next-generation candidates with improved potency and enhanced duration of effect, so we could stretch out the dosing interval and reduce exposure. I think we are now over that initial hurdle. We've received chronic toxicology results in both rodent and primate species for ARO-RAGE and ARO-MMP7. James will talk about the specifics, but the takeaway is that the NOAELs, or no observed adverse effect levels, suggest sufficient safety margins to move confidently into phase II studies. These were welcome results, and I believe represent substantial de-risking for the entire pulmonary platform. Once we select a dose and dose interval for each candidate, we plan to interact with the regulatory authorities in 2024 to discuss all results to date, including toxicology and our plans for further clinical development.
Next, we want to ensure that clinical safety and tolerability are acceptable. We now have three pulmonary programs in first-in-human studies, and safety results have been consistent, with no concerning safety signals across all three programs in 145 patients or healthy volunteers on active drug. Third, we need to ensure that our pulmonary drug candidates are doing what they are intended to do. We still need patient data in ARO-MMP7 and ARO-MUC5AC to understand this, but ARO-RAGE data have been very encouraging. Normal, healthy volunteers showed 89% mean max knockdown and 95% max knockdown of circulating sRAGE after two doses of 184 milligrams ARO-RAGE. At 92 milligrams, healthy volunteers showed a mean max knockdown of 80% and max knockdown of 90% after two doses.
We are still collecting data from asthma patients, but so far they are mapping on top of those from normal, healthy volunteers, as we expected. Together, I believe these data are important for the ARO-RAGE program and more broadly, serve to de-risk the entire pulmonary franchise. These data give us confidence that, 1, we have chronic tox coverage to move confidently into phase II studies for ARO-RAGE and ARO-MMP7. 2, the drug candidates have been generally well-tolerated in humans. And 3, we are seeing deep and durable knockdown in the ARO-RAGE clinical program that tracks with what we saw in animal studies. The next step is to interrogate whether RAGE knockdown leads to a favorable clinical effect in patients. Upstream of hard clinical outcomes or FEV1, there are biomarkers that can inform on whether ARO-RAGE is engaging inflammatory pathways.
We are approaching a time during the coming months where we may have data on ARO-RAGE in asthma patients to make that assessment. We are currently dosing mild to moderate asthma patients and enrolling patients with high baseline FeNO to potentially enrich for an anti-inflammatory signal. I believe that signal would represent a significant further de-risking event, so we are working quickly to get high FeNO patients enrolled. The next area where I think we are creating substantial value is our progress toward becoming a commercial company. Our phase III study of plozasiran in patients with familial chylomicronemia syndrome is approaching completion, and we expect the last patient visit to be in the second quarter of 2024. That is a big step for a development-stage biotech company. We are carefully considering launch strategies for plozasiran and look forward to speaking more about those soon.
So where do we go after FCS? Data from phase II studies of both Plozasiran and Zodasiran, formerly ARO-ANG3, have been very compelling, and our presentations and webcast around the American Heart Meeting earlier this month were well-received by physicians, industry, and the investment community. For plozasiran, we see a clear opportunity to treat patients with severe hypertriglyceridemia or sHTG. We believe there are 3-4 million people in the U.S. with triglycerides over 500 milligrams per deciliter, with approximately 1 million of them with TGs greater than 880. There are very limited treatment options for these patients. Further, we anticipate an sHTG approval based upon studies demonstrating a lower rate of triglycerides during oneone year of treatment with an adequate safety profile.
In phase II studies, plozasiran reduced TGs, reduced TGs to lower than 500 in virtually all patients, and many had TGs fall to normal levels. We are presented with a compelling set of facts, a large pool of patients without adequate treatment options, a clear and relatively short regulatory pathway, and a drug candidate that has been consistent and very effective in phase I and phase II studies with good tolerability. We've had productive interactions with FDA, including an end-of-phase II meeting, to discuss the design of a phase III clinical program in sHTG patients. We are finalizing planning, and I expect we will launch the studies early in 2024. Beyond FCS and sHTG, we continue to see attractive opportunities to help a broader population of patients with plozasiran or with the zodasiran.
Both candidates have shown to substantially reduce remnant cholesterol, an increasingly appreciated risk factor of cardiovascular disease. I expect that we will conduct a cardiovascular outcome trial, or CVOT, that we will launch and that we will launch it in the middle of 2024. We have been planning to run CVOT with plozasiran, but given the exciting data we presented at AHA in mixed dyslipidemia patients, we are now considering whether plozasiran or zodasiran would be a better candidate. We expect to decide which is better suited for this patient population over the coming months. This is a good problem to have, as both appear to be potentially powerful agents in this large market, and we simply want to try to ensure we are moving the best candidate forward in this space.
Also, on the late-stage side of our business, Takeda is enrolling patients in the phase III study of fazirsiran. It is my understanding that they intend to open approximately 90 sites worldwide to help ensure the program moves quickly to an approvable endpoint that could be met after two years of treatment. Our wholly owned programs, Discovery Engine and burgeoning commercial presence, are all exciting components of our business that we believe will create substantial value going forward. They will also require significant capital over the coming years, and we are focused on building out our balance sheet to ensure that we can make these important investments. To that end, we are actively working on opportunities to bring in capital in shareholder-friendly ways, and we believe there are several good options in front of us.
For instance, we are exploring specific product financing for the plozasiran sHTG phase III study and separately, a possible CVOT, whether done with plozasiran or zodasiran. We believe we could source sufficient capital for those studies in return for limited royalties on those products. In addition, we have discussed business development in the past. We now have five different platforms that incorporate the design of high-quality RNAi molecules that target five different cell types: Hepatocytes, Skeletal muscle, Pulmonary, Adipose, and CNS. We believe this broad ability to deliver highly potent RNAi molecules to a variety of tissues is both scarce and valuable and could enable dozens of new drugs. We believe there is ample work, there's ample room to work with partners and also continue to build an extensive wholly-owned pipeline.
That is intended to continue to let our discovery engine move quickly while ensuring that, one, we focus on a more limited set of wholly-owned assets that provide our commercial team with the level of synergy and efficiency. Two, we continue to have access to necessary capital outside the capital markets. Three, we can continue to build more passive value as our partners invest in development and commercialization. And four, we can continue to serve patients. As we are able to provide better clarity relating to the sources and magnitude of new capital, I believe a clear overhang in our stock may be removed. There is a lot of high-quality work going on at Arrowhead and substantial potential value to be unlocked as we solidify our balance sheet. Stay tuned for details when we're able to talk more about it.
I want to highlight one last event from the quarter that is important. We announced that GSK reached an agreement with Janssen to transfer exclusive worldwide rights to further develop and commercialize JNJ-3989 to GSK. If you recall, Janssen announced that they were discontinuing hepatitis B research and later announced that they were winding down most of their infectious disease and vaccine programs. JNJ-3989 was one of the discontinued programs of this strategic decision. That created uncertainty about the future. Janssen was a good partner, and we are confident that GSK will continue the diligent work that Janssen started. This transaction also builds on Arrowhead's relationship with GSK, which includes the 2021 exclusive license of GSK4532990, formerly ARO-HSD, an investigational RNAi therapeutic currently in a phase II study as a potential treatment for patients with alcohol-related and non-alcohol-related liver diseases.
We look forward to continuing our productive relationship with GSK. With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?
Javier San Martín (Chief Medical Officer)
Thank you, Chris, and good afternoon, everyone. I want to focus on the significant progress we've made on plozasiran, formerly ARO-APOC3, and zodasiran, formerly ARO-ANG3. This includes presentations at the American Heart Association meeting with phase II data on the MUIR and SHASTA-2 studies of plozasiran and the ARCHES-2 study of zodasiran. A KOL webinar on the significance of this data and recent interactions we have had with the FDA on our plans for phase III studies. Let's start with a review of what plozasiran is and then discuss the data presented at the AHA. 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 level by inhibiting breakdown of TRLs by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver.
Plozasiran is being developed as a treatment for patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and mixed dyslipidemia. These are three distinct patient populations with very different phenotypes. Familial chylomicronemia syndrome, or FCS, is a severe and ultra-rare genetic disease characterized by extremely high TG levels, typically over 1,000 milligrams per deciliter, leading to high risk of acute pancreatitis that usually requires hospitalizations and can be fatal. We're currently conducting the PALISADE phase III study in 75 patients with FCS. The primary endpoint of the study is % change from baseline in fasting TG. PALISADE is scheduled to complete in Q2 of 2024. Severe hypertriglyceridemia, or sHTG, is characterized by marked elevation in TG levels, typically over 500 milligrams per deciliter, which can also lead to increased risk of acute pancreatitis, as well as an increased risk for cardiovascular disease.
We conducted the phase II SHASTA-2 study and reported data at AHA. We're also working on initiating phase III studies, Shasta-3 and Shasta-4, in early 2024. I will discuss the AHA data and phase III study design in a moment. Lastly, mixed dyslipidemia is the presence of high TGs and remnant cholesterol, often with low HDL cholesterol. Remnant cholesterol is believed to be a major contribution to the residual risk of atherosclerotic cardiovascular disease after LDL is well controlled. We conducted the phase II MUIR study in patients with mixed dyslipidemia and reported those data at AHA. We're currently working on key features of the study design, including patient population selection, for a potential phase III study in patients with ASCVD and mixed dyslipidemia. We presented data at AHA for these last two patient populations, sHTG and mixed dyslipidemia.
In the phase II SHASTA-2 study of plozasiran in 226 subjects with sHTG who had baseline TGs greater than 500 mg/dL, two doses of 10, 25, or 50 mg of plozasiran once every 12 weeks reduced TGs to near normal level, and more than 90% of patients achieved TG levels below 500 mg/dL, which is the risk threshold for acute pancreatitis. Plozasiran achieved mean maximum reduction of up to 90% in ApoC3 and 87% in TGs. At 24 weeks, 12 weeks after the second dose, serum ApoC3 remained 79% below baseline, and TGs were 74% below baseline, with reduction in remnant cholesterol of 63%, while HDL cholesterol increased 68% above baseline.
In the phase II MUIR study of zodasiran in 353 subjects with mixed dyslipidemia, who had fasting TGs between 150-499 mg/dL, and either LDL cholesterol greater than 70 mg/dL or non-HDL cholesterol greater than 100 mg/dL. Subjects in this study received two doses of 10, 25, or 50 mg of zodasiran at baseline and at week 12, or two doses of 50 mg at baseline and week 24. Zodasiran-treated subjects demonstrated a mean maximum reduction in ApoC3 of up to 89% and robust reductions in atherogenic lipoproteins. At 24 weeks, zodasiran reduced TGs by 64%, remnant cholesterol by 54%, ApoB by 19%, and non-HDL cholesterol by 27%, while increasing HDL cholesterol by 51%. These were very encouraging results, and they received a lot of attention at the AHA.
After the presentations, we hosted a webcast featuring three experts in the treatment and management of lipid and lipoprotein disorders. Daniel Gaudet, Professor of Medicine at Université de Montréal, who discussed zodasiran in the context of the current treatment landscape for severe hypertriglyceridemia. Børge Nordestgaard, Professor and Chief Physician, Copenhagen University Hospital, University of Copenhagen, Denmark, who discussed the emerging role of remnant cholesterol in cardiovascular disease. Steven Nissen, Chief Academic Officer for the Heart and Vascular Institute at the Cleveland Clinic, who discussed why the decrease in atherogenic lipoproteins observed with zodasiran has the potential to prevent cardiovascular outcomes. A replay of that webcast is available on our website if you missed it. My takeaway was that all three experts agreed that zodasiran has a unique profile and great potential in FCS, sHTG, and in patients with ASCVD and mixed dyslipidemia.
The support of these notable experts gives us additional confidence as we embark on phase III studies to further evaluate zodasiran. So what will the sHTG phase III studies look like? We had an end of phase II meeting with the FDA, and our plan is to do two similar studies, SHASTA-3 and SHASTA-4, that together will be composed of approximately 700 patients, all with TGs greater than 500 milligrams per deciliter. The primary endpoint is lowering TGs after one year. We will include a subset of patients at higher risk of acute pancreatitis. We will provide more detail on that as we get the studies initiated in early 2024. We will also have a third study that involves patients with moderately elevated TGs to add to our safety database. We expect these studies to all be completed around the same time.
All in all, our interactions with FDA have been productive and helpful. We believe that we have incorporated their feedback and look forward to continue the dialog with the agency as we get closer to an NDA filing, following completion of the PALISADE study in patients with FCS and as we move forward with additional phase III studies in sHTG and mixed dyslipidemia. We also presented data at AHA on zodasiran, which received a lot of attention. Zodasiran is designed to reduce production of angiopoietin-like protein 3 or ANGPTL3, which is a hepatocyte-expressed regulator of lipid and lipoprotein metabolism, with multiple, multiple potential modes of action, including inhibition of lipoprotein lipase and endothelial lipase.
In the phase II ARCHES-2 study of zodasiran in 204 subjects with mixed dyslipidemia who had baseline TGs between 150 and 499 mg/dL, and either LDL cholesterol greater than 70 mg/dL or non-HDL cholesterol greater than 100 mg/dL. Two doses of 50 mg, 100 mg, or 200 mg of zodasiran once every 12 weeks, reduced the expression of ANGPTL3 and decreased atherogenic lipoproteins. Treatment with zodasiran resulted in substantial reductions of ANGPTL3 up to 74%, TGs up to 63%, LDL cholesterol up to 20%, remnant cholesterol up to 82%, and ApoB up to 22%, all at week 24. Zodasiran was also associated with a relative reduction in liver fat fraction at week 24, with no adverse events related to liver function test changes reported to date....
Plozasiran and Zodasiran continue to show favorable safety profiles. Treatment-emergent adverse events reported today reflect the comorbidities and underlying conditions of this study population. As I mentioned before, we're currently considering multiple phase III study designs and making decisions on patient population selection for mixed dyslipidemia in patients with atherosclerotic cardiovascular disease. We'll talk more about that in 2024 after we have further interactions with FDA about our proposed plan. I will now turn the call over to Dr. James Hamilton. James?
James Hamilton (Chief of Discovery and Translational Medicine)
Thank you, Javier. I believe the productivity of our discovery organization is unrivaled. This is partly due to the efficiency and scalability of siRNA therapeutics, and specifically of our proprietary TRiM platform, but more importantly, a product of the culture of speed and innovation at Arrowhead. We continue to find ways to outperform others in the RNA therapeutic space with a highly productive and lean organization. In 2023 alone, we completed discovery and optimization work across 5 different delivery platforms and nominated 9 clinical candidates. Each then may go on to the IND-enabling phase, including GLP toxicology studies, clinical supply manufacturing, as well as preparation and submission of regulatory filings. We are also working on a discovery pipeline of similar size for 2024. This high level of productivity is how we intend to reach our 2025 development goal.
Our discovery stage pipeline is, for the most part, kept confidential until we are approaching a CTA, or at times, until we file a CTA. So you will likely start hearing more about the newly nominated clinical candidates over the coming quarters. For example, yesterday we announced that we filed a CTA for ARO-DM1, our clinical candidate for the treatment of patients with type I myotonic dystrophy, or DM1, and our second clinical program using the TRiM platform for delivery to skeletal muscle. The phase I, two-way dose-escalating study will evaluate the safety, tolerability, and PK/PD profile of single and multiple ascending doses of ARO-DM1 compared to placebo in up to 48 patients with DM1. ARO-DM1 is designed to reduce expression of the dystrophia myotonica protein kinase, or DMPK gene. DM1 is the most common adult-onset muscular dystrophy, and there is currently no approved disease-modifying therapy.
Treatments have focused on symptomatic management, including physical therapy, exercise, ankle-foot orthoses, wheelchairs, and other assistive devices. ARO-DM1 represents a novel approach to treat DM1 by silencing aberrantly transcribed DMPK mRNA, which could lead to improvements in multiple symptoms, including muscle strength and function. We have several exciting early-stage clinical programs that target genes expressed in the liver, lung, muscle, and CNS, each of which is moving towards proof-of-concept data. However, I will focus on the three pulmonary programs. Specifically, I'd like to review safety and tolerability data to date, recent chronic toxicology results that I think help de-risk the pulmonary platform broadly, as well as some new PD data that further support our plans to rapidly move all programs forward.
To review, our three clinical-stage pulmonary programs are the following: 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. ARO-MUC5AC is designed to reduce production of mucin 5AC, or MUC5AC, as a potential treatment for mucobstructive pulmonary diseases. And ARO-MMP7 is designed to reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. All three of these programs are in phase I, II-A clinical trials, evaluating single and multiple doses in normal healthy volunteers and in patients. Across the three programs, 145 total subjects, both normal healthy volunteers and patients, have received active drug via inhalation, with another 31 receiving ARO-RAGE via the subcutaneous route. There have been no serious adverse events deemed to be related to drug.
There have been no patterns of drug-related adverse events, pulmonary adverse events, such as cough or shortness of breath, or adverse changes in lab or spirometry values. There has also been no evidence of local lung inflammation based on BAL cell count evaluation, and all chest X-rays have been read as normal. These safety and tolerability results have largely been consistent across the three programs and are highly encouraging for the pulmonary platform. Next, I'd like to cover the chronic toxicology results for ARO-RAGE and ARO-MMP7, which we recently received. These results are also highly encouraging and suggest that we have sufficient safety margins to proceed confidently to phase II. Specifically for ARO-RAGE, the no observed adverse effect level, or NOAEL, in the six-month rat study was the mid-dose, and in the nine-month monkey study, it was the highest dose studied.
For ARO-MMP7, the rat NOAEL was the highest dose, and the monkey NOAEL was the mid-dose. Keep in mind that dose levels selected for GLP toxicology studies are high multiples of the desired clinical dose. So some findings in a toxicology study are expected. The results for both ARO-RAGE and ARO-MMP7 suggest that the learnings and improvements we have made since our first-generation pulmonary candidate, ARO-ENaC, have improved the therapeutic index for our inhaled siRNA programs. Pending feedback from regulatory authorities, we are confident that we will have the required safety margins to begin phase two studies. This is an important step for the pulmonary platform at an important time as we look to design and initiate phase two studies in 2024. Now, moving on to the new pharmacodynamic data. ARO-RAGE continues to yield promising dose-dependent target engagement results.
We previously reported impressive reductions in soluble RAGE protein, or sRAGE, in serum and in bronchoalveolar lavage fluid, or BALF, in healthy volunteers. Previously reported at our June Analyst R&D Day, after two doses of 92mg given on days one and 29, serum sRAGE mean maximum reduction was 80%, with a maximal reduction of 90%. After a single dose of 184 milligrams, we observed a mean reduction of 90% and maximal reduction of 95% in BALF sRAGE, with mean maximum serum sRAGE reduction of 76% and maximal reduction of 91%. We have since received additional sRAGE data after two doses of 184 milligrams in healthy volunteers. After a second dose of 184 milligrams, serum sRAGE mean maximum reduction was 89%, with a maximal knockdown of 96%.
Additionally, reduction of serum RAGE, serum sRAGE, was similar in healthy volunteers and in patients with asthma at the 44 milligram dose level. So what are the next data points that we're watching? We're currently enrolling the top dose cohort in the mild to moderate asthma patients and have initiated a cohort of asthma patients with high baseline levels of fractional exhaled nitric oxide, or FeNO, which is a biomarker for the degree of IL-13-driven type 2 inflammation in the lung. These are both important to watch. If we continue to see consistency of PD effect in asthma patients, that would be encouraging. Also, it would be highly encouraging if RAGE lung knockdown leads to an anti-inflammatory effect via the FeNO biomarker in either the mild to moderate asthma patient cohorts, or more likely, in the high FeNO cohort.
The former should have data available during the coming months, and the latter will have the data around Q3 of 2024. I will now turn the call over to Ken Myszkowski. Ken?
Ken Myszkowski (CFO)
Thank you, James, and good afternoon, everyone. As we reported today, our net loss for fiscal 2023 was $205.3 million, or $1.92 per share, based on 106.8 million fully diluted weighted average shares outstanding. This compares with a net loss of $176.1 million, or $1.67 per share, based on 105.4 million fully diluted weighted average shares outstanding for 2022. Revenue for fiscal 2023 was $240.7 million, compared to $243.2 million for 2022. Revenue in the current period primarily relates to our collaboration agreements with Takeda, GSK, and Amgen. Revenue is recognized as we complete our performance obligations or key development milestones are reached.
For Takeda, revenue is recognized commensurate with our performance obligation, which includes managing the ongoing AAT phase II clinical trials. This means $866,000 of revenue to be recognized associated with the Takeda collaboration, which will be recognized in the next fiscal quarter. Revenue in the prior period primarily related to the recognition of payments received from our license and collaboration agreements with GSK and a portion of the payments received from our license and collaboration agreements with Takeda and Horizon. Total operating expenses for fiscal 2023 were $445.7 million, compared to $421.7 million.
Operator (participant)
Please remain on the line. Your conference will resume shortly. Again, please remain on the line. Your conference will resume shortly. Please remain on the line. Your conference will resume shortly. We are currently experiencing technical difficulties, and we are trying to get back online. Please bear with us.
Ken Myszkowski (CFO)
Hello? Hello.
Operator (participant)
Yes, you are now back online.
Ken Myszkowski (CFO)
Sorry, folks. We lost our internet connection. We're calling in as a cell phone, and I'll continue where I think we left off. Total operating expenses for fiscal 2023 were $445.7 million, compared to $421.7 million for 2022. This increase is driven primarily by increased candidate-specific and discovery R&D costs, as the company's pipeline of clinical candidates has both increased and advanced into later stages of development. Net cash used by operating activities during fiscal 2023 was $153.9 million, compared with net cash used by operating activities of $136.1 million during 2022. The increase in cash used by operating activities is primarily driven by higher research and development expenses.
We expect our operating cash burn to be $110-$130 million per quarter in fiscal 2024, and we expect full-year capital expenditures of approximately $150 million as we near completion of our GMP manufacturing facility. Turning to our balance sheet, our cash and investments totaled $403.6 million at September 30, 2023, compared to $482.3 million at September 30, 2022. The decrease in our cash and investments was primarily due to cash used for operating activities and capital expenditures, partially offset by cash inflows from financing activities. Our common shares outstanding at September 30, 2023, were 107.3 million. With that brief overview, I will now turn the call back to Chris.
Chris Anzalone (President and CEO)
Thanks, Ken. Arrowhead had another productive quarter, and we see wide-open space to accelerate our growth over the coming year. We expect 2024 to be a data and event-rich year, with many expected opportunities to create value, including readout of the plozasiran FCS phase III, filing our first NDA, launching a phase III for sHTG with plozasiran, launching a phase III CVOT with either plozasiran or zodasiran, readout in various patient populations with ARO-C3, initial CNS data in patients with ARO-SOD1, ARO-RAGE FeNO and knockdown data in asthma patients, ARO-MMP7 knockdown data in IPF patients, ARO-MUC5AC knockdown data in asthma and COPD patients, and initiation of first-in-human studies with our first adipose-targeting candidate. Thank you for joining us today, and I'd now like to open the call to your questions. Operator?
Operator (participant)
As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster, and we ask that you limit yourself to one question. One moment for our first question. Our first question comes from Edward Tenthoff from Piper Sandler. Your line is now open.
Edward Tenthoff (Managing Director and Senior Research Analyst)
Great. Thank you very much, and thanks for taking the question. I'm excited about all the progress on the cardiovascular side. I wanted to ask about the DM1 filing today, because now with this, I think you guys also recently maybe filed on DUX4, if I'm remembering correctly. So this is really a franchise you're starting to build in muscle. Is this going to be a core area, or could this be one of the areas for potential partnership that you're highlighting? Thanks.
Chris Anzalone (President and CEO)
Hey, Ted. Thanks very much. Again, we're really sorry for the technical problems.
Edward Tenthoff (Managing Director and Senior Research Analyst)
No worries.
Chris Anzalone (President and CEO)
I think you're right. You know, we view skeletal muscle as potentially another vertical, another franchise. We think both DM1 and DUX4 are good targets. We think, you know, these are you know, two, you know, large numbers of patients who desperately need treatment options, and so we're excited about these. We are looking at some additional targets as well, and so we'll see if this can grow to be something as large as we foresee pulmonary being, for instance. At this point, it's a little bit too early to tell, but I would agree that right now it appears to be, you know, a pretty interesting burgeoning franchise for us.
Edward Tenthoff (Managing Director and Senior Research Analyst)
Awesome. Great. Thank you. Looking forward to-
Chris Anzalone (President and CEO)
Thanks.
Edward Tenthoff (Managing Director and Senior Research Analyst)
Hearing more about it.
Chris Anzalone (President and CEO)
Thank you, Ted.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Ellie Merle from UBS. Your line is now open.
Ellie Merle (Equity Research Analyst)
Hey, guys, thanks so much for taking my question and, all the color on the timelines, for the pulmonary program. Maybe just in terms of understanding the biology of RAGE, particularly in the high FeNO cohort, I guess, what are you looking to see there, and what would you view as clinically meaningful? Thanks.
Chris Anzalone (President and CEO)
James, you want to start this?
James Hamilton (Chief of Discovery and Translational Medicine)
Sure. Yeah, I can take a stab at that. So we would expect to see the reductions in FeNO primarily based on our animal data. The work we did in the Alternaria model showed steep reductions in IL-13. We can't measure FeNO in the rats, but a large reduction in IL-13 should translate into a reduction in FeNO. And in terms of what would be clinically meaningful based on what was seen with tezepelumab or Dupixent, I think something in the, you know, the 30% or so range would put us in the range of what those other molecules have been able to show.
Chris Anzalone (President and CEO)
Javier, anything to add?
Javier San Martín (Chief Medical Officer)
No, I think that's.
Ellie Merle (Equity Research Analyst)
Great. Thanks.
Chris Anzalone (President and CEO)
Thank you.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Maury Raycroft from Jefferies. Your line is now open.
Maury Raycroft (Equity Research Analyst)
Hi, thanks for taking my question. I was going to ask one on ARO-RAGE too. You mentioned that in patients, the data is mapping with what you observed in healthy volunteer data. Can you elaborate on whether you're seeing this for your 92- and 184-mg asthma patients? And could you have the FEV1 data from these non-FeNO patients, potentially even by year-end or first quarter of next year? I guess maybe, if you could provide more granularity on the timeline there. And also, you talked a little, a little bit about the subq ARO-RAGE data. Can you remind what, or can you talk about what you're seeing there and remind what the purpose is of assessing that round of administration?
Chris Anzalone (President and CEO)
Sure. So I'll, I'll take those in reverse order. The subq, we're, you know, we're still about halfway through that study. The study's fully enrolled, but with healthy volunteers, but we're just collecting the data from some of the earlier cohorts. So we're not ready to share the sRAGE data from those studies yet. The idea there is that based on the animal work we've done, we were able to see significant levels of knockdown in both rodents and in monkeys with subq administration. So we wanted to, we view that as a potential additional option, an optional route of administration that could be different from an inhaled route of administration. Then the next question, I think, was on FEV1.
You know, we've seen those data as they come in, and it's primarily in there as a safety endpoint, and the cohort sizes are very small. We've not analyzed those data in the patient cohort that we have filled at this time, and so I think it's too early for us to say anything about FEV1 changes. Suffice it to say that the cohort sizes are single digits, and FEV1 can be a noisy metric. And then the first question was?
Vince Anzalone (VP of Investor Relations)
It was mapping of-
Chris Anzalone (President and CEO)
Oh, yeah, that's right. Yeah. We only have the sRAGE reduction data from the 44 milligram dose level in the patients. So we've not seen the sRAGE reduction data from 92mg or 184mg
Maury Raycroft (Equity Research Analyst)
Got it. Okay. And for FEV1 at baseline, is that something you can comment on for the asthma cohorts, the higher dose cohorts?
Chris Anzalone (President and CEO)
Yeah, again, I think we don't have all of the aggregated data as of yet, but-
Javier San Martin (Chief Medical Officer)
But the cohorts for the RAGE study were all mild asthma patients, so it's expected to have relatively normal baseline FEV1.
Maury Raycroft (Equity Research Analyst)
Got it.
Javier San Martin (Chief Medical Officer)
But about the most patients for the pheno cohorts, I mean, the max phase II program, but in the RAGE asthma, they are mild patients by definition.
Maury Raycroft (Equity Research Analyst)
Got it. So more mild patients in, in the asthma patients for those two higher dose cohorts. Okay. Thanks for taking my question.
Chris Anzalone (President and CEO)
Yeah. Thanks, Maury.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Mani Foroohar, from Leerink Partners. Your line is now open.
Mani Foroohar (Senior Managing Director)
Thanks for taking the question. I guess I'm going to zoom out on, like, an ultimately more macro and philosophical question. You talked about sort of monetizing, you know, some type of synthetic royalty or royalty sale monetization. You talked about a couple different approaches to finance the ongoing CVOT. That, in my mind, raises two questions. One, that is, by definition, anything that's a royalty is, you know, is a fairly high duration financing instrument, and that it's essentially a form of synthetic debt. How do you think about timing a royalty or, I guess, convert any type of debt, any type of rate-dependent transaction, given how volatile the funding rates of anyone who would be buying that royalty from you would be?
You do want to wait until rates come down to see if you could potentially get a tighter spread, et cetera. Just how do you think of that from a purely financial CFO macro perspective? And then secondarily, you know what? I'm going to stop. I'll ask my follow-up afterwards.
Ken Myszkowski (CFO)
Sure. So the short answer is no. You know, we are—we would not, you know, wait for macro environments to change. You know, who knows what, you know, who knows where those are going to go? You know, there are several funders, multiple funders that do this kind of work. And we have, you know, we've been chatting with some of them for a bit now, and we believe that there are—there could be attractive opportunities there that are not dependent upon, you know, fundamental changes in the macro environment. So we feel comfortable that there is capital there, you know, at a reasonable rate for us, you know, to finance these in this kind of manner.
You know, will we ultimately pull that lever? We have, you know, we haven't made that decision, but we just wanted to make clear that that is a lever and potentially an attractive lever that we could pull as part of an overall financing strategy.
Mani Foroohar (Senior Managing Director)
Great. I guess my follow-up is, if you're going to be selling part of the economics of an asset that you're going into a CVOT, how do you think about that versus partnering the asset entirely rather than the CVOT yourself? Presumably, a large pharma partner would ascribe a lower operational discount to their own carrying out of a CVOT versus you guys doing your first CVOT, implying a more attractive NPV if they were to acquire the asset from you in a partnership, but whether 100% purchase, royalty, 50/50, any under any terms, by definition, the economics of a partnership would be better than doing raising capital doing it yourself.
So, like, is there a reason why you see retaining it and then raising at an implied higher cost of capital as a better strategy rather than selling it at an implied lower or partnering at an implied lower cost of capital and eliminating the operating risk of having to do a CVOT yourselves?
Ken Myszkowski (CFO)
Yeah, look, you know, look, those are all things that we consider as we look at the array of funding opportunities ahead of us. You know, paying, you know, some amount of royalties on these is relatively cheap for us because we're not stacking royalties. We don't, we don't owe royalties on any of these assets. And so, and presumably also those royalties will be capped. Presumably, they would not go, you know, indefinitely. But, but you're right.
You know, as we look at all these, at all these opportunities, you know, we need to take all those things into consideration. You know, look, we see ourselves as a commercial company, and we think we can create a lot of value as a commercial company. And so assuming that our, you know, the relative cost of capital while holding onto these assets is reasonable, then that's something that we would do.
Mani Foroohar (Senior Managing Director)
All right. Thanks, guys. That's really helpful.
Ken Myszkowski (CFO)
Yep, you're welcome.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from David Lebowitz from Citi. Your line is now open.
David Lebowitz (Senior Research Analyst, Biotechnology)
Thank you very much for taking my question. Just piggybacking on the last question. As far as any licensing agreements you're looking at, are you planning to wait until after the pivotal data? And also, what activity level are you intending to really take within the partnership? Is this something where you're going to be very active licensing to kind of one of these royalty companies, or would this be something more specific, where you're basically giving control of the asset to a larger pharmaceutical player?
Chris Anzalone (President and CEO)
Yeah. The answer to that just depends upon the asset, of course. You know, we, we, we have done and will continue to do, asset licenses like we do with HSD or HBV or AAT. Well, I guess AAT is a little bit different, because we do have 50/50 profit share there. But, but, but, Or LPA. You know, there, we, we will do those going forward, you know, look, our, our—here's our goal. You know, we, we have a very large pipeline, and it's, and it's only gonna get larger, and so we've got plenty of room to license out some, some individual assets.
What we wanna be, what we wanna end up with is a series of verticals, where we can concentrate commercial build out, and, and we can give our commercial team, you know, several drugs to hold in the bag to, you know, to sell into various channels. I think we can do that, you know, given our franchises with pulmonary, muscle, cardiometabolic, CNS, et cetera, adipose, et cetera. So I think we can do that. And, and as we look at how to cluster those, you know, if we will find that there are some outliers, if you will, some that, that, that may not fit well into a commercial strategy. And those would be the easy ones. Those would be the easy ones to, to license out.
We also have the opportunity to do platform deals. We've talked about this in the past. I like that a lot. We now have five platforms, five different cell types that we can address. I like the idea of working with partners who can bring in targets to us, and we can help to create drugs for those partners. That for me is found value as long as those, you know, those targets are not what we're working on right now. And so, you know, maybe it's an unsatisfying answer because we'll be doing a number of different things, but that's the way we see the waterfront. And again, you know, if we are a one or two asset company, then the answer would be much simpler.
But we are, you know, we are a 20-plus, you know, asset company. And so we have the ability to, you know, to structure a number of different partnerships and go-to-market strategies for ourselves.
David Lebowitz (Senior Research Analyst, Biotechnology)
Well, thanks for taking my question.
Chris Anzalone (President and CEO)
You're welcome.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Luca Issi from RBC Capital. Your line is now open.
Luca Issi (Senior Biotechnology Research Analyst)
Oh, great, thanks so much for taking my question. Congrats on the progress. I have a quick one, maybe, Javier, if I may. I was under the impression that you were planning a cardiovascular outcome trial with ApoC3. While it sounds to me that you're now planning cardiovascular outcome trial either with ApoC3 or ANG3, assuming that that is correct, what drove the change in strategy? Was this informed by conversations with the FDA? And is this related in any sort, form, or shape with the numerical worsening in glycemic control that we've seen for ApoC3? Any color there much appreciated. Thanks so much.
Javier San Martin (Chief Medical Officer)
Well, thank you for that question, Luca. Really, really important, and I think this highlight how dynamic is drug development today and how fast science change and advance.... If we go back, I would say six to nine months, when we already were thinking and working on a CVOT trial design for zodasiran or APOC3, the focus was triglycerides, and the field was focused on triglycerides as a key component of the residual risk. In the last six months, I think that focus changed. And I'm saying in the last six months, because I don't know if you called into the KOL webinar at the American Heart Association, but Dr.
Nordestgaard showed a slide where you see the number of publications in remnant cholesterol as a component of the residual risk in the last 10 years, which was 10 or 20 papers a year versus 1,000 in the last one year. That means the change in this field is happening as we speak, and the understanding that it's not just TG, but it's remnant cholesterol, and it's the totality of the atherogenic lipoprotein, is a new development. And frankly, six months ago or nine months ago, it wasn't a key component of our decision making, and it is now, and it's been in the last three months. So now when you look at the two molecules and you focus on the concept of totality of atherogenic lipoproteins, not TG or not TG only, because remember, for TG, ApoC3 has better efficacy than H2.
But when you look at the totality of atherogenic lipoproteins, ARO-APOC3 reduce LDL cholesterol by 20+%, reduce remnant cholesterol by 80%. So it is substantially different. The population that we should address may not be exactly the same, and that's something that we're thinking and talking to experts right now. So I think we're, we're changing following the science. We did have conversation with some experts. We did not have any conversation about this with the FDA yet. And within the next month or so, we're going to get close to, to make a decision and start to define our next step from the regulatory perspective and from the clinical trial design perspective.
Chris Anzalone (President and CEO)
I don't think you were getting towards this, but let me just say it. You know, our increasing interest in ANG3 doesn't reflect a lack of confidence in APOC3. You know, we were moving forward to that, you know, forward on that, as you point out, for CVOT. But as the science has been moving, you know, as Javier said, over the last six months, we've had this growing wait a minute moment where we should be looking also at ANG3, just to ensure that we are pushing, you know, the best candidate that we can into a specific type of CVOT.
You know, we are still moving as quickly as we can. Obviously, with FCS, we will be finished with that phase III, I think, in the second quarter. We'll be starting, you know, the sHTG phase III early 2024. Now we've got a little bit of time to figure out kind of where we're going to place our bet with the CVOT.
Luca Issi (Senior Biotechnology Research Analyst)
Got it. Thanks so much, guys.
Chris Anzalone (President and CEO)
You're welcome.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Brendan Smith, from TD Cowen. Your line is now open.
Brendan Smith (Director and Senior Analyst)
Great. Hi, guys. Thanks for taking the questions. Congrats on the progress. Just a couple quick ones, if I could. I also want to have a follow-up just on the timing to pulmonary edema. Is it fair to say we'll see the high-dose RAGE data in asthma patients by Q2 of next year, with the high FeNO data in Q3? And then really, just any color you can give us on MUC5AC and MMP7, maybe when we might see some of that data next year would be great. And then quickly, I just wanted to see if there's any updates on the ARO-C3 program and, if there's any plans to put out any data from that next year either. Thanks.
Chris Anzalone (President and CEO)
Sure. James?
James Hamilton (Chief of Discovery and Translational Medicine)
Sure, yeah. The intention would be to release the sRAGE data from the asthma cohorts at when it becomes available to us. So probably, you know, the middle of the first half of next year, I would think, for the asthma, the high-dose asthma, sRAGE data. And then, in terms of FeNO, in the high FeNO cohorts, we're looking at Q3 for FeNO data in those patients. And then MUC5AC has been a little more challenging to enroll. There's some protocol requirements in there and the requirement of those patients being severe asthmatics. But likely towards the middle of the year for ARO-MUC5AC data. We still need to enroll the highest risk cohort of those patients. In terms of C3, we are in the process of enrolling the patient cohorts, the IgA nephropathy patients, as well as the C3G patients. So probably the second half of 2024 for proteinuria data.
Brendan Smith (Director and Senior Analyst)
All right, great. Thanks very much. Appreciate it.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Mayank Mamtani from B. Riley Securities. Your line is now open.
Mayank Mamtani (Senior Managing Director)
Good afternoon. Thanks for taking our question. So maybe, James, if you could dive a bit bit deeper on the safety margin difference that you've seen between MUC5 versus RAGE in the recent preclinical data that we received. And if you're able to comment on how the NOAEL doses for MUC5 correlate with the top dose that's being tested in the clinic. And maybe a high-level question on, like, what for MUC5 would be, you know, human proof of concept like investors think about for ARO-RAGE in terms of, you know, high asthma patients. Like you just commented, it's severe asthmatic patients, but what sort of biological signal would be relevant here, given obviously this is more downstream physiology to IL-4 IL-13?
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, I think, on the last question, it's a bit tough to, to pin down what's clinically relevant in terms of MUC5AC knockdown, since there's not a great correlate out there from, from other drugs. So I, I can't give you an exact number on that. In terms of the safety margins, comparing MMP7 or, or RAGE with, with ENaC, it... I guess it depends on the dose level. We used a low, mid, and high dose level for, for all of those chronic tox studies in the rats.
If you compare the cumulative dose given over a six-month rat study at, at the high dose level for, for RAGE, we had, it was a sevenfold difference between the high dose level, used in, in ENaC and in, in RAGE, and a four- to five-fold difference for, for MMP7 in the rat. So it's a significant difference between, you know, the, the total cumulative doses that were administered in, in those two, with those two different molecules.
Mayank Mamtani (Senior Managing Director)
Got it. Thank you. And then just on the muscle-targeting programs, DUX4 and DM1, could you just remind us the targeting receptor ligand approach here? And as obviously you guys know, you know, it's an active field. There are alternative antibody ASL approaches. Maybe how does sort of your preclinical data inform, you know, what you've seen? And maybe related to that, is the plan to secure non-dilutive capital for that no longer a near-term event, Chris, or you, you're just gonna be opportunistic, recognizing that there might be some more clinical data coming in from these targets, from any of your peers?
Chris Anzalone (President and CEO)
I'm sorry, I misunderstood. What kind of capital? Say that again.
Mayank Mamtani (Senior Managing Director)
Yeah. I think you had plans for non-dilutive capital at some point, which delayed the DUX4 program. So I'm just curious if you're no longer gonna do anything strategically there for the muscle in the near term.
Chris Anzalone (President and CEO)
Right. Yeah. Yeah, yeah. That ran its course for now. We are happy to run the DUX4 as well as DM1 clinical programs, and you know, which does not mean that we will never partner them. But we were exploring, as you know, we were exploring potentially partnering DUX4, and it just made sense to us to you know, to stop those discussions, and we're moving ourselves for right now. James, you want to-
James Hamilton (Chief of Discovery and Translational Medicine)
Sure. And then on the comparison with the other muscle-targeting platforms that are out there, for DM1, we've looked at knockdown in vivo and have achieved, I'd say, compared similar knockdown or similar duration of effect with what's been published for, for example, the transferrin-targeted platforms. We use a peptide targeting the alpha v beta 6 integrin, so it's a different way of getting the sRNA into the cell. I think, in terms of total drug dosage, our dosages should be much lower compared to the transferrin conjugates, which of course conjugating sRNA to a monoclonal antibody. And then I would also anticipate that we would not expect to see some of the transferrin-related safety issues that have been out there. Of course, the time will tell, and the data will tell us, but it's something we would not anticipate.
Mayank Mamtani (Senior Managing Director)
Okay. Thanks for taking our questions.
Chris Anzalone (President and CEO)
You're welcome.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Patrick Trucchio from H.C. Wainwright & Co. Your line is now open.
Patrick Trucchio (Managing Director of Equity Research)
Thanks. Good evening. Just regarding the 20% and 25% targeting goals, can you give us a sense of from which platforms the 20 drug candidates are expected to emerge from? Understanding several have been announced this year, and if, along with CNS, pulmonary, liver, adipose, and muscle, if additional tissues may be targeted with TRiM.
Chris Anzalone (President and CEO)
I don't have any guidance to tell you on additional cell types other than the fact that we will be in new cell types. You know, we've said publicly that we think we can get into a new cell type every 18-24 months. I think that continues. Look, I expect, you know, by the year 2025, we will have new or additional candidates in every one of those verticals.
Patrick Trucchio (Managing Director of Equity Research)
Got it. And then just a few follow-ups on the pulmonary compounds. Just first, regarding initial chronic tox results to the ARO-RAGE and ARO-MMP7, I'm wondering if you can tell us if or when further chronic tox data is expected and the level of confidence that data should continue to support advancement of those programs, and when you might have similar data for ARO-MUC5AC in 2024. And just to follow up on ARO-RAGE, if you can discuss the targeting mechanism of the subq administration and advantages that would be expected for this route relative to the inhaled route.
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, sure. So in terms of the chronic rat, or the chronic tox data for the pulmonary programs, that, that's it. I mean, that's the, that's the final, you know, that's from the final report. So there's, there's no more expectations. We won't be getting any more data around, chronic tox for MMP7 or RAGE. From, from MUC5AC, we're still planning the chronic tox study. We wanted to, to get some biomarker data from the clinical study to better inform on, on the dose frequency for the chronic tox study, since frequency of administration seems to be really important to, avoid entering into a, dose levels where we see toxicity. We really wanted to nail down dose frequency, so we need to get a duration of effect from the clinical studies before we finalize the chronic tox study for MUC5AC.
Chris Anzalone (President and CEO)
Regarding the subq, you know, our thinking there was twofold. One, there could be other targets and other indications where subq administration is just preferred to inhaled. And second, that could potentially also broaden or widen out our therapeutic index.
Patrick Trucchio (Managing Director of Equity Research)
Great. Thank you very much.
Chris Anzalone (President and CEO)
You're welcome.
Operator (participant)
And thank you. One moment for our next question. Our next question comes from Prakhar Agrawal from Cantor Fitzgerald. Your line is now open.
Prakhar Agrawal (Senior Biotech Analyst)
Hi, thanks for taking my questions, and congrats on the progress. So on your ARO-XDH program that was partnered with Horizon, it seems that Amgen has decided to terminate this agreement. Was there any data generated by XDH program, or was it just part of the recent strategic overhaul by Amgen after Horizon deal closed? And, what are your plans for this asset now? Develop internally, or will you be looking for a partner again? Thank you.
Chris Anzalone (President and CEO)
So it's early to say on that. We haven't seen data. I don't know that we will, but at least so far, we haven't seen any of the clinical data. And so we've not been told, you know, why that was being discontinued, whether it's strategic or something else. We have some theories. James, do you want to talk about the Alnylam program, for instance?
James Hamilton (Chief of Discovery and Translational Medicine)
Sure. Yeah. I think, another company had an siRNA targeting the same gene target, XDH. It was also discontinued due to lack of decline in uric acid in the blood, with even if you knock down all of the XDH in the liver, there are still hepatic sources. So liver knockdown might not have been enough.
Prakhar Agrawal (Senior Biotech Analyst)
Thank you.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Mike Ulz from Morgan Stanley. Your line is now open.
Mike Ulz (Executive Director of Biotechnology Equity Research)
Hey, guys. Thanks for taking the question. Maybe just a quick one on ARO-RAGE, just in terms of timing of a potential phase II study there. Now that the clinical, the chronic tox studies are done for ARO-RAGE, do you have enough data to now start to engage with the FDA, or is the plan more to wait for some of the, you know, other cohort data, like the asthma patients or high FeNO, before you start to do that? Thanks.
Javier San Martin (Chief Medical Officer)
We're thinking about starting phase II in 2024, for sure, and there's already work going into that. Study design, patient populations, selection of CROs. So we are already planning. As the data is coming in, it will help us to decide the dose and the dose frequency, but we are already planning on the next stage development for the ARO-RAGE.
Mike Ulz (Executive Director of Biotechnology Equity Research)
Okay. Thank you.
Chris Anzalone (President and CEO)
Welcome.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from William Pickering from Bernstein. Your line is now open.
William Pickering (Senior Research Analyst)
Hi. Thanks so much for squeezing me in. I had a few follow-ups on the DM1 announcement. So how is the drug designed to get your siRNA inside the nucleus, where the mRNA is accumulating? And maybe can you share any more color on what endpoints you'll be measuring that could suggest early signs of efficacy, for example, splicing assessment or any functional endpoints? Thank you.
Chris Anzalone (President and CEO)
Sure, yeah. So we, we will look at some of the same endpoints that other companies have looked at, and we'll look at total DMPK knockdown, changes in spliceopathy, and we'll also look at the video and opening time, as well as some of the other functional endpoints. And so your other question on knocking down siRNA in the nucleus, we've done some work in animals. We haven't published this yet or shared it publicly via a you know a poster or presentation, but we've shown at doses similar to what we plan on administering in the clinic, that we are able to get a level of knockdown of nuclear RNA, and that translates into improvements in spliceopathy. That was the impetus for us moving this program into the clinic, that we could get, even with modest levels of nuclear RNA knockdown, we could get improvements in spliceopathy.
William Pickering (Senior Research Analyst)
Great. Thanks so much, and congrats on the progress.
James Hamilton (Chief of Discovery and Translational Medicine)
Thanks.
Operator (participant)
Thank you. I would now like to turn the call back over to Chris Anzalone for closing remarks.
Chris Anzalone (President and CEO)
Thanks very much, everyone, for joining us today, and I wish you all a happy holiday season.
Operator (participant)
This concludes today's conference call. Thank you for participating. You may now disconnect.