Arrowhead Pharmaceuticals - Q3 2023
August 7, 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, Steven. Good afternoon, thank you for joining us today to discuss Arrowhead's results for its fiscal 2023 third quarter, ended June 30th, 2023. With us today for management, our 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 both 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 most recent annual report on Form 10-K and our quarterly reports on Form 10-Q. I'd now like to turn the call over to Chris Anzalone, President and CEO of the company. Chris?
Chris Anzalone (CEO)
Thanks, Vince. Good afternoon, everyone. Thank you for joining us today. Our industry is built on promise. Sometimes this promise can be stunning and carry with it the possibility of saving the lives of some and drastically improving life for others. Arrowhead's mission is to bring important new medicines to the people who need them and save lives and alleviate suffering where we can. While this is our guiding principle, and focusing on this promise has given us purpose and the motivation to, I believe, innovate at industry-leading levels and operate at speeds not seen before, it is not the only important focus for us. Another is risk. Our industry swims in a sea of risk.
We recognize that in order to succeed, we need to appreciate the great promise in front of us, but focus on all the risks between the idea and the medicine ultimately given to a patient. We are idealists, but we are not naive. One of our most important jobs is to mitigate and decrease risk where we can. We have made great progress on this broad front since our last call, and this is how I would like to frame our discussion today. Let's begin with pulmonary. We believe we've taken an important step toward further de-risking the entire pulmonary franchise, with the first chronic GLP toxicology results starting to come in. For ARO-MNP-7, the NOAEL, or No Observed Adverse Effect Level, was the highest dose we tested in our chronic rat study. In other words, even at the highest dose tested, we are not seeing anything that is deemed adverse.
The highest dose represents what we believe would be substantially greater exposure than would be applied to humans. We are waiting for final rat data from the ARO-RAGE chronic GLP tox study, but that also is looking like the NOAEL will be the highest dose we tested. We are still waiting for the nine-month monkey data in both candidates, but our experience with ARO-ENaC leads us to believe that the rat is the more sensitive species for these pulmonary tox studies. It is very encouraging to us that the rodent study looks so positive. This is potentially a big step forward for the platform. As you may recall, we saw lung inflammation in some of the chronic GLP tox doses for ARO-ENaC in 2021.
Based on our analysis of those results, we concluded that we needed to increase the potency of our pulmonary candidates. We clearly did that with ARO-MNP-7, ARO-RAGE, and ARO-MUC5AC. We were optimistic that these improvements would translate into better chronic tox results. Of course, we couldn't know until the data came in. As we are now seeing preliminary data from those studies come in, we are increasingly confident that ARO-MNP-7 and likely ARO-RAGE may have substantially wider tox windows than ARO-ENaC did. I believe this represents a significant de-risking event for the pulmonary franchise. We look forward to having the complete rat and monkey chronic GLP tox data for ARO-RAGE and ARO-MNP-7 in coming months and expect to have chronic GLP tox data for ARO-MUC5AC next year.
Encouraging pulmonary chronic GLP tox data follow prior de-risking events in the pulmonary franchise over the past quarter. Specifically, I believe the ARO-RAGE clinical data indicate 3 important things. First, the safety and tolerability reports to date have been good and nothing surprising has emerged. This is always a critical first step for a new platform and every new drug. Second, the activity data we have seen thus far have been impressive and showed continued dose response through the top dose level. After a single inhaled dose of 184 milligrams of ARO-RAGE, we saw up to 95% knockdown, with a mean of 90% in that cohort. Not only is this a high level of target gene knockdown, but it was extraordinarily consistent across participants in the cohort. Each subject had a good response.
This is in the same ballpark as what we now expect with optimized liver-targeted programs, and this is an important point. I think it is generally accepted that RNAi is a reliable modality to safely reduce expression of a target gene, and that when Arrowhead introduces a new liver program, there is high expectation, both internally and externally, that the drug candidate will reduce expression of the target protein as designed. I am hopeful that each new data set we are approaching. I'm sorry. I am hopeful that with each new data set that we are approaching this expectation in pulmonary. That is a giant leap forward and an important value inflection point. Lastly, we think the data also show that the duration of effect with ARO-RAGE supports a dosing interval of two months or more.
This is an important de-risking event because it limits accumulated drug exposure, increasing our confidence that the good safety profile seen thus far may continue during cryotreatment. It would also be a very patient-friendly dosing regimen. De-risking the pulmonary platform is important for its own sake. As we have said in the past, we see many potential drugs coming out of the franchise that could address a number of unmet medical needs, and we appear to be the only company able to effectively use RNAi in the lungs. The pulmonary franchise alone could be the basis of a large company. It's also important as an example of how we seek to de-risk our broader business. From our perspective, a one or two-drug company is a bet, not a business.
From the beginning, we have sought to create a broadly diversified business to increase the number of patients we serve, but also importantly, as a hedge against the unpredictability of biology. In our industry, the risk of failure is substantial, and our mitigation strategy has been part innovation and part brute force. We have sought to create a technological platform that works reliably and then move as fast as we can to create as many well-thought-out drug candidates as possible. We've built and continue to refine and expand the reach of our TRiM platform. This is a modular, structurally simple system to, 1, address multiple cell types, which allows our therapies to go where a disease is in a way that other RNA companies do not. 2, move rapidly from idea to the clinic and then efficiently through mid- and late-stage clinical studies.
Three, provide platform continuity and confidence, which gives us an enhanced expectation of success for new candidates that we believe far exceeds that of biotech broadly. Lessons learned developing each candidate informs the development of future candidates, our expectation of success grows stronger over time. We believe this translates to the potential for more candidates to become approved therapies than industry average. Our 20 in 25 initiative follows this platform development and represents, to some extent, the brute force component of our broader risk mitigation strategy. We have platforms that appear to work well, we have the responsibility to our patients and stakeholders to build as many new drugs as fast as we can. It is our goal to have 20 clinical-stage or marketed products by the year 2025.
Somewhat paradoxically, building such a large pipeline is part of our strategy to mitigate balance sheet risk. We are in a very expensive business, one could argue that the best way to ensure we are properly capitalized to bring drugs to market is to have a small, focused pipeline. We reject that. Rather, we believe that well-thought-out drug candidates with greater-than-industry-average chances of success can always find homes in partner companies' pipelines. As we mentioned at our R&D Day in June, we have brought in nearly $1 billion in partnering capital over the past six years and have not raised equity capital for over three and a half years.
In fact, GSK recently initiated a phase II-b study of GSK4532990, formerly called ARO-HSD, for the treatment of NASH, which earned us a $30 million milestone payment. In addition, Takeda initiated the phase III REDWOOD study of fazirsiran, being developed as a potential treatment for alpha-1 antitrypsin deficiency liver disease, which earned Arrowhead a $40 million milestone payment. We believe that partnering is a good cornerstone of a broader financing strategy and one that our platforms are uniquely suited for because of the quality of the candidates coming out of them and the scarcity of the companies that are skilled at generating RNAi-based therapeutics.
Our partnering strategy includes existing partnerships that are maturing and therefore eliciting higher payments, new potential partnerships that could combine our platforms with a partner's target or set of targets, and new partnerships on existing programs in our pipeline. Regarding the latter, on our last earnings call, I discussed that at the time we had paused the CTA filing because of some inbound interest in partnering ARO-DUX4. We continued to explore those options; however, we decided to move forward with the ARO-DUX4 CTA filing ourselves. Partnering discussions can take time, and we don't ultimately know if they will translate into license agreements. We felt it did not make sense to further delay the CTA filing and the phase I study. While partnering continues to be a cornerstone of our financing model, we are certainly cognizant of the risk of over-partnering.
We believe the best way to build a lot of value quickly is to retain some wholly owned candidates and drive toward commercialization. There is substantial risk with this course, but over the past quarter, we believe we have taken some off the table. We completed enrollment in the phase III PALISADE study of ARO-APOC3 in patients with familial chylomicronemia syndrome, or FCS. This is an important milestone for Arrowhead because it will likely be the first candidate and indication that we will seek regulatory approval for. The final study visit for the last patient in is scheduled for Q2 of 2024, we expect to start the NDA process next year. In addition to FCS, we are currently working on the phase III plans for severe hypertriglyceridemia and mixed dyslipidemia, which we will be discussing with regulators this year.
Shortly after those discussions, we plan to start phase III studies for those larger indications. Our other wholly owned cardiometabolic candidate, ARO-ANG3, also had an important milestone during the quarter. We presented data at the European Atherosclerosis Society Congress demonstrating that ARO-ANG3 achieved LDL-C reductions of 44% to 48% when added to existing standard of care treatments. These results are similar to results seen in studies of an approved monoclonal antibody targeting ANGPTL3 in patients with HoFH. These are important de-risking data as we move toward one or more phase III programs, which we are currently designing. We are actively working on go-to-market strategies for multiple candidates. We expect to have four drug candidates in phase III studies by the end of the year.
Two of these are currently wholly owned, ARO-APOC3 and ARO-ANG3, and a third, fazirsiran, is partnered with a 50/50 profit share in the US, so we have retained substantial economics. As I mentioned, we will have our first phase III registrational study readout mid-next year for our APOC3, our ARO-APOC3 program in FCS, and expect an NDA soon thereafter. As we look at our pipeline, we expect additional NDA filing opportunities on a very regular basis going forward. Moving to our earlier stage pipeline, we filed two CTAs for two new programs targeting gene expression in two different tissue types. I already mentioned ARO-DUX4 in skeletal muscle for the treatment of FSHD, and the other is ARO-SOD1 in the central nervous system for the treatment of ALS. We expect additional CTAs over the next few quarters using both the CNS and skeletal muscle platforms.
Of course, these are early, but they represent important de-risking events for potential CNS and skeletal muscle franchises. As with our advances in pulmonary, these are also illustrative of our desire to expand the reach of our technology and decrease the overall risk of our business by creating value across many different channels. Lastly, before handing the call over to Javier, I want to highlight the R&D Day that we hosted in June. During that presentation, which is still available to view on our website, we gave updates and had external KOLs talk about some existing clinical programs in cardiometabolic and pulmonary disease, and discuss what's next for us in CNS tissue, including potentially systemic delivery and delivery to adipose tissue. The R&D Day had a lot of detail. We are constantly pushing our technology forward and expanding its reach.
With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?
Javier San Martin (Chief Medical Officer)
Thank you, Chris, and good afternoon, everyone. The design, planning, and preparation of the late-stage studies of our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3, is well underway. We're making good progress towards our goal of conducting multiple end-of-phase II meeting with regulators this year and initiating multiple phase III study late this year and early next year. We also intend to present final phase II data at the American Heart Association meeting in November, pending a track acceptance for multiple studies for both ARO-APOC3 and ARO-ANG3. Let's take a moment to review the various studies we have conducted, and then I will provide our current thinking around the phase III studies, how the phase III studies may look like for each clinical indication. I will start with ARO-APOC3. Our investigational RNAi therapeutic being developed as a treatment for patients with mixed dyslipidemia, severe hypertriglyceridemia, and familial chylomicronemia syndrome.
ARO-APOC3 is designed to reduce production of apolipoprotein C3 or APOC3, a component of triglyceride-rich lipoproteins, including very low-density lipoproteins or VLDL, and chylomicrons, and is a key regulator of triglycerides metabolism. Knocking down the hepatic production of APOC3 by RNAi results in reduced VLDL synthesis and assembly, enhanced breakdown of triglyceride-rich lipoproteins, and better clearance of VLDL and chylomicron remnant via LPL-dependent and independent pathways. We view ARO-APOC3 as having the potential to address many patients population with various lipid disorders that can lead to different clinical complications and phenotypes. Familial chylomicronemia syndrome, or FCS, is characterized by extremely high TG levels, typically over 1,000 milligrams per deciliter and as high as 5,000 milligrams per deciliter, leading to high risk of acute pancreatitis that usually requires hospitalization and can be fatal.
Patients with FCS may also experience chronic abdominal pain, and they have to adhere to a very strict diet with very low fat content, leading to impaired their quality of life. FCS is a severe and ultra rare genetic disease that affect hundreds to a few thousand patients in the US. Severe hypertriglyceridemia, or SHTG, is characterized by a marked elevation in TG levels, typically over 500 milligrams per deciliter, which can lead to increased risk of acute pancreatitis, as well as an increased risk of cardiovascular disease. This condition is estimated to affect several million patients in the US. Lastly, mixed dyslipidemia is defined as the presence of high LDL cholesterol combined with TGs, remnant cholesterol, and low HDL. The lipid profile is a major component of the risk factor for atherosclerosis cardiovascular disease.
There are likely tens of millions of patients in the US with mixed dyslipidemia who are not adequately controlled with current standard of care. The studies of ARO-APOC3 that we have conducted or are planning to conduct for each population are as follows: For FCS, we are conducting the PALISADE study, which is a phase III placebo-controlled study to evaluate the efficacy and safety of ARO-APOC3 in adults with FCS. The primary endpoint for the study is % change from baseline in fasting TG at month 10. This study was fully enrolled in May with a total of 75 subjects distributed across 39 different sites in 18 countries who were randomized to receive 25 milligrams of ARO-APOC3, 50 milligrams of ARO-APOC3, or matching placebo once every three months.
This puts us on schedule for study completion in Q2 of 2024, a data readout shortly thereafter, and then NDA preparation for regulatory filings. Participants who complete the randomized portion of PALISADE are also eligible to continue in an extension period, where all participants will receive ARO-APOC3. For SHTG, we're conducting the SHASTA-2 phase II study in 229 patients, randomized 3 to 1 to receive 10, 25, or 50 milligrams of ARO-APOC3, or placebo on day 1 and week 12. Patients with FCS were excluded from this study. The primary endpoint is % change from baseline fasting TG at week 24. SHASTA-2 was the study that enabled us to begin planning and design for our phase III plan in SHTG patients. The data strongly support advancement into phase III, and we plan to present results at the American Heart Association in November.
The current phase III plan for SHTG includes two separate studies, which will be called SHASTA-3 and SHASTA-4. The idea behind the two studies is to have first, a faster path to regulatory submission with the SHASTA-3 study, a double-blind, 12-month randomized controlled study of approximately 600 patients with TGs greater than 500 milligrams per deciliter. We believe this study, plus the large safety database from our phase I and II study, will be an appropriate package for an initial filing for the SHTG indication. The second study, SHASTA-4, is designed to investigate the effect of APOC3 in a more severe population at high risk of developing pancreatitis. SHASTA-4 will include patients with TG greater than 880 milligrams per deciliter and recent history of pancreatitis.
The duration of the double-blind portion of the study will be two years, and it will be powered to detect difference in the incidence of pancreatitis. This data could enable label expansion to include the indication statement of pancreatitis risk reduction, a key clinical outcome relevant to patients and reimbursement authorities. We have made a lot of progress on the planning and design of these studies and intend to have discussion with regulators this year and move forward rapidly with studies initiation. We will provide more details on the studies when they begin. In the broader mixed dyslipidemia population, we're conducting the NEAR phase II study in 653 patients, randomized 3 to 1, to receive 10, 25, or 50 milligrams of ARO-APOC3, or placebo on day one and at week 12. We include an additional cohort of participants receiving 50 milligrams on day one and week 24.
The primary endpoint is % change from baseline in fasting TG at week 24, with additional assessment of the changes in various lipids, lipid parameters such as LDL-C, non-HDL-C, HDL, ApoB, and VLDL, and other biomarkers. Similar to the SHTG study results, we believe the phase II data from the NEAR study strongly support advancement into a phase III study, and we also plan to present these results at the American Heart. The phase III program for this population will be a cardiovascular outcome trial called CASCADE. ARO-APOC3 has demonstrated a positive effect on several lipid parameters that represent residual risk factors for atherosclerosis cardiovascular disease, even after LDL-C is well controlled. The CASCADE study will select the patient population, which has high risk driven by the high TGs, remnant cholesterol, and low HDL, all of which are effectively addressed by ARO-APOC3.
The study will be designed in collaboration with an academic research organization or ARO. We're working on all aspects of the study design, including selection of the patient population, understanding and modeling background event rates, the potential effect size, with that information, we'll define the sample size and duration of exposure to be able to detect a clinically meaningful reduction in cardiovascular events. For a final asset agreement with the selected CRO and ARO to help us conduct this important study, we are scheduled to engage with regulators later this year and plan to initiate the CASCADE study in 2024. Our strategy for ARO-APOC3 is to progressively study in larger and longer studies to potentially bring it to very high prevalence disease population that currently do not have adequate treatment options. Our strategy for ARO-ANG3 is more focused on smaller, well-defined populations.
ARO-ANG3 is being developed as a treatment for homozygous familial hypercholesterolemia or HoFH, and potentially in the future, subsets of heterozygous familial hypercholesterolemia or HeFH. The phase II program for ARO-ANG3 involved 2 studies. The ARCHES 2, phase II study in 204 patients with mixed dyslipidemia, and the GATEWAY study in 18 patients with HoFH. Interim data from the GATEWAY study was presented at the 91st European Atherosclerosis Society Congress in May 2023. A study week 20 administration of 200 mg or 300 mg ARO-ANG3 on day 1 and day 84 led to mean reductions in LDL cholesterol of 48.1% and 44%, respectively. These reductions were achieved on top of continued standard of care, including statins, ezetimibe, PCSK9 inhibitors, and apheresis. These results were on par with an approved monoclonal antibody that also targets ANGPTL3.
ARO-ANG3 has a much more convenient and patient-friendly dosing regimen of one subcutaneous injection every 3 months, versus the antibody, which requires an intravenous infusion once a month. We're currently working on a phase III study design and plan for ARO-ANG3 in HoFH, and assessing potential other population for future studies. I spoke in a bit more detail on both ARO-APOC3 and ARO-ANG3 during our R&D Day in June. I recommend you view the archive webcast or presentation slides on our website if you want more background on the biology of the target, some of the clinical data, the rationale for our belief in their potential, and more specific information about our plans for clinical development. The other late-stage program we're working on with our partner, Takeda, is fazirsiran for the treatment of AATD liver disease.
In June, updated phase II clinical data from the SEQUOIA study were presented at EASL Congress 2023 and in oral presentation. The clinical results from the phase II SEQUOIA study of fazirsiran were clear and compelling. Fazirsiran treatment demonstrated substantial effect on several key markers of liver disease. Takeda has taken the lead in conducting the phase III REDWOOD clinical study. It is designed to enroll 160 adult patients with F2 to F4 fibrosis. The primary endpoint of the study is to decrease from baseline of at least one stage at week 106 in patients with F2 and F3 fibrosis. Takeda is doing an outstanding job at bringing global sites online for the REDWOOD study and enrolling patients efficiently. Additional information on the REDWOOD study can be found at the redwoodliverstudy.com.
I will now turn the call over to Dr. James Hamilton. James?
James Hamilton (Chief of Discovery and Translational Medicine)
Thank you, Javier. Our pipeline of early-stage clinical candidates now includes 8 programs addressing various diseases with gene expression in 4 tissue types, including liver, lung, and now muscle and CNS. Of these 8 programs, most are wholly owned and in our core areas of focus. They are in pulmonary, ARO-RAGE, ARO-MUC5AC, ARO-MMP7, in cardiometabolic, ARO-PNPLA3, in neuromuscular, ARO-DUX4 and ARO-SOD1, and we also have ARO-C3 for complement-mediated diseases and HZN-457, partnered with Horizon for gout. In addition, we have many undisclosed preclinical programs that should continue to feed our pipeline for years to come. We are increasingly looking for opportunities to focus around core areas, and we are fortunate that our platform provides us with so many opportunities. Our discovery and clinical development teams continue to be highly productive and efficient.
One main benefit of drug development based on a proprietary technology platform, is that it allows us to apply learnings from prior programs to each new program. This makes us faster, more precise, and I believe yields drug candidates with a higher probability of success. The TRiM platform has given us that advantage for liver-directed programs for a few years now. We believe we are now in a period where those same advantages exist for lung-directed programs, and we have the potential to get there over the next 2 years for muscle and CNS. We held a very comprehensive R&D Day during the quarter, so I'm not going to review all of Arrowhead's discovery and early development programs. I'd like to focus on some important, potentially de-risking data from our ARO-RAGE program.
ARO-RAGE is our RNAi therapeutic candidate designed to reduce expression of the receptor for advanced glycation end products, or RAGE, as a potential treatment for inflammatory pulmonary diseases such as asthma. We are currently conducting a phase 1/2a clinical trial in normal healthy volunteers and in patients with mild to moderate asthma. We have also recently filed an amendment to add 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. Let's talk briefly about what data we generated and reported at the R&D Day. First, with respect to safety and tolerability, to date, there have been no reported serious or severe adverse events, no study withdrawals or drug discontinuations due to adverse events, and safety labs have shown no pattern of adverse changes.
There have also been no change in the pattern of airway immune cells. All chest X-rays have been read as normal. These encouraging results have also been generally consistent in the ARO-MMP7 and ARO-MUC5AC programs. With respect to activity, the results to date, especially at the highest dose level, have exceeded our estimates and really represent a best-case scenario for target engagement. We are measuring soluble RAGE protein, or sRAGE, in serum after multiple doses in both healthy volunteers and in patients, and in BALF after a single dose in healthy volunteers and after multiple doses at the top dose level.
The mean maximum reduction in sRAGE at the 92 mg dose level after two doses on days 1 and 29, was 80%, with a maximum reduction of 90%, with a long duration of effect that supports every other month dosing. At the highest dose of 184 mg, we achieved a similar result after just a single dose, with mean sRAGE reduction of up to 76% and maximal reduction of 91%. We also observed a continued dose response in BALF with a single inhaled dose of 184 mg, achieving mean reduction of 90% and maximal reduction of 95%. We are still collecting data that we intend to report on later this year, including presentations at the European Respiratory Society International Congress in September.
We believe this is the first compelling clinical evidence of gene target silencing in the lung using siRNA. We also believe that these clinical results have a good chance of being predictive of clinical results in other pulmonary programs, including ARO-MUC5AC and ARO-MMP7, and additional undisclosed preclinical programs. Lastly, on RAGE, what data are we generating over the coming months? We will have the chronic monkey GLP toxicology results before the end of the year, which will be needed prior to phase II initiation. We will be getting additional longer-term follow-up and multiple dose data at the highest doses in healthy volunteers and in patients later this year and into next year. Lastly, we will be getting data from the high-FeNO cohorts, which is designed to assess if RAGE knockdown leads to an IL-13-specific anti-inflammatory effect.
This study is not long enough or large enough to expect an efficacy signal, but signals of inflammatory pathway inhibition after a short course of exposure would be a welcome result. We expect these data in 2024. I also want to provide an update on our earliest clinical candidates. During the last quarter, we filed CTAs for our first muscle and CNS candidates, ARO-DUX4 and ARO-SOD1, respectively. ARO-DUX4 is the first clinical candidate utilizing the TRiM platform to target disease-associated genes in skeletal muscle. ARO-DUX4 is an investigational RNAi therapeutic designed to reduce expression of the gene that encodes the human double homeobox 4, or DUX4 protein, as a potential treatment for facioscapulohumeral muscular dystrophy, or FSHD. Pending regulatory clearance, we intend to proceed with a phase I-IIa dose-escalating study to evaluate ARO-DUX4 in adult patients with FSHD Type I.
The study is designed to enroll up to 52 patients. The other CTA filed during the quarter was for ARO-SOD1, the first therapeutic candidate designed for delivery to the CNS, again, leveraging the TRiM platform. ARO-SOD1 is designed to reduce expression of superoxide dismutase 1, or SOD1, in CNS as a potential treatment for patients with amyotrophic lateral sclerosis, or ALS, caused by SOD1 mutations. Pending regulatory clearance, we intend to proceed with a phase I dose-escalating study to evaluate ARO-SOD1 in adult patients with ALS harboring a SOD1 mutation, which is considered to be causative of ALS. The study is designed to enroll up to 24 patients. I will now turn the call over to Ken Myszkowski. Ken?
Ken Myszkowski (CFO)
Thank you, James. Good afternoon, everyone. As we reported today, our net loss for the quarter ended June 30, 2023, was $102.9 million, or $0.96 per share, based on 107 million fully diluted weighted average shares outstanding. This compares with a net loss of $72 million or $0.68 per share, based on 105.8 million fully diluted weighted average shares outstanding for the quarter ended June 30, 2022. Revenue for the quarter ended June 30, 2023, was $15.8 million, compared to $32.4 million for the quarter ended June 30, 2022. Revenue in the current period primarily relates to our collaboration agreement with Takeda. Revenue is recognized as we complete our performance obligations, which include managing the ongoing AAT phase II clinical trials for Takeda.
There remains $17 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over the next year. Total operating expenses for the quarter ended June 30, 2023, were $118.5 million, compared with $105.3 million for the quarter ended June 30, 2022. The key drivers of this change were increased candidate costs, partially offset by lower stock compensation expense. The increased candidate costs were primarily due to the progression of the company's pipeline of candidates into and through clinical trials, which resulted in higher outsourced clinical trial, toxicity study, and manufacturing costs.
Net cash used in operating activities during the three months ended June 30, 2023, was $21.4 million, compared with net cash used in operating activities of $68.9 million for the three months ended June 30, 2022. We expect our operating cash burn to be $80 million-$90 million next quarter. We expect to spend between $160 million and $180 million over the next three quarters to complete our GMP manufacturing facility and related laboratories in Verona, Wisconsin. Turning to our balance sheet, our cash and investments total $494.5 million at June 30, 2023, compared to $482.3 million at September 30, 2022.
The increase in our cash and investments was primarily related to the $250 million payment from the royalty, from Royalty Pharma, as well as other licensing cash inflows, offset by our operating cash burn, along with continuing capital projects. Our common shares outstanding at June 30, 2023, were 107.1 million. With that brief overview, I will now turn the call back to Chris.
Chris Anzalone (CEO)
Thanks, Ken. We are well on our way to reaching our 2025 goal to grow our pipeline of RNAi therapeutics to a total of 20 clinical stage or marketed products in the year 2025. Pipeline expansion is just a means to an end. The ultimate goal and the reason we continue to invest in expanding our platform, discovering new candidates, advancing our clinical programs, and streamlining the drug manufacturing process, is that it allows us to get important new medicines to patients in need as quickly and efficiently as possible. Doing this will also create a sustainable business and provide a steady stream of commercial revenue, which we now have a better line of sight on and a plan that we are executing to get there. Thank you for joining us today. I would now like to open the call to your questions. Operator?
Operator (participant)
Thank you. We will now conduct a question and answer session. 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. We ask that you please limit your questions to 1, and if you would like to ask another question, please re-queue. Please stand by while we compile the Q&A roster. Our first question comes from Luca Issi of RBC Capital.
Luca Issi (Senior Biotechnology Analyst)
Oh, great. Thanks so much for taking my question. Just a quick one here. I'm wondering if you can comment on what was your reaction to the Roche and Alnylam's deal. I guess two question there: is AGT a target that you may be willing to pursue? Two, how should we think about read-through to your cardiovascular franchise? Then maybe super quick one for Javier, for severe hypertriglyceridemia. I was under the impression that you were planning a single pivotal trial with triglycerides as the primary endpoint and pancreatitis as a secondary endpoint. However, it sounds today like you're planning two separate studies, so wondering what drove that change. Thanks so much.
Chris Anzalone (CEO)
Sure. I don't know that we have really a position on the Alnylam Roche deal. Good for them. We are not working on, on that target. It just didn't, it didn't fit into, to where we see opportunities in this space. I don't think it reads through to our cardiometabolic assets. I think those, I think those are, those are really orthogonal to each other. Javier, do you want to address that?
Javier San Martin (Chief Medical Officer)
Yeah. hi, Luca. I think when we presented the clinical program for LOX3 at the R&D Day, I think I mentioned that we're doing 2 studies. The first one, which is the one that would be the primary source of registration, is the SHASTA-3, which is 600 patients, approximately, with TG higher than 500. We will start in parallel, the study SHASTA-4, in patients with higher TG levels and recent past history of pancreatitis. That study would be approximately 200 patients, and that will not be part of the initial filing, but it will be a subsequent interaction with the agency, hopefully, to get pancreatitis risk reduction in that study and eventually add that to the label. It was planned, but there is a sequence here. First, SHASTA-3, registration, and second, SHASTA-4, label expansion.
Luca Issi (Senior Biotechnology Analyst)
Thank you.
Operator (participant)
Okay. Thank you. 1 moment for our next question. Our next questions come from Maury Raycroft of Jefferies.
Maury Raycroft (Equity Research Analyst)
Hi, congrats on the progress, thanks for taking my questions. For your pulmonary platform, you've got the late-breaker title for your RAGE program at ERS next month. How much asthma patient data can we expect in this update? Will it be longer-term follow-up from the sad and mad healthy volunteer part of the study? Separately, wanted to clarify for the pre-clin tox studies, are those 6 months or 12 months? It sounds like you're somewhat beyond where you were with ENaC on safety. Can you just elaborate more on that as it relates to the preclinical and clinical data that you've got so far?
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, sure. I can take the first part of the question. The data that will be presented at European Respiratory is primarily an update on the healthy volunteer sad and mad duration. We may have a little bit more duration data from the first patient cohort, the asthmatic patient cohort, but we won't have additional patient data at that time. Regarding the tox studies, this is the six-month rat tox study that Chris was referring to for both RAGE and MMP7.
Chris Anzalone (CEO)
Yeah, we're. We're still waiting on the nine-month monkey tox. You mentioned that it sounds like we are beyond where we were with ARO-ENaC, and I think that is true. We are using substantially less material in all of these candidates in the chronic tox studies, and that appears to be bearing fruit for us.
Maury Raycroft (Equity Research Analyst)
Got it. Okay, thanks for taking my questions.
Chris Anzalone (CEO)
You're welcome.
Operator (participant)
All right. Thank you. One moment for our next question. Our next question comes from Patrick Trucchio of HC Wainwright & Company.
Patrick Trucchio (Managing Director of Equity Research)
Thanks, and good afternoon. Just a few follow-up questions. The first one is just around the ARO-RAGE chronic tox data. Can you just clarify, is this data, would it be expected in the third quarter or fourth quarter of calendar 2023? How would you expect it to differ for that, which was reported from ARO-ENaC, just in terms of how are the doses for these compounds compared to ENaC in these studies specifically? Then separately, just also regarding the pulmonary programs in clinical development, you know, there are several- three programs in clinical development, at least one in preclinical development. Can you give us an idea of what targets you could include for your pulmonary platform as it expands?
To what degree would you be looking at targets with genetic or clinical validation as you look to build out this pulmonary pipeline going forward?
Chris Anzalone (CEO)
I'll take the second, and James can take the first. I've got the easy one. The answer is, you know, we can't give you too much guidance on undisclosed targets. I get your point that of course, we will be looking at genetically validated targets and clinically validated targets, and that is always our preference. You know, you've heard us say before, you know, our goal here is to take as little target risk as we can, and one way to do that is to work on the most validated targets that we can. We will certainly be doing that. Will we expand beyond that into some targets that have less validation?
Probably, my hope is that in the near to midterm at least, you know, the targets we're focusing on, will, will be well-validated. James, you want to address the tox?
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, sure. Hi, Patrick. Thanks for the question. Regarding tox, the, so the doses are across the board, lower for the new pulmonary programs, lower in terms of exposure. I think most importantly, less frequent. If you recall, we used a day 1, 2, 3, every 2-week dosing regimen for ARO-ENaC, and then for our current programs, the dose frequency is spread out much, much less frequent. We're dosing either monthly or every 2 months in the chronic tox studies.
Chris Anzalone (CEO)
If you look... If you compare the, the, the exposure, I want to say it, it spans from, from, you know, ENaC being 4 times to ENaC being 20 times the amount of material compared to, to the various, newer compounds we're, we're working on. That is entirely a testament to, to how much more potent these, these follow-on, compounds are.
Patrick Trucchio (Managing Director of Equity Research)
Great. Thank you so much.
Chris Anzalone (CEO)
You're welcome.
Operator (participant)
Thank you. One moment while we queue our next question. Next question is from Key Nakai of Chardon.
Kay Nakai (Analyst)
Hi, thanks. Question about partnering specifically for the Cb assets. You know, you're gonna go it alone initially with some of these phase 3s, but you do have an outcome study out there planned. If you see success going it alone, does that make it more or less likely that you'll want a partner to do an outcome study?
Chris Anzalone (CEO)
We are planning on doing the outcome study for ARO-APOC3 by ourselves. You know, we see that as a very interesting asset, and the data have been very compelling, so we are happy to take that on ourselves. Doesn't mean that we're not going to partner that at some point geographically, potentially, who knows? We are happy to take on the CBOT risk ourselves, and that's our plan right now.
Kay Nakai (Analyst)
Okay, thanks.
Chris Anzalone (CEO)
You're welcome.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Edward Tentoff of Piper Sandler.
Edward Tenthoff (Managing Director and Senior Research Analyst)
Great. Thank you very much. so much going on and excited about the progress. As we look at the pipeline, you know, what should we be expecting from C three? I know that we're in these patient cohorts now of C three glomerulopathy and maybe IgA nephropathy. When, when could we get data from those, and what would be your ultimate view for advancing ARO-C three further? Thanks.
Chris Anzalone (CEO)
James?
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, in, in terms of when we should get data, we're probably looking at end of next year, so end of 2024. What, what was the other part of the question?
Edward Tenthoff (Managing Director and Senior Research Analyst)
Just how would you anticipate progressing from there?
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, I mean, I think it depends on what the data show us. I think there are several other examples out there of of phase III programs that are ongoing for IgA nephropathy, and C3 glomerulopathy with with biomarkers as primary endpoints. I think our, our late stage programs would probably look something similar to those.
Edward Tenthoff (Managing Director and Senior Research Analyst)
Okay, great. Thank you.
James Hamilton (Chief of Discovery and Translational Medicine)
Thank you.
Operator (participant)
Thank you. One moment for our next question. Our next question comes from Mani Foroohar of Learinc Partners.
Mani Foroohar (Senior Research Analyst)
Hey, guys. Thanks for taking my question. A quick one around how you think about building the CV side of the franchise. Could you lay out what your estimation is for what is that C bot should cost, and probably cascade now? Presumably, given that you plan to go it alone, I would assume that you've got a reasonable budget estimate for what that might cost. Can you walk us through sort of how we should think about sort of expansion and OpEx as you build out the infrastructure to support what will be a larger study than you guys have ever done standalone before?
James Hamilton (Chief of Discovery and Translational Medicine)
Sure. So we can't, we can't give you. We... Yes, we are putting together estimates about what that's gonna cost. However, we still haven't had our end of phase II meeting with the FDA. We are putting together our proposal, and so I expect that we'll be speaking with them this year. Until we have that, that conversation, until we have feedback from them, it's gonna be very difficult for us to give you good numbers just because, you know, because we want better clarity. We will be happy to give you some estimates, some guidance, you know, once we have those discussions, but at this point, it's a bit premature.
Mani Foroohar (Senior Research Analyst)
Okay, we should expect some, like, we should expect some numerical guidance around that, post the end of phase II meeting? Is that, is that a reasonable expectation for us to have?
James Hamilton (Chief of Discovery and Translational Medicine)
Yes, I think, I think that's, I think that's, that is reasonable. You know, we need, we need to have feedback from the FDA. We need to incorporate that into our plans and then, and then, and then have that, that filtered down into our budget. Sometime, you know, sometime over the next couple of quarters, you know, we should have a good estimate for you, and then we will be happy to chat about it at that point.
Mani Foroohar (Senior Research Analyst)
Okay, that's helpful. Thanks, guys.
James Hamilton (Chief of Discovery and Translational Medicine)
Sure. You're welcome.
Operator (participant)
All right. Thank you. One moment for our next question. Next question comes from Mike Boles of Morgan Stanley.
Mike Boles (Client Service Manager)
Hey, guys. Thanks for taking the question. maybe just a follow-up on the pulmonary program, specifically to the MMP-7 program. Can you just remind us when we might see the initial clinical data there? Should the focus be just on target knockdown, or are there other data points that we should be focused on as well? Thank you.
James Hamilton (Chief of Discovery and Translational Medicine)
I think so that as we had stated at the, the Analyst Day meeting, we, we really think the focus there should be on the, the patients, since those are that's the population that has upregulated MMP-7 in, in the BALF and in the serum. That's what we'll be focusing on. We're still in the healthy volunteer, component of the study, and, you know, we don't know how the patient cohorts will enroll just yet. Depending on enrollment, it's conceivable we could have some data by end of next year.
Mike Boles (Client Service Manager)
Got it. Thank you.
Operator (participant)
All right. Thank you. One moment for our next question. Our next question is from Mayank Mamtani of B. Riley Securities.
Mayank Mamtani (Senior Managing Director and Group Head of Healthcare Research)
Good afternoon, team. Thanks for taking our question. Maybe just on the pheno high asthma patient cohorts that, you know, you're just starting to enroll, could you, could you clarify the dose levels being looked at and, and sort of what initial number of patients you, you know, intend to have before you may look to disclose something externally? If you could comment, you know, how this could be same or different relative to, you know, your execution on the mild to moderate asthma MAD patient cohort. I have a quick follow-up.
James Hamilton (Chief of Discovery and Translational Medicine)
Sure. There, there are the two highest dose levels is what we're looking at in the pheno cohorts, so that's the 92 and the 184 mg dose levels that we studied in the healthy volunteers. We'll investigate those doses in the pheno cohorts as well, and we're doing it 16 per cohort. In terms of how many we'd have to have enrolled before we disclose data, I, I can't really give you a clear answer to that. Yeah, yeah, let's just assume that, that we'll disclose those once, once those cohorts are complete. You know, it wouldn't, wouldn't make much sense for us to, to feed that out in dribs and drabs. I think we'll wait till that, the study's over.
Mayank Mamtani (Senior Managing Director and Group Head of Healthcare Research)
Got it. In terms of your asthma cohort data before the end of the year, could you just clarify, would you also include some BAL bronchoscopy data, also in addition to serum data on the higher dose levels? Just clarify that.
James Hamilton (Chief of Discovery and Translational Medicine)
The asthma patients actually don't undergo bronchoscopy, so we don't have a BALF data from the asthma patients. The only S rage measure we get is from the serum in the asthma patients.
Mayank Mamtani (Senior Managing Director and Group Head of Healthcare Research)
Got it. And just lastly, on the financials, the 2 milestones, 2 milestones earned from GSK and the data, could you just clarify how they will be sort of modeled on your P&L in terms of, you know, recorded revenues, amortization schedule, et cetera?
James Hamilton (Chief of Discovery and Translational Medicine)
Those milestones have already been recorded in revenue. They are not amortized over time. We actually recorded those the quarter before last. We received the cash in this past quarter.
Javier San Martin (Chief Medical Officer)
Understood. Thanks for taking our questions.
James Hamilton (Chief of Discovery and Translational Medicine)
Thank you.
Operator (participant)
Okay, thank you. One moment for our next question. The next question comes from Ellie Merle of UBS.
Ellie Merle (Executive Director of Biotech Equity Research)
Hey, guys. Thanks so much for taking the question. Just a follow-up on the pulmonary patient cohort timing. I guess for RAGE, just where are you in the enrollment of those high pheno cohorts? I think you just mentioned you had 16 for cohort. Then for MUC5AC, I guess, where are you in enrollment of the asthma patient cohorts? Have you started enrolling in the COPD cohorts? Then just for MUC5AC, what should we expect in terms of the timing of potential patient data there? Thanks.
James Hamilton (Chief of Discovery and Translational Medicine)
On the pheno cohorts, those, the amendments to add those cohorts, I think, are just they've been filed, and so they're working their way through the various regulatory bodies and ethics committees. We haven't enrolled any high pheno patients just yet. The MUC5AC patient cohorts, we're enrolling into this. Actually, all the cohorts are open, so all of the asthma patient cohorts are currently open for MUC5AC. We'd be looking, assuming enrollment goes well, probably having data mid to late next year as well. Your last question, I believe, was on the COPD cohorts for MUC5AC. That's a similar situation to the pheno cohorts.
We've got the amendments filed. Those are working their way through to get ethics and regulatory approval. We'd expect to have those being enrolled later this year, aiming to have data maybe end of next year.
Ellie Merle (Executive Director of Biotech Equity Research)
Great. Thank you so much.
Operator (participant)
All right, thank you so much. One moment for our next question. Our next question is from William Pickering of Bernstein.
William Pickering (Senior Analyst)
Good afternoon. Thanks for taking my question. On Adipose, you gave a really interesting update at the R&D Day, but you didn't disclose the target. I was wondering what the next steps on that program are and when we might learn more about it. Thank you.
James Hamilton (Chief of Discovery and Translational Medicine)
Yeah, we, we have not disclosed targets. We, we are still in the early days a bit with Adipose. We have, we, we have some ideas for targets, but we are not prepared to, to show any, any more data there quite yet. My, my hope is that, is that you'll start to hear more about the clinical plan for Adipose in 2024.
William Pickering (Senior Analyst)
Got it. Thanks. Then on HoFH, it sounds like you've become less definitive on the, the path forward for ARO-ANG3 in that indication versus last year. I was wondering if you could just talk about sort of what aspects of your thinking have evolved and, and how sure you are that you will, in fact, take it forward to phase III?
Javier San Martin (Chief Medical Officer)
Yeah, so I think the issue here is whether we can develop the indication of HoFH without a full cardiovascular outcome trial. There is some precedents that support that and some others don't. We are working our way to understand if there is a subpopulation of HoFH that can be pushed forward into a regulatory path without the requirement of a cardiovascular outcome trial. That's kind of where we're right now.
William Pickering (Senior Analyst)
Got it. Thank you so much.
Operator (participant)
Okay, thank you. One moment for our next question. Next question is from Luca Issi of RBC Capital.
Luca Issi (Senior Biotechnology Analyst)
Oh, great. Thanks so much. Excuse me, again. maybe circling back on RAGE, James or Javier, what are you hoping to see for the initial readout for pheno? I understand the follow-up will be short, but what levels do you anticipate at baseline, and what kind of reduction are you hoping to see there? Again, just trying to understand what's the bogey for initial success there? Then maybe, Ken, if I may, I think your prior 10-Q suggested that the build, the facility in Verona, Wisconsin, was going to cost $200 to 260 million. However, the Ten-Q today suggested that number has gone up to $260 to 280 million. One, is that correct? If two, what drove that change? Thanks so much.
James Hamilton (Chief of Discovery and Translational Medicine)
Ken, do you want to start that?
We have seen certain, cost increases as well as about a quarter of a delay in that project. You will see that, that, total cost comes in a bit higher than we had, originally estimated. That's really it. Okay.
Javier San Martin (Chief Medical Officer)
Yes. Luca, we do have a good point of reference for the phenotherapeutic effect, and that's the Dupilumab and Trispilumab programs, in which say so somewhere between 40% and 48% reduction. I think it's either, I don't recall which one, but that's the range that, you know, I think we believe will be convincing that the RAGE inhibition, it does work through the IL-13. That's the range that we're seeing. I think the baseline is 20.
Chris Anzalone (CEO)
... greater than 20, pheno and people with eosinophils greater than 200. It's the same population, very much, of those, point of reference, if you will, studies, and we expect to see something similar. Thanks so much.
Operator (participant)
All right, thank you. one moment for our last question. This question is from Brendan Smith of TD Cowen.
Brendan Smith (Director and Senior Analyst of Life Science Tools and Diagnostics)
Hi, guys. Thanks for taking the questions. Maybe a couple quick ones from us. First, just wanted to ask actually about some of the CNS programs that you alluded to, that you're gonna kind of announce and bring into the clinic over the next couple of years. Really, I guess, how are you kind of thinking about which indications to move there? Are you, are you really thinking to focus more on final indications, given that the tissue is a little bit easier to get to? Or really, what is kind of your strategy in deciding where to go there? Kind of just trying to understand where you think is especially right for RNAi. And then if I could, just really quickly, wanted to ask a little bit more about kind of your financing plan.
Obviously, you have a decent balance sheet for now, but I mean, to your point, you haven't raised equity in a, in a few years, but you have a fair number of important readouts coming up, and a lot of studies going on. As we're kind of just looking at cash burn over the next 18 to 24 months?
Chris Anzalone (CEO)
Sure. I'll take that, and then I'll, and then I'll let Javier and James take the prior one. Look, as I, as I mentioned in the prepared remarks, partnering is, is really a cornerstone of our financing strategy, and so, and so we are exploring a number of different options, really, as we speak, that, that, that are important for us. There are also, you know, other, other avenues. You know, we are, we are also exploring the possibility of doing some specific product financing, you know, for APOC3. You know, we know that's going to be a CBOT. We know that's going to be expensive, and, and we are exploring the cost of capital for, for financing that in, in return for some royalties on that product for some period of time, things of that nature.
I think that we can... I think we can get a long way to our, to our financing needs, you know, through those, those levers, and we are looking to pull those levers, you know, certainly in the, in the near to midterm. I think it's important for us.
James Hamilton (Chief of Discovery and Translational Medicine)
Then in regards to the CNS targets, you know, we're, we're interested in targets that may involve the spinal cord, as you mentioned, but also targets in the cortex. We can get good knockdown in various parts of the cortex, and we're looking at some targets in the deeper brain, although that, that can be a little bit more challenging to achieve the same level of knockdown. Then we like, as we do for other tissue types, targets with a degree of genetic validation that are either genetically defined or have some level of genetic validation behind them, and preferably a degree of clinical validation with, you know, other modalities that are, are out there that have shown success that we could follow on.
Brendan Smith (Director and Senior Analyst of Life Science Tools and Diagnostics)
All right. Great. Thanks, guys.
Operator (participant)
Okay, thank you. I'm showing no further questions at this time. I would now like to turn the conference back to Chris Anzalone for closing remarks.
Chris Anzalone (CEO)
Thanks, everyone, for joining us today, and I hope you have an enjoyable summer, and we look forward to talking to you soon.
Operator (participant)
All right. This concludes today's conference call.
Bye-bye.
Thank you for participating. You may now disconnect.