Arrowhead Pharmaceuticals Inc (ARWR) 2020 Q2 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call. (Operator Instructions)

I will now hand the conference over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

Thanks, Buena. And sorry about the delay everybody. We were having some technical difficulties on the line. Good afternoon. Thank you for joining us today to discuss Arrowhead's results for its fiscal second quarter ended March 31, 2020.

With us today from management are President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter; Dr. Javier San Martin, Chief Medical Officer, who will discuss our clinical programs; Dr. Curt Bradshaw, our Chief Scientific Officer, who will discuss our discovery, platform development and manufacturing efforts; and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hassard, our Chief Commercial Officer, will be available during the Q&A session of today's call.

This is the first earnings call without Dr. Bruce Given, who retired last week since he joined the company 10 years ago. I want to start by thanking Bruce for all of his contributions to Arrowhead. Bruce developed strong relationships with the investment community over the years, and I'm certain that Javier, Curt and Jim will do the same.

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, Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact, including, without limitation, those with respect to Arrowhead's goals, plans and strategies are forward-looking statements.

These include statements regarding our expectations around the development, safety and efficacy of our drug candidates, projected cash runway and expected future development and commercialization activities. These statements represent management's current expectations and are inherently uncertain. Thus, actual results may differ materially. Arrowhead disclaims any intent and undertakes no duty to update any of the forward-looking statements discussed on today's call.

You should refer to the discussions under Risk Factors in Arrowhead's annual report on Form 10-K in the company's subsequent quarterly reports on Form 10-Q for additional matters to be considered in this regard, including risks and other considerations that could cause actual results to vary from the presently expected results expressed in today's call.

With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company. Chris?

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. I'd like to start by thanking Dr. Bruce Given. He did a fantastic job developing the R&D organization and instilling a culture of innovation that will be a lasting legacy. Bruce's contributions are clear to all who know him or have worked with him, and I am confident that we have assembled and developed the right team to enable us to continue to execute in true Arrowhead fashion. Javier, Curt and Jim are seasoned executives who are expanding and professionalizing their respective functions and have put Arrowhead in a very strong position to prosper during this next page growth.

2020 is the year that we intend to make the promise of RNAi outside the liver a reality. We hope to gain clinical proof-of-concept in the lung and solid tumors and then rapidly expand our pipeline, much as we did with our hepatocyte-targeted pipeline in 2018 and 2019. This could provide new treatment options for countless patients and provide Arrowhead's shareholders with continued value growth.

While, of course, we're looking to expand our reach, we are also looking to squeeze as much risk out of our business as we can. We have also made good progress on this front. First, we are well-capitalized. Second, we are developing an increasingly validated platform in TRiM. We've treated a total of 273 human subjects with 570 doses across our clinical programs. And keep in mind that this does not include all the people who have been treated by Janssen and Amgen with our partner candidates. Third, RNAi is an increasingly validated modality. Fourth, we are addressing gene targets that experts generally view as well-validated. Fifth, we are addressing unmet medical needs. And sixth, we are the first RNAi player in all of our clinical programs. All of this puts us on solid footing, but the elephant risk in the room is COVID-19. This has to be the lens through which you view our business at least in the near to midterm. Therefore, I will use my portion of this call to provide a high-level overview of our programs and how they may be affected by the outbreak.

Let's start with ARO-AAT, our investigational medicine against alpha-1 liver disease. In March, we voluntarily paused new patient screening and enrollment for at least a 4-week period in the Phase II/III SEQUOIA study and the AROAAT2002 open-label study. We are now working with sites and investigators to begin the process of resuming screening and enrollment. Any patients already enrolled in these studies continue to be dosed per protocol and continue to come in for their follow-up visits. Importantly, protocol deviations have not been out of the ordinary. Before the enrollment pause, we were already fully enrolled in the first cohort of the 2002 study, so we are still on schedule to collect 6-month biopsies in the summer. We intend to report those data in the fall at an appropriate venue.

We believe this is an important readout for the program and to the field. While we don't expect to see histological changes after that short amount of treatment, it may provide an early indication that the drug is doing what it is designed to do, which is to reduce new production of the mutant misfolded AAT protein. This will be assessed by measuring the amount of AAT monomer in hepatocytes. Further, it will be interesting to compare pre- and post-treatment levels of accumulated AAT polymer. This might give us a view of the pace at which hepatocytes can break down and clear the polymerized protein, which is the root cause of the progressive liver disease in patients with homozygous ZZ mutation. We believe these data are important for us and the field, and we expect this readout to be the first of its kind anywhere. This underlines both our substantial lead in developing a treatment for alpha-1 liver disease and our position as thought leaders in the field.

There are other RNAi based approaches, but to-date, none have reported data demonstrating tolerability and pharmacologic activity even in normal healthy volunteers. In addition, there are other approaches to treating AAT deficiency by correcting the mutant AAT protein in hopes of allowing it to be more efficiently exported from hepatocytes. We see some serious challenges for that approach to show clinical benefit for patients with liver manifestations of AAT deficiency. First, the liver produces an estimated 2 grams of AAT protein per day. We do not believe it is feasible to administer enough small molecule corrector to address that level of protein production, so we think some portion will likely still accumulate in the liver. So if the goal is to correct 20% to 30% of protein, which would still require a very large amount of corrector, that would mean 70% to 80% of the misfolded protein is still present, which is a lot for the liver to handle. Our data suggests that ARO-AAT is nearly completely suppressing liver production of the mutant Z-AAT protein, and we still believe that it may take 2 years of treatment to show a meaningful change in liver histology. So how long would you have to treat with a corrector that is leaving a large majority of Z-AAT protein in the liver? 8 years, 10 years? We think that presents a serious challenge in a clinical trial setting and gives us confidence that we are in a strong competitive position.

Let's now talk about the status of our 2 cardiometabolic candidates, ARO-APOC3 and ARO-ANG3. ARO-APOC3 is being developed as a potential treatment for patients with severe hypertriglyceridemia and a history or high risk of pancreatitis. Some of these patients have a single genetic cause for their disease, such as familial chylomicronemia syndrome, or FCS, but a significantly larger population has polygenic causes for their hypertriglyceridemia. This is called the multifactorial chylomicronemia, or MCM, and we believe there are around 30,000 patients with this condition in the U.S. alone. FCS and MCM have very similar clinical manifestations. There are both severe diseases that can lead to severe abdominal pain, recurrent pancreatitis, emergency room visits and hospitalizations and even death. These come with a very high cost with respect to both patient quality of life and economic cost to the health care system.

We have decided to focus on the MCM population and are working on a plan for a potentially pivotal study in MCM patients. We intend to request a meeting with the FDA and EMA this year to discuss some key study design considerations for a registrational study. We designed the Phase I/II study to provide sufficient data to enable rolling directly to a Phase III study. We will know more after we speak with regulators, but our hope is that we can start a pivotal study in the first half of 2021. We believe that should be a relatively short study, so we continue to believe that ARO-APOC3 could be our first market product. We continue to generate data in the Phase I/II clinical study. It was nearly fully enrolled prior to the COVID-19 outbreak, and we have experienced a slight delay in accruing the remaining patients. We already have a substantial amount of data that we intend to present at various times this year and are hopeful that we may -- that we will be able to present a full data set later this year. With the disruptions to the traditional medical meeting cycle because of the COVID-19 outbreak, it is unclear what form these data releases will take. We are committed to finding alternative ways to present data if medical meetings continue to be canceled or postponed.

The early data have been exciting, and we expect that trend to continue. As we reported on our last conference call, we have seen approximately 95% reduction of circulating triglycerides in hypertriglyceridemic patients after only a single dose of ARO-APOC3. This is truly stunning. These patients have triglycerides in the thousands, so we would expect a reduction of this magnitude to be quite meaningful for patients like these. We are in a slightly more advanced position with ARO-ANG3, which is being developed as a potential treatment for patients with mixed dyslipidemia. Let's talk about that patient population for a moment. Mixed dyslipidemia patients have both elevated triglycerides and elevated LDL cholesterol and are at heightened risk of atheroslerotic cardiovascular disease. There are strong evidence that both triglycerides and LDL contribute to that risk. This is a very high prevalence disease with an estimated potential patient population of between 10 million to 15 million people in the U.S. alone and it is not adequately addressed with current standard of care. We see ARO-ANG3 potentially being able to reduce triglycerides to a far higher degree than other available treatments and also reduce LDL in a non-LDL receptor-mediated manner, making LDL reduction potentially greater than with statins and PCSK9 inhibitors alone. As with ARO-APOC3, we reported early patient data at our last conference call, and I believe that was impressive. We saw approximately 80% reduction in triglycerides and 40% reduction in LDL after only a single dose of ARO-ANG3. Importantly, all of these patients were already on LDL-lowering drugs, such as statins and PCSK9 inhibitors. The patient population we expect to address is quite large and a pivotal study to show a reduction in cardiovascular events would also be large. We, and we think most experts in the field believe strongly that mixed dyslipidemia patients are in need of new treatment options, and we believe the mechanism of ANGPTL3 reduction is very intriguing. So we are now determining what the regulatory and development path would look like for that indication.

Because of our focus on this high prevalence population, we will likely need to run a Phase IIb study instead of roll in directly into a pivotal study as we may be able to do with ARO-APOC3. We plan on engaging with FDA this year and hope to initiate the Phase IIb in the first half of 2021. The ARO-ANG3 Phase I/II study is making good progress even in the COVID-19 environment. The study is fully enrolled, so we do not expect any real delays as we continue to follow patients and generate data. We believe we will have a full data set to report later in the year, and we'll also look for opportunities to share data subsets throughout the year. Just like ARO-APOC3, we will assess alternative ways to present data if medical meetings continue to be canceled or postponed.

I would now like to move on to our newest clinical candidates: ARO-HIF2 in development to treat the clear cell form of renal cell carcinoma, for which we filed an IND in December; ARO-HSD in development to treat alcohol and nonalcohol-related liver disease, for which we filed a CTA in December; and ARO-ENaC in development to treat cystic fibrosis, for which we filed a CTA recently.

We expect the ARO-HIF2 Phase I study to begin enrolling shortly. We have one site open now for screening and enrollment, and we anticipate the first patients will be dosed this quarter. The start-up process for this study has taken longer than we had hoped, which is likely due in part to COVID-19. Many of the investigators are at academic centers, and the contracting and initiation process may be experiencing delays due to health and safety precautions. We expect to potentially have proof-of-concept data for the candidates and for the tumor-targeted TRiM platform this year, but the timing may be too tight to report anything publicly until next year. We should have a better idea about this as we see the pace of enrollment. We are already thinking about additional targets for the tumor program, and we intend to build out the pipeline once we have clinical proof-of-concept on our own and potentially in collaboration with a partner. So what does success look like for the current Phase I? We will be taking biopsies from metastases, and if we see good HIF2-alpha knockdown, we will be happy that we are on the right track. First, because HIF2-alpha is a well-validated target for the approximately 80% patients with clear cell RCC, who have the von Hippel-Lindau mutation, we would have an expectation that ARO-HIF2 could be helpful for these patients.

Second, because our targeting strategy is intended to work across different solid tumor types rather than just in RCC, HIF2-alpha knockdown would suggest that we might have a broad solid tumor franchise. Once we achieve clinical proof-of-concept that we are knocking down HIF2-alpha, our goal is to quickly expand into new solid tumors against new targets. We view this as a scalable and rapid value creation strategy. ARO-HSD began dosing in the Phase I/II study in March. We are through the first cohort, and we previously received approval from the safety monitoring committee to escalate to the next higher dose. Because of COVID-19-related restrictions in New Zealand, enrollment of this second cohort was paused, but we expect it to reopen for healthy volunteers shortly and patients sometime after that. We are working with the site on plans to restart enrollment and believe this is only a minor delay that we don't think will have any lasting effects on the program or our general guidelines.

For ARO-ENaC, we filed a CTA last month to begin a Phase I/II study in healthy volunteers and in patients with cystic fibrosis. It's too early to say if there will be any COVID-19 related delays in this program. That largely depends on what happens in the next couple of months and beyond. Our belief is that we will be able to generate data on the safety and activity of the compound and by proxy, the pulmonary platform. But we don't know if we'll have enough data by key abstract deadlines to present data at key scientific conferences this year. I want to talk briefly about the CF patients we hope to help. Clearly, there has been an enormous amount of progress over the last several years in CF treatment options. But there are still opportunities to, a, help those who don't respond to standard of care; and b, to make those that do respond even better. The gene target of ARO-ENaC is the epithelial sodium channel, or ENaC. There is good genetic validation that CF patients who are also essentially heterozygous ENaC knockouts have a mild form of CF or even no discernible lung complications several decades into life. We see this as an indication that therapeutic ENaC inhibition in the lung may benefit all patients with CF regardless of genotype. The idea is that reduction of ENaC expression in the lung helps to rehydrate CF-related dehydrated mucus and may help improve mucociliary clearance.

Importantly, this first study is designed to give us a readout on both tolerability and efficacy in the target patient population. This could be a potentially important value inflection point for both ARO-ENaC and for the pulmonary platform broadly. If the data are supportive of further development, we hope to launch a Phase III study in 2021 and move rapidly to expand the pipeline with product candidates that address other underserved pulmonary diseases, such as COPD, asthma and pulmonary fibrosis. Toward that goal, I'm pleased to announce that we have completed discovery and optimization work on our second lung-targeted program and have nominated ARO-Lung2 as our next candidate. We are not disclosing the target at this point, but we can say that it is designed to address COPD patients. We have been very encouraged by the data in this program and for ARO-ENaC and are eager to begin the expansion of our pulmonary franchise. We are now working on manufacturing and IND-enabling toxicology studies for ARO-Lung2 and plan on filing a CTA in the first half of 2021 to begin first-in-human studies. We had previously hoped this could happen by the end of this year, but COVID has slowed development down a bit and will delay first-in-human studies by probably 1 or 2 quarters.

In the past, we've discussed our excitement in establishing a rapidly expanding pulmonary franchise, and you are seeing that start to play out now. Given our studies in rodents, primate and sheep models spanning several years, we have a high degree of confidence that our inhaled delivery will be well tolerated and active in humans. Further, the lung represents a target-rich environment that enables us to address a number of indications in innovative ways. So we see this as a big opportunity for patients and a significant value driver for our shareholders. In addition to CF, COPD, asthma and IPF, people have asked us about applying inhaled TRiM to coronavirus. We have not disclosed any work previously, but are happy to report today that we have an active program to address the current novel coronavirus that causes COVID-19 and other possible future pulmonary-borne pathogens. We are not disclosing more details about this program or the strategy, but we wanted to provide this update.

We are looking to bring the same ingenuity and innovative thinking to this issue that we did in revolutionizing the approach to Hepatitis B. All of us who work in biopharma and drug development play a role in improving global health, and Arrowhead is proud to say that we have joined the fight. A number of factors give us confidence that we could play an important role in the current novel coronavirus, in future coronaviruses and other pulmonary-borne pathogens. First, we are clear RNAi leaders in addressing the lung and have a clinic-ready inhaled program; second, history suggests that we are faster than any RNAi company and arguably any other biotech company going from concept to clinic; and third, we are the leading RNAi company in antivirals and are known as HBV thought leaders. We look forward to keeping you up-to-date on progress with this program.

The final program I'd like to mention is our muscle-targeted program. We have not yet disclosed the initial indication or gene target of our first clinical candidates. But consistent with our other programs, we view the indication as having a substantial unmet medical need, the gene target is well validated, and we expect to be the first RNAi company there. As with the solid tumor and pulmonary franchises, we view our ability to address skeletal muscle as the sharp end of the spear. Once we achieve clinical proof of concept, we expect to rapidly expand our pipeline into new indications and gene targets addressable via muscle delivery. We remain on track to file a CTA by the very end of 2020.

I believe we have unmatched reach into diverse indications, unmatched speed to the clinic and unmatched depth of pipeline for a company of our size. Our partner programs continue to look good as well. Amgen stated on its recent quarterly conference call that it expects to begin a Phase II study with AMG 890 in the second half of this year. Janssen continues to conduct its first 2 Phase IIb studies with JNJ-3989 against chronic HBV, and we are actively working together on the 3 undisclosed additional targets.

COVID-19 has introduced a new set of challenges, but Arrowhead is adapting. We believe that we have important new medicines that can potentially help countless patients. So we feel very fortunate that the current environment has only caused minor delays to our development programs and that we are well resourced. Our employees continue to be a great inspiration to me as their focus, work ethic and innovative spirit have never waned during these difficult times.

With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?

Thank you, Chris. I'm happy to join the call and hope I can be give results to everyone listening today. Chris gave a good overview of the clinical development programs. I will provide some further details on the status and study designs.

Let's begin with ARO-APOC3, our candidate targeting apolipoprotein C-III being developed as potential treatment for patients with hypertriglyceridemia. As Chris mentioned, we believe this may be a good treatment option for MCM patients that have severely elevated triglycerides, often in the thousand of milligram per deciliters. These patients can experience recurrent abdominal pain at a high risk for pancreatitis and in some cases, can require frequent visit to the ER and be admitted for multiple days hospital stay. In the most severe cases of pancreatitis, these attacks can even be fatal. In addition, this patient live with a very restricted diet that becomes difficult to maintain, and even if they comply, they still can have extremely high triglyceride levels. These patients have severely impacted quality of life and are desperately need for better therapies that can achieve deep and durable reductions in triglyceride levels and therefore, reduce the risk of pancreatitis and allow for a better quality of life.

As Chris mentioned, we previously announced some preliminary results in the patient population, but I want to review them today because they were very encouraging. After a single dose of 50 milligrams of ARO-APOC3 in patients with severe hypertriglyceridemia, we demonstrated reduction of around 95% in circulating triglycerides.

We would expect this type of reduction to have substantial clinical benefits, particularly in patients with a history of pancreatitis. We are currently conducting our Phase I single- and multiple-dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-APOC3. The single-dose portion of the study is in adult healthy volunteers and the multiple-dose portion includes patients with severe hypertriglyceridemia. 71 subjects have been enrolled and dosed in this study. We still have a few patients to go in order to reach the planned enrollment. We are working with investigators and sites to ensure that we reach this planned enrollment as soon as possible. We look forward to the opportunity to present additional results from this study later in the year. Our other cardiometabolic candidate is ARO-ANG3, targeting angiopoietin like protein 3, or ANGPTL3, and is being developed as a potential treatment for patients with mixed dyslipidemia. This program is also moving forward efficiently. ANGPTL3 is a regulator of lipid and lipoprotein metabolism. Inhibiting ANGPTL3 should result in lower triglycerides and LDL cholesterol, and potentially provide improvements in other lipid and metabolic markers. Our data in animal models and our early clinical data strongly support that. For example, at doses of 200 or 300 mg, maximum mean triglyceride reductions in the high triglyceride cohort approach 80% and the maximum mean reductions in LDL cholesterol in the various high-LDL cohorts are averaging around 40%. These patients were already on maximal medical care consisting of statins plus or minus ezetimibe with PCSK9 inhibitors in some of them. Lowering both triglycerides and LDL to this extent was an exciting result and we think could serve to hit multiple cardiovascular risk factors simultaneously. The current clinical study is a Phase I/II single and multiple dose study to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic effects. The single-dose portion of the study is in adult healthy volunteers. The multiple-dose portion is in normal volunteers and in patients with various types of dyslipidemia. This includes patients with: hypertriglyceridemia; patients on a stable LDL treatment regimen but with persistently elevated

LDL cholesterol; patients with heterozygous or homozygous familial hypercholesterolemia; and patients with non-alcoholic fatty liver disease.

We have enrolled and dosed 93 subjects in this study and have reached full planned enrollment. The data for both ARO-APOC3 and ARO-ANG3 strongly support further development and we intend to find appropriate ways to share the data publicly this year. Earlier, Chris discussed some of our future plans for ARO-ANG3. It seems likely that a Phase IIb study that assesses various dose levels and dosing intervals would be a smart addition to our data package before embarking on a Phase III Cardiovascular Outcomes Trial. This will give us more certainty on the magnitude of treatment effect in a larger data set, allow us to select the right dosing regimen and also build our safety database. We are developing our strategy and plan to engage with regulators this year to discuss the development and regulatory path. ARO-HSD, our new investigational candidate targeting HSD17B13 for the potential treatment of alcohol and/or nonalcohol-related liver disease, is another exciting program that has made progress recently. We see this as the most intriguing target for NASH at the moment. Population-based genetic data have shown strong protection against NASH cirrhosis, and alcoholic hepatitis and cirrhosis in humans that possess loss-of-function mutations in the HSD17B13 enzyme. We are eager to see how that translates therapeutically in patients that receive ARO-HSD treatment. Our current clinical study is a Phase I single and multiple dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-HSD in normal healthy volunteers as well as in patients with NASH or suspected NASH. Additional exploratory objectives include assessment of various measures of drug activity using liver biopsy. The first cohort of volunteers received their dose, and tolerability data was collected. The DSMB reviewed those data and recommended continuing dose escalation. The study will resume enrollment shortly, once some of the COVID-19 related restrictions are eased in New Zealand. We expect to begin enrolling the first cohort of NASH patients in the multiple-dose portion of the study after the review of safety parameters from the second cohort of healthy volunteers. This parallel design strategy makes the time to patient activity data far shorter than a traditional sequential Phase I SAD to Phase II MAD design. It’s another innovative way that Arrowhead operates.

Lastly, I want to give an update on ARO-AAT, our second-generation investigational RNAi therapeutic being developed as a treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency. There are two ongoing clinical studies: the potentially pivotal SEQUOIA study and the open-label 2002 study. We voluntarily put both on a 4-week pause for new screening and enrollment due to concerns around COVID-19. Many alpha-1 patients have compromised lung function and may be at increased risk of severe illness in the event of COVID-19 infection. Continuing to enroll new patients might have also jeopardized the integrity of study data as patients could have difficulty completing study visits and could miss doses or relevant study related procedures as a result of travel restrictions or concomitant illness. We are now working with participating sites to restart screening and enrollment where and when it is prudent to do so. We are still on schedule to collect 6-month biopsies for cohort 1 of the 2002 studies by the end of the summer. We will then work on processing and analyzing results, and subsequently plan on sharing those data in an appropriate venue. This may be the first liver biopsy data of patients treated with any therapy designed to address alpha-1 liver disease. We will be looking intently to learn what happens to Z-AAT monomer levels and accumulated Z-AAT polymer, in addition to other possible measures. I will now turn the call over to Dr. Curt Bradshaw, Arrowhead’s Chief Scientific Officer. Curt?

Thank you, Javier and good afternoon, everyone. I’m pleased to meet you all virtually and hope to connect more when things ease up a bit. I want to give a little color on what we're working on in our early programs and how we're addressing resource needs in research and manufacturing. First, from a discovery standpoint we have a lot of programs in active development and more in the planning stages.

As Chris mentioned, ARO-Lung2 has already been nominated and we are now in the manufacturing and IND-enabling study phase for that program. We have been highly encouraged by our nonclinical results with ARO-ENaC and Lung2, so we are moving as quickly as possible into new targets that leverage our success with the pulmonary TRiM structure. This includes some ideas and initial work on pulmonary infectious diseases, like the novel coronavirus that causes COVID-19 and other corona and non-coronaviruses where knockdown of a target in the pulmonary epithelium may be helpful. The idea of a long-duration intervention, which RNAi generally has demonstrated, gives some unique advantages over other approaches. Our inhaled delivery platform has been developed and optimized over the last several years, so we think we have a significant leg up over other potential RNAi solutions.

Moving on to our other more advanced preclinical efforts. In the liver, we are working towards several new programs. Importantly, these include new targets as well as possible dimer or bispecific programs designed to silence 2 gene targets with a single drug candidate. In muscle, we have 1 lead program and another 2 that are in active development but earlier stage. So how are we building and allocating resources to support these plans? One of the positive aspects of being a company built around a single mechanism and a single scalable platform, is that learnings from one program tend to inform the development of others. This is absolutely true for the Arrowhead research team. We have not needed to drastically increase headcount and are only selectively adding when specialized expertise is needed. For example, we are adding a few folks to support the growing pulmonary area. There will be some additional needs for some of the new cell types we are working on. This is partly why the new San Diego R&D facility, which we opened last month, is helpful. It allows us to tap into additional skill sets in one the country’s premier biotech hubs. It has also expanded our capacity for preclinical models, so we are able to do more of the early work in parallel.

Lastly, I want to touch on our manufacturing capabilities and what we are seeing in this COVID-19 environment. We are monitoring the situation very closely because we never want drug manufacturing to delay a clinical study. So far we have not seen any supply disruptions. We have not encountered any material delay in receiving raw materials needed for the manufacturing process and have not seen any contract manufacturer delays either. We utilize a combination of internal GMP manufacturing and external CMOs. So we typically manufacture all material for pre-clinical tox studies and Phase I clinical studies in-house and then use CMOs for Phase II and beyond. We maintain redundancies both internally and with various CMOs in different geographies in order to guard against the risk of supply disruptions. So, to summarize, we think we are probably in a good position to supply the needs of our clinical development team now and into the future, even with the uncertainty of COVID-19.

I will now turn the call over to Ken Myszkowski, Arrowhead’s Chief Financial Officer. Ken?

Thank you, Kurt. As we reported today, our net loss for the quarter ended March 31, 2020, was $19.8 million or $0.20 per share based on 101.7 million fully diluted weighted average shares outstanding. This compares with net income of $23.9 million or $0.24 per share based on 98.1 million fully diluted weighted average shares outstanding for the quarter ended March 31, 2019.

Revenue for the quarter ended March 31, 2020, was $23.5 million compared to $48.1 million for the quarter ended March 31, 2019. Revenue in both periods related relates to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen. So we continue to work toward completing our performance obligation of managing the current Phase I/II HBV clinical trial. Revenue from the Janssen agreement is recognized based on our estimate of the proportion of effort expended toward fulfilling our performance obligations primarily overseeing the completion of the current Phase I/II clinical program. We expect the remaining $33.2 million of deferred revenue to be recognized in this calendar year. Any additional milestones achieved with Janssen or Amgen will be additive to this projection.

Total operating expenses for the quarter ended March 31, 2020, were $45.8 million compared to $26.1 million for the quarter ended March 31, 2019. This increase is primarily due to increased noncash stock compensation expense. Stock compensation expense has increased because the valuation of our new stock options and restricted stock awards granted has increased with the growth of our stock price. Additionally, stock compensation expense increased due to the timing of the achievement of certain performance-based awards in each period. The increase in total operating expenses was also driven by increased clinical trial costs. As our pipeline of clinical candidates has increased and increased personnel costs both -- in both R&D and G&A as our headcount continues to grow.

Net cash used by operating activities during the quarter ended March 31, 2020, was $27.6 million compared with net cash used by operating activities of $19.6 million during the quarter ended March 31, 2019. The increase in cash used by operating expenses during the quarter is consistent with the increase in our cash operating expenses. We estimate our near-term cash burn to average $30 million to $35 million per quarter.

Turning to our balance sheet. Our cash and investments totaled $498.2 million at March 31, 2020, compared to $302.9 million at September 30, 2019. The increase in our cash and investments is primarily due to the December 2019 equity financing we completed, which generated $250.5 million in net cash proceeds for the company. Our common shares outstanding at March 31, 2020, were 101.7 million.

With that brief overview, I will now turn the call back to Chris.

Thanks, Ken. COVID-19 has caused everyone to rethink how they operate in their personal and professional lives. We at Arrowhead are not immune to that. We are committed to protecting our employees, business partners and patients that participate in our studies and have taken decisive action toward that goal. From an investment standpoint, we are encouraged that the outbreak has not so far caused wide-scale disruptions to our business, and at worst, we have seen some minor extensions to our anticipated development timelines.

Importantly, we are excited to be leveraging our leading inhalation franchise and actively working on treatments for the current novel coronavirus as well as future pulmonary viruses. This is directly in our wheelhouse, and we are confident that we have much to offer. In addition, we believe 2020 holds great potential to be an important year for the company in terms of expanding our reach into new indications and continuing to validate the TRiM platform in hepatocytes, solid tumors, the lung and skeletal muscle. We intend to have readouts across most of our programs, and we expect these to be important data.

We also expect to start to gain clinical proof-of-concept for our extrahepatic platforms, begin the pipeline expansion phase of our growing pulmonary platform, expand the TRiM platform into new opportunities, engaging the regulators to gain clarity on our plans to move our cardiometabolic candidates into pivotal studies and may even have a breakthrough or 2 to discuss. We've had equally ambitious plans in the past, and we think we have a pretty good track record of meeting or exceeding those expectations.

Thanks again for joining us today. I would now like to open the call to your questions. Operator?

(Operator Instructions) Your first question comes from the line of Maury Raycroft.

Just wanted to add a quick congrats to Bruce, and best wishes and next steps in retirement. For AAT, you mentioned you don't expect to see histological changes at 6 months. Just wondering if that's based on preclinical data, modeling estimates or something else?

Javier?

Yes. Sure. So both. One of the things that we've been doing is looking at all the preclinical data. This is a huge opportunity for translation drug development, so we're learning a lot about that. And what I would say is the 2 major parameters that we aim to see results earlier: one is the amount of monomers and polymers, and second is inflammation. So we're focused on those 2 parameters as the earlier possible response rate. But as you know, and looking at other diseases that may behave similarly, in order to see definitive finite histological changes, particularly around fibrosis, it might take longer. This initial biopsy is that we hopefully may present later this year at only 6-month treatment for the first 4 patients in cohort 1 in Study 2002.

Got it. And for -- you mentioned the inflammation. Are you going to be looking at specific inflammatory biomarker data? And also for the serum biomarkers, do you plan on reporting those? And -- or I guess, can you remind what kind of serum biomarkers you're going to report on? And do you expect those to correlate to the liver data?

Sure. So the key serum biomarker is AAT, of course, it's the mutant and total protein, and we're working on that. We are going to disclose that data when we have it. So that's number one. And with regard to inflammation, we're working on that. As we speak, we're trying to define a way to quantify inflammation in a way that we can validate that in being a reliable approach to compare baseline to endpoint and compare between treatment groups. So this is work in progress. And what I can tell you is that we're planning to go to the FDA with our proposed approach to this primary endpoint that will be mainly focused, as I said, in protein accumulation and inflammation. So a number of things are going into that. I can't go into a lot more detail now. But as I said later in the year, we will disclose more specifics around the inflammation component of this core system that will be used as primary endpoint.

Got it. That's very helpful. And I may have missed this, but for the updated development plans for ANG3 and APOC3, can you say if these updates are based on preliminary feedback from FDA?

We're going to the FDA or sending the FDA briefing document for APOC in about 3 weeks to a month from now. We already request the meeting. We're going to have an interaction with them and might not be a face-to-face meeting, but it would be either a call or a written discussion with them. So that is with regard APOC. For ANG, we are going to go to the FDA approximately in August, September of this year with a similar approach. Chris already mentioned the 2 different plans with APOC. We are going now with a pre-IND proposed in a Phase II/III study with the objective to have a recitation study in MCM population. With ANG, as you know, we're going to propose a Phase IIb study to define the dose, the dose regimen and the overall study design for a final clinical outcome study of cardiovascular outcome trial. So both interactions this year, about 2 months apart.

Got it. That's helpful. And as you're preparing those briefing documents, do you have any initial thoughts on the trial sizes and time lines or any other details on the trials that you can provide?

Yes. So for APOC, we think it's going to be the first study, about 300 patients. We don't need 300 patients actually to show statistical significant difference in triglycerides level by any stretch, but we want to enlarge the study to have sufficient safety data set so the agency will be hopefully okay with this one Phase II, Phase III study for this first indication. For ANG, it's a Phase IIb study. We still need to figure out exactly. We're going to study more than one regimen and definitely more than one dose level. We're still waiting for the final data from the current study in order to define that precisely. But a Phase IIb study is going to be in that same range, as I said, for the APOC3.

Your next question is from the line of Ted Tenthoff.

I wanted to kind of get a sense for what could be next steps in terms of APOC. Is this something where you really do think you could move rapidly to a pivotal study or targeted patients? And how do you kind of balance sort of the development plans between more targeted orphan diseases with higher trig levels versus broader population?

Well, that's a great question. And what I can say is we're working on that right now. I think we have a good case because the goal of treatment for this patient is really to reduce the risk of pancreatitis, which, as you know, is a very severe condition. And yes, the patient in the rare very severe FCS population at a very high risk of pancreatitis. But those patients that are MCM and have past history of pancreatitis also have very significant rates. Also, some of those patients have very extreme levels of triglyceride level. So we're working together with the agencies to define what is that right patient population that will benefit from this intervention. And again, the goal of therapy is reduce the risk of pancreatitis, so we're going to define a population that is at risk of that condition.

But to your point, though, Ted, and I appreciate that question. There's a lot of things that are really interesting about this drug candidate to us. Factor one is that it appears to be a very potent drug candidate. As we talked about the data, we're seeing -- after just a single dose of 50 milligrams, we're seeing 95% reduction in triglycerides in hypertriglyceridemic patients. That is truly just stunning to us, and so that's helpful. But second, we really like the optionality of this. There is an orphan population within these MCM patients or an orphan population, but it's not an ultra-orphan of 30,000 patients that are -- that have severely impaired quality of life and are relatively expensive to the health care system. We think we can do a lot of good for them. We think that's a relatively short pivotal study, maybe relatively small as well. But look, beyond that, I think as we're treating them and as we are increasing our data set, look, we can always decide to do a follow-on study in much larger populations. We are pretty confident that elevated triglycerides are an independent risk factor. And the fact that we can really whack triglycerides with APOC3, we think, is a pretty powerful tool. And so while we are focused on MCM in the near term, look, I wouldn't be surprised if we do follow-on longer studies to expand that a bit.

Chris, if I may add another thing. So I'm a newcomer to the company, as you know, and one thing that is really impressive about this, when you look at the APOC study, there is a number of different populations from normal all the way to patients with severe hyperlipidemia. And the magnitude of treatment effect is consistent, and the response rate is 100%. So you don't see that very frequently. And so that, I think, support the idea that we can expand from population to population because the underlying problem is the same, and the magnitude of the treatment at is also very consistent.

That's great. And one real quick follow-up. We've seen certainly the potency of siRNA as an antiviral mechanism. And while I'm not looking to jump on bandwagon here, have you guys considered developing siRNAs against SARS-CoV-2, either in a partnership or with the government or anything along those lines?

Yes, we have an active program that we discussed in -- against the current novel coronavirus as well as potentially future coronavirus outbreaks. And we think that we have a real role to play here. A, we think that we are best in the field in the RNAi field at antivirals. We've got a lot of good experience with HBV. I think we revolutionized that field with the way that we were treating it. Second, look, we've been working on lung delivery for several years now. It's taken an awful lot of work, but we have [don't have any] amount of time there. And so I expect that we'll have something that should be active and well tolerated that could give us a long durability of action. So we're excited about the program. It's ongoing. And so we expect to have more to tell you about that throughout the year.

Your next question is from the line of Mani Foroohar.

This is Rick on the line for Mani. Congrats on all the progress. First, I wanted to discuss the ENaC. So if you compare this to the Phase I trials of a ARO-ANG3 and ARO-APOC3, are you able to assess target knockdown in healthy volunteers in those studies, given that those are proteins that are expressed in the serum? Will there be an opportunity or anything analogous to this book into the clinical studies of ENaC so you can gauge target engagement in the healthy volunteers? Or is the first readout of potential efficacy going to be the FEV readouts in cystic fibrosis patients?

Yes. So for ARO-ENaC, we're not going to look at that in normal, healthy volunteers. So the answer to that question is no. We're going to have -- in this same study, patients with cystic fibrosis, and we're measuring pharmacodynamic parameters, F1, quality of life. So we have a sizable study, and we hope to enroll this study relatively fast. We're doing this in New Zealand and South Korea, for example, and Hong Kong. So that's the first part of the question. I didn't get the second one.

I thinks that's it.

All right. I did have a follow-up question. So it sounds like for the ARO-ANG3 program, you're going to be conducting a Phase II trial in addition to a larger cardiovascular outcome study. So can you maybe share your most current thoughts on potentially partnering this asset versus developing it alone? And if that is something that's on the table, at what stage of the development would make sense to start looking for a partner?

Yes. So here's what we think about both ARO-APOC3 and ARO-ANG3. We just think those are really exciting targets, and we think we have really good drug candidates against both of them. That's first point. Second point is we're well capitalized now, and we can certainly afford to push those programs deep in the clinic. And so look, we will -- we're happy to talk to people, but there's not a forcing function, at least right now, for us to jump into a partnership. If the right one should present itself, we're happy to talk but we're also happy to go it alone, at least for right now. Again, these assets are just too valuable, I think, to jump into a partnership that is not quite right.

Your next question is from the line of Alethia Young.

A couple for me. One, I mean, you guys kind of have a problem of britches, which is many pipeline items. I just wonder in light of what's going on with all the variable kind of clinical trial delays and adjustments, does this change your prioritization of your pipeline anyway? The second question is, when you're thinking about AAT and the biopsies, it sounded like you were quite confident around the summer. Is there a potential grace period perhaps if time lines were to slip? Or anything that would kind of be kind of buffer at that point? And the third point is just curious about hearing about more of your confidence around by after COPD in light of what you are seeing with ENaC or maybe not. Just like -- just kind of want to go another feel for kind of increased confidence on the long platform you have there with emerging things.

Okay. So let's see if I can give you all. So first, with respect to -- has COVID caused us to reprioritize our...

pipelines.

The answer -- yes, pipeline. The answer is no at this point. We have not seen any effect on COVID that has really drastically affecting any of our time lines. It has affected all of our time lines to some extent, but generally, not in a material way as we don't think. And so we are still business as usual, at least right now, pushing them all forward. The one thing, I guess, it has done is it has opened up a new opportunity for us. To be totally honest, maybe we should have been thinking about this in December or November of last year, but we just weren't. This has opened up an opportunity to go after coronaviruses more broadly and the novel coronavirus that causes COVID-19, specifically. We think that we've got a lot to offer there. We've got good experience in lung drug. We've good experience in antivirals. When we started that, we were excited to be part of that fight, and so it's added some work to our nonclinical teams. But look, everyone is on board with us, and so that has not slowed down the other the programs. So it's a long way of saying no, COVID has not reprioritized any of our pipeline. Second, you mentioned AAT biopsies in mid of the summer. And could that time line slip? The answer is sure, it could. We feel pretty good about it though. Look, we -- that cohort is still enrolled. They're due for biopsies, I think, in the August or so time frame. Look, it is possible that 1 or 2 of them may be delayed a little bit. I don't expect that, but it's possible. But what's here -- what's great about this drug and frankly, all of our drugs is that the durability is such that that if somebody came in a week or 2 or 3 weeks later or even more, I don't think it really affects our data because it's not like we would expect a big drop-off in activity. This drug, I expect many months, maybe 6 months of activity after one dose. So we don't expect any problem there. And again, if there are some minor problems, we don't expect it to change the integrity of the data. And look, I think these are important data. No one's ever seen what the liver looks like after some period of reducing production of AAT. I think it's important, and I think that we -- look we're excited to see what the monomer looks like, what the polymer looks like. We're excited to see what inflation looks like. And as I said in my prepared remarks, I think this underlines not only our substantial lead in this space, but also our position as a thought leader in the field. And third, you mentioned our confidence in COPD. So a couple of things give us confidence in this new program, ARO-Lung2. I think one is that, look, our nonclinical data with the pulmonary platform have been quite good, and it's not good in 1 or 2 animals, but it's been good in rodent models, in nonhuman primate models and sheep models. And so it wasn't like we just started this a year ago, this is something we've been working on for quite some time, and we think we're there. And second, look, as I mentioned in the prepared remarks, the lung is interesting because it's a target-rich environment. There's a lot of good validated gene targets to go after, and that also applies to COPD. So we feel like the biology is in our favor here, and our data are quite good, too. So we're excited about that. We think this is a big year for pulmonary. We've said it before that we think the pulmonary franchise is a big value driver for us going forward. And we are taking the first steps now in really blowing out that franchise, I think.

Our next question is from the line of Mayank Mamtani.

Just a quick follow-up on the AAT. Relative to sort of what we've heard from you before, maybe could you just call out the bookend kind of scenario that you think? And again, assuming this is still the lowest dose you're working within the open-label study and there is the optionality to grow higher on the doses with the longer-term study. So could you just lay out what do you expect to see there in the different outcomes?

So Mayank, just so I understand, so you're asking what we expect to see in the 6-month biopsy data for the open-label study?

Yes, just the bookend of scenarios the expectation because, obviously, you have the serum protein data, and then you have the biopsy data. But I was just curious like -- it's still a lower dose you're studying, right? And you have the optionality to go to a high -- you're studying, in parallel, a higher dose. So just could you just lay out how you think about the impact of the broader study?

Yes. So I'll leave that to Javier. But just to clarify, so the open-label study is not a dose-escalation study. All the patients are receiving 200-milligram doses.

Yes. So we are not using 2002 for that. What we are doing, as you probably know, is the 2001 study, the potential registration study has 2 parts. Part A is the one where we're assessing 3 different doses, first 36 patients. At the end of that part, we're evaluating the PD response and safety, and the DSMB will help to selected. So the rest of the study will be enrolled. And when we get to the Part D, which will be what I would call the Phase III or the registration part of that study, that will go on with just the decided or the defined final dose. But based on the Phase I study, all doses have a very profound suppression of AAT. So I'm really interesting to see how all 3 doses from the 2001 study will look like. But again, at the end of those first 36 patients, we're going to look the data and make the call to continue on the final Phase III part of the 2001 study.

And Mayank, the data that we're talking about reporting publicly are just from the open-label study. We won't be reporting any of the pivotal study data publicly until it's complete.

Understood. And then ANG3, of the 93 patients, how many are NAFLD patients? And just -- not just for NAFLD, what is the median follow-up you'd have in the next update you may have?

The NAFLD patients, about 8 patients approximately, give or take 1 or 2. By when we're going to have the data? Probably at the end of this year. In that particular patient population, we're also on top of the metabolic part profile, we're doing MRI and that data may be available at the end of the year, maybe Q1. Okay.

So assumed mix dyslipidemia study would only focus on the lipid part of the metabolic syndrome disease? Is that right, the Phase IIb study?

Yes. So the -- what we're thinking about for the Phase IIb study next year. And again, there's 1,000 caveats, not least which is -- we have not discussed with the FDA yet. But what we're thinking of is the mix dyslipidemia. We're not right now contemplating more metabolic syndrome type patients just because, look, we don't have insulin sensitivity data yet. We don't have liver fat data yet. That's still a little bit up in the air. What we do know is that this drug does a great job of reducing triglycerides and does a great job of reducing LDL in a non-LDL receptor-mediated fashion. So we're running with that. Anything else could be gravy, but that's our focus for right now.

And it's likely to that populations, some of them will have metabolic syndrome, of course.

Great. Appreciate the clarification. And last question on the HIF2-alpha program. I understand these are obviously, cancer patients, so enrollment may not be as impacted. Just curious in your guidance for the update by the end of the year as proof of concept, what do you expect in terms of number of number of patients or in follow-up you could have then?

Yes. We don't want to speculate on that now because it's just a bit early, right? We only have one site open. We haven't dosed patients yet. So give us some time to start enrolling patients and see how this goes. I think that -- and let me just be clear on the proof of concept that you mentioned. I think that we're going to know if this is working, at least internally by the end of the year. Will we have enough data by key abstract headlines to submit an abstract then to present these publicly? I don't know yet. That could certainly be tight, and who knows what's going to happen with those conferences anyway. So look, we feel good about where we are now. It's been a bit slower than we expected because COVID has slowed our opening of sites. But I expect, we'll start dosing patients this quarter, and then we'll see how this goes.

Just -- can you remind us the dose escalation, the doses you're looking at in that -- if that is disclosed yet?

It's 3, 9 and 13 mg per kg weekly IV.

Single dose?

Weekly. This is weekly. Week 2, right? Yes, its 3, 9 and 13 mg per kilograms weekly IV.

Your next question is from the line of Madhu Kumar.

So I'm curious about the APOC3 program, the focus on multifactorial chylomicronemia syndrome. How does like targeting that population affects the kind of endpoints you might look at? So obviously, there's evidence that multifactorial chylomicronemia syndrome has a lower pancreatitis incidence. It has an acute pancreatitis incidence in FCS. It has a higher incidence of cardiovascular complications. So do you plan to look at both as endpoints? Or how do you think about that?

Well, so that's a great question, and we've been thinking about that quite a bit. What I would say is the number one study, it would be looking at triglyceride level. And we want to have a conversation with the agency. There is precedent for that. This is not only the first drug approved to treat patients with about 500 milligrams per deciliter without specifically clinical outcome as an endpoint. Yes, the goal of therapy will be to reduce pancreatitis risk, and the risk of pancreatitis is in this population vary. You have people with very high risk and very high triglycerides level, and you have people with lower rates. So we're working on the study design because we do want to select a population that will be in excess risk compared with the average hypertriglyceridemia patients to be part of the study. So this is an important discussion that we have to have we're going to do this in the next couple of months, and so we'll see how it goes. But of course, in the future, I think APOC has huge potential for the cardiovascular outcomes and something that I think we need to think. About I don't know, Chris, you want to comment on that?

No. I think it's good. If -- for 2021, think of this as likely focused on the MCM population and then going forward, we can consider broadening that out at some point. We'll see.

Okay. And then for an MCM trial would you restrict are there concomitant triglyceride lowering medications? Or would you allow them to kind of stay on concomitant medications in parallel?

We will allow them to stay on concomitant medication. The data we have from the Phase I study in those patients who are on concomitant medication is extremely good. You can't tell the difference. So I think we will probably allow for other medications that people are starting, so any other thing for dyslipidemia, they will remain on it.

Okay. And then stepping back, you've mentioned several times in the prepared remarks, the idea of finding an appropriate venue. So kind of like if push comes to shove and kind of there's a prolonged dearth of medical conferences for presenting just kind of assemblage of clinical data you guys are building over this year. Would you plan to kind of do something internally or how are you envisioning that?

Yes. Thanks for asking the question. So yes, we are -- look, we're committed to pushing data out where we can. As you know, Madhu, we've been really good, I think, not press releasing data generally, but presenting it at appropriate conferences. We just think got the right way to go, and so that's obviously our preference. Should these conferences continue to be disrupted, then we will find other ways to do it. And that could via press release, via webinar, what have you. I'll give you an example, though. We're still submitting abstracts, of course. In fact, we have approval we've got abstracts approved from both the APOC3 and ANGPTL3 at...

NLA.

The National Lipid Association Conference, again, both those as well as the European Society of Cardiology.

Your next question is from the line of [Robert Tutzitki].

Congrats on an exciting quarter. I was curious about your new facility in San Diego. When do you expect it to be fully staffed and running? Will it focus on a specific area of development, such as pulmonary and what benefit or advantage are you looking to gain with it? For example, will it help increase the number of drugs to clinic on a yearly basis?

Curt, do you want to address on that, at least?

Certainly that -- I mean, it's not of course, if we had chosen our timing, it's unfortunate in terms of the current environment, but we are staffing it today, and we're in the early stages of filling the facility up. And really, the intention there is, yes, to increase our capacity in our drug pipeline ultimately. And it also to tap into scientific expertise in the California, from California biotechs. So there's a lot of skill sets that we're looking for to increase both our throughput and our sophistication in terms of the some of the newer programs that we have underway.

Yes. Look, as you know, we've got this platform that is so flexible. And now that we've gotten outside the liver, we can go after so many indications, Sony gene targets that it's incumbent on us to maximize that value. And while Madison has been great and will continue to be great. And we've got a phenomenal team there. We've had no problem staffing that up and building that out. I don't think there's any 1 single area anywhere where you can attract all the talent that you want with a platform, this flexible and this broad. So it just makes sense for us to open up a second R&D facility. We'll see how it goes. I don't know that we know right now. How that's going to interact with Madison and what each facility is going to do. We're going to see what our needs are and see where we can bring people, whether it's Madison or San Diego, but it's going to be a big help of us. I think it's going to allow us to continue to push a lot of drug candidates into the clinic.

And congrats to Bruce out there on his retirement.

Thanks, very much.

At this time, I would like to turn it back to Chris Anzalone for any further comments.

Well, thanks, everyone, for joining the call today, and I hope everyone stays safe. Talk to you soon.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.