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 Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.
Thank you, Jeff. Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal third quarter ended June 30, 2020. With us today for management, our 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, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hassard, our Chief Commercial Officer, and Dr. James Hamilton, our Chief Scientific Officer, will be available during the Q&A session of today's 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, 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 and 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'll 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. We've already made a lot of progress this year, notwithstanding the challenges that COVID-19 has presented to the world broadly, and particularly to those of us developing new medicines. We took decisive action and placed a voluntary pause on new patient screening and enrollment in some of our clinical studies in order to limit the risk of participants. We take very seriously our obligation to protect the health and safety of our employees, business partners, and patients that participate in our studies. That was the right thing to do. The good news is that we don't believe any of our development programs were affected in a material way. That is a testament to the Arrowhead drive toward innovation, speed, and precision. We find a way forward even when the way is not clear.
This is a hallmark of the Arrowhead culture and something that I am very proud of. Even though COVID still presents some uncertainty, we are confident that 2020 can continue to be a highly productive last part of the year as we work to, one, expand our pipeline. Two, make progress and provide data readouts on multiple clinical programs. Three, gain clinical proof of concept for our first extrahepatic candidates. What have we done, and what are our plans in order to achieve these three important goals? Let's answer that by reviewing some key programs. I'll start by speaking broadly about our discovery stage programs. The partnership we signed with Janssen in 2018 included three potential new products against targets to be selected by Janssen.
While I can't disclose the targets, the specific stage, or report data on these potential product candidates, we can say that we have made good progress on all three. We previously talked about ARO-JNJ-01 because the first target was selected early on in the partnership and work began soon after. We are now at a sufficiently advanced stage of the other two potential product candidates to add them to our pipeline and designate them as ARO-JNJ-02 and ARO-JNJ-03. The partnership with Janssen has been very productive including for ARO-HBV, now called JNJ-3989, which continues to progress rapidly in multiple phase II-B studies being conducted by Janssen. Staying with earlier stage development, let's move on to our preclinical programs that utilize our TRiM platform targeting the pulmonary space. Our second program after ARO-ENaC is ARO-LUNG2, designed to treat COPD by inhibiting an undisclosed target in pulmonary epithelia.
We previously announced that it had officially been nominated as a candidate and moved from preclinical to pre-IND stage. We have continued to make good progress on the IND-enabling studies and are on track to potentially file a CTA for ARO-LUNG2 at the end of this year. It has been our goal to gain clinical proof of concept and move into a rapid pipeline expansion phase for the pulmonary platform. We think we are just on the cusp of that phase now. To that end, we continue to work in parallel on multiple additional targets in the pulmonary space. We think the lung is a target-rich environment with multiple opportunities for asthma, COPD, idiopathic pulmonary fibrosis, and other diseases that are not adequately treated. We've also made good progress on several potential candidates designed to treat the novel coronavirus that causes COVID-19.
This is the first time we have disclosed that we are pursuing multiple different therapeutics at the same time, and I think it's important. This is a difficult virus, and we believe the best way forward is to address multiple strategies. One is to close the front door, if you will, by knocking down a receptor that the virus uses to gain entry into cells. A second is a direct antiviral approach that targets the viral mRNA, and a third is to pursue anti-inflammatory pathways. We are pursuing all of these in parallel and believe this broad holistic strategy gives us multiple shots on goal and a more complete approach to a poorly understood virus. Given our experience in the lung and our work in HBV, I believe we're well-positioned to play a role in addressing COVID-19 and possibly future coronavirus outbreaks.
With ARO-ENaC, ARO-LUNG2, our suite of COVID-19 programs, and the additional potential candidates that are progressing rapidly, we are confident in our belief that the emerging lung pipeline can be an engine that drives substantial value in the near to midterm. What we have done and continue to do in the liver, we now seek to do in the lung. Moving on to our clinical pipeline. I'll start with ARO-AAT, our phase II/III candidate against a rare genetic liver disease associated with alpha-1 antitrypsin deficiency. We have fully enrolled, dosed, and collected six-month repeat biopsies for the first cohort of the open label 2002 study. Biopsies are now being analyzed, and we plan to present data before the end of the year. This is important progress and an important readout.
It will be the first data for a therapeutic targeted at alpha-1 liver disease, and it will be an important step in understanding what happens at the hepatocyte level after patients are treated. We will be looking at many measures of alpha-1 liver disease, but most focused on the change from baseline in Z-AAT monomer. That is a direct measure of the drug's ability to inhibit production of the faulty mutant protein. We have a high level of confidence in our ability to show improvements here. We will also be assessing other measures that will likely require longer drug exposure to show treatment effect. That includes Z-AAT polymer content and inflammation. We don't believe that six months of therapy is enough time to see changes, but we are the first company to investigate this disease in humans, so we really don't know what to expect.
Remember that in the phase II/III SEQUOIA study, patients will receive around two years of treatment. If we see signs of improvement at earlier time points than expected, that would be a very exciting result and could cause us to consider working with the regulators to change the parameters of the study. I will now talk about our cardiometabolic programs. Let's start with AMG 890, the candidate we licensed to Amgen targeting Lp(a) for the treatment of cardiovascular disease. We announced last week that Amgen started a phase II study and that this triggered a $20 million milestone payment. These represent important steps forward for the AMG 890 program and support Arrowhead's strategy of utilizing our platform and expertise in RNAi therapeutics to build a valuable pipeline of both wholly owned and partnered drug candidates.
Amgen has extensive experience in developing and commercializing innovative cardiovascular medicines. We are excited to see the program continue to advance. Our two wholly owned cardiometabolic candidates, ARO-APOC3 and ARO-ANG3, are both progressing rapidly toward value inflection points, including multiple data readouts this year and advancement into the next stages of clinical development. The second half of 2020 is going to be an important time for both programs. Both candidates are in phase I/II studies and together have enrolled nearly 200 healthy volunteers and patients. Both studies include single and multiple dose assessments. Both have various cohorts with specific patient populations. This accelerated first-in-human study design yields data on safety and tolerability, dose response, duration of effect, and how different types of patients respond to the therapy. It allows us to give data readouts from both programs at two or three conferences over the next few months.
It also gives us enough actionable information about each candidate to engage regulators and discuss the next stages of clinical development, up to and including potential registrational studies. We've already been communicating with the FDA on ARO-APOC3, and our plan is beginning to take shape. We will have similar discussions on ARO-ANG3 and also engage with European authorities to gain clarity on various study design characteristics, endpoints, and target patient populations. Importantly, both candidates provide a high level of optionality on which patient populations and disease characteristics to focus on and how to stage the clinical studies to assess the candidate's utility. For example, for ARO-APOC3, there are potential patient populations that range from ultra-rare, genetically defined, such as FCS, in which patients have triglycerides in the thousands of milligrams per deciliter, to extremely high prevalence disease such as patients with mildly elevated triglycerides above 150 milligrams per deciliter.
There are also various levels in between these extremes that each have their own characteristics and would require a different clinical design with respect to size of the study, duration of treatment, and acceptable endpoints. Taken together, this represents a very large market opportunity. In the U.S. alone, there are estimated to be approximately one million adults with triglycerides greater than 1,000 milligrams per deciliter. More than three million adults with triglycerides between 500 and 1,000, and more than 41 million with triglycerides between 200 and 500. Of course, not all of these patients will be potential candidates for therapy, but thinking of ARO-APOC3 solely as an orphan indication drug candidate is missing the larger breadth of opportunities it has. This type of opportunity also exists for ARO-ANG3 in patients with mixed dyslipidemias, specifically triglycerides, LDL-C, and other measures of cardiovascular and metabolic disease.
I don't think investors fully appreciate the size of the potential commercial opportunities for both ARO-APOC3 and ARO-ANG3. This is an exciting time for these programs as we are beginning to see potential paths to commercialization. We'll be talking about these paths and timelines in the future, which should provide a level of detail for investors to properly assess how significant the opportunity is to help very large populations of patients that could benefit from new treatment options. We have also made good progress on ARO-HSD in developments to treat alcohol-related and non-alcohol related liver disease. We began dosing in a phase I/II study in March. We have since completed all healthy volunteer cohorts and have activated the cohorts in enrolled patients with NASH or suspected NASH. The target, HSD17B13, is not a secreted protein, so we'll be collecting liver biopsies to measure target engagement.
This program experienced a short pause in screening and enrollment due to the COVID-19 situation. Similar to other programs, we don't think this had a material effect on our anticipated timelines. As long as patient screen and enrollment continue to move forward as planned, we should be generating data through the end of 2020 and be in a position to present in the first half of 2021. Lastly, I want to mention ARO-ENaC, our first inhaled RNAi candidate to target the pulmonary epithelium. We anticipate dosing to start this month in our phase I/II study in healthy volunteers and in patients with cystic fibrosis. The candidate is designed to reduce expression of the epithelial sodium channel, or ENaC, in the lungs to help rehydrate CF-related dehydrated mucus and potentially help improve mucociliary clearance.
As we discussed on our ENaC webinar last week, there has been great progress in new therapies to treat CF over the last decade, significant unmet needs still exist. We estimate that there are approximately 14,000 patients in the U.S. alone that are either not eligible for the most advanced therapies because of their specific genotype or have been shown in clinical trials to be non-responders or insufficient responders. This is a lot of patients who still suffer from CF and are in need of alternative treatments. We think ENaC may be that alternative, importantly, the mechanism of action should theoretically be genotype agnostic. This is an exciting program, we hope to generate data through the rest of 2020 that may enable us to have a data readout in the first half of 2021.
Our pre-clinical data has been highly promising, and we are eager to see the translation of animal data to humans in our new pulmonary treatment platform. With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?
Thank you, Chris. Good afternoon to everybody on the call. I want to highlight a few of our clinical programs and some key progress we made since our last conference call. Just like all biotech companies, COVID had an effect on some of our programs, but I'm very pleased to say that it appears the effect has been generally minor. In fact, some programs experienced little to no delay in our anticipated timelines. We continue to monitor the situation closely to ensure the study participants are not being exposed to additional risk, while at the same time moving forward rapidly when it's safe to do so. Even in the challenging environment of the last several months, I'm proud that Arrowhead's clinical development team has executed at a very high level.
Let's start with ARO-AAT, our second-generation investigational RNAi therapeutic being developed as treatment for a rare genetic liver disease associated with alpha-one antitrypsin deficiency. As we announced last quarter, we voluntarily put the SEQUOIA phase II/III study and the 2002 open-label study on a temporary pause for new screening and enrollment due to concerns around COVID-19. Both studies are now back up and running and open to new patient screening and enrollment. The pause caused a delay of approximately eight weeks for SEQUOIA and for the second cohort in 2002, after which sites began to reopen and resume patient screening. The first cohort in 2002 was already fully enrolled, and importantly, we did not experience any concerning protocol deviation for those already on the study.
Let's talk more about 2002 open-label study because we plan to have data readout this year. To review, the study is designed to enroll approximately 12 participants in two sequential cohorts. Between the two cohorts, biopsy data will be assessed at baseline and after six months, 12, 18, and 24 months of treatment with ARO-AAT. As I mentioned, the first cohort, which is four patients, was already fully enrolled prior to COVID-19, patients have continued on study as planned. All doses were administered, the six-month repeat biopsy have all been collected. Samples are being processed as we speak, our plan is to have analysis completed in time to submit a late breaker abstract to the AASLD Liver Meeting later this year.
This is a potentially important readout for the program and for the field because it is the first view of what happens inside the liver in alpha-one patient after receiving therapy. We will be assessing reduction in the Z-AAT monomers, which we would expect based on the plasma data from our phase I healthy volunteer study. The phase I data demonstrated that ARO-AAT treatment led to reduction in serum AAT levels down to below the level of quantitation with a multi-month duration of effects. This suggests that we may be achieving near complete suppression of the liver production of the mutant Z-AAT protein. At this time, no other therapy has shown this type of result using any modality. We will also be looking at whether the accumulated Z-AAT polymers can start to decrease after six months, which are not expected but would be a pleasant surprise to see.
In addition, we will look at changes in inflammation and in various histologic parameters. Again, we wouldn't expect to see these measures change after only six months of treatment, but it would be very exciting result if we were to see improvement this quickly. Let's now move to our cardiometabolic pipeline. I will start with AMG 890, an investigational siRNA therapeutic designed to lower lipoprotein(a) or Lp(a) for the treatment of cardiovascular disease, which is licensed to Amgen. As Chris mentioned, Amgen recently started a phase II study, which I'm very excited about. The study is double-blind, randomized, placebo-controlled phase II study to evaluate efficacy, safety, and tolerability of AMG 890 in approximately 240 subjects with elevated Lp(a). The primary endpoint is the % change in Lp(a) from baseline to week 36.
Key secondary endpoints include the % change in Lp(a) from baseline to week 48, % change in LDL cholesterol, and ApoB from baseline to week 36 and 48. Moving to our two wholly-owned cardiometabolic candidates, ARO-APOC3 and ARO-ANG3. Let's begin with ARO-APOC3, our candidate targeting apolipoprotein C-III, being developed as a potential treatment for patients with hypertriglyceridemia. We continue to be very impressed and encouraged by results from the ongoing phase I/II clinical study called AROAPOC31001. I will talk about the study design and progress, let's discuss where and when we expect to present data. AROAPOC31001 is a phase I/II single and multiple dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effect of ARO-APOC3. There is a single dose and multiple dose portion of the study in adult healthy volunteers and multiple dose portion of the study in patients with hypertriglyceridemia.
The study reached full plan enrollment of 80 subjects, and we subsequently expanded the study to assess a total of up to 112 subjects. As of today, 100 subjects have been treated. The first data from the single-dose healthy volunteer portion was presented at the American Heart Association in 2019. We have been accepted to present additional data at the European Society of Cardiology meeting, the National Lipid Association meeting, and we might potentially have additional data at the American Heart pending abstract acceptance. Between this team in the second half of 2020, we plan to have multiple dose and follow-up data in both healthy volunteers and patient cohorts. Together, this represents a rather full data set and should be a good view on the safety and activity of ARO-APOC3.
Data from the ARO-APOC3 phase I/II study have indicated a very potent triglyceride reduction, frankly, more potent than anything I've seen before. We are exploring potential designs for the next stages of clinical development to study the role in multiple patient populations that might benefit from triglyceride reduction. We have been engaging with regulators on that topic and hope to provide some clarity later this year. We're hopeful that during the first half of 2021, we will be able to initiate a phase III study in a smaller population and a phase II-B study in a larger population. Our other wholly-owned cardiometabolic candidate is ARO-ANG3, targeting angiopoietin-like protein three or ANGPTL3, it's being developed as a potential treatment for patients with mixed dyslipidemia. The current clinical study is called AROANG1001.
It is a phase I/II single and multiple-dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamic effect. Both the healthy volunteer and patient portions of this study have reached full plan enrollment of 93 subjects. Similar to ARO-APOC3, we continue to be very encouraged by the clinical data and plan to present at ECS and NLA, and hope to also present at the American Heart Association pending abstract acceptance. We're working on clinical development plan and will be engaging with regulators shortly to discuss this plan. Our hope is to start a phase II study in the first half of 2021 in appropriate patient population that might benefit from a lowering of both triglycerides and LDL cholesterol. This may affect multiple cardiovascular risk factors simultaneously, which is potentially very exciting. I will now briefly touch on progress in our earlier stage pipeline.
ARO-HSD is our investigational candidate for the potential treatment of alcohol and/or non-alcohol related liver disease. The genetic validation is strong for inhibiting the target HSD17B13 in NASH cirrhosis and alcoholic hepatitis and cirrhosis patients. This is an exciting program for us as it is the first candidate against this novel target using any modality to enter clinical study. We're conducting a phase I/II single- and multiple-dose escalating study to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effect of ARO-HSD in normal healthy volunteer, as well as in patients with NASH or suspected NASH. Additional exploratory objectives include assessment of various measures of drug activity using liver biopsy. We have completed enrollment and dosing of the healthy volunteer portion of the study. We have initiated the multiple-dose portion of the study.
There was a short delay in this study due to COVID-19. It did not materially affect our anticipated timeline. We anticipate that initial data should be available to present in 2021. Our two other early-stage programs, ARO-HIF2 and ARO-ENaC, are also our first candidate targeting tissues outside the liver. ARO-HIF2 is designed to treat renal cell carcinoma. We're currently screening patients to begin a phase I-B study. ARO-ENaC, designed to treat cystic fibrosis, is scheduled to begin dosing in phase I/II study this month. We hosted a webinar last week to talk about the target, the preclinical data, and the plan for the candidate. The webinar also featured outside cystic fibrosis expert, Dr. Marcus Mall. It was full of good information about the program. I highly recommend you watch a replay if you didn't see it live.
It is still available on the Events and Presentation page on our website. I will now turn the call over to Ken Myszkowski, Arrowhead's Chief Financial Officer. Ken?
Thank you, Javier. As we reported today, our net loss for the quarter ended June 30, 2020, was $13.6 million or $0.13 per share based on 101.8 million fully diluted weighted average shares outstanding. This compares with net income of $20.3 million or $0.21 per share based on 98.9 million fully diluted weighted average shares outstanding for the quarter ended June 30th, 2019. Revenue for the quarter ended June 30, 2020, was $27.4 million, compared to $42.7 million for the quarter ended June 30, 2019. Revenue in the current period relates to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen, as 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 towards fulfilling our performance obligations, primarily overseeing the completion of the current phase I/II HBV clinical trial. We expect the remaining $26.3 million of deferred revenue to be recognized in this calendar year. In addition, current period revenue also included the $20 million milestone payment we accrued due to Amgen initiating their phase II clinical trial for AMG 890. Revenue in the prior period related to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen. Total operating expenses for the quarter ended June 30, 2020, were $43.3 million, compared to $24.1 million for the quarter ended June 30, 2019. This increase is primarily due to increased non-cash stock compensation expense.
Stock compensation expense has increased because the valuation of new stock option and restricted stock awards granted has increased with the growth in our stock price. Additionally, stock compensation expense increased due to the timing of achievement of certain performance-based awards in each period. The increase in our total operating expenses was also driven by the increased clinical trial costs as our pipeline of clinical candidates has increased and increased personnel costs in both R&D and G&A as our head count continues to grow. Net cash used by operating activities during the quarter ended June 30, 2020, was $33.4 million, compared with net cash provided by operating activities of $10.5 million during the quarter ended June 30, 2019. The increase in cash used by operating expenses during the quarter is consistent with the increase in our cash operating expenses.
The cash provided by operating activities in the prior period was driven by the receipt of a $25 million milestone payment from Janssen due to the initiation of the triple combination cohort in the HBV phase I/II clinical study. We estimate our near-term cash burn to average $30 million-$35 million per quarter. Turning to our balance sheet, our cash and investments totaled $464.6 million at June 30, 2020, compared to $302.9 million at September 30, 2019. The increase in our cash and investments was 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 June 30, 2020, were 102.3 million. With that brief overview, I will now turn the call back to Chris.
Thanks, Ken. As we have discussed, Arrowhead has a lot going on in all of the following stages. One, platform development and expansion into new extrahepatic tissues such as lung, tumor, muscle, and other cell types. Two, early discovery as evidenced by several COVID-related programs, ARO-JNJ-1, 2, and 3, and other undisclosed programs. Three, early development such as ARO-LUNG2, ARO-HIF2, ARO-ENaC, and ARO-HSD. Four, emerging mid to later-stage development such as ARO-AAT, ARO-APOC3, ARO-ANG3, and partner programs JNJ-3989 and AMG 890. This is a very large pipeline with enormous opportunity for a company of only 200 people that currently only burns between $30 million-$35 million per quarter and has a market cap less than $5 billion. This again speaks to Arrowhead culture of finding a way forward and not allowing bureaucracy or legacy processes to block innovation.
It is also a testament to our commitment to capital efficiency and being good, responsible stewards of the capital that we have been entrusted with. Even as we continue to grow, these attributes will be important parts of the Arrowhead culture. The rest of 2020 is going to be very busy. We anticipate multiple data readouts, important clarity on the future paths and timelines for some of our programs, and new announcements about previously undisclosed targets and candidates. Our existing programs continue to advance, and the reach of our technology platform continues to expand. This is a very exciting place to be. Thanks again for joining us today. I would now like to open the call to your questions. Operator?
Thank you. At this time, if you wish to ask a question, please press star one on your telephone. Our first question from the line of Alethia Young. Your line is now open.
Hi, thank you. This is Alberto on for Alethia from Cantor Fitzgerald. Congratulations on the quarter. I had two quick questions. First is the ARO-HIF2 program, which you started in December, if I recall correctly. We were just curious about how you're thinking regarding updating the street on that. Will you do an interim readout later this year, or are you waiting for all patients to be treated?
Thanks for that question. We're not planning an interim readout this year. I'll tell you, that has progressed a bit more slowly than we had hoped. As you mentioned, we filed that IND in December, frankly, I expected us to be dosing that by June. COVID really slowed us down on that. Because it's a biopsy study, we are focused, not entirely, but largely in academic institutions, that's just taken a long time to get contracting done to start that study. We are hopeful that we'll start to dose that shortly. Look, it's our anticipation to report that once that study is complete. By the end of this year, it is unlikely. Maybe the middle of next year, we'll see how that goes. We'll give you better guidance once we start dosing that.
Thank you for that. Then just on the AHC asset, do you have a view on potential differentiation that different RNAi approaches can have in liver disease? Along those lines, is it still your goal to find a partner for this program, or are you considering going at it alone? If so, or either way, I guess, what gives you the confidence to continue investing in this given the challenging space?
Sorry, which program? HSD, did you say?
Yes.
Okay. Yeah. Look, I'll tell you, our initial differentiator is our speed. As I understand it, I think we're the first company of any modality to bring an HSD-based therapeutic to the clinic. That's going to be interesting. That's first. Second, look, I expect that to be a good therapeutic. I expect that to be potent, and I expect good deep knockdown. I think we've got a very good shot at having something that's going to knock down that protein. Here are the challenges. Challenge one is that it's not a secreted protein, and so at least right now, there's no secreted biomarkers, and so it's going to have to be, at least in the near term, a biopsy study.
We are okay with that. As you know, the current study enables that. I think that we can roll that, no problem. That's going to be a bit of a challenge. The second challenge is that the mechanisms of this target are not well understood. The genetic validation is clear. It appears that knocking HSD down should be very beneficial for NASH, even more beneficial potentially for alcohol-related hepatitis. The biology of that still is a bit lagging, we'll see where that goes. We are excited about the program. At some point, could that be something that we target? Sure. At least right now, we are happy to push that forward as it is. We can handle it as it is. NASH is a complicated space, at least at this early stage of this program, we're happy to continue moving forward.
We'll just be optimistic. Should a good deal at some point happen, we're happy to listen, but right now we're happy to continue to treat patients.
Thanks again for that, and congratulations.
Sure. Thank you.
Taking next question from the line of Salveen Richter of Goldman Sachs. Your line is now open.
Great. Thank you for taking the question. What levels of the polymer reduction do you expect to see in the six-month AAT liver biopsies? What do you think is necessary in order to you guys approach the FDA on changing the primary endpoint and/or shortening the phase II, III trial? I just have a follow-up on the ENaC program.
Sure. I'm glad you asked that question because I want to be clear on this. We don't expect changes in polymer content after just six months. We do expect substantial monomer reduction, and that would be reflective of our expected activity of this drug, as we saw in the healthy volunteer study. Although those are plasma levels, we saw good deep reduction, as Javier mentioned. We expect good reduction in monomer at this point. Polymer is a different story. Look, it's not clear how that's metabolized. The good news, bad news of being pioneers here is that, yes, we're first, but bad news is we're first, and so there's a lot of things we have to learn here. One of the things is how this polymer is metabolized.
It could be that we are relying on the hepatocytes to turn over to decrease that polymer because we don't know. It's possible that metabolism is very slow if they can metabolize at all. Our take home message is, look, we do expect good deep reduction of monomer. We expect virtually no reduction in polymer, and probably no changes in inflammation at this early point at six months. I think there's a better likelihood that we would see some of those changes starting after maybe a year of therapy.
Got it. That's helpful. On the ARO-ENaC program, what dose level would you penetrate the tissue and how do you see your asset differentiated from the competitors in the space?
Javier?
This is how we're dosing patients, health volunteers first and then patients. This is coming from the experiments in the preclinical lab. When you see the total dose that we will dose patient, approximately 25% of that dose is expected to be delivered to the lung. That is an efficiency related to the nebulization process. That's an estimation. Right now, we don't know for sure, but that's what we've seen in the preclinical work and expected to see in the clinical work. However, in clinic, it's very difficult to know, of course. What was the second part?
Yeah. Regarding competition, look, I think we sit favorably, from a competitive standpoint. It's a well-validated target. People have gone after ENaC with small molecules in the past, but have generally not been able to reduce it enough in the lung, but spare in the kidneys. We are confident that we will not reduce in the kidneys. We've done exhaustive studies in animals to suggest that we don't expect reduction in the kidneys. Look, I think that we are virtually alone, at least with this target right now, in cystic fibrosis. There have been some antisense programs, but I think that those will likely have the same issues that other antisense programs have had, which has been related to tox.
Great. Thank you.
Take your next question from the line of Ted Tenthoff from Piper Sandler. Your line is now open.
Great. Thank you very much for taking the question. I wanted to ask a little bit more in terms of the COVID program. With so much going on in the space, what are the benefits of RNAi mechanism potentially for COVID, and can you tell us a little bit more about sort of maybe how that clinical program looks? Thanks.
Sure. There's not much we can tell you on that because we're still early there and we're still really exploring a lot of things. As I mentioned in the prepared remarks, there are 3 broad areas that we are interrogating simultaneously. One is knocking out or knocking down receptors in the lung that enable the virus to get in. That biology is reasonably clear or as clear as it can be for this virus. We will be going after that. I think we have a role to play there. Look, we've got a clinic-ready lung program. We've been leaders in HBV. We were the first ones to show a good potent antiviral effect in hepatitis B, and so I think we're well-positioned to play here. We feel good about that. Second is direct antivirals. Again, we showed with HBV that we're pretty good at that.
I think the opportunity here is not just to look at the current coronavirus, but to think of this more broadly. If one were to expect there will be coronavirus outbreaks in the future and the past is prelude, that's probably a good assumption. We would hope to find some well-conserved regions among known coronaviruses that we could knock down and have antiviral effects. We are interrogating that right now. We think we can play in that space. Third, with anti-inflammatory. This jives well with our other lung programs. We think that there are good indications for anti-inflammatories. We're developing that right now, and we think that might play a role in a therapeutic for coronavirus.
Cool. Sounds interesting. I look forward to hearing more.
Yeah. Thanks, Ted.
Next question from the line of Luca Issi of RBC Capital. Your line is now open.
Oh, terrific. Thanks for taking my question. Luca Issi from RBC Capital. two questions, maybe one for Javier on A1AT and maybe one bigger picture question for you, Chris. On A1AT, it sounds to me that you're saying that there is somewhat of a time lag between the reduction in the monomer versus the reduction in the polymer. However, when I see the preclinical data published at JCI, I don't see that much of a lag there, as actually it appears that the monomer and the polymer gets reduced concurrently there. Just curious about what am I missing there? That's the first question. Then the second question, Chris, on the strategy. You obviously have a very impressive pipeline at this point.
Can you just maybe dichotomize the world for us between assets that you feel you have generated enough data that you would consider a partnership now versus assets that you want to further de-risk before entertaining any type of partnership? Thank you.
All right. The first part of the question related to how the preclinical work correlates to the clinical. I think the first difference is that we haven't looked at very early time point in the preclinical work. It's more like on the longer term. I don't think we have a way to see the dynamic inhibition or reduction of different component of the mutant protein in the liver. That's one component that I think we need to understand. The second, I think we are now getting more and more information from the natural history study that we've done, and we're collaborating with others, that this is clearly a dynamic, progressive, chronic diseases, and it happens in different stages as we are learning.
The main problem is the production of this abnormal misfold protein that gets accumulated in the liver, initially as monomers, but then eventually get organized as polymers as the time goes by, become these globules. This is the reason why then patients develop inflammation, and as this continue, develop fibrosis and finish with late-stage liver disease. We see this as a very dynamic process that start with something that can be addressed immediately, which is inhibit production of this mutant protein, and that, over time, will be associated with a decrease in the monomers in the liver and then polymers, and eventually that will reduce the insult that cause the inflammation, the progression of the liver disease. That's how we're thinking.
Actually, the 2002 study likely will answer this question more precisely because we're looking at biopsies at four time points post initiation of therapy, six, 12, 18, and 24 months. Probably we'll be able to map out how this dynamic sequence of events happen and how we can intervene by inhibiting the insult and allowing the liver to heal.
Yeah, thanks. With regard to your more strategic question, that's a key question for our strategy. As you know, we have been really focused on building this large pipeline, and not slowing down. You've heard me say it before, look, I think we're going to have 10 clinical programs pretty soon. I think we double that to 20 in the next few years. What that gives us is an awful lot of currency to do some partnerships. Because look, we are frankly no company, I don't think, nearly our size, even double our size, even triple our size, could commercialize all those for good sakes. We've got the ability to go through that and find clusters of assets that we can commercialize ourselves to bring us to that next level of growth. Partner other ones out.
With respect to which ones we can partner right now, if you look at the current clinical programs where we have data, ARO-AAT, ARO-APOC3, and ARO-ANG3, I'd be willing to suggest that we have enough data to partner any of those. The data have been quite good on all of them. ARO-AAT, as Javier showed, in healthy volunteers, we were showing decreasing levels of plasma down below the level of quantitation. We'll have biopsy data shortly to see what that looks like intrahepatically. I think that we have already, from my perspective, we have already achieved clinical proof of concept there that we are doing what we expect to do in a well-tolerated manner. ARO-APOC3, we're seeing 95% reduction of triglycerides in patients. Also a lowering of LDL also in these patients. So far have been well-tolerated. I think enough data have been generated there.
I think we've dosed 100 patients so far, or human subjects between patients and healthy volunteers. I think there's enough data there to partner that, should we want to. ARO-ANG3, we're seeing 85% reduction of triglycerides, 40% reduction of LDL in non-LDL receptor-mediated fashion. Well-tolerated. Same thing there. We dosed, what? 93 patients, I guess, so far and been well-tolerated and been active. I think that we've hurdled that bar as well. The point is, I think those are all partnerable now. I think it's now incumbent upon us to continue to move these and other programs forward to figure out which ones and at what time we're going to want to partner.
Super. Thank you. Thank you again. Congrats on all the progress.
Thank you.
Next question from the line of Maury Raycroft of Jefferies. Your line is open.
Hi, everyone. Congrats on the progress, and thanks for taking my questions. First question was on ARO-AAT. Just wondering if you validated an inflammatory biomarker assay yet for that program.
We haven't validated ourselves. There is a very valid way to look at inflammation. We likely going to do an early look at the same way we look at in the pre-clinical work, which is quantify forces of inflammation by field and by portal areas. The first read of inflammation will be very standard, I think, well-described, quantifiable, and that you can believe it's reliable, and you can compare baseline to post baseline.
Got it. Wondering for that program, too, if you can provide any details on the baseline characteristics of the patients that you've got in the open label study, and how do those baseline characteristics compare to some of the patients that you've enrolled in the pivotal phase II, III?
I don't have any details right now. We can follow up if you want offline. I don't recall exactly, but we can get back to you later.
Of course. The goal there was to be treating similar patients. What we see in the open label study, our anticipation is that will read on what is likely happening within the blinded study. If the question is, are they different slice of patients? The answer is they really shouldn't be.
The inclusion criteria is similar. I was about to repeat that, but essentially, the age groups is 18 - 50 or 55. Of course, they have Kaplan FE1 higher than 65. The inclusion criteria are very, very similar. We expect that this result will be applicable to understand what happened on the larger phase II, III study.
Got it. I think in the prepared remarks, you said you've been having discussions with regulators for APOC3 and ANG3. Can you provide more clarity on when you're going to finalize plans and disclose some more of the details from your discussions with the regulators in the U.S. and the EU?
Yeah, I don't think we're ready to provide guidance on that yet. We did have interactions with the FDA over the summer. We're still formulating our strategies there.
Got it. Okay, thanks for taking my questions.
You're welcome.
The next question from the line of Madhu Kumar, your line is open.
Hey, everyone. Thanks for taking our question. My first one is on AAT. Kind of following up on Luca's question. You can imagine there are two schools of thought around clinical benefit in the alpha-1 antitrypsin liver disease relating to either reversal of polymer and globule formation versus liver cell turnover. Based on your belief that six months will not be enough for AAT knockdown to translate to clinical benefit, do you put yourself in the kind of liver turnover school of thought, or do you think you're kind of spread between the two? How do you think about it in terms of which realm do you think you'll get benefit in terms of the alpha-1 antitrypsin liver disease?
I'll let Javier expand this. I don't think we know. Look, we know that polymer should be reduced via hepatocyte turnover. That's what we think we know, and that's about it. I don't think we have a good idea about metabolism, but beyond that. Javier?
Yeah, I think, as I said before, this is one of those liver diseases that start with an insult, such as hepatitis, such as NASH. As you know, when you remove insult, more likely liver improve, and that has been shown in many different circumstances like this. This is a treatment that will remove the insult, that is new, and with time, the remodeling will get rid of the polymers and globules, and that will hopefully allow the cells, the hepatocytes, to heal and prevent the complication and the progression of the disease to a stage cirrhosis. That's how we're thinking about this.
Interesting. Y'all don't think the preclinical data suggests there's a back reaction that occurs where polymer or monomer converts back to a state. You don't have a nascent AAT forming. You don't think there's a back reaction that happens?
A back reaction meaning an unpolymerization, if you will?
Exactly.
Yeah. We just don't know.
Okay. On ARO-ENaC, you obviously have gone into the lung, and that's really exciting as an opportunity. What data do you need to see from ARO-ENaC to more broadly pursue the lung, including the COPD indication, the other pulmonary epithelium-directed lung indications? What do you need to see? Do you need to see FEV1 benefit, or do you need to see something more proximal to that that will give you confidence that you can hit targets in the lung?
This is a phase I study, of course, but we're doing two assessments in patients, which is FEV1, so spirometry, well-established, and then LCI or lung clearance index. We think that that is particularly sensitive methodology to assess early changes and somehow are probably related to or correlated to the MCC or the mucociliary clearance. We did a webinar about a week ago, and there are a number of details in that webinar that you may want to, if you haven't seen it, you can take a look because it's in our webpage. I think the LCI, we have enough patients in this phase I study to likely see difference in LCI or changes.
Also, if you put all the patients together, because LCI will be done in a subset of patients with an FEV1 greater than 70%, because the methodology is precise in that kind of patient population. We're doing FEV1 in all patients, all three cohorts of patients with CF fibrosis. We think that we are in a good situation to look at change from baseline and perhaps see an initial difference, assuming a significant change. We do believe that we will have proof of concept data. Well, at least the study is designed to achieve that goal, in the phase I.
Okay. Following that logic, the lung clearance index as a measure for ENaC inhibition, like a surrogate measure for ENaC inhibition, that's the kind of key barometer for you to kind of broadly pursue the lung?
Well, no, it will give us information that there is a pharmacodynamic effect, not necessarily only the inhibition. That will tell us that there is an improvement in respiratory ventilation homogeneity, which is related to MCC and eventually clinical benefit. It's actually a pharmacodynamic. It's not just a level of ENaC. We won't be able to measure that, of course, clinically with this target because you have to have a lung biopsy. It's going to be really a pharmacodynamic result, and the study is designed to be able to see those changes, definitely with LCI and hopefully also with FEV1.
Got you. Awesome. Stepping back and thinking, I know previously we've all talked about this idea of the fancy term, I guess, is bispecific or hitting multiple targets at the same time. Where is your progress on that, and where are you thinking about pursuing that, considering you've got this whole basket of cardiometabolic targets where I think a not unreasonable expectation would be, well, why not go after multiple targets at the same time? How are you thinking about that? What do you need to do to really pursue that in gusto?
Yeah. That's a very smart question, I think. It's something we think about a lot because you're right. Cardiometabolic, the data we've seen so far with APOC3 and ANG3 are so intriguing that if you would combine those, that's even more intriguing. You can also imagine that within the lung, there are several targets that could be very interesting by combining those. You can also think of this in NASH as well. There are multiple pathways that you could address if you could go after what you call a bispecific or dimer. Yes, we are on the same page with the great possibility of the bispecific or dimers. We're still working on that. There are challenges there associated with potency and such, and we're still working there. I think we can see it, but we're not there yet. Stay tuned.
We'll have additional updates as we can approach the clinic with one of these. It's still early-ish days on this concept.
Okay, great. Thanks very much, guys.
Yeah. Mm-hmm.
Next question from the line of Mani Foroohar of SVB Leerink. Your line is open.
Thank you very much. I don't think I can match the elegance of Madhu's question around law of mass action with respect to A1AT. Thinking about it in perhaps a more, well, we'll say a little bit more of a craft way, going back up 10,000 feet. When you think about the time horizon to see a polymer benefit, and clearly it's not going to be six months, it'll be some longer period, versus the time horizon to see histology improvement, should we expect polymer benefit to lead histology improvement by a year, two years, some very long period of time, or should it be very quick, one striking after the other, given what we know about from the pre-clinical data and natural history? I have one quick follow-up on a boring finance question.
Well, we really don't know. The good news, I think we're going to answer the question as we go along. The phase II study, the post-baseline biopsy is right now at two years post initiation of the study. We're taking right now a relatively conservative approach to do the post-baseline biopsy two year after the initiation of therapy to allow enough time to be able to see what we've seen in the pre-clinical work. Now, exactly how that will look like, I don't know. 2002, as a sequence of biopsy at different time point and different patient population might help us to fine tune the timeframe of changes, monomer, polymer, globules, and the consequence liver damage associated with that. More to come on this.
Yeah. Just to reiterate our time and expectations here. As we mentioned, we are processing and analyzing the biopsies right now. It is our anticipation that we'll have data in time to submit a late breaker abstract to AASLD. My hope is that we get accepted there, and so I think we can have more educated conversations about what we're seeing and what we could be seeing in the future sometime around then. It's just too early to tell. Look, our pre-clinical data were interesting. We saw improvements in all of these measures. We just don't know how the kinetics of those are going to translate from rodents to humans.
That's really helpful. On the more boring finance question, you spoke a little bit about the impact of stock-based compensation, et cetera. Clearly your stock has been volatile the last couple of years, which is not surprising given the amount of data that you've produced, and the milestones that you've hit, et cetera. When we think about modeling stock-based comp, we think about it in terms of shares issued as opposed to dollars, which takes that impact out a little bit. Should we expect shares issued or options issued in a notional sense to be about flat versus this year, up materially, down slightly? How should we think about that as we model that going forward on a stock issuance perspective as opposed to trying to use a dollar amount for a pretty volatile equity security like yours?
Yeah. I would expect that to be pretty flat on a stock basis. Again, to use your differentiation, right? Not on a dollar basis, but on a number of share basis.
Great. That's really helpful. Thanks, guys.
You're welcome.
Thank you. Next question from the line of Mayank Mamtani of B. Riley. Your line is open.
Congrats team on the progress. Just no more A1AT question. I just want to drill down on the cardiometabolic portfolio. Starting with the AMG 890, the Amgen compound. Could you just comment on what data they have presented or they will present and in context of another agent that is already in outcome study, just anything that is out there, you can talk about the data that they have so far.
Right. Yeah. As far as I know, they've not presented any data. I'm not in any jeopardy of telling you something that I shouldn't tell you because they haven't told us anything. My expectation is that they would present some data by the end of this year. At what venue, what time? I don't know. What are they going to see? I don't know. We are optimistic that they should be good data because, look, we thought that was a really good trigger. We expected it to be potent, we expected it to lead to good, deep and durable Lp knockdown. That was just speculation based on the animal models. We'll be looking forward to seeing that side by side with you.
Okay. On APOC3, I'm sensing there's a little bit of change relative to, I think what you were talking about earlier, with ARO-ANG3 maybe positioned for the broader population. It seems like you want to do APOC3 also in the broader hypertriglyceridemia space. Just curious, is it more to do with how the landscape there is evolving or with the regulatory dialogue you're having in real time? Is it like the data that we'll get to see more at NLA and other conferences? Could you just maybe give more color there?
Yeah. Thanks for asking that question because I think it's important. Part of this may be that we could have messaged this better. Another part is that our thinking really has evolved. We've talked a lot about addressing smaller populations because that looked like a near term path to commercialization. We've always thought that that's how we approach this asset. We get into these smaller populations relatively quickly and then expand the label by essentially walking down the triglyceride levels. If you think of this just in broad terms of, say, above 1,000 and then say 500 - 1,000 and then say 200 - 500, as we talked about in the prepared remarks. I think Vascepa, I think their first tranche, if you will, was 500 - 1,000, I think, was the first group that got approved on.
In any event, A, we are trying to message this a bit better that we see this as a whole spectrum of patients that we can address, from small market to larger market. I want to talk about that a bit more. Also as I mentioned, I think that our thinking has changed here a bit, in part because the data have just been so good. As we look at the safety profile and as we look at the depth of triglyceride knockdown we're seeing and frankly, the increase in HDL we have not talked very much about, but we think still could be important. As we look at all that, we just say to ourselves, we've got something here that really should be brought to larger populations.
Again, our goal here is to maybe start with small populations because we can get to that commercial opportunity most rapidly. Then to expand this out and look, I think this is at least as large a market opportunity as ARO-ANG3, maybe larger, but at least as large as that given the type of patients that we can address. The numbers we talked about. 41 million adults are estimated to have triglycerides between 200-500 in the U.S. alone. That's a pretty big swath for us to potentially treat some subset of them.
Okay, great. On the ARO-ANG3, just can you confirm if you still have some fatty liver disease subjects being enrolled there? Are you still planning to do PDFF on some of these subjects?
Yeah. So Javier, couldn't understand what you said. You're talking about the various patient cohorts and are we still enrolling?
ARO-ANG3 is completely enrolled. We completed that study. We're starting to look at the data that's come. No, we completed that study altogether. As Chris said, we're planning on the first interaction with the regulatory agency here, the FDA, to plan the phase IIb study to start hopefully at the beginning of the first half of 2021. The study is complete in term of enrollment, and very soon we'll have completed the 113 days final data for all patients, all subjects and patients in the study.
We've talked about lipid panels for all these patients and what has always excited us about this pathway and this target has been the possibility of lowering LDL in a non-LDL receptor-mediated fashion and lowering triglycerides. That's been the core of our interest. If you go a bit beyond that and you look at the possibility of insulin sensitivity and liver fat, the data that we and others have seen in animal models have been interesting. That was nice to have, but not a need to have, if you will. We were looking forward to seeing whether or not we see that translate into humans. Given the data from antisense candidates, we are not expecting to see that translate. We're not expecting to see changes in or improvement in insulin sensitivity. We're not expecting to see changes in liver fats.
We haven't seen the data yet, maybe we're wrong there. Just given what we've seen from antisense, we're not expecting to see that. We think that's fine because it's the triglycerides and LDL that make this a really powerful asset. We do have those cohorts enrolled, we'll find that out and we'll be reporting on those as well.
Excellent. Look forward to those updates. Thanks for taking my questions.
You're welcome.
Thank you. The last question from Robert Tokuchi of biobuzz.com. Sir, your line is open.
Hi. Thank you so much for taking my questions. First off, congrats on your progress and continued growth. I only have a couple quick matters as you've covered my other questions. I'm sorry if I missed it, did SEQUOIA Part B start dosing yet?
No, it has not.
Okay. I know that you mentioned before that Arrowhead is comfortable in rolling out its own orphan drugs. Would you consider partnering or selling any of your orphan drugs, especially ENaC or AAT, or are your orphan drugs off the table when it comes to these kinds of deals?
No, I wouldn't say they're off the table. Don't think of us as an orphan indication company, but also don't think of us as holding onto everything that we have in those spaces. I think that if you fast-forward five or 10 years from now, I think you'll see a portfolio of drugs, some of which are small indications, some are large indications, some could be very large indications. No, there's nothing about smaller indications that would indicate that we are absolutely going to hold on to those, come hell or high water.
Okay. That's all I have. Thank you so much.
All right. Thank you.
Thank you. There are no further question at this time. I would like to turn it over to Chris Anzalone for closing remarks.
Thanks, everyone, for joining our call today, and I hope everyone stays safe and enjoy the rest of your summer to the extent that you can.
Thank you. That concludes today's conference. Thank you everyone for participating. You may now all disconnect.