Arrowhead Pharmaceuticals - Earnings Call - Q1 2021
February 4, 2021
Transcript
Speaker 0
Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference Call. Throughout today's recorded presentation, all participants will be in a listen only mode. After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vince Anzalino, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.
Speaker 1
Thanks, Jonathan. Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal twenty twenty one first quarter ended 12/31/2020. With us today from management are President and CEO, Doctor. Christopher Anzalone, who will provide an overview of the quarter Doctor.
James Hamilton, our Senior Vice President of Discovery and Translational Medicine, who has graciously agreed to sub in for Doctor. Javier San Martin, while he is out ill today and Ken Myszkowski, our Chief Financial Officer, will give a review of the financials. In addition, James Hazard, our Chief Commercial Officer, will be available during the Q and A portion 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 subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10 ks and subsequent quarterly reports on Form 10 Q. Arrowhead disclaims any intent and undertakes no duty to update any of the forward looking statements discussed on today's call. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company.
Chris?
Speaker 2
Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. The last quarter was an important period for us and our shareholders because we demonstrated clear advances in multiple development programs that we believe represent key value drivers for the respective product candidates and our proprietary Trim platform. We see this as positioning us well to build substantial value throughout 2021. We seek to create value in two primary ways.
First, we push RNAi and our platform forward to address new diseases, therapeutic areas and organ systems. This is fundamentally difficult and uncertain because it relies on innovation. Second, we drive our existing pipeline into later stage clinical studies toward eventual commercialization. This can be more straightforward and we believe increasingly predictable as we generate large amounts of data regarding how well the TRiM platform works. We would expect the progress in either of these areas would drive value for us, but our goal is to show measurable progress in both.
As we look at 2021, we expect substantial progress on both fronts with several opportunities in the first half of the calendar year alone. For instance, by the middle of the year, we could have clinical proof of concept for our ability to bring RNAi outside the liver, opening a whole new range of addressable diseases without adequate treatments. We also expect to begin three large Phase IIb studies and a Phase III study during this time frame, and we may also have a better idea about how we and Takeda may be able to streamline the ARO AAT clinical program to accelerate that drug candidate to market. Let's begin by looking at our earlier stage programs. The power of Arrowhead's TRiM platform is our ability to rapidly discover and develop multiple new drugs targeting diverse disease areas in a way that has been predictable, reproducible and with an attractive safety profile.
Each new program builds upon prior programs, which could make them progressively lower risk. We've seen this in our liver targeted programs and are applying this concept to our extrahepatic initiatives. We hope to do in many other tissues what we have done in the liver. Given our clinical experience in hepatocyte targeted programs, specifically in HBV, AAT, APOC3, ANG3 and Lp, generally expect future hepatocyte directed candidates such as ARO HSD and others to also be highly potent and well tolerated. As Creating this type of expectation in a new cell type could represent a substantial value creation event.
Now imagine leveraging that not only in a single new cell type, but with many new cell types. As we have said in the past, we expect to be able to target a new cell type every eighteen to twenty four months. If we can pull this off, we would expect it to provide a huge amount of leverage in value creation. This is exciting, and it's one reason I believe that the progress we've made over the recent time periods could be just a prelude to something bigger. We think we are now on the cusp of having clinical data to assess the ability of TRiM to knock down target genes in the lung and in solid tumors and are working toward bringing our first muscle targeted program into the clinic late this summer.
What will success look like for these new programs? And what have we seen so far? First and foremost, we need to have an acceptable safety profile. The TRiM platform for liver delivery has been administered in literally thousands of patients, so we have a good idea about how that performs. While the new tissue types are built on the same idea and same fundamental platform, they are structurally distinct.
So first, we need to establish that these new molecules are well tolerated before we can take a breath and exhale and then focus on assessing efficacy in humans. We think we are almost at that exhale stage now. The studies are still ongoing and data collection continues. But so far, we have not seen anything concerning on the safety and tolerability front for ARO ENaC, which is our first lung targeted program or for ARO HIF2, our first tumor targeted program. We still have not seen activity data from either program, but expect to start to see data in coming months.
We hope to share some early data by the middle of the year for both programs. Regarding ARO ENaC, we hope to have preliminary FEV1 data in patients from the first one or two dose levels and also have some ENaC knockdown data in healthy volunteers via bronchial brushing and lavage. While longer term, we are of course focused on functional improvements in patients, the healthy volunteer data at this point may be more informative. Given the small number of patients we will be treating in the current study, only four per cohort on active drug, it may be difficult to discern FEV1 changes. However, ENaC knockdown in healthy volunteers should be much easier to interpret.
Therefore, this is our primary focus right now. Should this be positive, it would represent a huge leap forward for our company and for the entire RNAi field. We believe it would suggest we may not only have a drug in ARO ENaC, but we may also have a lung franchise that could be leveraged against many gene targets from many different diseases. This would indeed be a big event. Regarding ARO HIF2, we hope to have some preliminary knockdown data to share by the middle of the calendar year.
We're taking biopsies for metastases pretreatment and during treatment, and we'll be assessing HIF2 alpha knockdown. This is too small a study and too short an observation period to be focused on progression free survival, but we think if we are able to show good reduction in HIF2 alpha expression in these metastases, we will have demonstrated something truly important. HIF2 alpha is a well validated target, particularly for the clear cell form of renal cell carcinoma, so demonstrating the consistent reduction in expression could be strong evidence that we have a drug. Further, and potentially more importantly, we believe it could also suggest that we have a solid tumor franchise. Our targeting strategy is not designed to be RCC specific, but rather to enable delivery to a variety of solid tumor types.
If we can show reduction of any gene product inside of solid tumors, in this case, CX-two alpha, it would suggest to us that we can address a wide variety of cancer targets across different solid tumors. As a clinical proof of concept in the lung, this would be a giant leap forward and could represent a substantial value inflection point. By the end of the second calendar quarter, we could have proof of concept that we can silence gene expression with RNAi in three different cell types across eight different clinical programs. I don't believe there is another company on the planet that can say that. Later in the summer, we expect to increase our reach to a fourth cell type when we expect to file a CTA for our first skeletal muscle targeted program.
While we're conducting these clinical studies, we continue to work in parallel on multiple additional targets in tumor and pulmonary. For the latter, we have a number of early programs in development, and I expect us to file at least two pulmonary CTAs in calendar twenty twenty one. We also continue work on our COVID-nineteen program. We are focused on developing an antiviral approach and are interrogating a number of different RNAi triggers targeting different positions within the current virus and potentially other coronavirus as well. While we are excited about the various vaccines, mutations in the current virus and preparation for the next coronavirus suggest to us that our work continues to be important.
In addition, we are now starting to see promising early results on pulmonary formulation work that may open up some important new possibilities. Specifically, we've been evaluating the possibility of using an inhaler device as opposed to a nebulized formulation for some indications. That would improve convenience and could make for a more viable commercial product for higher prevalence diseases for large patient populations. Our plan for ARO Lung2, which is in development to treat COPD, was to begin the clinical program with a nebulized formulation and then to work out the necessary, technology to switch, over to an inhaler. We have decided to hold off on the CTA for now since we are increasingly encouraged by our new possibilities.
We don't think this slows, the program's time to market and in the end may actually shave some time off overall development if the inhaler formulation work enables a more direct path. The ultimate goal is to take forward a therapeutic with optimal efficacy, safety and convenience in a form that is useful to physicians and their patients. We will provide an update over the next quarter, pending completion of a few ongoing studies. Let's now shift to our later stage programs and discuss our progress toward commercialization. Last quarter, we presented positive data from our ARO AAT, ARO APOC3 and ARO ANG3 programs.
We are very encouraged by the results and believe they support rapid advancement of these programs. Specifically, we presented Phase II data at AASLD on ARO AAT showing strong reductions in the production of the mutant protein and improvements in multiple biomarkers of alpha-one liver disease. This was exciting for us, for the alpha-one field and for our partner Takeda. These data work from biopsies after only six months of treatment. We also expect to have twelve month biopsy data over the next month or two.
We plan on discussing those data with the FDA and proposing some changes to the study design and endpoints with a goal of shortening the time to a potential NDA. For ARO APOC3 and ARO ANG3, we presented new data on Phase onetwo studies at multiple medical meetings, including the European Society of Cardiology and the American Heart Association meetings and subsequently hosted KOL webinars to discuss the data and our plans for their future development. These plans have continued to progress, and we are now preparing to begin the next stages of development. In fact, we have already filed an IND for ARO ANG3 and intend to proceed with a Phase IIb study pending FDA review. ARO AAT, ARO APOC3, and ARO ANG3 are all getting to points where the regulatory and development path and potential timelines become clearer.
This, I believe, is a key event. For all three programs, the data generated to date have suggested that the drugs are doing what they are designed to do. There's also a clear need in each disease for new therapeutics. With increased regulatory clarity, we may soon have a direct line of sight for the timelines required to have multiple potential commercial products as long as the data continue to support advancement and we continue to execute efficiently. We have a high level of confidence about both.
In the first half of the year, we expect the following: one, pending FDA review, we intend to begin a Phase 2b dose finding clinical study of ARO ANG3. Two, file an IND for ARO APOC3 and then later following FDA review, begin two Phase 2b studies and potentially a Phase three study in patients with familial chylomicronemia syndrome. Three, engage with FDA on design, endpoints, size and duration of treatment for a potentially streamlined ARO AAT study. And four, potentially report on twelve month biopsy results from the 2,002 open label study of ARO AAT. By the middle of the year, we plan to be on track to share preliminary data for ARO HSD in healthy volunteers and in patients with NASH and suspected NASH.
We expect to be the first company to have clinical data using any modality against the target HSD17 beta-thirteen. The genetic validation is strong for inhibiting the target, and there's clearly substantial unmet need in NASH. So we are eager to see these data and evaluate the next steps for this program. Silencing HSD is thought to confer a possible protective effect against liver disease. But given the biology of this target, we would not expect a decrease in liver fat.
Therefore, what we are looking for is simply depth and duration of knockdown. We expect ARO HSD to be a potent drug candidate as has been the case for our other hepatocyte targeted drug candidates. In the second half of the year, expect the following: one, collect and potentially report on eighteen month biopsies from the 2002 open label study of ARO AAT two, potentially begin Phase IIb studies for ARO ENaC, ARO HIF2 and ARO HSD and three, begin a number of smaller Phase IIb studies for ARO ANG3 and ARO APOC3 that will run-in parallel with the studies I've already described. There are a number of questions that we would like to answer in both programs that we could address in short and open label studies. So we expect regular data readouts for these programs while the longer blinded studies are ongoing.
With that overview, I'd now like to turn the call over to Doctor. James Hamilton. James?
Speaker 3
Thank you, Chris, and good afternoon, everyone. Since we plan to have preliminary data this year for ARO ENaC, ARO HIF2 and ARO HSD, I would like to go through the general designs for those clinical studies and provide an update on their status. First, I will discuss ARO ENaC, our inhaled RNAi therapeutic candidate designed to target the epithelial sodium channel to treat cystic fibrosis, or CF. CF is a rare disease caused by a genetic mutation that leads to mucus buildup in the lungs. It is characterized by airway dehydration and reduced mucociliary transport.
Patients with CF can have difficulty breathing and experience frequent and persistent lung infections. ARO ENaC is in a Phase III dose escalating study to evaluate the safety, tolerability, and pharmacokinetic effects of ARO ENaC in up to 24 normal healthy volunteers and to evaluate the safety, tolerability, and efficacy in up to 24 patients with CF. The patient portion of the study includes three cohorts, two with six patients each and one with 12 patients. This was the initially planned design. We intend to make protocol changes shortly that will add an additional 12 healthy volunteers who will undergo bronchoscopy with bronchial brushings and bronchio alveolar lavage, or BAL, to evaluate ENaC knockdown in the lung.
We are also considering expanding the CF patient cohorts as well. We've completed dosing in all initially planned single dose healthy volunteer cohorts, and we have been pleased with the safety and tolerability results to date. We believe this is an important finding for ARO ENaC and for the pulmonary TRiM platform as we begin to expand our pipeline into additional diseases in the lung. This is particularly relevant to drugs inhibiting ENaC as many of the small molecule ENaC inhibitors have been dose limited by toxicity. We are now dosing CF patients in the first cohort, which we expect to be fully enrolled before the end of next month, at which time we plan to begin enrolling the second patient cohort.
So what data do we expect from this study? First and most importantly, we are assessing safety and tolerability in all cohorts. In the expanded healthy volunteer cohort, as I mentioned, we will be conducting bronchial brushings and BAL. This method may give us a signal on target engagement and a better understanding of pharmacologic activity. Remember that ENaC is not secreted, so we are not able to measure target engagement in the blood as we are typically able to do for our liver targeted programs.
In addition, in CF patients, we will be measuring changes in FEV1 and in Lung Clearance Index, or LCI. These would be indications of functional improvements in mucociliary clearance and lung function. There is clearly a lot of data coming out of this first in human study, so we are eager to see the ARO ENaC results. The next program I'd like to highlight is ARO HIF2. ARO HIF2 is designed to treat clear cell renal cell carcinoma, or RCC, and we are currently dosing RCC patients in a Phase Ib dose finding clinical study in three cohorts of at least six patients each for a total of 18 patients with advanced clear cell RCC.
The study is designed to evaluate the safety of ARO HIF2 and to determine the recommended Phase II dose. We are also assessing pharmacokinetics and preliminary efficacy based on RECIST as well as post dose tumoral expression of HIF2 alpha and HIF associated genes. We are dosing the second cohort at this time, which we expect to be fully enrolled this month. The patients in this study are heavily pretreated and have failed multiple lines of therapies, so a positive result for this first in human study would include data suggesting delivery to tumors as well as measurable levels of HIF-two knockdown. Similar to ARO ENaC, we are also looking to characterize safety and tolerability and to select a dose for further studies in Phase II.
The last program I'd like to describe is ARO HSD, our investigational candidate for the potential treatment of alcohol and non alcohol related liver disease. There is strong genetic data supporting HSD17B13 as a target for NASH and alcoholic liver disease. We are conducting a Phase III 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. We have completed the single dose portion of the study in healthy volunteers. We are currently enrolling and dosing the multiple dose patient portion of the study in NASH or suspected NASH patients.
We have completed the first patient cohort and expect to complete enrollment of the second patient cohort this month. After that is complete, there are two more patient cohorts to enroll sequentially. This target is also not secreted. So in order to assess target engagement, we utilize liver biopsies. It's important to mention that this study only involves two doses, which relative to other later stage NASH studies is only a short duration of exposure.
So we don't expect to see substantial signs of disease improvement, but rather we are focused on selecting the dose level and regimen achieving optimal gene target silencing. However, we know the platform is highly effective at silencing hepatocyte expressed genes, so we would expect a high level of target engagement. In addition, we are the first to study inhibition of this target in humans, so we will see if there are any early encouraging signs of efficacy, even though this would be unexpected. As mentioned earlier, we expect all three of these programs to have preliminary data readouts around the middle of the year. It's too early to know in which order they will come, but we expect this to be an exciting period with all these potential data reports coalescing roughly around the same time.
Our intention would be to report top line data highlights in a press release and then further present a fuller dataset at an appropriate medical meeting. I will now turn the call over to Ken Myszkowski, Arrowhead's Chief Financial Officer. Ken?
Speaker 4
Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended 12/31/2020 was $20,700,000 or $0.20 per share based on 102,800,000.0 fully diluted weighted average shares outstanding. This compares with a net loss of $2,700,000 or $03 per share based on 97,100,000.0 fully diluted weighted average shares outstanding for the quarter ended December 3139. Revenue for the quarter ended 12/31/2020 was $21,300,000 compared to $29,500,000 for the quarter ended December 3139. Revenue in both periods relates to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen.
And revenue in the current period also includes the recognition of a portion of the 300,000,000 upfront payment due upon the signing of the collaboration agreement with Takeda. This payment was received in January. Revenue
Speaker 5
for the
Speaker 4
Janssen and Takeda agreements will be recognized as we continue to work toward completing our performance obligations of managing clinical trials, the clinical trials in process and certain manufacturing related services. We anticipate the remaining deferred revenue of 6,700,000.0 associated with the Janssen collaboration will be recognized in the next fiscal quarter. The remaining $292,000,000 of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately two years. Any additional milestones achieved with our collaboration partners would be additive projection. Total operating expenses for the quarter ended 12/31/2020 were $45,400,000 compared to $34,300,000 for the quarter ended December 3139.
This increase is primarily due to increased personnel cost and non cash stock compensation in R and D as our headcount continues to grow. The increase is also due to increased candidate specific and discovery R and D costs. Costs. Net cash used in operating activities during the quarter ended 12/31/2020 was $38,900,000 compared with net cash used in operating activities of $23,500,000 during the quarter ended December 3139. The key driver of this change was the increased R and D cost discussed.
We continue to estimate our full year cash burn to be between $200,000,000 and $250,000,000 Turning to our balance sheet, our cash and investments totaled $416,200,000 at 12/31/2020 compared with $453,000,000 at 09/30/2020. The decrease in our cash and investments is primarily due to cash used for operating activities. With the collection of the $300,000,000 upfront payment in January 2021, our cash our current cash and investments total approximately $700,000,000 Our common shares outstanding at 12/31/2020 were $103,200,000 With that brief overview, I will now turn the call back to Chris.
Speaker 2
Thanks, Ken. We have a lot in front of us this year. We expect waves of clinical data readouts throughout the year from ARO HSD, ARO ENaC, ARO HIF2, ARO APOC3, ARO ANG3 and ARO AAT. We expect to gain clarity potentially streamlining and accelerating the ARO AAT development program. We expect to initiate multiple Phase IIb studies for ARO HSD, ARO APOC3 and ARO ANG3 and possibly for ARO ENaC and ARO HIF2.
We also expect to initiate a Phase III study for ARO APOC3 and FCS patients. We expect to file at least three new CTAs this year, including our first for a candidate targeting skeletal muscle. And by the end of the year, I expect Arrowhead to have at least 11 clinical programs targeting four different cell types, and eight of those clinical programs could be wholly owned. This is indeed We feel great about where Arrowhead is today, and we're confident about what we can accomplish going forward. It seems like all the pieces are in place for scalable and sustainable growth.
We have a strong balance sheet and are disciplined in our use of cash, which allows us to move forward rapidly in a capital efficient manner. We also are eligible for substantial non dilutive capital in the form of milestone payments from Amgen, Janssen and Takeda as our partner programs continue to advance. And ultimately, if any of the products are commercialized, we will be eligible for royalties on sales. We have an increasingly validated technology platform in TRiM, and we believe TRiM is on the verge of potentially showing that RNAi can be a powerful therapeutic mechanism for diseases throughout the body. We have a large and rapidly growing pipeline of differentiated product candidates addressing diseases without adequate treatment options.
These are all innovative first in class molecules, not fast follower, incremental or Me Too products. And lastly, we have the right team in place and an unwavering culture of challenging the norms of drug development. Arrowhead always finds a way to be better, faster and more efficient than others in the field. This is and it gives us the opportunity to make a difference in the way numerous diseases are treated. Thanks again for joining us today.
I would now like to open the call to your questions. Operator?
Speaker 0
Our first question comes from the line of Salveen Richter from Goldman Sachs. Your question please.
Speaker 6
Good afternoon. Thanks for taking my questions. So just one on the ENaC program. Could you help us understand kind of the threshold knockdown that you want to see here and what you saw preclinically that could translate? And then on the HIF-two program, what gives you confidence or optimism with regard to the translation in man?
You.
Speaker 2
Salveen, thanks very much. So let me start with ENaC. That's a tricky question. There's good experimental evidence, there's good genetic evidence, on the possibility of knocking down ENaC and helping that mucociliary clearance in these types of patients. But the fact of the matter is no one's been able to create a therapeutic that can do that safely.
And so we are true pioneers here. So it's hard to say what sort of knockdown could be helpful. The best idea we've got, I suppose, is if you look at the genetic analysis, heterozygotes, essentially heterozygote knockouts in humans, do see a clinical benefit, we think. And so it feels like if we can reach 50% or so knockdown, we could see something helpful. There's an awful lot of green between where we are and the pocket, as they say, in billiards.
And so we still have a lot to learn. But that sort of feels like the bogey to us right now, is 50% knockdown could be helpful. With respect to HIF2alpha, that's also a hard one. We have done as much as we have could as we've been able to do in animal models. But as you know, translation is always a trick with oncology.
And so we're just waiting to see. We're looking forward to seeing the data over the next couple of months, and we'll see where we are. The animal data have been good. We feel confident that we'll see knockdown. We don't have a good idea about how much knockdown you really need to see to see a clinical benefit.
But similar here, I think we would call a win 50% or so knockdown. That's a bit arbitrary, but that feels reasonable to us. And so we'll see how we stack up against that over the next few months.
Speaker 0
Our next question comes from the line of Maury Raycroft from Jefferies. Your question please.
Speaker 7
Hi, everyone. Thanks for taking my questions. So I just wanted to do a quick check on timing for the three Phase one readouts. It sounds like you can't predict the order of the readouts, but Chris, I think you mentioned by end of 2Q in your prepared remarks. So just checking if the guidance is for end of 2Q or is it softer and a possible update could come in 3Q?
Speaker 2
No. We're shooting for the end of the second quarter. These are ongoing studies, and so nothing is going to be finished by then. And so we'll see what we have in hand, and we'll see if we can make an interpretable we'll see if we have an interpretable data. That's going to really be the kicker for us.
I think that we can hit that by the end of the second quarter. That's our goal.
Speaker 7
Got it. Okay. So you'll report the data by the end of the second quarter then? That's the goal.
Speaker 2
Yes. Just again, it's going to be a subset of data. It will be just top line. As James mentioned in the prepared remarks, our goal here is to show a fuller data set at appropriate medical meetings. So it will our goal here is to give you a taste to show you whether or not it appears the drugs are working.
And then we'll disclose more going forward.
Speaker 7
Got it. Okay. And then for the ENaC data, can you clarify how many subjects you plan on reporting there? And with the additional 12 subjects that you're planning on enrolling, do you have an idea of what the doses and dose range will be?
Speaker 2
So let me let's see if we can unpack that. I don't I can't tell you how many patients we're going to be reporting on because I just don't know. As I said, I think we'll be talking about this sort of midstream, but my hope is that we'll have some data from the first and maybe the second dose cohort in the patient population. With respect to the healthy volunteers and the bronchial brushing and lavage, James, you want
Speaker 3
to address what those doses are? Yeah, sure. So that dose is actually up to us to select, based on what we see in the previous cohorts, in the healthy volunteer cohorts. It's likely that since the safety profile has been favorable, we'll go with the highest dose cohort to give us the best chance of showing knockdown either in bronchial brushings or BAL.
Speaker 7
Okay. Okay. Fair enough. And last quick question just for the HIF2 patients. Can you say how many biopsies you have already and maybe give a sense of what baseline HIF2 expression levels look like?
Speaker 2
So we haven't seen the data yet. These are going to be batched, and so we haven't seen any data yet. Although, James, you want to talk about how many biopsies we've had so far?
Speaker 3
Yes, sure. So we've completed pre and post dose biopsies in in all six of the cohort one patients and then pre dose in five of the cohort two patients. And now we won't know about viability of those until we start staining the slides. So how many of those will be able to analyze? We don't know that yet.
But that's how many biopsies have been completed.
Speaker 8
Got it.
Speaker 7
Okay. Thank you very much for taking my questions.
Speaker 2
You're welcome.
Speaker 0
Thank you. Our next question comes from the line of Sean Egan from Citi. Your question please.
Speaker 5
Hi guys. Thank you for the comprehensive update. Are you able to provide any more details on the safety update you provided today for E and J? Just how many patients? Is it just healthy volunteers?
Are there actually CF patients in there as well? And then I have one follow-up on the skeletal muscle program.
Speaker 2
Sorry, you broke up there a little bit. So you're asking how many patients have been treated so far with ENaC between healthy volunteers and patients? Is that was that a question?
Speaker 5
Just the safety update you gave today that everything looks good so far. How many patients does that include?
Speaker 3
Sure. That includes all the healthy volunteers and the first four patients in the study that's upholding through.
Speaker 2
And you wanna and you wanna go into how many how many healthy volunteers that is?
Speaker 3
Yeah. Sure. So that's a total of 24 healthy volunteers, six per cohort, and then we'll add that additional 12 for the the PAL studies.
Speaker 5
Great. Great. Thank you. And then for the skeletal muscle, it seems like it's an area of active area for RNAi and antisense oligo. Are the gating steps for that program is it compound optimization at this point, or is it more about being strategic for the indication that you're going after?
Speaker 2
We're for this first one, we're just on the conveyor belt now. Once you've got once you have nominations such, there's just sort of a time it takes to get through GLP talks and the like, and we're just in that right now. And so we feel comfortable that we've got a drug candidate. We just need to complete the IND enabling steps, and we are in that process right now. We feel comfortable we are on track to file that CTA sometime in the summer.
Speaker 0
Our next question comes from the line of Luca Izzi from RBC Capital.
Speaker 9
Terrific. Thanks so much for taking the question and congrats on the progress. Maybe one on A118. I think you mentioned optionality to streamline the SEQUOIA trial and the upcoming FDA meeting. Can you just give us a sense of what's on the agenda for that meeting?
And what are some of the key goals that you're hoping to achieve during that meeting? So that's one. And then the second on HIF-two alpha, maybe bigger picture. Can you explain a little bit more on what's the bony for success here? I understand that this is a trial primarily dose escalation and you're looking at PKs.
But what are some of the key biomarkers that you're really focused on to know whether this is a molecule that is worth further pursuing? Thank you.
Speaker 2
Sure. So first with AAT, I can't go into that too much because we really haven't started discussions with the FDA yet. We are we're still collecting some data. We want to collect the 12 paired biopsy data and then go to the FDA and have an open discussion about how we may be able to change endpoints. Certainly, we will want to change the length of the study because what we think we've learned is that we see a pretty substantial effect much earlier than we expected.
As you may recall, we were first planning on treating patients for at least two years. That does not appear to be required at this point. And so we'll shorten the study. But then we also want to see if we can agree on some maybe more appropriate endpoints. So let us have those discussions, and then we'll get back to you on what the FDA has advised.
With regard to HIF-two alpha, I tell you, since this is our first solid tumor targeting program, we're really just focused our primary focus here is just two things: safety and tolerability, of course. And so far, that's been acceptable. And second, knockdown. And as I mentioned there, we just haven't seen data yet. Those biopsies are going to be batched, and we'll have an idea over the next several months what kind knockdown we'll get.
But we're really focused on knockdown, not only for the drug, for ARO HIF2, but also for the franchise. If we see that we are getting consistent and good knockdown and what does good mean? It's hard to say, but it sort of feels like if we are in the 50 or so percent knockdown range, we feel pretty good about that. If we can hit that, then we think we've got a drug, and we think we've got a franchise. HIF-two alpha, as you know, is a well validated target.
There have been other, there's another drug right now in development that looks quite good. And so we think that as long as we can show reasonable knockdown, there's a place for us, with this drug. And then again, we see a lot of upside, if we can knock down H2 alpha in solid tumors, we can knock down, we think, a whole host of other cancer targets. And so fill in the blank. There's a number of targets that we're going to want to go after, maybe ourselves, maybe in partnership with others, against various tumors.
So we're in a really interesting, really exciting spot right now where we're just waiting for data. And if those data look positive, then I think we're off to the races.
Speaker 9
Very helpful. Thank you.
Speaker 2
You're welcome.
Speaker 0
Thank you. Our next question comes from the line of Esther Ragopinno from UBS. Your question please.
Speaker 10
Hey, thanks Chris and team. I have a couple on APOC3 and then, one on AAT. So in the past you've talked about initiating a Phase III registrational trial in FCS and your comments today seem to suggest that that's a potential. Am I reading too much into it or are you still sort of going strong with the FCS? And then with regards to the Phase II trials, the two Phase II trials that you're going to start in patients with I believe what you said in the past with severe hypertriglyceridemia and those with levels greater than 150.
But I noticed that the trial in the severe Phase II patients, you're excluding patients who have recent pancreatitis. So why is that? Two questions in there.
Speaker 2
Sure. So with respect to FCS, yes, you are reading too much into that. We are going full speed ahead on a pivotal study for in those patients. The our timing of this is we plan to file an IND for APOC3 first and then follow that up with plans for that pivotal study. But it is still our intention to move forward as quickly as we can on that population.
We think it's a strong unmet medical need. We think that ARO APOC3 is going to be a really important drug for those patients. And so we are full speed ahead there. With respect to APOC3, I'll just say a couple of things, and I'll hand it over to James. So so the two Phase IIb studies, you know, as you know, are gonna be in patients, with severe hypertriglyceridemia.
So those patients above five hundred, you know, we view that as as as kind of our fat market. Right? We think it's a grossly underserved market. And the regulatory pathway there, we think, is reasonably clear, and we think it's a pretty large population. So it's one that we're really focused on.
Now we also want to look at, in a Phase IIb study, those patients, who have elevated triglycerides, so say between one hundred fifty and four ninety nine. We think that that is also an unmet medical need. That we think would require a more comprehensive Phase III study, probably an outcome study. I don't know that we're going to do that, but we want to retain the optionality. And so we want to do that Phase IIb study right now just in case, in the future, we're going to want to expand into that patient population.
So with that, anyway, I'll hand it over
Speaker 0
to James.
Speaker 3
Sure. The question was about excluding patients with pancreatitis in the APOC3. Is that right?
Speaker 10
Yeah. That's right.
Speaker 3
So we actually don't exclude patients with pancreatitis in either of those Phase IIb studies and either the severe hypertriglyceridemia or the kind of middle of the road greater than 150, high triglycerides study. We do have an exclusion for, any patients with active pancreatitis within the last twelve weeks. So we just don't want anyone in the study who has, recently had pancreatitis and may still be suffering from associated sequelae. So we actually have some, endpoints in the severe hypertriglyceridemic study looking at rates of pancreatitis and things like that. So we don't exclude those patients.
Speaker 10
Got it. So it's only if they've had it within the last twelve weeks or so that you're not going to include them?
Speaker 3
Right. Prior to their first dose. So we just don't excluding patients who have very recently had pancreatitis.
Speaker 10
Got it. Okay. And then on AAT, you have a few readouts in 2021. And, can you frame for us some of the scenarios for that twelve month readout and what the read through could be for the Phase III trial? It sounds like in your response to a prior question, you seem to have more confidence Chris that you may not need that two point reduction in fibrosis score for registration.
So how are you thinking about it? I mean are you going for that polymer reduction rate and maybe tying that to other studies that have shown a link between polymer reduction and fibrosis?
Speaker 2
Yes. Again, don't want to speak too much on this because I don't want to get out ahead of our discussions with the FDA. In a nutshell, yes, I think that it's clear that the accumulation of the Z protein is what causes alpha-one liver disease. I think it's clear as day. And so we think that we can make an argument that, that could be an approval endpoint or at least part of a composite endpoint that we might that we shouldn't have to show a reduction in fibrosis.
I mean, you don't if that's not an approval endpoint for NASH, we don't think that should be an approval endpoint for this kind of rare disease. So it will be and frankly, the Sequoia study wasn't looking wasn't dependent upon resolution of fibrosis either. It was improvement in a histologic grading scale without worsening of fibrosis. Our hope is that we can move that a bit as well because, again, we think that the biology is increasingly clear, on these folks and that simply reducing Z burden could be a good marker.
Speaker 11
Okay. Thank you.
Speaker 5
You're welcome.
Speaker 0
Thank you. Our next question comes from the line of Ted Tenthoff Your question please.
Speaker 12
Great. Thanks guys. Thanks for the update. Kind of changing tact a little bit. I mean, much going on here.
You guys have had a lot of success with partnering assets for hepatitis b and, obviously, AAT. As we kinda look forward, what are what are what is Arrowhead gonna be when you grow up? Like, are you gonna be a targeted cardiovascular company? You know, with so much going on in oncology with respect to combos, is that something that might be a partnerable asset, Liver disease similarly? Give us kind of a broader sense for how you're looking at these different assets and what you think is going to be core in the future.
Thanks.
Speaker 2
Yeah. Thanks, Ted. That's a great question. And it's and it's a dynamic question because Yep. You know, what we are capable of focusing on, will, of course, change as we grow and such.
Here's what we see broadly. As you know, Ted, you've followed us for quite some time. Even when we were a $40,000,000 company, we never saw ourselves in the future as a company that focused only on a specific therapeutic area. We just thought this technology was too powerful, and we thought there was too much value to create to focus that narrowly. And so we've done an awful lot of work over the last decade.
And again, we've seen most of that, looking to push this technology into other cell types. And we're now just on the cusp of that. So then it gets to the question, okay, with this embarrassment of riches that we've talked about a lot, what do we keep in house, and what do we look to partners on? As we said in the past, at least for right now, cardiovascular and pulmonary make a lot of sense to us. We like the synergy of those two areas.
We've got an awful lot to offer those types of physicians. Those will not be the last areas we're going to focus on. That, I can virtually guarantee you. As we build up other franchises, I am quite certain that we will build out sales infrastructure and marketing infrastructure, in other areas as well. Will that be oncology?
It could be. In the near term, though, look, oncology is hard. My hope is that we see some good positive data in ARO HIF2 that would enable us to bring in a good partner to start to really blow out that franchise. It doesn't mean that we won't have our own wholly owned offerings, but at some point, it would be we'd be certainly open you know, to working with, you know, with a with a a broad based oncology company with deep expertise to help us, you know, prioritize targets and such. We're not there yet.
You know? We wanna generate some data first. But at some point, that that probably makes some sense for us.
Speaker 12
Yes. Perfect. Makes a lot of sense.
Speaker 0
Yes. Thanks, Ted. Thank you. Our next question comes from the line of Alethia Young from Cantor. Your question please.
Speaker 11
Hi guys, this is Lee on for Alethia. Thanks for taking our call. So just wondering if the HIF-two program looks successful, what other targets might be of interest to you in oncology? And then how are you thinking about other companies with similar NASH targets? Thank you.
Speaker 2
Sorry. So the question was other oncology targets then how do we fit with okay. And then the other one was how do we fit with other NASH strategies. Is that where we're going?
Speaker 10
Yes.
Speaker 2
Okay. Yes. I don't have much to tell you on the oncology targets. We are working with some other targets. We haven't disclosed any we haven't disclosed anything there.
But we are we do have some internal programs. As I mentioned just a second ago, we would like to bring in a partner at some point. I don't know when the right time is. I don't know if it's this year or next year or some other time. But to the extent that we have positive data, we would like to do this to do at least part of oncology with a partner.
And so I don't have much to offer on other targets we're thinking about right now. With respect to NASH, boy, NASH is hard. We like the genetic data for HSD. It is compelling that if you can knock down HSD, it does seem to have a bit of a protective effect against NASH. Doesn't mean that that should be a silver bullet.
In fact, I would expect that NASH is going to be more like HBV in that it's going to be a combination approach. I have no idea what the right combination is. And frankly, it's probably a different combination for different patient I think we're learning that it's probably a number of different diseases. We think that HSD could be a really nice backbone and could help a variety of these patient populations. Then you can layer on top of ARO HSD some other compounds.
It's too early for us to tell right now because again, we haven't even seen any data yet. But that's sort of how we see it. We've also said in the past that we like the idea of HSD for alcoholic hepatitis as well. The genetic, data there were at least as exciting as they were for NASH. And so while we're not doing anything right now in those patient populations, I could foresee us getting into that at some point in the future.
So sorry, that's sort of a non answer answer. But that's how we're thinking about NASH right now.
Speaker 0
You. Our next question comes from the line of Patrick Trucchio from H. C. Wainwright. Your question please.
Speaker 12
Thanks. Good afternoon. I have a follow-up on the cardiometabolic programs. So I'm wondering what questions you're looking to answer in the smaller open label studies with ARO APOC3 and ARO ANG3? Secondly, how many studies would you anticipate and how many patients would you anticipate enrolling in these studies?
And when would the data from these studies be expected?
Speaker 2
Yes, thanks. I'm glad you picked that up. I think it's an important point. We've talked in the past about the two Phase 2b studies for APOC3 and the one Phase 2b study for ARO ANG3 and of course the Phase III in APOC3 for FCS patients. We've talked about those a lot.
We are now just starting to explore some other questions for these smaller studies. We haven't set on those yet. I assume that by our next conference call, we'll have set those and probably set those in motion a bit so I can talk about that more then. But at this point, we are exploring what those mean. There's going to be a handful of these things.
You know, our our goal here was was twofold. One is is to is to answer as many questions as we can during this time frame because, you know, these phase two b studies are gonna be blinded, and they're gonna be not long, but, say, a year of of exposure. And so there's gonna be a time, that we just we can't a time frame that we can't move into a pivotal study until those are finished. And so we might as well take advantage of that time to answer some other questions. We're looking to do that.
I think these are gonna be shorter studies. Many of them or some of them can be open label. And so it gives us a chance to report on some of these studies while the longer ones are still in process. And so it allows us to continue to talk about these and tell you about what we're seeing. But I really can't give you specifics yet because we're still sort of in the trenches on that.
I expect that we'll have those set over the next couple of months or so.
Speaker 12
Got it. And then just a few on the lung programs follow ups. First on ARO ENaC. What drove the decision for the protocol changes? Is that something FDA asked for?
Or what specifically is the driver of those changes? And then an CoV, a competing RNAi program, had been delayed because of the need to conduct more work in a hamster model. So I'm wondering how things are progressing for ARO CoV and if this program could begin human trials in 2021? And then secondly, to what extent are the new emerging variants impacting this program? Should we expect two or more RNAi triggers to avoid resistance?
And how do you view RNAi antiviral positioning as compared to the monoclonal antibodies, several of which, you know, have the EUA authorizations, emergency use authorizations in The US, but they appear to have some resistance issues with these new variants.
Speaker 2
Okay. There's a lot of questions there. So let's start with ENaC. The changes in the protocol were driven entirely by, our desire to see, you know, to look at knockdown healthy volunteers. It wasn't required by anybody.
It wasn't included in the first protocol because because, frankly, we we didn't have an assay yet. We weren't really sure we could we could measure it. Since then, we have developed this assay, we're ready to go. And so now we want to look at bronchial brushing and bronchial lavage, in order to see knockdown in healthy volunteers. That's going to be a really important measure for us because as I mentioned in the prepared remarks, this is a small study in patients.
And so it is likely that, it's going to be difficult to see, FEV1 changes in four patients in a given cohort just because it's too small. And so this gives us a better measure on how well this drug is working and how well it's delivering to pulmonary epithelial cells. So that was the rationale for changing the protocol and including those folks. Now with respect to COVID, COVID has we've not been able to move as fast as we wanted to on COVID, in large part, because the animal models are just we don't control the animal models, and it's been hard to get slots to do these animal studies. So, you know, we have not been as fast as we have been in in other areas where we can can do our own studies or we or we've got, you know, a larger variety of of CROs that we can work with.
So it's so it's laggative because of that. We're still excited about it, of course. The that you mentioned the new variants that people are talking about, that does not that has not affected our program, but it has just reinforced our our, our belief that there is a real role here for RNAi mediated antivirals, all right? It is certainly possible that at some point, this virus is going to mutate around the vaccines. And so our goal here was to make a broad based antiviral that not only could work against this current coronavirus, but also potentially future coronaviruses.
And so this is sort of playing out the way we thought it might play out. And again, it just underlines the need for our kind of therapeutic. As we've shown with HPV, we know we're pretty good at playing antivirals. And your point is a good one about multiple triggers. The way we view this is probably multiple triggers is going to be better than within a single trigger for the same reason that it was for HPV.
As you may remember, our HPV compound has two different triggers. One reason is to guard against mutation, but the other reason is to give you broader coverage across genotypes. That will be the case here as well for the wide variety of coronaviruses that are out there.
Speaker 12
It. That's helpful. Thank you very much.
Speaker 2
You're welcome.
Speaker 0
Thank you. Our next question comes from the line of Mike Menten from B. Riley Securities. Your question please.
Speaker 13
Hi, congrats on a productive 2020 and seems like even a busier 2021 ahead for you. Thanks for taking my question. So a quick follow-up on ENaC. Is there anything you've learned on the from a PD standpoint or anything from an alternative approach, and the sense that gives you confidence at this point on target engagement? Anything you can comment on that?
Speaker 2
Yes, that's a good question. It's hard for us to interpret the antisense data that we've seen. So there's been no bad news there for us, but there's been no good news either the way we look at it. And so no, unfortunately. You know, we'll have to wait to see what those data look like, and we're, of course, anxious to see what our data look like.
We're gonna know a heck of a lot more over the next couple of months. That's for sure.
Speaker 13
Okay. And then, just a quick follow-up on the, biopsy duration for the HSD program. And, anything, if at all, we learned from the surprise six month biopsy we got from the AAT program? Is there any read through to, again, I understand, you know, the it's it's different proteins we are talking about, different types of knockdown, complicated disease. Any any read through you guys think internally about, you know, as you think about the NASH program?
Speaker 2
I don't know that there's read through. You know, what we've learned, what we've learned in in all these programs is that is that is that is that you know, all these proteins are different. And so so, you know, the the and all the triggers are different. Depending upon the trigger and the protein, knockdown, depth and duration are going to be different. And so we are confident that we will see good deep and durable knockdown in ARO HSD because of our experience with HBV and AAT and APOC3 and ANG3 and Lp and others.
But I don't know that we learned anything in particular with AAT that we can apply to HSD. I think success here is pretty narrow. We're just really looking at depth and duration of knockdown. As we mentioned, we're not really looking for alleviation of disease in this very short study, we don't expect it. So we're just looking at we're trying to pick a dose.
And unfortunately, since we don't know of a circulating biomarker, the only way to choose a dose is to get in there and take a biopsy and and see how deep and durable the knockdown is. And then and then we'll take that into a larger phase 2b study that would that that may give us some idea about about disease progression. But but we don't expect to learn anything about that at this point.
Speaker 13
And and to clarify, six month duration biopsy, right, or or twelve months?
Speaker 3
Yeah. So we do two different post dose biopsy time points. One is at day seventy one post dose, and the other is at after the last dose, these patients get two doses, and the other is at day one hundred sixty nine. So we staggered them to get a better idea of duration.
Speaker 13
Okay. Great. And my final question on as you think about cash flows, and you obviously have some
Speaker 1
We might have lost you here. Very quiet, Mike.
Speaker 13
Can you hear me now? Can you hear me now?
Speaker 2
Yes. You're back.
Speaker 13
Yes. Go ahead. Yes. So final question was on cash flows. As you think about 2021 and think about the different partner milestones from J and J, Amgen and Takeda, how should we think about your burn rate?
Again, in context of some of the commercial stage programs might be getting pushed out a little bit, like APOC3 and AAT obviously being partnered out. How should we think about the expense for 2021?
Speaker 2
Well, so we reiterated today that we expect to burn between 200,000,000
Speaker 3
and $250,000,000
Speaker 2
in fiscal twenty twenty one. We've got plenty of cash to afford that, and that's and I do think that we have a chance of triggering some milestone payments during that time. We can't give you any guidance on any of that because, a, it's uncertain and b, even if it was certain, I can't tell you until we get it. But I think it's possible. But again, worst case is we don't trigger any of those this year.
That's okay. We have plenty of cash right now to absorb that kind of burn. And then next year, again, I feel quite comfortable that we can have access to additional milestone payments. And so look, I feel good about our balance sheet right now. I feel good about our access to additional capital, between all three partnerships.
Speaker 13
Excellent. Thanks for taking my question.
Speaker 2
You're welcome.
Speaker 0
Thank you. Our next question comes from the line of Keith Mankey from Chartered. Your question please.
Speaker 12
Yes, thanks. Chris with respect to HIF, if your working thesis right now is that 50% knockdown could have an effect on the disease, should that prove to be too low based on your current dose levels and dose intervals? Do you believe you could go higher than that to achieve a higher knockdown if needed?
Speaker 2
Yes, we'll see. It will be really helpful to see what the dose response looks like. If, in fact, we see 50% knockdown at the highest dose we're giving, at least what we've seen so far, we see no signs that we can't escalate more. This is not it's not a traditional cancer trial, right, where we dose as high as we can until we get people sick and then we knock the dose down. We don't respect dose limiting toxicities.
And so to your point, sure, it is certainly possible that we get 50% knockdowns, and we still think if there's more knockdown to be had, as long as we're not seeing DLTs, we're happy to escalate. And like I said, neither in HIF2alpha nor in ENaC so far have we seen evidence that we've got a safety issue.
Speaker 12
Great. Thank you.
Speaker 2
You're welcome.
Speaker 0
Thank you. Our next question comes from the line of Manny Faroohar from SVB Leerink. Your question please.
Speaker 8
Thanks for taking the question guys. I want to quickly follow-up on something I think it was Maury actually touched base on this. Around the ENaC readout you mentioned in your prepared comments it's reasonably possible to see an uninterpretable or unclear FEV benefit, while seeing a very substantial knockdown benefit in the healthy normal volunteers. Should you see that dataset, which is one that's a profile that we'll see in the early datasets from Vertex, Translate Bio, etcetera, many others, how do you interpret that as either I'd a, the target isn't effective, or b, you need to dose higher? Like how do you choose to move forward from a data set that doesn't necessarily give a relationship between knockdown and dose and efficacy?
Speaker 2
Yes. So look, there's a lot of it's hard to play that game until we see the data. But I guess the broad answer would be, look, if we saw good knockdown, but in those four patients, we can't discern FEV1 changes, I don't think that we're so worried at this point. We say to ourselves, this is good news. We've got a drug that is working the way we want it to.
We've got a franchise certainly that we can we think that we can go into other disease areas. And so now with CF, look, let's treat some more patients because four is not a very large number in a cohort. Let's see if we can start to see an FEV1 change if we get to 10 or so patients. That's one. Second is, look, this is it's a pretty short study as well.
And so we'd be happy to say to assume we're getting good knockdown. Maybe we just need a bit more in the way of dosing to start to see those manifest in FEV1 changes. So all is not lost if we cannot register an FEV1 change, but we see good knockdown. To the contrary, I think that suggests that we have something that's really powerful. And we've got plenty of time this year to treat some more patients, as well as treat them a bit longer, or at least monitor them longer to see if we can see some FEV1
Speaker 1
to go. And and also, there would be the the baseline characteristics of the patients. When you're talking about small n's like this, that that may make a difference. You know, it shouldn't it shouldn't matter theoretically, you know, what the genotype is or background therapy, but but, know, with this is a small n. So I think the the main point here is that we get knocked down, we get functional delivery, and we're safe.
And then that that's a win.
Speaker 2
Right. You know, that that that's what we wanna be able to focus on. You know, let's Let's look at FPV1, of course, because that ultimately is going to be important. But when we're looking at this drug over the next couple of quarters, what we're really focused on are those the knockdown data and, of course, the safety and tolerability of the drug. If both those are positive, we are off to the races.
And we'll continue to look at patients going forward.
Speaker 8
That's really helpful. And then hopping over to NASH, there have been a couple of other companies that also commented on the genetic data. Obviously, there's some evidence unclear if it's correlative or causative in terms of potential benefit in both alcoholic and nonalcoholic steatohepatitis. What kind of data sets would you need to see maybe in later stage studies from you guys to parse that out and say, okay, this is really positive and, you know, a knockdown of HSD is going to be reasonably expected to show benefit in a longer term pivotal trial? Are there biomarkers you're tracking?
Are there early clinical data sets that we might see as early as 2022, to sort of parse out that causation correlation issue?
Speaker 3
Yeah, sure. I'll take that one. I mean, yeah, the easy one for this target is ALT. And that's been correlative to the loss of function mutation that those individuals tend to have lower ALTs. So that's an easy biomarker for us to read out in early stage studies and beyond.
Beyond that, there's not a whole lot else from a biomarker standpoint in terms of imaging or other blood tests. I think then you're looking at Phase IIb biopsy studies to show proof of pharmacologic effect and benefit.
Speaker 8
Great. That's really helpful. Thank you. Thanks for taking my questions.
Speaker 3
You're welcome.
Speaker 0
Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Chris Anzalone for any further remarks.
Speaker 2
Thanks everyone for joining us today. It's been a pleasure to speak with you and we'll talk to you next quarter.
Speaker 0
Thank you, ladies and gentlemen, your participation in today's conference. This does conclude the program. You may now disconnect. Good day.
