Arrowhead Pharmaceuticals - Earnings Call - Q4 2019

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 Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

Speaker 1

Thanks, Carmen. Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal year ended September 3039. With us today from management are President and CEO, Doctor. Christopher Anzalone, who will provide an overview of the year Doctor.

Bruce Given, our Chief Operating Officer and Head of R and D, who will discuss our clinical programs and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. We will then open up the call to your questions. 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 activities.

These statements represent management's current expectations and are inherently uncertain. Thus, 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 ks and the company's 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. I want to quickly acknowledge a couple of new analysts that recently began covering Arrowhead that will be on our call for the first time.

They are Madhu Kumar from Baird and Alethia Young from Cantor Fitzgerald. Both have covered Arrowhead at prior firms and I'm happy to welcome them back. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company. Chris?

Speaker 2

Thanks, Vincent. Good afternoon, everyone, and thank you for joining us today. I wanna start by welcoming the newest members of the Arrowhead management team, Doctor. Javier San Martin, who joins us in the role of Chief Medical Officer, and Doctor. Kurt Bradshaw, who joins us as Chief Scientific Officer.

We are very fortunate to have these talented and seasoned leaders on the team. I also wanna say thank you to Doctor. Bruce Given, who will be retiring on 05/01/2020. He will continue in his current role over the next six months as he transitions responsibilities to Javier and Kurt. He has also agreed to remain in an advisory role to the company after May 1 as needed.

Bruce has been an important asset to Arrowhead for almost a decade and to the biopharma industry for over thirty years. We wish him all the best during his retirement. Now turning to our business and the progress we've made over the last year. We've demonstrated once again that we can consistently achieve best in class speed and execution. Arrowhead's TRiM platform is enormously flexible, and we have numerous and growing opportunities to develop innovative new medicines that address important medical conditions, and potentially make differences in a lot of people's lives.

This is an enviable place to be in for any biotech company. But technology and opportunity alone do not guarantee success. We think our unwavering commitment to innovation is what really sets us apart. There are now five TRiM enabled candidates in the clinic, three of which are wholly owned and two are partnered. Over the next month, we plan to submit regulatory filings for two additional clinical candidates.

And by the end of twenty twenty, we intend to have 10 TRiM enabled candidates in in clinical studies targeting four different cell types. Further, we expect to be in three pivotal studies by the end of twenty twenty. Let that all sink in for a moment. We believe this is a strikingly unique position for a company our size. We feel confident about our ability to achieve these aggressive targets, and we have good reason to believe in the ultimate success of these clinical programs, for a number of reasons.

First, we have an increasingly validated technology in the TRiM platform. Keep in mind that over two fifty people have been treated with over four fifty doses of TRiM enabled candidates. We continue to see very good activity, and a benign safety profile in all programs. Second, we focus on well validated targets. We tend to select gene targets where there is a widely accepted belief in the scientific community that if you can knock the target down, there will be clinical benefits without known negative phenotypes.

In other words, we leverage prior genetic studies to minimize our target and biology risk. With the expanding body of knowledge on genetics, and ever expanding published GWAS datasets, we believe new and interesting targets will continue to emerge. Third, the RNAi field is just beginning what we believe to be a golden age. This modality is increasingly accepted as a reliable and powerful way to treat a variety of diseases, after two decades of intensive study and development. While the potential and value of direct conjugation delivery in unlocking the potential of RNAi was clear to us by 2016, broader confidence took longer.

Interestingly, the increasing validation of RNAi is growing amid a backdrop of scarcity related to companies capable of leveraging it therapeutically, and near absolute scarcity of bringing RNAi outside the liver. We think we are probably years ahead of anyone else in this regard. Lastly, and as we discussed at our R and D Day last month, Arrowhead is constantly finding innovative ways to shave days, weeks, and even months off of the traditional development cycle. We effectively try to take all the wasted time out of the R and D process without ever sacrificing quality or cutting regulatory corners. And we think we have demonstrated a level of speed and efficiency that has not been seen before.

So at once, we are expanding the potential uses and upside of our technology, while squeezing more and more risk and development time out of the programs. This is a powerful idea indeed. During our R and D day last month, we went into some detail about several of our development programs. I'll now give a quick review of the day. At the event we discussed our two cardiometabolic candidates, one, APOC3, targeting apolipoprotein C3, being developed as a potential treatment for patients with severe hypertriglyceridemia and familial chylomicronemia syndrome, or FCS.

And two, ARO ANG3, targeting angiopoietin like protein three being developed for the treatment of dyslipidemias, such as homozygous familial hypercholesterolemia, or HoFH, and metabolic diseases. We believe that these are very powerful targets. There is strong genetic validation that loss of function mutations in ANGPTL3 or APOC3 result in improved cardiovascular outcomes relative to the population at large. Importantly, these loss of function mutations have not been associated with demonstrated adverse phenotypes, which means nobody has reported any symptoms or disease resulting from the loss of the protein. This has also been demonstrated in the clinic with other agents using other mechanisms, which gives us confidence that the targets likely have multiple points of validation.

In addition, we believe that compounds are using other mechanisms to reduce these proteins have vulnerabilities, positioning RNAi as an important potential new option for patients. Bruce will discuss some specific clinical data from our phase one studies that we recently presented at on ARO APOC3 and ARO ANG3. But I will say that we have been thrilled with the results thus far, and believe that they strongly support our plans to initiate phase three studies in 2020. We've seen deep reductions in triglycerides after single doses of ARO APOC3, and believe there are relatively clear regulatory pathways to treat patients with rare conditions, such as FCS, as well as those with more common conditions leading to elevated triglycerides and associated pancreatitis. ARO ANG3 has even greater optionality and opportunities.

We expect it to lower triglycerides and LDL cholesterol, and previous studies suggest that we could expect it to improve insulin sensitivity and decrease liver fat. Together, these are huge opportunities, and we believe ARO ANG3 has the potential to treat a large variety of patients. We also covered ARO AAT, our second generation subcutaneously administered RNAi therapeutic being developed as a treatment for liver disease associated with alpha one antitrypsin deficiency, which is a rare genetic disorder. ARO AAT is designed to reduce production of the mutant Z AAT protein by silencing the AAT gene in hepatocytes in order to potentially prevent accumulation of Z AAT in the liver, allow clearance of the accumulated protein, prevent repeated cycles of cellular damage, and possibly prevent or even reverse the progression of liver fibrosis. In preclinical studies in PIV mice, RNAi treatment restored normal hepatocyte ultra structure.

In our phase one clinical study, ARO AAT led to significant reductions in serum AAT levels down to the lower limits of quantitation, with a long duration of effect that supports quarterly or even less frequent dosing. We are currently conducting the SEQUOIA study, an adaptive design potentially pivotal phase twothree clinical study. And ARO AAT2002, which is an open label phase two clinical study to assess changes in a novel histological grading scale after six months, twelve months, eighteen months, and twenty four months of treatment. During the R and D day, we also discussed our three most advanced preclinical candidates. One, ARO HSD against the target HSD17 beta 13 being development sorry, being developed as a treatment for alcohol and non alcohol related liver diseases.

Published human genetic data indicate that a loss of function mutation in HSD17 beta thirteen provides strong protection against NASH cirrhosis and alcoholic hepatitis and cirrhosis, with approximately thirty to fifty percent risk reduction compared to non carriers. We expect to file a CTA for ARO HSD by the end of the year. Two, ARO HIF2 against the target HIF2 alpha being developed as a potential treatment for for clear cell renal cell carcinoma or RCC. This will be the first TRiM enabled candidate targeting a tissue outside the liver to enter clinical trials. We expect to file an IND for ARO HIF2 before the end of the year.

And three, ARO ENaC against the epithelial sodium channel or ENaC being developed to treat cystic fibrosis. In cystic fibrosis patients, increased ENaC, activity contributes to airway dehydration and and reduced mucociliary transport. Human Genetic studies have validated ENAC as a CF target. This will be our first inhaled candidate targeting, lung tissue using the TRiM system. IND enabling studies are ongoing support regulatory filings for first in human studies in 2020.

We also discussed broadly our product development strategy as we continue to expand our pipeline and detailed the guiding principles that make our R and D organization best in class for execution and speed. In addition, we detailed advances in the TRiM system. We presented our second generation muscle delivery platform that is highly active and amenable to subcutaneous administration. And we also discussed a new TRiM dimer structure that delivers multiple siRNA sequences together that can achieve high levels of knockdown of two different genes simultaneously. These important advances dramatically increase the number of potential diseases that we may be able to address over the coming years.

This gives us a distinct strategic and technical advantage over other RNAi companies. It can also drive a significant amount of value for us, and more importantly gives us the opportunity to potentially provide options for many patients without adequate treatments. The R and D Day had a very informative set of presentations, so I highly recommend that you listen to the replay on the website if you're looking to get detailed overview about Arrowhead. In addition to the R and D day, the period since the last conference call has been enormously productive. Included in our accomplishments were the following.

One, we began dosing patients in the SEQUOIA study of ARO AAT, our first potentially pivotal study. Two, our collaborator Janssen began dosing patients in the REEF one phase 2B triple combination study in four fifty patients with chronic hepatitis B infection. In connection with the start of the study, we earned a $25,000,000 milestone payment from Janssen. Three, we presented additional preclinical data on ARO ENaC at the North American Cystic Fibrosis Conference, showing that ARO ENaC can accelerate mucociliary clearance in normal sheep, and also preserve airway physiology in a sheep disease model of impaired mucociliary clearance. Four, with our collaborator Janssen, we presented additional data on expanded cohorts of patients receiving the doublet of JNJ-three thousand nine hundred eighty nine, formerly called ARO HBV, and a NUC.

And the first clinical data of triple HBV therapy, in this case the triplet of JNJ-three thousand nine hundred and eighty nine, the capsid assembly modulator JNJ-six thousand three and seventy nine, and a NUC. Five, we expanded our management team to include, Javier San Martin as CMO and Kurt Bradshaw as CSO, who I introduced at the outset of the call. And six, lastly and most recently, we presented new clinical data on ARO APOC3 and ARO ANG3 in back to back late breaker presentations, a very rare honor, at the American Heart Association Scientific Sessions. We've made a lot of progress this year and we have great confidence that 2020 can be even more productive as we continue to expand our pipeline and begin to gain proof of concept in multiple extrahepatic tissues. With that overview, I'd now like to turn the call over to Doctor.

Bruce Given.

Speaker 3

Bruce? Thank you, Chris. Good afternoon, everyone. I wanna talk about data recently presented in two late breaking oral presentations at the American Heart Association Scientific Sessions on our two wholly owned cardiometabolic candidates, ARO APOC3 and ARO ANG3. And then I'll give a status update on the clinical programs.

As Chris mentioned earlier, we were thrilled with the data for both ARO APOC3 and ARO ANG3. The data were very well received at the conference and have continued to generate a good amount of attention since then. I will start with ARO APOC3. ARO had subcutaneously administered RNAi therapeutic targeting Apolipoprotein C3 being developed as a potential treatment for patients with hypertriglyceridemia. The ARO APOC3 first in human study is called ARO APOC3-one thousand and one.

It is a phase one single and multiple dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO APOC3. The single dose portion of the study is in adult healthy volunteers. And the multiple dose portion includes patients with severe hypertriglyceridemia and familial chylomicronemia syndrome. The single dose portion of the study, was presented at Consistent with our other clinical programs for liver targeted TRiM enabled candidates, the safety and tolerability appeared unremarkable for a first in human study. Forty subjects were enrolled to receive a single dose, where twenty four received active drug and 16 placebo.

There were no serious or severe adverse events reported. One adverse event, or AE, of moderate transient ALT elevation was reported with a peak of two ten units per liter on day twenty two in a subject receiving ARO APOC3. This subject had elevated ALT at baseline and returned to baseline by day eighty five. There were eight local injection site reactions all rated mild. Moving on to activity.

We observed dose dependent reductions in serum APOC3 with mean maximum reductions ranging from 72 to 94%. Reductions were maintained through the end of study, which was sixteen weeks after dosing, with mean reductions of 70 to 91%. Reductions in triglycerides and VLDL cholesterol were also observed with mean maximum reduction in triglycerides ranging from 53 to 64% and reductions in VLDL C ranging from 53% to 68. Reductions were maintained through the end of the study, with week sixteen mean reductions of 41 to 55% for triglycerides and 42 to 53% for VLDL C. ARO APOC3 also led to changes in LDL and HDL cholesterol.

The mean maximum reduction from baseline in serum LDL C was 12% to 25% and the mean maximum increase from baseline in serum HDL C was 30 to 69%. Now let's turn to ARO ANG3. ARO had subcutaneously administered RNAi therapeutic targeting angiopoietin like protein three, or ANGPTL3, being developed as a potential treatment for patients with dyslipidemias and possible metabolic diseases. The ARO ANG3 first in human study is called ARO ANG one thousand and one. It is a phase one single and multiple dose study to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic effects of ARO ANG3.

The single dose portion of the study is in healthy volunteers, and the multiple dose portion includes patients with various, types of dyslipidemia, including patients with nonalcoholic fatty liver disease, better known as NASH, patients on a stable statin treatment regimen with persistently elevated LDL cholesterol. Patients with heterozygous or homozygous familial hypercholesterolemia, and patients with hypertriglyceridemia. Safety and tolerability for the single dose portion of ARO ANG1001 was as expected and also consistent with prior clinical safety readouts for TRiM hepatic targeted drugs. Forty subjects were enrolled with twenty four receiving active drug and 16 placebo. No drug related severe or serious AEs were observed.

Two AEs of mild transient elevations in ALT were observed. One in a subject receiving ARO ANG3 and one in a subject receiving placebo. The ALT elevation in one subject in ARO ANG3 was confounded by concomitant ingestion of an herbal supplement with a known liver toxic profile. There was also one mild local injection site reaction. ARO ANG3 was active across measures and had good durability.

Dose dependent reductions in serum ANGPTL3 were observed with mean maximum reductions ranging from 55 to 83%. Reductions were maintained through end of study with week sixteen mean reductions of 43 to 75%. Dose dependent reductions in triglycerides and VLDL C were also observed with mean maximum triglyceride reductions of 31 to 66% and VLDL C reductions of 33, I'm sorry, 30 to 65%. Reductions in triglyceride and VLDL C were maintained through end of study in the two hundred milligram and three hundred milligram cohorts, with week sixteen mean reductions of 47 to 53% for triglycerides and 49 to 51% for VLDL C. Changes in LDL and HDL cholesterol were also observed with mean maximum HDLC reduced by eight to 26% and LDL C reduced by nine to 30%.

Mean maximum reduction in LDL C with the two hundred milligram single dose was blunted by two subjects in this cohort with increased LDL post dose. The multiple dose healthy volunteer data two hundred milligram dose demonstrates similar reductions to one hundred and three hundred milligrams of 33 to 46% reduction in LDL C from baseline two weeks after a second dose, with the second dose given at week four. I should say when we say similar reductions, we mean for the two hundred milligram dose relative to the one hundred and three hundred milligram dose. Let me point out that both presentations can be accessed from the Arrowhead website and are worth taking a look at if you haven't seen them already. We feel very good about the data for both candidates and we are currently enrolling and dosing the various multiple dose cohorts.

The data from these multiple dose cohorts will inform our future development plans. We hope to have those data in the first half of twenty twenty and intend to pursue abstract submissions to present at appropriate medical meetings. I would now like to give an update on where we are with the other wholly owned candidates and that are in or approaching the clinic. I will start with ARO AAT. We started dosing the SEQUOIA adaptive design phase twothree study in August.

SEQUOIA is designed to enroll 120 patients who will receive at least nine doses, or approximately two years of treatment, with ARO AAT or placebo. By protocol, efficacy will be assessed by the proportion of ARO AAT treated patients relative to placebo, achieving a two point improvement in histological grading scale of alpha-one antitrypsin deficiency associated liver disease. And no worsening of liver fibrosis on end of study biopsy. We intend to open around 40 sites in The US, Canada, and Europe. There are currently seven sites open, and we are working diligently to bring more into the study as quickly as possible.

The second study we are running for ARO AAT is ARO AAT 2,002. It is a pilot open label, multiple dose, phase two study to assess changes in a novel histological activity scale in approximately 12 participants in two sequential cohorts. 2,002 is now open for enrollment, and will only be conducted in Europe. Patient screening has begun, and some patients are expected to receive their first dose before year end. Moving on to our two candidates that are closest to submissions asking to start clinical trials.

First, ARO HIF2 is our candidate being developed to treat clear cell renal cell carcinoma. We are in the process of preparing the IND filing, which we anticipate before the end of the year. Our plan is to launch a phase one dose ranging study in The US. This will be conducted in clear cell renal cell carcinoma patients that have been refractory to immuno oncology treatment with or without anti VEGF agents, or separately refractory to anti VEGF monotherapy. The primary objectives of this study will be safety as well as determination of a phase two dose.

Secondary objectives will include pharmacokinetics and then efficacy based on RECIST criteria using either CT or MRI imaging. A key exploratory objective for HIF2 will be gene target knockdown in the tumors using tumor biopsy. Lastly, I'll talk about our plans for ARO HSD. This is a somewhat new target in which genetic data indicates that loss of function mutations in the HSD17 beta-thirteen enzyme provide the strongest known genetic protection against NASH cirrhosis and alcoholic hepatitis in cirrhosis. One of the key challenges for the clinical program here is that there is no known serum biomarker for this target.

But the design of the first in human study is likely to resemble other Arrowhead phase onetwo studies. Our plan is to do a single dose study in normal volunteers and a multiple dose study in patients with either suspected or documented NASH. We think we will have to do liver biopsies in this first trial to assess not only the depth of knockdown, but also the duration of effect. The in life portion of the GLP toxicology studies is complete, and we are awaiting results in order to prepare the regulatory submissions. Our plan is to submit before the end of the year.

So we're pretty close in this one as well. With that brief overview of our clinical programs, I'd like to turn the call over to Ken Biszkowski, Arrowhead's Chief Financial Officer. Ken?

Speaker 4

Thank you, Bruce, good afternoon, everyone. As we reported today, our net income for fiscal twenty nineteen was $68,000,000 or $0.69 per share based on 98,600,000.0 weighted average shares outstanding. This compares with a net loss of $54,500,000 or $0.65 per share based on 83,600,000.0 weighted average diluted shares outstanding for fiscal twenty eighteen. Revenue for fiscal twenty nineteen was $168,800,000 compared to $16,100,000 for fiscal twenty eighteen. Revenue in the current period relates to the recognition of a portion of the upfront payments and milestones for our license and collaboration agreements with Janssen.

While revenue in the prior period related to the recognition of a portion of the upfront payments from our license and collaboration agreements with Amgen. Revenue from the Janssen agreement will be recognized based on our estimate of the proportion of effort expended toward fulfilling our performance obligations, primarily overseeing the completion of the current Phase onetwo HBV clinical trial. In fiscal twenty twenty, we anticipate recognizing approximately $80,000,000 of the upfront payments and milestones already received that are currently reflected as deferred revenue in our balance sheet. Any additional milestones achieved with Janssen or Amgen will be additive to this projection. Total operating expenses for the year ended September 3039 were $107,600,000 compared to $72,100,000 for the year ended September 3038.

This increase is primarily due to increased drug manufacturing, toxicology, and clinical trial costs as our pipeline of clinical candidates has increased. Net cash by operating activities in fiscal twenty nineteen was a $173,000,000 compared with net cash used in operating activities of 47,200,000.0 for fiscal twenty eighteen. The operating cash generated in fiscal twenty nineteen reflects the 175,000,000 upfront payment and $225,000,000 milestone payments received from Janssen, offset by cash used for operations. Turning to our balance sheet, our cash and investments of cash balances totaled 302,900,000.0 at 09/30/2019, compared to $76,500,000 at September 3038. The increase in our cash and investments balances was driven by the payment received from Janssen.

Next year, we anticipate a 25,000,000 to $30,000,000 quarterly burn. Our common shares outstanding at September 3039 were $95,500,000,000 With that brief overview, I will now turn the call back to Chris.

Speaker 2

Thanks Ken. These are exciting and important times at Arrowhead. We have always thought to follow science and drive the RNAi field forward with new innovation and technologies. We'll continue this with a series of firsts for the industry. I think that we'll see the first clinically relevant oncology RNAi drug candidate in ARO HIF2.

I think we'll have the first meaningful lung targeted RNAi drug candidate in ARO ENaC. I think we'll be the first to develop a muscle targeted RNAi drug candidate. And I think we'll be the first to develop an RNAi drug candidate that silences two genes simultaneously. Together these significantly expand the universe of diseases and conditions we expect to treat. The new cell types we are now able to target are key to our pipeline expansion model.

We hope, my hope, is that we will have early clinical validation for ARO ENaC by the end of twenty twenty. That could serve as a springboard for rapidly expanding our lung franchise, as we go after various gene targets for diseases such as COPD, asthma, and pulmonary fibrosis. We could develop some of these by ourselves, and some in collaboration with partners. Similarly, I expect that we could have early clinical validation for ARO HIF2 by the end of twenty twenty. And that could trigger a rapid push into new solid tumor types and new gene targets.

A bit further off, I expect to be filing to go into the clinic with our first muscle targeted program by the end of twenty twenty, with possible early clinical validation the following year. We could then look to rapidly expand our pipeline with new muscle targets. All of these are important in our push to continue Arrowhead's growth. In 2018, ARO AAT and ARO HBV were sources of significant value creation at Arrowhead. In 2019, ARO APOC3 and ARO ANG3 have combined with ARO AAT and ARO HBV to drive tremendous value growth for us.

So where do we go from here in 2020? We believe the next big value drivers will be highly distributed, and that is helpful from a risk mitigation standpoint, as well as from the standpoint of maximizing our growth potential. I expect that you will see a company with the following attributes. A broad and deep pipeline, the ability to target four different cell types, a pipeline expansion model that is rapid and scalable, and drug candidates with a good mix of early, mid, and late stage clinical programs. Most biopharma companies have historically sought to build value, sometimes substantial value, as we saw today with Novartis' $9,700,000,000 acquisition of The Medicines Company, by only developing one or a few drugs.

We have a different approach. We have spent our time building out the TRiM platform, with the hope that it could be the basis not for one or two drugs, but potentially for dozens of drugs across many disease areas. This is a truly exciting concept. We are now well down that road, and as I mentioned earlier in the call, we expect there to be 10 TRiM enabled drug candidates in the clinic by the end of next year, three of which we expect to be in pivotal studies. I also believe that it is reasonable to expect that those 10 clinical candidates could double to 20 just three years later.

We've always believed that this is where we have been headed, and it now seems that the rest of the world is just starting to appreciate this. Thanks again for joining us today. I would now like to open the call to your questions. Operator?

Speaker 0

Thank you. And our first question is from Ted Tenthoff with Piper Jaffray. Please go ahead.

Speaker 5

Great. Thank you so much for all the update and all the great progress. Really exciting to see and just exciting times for the whole RNAi field. I'm so pleased to see the stock doing so well. Just with respect to APOC3 and ANS-three with the data that you're presenting and the studies ongoing next year, and specifically with the interest expressed by Novartis for Inclisiran, are you guys getting increased partnering inbound interest?

And what are your views on these assets? Are these, drugs that you would intend to take further yourself or ultimately partner? Thanks so much.

Speaker 2

Hey Ted, thanks very much. So sure, think it's fair to say that if we needed to partner those programs today, we could probably do that. We don't think it's the right move for us at this point however. You know, we talked about this in the past that one of the really important aspects of the Janssen deal for HBV and the other three targets is that it gave us capital and access to additional capital, especially when combined with the Amgen partnership, to really think of our pipeline as portfolio that we can take towards commercialization. You know, I think that in order to make that leap from a good biotech company, you know, to a large pharma company, you know, it really takes the, it really takes several drugs that you take into commercialization.

Look, we're really excited about APOC3 and ANGPTL3. And so we have no interest right now partnering either of those. We'll take those aggressively into later stage clinical studies. And it could be at some point that it might make sense to partner one of those or both of those. But certainly in the near to mid term, we have no appetite for that.

Speaker 5

Great. I think that makes a lot of sense. And, looking forward to seeing you guys at our health care conference next week. Happy Thanksgiving.

Speaker 2

Thanks very much.

Speaker 0

Thank you. Our next question is from Matthew Kumar W. Baird. Please go ahead.

Speaker 6

Hey, guys. Thanks for taking our questions. So I'll start with hepatitis B. So we understand at the LiverMain there was a discussion about the potential to publish the follow-up from the ARK520, five twenty one patients in Phase Ib data for ARO HBV. Do you guys have any sense of timing for a potential publication of those results?

Speaker 3

Hi, Madhu. It's Bruce. I mean, we're writing that now. So we're far along actually in preparation of the manuscript. So submission, I would say, should come in the next few months.

That's not the same as sources, of course, as publication. And it's very hard to ever predict sort of what will happen in the review process and whether comments will be easy to address very quickly or sometimes it just takes time to address the comments. So it's a little hard to ever predict when publication will happen, we are actually writing it up. I do anticipate it being submitted fairly soon.

Speaker 6

Okay. And then on the LP program, the AMG eight ninety, when so in the k, you mentioned that you expect Amgen to start a Phase II trial in the first half of twenty twenty. Is there any expectation when we might get data from the Phase I trial of eight ninety?

Speaker 3

No. We really don't

Speaker 2

have any guidance on that. You have to ask Amgen about that.

Speaker 6

Okay. Fair. And then stepping back and thinking about when you mentioned both the R and D names this afternoon, the idea of dual target RNAi agents. Are there disease areas which you'd specifically like to explore, the idea of dual target RNAi drugs, things like cardiometabolic disease, hepatitis B, or some other states entirely?

Speaker 2

Yeah, look I can answer that broadly. Sure, this is something we think about and we've got some ideas on that. It's not something that we're prepared to talk about publicly at this point. But we think it's a really powerful tool to enable knocking down two genes simultaneously without making that combination product. So we think of it as an important tool for disease, but also a nice tool from a regulatory standpoint.

Speaker 6

Okay, great. Thanks for taking my questions and happy Thanksgiving all.

Speaker 2

Sure, you too.

Speaker 0

Thank you. And next question comes from Maury Raycroft with Jefferies. Please go ahead.

Speaker 7

Hi everyone. Congrats on the progress and congrats to you Bruce for your retirement. And thanks for taking my questions. So to start for APOC3 you're seeing a dose response but the response on triglycerides and VLDLCs is less clear. So providing those safety concerns, what criteria are you focused on for dose selection moving forward?

Speaker 3

Yeah, that's a good question. So you're right that there's more of a dose response for plasma concentration than for triglycerides. And I think all that's really saying is that you don't need a 90 plus percent knockdown to necessarily maximize the benefit at the level of triglyceride reductions, at least in normal volunteers. We'll see when we get into a patient population where they have specific genetic abnormalities, whether that still holds or whether there's more of a need for a higher dose there. We just don't know at this point.

But we'll see, we'll learn that I think from the multiple dose cohorts. The other thing is I would say that sometimes multiple dose gives you a little bit different picture than single dose does. So we're interested in seeing what happens with multiple dose. But that interpretation of at least the single dose normal volunteer data I would say is correct, if that answers your question.

Speaker 7

Definitely. Yeah, it's helpful. And it's interesting for the ANG3 program. So you showed some data where you dosed twice with ARO ANG3 at day zero and at week four. And the second dose does look better than the single dose.

So I'm wondering if you can comment qualitatively if that second dose has had a durable effect with the LDL remaining reduced and how you're thinking about dosing with that agent? I guess with this program, could you potentially use some sort of a loading dose strategy for a few months and then do a maintenance dose every three or six months?

Speaker 3

Yeah, I think that's exactly what we're thinking. Think the the single dose normal volunteer data already tells you that the worst case is probably every four month dosing. But we do believe that a loading dose makes a difference. We came to that conclusion based on what we saw with AAT. We anticipate we'll see the same thing with ARO AAT.

We anticipate we'll see the same thing here. So we're going to be very interested to see what happens with that approach. So just as we're dosing in Sequoia on day one, day twenty eight and then every three months thereafter, I think the likelihood for APOC3 and ANGPTL3 is the worst case is likely to be day one, day 28 and then every four months thereafter. That would be my current thinking. We'll see what the data tells us.

But it could very well be day one, day 28, and then every six months thereafter. That would not surprise me at all based on how the single dose data is looking. As for the first part of the question, that multi dose data that we showed at was pretty fresh data. So I don't have a lot more data beyond that to be honest with you. We, over the next month or two, we're gonna start getting a much better idea of sort of how that multiple dose data looks, both from a sort of depth and durability.

But certainly that six week data after the second two weeks after the second dose, six weeks overall, that was pretty intriguing data.

Speaker 7

Got it, yeah, that's helpful. And last question is just on the NAFLD Cohort five for Ang3. If you can provide any more background in those patients, how severe are they, and how many patients have you currently dosed?

Speaker 3

Well, can't tell you how many patients we currently dosed because we kind of don't give those blow by blows. And it's not that we were necessarily looking for severity. Required enough liver fat at baseline that we had dynamic range so we could certainly see whether we changed liver fat. But we weren't necessarily looking for severe quote unquote patients. It's enrolling, it's enrolling fine.

And we'll certainly have data in our hands in the first half I would expect. It is double blind. So until all the patients are enrolled and have reached a certain point, we won't be unblinded. But that said, it really is effective for this group of patients,

Speaker 2

which we hope it will

Speaker 3

be, we should see relatively different results you know, that sort of segregate the data, much like we saw for instance for AAT. So we should have a pretty good idea fairly soon. When exactly we'll be able to share that with the street is a little hard for me to say at the moment.

Speaker 7

Got it. That's helpful. Thanks everyone and happy Thanksgiving.

Speaker 2

Thank Thank you.

Speaker 0

And our next question is from Alethia Young with Cantor Fitzgerald. Please go ahead. Your line is open.

Speaker 8

Hi, this is Emma on for Alethia. So with the novel HSD target, do you have any thoughts from your preclinical work on any potential synergies with ANGPTL3 or any other NASH specific targets?

Speaker 3

Thoughts? Yes, but anything I'd say out loud, no.

Speaker 2

But I think you're thinking about that in the right way. You know, NASH is a tough disease and frankly it's probably several tough diseases. And I think internally we would not be surprised, if that's gonna be best treated, with a cocktail approach. We are excited about attacking that from several different approaches, with HSD and with ANGPTL3 and potentially with others.

Speaker 8

Got it, so we'll stay tuned for that. And then just on the platform can you discuss some of the recent progress that you've made in extrahepatic targeting and specifically innovations that have enabled muscle cell targeting?

Speaker 3

Well, yeah, let me just say what I've always said is that there's a reason that most everybody in the field that's been in RNAi for a while started with hepatocytes. It is the easiest cell type to target for sure. We're targeting a clearance receptor in a clearance organ that's designed to sweep the blood and that has a very high rapid recycling rate. It's just an optimal situation. Once you get outside of hepatocytes, I wouldn't say outside the liver, even just outside of hepatocytes Because even targeting other cell types in the liver like stellate cells for instance is much harder than targeting hepatocytes.

So once you get away from hepatocytes now everything is harder which means to be effective in targeting other cell types, now you have to play really, really perfect baseball. Modified. You've gotta have a great targeting ligand. Oftentimes you have to do something that helps prolong circulation time. And they all have to play well together.

Even things like linkers that don't matter really for hepatocytes very much at all become very important when you go outside of hepatocytes. So the reason other people really probably aren't very involved is because it's really, really hard. We're and not or. So we still do hepatocyte targets frequently and do them well. But we invested considerable effort over the last eight or nine years to stay after the non hepatocyte targets.

Cause we knew that in the long run that was gonna really pay off and that was gonna be very important for RNAi. So even when we were a much smaller company, we always maintained a pretty active and scientifically focused effort to make it outside the hepatocytes and now it's bearing fruit. So it bears fruit in muscle, bears fruit in the lung and bears fruit with tumors as well assuming all of our preclinical work translates into humans. Which we have decent reason to believe that it will, but we still have to show it.

Speaker 8

Great, thanks very much.

Speaker 2

You're welcome.

Speaker 0

Thank you. And our next question comes from Mayank Namtani with B. Riley FBR. Please go ahead.

Speaker 9

Thanks for taking my question and congrats to you on the progress. Just if I may ask one follow-up to Chris. Relative to your prior thoughts on PCSK9 relative to ANGPTL3, was there at when you saw your data versus obviously what we've seen from Medicines Company, Were there any, considerations that you thought as you think about the broader lipid indication for ANGPTL3 could you talk to?

Speaker 2

Look, we're excited about ANGPTL3. As we've talked about on a number of occasions, it's this fascinating pathway that we think will allow us to lower LDL, to lower triglycerides, to increase, or to improve insulin sensitivity and to decrease liver fat. Know, I haven't seen a drug candidate that can attack so many different pathways associated with cardiovascular disease. So, know, look, we're really excited about that. I think that the PCSK9s look like they're pretty good drugs as well.

I don't wanna compare them until we have a full dataset across a number of different patient populations. But look, we are as bullish as ever on the target, and in particular on ARO ANG3. We think it's a real winner for us.

Speaker 3

And I think I would add to that. In mind that triglycerides are an independent risk factor. They're independent of LDL cholesterol. So PCSK9 is kind of that last step in trying to exploit the LDL pathway for most patients. There are gonna be some genetic abnormalities in LDL metabolism that PCSK9s don't work for, as well as statins.

And where ANGPTL3 could well turn out to be a useful drug, where PCSK9s just don't work. Triglycerides are also a very important part of cardiovascular risk just like Lp is. And those are gonna have to be addressed directly. Statins aren't really don't do much and neither does the PCSK9. So the LDL part of ANGPTL3 is a pleasant kicker to its beneficial effects.

But triglycerides are a big part of that story. And that's that's something PCSK9s really aren't gonna be of any, you know, very much value for.

Speaker 9

And if I can ask a follow-up on that triglyceridemia as a as a condition and and triglyceride as an endpoint, was there anything you thought we learned from the AdCom that could basically help, with this next leg of cholesterol lowering, if you may, as an acceptable endpoint?

Speaker 3

You mean triglyceride lowering? Yep. I think it's a little hard to say just because those fish oils have a variety of effects. I mean, think people were convinced that that's an effective drug. And I think they're probably even convinced that the triglyceride reductions are beneficial and a helpful piece of that.

But ultimately, it's a little, the thing that's different about ANGPTL3 and APOC3 is they're a little more pure drugs. They do one thing, they knock down a protein and they result in those effects. The fish oil probably affects a variety of medical systems. And it's a little harder, I think, to nail it down and say it reduced cardiovascular risk for this specific reason or that specific reason. Certainly the triglycerides helped.

That was not a harmful effect, but what else is going on there? Who knows?

Speaker 9

Understood. And then on the HSD program, I understand you're doing the healthy volunteer first, but on the biopsy part, do you expect to do every six month biopsies or longer, given obviously the strong genetics you have on the cirrhotic protection part?

Speaker 3

Yeah, We haven't gone through the regulatory or IRP process yet. So I'd rather hold off on describing the clinical study until we've pushed through that. But But we recognize, as I tried to say in my remarks, that we need to understand both the depth and the duration and to try to find that out here in this first study. So that's probably all the further I should go at this point, Mayak, in describing

Speaker 2

that.

Speaker 9

Great. And my final question on the extrahepatic. Is the first readout, I know lung was, one that we, had been talking about for a while, but is kidney, is the cancer readout going to be likely be the first one where we see a signal?

Speaker 3

It wouldn't be a surprise, but keep in mind, cancer phase one studies, that's not exactly like recruiting your normal sort of phase one, two study. Cancer, those studies oftentimes take a year, a year and a half, even two years to enroll because you're looking for a specific type of patient and a specific cancer. So I'm hesitant to try to give guidance on that. It's possible that we'll get a read next year. We certainly hope we'll get a read next year.

But but I, you know, I think it's I wouldn't get too far out over our skis on that one. I mean, we will try. We're hopeful, but but I wouldn't consider that really the same as guidance.

Speaker 9

Thanks for taking my questions. Happy Thanksgiving. Thanks, you Thank

Speaker 0

you. And we have a question from the line of with Chardan. Please go ahead.

Speaker 10

Yes, thanks. Bruce, just back to HSD and the biopsies. Understanding that, you know, you certainly want the knockdown data first. But is a patient that signs up for that a patient you think is more willing to have a repeat biopsy further out that you could capture more information from?

Speaker 3

Well, I mean, that's what they'll be consenting for. Presumptively they're going to be willing to do it. The one thing we are not planning on doing in this study is we are not planning to biopsy patients to qualify. As long as they have suspected NASH or they have a previous diagnosis of NASH on biopsy, once they get that initial biopsy, they're going to be able to get active drug and then get their follow-up biopsy. So we're hoping that they'll be willing to do that knowing that they don't run the risk of doing a biopsy and not qualifying for the study.

Because we're just looking for knockdown here. We would like suspected NASH or NASH because that would certainly tell us whether there's any concern about how well they'll get knocked down when they have obviously significant fatty liver disease and probably if they don't have NASH they're heading that way. So I hope that answers your question. But yeah, I mean, they will be consenting to two biopsies by agreeing to go into the cohort.

Speaker 10

Okay. And when when do you anticipate you'll be able to provide us more more information about that trial design?

Speaker 3

I would I would think probably at the point that it gets, you know, that it that gets cleared for moving forward. So that would be likely to be in the first quarter, I would think. That's the most likely case.

Speaker 10

Okay. Thanks a lot.

Speaker 3

You bet.

Speaker 0

Thank you. And this concludes our Q and A session. I will, turn the call back to Chris Anzalone for his, final remarks.

Speaker 2

Thanks everyone for joining us today and I hope you all have a happy Thanksgiving weekend.

Speaker 0

And thank you ladies and gentlemen. This concludes today's conference call. Thank you for participating. You may now disconnect.