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spk14: our Chief Financial Officer, will give a review of the financials. We will then open the call up to your questions. Before we begin, I would like to remind you the comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact are forward-looking that could cause actual results to differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company. Chris?
spk17: Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. I want to start by thanking you, I want to start by saying thank you to all those who joined us yesterday in Verona, Wisconsin for the groundbreaking ceremony at the site of our new manufacturing and lab facilities, including Mayor Diaz, Secretary Hughes, and Governor Evers. Many people from BioForward, the local universities, the cities of Madison and Verona, and the state of Wisconsin have been very supportive of Arrowhead over the years. We appreciate their partnership as we grow our business and capabilities to support the potential future commercial opportunities for our investigational RNAi-based medicines. To that end, we announced yesterday that we received awards of up to $18.5 million in incentives to invest in the local region and create new jobs. These incentives help to defray some of the build-out costs for our Verona facility, but importantly, they demonstrate the commitment of the region to expand the number of highly skilled jobs and attract talent. We have been very impressed with the quality of the workforce and intend to be a longtime contributor to the growing biotech ecosystem in Wisconsin. So what does this new manufacturing facility and associated office and lab facility do for Arrowhead? First, it increases our control over manufacturing at all scales, which should decrease costs and increase our speed and flexibility. Second, it enables us to better control IP as we develop new methods of manufacturing aimed at decreasing costs and increasing purity and scale. Third, it makes us a better and more complete partner to those companies bringing the drugs we create to patients. And fourth, it provides additional specialized lab space to enable continued growth and innovation as we bring RNAi to new cell types and address new diseases. This is an investment in Arrowhead's future as a vertically integrated commercial stage pharmaceutical company. We are making this investment now because we have a high degree of confidence in our investigational medicines, both wholly owned and partnered. This is an important step when a development stage company is serious about becoming a commercial entity. Let's now talk about some of the recent progress we've made toward that transition. First, we initiated the Palisade study, Arrowhead's first Phase III study of AeroApoC3 in patients with familial chylomicronemia syndrome, or FCS. FCS is a rare disease in which patients have extraordinarily high triglyceride levels, often in the thousands of milligrams per deciliter. This can lead to severe and recurrent bouts of pancreatitis, which often involves hospitalization and can be fatal. In addition, these patients experience multiple additional symptoms which adversely impact quality of life. These patients have no FDA-approved treatment options. Our clinical data and prior studies of AeroApoC3 have shown clear and dramatic reductions in triglycerides, so we are confident that AeroApoC3 is doing what it is designed to do. We are working to accrue patients in the Palisade study as quickly as possible since there is such high unmet need for these patients. In addition to starting our first Phase III study, we also completed enrollment in the Phase IIb ARCHES II study of aeroANG3, our other wholly-owned investigational cardiometabolic candidate for patients with mixed dyslipidemia. This study enrolled over 200 patients with LBH triglycerides and LDL cholesterol. Completion of ARCHES II is anticipated around the end of this year, and we intend to release top-line data in the first half of 2023. These data will inform the next phase of development, and potentially provide a path to another late-stage clinical study that we hope will be registrational. We also recently initiated the gateway study of AeroAng3 in patients with homozygous familial hypercholesterolemia, or HOFH. This study will evaluate the ability of AeroAng3 to reduce LDL cholesterol in patients with the most serious and rare form of familial hypercholesterolemia. We view the HOFH opportunity in a similar way to the FCS opportunity for AeroApoC3, where there may be a rapid path to approval in a narrow patient population with severe disease while we conduct larger clinical studies in higher prevalence indications. As I mentioned earlier, our investment in the new manufacturing facility is to support our growth into a commercial stage company. We think there are multiple opportunities to get there in the near to midterm, and we are preparing on all fronts. To that end, we appointed a new member of our board of directors. Vicki Vecchino is an accomplished commercial pharmaceutical executive with decades of experience building commercial organizations and launching new products across multiple therapeutic areas. She will have an important voice on the board and provide valuable input as our commercial strategy maps out. I also want to give a brief update on our later stage partner candidates. These are Olpasaran, targeting LP little a with Amgen, AeroAAT, also called TAC999 with Takeda, J&J3989, formerly AeroHBV for chronic hepatitis B infection with Janssen, and AeroHSD for treatment of NASH with GSK. Amgen has indicated publicly that Phase II clinical data for Olpaceran is expected around the middle of the year. They've also indicated that if the data are consistent with the positive data seen in Phase I, that they would move rapidly to start a Phase III study. We are very excited about this program and eager to see the phase two data. We believe that LBAT triglycerides, LP little a, LDL cholesterol, and possibly low levels or poorly functioning HDL are all contributors to the substantial remaining risk of cardiovascular disease, even in patients on maximal LDL lowering therapies. We have candidates addressing all of these. Our two wholly owned programs, AeroApoC3 and AeroAng3, and our partner program with Amgen may be able to address multiple lipids that contribute to this risk. We still need to conduct clinical studies to assess their efficacy and safety, but we have a high degree of confidence in these programs. Moving on to TAC 999, we are on schedule to collect the last 12-month biopsy from the last patient in the Sequoia study in June or July of this year. After the sample is taken, all clinical samples will be processed and analyzed, and biopsies will be prepped and read This process will likely take a few months, so we should have data available in the fall. Our intention would be to present those data in an appropriate forum. According to our agreement, Decatur will lead clinical developments and regulatory interactions after phase two. We will still be closely involved with the process and have had a very productive relationship with our colleagues at Decatur. We look forward to additional regulatory interactions this year and moving the program forward rapidly. J&J 3989, formerly Arrow HPV, is being investigated in multiple large Phase II studies that all include a follow-up phase. Together, these will include close to 1,000 patients on various combination therapies, and we would expect regular readouts for the foreseeable future as data come in. Public data thus far suggests that J&J 3989 is doing what it is designed to do and substantially reducing viral antigens. We are excited to see these data and are hopeful that they will point to a treatment that is desperately needed by the 300 million people thought to suffer from chronic hepatitis B infection worldwide. Our partnership with GSK for AeroHSD closed at the end of the first quarter this year. Since then, we have been working productively together and expect GSK to initiate a phase two study this year in patients with NASH. This represents a large unmet medical need. HSD is a genetically validated target. We believe we were the first to address this target clinically and our Phase I data were compelling in terms of knockdown, tolerability, and transaminase decreases in patients with suspected NASH. Complementing our mid- and later-stage pipeline, we were also active during the quarter expanding our early-stage clinical pipeline. We believe sustainable growth requires a diversified portfolio of candidates across the therapeutic areas, disease prevalence, and patient population size, and across stages of development. so it's critical that we both advance our later stage programs and also constantly expand our early stage pipeline. We must also remember that Arrowhead is really good at moving rapidly from idea to the clinic. We likely will not have the bandwidth to commercialize everything we produce, and we certainly do not intend to tap the brakes on early development. As such, some of those programs will be partnered to A, put them in the hands of companies that will move aggressively to get them to the patients who need them, and B, provide capital for us to commercialize our wholly owned assets. Developing important new medicines is an expensive business and we have the luxury of not being solely dependent upon the capital markets to fund this. We expect this year and every year for the foreseeable future to bring in significant capital from new and existing partnerships. I expect Arrowhead to commercialize a variety of important medicines and a targeted partnership strategy helps provide necessary capital for this while also providing potentially substantial long-term economics. We had three new clinical programs over the recent period. Arrow C3 for treatment of complement-mediated diseases, for which we initiated a Phase I-II clinical study, and our second and third pulmonary programs, Arrow RAGE and Arrow MUC5AC, for which we filed CTAs to initiate Phase I-II clinical studies. We'll talk more about Arrow RAGE and Arrow MUC5AC at our upcoming pulmonary R&D day, on May 26th. Arrowhead team members and two external key opinion leaders will talk about the treatment landscape for various mucloobstructive and inflammatory lung diseases and the role that RAGE and MUC5AC may play in addressing them. We will also discuss other advancements in the pulmonary platform and disclose the next pulmonary candidate we expect to bring to the clinic. During the quarter, we also presented interim results for a Phase 1b dose-finding study of ArrowHIF2, are investigational candidate for patients with clear cell renal cell carcinoma. The data presented provide initial proof of concept, I'm sorry, initial proof of target engagement based on reductions in HIF-2-alpha expression. We have been working on a HIF program for over a decade using different strategies and many different iterations of our delivery technologies. Our goals for that program were threefold. One, we wanted to develop a HIF-2-alpha targeted therapy because there is supportive evidence that it could have an effect for RCC patients and it had historically been undruggable with small molecules or monoclonal antibodies. Two, we wanted to validate that we could get functional delivery of siRNA to solid tumors, indicating that we may have a platform that can be applied to additional targets and cancer types. And three, we wanted to use the tumor delivery program as a way for us to learn critical lessons that could be applied to delivery systems targeted to various other extrahepatic tissues. We think we accomplished numbers two and three the therapeutic landscape has changed for goal number one the competitive environment is dramatically different today than it was just a few years ago with one small molecule hip2 alpha inhibitor fda approved and others in clinical development we have examined the data from our clinical study at this point based on the competitive environment we have decided not to continue further development of arrow hip2 this decision was made after significant deliberation and analysis and we would like to acknowledge and give our sincere thanks to the investigators, site staff, and of course patients who participated in our clinical study. However, as I mentioned, we did accomplish some important things with our first tumor targeted program. Probably the most critical piece that has wide ranging implications is that we learned more about how to optimize each individual component of the system to squeeze as much knockdown as possible out of each siRNA molecule. These lessons made it possible for us to develop the technology to get to various other extrahepatic tissues. We believe we are now much better at several things, including trigger design, optimizing chemical modifications, ligand design and selection, linker optimization, and design and use of PK-PD enhancing structures, as well as other things that can optimize target engagement. We also believe that we have a good start in our oncology platform. We saw clear target engagement, suggesting that we are able to deliver to solid tumors. In short, we are on the board. We are now using the lessons we learned from that study to further optimize the platform for use in other tumor types against new targets. We believe that RNAi can play a role in cancer treatment, and we are pushing in that direction. I want to highlight one more piece of corporate news. We recently announced that Arrowhead formed a joint venture called Vicerna Therapeutics with Vivo Capital to expand the reach of innovative medicines in greater China. Bevo provided initial funding of $60 million to Vicerna, which will have exclusive rights to develop and commercialize four of Arrowhead's investigational therapeutics for cardiometabolic diseases in mainland China, Hong Kong, Macau, and Taiwan. Arrowhead has a majority stake in Vicerna after accounting for shares reserved for the employee stock ownership plan and is further eligible to receive potential royalties on commercial sales. China is an increasingly important market for global pharmaceutical products. We believe to be successful in China, you are better off in a dedicated entity with its own management and development staff that understand and are solely focused on the intricacies of China's clinical, regulatory, and commercial environment. That is what we envision Vicerna becoming. We are looking for more than just a financial investor, and Vivo checked all the necessary boxes. Vivo has unique experience, expertise, and a local network to draw upon. that makes them a very valuable partner in this joint venture. We think this transaction allows us to maximize value and maximize the probability of success without losing focus on our core target markets for future commercialization. Really a win-win scenario and a transaction that we think over time has the potential to become substantially more valuable. We view this as another quarter where we executed well and achieved some key corporate goals. For a company our size with respect to headcount and market value, we have a uniquely broad and diverse set of assets. A key part of the Arrowhead DNA is a devotion to speed and precision, and a commitment to bring RNAi to intractable diseases. This prior period is a good example of that. With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?
spk09: Thank you, Chris, and good afternoon, everyone. I will provide updates on enrollment for the VISTA set of studies for ARO-H3 and the summit study for ARO-ApoC3 and give some forward guidance on anticipated timelines. I will start with the VISTA studies of ARO-H3, our investigational medicine designed to reduce production of angiopoietin-like protein-3 as a potential treatment for patients with dyslipidemia. There are currently two ARCHES studies, ARCHES-II in patients with mixed dyslipidemia and GATEWAY in patients with HOFH. ARCHES-II is a double-blind placebo-controlled Phase IIb study ARCHES II is a fully enrolled with 204 patients with triglycerides between 150 and 500 milligrams per deciliter, and non-HDL cholesterol greater than 100 milligrams per deciliter, or LDL cholesterol greater than 70 milligrams per deciliter. Being randomized in a three-to-one ratio to receive either subcutaneous injection of aero-H3 or placebo on day one and week 12, three dose levels of aero-H3 50 milligrams, 100 milligrams, and 200 milligrams are being evaluated against placebo. The duration of the study is approximately 42 weeks from screening to the week 36 end of study examination. After completing the week 36 visit, participant will be eligible to continue in an open-label extension period. Anticipated ARGES II will be completed around the end of 2022. and top-line data will be available to share in the first half of 2023. The next active study is GATEWAY, an open-level Phase II clinical study to evaluate the efficacy and safety of investigational ROH3 in up to 16 subjects with HOFH. Two dose levels of ROH3, 200 and 300 milligrams, will be evaluated in subjects with documented HOFH based on genotype or clinical criteria. and with fasting LDL cholesterol greater than 100 milligrams per deciliter and fasting triglycerides less than 300 milligrams per deciliter at screening. TAPCHES will receive a subcutaneous injection of AROH3 on day one and day 84 and may be eligible to participate in an optional open-label extension study. The primary objective of the gateway study is to evaluate the efficacy and safety of AROH3 in TAPCHES with HOFH And the primary input is the percent change in fasting-calculated LDL cholesterol from baseline to week 24. We just started opening clinical sites and enrolling gateway a few weeks ago, so we don't have a great visibility into how long it may take to accrue all 16 patients. Our goal is to have the study fully enrolled or at least have a meaningful amount of patients enrolled by the end of this year. Since this is an open-label study, we may be able to view results in somewhat real-time, so we intend to share data in 2023 when possible. Next, I will provide an update on the summit study of AeroApoC3, our investigation of the medicine targeting apolipoprotein C3 being studied in patients with various lipid disorders. There are three active studies. Just a two in patients with severe hyperthelicidemia, or SHTG, Neur in patients with mixed dyslipidemia, and Palisades in patients with FCS. CHASTA-2 is a double-blind placebo-controlled Phase IIb study in approximately 216 patients with triglycerides greater than 500 milligrams per deciliter. Three dose levels of AeroApoC3, 10 milligrams, 25 milligrams, and 50 milligrams, will be evaluated against placebo. The primary objective of the SHER-STAT-2 study is to evaluate the safety and efficacy of aeroeposy-3 and to select those in regimen for later stage clinical studies in this patient population. Moving on to the MIR study, which is a double-blind placebo-controlled Phase IIb study in approximately 320 patients with triglycerides between 150 and 500 milligrams per deciliter and known HDL cholesterol greater than 100 milligrams per deciliter. or LDL cholesterol greater than 70 milligrams per deciliter. In three cohorts, 10, 25, and 50 milligrams, each participant will receive subcutaneous injection on day one and week 12 for a total of two injections. And in one additional 50 milligram cohort, each participant will receive a subcutaneous injection on day one and week 24 for a total of two injections. The primary objective of the new year's study is to evaluate the safety and efficacy of aeroeposite 3 and to select the dose and dosing regimen for later stage clinical studies in patients with mixed dyslipidemia. TASTA-2 and MUIR are both approximately 50% enrolled, and we anticipate full enrollment in the fourth quarter of 2022. This would allow for study completions in 2023. The last study is the Summit Program in Palisades, a Phase III study in approximately 72 patients with FCS. Primary endpoint of palisades is the percentage from baseline at month 10 in fasting triglycerides. Additionally, secondary and exploratory endpoints include the change in other lead parameters, incidence of acute pancreatitis, and other measures. We're working hard to open clinical sites around the world to accrue the study as fast as possible. We originally anticipated recruiting a number of patients in Russia, Ukraine, and Belarus. However, due to the ongoing conflict, we have closed all clinical sites in the region. We're adding clinical sites in additional countries to maintain patient accrual. Our current goal is to have palisades fully enrolled in the middle of 2023, which would allow for study completion in 2024. I will now turn the call over to Dr. James Hamilton. James?
spk02: Thank you, Javier. I want to give updates on a few of our early stage clinical programs and preclinical programs. Let's start with ARROW-C3, our investigational RNAi therapeutic designed to reduce production of complement component 3, or C3, as a potential therapy for various complement-mediated diseases. During the quarter, we dosed the first subjects in a clinical study. This is a phase 1-2 placebo-controlled dose escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AeroC3 in up to 24 adult healthy volunteers and up to 24 patients with paroxysmal nocturnal hemoglobinuria or PNH. And up to 14 adult patients with complement mediated renal disease. In part one, healthy volunteers will receive a single subcutaneous injection of AeroC3 or placebo. In part two, eligible subjects with PNH or complement mediated renal disease will be enrolled to receive open-label AeroC3. We have completed dosing in three of four planned cohorts in part one and expect to dose escalate to the final planned cohort. We intend to initiate part two in patients when we have selected a dose from part one in the next quarter or so. Moving on to our first planned skeletal muscle targeted candidate, AeroDUX4, our investigational candidate designed to target the gene that encodes human double homeobox 4 protein, or DUX4, as a potential treatment for patients with fascioscapulohumeral muscular dystrophy, or FSHD. FSHD patients have no real therapeutic options, so we are moving as quickly as possible to begin clinical studies. However, it has been challenging for the field to identify a reliable biomarker of Dux4 expression or of disease activity in patients with FSHD. Thus, it is likely that Phase I results may not be informative with regards to pharmacodynamic biomarkers and may only inform on initial safety. Longer Phase II studies may be required to see any signs of favorable changes on imaging or in clinical endpoints. As such, in an effort to de-risk phase two studies, we have opted to wait for the results of chronic toxicology studies prior to filing a CTA for ARO-DUX4. We will provide an update on timing of the CTA when we have a clear assessment on chronic tox results. The next update I want to give is on our discovery stage programs with Janssen called ARO-JNJ2 and ARO-JNJ3. We previously delivered candidates to Janssen that met the parameters described in the research plan. Both candidates achieved the desired level of safety and activity. Janssen then had a period in which to do disease model and biology work on the targets they selected before having to opt in and exercise the option to take an exclusive license to these candidates. That period has now expired and Janssen did not elect to exercise their option. Because of this, we are removing the programs from our active pipeline. The first discovery program outside of hepatitis B in our collaboration with Janssen is JNJ75220795, formerly called AeroJNJ1. This is an investigational sRNA therapeutic developed using Arrowhead's proprietary trim platform and is designed to reduce expression in the liver of pathetin-like phospholipase domain-containing 3, or PNPLA3, as a potential treatment for patients with non-alcoholic steatohepatitis, or NASH. This program is in a phase one clinical study and continues to progress as planned in clinical development. The last programs I want to discuss are our newest pulmonary candidates, AeroRage and Aeromuc5AC. We filed CTAs last quarter, and I am pleased to announce that both programs have received provisional approval from an ethics committee and now have regulatory clearance to begin clinical studies. We anticipate first-in-human studies will begin around the middle of 2022. The first program, ARAMUK5AC, targets expression of MUK5AC, a mucin protein with upregulated expression in the asthmatic airway. Aeromuck 5AC is an extremely exciting program in part because it represents a fundamentally new way of treating mucoobstructive disease. Second program, Aerorage, targets expression of the receptor for advanced glycation end products or RAGE. RAGE represents an upstream mediator of the inflammatory cascade. We believe they both have a differentiated mechanism and offer potential advantages over currently available therapies for various mucobstructive and inflammatory pulmonary diseases. We will describe these programs in more detail at our pulmonary R&D day on May 26th. I will now turn the call over to Ken Miszkowski.
spk13: Ken? Thank you, James, and good afternoon, everyone. As we reported today, our net income for the three months ended March 31st, 2022 was 44.4 million or 41 cents per share based on 107.9 million fully diluted weighted average shares outstanding. This compares with a net loss of 26.8 million or 26 cents per share based on 103.9 million fully diluted weighted average shares outstanding for the three months ended March 31st, 2021. Revenue for the quarter ended March 31st, 2022 was 151.8 million compared to $32.8 million for the quarter ended March 31st, 2021. Revenue in the current period primarily relates to the recognition of $120 million upfront payment received under our collaboration agreement with GSK and recognition of a portion of the upfront payments received from our license and collaboration agreements with Takeda and Horizon. The upfront payment for GSK was recognized as revenue entirely in this quarter as our performance obligations are substantially complete. Revenue for our collaboration agreements with Takeda and Horizon will be recognized as we complete our performance obligations, which include managing the ongoing AAT Phase 2 clinical trials for Takeda and delivering a Phase 1 ready candidate to Horizon. There remains $167.6 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate to be recognized over approximately two to three years. And there remains $20 million of revenue to be recognized for Horizon, which we anticipate will be recognized by the end of calendar 2022. Revenue in the prior period, primarily related to a recognition of a portion of the milestones received from our licensing collaboration agreements with Janssen and Takeda. Total operating expenses for the quarter ended March 31st, 2022 were $110.3 million compared to $61 million for the quarter ended March 31st, 2021. This increase is primarily due to increased clinical candidate costs as our pipeline is expanded and advanced through clinical trial stages, as well as increased compensation expense. Net cash provided by operating activities during the six months ended March 31, 2022 was $1.4 million compared with net cash provided by operating activities of $225 million during the six months ended March 31, 2021. The key driver of this change was the collection of the $120 million upfront payment from GSK in the current period versus the collection of the $300 million upfront payment received from Takeda in the prior period. We continue to estimate our operating cash burn to be $60 to $80 million per quarter in fiscal 2022, excluding any incoming milestone payments from our partners. In addition, we are expanding our manufacturing capabilities and our R&D facilities. Because these two projects have only recently begun, our capital expenditures in fiscal 2022 will be lower than originally estimated, but capital expenditures will increase next year. Turning to our balance sheet, our cash and investments totaled $603.5 million at March 31, 2022, compared to $613.4 million at September 30, 2021. The decrease in our cash and investments was primarily due to cash used for operating activities offset by the cash collection of $120 million upfront payment from GSK in January 2022. Our common shares outstanding at March 31st, 2022 were 105.7 million. With that brief overview, I will now turn the call back to Chris.
spk17: Thanks, Ken, and thanks to all of you for joining us today. When markets go through cycles of intense pressure as they are today, investors seek value. Each investor needs to define for themselves what value means, but I see value in a biotech company through several questions. Does the company have multiple potential drugs? Are those potential drugs built on a platform with known safety and activity parameters? Are those drugs addressing real unmet medical needs in a unique way? Does the company have sufficient capital and access to capital? Does the company have a track record of execution? Does the company have the ability and commitment to continued pipeline growth? And is the company focused on long-term growth and getting drugs to patients? These may seem simple and straightforward, but precious few companies our size can answer all of these questions in the affirmative. I believe that we do. And by focusing on core principles such as these, Arrowhead is well positioned to do right by the patients we serve and create substantial value for our shareholders. I believe we have a pipeline that is substantially larger than any company our size and larger than most companies several times our size. Everything we do is built on RNAI and the TRIM platform, both of which are increasingly validated clinically. Whether addressing chronic HPV, where it is thought that someone in the world dies every 30 seconds from complications of the infection, or cardiovascular disease, we are addressing clear, unmet medical needs, and we believe we are the first to use RNAi against every target we are going after. We have a strong balance sheet and, importantly, access to ongoing capital as our current partnerships mature and trigger milestone payments. We have demonstrated our consistent ability to move rapidly to the clinic and into later stage trials. Our pipeline continues to grow with three new candidates entering clinical studies over the past six months alone, and we expect more through the end of the year. While the current market dynamics are uncomfortable, we are laser-focused on getting our current and future drug candidates to the patients who need them, and trust that this commitment will create substantial value for our shareholders. Thank you for joining us today, and I would now like to open the call to your questions. Operator?
spk10: Certainly. As a reminder, to ask a question, you will need to press star 1 on your telephone. And to withdraw that question, please press the pound key. Our first question comes from Maury Raycroft of Jefferies. Your line is open.
spk11: Hi. Thanks for taking my questions. I was going to ask a question on AAP. If you could talk more about the expectations for the upcoming regulatory interaction in the spring ahead of the Phase 2 12-month biopsy readout and how you're planning on updating investors after the meeting has completed.
spk17: I'll be happy to address that.
spk09: Sure. As you know, we're working with Takeda, and Takeda is leading the interaction with the FDA from now on. So they will lead the next meeting, which is the end of Phase 2 meeting that will happen within the next few months. And that meeting, as you know, the key discussion point will be the design of the Phase 3 study that includes endpoints, sample size, dose, So that's the status with regard to regulatory. We expect to have a decision and an agreement at one point in the second half of this year. The study 2001, which was the dose range study for the dose range in component is completed and it will be part of the package. As Chris said, the study will be completed in terms of the biopsy by July of this year. So we have everything we need. to have this meeting with the FDA. Takeda is doing a very good job and we're collaborating very closely. And so I think we will have more about this in the next call for sure.
spk17: And also to be clear, As Xavier said, the dose-finding portion of that study has read out, and given those data, Takeda has initiated interactions with the FDA. So that's already begun. You know, we expect them to have a formal meeting in the next coming months, and so we'll see how that phase three is designed. The whole, you know, We look forward to seeing the biopsy data sometime this fall from the Sequoia study. That, as you know, is blinded, so we haven't seen anything there. And that's a bit of a wild card. We look forward to seeing what those look like. And I think we have to focus on, or Takeda has to focus on, designing this phase three right now. And then once we see those data from the Sequoia biopsy, we'll see if that affects their actions going forward with the FDA.
spk11: Got it. That's helpful. And will the upcoming end of Phase II meeting, will that determine what the endpoint is? And when you get the biopsy data, could the endpoint change? Or I guess, how should we think about that?
spk09: Yeah, exactly. The end of Phase II meeting, the goal is to have an agreement on the specific Phase III study design, which will include the primary endpoint, the duration, the dose, and the sample size, so all the details about the phase three study, and also the end of phase two will include CMC, the conversation, so everything needs to be in place to set the registration phase three study right after that meeting.
spk11: Got it. Okay. And maybe just a quick question on Dux4. Just wanted to clarify if you're seeing any signals in the healthy volunteers prior to starting part two, or are you just being conservative waiting for the chronic tox data?
spk02: So if you're asking about Dux4, that study has not yet started in the clinic yet. So that's still preclinical.
spk17: We have not enrolled any healthy volunteers. Yeah, just given in the prepared remarks and James' prepared remarks, as he described, we learned from prior clinical studies that it's difficult to measure Dux4. And so given that, it made sense to us you know, to maybe go a bit slower on the front end so we can go faster on the later stages. And so we're waiting to see what those chronic tox data might look like before we design the, you know, the study and initiate the study.
spk11: Got it. Okay, that makes sense. Okay, thanks for taking my questions. You're welcome.
spk10: Our next question comes from Luca Issi of RBC Capital. Your line is open.
spk05: Oh, great. Thanks so much for taking my question. Maybe circle back on Maura's question earlier. Maybe ask a little bit more directly. Is there a scenario where you can file early for A118 in the second half of the year? Should the biopsy data check the box, given that you have breakthrough therapy designation? Again, any call there would be great. And then maybe on hepatitis B, I think we've seen J&J obviously discontinue their collaboration with Bevere and Nordic. So wondering if that's just one-off or maybe if it reflects like a lower interest rate. interest in the space for them more broadly, also any call there would be great. Thanks so much.
spk17: Sure, sir. So let me take HPV first. We don't see any evidence that J&J is losing interest in HPV. To the contrary, you know, they're working as fast as ever and they're expanding these studies It almost seems like every day into different patient populations and such. And so we see, you know, we see a strong interest in HPV. I don't know what the, you know, what led them to terminate those other partnerships, but ours is going strong and we still feel confident about our drug and we feel confident about them as a partner in their commitment to the disease. So, you know, we're still guns a blazing there. With respect to AAT, you know, it's hard. I don't really want to speculate. on what we could do with those biopsy data just because there's too many unknowns. Right now, we and Decatur together have to focus on negotiating with the FDA, on finding common ground with the FDA, on what a phase three study will look like, how large study it is, what the endpoints are, how long a study it is, and the like. We think we'll get there because the FDA has been quite collaborative so far. And as you point out, we do have breakthrough therapy destinations so we can have these discussions. So we're confident that we will, or that Decata, you know, will design, you know, an enrollable good study that will be beneficial to the ultimate drug, I think. Now, having said that, we look forward to seeing what those biopsy data look like. And once, you know, once all of that is unblinded, We and Takeda together will take a look at it, and it's certainly conceivable that should those data be extraordinarily compelling, that it could lead to discussions with the FDA under our designation with them. So it's too early to predict what those could mean, but we are certainly interested in looking at that, and we are excited to see what those data are, and we're excited to continue the conversations with the FDA. Okay.
spk05: Super helpful. And then maybe, if I may, on capital expenditure, I think in the past you've guided $80 million to $90 million for fiscal 2022. However, it sounds like you're lowering that guidance, so I'm wondering if you can give us a little more kind of quantitative color on that. That'd be great. Thanks so much.
spk13: Yeah, we are lowering our guidance on capital expenditures this year. As I mentioned in our remarks, the two major projects had just recently started, so we might expect – our cap acts to be something like 25 to 50% of what we originally estimated. And as I said, those projects will move quickly at the end of this year and will increase our capital expenditures in fiscal 2023. Super helpful.
spk05: Thanks so much, Eric.
spk13: You're welcome.
spk10: Thank you. Our next question comes from Madhu Kumar of Goldman Sachs. Your line is open.
spk04: This is Omari Orn from MADU. We have a handful of questions. So first, can you remind us of the cadence of news flow from the AAT program in 2022? More specifically, can we expect top line data at a medical meeting and disclosure of regulatory interactions?
spk17: Javier, do you want to address that?
spk09: So we will present the data in 2002 at ESL. to the end of June and the meeting in London. So that will be the, I think at this point, the only presentation. We made this close when we completed 2001 analysis the second half of this year. And with regard to the regulatory deduction, we said within the next few months, we have the end of phase two meeting and the expectation is to start the phase three this year. So that's
spk17: Right, yeah, and so, you know, I don't think we're, we don't expect you to provide a below by below, but once we have alignment with the FDA on what that phase three looks like, you know, we'll be happy to, of course, disclose that.
spk09: And I wanted to also say that we're working on the manuscript from 2002, so we're in the final preparation here to submit that manuscript, so hopefully that will be published this year.
spk16: All right, thank you.
spk04: And then this may be jumping the gun for the pulmonary R&D day in a few weeks, but what does the clinical proof of concept look like to you for the lead lung programs?
spk02: James, do you want to address that? Yeah, sure. I think we will be talking a lot more about that at the R&D day end of the month. But in terms of what we're really looking for in both of these programs in phase one is proof of target engagement. that we can knock down the targets and that we have a good dose response there. So I think that's the most important thing we expect to get out of phase one.
spk17: And we have circulating biomarkers there. So, you know, it'll be much more straightforward to look at that with RAGE and MUC5C than it was with ENAC.
spk16: And if I could take two more questions then.
spk04: How should we think about the upcoming and then how far do you plan to take AeroAng3 and AeroApoC3 in cardiovascular disease? Is there any plan to perform CBOPS?
spk17: Yeah, so I'll take that one first. Look, it is our plan right now to take AeroAng3 and AeroApoC3, you know, through to registration. We think those are potentially very important drugs, and we think that they – that they will provide important new tools to cardiologists and lipid clinics. And I've said this in the past, and I don't want to overstate it, but it really feels like those are important drugs. And so we are fully committed to those, and I think we're going to commercialize those. The first question was with respect to El Pasaran. I don't know what else I can tell you on this. We haven't seen any data, so there's nothing I can accidentally tell you. We are waiting to see what those data look like, just like the rest of us. just like the rest of you, the phase one data were compelling. That looks like it's a very potent drug candidate. I think the genetic validation with respect to that target is clear. That drug candidate appears to be doing what we want it to do. It appears to be well tolerated. And so, you know, we're excited to see those data. And to be honest, we fully expect for Amgen to push that into a pivotal study quite quickly.
spk16: All right, thanks for taking our questions.
spk15: You're welcome.
spk10: Our next question comes from Ellie Merle of UBS. Your line is open.
spk01: Hey, guys. Thanks for taking the question. Just a follow-up on the RAGE and MUC 5AC programs. I guess if you're starting to dose patients or mid-year, how should we think about the timing to seeing initial circulating biomarker data just given the the potential to show proof of target engagement and delivery, even albeit in small patient numbers. And then I guess just in terms of the C3 program, given that it seems like you're progressing through the cohorts and healthies, I guess how should we think about timing to initial data there and what you're looking to see for dose selection, such as a particular degree or level? of knockdown and C3 as you think about dose selection for patients, thanks.
spk17: Sure, those are good questions. I can't give you, I can't give you, Terribly straightforward guidance on any of those. I will say with C3, though, I do expect that we will have some, you know, at least top-line data this year. I don't know when. I don't know what's going to be in it. You know, we need to finish dose escalation, healthy volunteers, before we start to look for patients. I don't know how long it will take to dose people. uh patients you know in that in that cohort so it's really too early to give any guidance there but i do i i do truly though expect we'll have some data that we can talk about uh this year um with c3 but that that that's at least healthy volunteers so far is enrolling quite well with rage and muck um we haven't started dosing patients yet um that will be as you point out sometime in the middle of the year and so so similarly it's a bit too too early to to um you know, to guide when we might see some, when we might present some data. I expect that we'll see data this year, but I don't know, you know, when we'll have enough, you know, to package up in something that will be digestible, you know, by the outside. My hope is that sometime, you know, sometime in the third quarter we'll have a much better idea about that and I can give you more specific guidance.
spk01: Got it. And then just to follow up on FSHD, maybe just In terms of the decision to sort of wait for more of the chronic GLP-TOX data, I mean, I guess, was there anything that you saw preclinically that, you know, influenced this decision, or if you could just maybe elaborate on any sort of preclinical data points that maybe prompted this?
spk02: Yeah, sure. So the key driver of that decision is what we had described already on the call, is that this, we may not have a clear evidence of a PD effect or efficacy until the end of phase two, really. So we felt like it was important to de-risk that. That could be, I mean, you look back at the fulcrum study and their design, it could be a longer study. So we really wanted to make sure that the tox profile would support such a longer study.
spk01: Got it. Thanks.
spk10: And our next question comes from Joel Beattie of Baird. Your line is open.
spk06: Hi, thanks for taking the questions. The first one's on the AAT program. Thinking ahead to the discussions with FDA on the Phase III trial design, how might that trial design be different from Sequoia, and is there any possibility that it ends up looking pretty similar to what's already in Sequoia?
spk09: Well, let's revisit Sequoia. I don't know if you remember that we changed the design of the Sequoia. So the initial Sequoia adaptive trial design that had the objective to be a registration study is no longer in place. We amended that protocol. We made it a specific dose finding study. We enrolled 40 patients in three dose levels or placebo. And that is a double-blind study. We had the initial analysis looking at the serum Z protein up to week 16 for dose selection. And as we said in the call, we will have the last biopsy for the 40 patients in June or July of this year. So the data will be available later. So the phase three registration study will not be similar to Sequoia. In Sequoia, we end up enrolling patients with F0, so no fibrosis, because that was irrelevant with regard to the serum C level of the protein for those selections, which that was the primary PD marker for those selections. So it's going to be different. Of course, we need to get into the details later when we have a meeting with the agency, but it's not going to be similar to the Sequoia study.
spk06: Got it. That's helpful. And then on the two new lung programs entering the clinic mid-year, what dose levels will you be testing, and how do those dose levels compare to the dosing that was used in the previous ENAC study?
spk02: Have you disclosed anything on starting dose for either of those programs at this point?
spk17: But it's a good question, and what I assume you're getting at is, you know, is do we expect to be using as much drug for these studies as we are for ENAC? And I think the answer is we do not, you know, given the duration, the time interval between doses. Got it. Thank you.
spk10: And our next question comes from Patrick Truccio of HC Wainwright. Your line's open.
spk07: Thanks. Good afternoon. Just to follow up on the PIP2 and the oncology platform, there was discussion in the prepared remarks around the program and that clear target engagement had been demonstrated and that RNAi has a place in treating cancer. The improvements on existing constructs are needed to move forward. I'm wondering if you can elaborate on this commentary, specifically give us an idea of when You could expect to have a next-generation compound or compounds in the oncology platform ready for an IND or CTA-enabling studies. What improvements specifically would be expected to be part of this program compared to a HIP-2 program? And would the target be the same, or could we also have new targets as part of the broader oncology platform?
spk17: Sure. So first, I'll take the easier part of that first, which is targets. It will be a different target. As we mentioned earlier, The great news for clear cell renal cell carcinoma patients is that there are now good alternatives. There are now good-looking drugs that address the HIF-2-alpha pathway. And so I think we'll make bets in other targets. There's a lot of other targets, I think, that we could go after. Now, with respect to timing, you know, that's hard to know. I can't give you any guidance, certainly nothing this year. um, we were encouraged by the data. You know, we, we are seeing knockdown. We can get into tumors. We can, we can get knocked down in tumors. That's all good news. Um, but I think we can do a bit better. I think we can, I think we can, we can get deeper knockdown. I think we can get more durable knockdown. Um, and so we're trying a number of different strategies to get there. Um, um, and so, and so it's, it's still a bit early to, to give you too much, to give you guidance on when we think we're back into the clinic. And also, and I've said this publicly before, um, at some point, uh, it would make sense for us to find a good partner for oncology. It's a difficult space, and it'd be great at some point if we can find a partner to work with on new targets as well as on possible delivery strategies. So we're still in the first few innings of this game. But the good news is, again, you know, as I mentioned, I do believe we are on the board. I think we've got a good first, I think to mix my metaphors, I think we've got a good first step, you know, at this platform.
spk07: Yeah, that's helpful. And just to follow up on ARCHES II program, first, can you discuss level of confidence that the program will not have the same setback as Rupert Norris? And secondly, what would be considered home run data in ARCHES II and when the data is reported in the first half of 2023? And then lastly, just how do we think about the clinical development path forward in mixed dyslipidemia in phase three and potential commercial launch trajectory if the drug is approved?
spk09: All right. Let's see. With regard to the ARCH2 program, will you repeat the first part of the question that I kind of missed it?
spk14: What are our expectations?
spk09: Oh, I think our expectation that we're going to have a very clear safety profile and a very clear pattern of efficacy. I mean, we already have a lot of data. Our phase one study was over 100 patients with four different types of patients, populations, and the results are very, very consistent. So I don't see any possibility for a drawback of any type there. So the data is already strong enough So I feel very comfortable and confident about that. And the Phase II study is going to read first quarter of this coming year. So we will have a full answer. What we're doing in significant detail is working internally and with KOS to really understand what is the best path forward for both molecules when you think about mixed dyslipidemia. And we may talk about that in more detail in the near future. There's a lot of work going on to really understand who will be the patient population that might benefit from either or these two drugs. The therapeutic profile are clearly different. We believe that there are patient population that will uniquely benefit from either of these two drugs. But we are doing the work right now by looking at the biology, the specific biology, and ask of the HDL biology specifically, but also looking at databases and major clinical trials to understand where the residual risk for cardiovascular disease is in patients with mixed dyslipidemia. And so there is a lot of work that we want to finish by the end of this year. So we're ready for the end of phase two. We're ready to start to look at four companies and CROs and so forth to think about the major cardiovascular outcome trials. So I think we are like I said, we're doing a lot of work right now to be ready to receive that phase two data and have a plan to move forward, going to the agency, plan our long-term strategy and our phase two meeting.
spk17: Yeah, so we expect to have a cardiometabolic day later this year. And so I think we'll have, you know, we can really kind of spread out and talk about plans and what we see at that point. But look, we're going to learn a lot with all of these phase two studies over the next year plus. We're dosing an awful lot of patients, different populations, and I think we're going to learn a lot about how ANG versus APO will address various populations. Having said that, at this point, the way we're thinking about these is as follows. For APO C3, we see a good relatively near-term opportunity in FCS population. We think we can get to market relatively quickly there and become a commercial entity while we are doing, you know, larger, longer studies to support the use of ApoC3 against severe hypertriglyceridemia. We're also, as you know, doing studies in mixed distal epidemia, and so that gives us optionality to maybe or maybe not do a very large outcomes trial for that compound. On the ANG side, similar, we see an HOFH possibility there, similar to the FCS opportunity, where we can get to market relatively quickly while we are doing larger studies. We do believe that a large outcome study you know, would be interesting for ANG3, given what we've seen so far in, you know, in the phase one study. And so that's our expectation at this point, you know, to go after the large dyslipidemia population with that drug. Again, we'll learn a lot over the next year plus with these phase twos. And so some of those opinions may change a bit, but right now that's what we're thinking.
spk07: Yeah, that's very helpful. Thanks. You're welcome.
spk10: And our next question comes from Mayank Mamtani of B Reilly Securities.
spk08: Good afternoon, team. Thanks for taking our questions, and congrats on the manufacturing facility and the formation of iCERNA. Actually, if I could go back on this topic that Chris and Xavier, you were commenting on. Can you just summarize for us what is the opportunity you see in sort of improving the perception of ANCH-PD-L3 as a target? and sort of obviously in light of what we have seen with other modalities and given the initial promise we had from the Mendelian work, just, you know, as you're thinking about the cardiometabolic day, it would be helpful, I think, if you could comment on, you know, where there might be some misunderstanding versus where maybe we need to learn something more. And then I have a follow-up question on the lung programs.
spk17: Yeah, so as Javier said, our data were clear in our Phase I-II studies. We dosed a large number of patients. We saw consistent reductions in LDL. We saw good safety profile. We saw consistent reductions in triglycerides. And so whatever other folks saw with their drugs It's interesting to look at, I suppose, but I think our take-home message is that our data were strong and we expect that to continue. Now, we'll have an awful lot of data this time next year, but given the data we have so far, we feel as bullish as ever on that pathway and on our drug.
spk08: Got it. And then as you start working on your phase one studies for muck and rage and deploy learnings from the ENAC program, and then, you know, just the rat study that I think is published at a conference about, you know, how are you thinking about the dose level versus knockdown? You know, it looks like you're working with some lower doses here with the newer targets. But like with ENAC, it was about 66% knockdown, but I think you're getting higher knockdown with some of these newer targets. So can you just remind us like how much knockdown we need with these newer targets and then just maybe how far along you are with the chronic talk studies for these two new programs?
spk02: Yeah, sure. So we will be presenting data on both of those programs, MUC5AC and RAGE, at the ATS conference that starts next week. And you're right. We previously described for ENAC about 66% knockdown in the RAT, and we are seeing better knockdown than that with both SIRNA targeting MUC5AC and RAGE rodents, but also in non-human primates. And we'll be sharing some of those data. The key to that story is it's not only a matter of just lower dose levels, but lower overall exposure. So the less frequent dosing intervals, as Chris alluded to before, are really important, I think, for both muck and rage. Was there another piece of that question?
spk08: Chronic tox studies, how long have you gone there in the preclinical model?
spk02: The chronic tox has not yet started for either of those. We've completed the IND or CTA-enabling tox, and that's complete for both muck and rage.
spk17: And let's be clear on that. That's intentional. You know, we want to see what the durability look like in humans before we do a chronic tox study in animals, just so we have a good idea about what sort of intervals we should be testing, right? You know, if we are dosing once a month, you know, if we've seen durability the last 30 days, that would... suggest a certain kind of chronic tox study. If we are seeing durability of the last two months or three months, that's another one. And so we'd like to get a flavor for what we're seeing before we start those studies.
spk08: Great. Thank you for that clarification. And then just one final question, higher level. Has there any exploratory work done of delivering RNAi to the retinol or broadly CNS as oligonucleotides have been also deployed. Have you guys done any work around that preclinical?
spk17: We haven't talked about any other cell types that we are going after internally, but you've been around us long enough to know that we are always looking for new cell types. We've not disclosed what our next cell type is yet.
spk08: Okay, look forward to some of those disclosures and your preliminary day later this month. Thanks for taking our questions. Great, thank you.
spk10: And our next question comes from Kay Nicky of Chardon. Your line's open.
spk12: Yes, thank you for the question. With respect to HIF-2, I'm going after additional oncology targets. I guess my question is why? Why do that as opposed to you know, just on your last question, other targets, let's say outside deliver?
spk17: Yeah, you know, that's a great question. I don't mean to be flip, but when we can, we are more of an and company than an or company. And I think we've got the bandwidth to both of those things. I think your point is a good one. You know, we've got really good leads in other cell types. And so if we were If we were more bandwidth constrained, then one could argue that we should maybe slow walk the oncology a bit because we've got really good, exciting opportunities in other places. But I think we can do both. And also, as I said in the preparative marks, one of the reasons that the oncology program was important for us is that it gave us the chance to learn broadly how to deliver extra-hepatically. And I think that will still be the case. So it makes sense strategically there. But, you know, the underlying point there is a strong one. Oncology is difficult. And so we would not like to be solely an oncology company. That's a risky endeavor. But it's something that I think we owe it to patients to investigate because I think we could do it. You know, we've got a good first step, as I mentioned, with our HIF-2-alpha program. And I think that just with a little bit of tweaking, we might have something that, you know, that could be usable across other tumor types.
spk12: Okay, thanks, Chris. You're welcome.
spk10: And our next question comes from Manny Forhar of SVP Securities. Your line is open.
spk03: Hey, guys, thanks for taking the question. You've always focused on speed into the clinic as one of your core competencies and sort of philosophy of the company. One of the challenges there is making sure that everybody Target is appropriately vetted every market opportunity actually exists. So could you help us understand your rationale for why it is an opportunity for you in PNH? How you think about other complicated diseases where I'll Nile them and others with many times your resources and expertise in our day I have Faced real challenges and then secondarily are we ever going to see the further? the further safety data that we saw in terms of that safety signal that showed up in ENAC, or do you intend to sort of hold that internally and not disclose it in more detail? Thanks, guys.
spk17: Yeah, so I'll let James handle the P&H question quickly on the ENAC. So we're still considering a second, or we're still working on a second generation ENAC. And so I think until and unless We have that ready to go. It doesn't make much sense for us to focus on prior data. So we'll hold off until we see where the ENAC2 is going to go. James, you want to address C3?
spk02: Yeah, sure. So with regards to P&H specifically, what interests us there is the data out of other companies with C3 inhibition specifically. There's only one C3 inhibitor that is out there and that is approved and really showed significant improvement even compared to C5 inhibition in the PNH population. The issue with that C3 inhibitor is that it's, you know, sub-Q infusion that's given at high doses every other day or I think almost daily in some circumstances. So that is limiting. At an equivalent level of C3 inhibition with a single subcutaneous dose with C3 knockdown that lasts three months, I think assuming it has the same inhibition of complement activity and assuming you get the same changes in hemoglobin, I think that's pretty compelling. So that's the argument for PNH.
spk16: Okay, that's helpful. And with the speed with which you're adding programs to the clinic,
spk03: How should we be thinking about the tempo of OPEX maturation over the next couple of years? You commented on timing for CAPEX being pushed out to next year. How should we think about the scaling of OPEX? Should it be largely proportional to the size of these studies that you're enrolling? Will it be chunkier around the lipid studies? Just kind of give us a sense of how we should model that between now and, say, the next two or three years.
spk13: Yeah, so we gave guidance earlier in this year, and we expect to update that at our call two quarters from now. We only look forward really 12 months on that forecast, so we'll have more to come on that.
spk15: Okay.
spk13: Thanks, guys.
spk10: And I'm showing no further questions. I would now like to turn the call over to Chris Anzalone for closing remarks.
spk17: Thanks, everyone, for joining us on the call today, and we'll talk to you next quarter.
spk10: This concludes today's conference. You may now disconnect.
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