Q2 2022 Arrowhead Pharmaceuticals Inc Earnings Call

[music].

Okay.

Unknown Executive: Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode.

Ladies and gentlemen, and welcome to the Arrowhead Pharmaceuticals Conference call throughout today's recorded presentation, all participants will be in a listen only mode.

Vincent Anzalone: After the presentation, there will be an opportunity to ask questions. I will now hand the conference over to Vincent Anzalone, Vice President of Finance and Investor Relations for Arrowhead. Please go ahead, Vince.

After the presentation, there will be an opportunity to ask questions I will now hand, the conference over to Vincent Anzalone, Vice President of Finance and Investor Relations for Arrowhead. Please go ahead Vince.

Vincent Anzalone: Thank you for your patience.

Vincent Anzalone: Thank you, LaTanya, and good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2022 second quarter ended March 31st, 2022. With us today for management are President and CEO Dr. Christopher Anzalone, who will provide an overview of the quarter. Dr. Javier San Martin, our Chief Medical Officer, will provide an update on our mid and later stage clinical pipeline. Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, will provide an update on our earlier stage programs. And Ken Myszkowski, our Chief Financial Officer, will give a review of the financials.

Latanya and good afternoon, everyone. Thank you for joining us today to discuss arrowheads results for its fiscal 2022 second quarter ended March 31, 2022 with US today from management are president and CEO , Dr. Christopher Anzalone, who will provide an overview of the quarter Dr. Javier San Martin.

Vincent Anzalone: Please stay on the line for the next available operator.

Our Chief Medical Officer will provide an update on our mid and later stage clinical pipeline Dr. James Hamilton, Our senior Vice President of Discovery and translational medicine will provide an update on our earlier stage programs and Ken Moskovsky, Our Chief Financial Officer will give a review of the financials. We'll then open the call up to your question.

Yeah.

Vincent Anzalone: We will then open the call up 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 are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statement, for further details concerning these risks and uncertainties.

Before we begin I would like to remind you that comments made during today's call contains certain forward looking statements within the meaning of section 27 a.

Of the Securities Act of $19 33, and section 21 E of the Securities Exchange Act of 1934, all statements other than statements of historical fact are forward looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward looking statements.

For further details concerning these risks and uncertainties. Please refer to our SEC filings, including our most recent annual report on Form 10-K, and our quarterly reports on Form 10-Q.

Vincent Anzalone: 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.

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

Vincent Anzalone: Thank you for calling.

Thanks Vince.

Christopher Anzalone: Thanks, Ben. 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.

Good afternoon, everyone and thank you for joining us today.

Christopher Anzalone: We appreciate their partnership as we grow our business and capabilities to support the potential future commercial opportunities for our investigational RNAi-based medicine. 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 to demonstrate the commitment of the region to expand the number of highly skilled jobs and attract talent.

Christopher Anzalone: Can I have the conference you would like to join today?

Want to start by thanking you.

I want to start by saying, Thank you to all those who joined US yesterday number one in Wisconsin on the groundbreaking ceremony at the site of our new manufacturing and lab facilities, including Mayor DFS Secretary Hughes and Governor Evers.

People from bio forward the local universities, the cities of Madison, and Verona and the state of Wisconsin had 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 RNA 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 helps 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.

Christopher Anzalone: 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.

We have been very impressed with the quality of the workforce and intend to be a long time contributor to the growing biotech ecosystem in Wisconsin.

Christopher Anzalone: 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.

So what does this new manufacturing facility and associated office and lab facility due for Arrowhead first it increases our control over manufacturing at all scales, which should decrease cost and increase our speed and flexibility.

It enables us to better control IP as we develop new methods of manufacturing aimed at decreasing costs and increase in 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 rei to new cell types and address new diseases.

This is an investment in <unk> future as a vertically integrated commercial stage pharmaceutical company, where.

Christopher Anzalone: 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, Let's now talk about some of the recent progress we've made toward that transition. First, we initiated the Paliphate Study, Arrowhead's first Phase III study of Arrow ApoC-3 in patients with familial chylomicronemia syndrome, or FCS.

We are making this investment now because we have a high degree of confidence in our investigational medicines, both wholly owned and partnered this.

This is an important step when a development stage.

The development stage company is serious about becoming a commercial entity.

Christopher Anzalone: Sure, I'd like to join Arrowhead Pharmaceuticals, earnings call, please.

Let's now talk about some of the recent progress we've made toward that transition.

Christopher Anzalone: Thank you.

First we initiated the palisade study arrowheads arrowheads first phase III study of the Aero Apoc, III and patients with familial Cabot micro anemia syndrome or Fcs.

Christopher Anzalone: Could I have your first and last name?

Christopher Anzalone: Sure, that's David Brown.

Christopher Anzalone: FDS 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.

FCS is a rare disease in which patients have extraordinarily high triglyceride levels often in the thousands of milligrams per deciliter.

Christopher Anzalone: Thank you.

This can lead to severe and recurrent bouts of pancreatitis, which often involves hospitalization and can be fatal.

Christopher Anzalone: 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 Arrow ApoC-3 have shown clear and dramatic reductions in triglycerides, so we are confident that Arrow ApoC-3 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, these patients experience multiple additional symptoms, which adversely impact quality of life.

These patients have no FDA approved treatment options.

Christopher Anzalone: And may I get your company name?

Our clinical data in prior studies of Aero Apoc, III have shown clear and dramatic reductions in triglycerides. So we're confident that arrow apoc III is doing what it's designed to do.

Christopher Anzalone: Arrowhead, that's A-I-E-R-A.

Christopher Anzalone: Thank you very much.

Christopher Anzalone: I am connecting you to the call.

We are working to accrue patients in the palisade study as quickly as possible since there is such high unmet need for these patients.

Christopher Anzalone: There is music until it begins.

Christopher Anzalone: Thank you.

Christopher Anzalone: [music] Thank you, LaTanya, and good afternoon, everyone.

Christopher Anzalone: In addition to starting our first Phase 3 study, we also completed enrollment in the Phase 2B, Arches 2 study of Arrow Ange 3, our other wholly-owned investigational cardiometabolic candidate for patients with mixed dyslipidemia. This study enrolled over 200 patients with elevated triglycerides and LDL cholesterol.

Christopher Anzalone: Thank you for joining us today to discuss Arrowhead's results for its fiscal 2022 second quarter, ended March 31, 2022.

In addition to starting our first phase III study. We also completed enrollment in the phase <unk> <unk> two study of Aro and three our other wholly owned investigational cardio metabolic a candidate for patients with mixed dyslipidemia.

Christopher Anzalone: With us today, for management are President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter.

Christopher Anzalone: Dr. Javier San Martin, our Chief Medical Officer, will provide an update on our mid and later stage clinical pipeline.

Christopher Anzalone: Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, will provide an update on our earlier, stage programs.

Christopher Anzalone: And Ken Myszkowski, our Chief Financial Officer, will give a review of the financials.

Christopher Anzalone: We will then open the call up to your questions.

Christopher Anzalone: 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.

This study enrolled over 200 patients with elevated triglycerides and LDL cholesterol.

Christopher Anzalone: All statements other than statements of historical, fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

Christopher Anzalone: Completion of Arches 2 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 registration. We also recently initiated the gateway study of Arrow Ang3 in patients with homozygous familial hypercholesterolemia, or HOFH. This study will evaluate the ability of Arrow Ang3 to reduce LDL cholesterol in patients with the most serious and rare form of familial hypercholesterolemia.

Completion of arches, two 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 <unk> in patients with homozygous familial hypercholesterolemia or HOS H. This study will evaluate the ability of Aero age three to reduce LDL cholesterol in patients with the most serious and rare form of familial hypercholesterolemia.

Christopher Anzalone: We view the HOFH opportunity in a similar way to the FCS opportunity for Arrow ApoC3, 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.

The H O F H opportunity in a similar way to the FCS opportunity for Aero Apoc, III, where there may be a rapid path to approval and a narrow patient population with severe disease, while we conduct larger clinical studies and higher prevalence indications.

Christopher Anzalone: 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.

As I mentioned earlier, our investment in the new manufacturing facility is to support our growth into a commercial stage company.

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

Christopher Anzalone: Chris?

We think there are multiple opportunities to get there in the near to mid term and we are preparing on all fronts.

Christopher Anzalone: Thanks, Vince.

Christopher Anzalone: Vicky Bikiner is an accomplished commercial pharmaceutical executive with decades of experience building commercial organizations and launching new products across multiple therapeutic areas. You'll 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 partnered candidates. These are Opasaran targeting LP little a with Amgen, Arrow AAT also called TAC 999 with Cicada, J&J 3989, formerly Arrow HBV, for chronic hepatitis B infection with Janssen, and Arrow HSD for treatment of NASH with GSK.

Christopher Anzalone: Good afternoon, everyone, and thank you for joining us today.

To that end, we appointed a new member of our board of directors.

Keep it cleaner isn't accomplished commercial pharmaceutical executive with decades of experience building commercial organizations and launching new products across multiple therapeutic areas.

As you will have an important voice on the board and provide valuable input as our commercial strategy mapped out.

Christopher Anzalone: I want to, start by thanking you.

I also want to give a brief update on our later stage partner candidates. These are old passerine targeting LP little a with Amgen Aero 80 also called Tak 999 with Takeda.

Christopher Anzalone: 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.

Christopher Anzalone: 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 helped 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.

Christopher Anzalone: We have been very impressed with the quality of the workforce and intend to be a long-time contributor to the growing biotech ecosystem in Wisconsin.

J&J is $39 89, formerly Aro HBV for chronic hepatitis b infection, with Janssen and Aero HST for treatment of Nash with GSK.

Christopher Anzalone: 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.

Christopher Anzalone: Second, it enables us to better control IP as we develop new methods of manufacturing aimed at decreasing costs and increasing purity and scale.

Christopher Anzalone: Third, it makes us a better and more complete partner to those companies bringing the drugs we create to patients.

Christopher Anzalone: 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.

Christopher Anzalone: This is an investment in Arrowhead's future as a vertically integrated commercial stage pharmaceutical company.

Christopher Anzalone: Amgen has indicated publicly that Phase 2 clinical data for alpacaran 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 1, that they would move rapidly to start a Phase 3 study. We are very excited about this program and eager to see the phase two data. We believe that elevated 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 therapy. We have candidates addressing all of them.

Amgen has indicated publicly the phase III clinical data for El Paso, and as expected around the middle of the year. They've also indicated that if the data are consistent with the positive data seen in phase one.

That they would move rapidly to start a phase III study. We are very excited about this program and eager to see the phase II data, we believe that elevated triglycerides L. P. 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 Maxim.

Christopher Anzalone: We are making this investment now because we have a high degree of confidence in our investigational medicines both wholly owned and partnered.

Christopher Anzalone: This is an important step when a development stage company is serious about becoming a commercial entity.

Christopher Anzalone: Let's now talk about some of the recent progress we've made toward that transition.

LDL lowering therapies.

Candidates addressing all of these are two wholly owned programs Arrow Apoc, III <unk> III and our partnered program with Amgen may be able to address multiple lipids and contribute to this risk.

Christopher Anzalone: Our two wholly-owned programs, Arrow ApoC3 and Arrow Anz3, 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.

Christopher Anzalone: First we initiated the PALIFADE study, Arrowhead's first Phase III study of Arrow ApoC-3 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.

Christopher Anzalone: These patients have no FDA-approved treatment options. Our clinical data and prior studies of Arrow ApoC-3 have shown clear, and dramatic reductions in triglycerides.

Christopher Anzalone: So we are confident that Arrow ApoC-3 is doing what it is designed to do.

We still need to conduct clinical studies to assess their efficacy and safety, but we have a high degree of confidence in these programs.

Christopher Anzalone: We are working to accrue patients in the PALIFADE study as quickly as possible, since there is such high unmet need for these patients.

Christopher Anzalone: In addition to starting our first Phase III study, we also completed enrollment, in the Phase IIb ARCHES II study of Arrow Ang-3, our other wholly-owned investigational cardiometabolic candidate for patients with mixed dyslipidemia. This study enrolled over 200 patients with elevated 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.

Christopher Anzalone: 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.

Moving on to tack 99, nine we are on schedule to collect.

Christopher Anzalone: We also recently initiated the gateway study of Arrow Ang-3 in patients, with homozygous familial hypercholesterolemia, or HOFH. This study will evaluate the ability of Arrow Ang-3 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 Arrow ApoC-3, 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.

Christopher Anzalone: 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, DECADA will lead clinical developments and regulatory interactions after Phase 2. We will still be closely involved with the process and have had a very productive relationship with our colleagues at DECADA.

Christopher Anzalone: As I mentioned earlier, our investment in the new manufacturing facility is, to support our growth into a commercial-stage company.

Christopher Anzalone: We think there are multiple opportunities to get there in the near-to-midterm, and we are preparing on all fronts.

Christopher Anzalone: To that end, we appointed a new member of our board of directors. Vicky Bikiner 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.

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.

Christopher Anzalone: I also want to give a brief update on our later-stage partner candidates. These are Olpasseran targeting LP little a with Amgen, Arrow AAT also called TAC999 with Zikaida, J&J3989 formerly Arrow HBV for chronic hepatitis B infection with Janssen, and Arrow HSD for treatment of NASH with GSK. Amgen has indicated publicly that phase two clinical data, for Olpasseran 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 one, that they would move rapidly to start a phase three study.

Christopher Anzalone: We are very excited about this program and eager to see the phase two data.

Christopher Anzalone: We believe that L-beta-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 therapy. We have candidates addressing all of these.

Christopher Anzalone: Our two wholly owned programs, Arrow ApoC3 and Arrow Anz3, 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.

Christopher Anzalone: 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.

Christopher Anzalone: This process will likely take a few months, so we should have data available in the fall.

Christopher Anzalone: Our intention would be to present those data in an appropriate forum.

Our intention would be to present those data in an appropriate forum.

Christopher Anzalone: According to our agreement, DECADA 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 DECADA.

According to our agreement Takeda will lead clinical development and regulatory interactions after phase III, we will still be closely involved with the process.

And we've had a very productive relationship with our colleagues at Takeda, we look forward to additional regulatory interactions this year and moving the program forward rapidly.

Christopher Anzalone: We look forward to additional regulatory interactions this year and moving the program forward rapidly, formerly Arrow HPV, is being investigated in multiple large Phase II, 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 antigen, 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 Arrow HSD closed at the end of the first quarter this year.

Christopher Anzalone: We look forward to additional regulatory interactions this year and moving the program, forward rapidly.

Christopher Anzalone: J&J3989, formerly Arrow HPV, is being investigated in multiple large phase two 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.

J&J 39, 89, formerly Aro HBV is being investigated in multiple large phase II studies that all include a follow up phase.

Together. These will include close to a 1000 patients on various combination therapies and we would expect regular readouts for the foreseeable future as data come in.

Christopher Anzalone: Public data thus far suggests that J&J3989 is doing what it is designed to do and substantially, reducing viral antigens.

Public data thus far suggests the J&J <unk> thousand 989 is doing what it is designed to do and substantially reducing viral antigens.

Christopher Anzalone: 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.

We're excited to see these data and are hopeful that they will point to a treatment that is desperately needed by the 300 million people suffer from chronic hepatitis b infection worldwide.

Christopher Anzalone: Our partnership with GSK for Arrow HSD 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 one data, were compelling in terms of knockdown, tolerability, and transaminase decreases in patients with suspected NASH.

Our partnership with GSK for Arrow HST 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 II study this year in patients with Nash.

Christopher Anzalone: Since then, we have been working productively together and expect GSK to initiate a phase two study this year in patience with NASH. This represents a large unmet medical need. HSD is a genetically validated target.

This represents a large unmet medical need.

<unk> is a genetically validated targets. We believe we were the first to address this targeted clinically in our phase one data were compelling in terms of knockdown tolerability and transaminase decreases in patients with respect to Nash.

Christopher Anzalone: We believe we were the first to address this target clinically. And our phase one data were compelling in terms of knockdown, tolerability and transaminase decreases in patients with Aspecta Nash. Complimenting our mid and later stage pipeline, we are 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.

Complementing our mid and later stage pipeline. We're 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 cross stage of development. So it's critical that we both advance our later stage.

Christopher Anzalone: Implementing our mid and later stage pipeline, we are also active during the quarter expanding, our early stage clinical pipeline.

Christopher Anzalone: We believe sustainable growth requires a diversified portfolio of candidates across the therapeutic, areas, disease prevalence, and patient population size, and across stage of development.

Christopher Anzalone: So it's critical that we both advance our later stage programs and also constantly expand, our early stage pipeline.

Christopher Anzalone: 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've, And we certainly do not intend to tap the brakes on early development.

Grams, and also constantly expand our early stage pipeline.

Christopher Anzalone: We must also remember that Arrowhead is really good at moving rapidly from idea to the clinic.

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.

Christopher Anzalone: 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.

Christopher Anzalone: 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.., and a targeted partnership strategy helps provide necessary capital for this while also providing potentially substantial long-term economic.

As such some of those programs will be partner 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.

Christopher Anzalone: 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.

An important new medicines is an expensive business and we have the luxury of not being solely dependent upon the capital markets to fund this week.

Christopher Anzalone: 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 expect this year and every year for this 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.

Christopher Anzalone: We added 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.

Christopher Anzalone: We added 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 and II clinical studies. We'll talk more about AeroRage and AeroMuc5AC 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 mucoobstructive and inflammatory lung diseases and the role that RAGE and MUC5AC may play in addressing them.

We added three new clinical programs over the recent period.

<unk> three for treatment of complement mediated diseases, or which we initiated a phase <unk> clinical study.

And our second and third pulmonary programs Aero Rage, and Aero market by Basi for which we filed a cta to initiate phase one two clinical studies.

Christopher Anzalone: 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 mucoobstructive and inflammatory lung diseases, and the role that, RAGE and MUC5AC may play in addressing them.

We will talk more about Aero rage in air <unk> Sea at our upcoming pulmonary R&D day on May 26.

<unk> team members and two external key opinion leaders will talk about the treatment landscape for various mutual obstructive and inflammatory lung diseases and the role that rage and <unk> may play in addressing them.

Christopher Anzalone: 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 binding study of ArrowHIF-2, our investigational candidate for patients with clear cell renal cell carcinoma.

Christopher Anzalone: We will also discuss other advancements in the pulmonary platform, and disclose the next, pulmonary candidate we expect to bring to the clinic.

We will also discuss other advancements in the pulmonary platform and disclose the next pulmonary candidate we expect to bring to the clinic.

Christopher Anzalone: During the quarter, we also presented interim results for a Phase I-B dose-finding study, of Arrow HIF-2, our investigational candidate for patients with clear-cell renal cell carcinoma. The data presented provided initial proof of concept, I'm sorry, initial proof of target, engagement based on reductions in HIF-2 alpha expression.

During the quarter. We also presented interim results for a phase <unk> dose finding study of Aro <unk>, our investigational candidate for patients with clear cell renal cell carcinoma.

Christopher Anzalone: 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 technology. Our goals for that program were threefold. One, we wanted to develop a hip 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. 2.

The data presented provide initial proof of concept I'm sorry initial proof of target engagement based on reductions in hip two alpha expression.

Christopher Anzalone: We have been working on a HIF program for over a decade using different strategies and, many different iterations of our delivery technologies.

We have been working on our hip program for over a decade using different strategies in many different iterations of our delivery technologies.

Christopher Anzalone: 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 in cancer, 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 2 and 3, but the therapeutic landscape has changed for goal number 1.

Christopher Anzalone: Our goals for that program were threefold.

Our goals for that program were threefold, one we wanted to develop a hip to offer targeted therapy, because they're a supportive evidence that it could have an effect for RCC patients and it had historically been undruggable with small molecules or monoclonal antibodies.

Christopher Anzalone: 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.

Christopher Anzalone: 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.

Two we wanted to validate that we could get functional delivery of S. Irony to solid tumors, indicating that we may have a platform that can be applied to additional targets in cancer types.

Christopher Anzalone: 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 extra hepatic tissues.

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 extra hepatic tissues.

Christopher Anzalone: We think we accomplished numbers two and three, but the therapeutic landscape has changed, for goal number one.

We think we accomplished numbers two and three but the therapeutic landscape has changed for gold number one.

Christopher Anzalone: The competitive environment is dramatically different today than it was just a few years, ago, with one small molecule HIF-2 alpha inhibitor FDA approved and others in clinical development.

Christopher Anzalone: The competitive environment is dramatically different today than it was just a few years ago, with one small molecule HIF-2 alpha inhibitor FDA approved and others in clinical development. We have examined the data from our clinical study, and at this point, based on the competitive environment, we have decided not to continue further development of Arrowhead 2. 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.

The competitive environment is dramatically different today than it was just a few years ago with one small molecule <unk> two alpha inhibitor FDA approved and others in clinical development.

Christopher Anzalone: We have examined the data from our clinical study, and at this point, based on the competitive, environment, we have decided not to continue further development of arrow HIF-2.

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 arrowhead to.

Christopher Anzalone: 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.

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.

Christopher Anzalone: 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.

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.

However, as I mentioned, we did accomplished 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. The squeeze as much knockdown as possible out of each SA RNA molecule.

Christopher Anzalone: These lessons made it possible for us to develop the technology to get to various other extra, hepatic tissues.

These lessons made it possible for us to develop the technology to get to various other extra hepatic tissues.

Christopher Anzalone: 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 believe we are now much better at several things, including trigger design, optimizing chemical modifications log and design and selection linker optimization.

And design and use of PK PD enhancing structures as well as other things that can optimize target engagement.

Christopher Anzalone: 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.

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.

Christopher Anzalone: In short, we are on the board.

Christopher Anzalone: 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.

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 Arnie I can play a role in cancer treatment and we are pushing in that direction.

Christopher Anzalone: We believe that RNAi can play a role in cancer treatment, and we are pushing in that direction.

Christopher Anzalone: 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. Vivo 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.

Well highlight one more piece of corporate news, we recently announced that Arrowhead form a joint venture called by Sirna Therapeutics with vivo capital to expand the reach of innovative medicines in greater China.

Evo provided initial funding of $60 million to buy sirna, which will have exclusive rights to develop and commercialize four of arrowheads investigational therapeutics for cardio metabolic diseases in mainland, China, Hong Kong, Macau and Taiwan.

Arrowhead has a majority stake in VI sirna after accounting for shares reserved for the employee stock ownership plan and is further eligible to receive potential royalties on commercial sales.

Christopher Anzalone: 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.

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, China's clinical regulatory and commercial environment.

Christopher Anzalone: That is what we envision Vicerna becoming.

That is what we envision by certain it becoming.

Christopher Anzalone: We are looking for more than just a financial investor and Vivo checked all the necessary, boxes.

We are looking for more than just a financial investor and vivo checked all of the necessary boxes people has unique experience expertise and our 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 our probability of success without losing focus on our core target Mark.

Christopher Anzalone: Vivo has unique experience, expertise, and a local network to draw upon. That makes them a very valuable partner in this joint venture.

Christopher Anzalone: 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.

That's for future commercialization.

Christopher Anzalone: This is a win-win scenario and a transaction that we think, over time, has the potential, to become substantially more valuable.

Really a win win scenario and a transaction that we think over time has the potential to become substantially more valuable.

Christopher Anzalone: We view this as another quarter where we executed well and achieved some key corporate goals.

We view this is another quarter, where we executed well and achieved some key corporate goals for a company our size with respect to head count and market value, we have a uniquely broad and diverse set of assets.

Christopher Anzalone: For a company our size with respect to headcount and market value, we have a uniquely broad, and diverse set of assets.

Christopher Anzalone: A key part of the Arrowhead DNA is a devotion to speed and precision and a commitment to, bring RNAi to intractable diseases.

Part of the Arrowhead DNA is a devotion to speed and precision and a commitment to bring <unk> to intractable diseases. This prior period is a good example of that.

Christopher Anzalone: This prior period is a good example of that.

Christopher Anzalone: With that over to you, I'd now like to turn the call over to Dr. Javier San Martin.

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

Christopher Anzalone: Javier?

Christopher Anzalone: Thank you, Chris, and good afternoon, everyone.

Thank you Kris and good afternoon, everyone I will provide updates on enrollment for this test set of studies for <unk> HD and <unk>.

Christopher Anzalone: I will provide updates on enrollment for the VISTA set of studies for AOH3 and the SUMMIT, study for Arrow ApoC3 and give some forward guidance on anticipated timelines. I will start with the VISTA studies of AOH3, our investigational medicine designed to reduce, production of angiopoietin-like protein 3 as a potential treatment for patients with dyslipidemia. There are currently two active studies, ARCHES-2 in patients with mixed dyslipidemia and GATEWAY, in patients with HOFA.

<unk> and gave some forward guidance and anticipate the highlights I will start with the Vista studies of <unk>, Our investigational medicine designed to reduce pollution of angiopoietin like protein fee simple potential treatment for patients with dyslipidemia.

Christopher Anzalone: ARCHES-2 is a double-blind, placebo-controlled, phase 2b study. ARCHES-2 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. In randomized in a 3-to-1 ratio to receive either subcutaneous injection of AOH3 or placebo, on day one and week 12, levels of AOH3, 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.

There are currently two studies two in patients with mixed Dyslipidemia and gateway inpatient with HOA fee.

<unk> two is a double blind placebo control phase II study.

Two is fully enrolled with 204 patients with regulators just between the <unk> hundred 50, and 500 million escrow deciliter and non HDL cholesterol greater than 100 meeting deciliter LDL cholesterol regular 17 meeting.

The randomized in a three to one ratio to receive either.

Subcutaneous injection of <unk> T or placebo on day, one and week 12.

<unk>, the $50 million and immediate on some 200 million.

Evaluated against placebo.

The ratio of this study is approximately 42 weeks from screening to the week 36, and a study examination. After completing the week 36. This is LTE spend will be eligible to continue in an open label extension period.

Christopher Anzalone: We anticipate that ARCHES II will be completed around the end of 2022, and top-line data, will be available to share in the first half of 2023.

We anticipate that arent just two will be completed around the end of 2022 and top line data will be available to share in the first half of 2023.

Christopher Anzalone: The next active study is GATEWAY, an open-label Phase II clinical study to evaluate the efficacy, and safety of investigational Arrowhead H3 in up to 16 subjects with HOFH. Two-dose level of Arrowhead H3, 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. Subjects will receive a subcutaneous injection of Arrowhead H3 on day one and day 84 and, may be eligible to participate in an optional open-label extension study.

Instead, these gateway and open label Phase II clinical study to evaluate the efficacy and safety of investigation of <unk> T. In up to 16 statue with HOA, a phase two dose level of <unk>.

<unk> 200, 300 million that will be evaluated in subjects with documented HOS, which is H based on genotype or clinical criteria.

First an LDL cholesterol greater than 100 meeting that for this EBITDA.

The issue is less than 300 million put this into the screen.

<unk> will receive a subcutaneous injection of <unk> three on day, one and they may be eligible to participate in an optional open label extension study.

Christopher Anzalone: The primary objective of the GATEWAY study is to evaluate the efficacy and safety of, Arrowhead H3 in subjects with HOFH, and the primary input is the percent change in fasting calculated LDL cholesterol from baseline to week 24.

I'm in the affinity of the Gateway study to evaluate the efficacy and safety of Arrow HPV infection.

Page and the primary endpoints the percent change in fasting calculated LDL cholesterol from baseline to week 24.

Christopher Anzalone: 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.

We just tested opening clinical sites and enrolling gateway.

Weeks ago. So we don't have visibility into how long it may take to accrue all 16 patients how everybody has to have the study fully enrolled at least a meaningful amount of patients enrolled by the end of this year.

Christopher Anzalone: Our goal is to have the study fully enrolled or at least have a meaningful amount of patient, enrolled by the end of this year.

Christopher Anzalone: 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.

This is an open label study, we may be able to view results in somewhat real time, so we intend to share data in 2021 plus.

Christopher Anzalone: Next, I will provide an update on the SAMH study of Arrowhead H3, our investigational, medicine targeting apolipoprotein C3 being studied in patients with various lipid disorders. There are three active studies, TASTA-2 in patients with severe hypertriglycemia or SHTG, NUIR in patients with mixed dyslipidemia, and PALYSASE in patients with FCS. TASTA-2 is a double-blind placebo-controlled phase 2b study in approximately 216 patients, with triglycerides greater than 500 mg per deciliter. Three dose levels of Arrowhead C3, 10 mg, 25 mg, and 50 mg, will be evaluated against placebo. The primary objective of the TASTA-2 study is to evaluate the safety and efficacy of, Arrowhead C3 and to select dosing regimen for later stage clinical studies in this patient population.

Next I.

I will provide an update on the summit study.

<unk>, our investigational medicines targeting apolipoprotein <unk> being studied in patients with <unk>.

So those.

<unk> active.

Yes, the two in patients with severe hypercholesterolemia.

H T G.

In patients with mixed Dyslipidemia and Palisades in patients with Fcs.

So it's a double blind placebo control phase II study.

So approximately 216 patients with regulators with greater than 500 and mitigate this.

The dose levels.

<unk> 10, meaning 25 million and 50 media ads will be evaluated against placebo depending of shake too ambitious to studies to evaluate the safety and efficacy.

And to select the dosing regimen for later stage clinical studies in these patient populations.

Christopher Anzalone: Moving on to the NUIR study, which is a double-blind placebo-controlled phase 2b study, in approximately 320 patients with triglycerides between 150 and 500 mg per deciliter, and known HDL cholesterol greater than 100 mg per deciliter, or LDL cholesterol greater than 70 mg per deciliter. In three cohorts, 10, 25, and 50 mg, each participant will receive subcutaneous injection on day one and week 12 for a total of two injections. And in one additional 50 mg cohort, each participant will receive a subcutaneous injection on day one and week 24, for a total of two injections.

Moving onto the EMEA study, which is a double blind placebo controlled phase II study in approximately 320 patients. We take basically between 150 500 milligrams per deciliter, and known HDL cholesterol greater than a 100 milligrams per deciliter or LDL cholesterol greater than 70 meeting after this.

Yeah.

In three cohorts $10 2500 $50 million each participant will recede subcutaneous injection on day, one and week 12 for a total of two injections and one additional 50 milligram cohort each participant will receive a subcutaneous injection on day, one and week 24 for a total of two injections.

Christopher Anzalone: The primary objective of the NUIR study is to evaluate the safety and efficacy of Arrowhead C3 and to select the dose and dosing regimen for later stage clinical studies in patients with mixed dyslipidemia.

The objective of the study to evaluate the safety and efficacy of <unk> and to select the dose and dosing regimen for later stage clinical studies in patients with mixed Dyslipidemia.

Christopher Anzalone: Testa 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 SAMHEC program in palisades, a phase 3 study in approximately 72 patients, with FCS. The primary endpoint of palisades is the percentage inflammation at month end fasting triglycerides. Additionally, secondary and exploratory endpoints include the change in other lead parameters, incidence of acute pancreatitis, and other measures.

Just the two of them you need both approximately 50% enrolled and we anticipate full enrollment in the fourth quarter of 2022. This would allow for study completion in 2023.

The last study systemic program in palisade Phase III study in approximately 72 patients with FCS primary endpoint of Palisades is sick of Synching from basin spanning fasting taken initiatives.

Additionally, secondary and exploratory endpoints include the change in other lipid parameters incident acute pancreatitis and other measures.

Christopher Anzalone: We're working hard to open clinical sites around the world to approve the study as fast as possible.

By working hard to open clinical sites around the world to accrue the study as fast as possible. We will initially anticipated recruited a number of patients in Russia, Ukraine and.

Christopher Anzalone: 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.

However, due to the ongoing conflict, we have closed all clinical sites in the region, we're adding clinical sites and additional countries to maintain patient accrual. Our current goal is to have palisade fully enrolled in the middle of 2023, which will allow for study completion in 2024.

Christopher Anzalone: Our current goal is to have palisades fully enrolled in the middle of 2023, which would allow for study completion in 2024.

Christopher Anzalone: I will now turn the call over to Dr. James Hamilton.

I will now turn the call over to dose of change.

James.

Christopher Anzalone: James?

Thank you Javier I want to give updates on a few of our early stage clinical programs and preclinical programs.

Christopher Anzalone: Thank you, Javier.

Let's start with <unk> three our investigational <unk> therapeutic designed to reduce production of complement component <unk> III or <unk> three is.

As a potential therapy for various complement mediated diseases.

Christopher Anzalone: I want to give updates on a few of our early stage clinical programs, and preclinical programs.

During the quarter, we dosed the first subjects in the clinical study.

Christopher Anzalone: Let's start with AeroC3, 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 dose 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 1, healthy volunteers will receive a single subcutaneous injection of AeroC3 or placebo.

This is a phase <unk> placebo controlled dose escalating study to evaluate the safety Tolerability pharmacokinetics and pharmacodynamics of <unk>, three and up to 24 adult healthy volunteers and up to 24 patients with paroxysmal nocturnal hemoglobinuria or <unk>.

<unk>.

And up to 14 adult patients with complement mediated renal disease.

In part one healthy volunteers will receive a single subcutaneous injection of <unk> three or placebo.

Christopher Anzalone: In part 2, eligible subjects with PNH or complement-mediated renal disease will be, enrolled to receive open-label AeroC3.

And part two eligible subjects with <unk> or complement mediated renal disease will be enrolled to receive open label <unk>.

Christopher Anzalone: We have completed dosing in three of four planned cohorts in part 1 and expect to dose escalate to the final planned cohort. We intend to initiate part 2 in patients when we have selected a dose from part 1 in the next quarter or so.

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 and patients when we have selected a dose from part one of the next quarter or so.

Christopher Anzalone: 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 fascia scapulae humoral muscular dystrophy, or FSHD. FSHD patients have no real therapeutic options, so we are moving as quickly as possible to begin clinical studies.

Moving onto our first planned skeletal muscle targeted candidate Aero Dux for our investigational candidate designed to target the gene that encodes human double hold me a box for protein for dux for.

As a potential treatment for patients with Facioscapulohumeral muscular dystrophy or.

Sshd.

Sshd patients have no real therapeutic options. So we're moving as quickly as possible to begin clinical studies. However.

Christopher Anzalone: However, it has been challenging for the field to identify a reliable biomarker of DUX4 expression or of disease activity in patients with FSHD.

However, it has been challenging for the field to identify reliable biomarker of ducks for expression of disease activity in patients with Sshd.

Christopher Anzalone: Thus, it is likely that Phase 1 results may not be informative with regards to pharmacodynamic, biomarkers and may only inform on initial safety. Longer Phase 2 studies may be required to see any signs of favorable changes on imaging or in clinical endpoints.

Thus it is likely the phase one results may not be informative with regards to Pharmacodynamic Biomarkers and may only inform an initial safety.

Longer phase two studies may be required to see any signs of favorable changes on imaging or in clinical endpoints.

Christopher Anzalone: As such, in an effort to de-risk Phase 2 studies, we have opted to wait for the results of chronic toxicology studies prior to filing a CTA for Arrowdux 4.

As such in an effort to Derisk phase two studies, we have opted to wait for the results of chronic toxicology studies prior to filing a cta for <unk> four.

Christopher Anzalone: We will provide an update on timing of the CTA when we have a clear assessment on chronic tox results.

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 us on our discovery stage programs with Janssen.

Christopher Anzalone: The next update I want to give is on our discovery stage programs with Janssen called Arrow J&J 2 and Arrow J&J 3. 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, 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.

At Arrow J&J to an era of J&J <unk> III.

Christopher Anzalone: That period has now expired and Janssen did not elect to exercise their option.

We previously delivered candidates to Janssen that met the parameter as described in the research plan.

Both candidates achieved the desired level of safety and activity.

Janssen, then had a period a period in which to do disease model in biology work on the targets they selected before having to opt in and exercise the option to take an exclusive license to these candidates.

Christopher Anzalone: Because of this, we are removing the programs from our active pipeline.

That period has now expired and janssen 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 and our collaboration with Janssen as J&J $75 207 hundred 95, formerly called Aro J&J one.

Christopher Anzalone: The first discovery program outside of hepatitis B in our collaboration with Janssen is J&J 75220795, formerly called Arrow J&J 1.

Christopher Anzalone: This is an investigational sRNA therapeutic developed using Arrowhead's proprietary, trim platform and is designed to reduce expression in the liver of petitin-like phospholipase domain containing 3 or PNPLA3 as a potential treatment for patients with non-alcoholic steatohepatitis or NASH.

This is an investigational <unk> therapeutic developed using arrowheads proprietary trim platform and is designed to reduce expression in the liver.

It didn't like phospholipase domain containing three or <unk>, three as a potential treatment for patients with nonalcoholic <unk> hepatitis or Nash.

Christopher Anzalone: This program is in a phase one clinical study and continues to progress as planned in clinical development.

This program is in a phase one clinical study and continues to progress as planned in clinical development.

Christopher Anzalone: The last programs I want to discuss are our newest pulmonary candidates, Arrow RAGE, and Arrow MUC5AC. 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, Arrow MUC5AC, targets expression of MUC5AC, a mucin protein, with upregulated expression in the asthmatic airway. Arrow MUC5AC is an extremely exciting program in part because it represents a fundamentally new way of treating mucoobstructive disease.

The last program I want to discuss our our newest pulmonary candidates era rage and Aero modified they see.

We filed a cta as 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 Arrow multi they see targets expression of multiply they see a mucin protein was up regulate the expression in the asthmatic here with <unk>.

<unk> is an extremely exciting program in part because it represents a fundamentally new way of treating nuclear obstructive disease.

Christopher Anzalone: Second program, Arrow RAGE, targets expression of the receptor for advanced glycation end products or RAGE. RAGE represents an upstream mediator of the inflammatory cascade.

Second program Arrow Rage.

Targets expression of the receptor for advanced location and products or rage rage represents an upstream mediator of the inflammatory cascade.

Christopher Anzalone: We believe they both have a differentiated mechanism and offer potential advantages, over currently available therapies for various mucoobstructive and inflammatory pulmonary diseases.

We believe they both have a differentiated mechanism and offer potential advantages over currently available therapies for various mutual obstructive and inflammatory pulmonary diseases.

Christopher Anzalone: We will describe these programs in more detail at our pulmonary R&D day on May 26.

We will describe these programs in more detail at our pulmonary R&D day on May 26.

Christopher Anzalone: I will now turn the call over to Ken Myszkowski.

I'll now turn the call over to Ken Moskovsky Ken.

Christopher Anzalone: Ken?

Thank you James and good afternoon, everyone.

As we reported today, our net income for the three months ended March 31, 2022 was $44 4 million or <unk> 41.

Share based on 100 and 107 nine.

Fully diluted weighted average shares outstanding.

This compares with a net loss of $26 8 million or <unk> 26 per share based on $103 9 million fully diluted weighted average shares outstanding.

For the three months ended March 31 2021.

Revenue for the quarter ended March 31, 2022 was $151 8 million compared to $32 8 million for the quarter ended March 31 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 in Horizon will be recognized as we complete our performance obligations, which include managing the ongoing <unk> phase III clinical trials for Takeda and delivering a phase one ready candidate to horizon.

Christopher Anzalone: Thank you, James, and good afternoon, everyone.

So it remains a $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.

Christopher Anzalone: As we reported today, our net income for the three months ended March 31, 2022, was $44.4 million, or $0.41 per share, based on $107.9 million fully diluted weighted average shares outstanding. This compares with a net loss of $26.8 million, or $0.26 per share, based on $103.9 million fully diluted weighted average shares outstanding, for the three months ended March 31, 2021.

Christopher Anzalone: Revenue for the quarter ended March 31, 2022, was $151.8 million, compared to $32.8 million for the quarter ended March 31, 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 in the prior period, primarily related to a recognition of a portion of the milestones received from our license and collaboration agreements with Janssen and Takeda.

Total operating expenses for the quarter ended March 31, 2022 were $110 3 million compared to 61 $61 million for the quarter ended March 31 2021.

This increase is primarily due to increased clinical candidate costs as our pipeline has expanded.

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 from the prior period.

We continue to estimate our operating cash burn to be $60 million to $80 million per quarter in fiscal 2022.

Excluding any incoming milestone payments from our partners.

In addition, we are expanding our manufacturing capabilities in our R&D facilities. Because these two projects have only recently begun our capital expenditures in fiscal 2022 will be lower than originally estimated capital expenditures will increase next year.

Christopher Anzalone: 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 two clinical trials for Takeda, and delivering a phase one 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.

Turning to our balance sheet, our cash and investments totaled $603 5 million at March 31, 2022, compared to $613 4 million at September 32021.

The decrease in our cash and cash.

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 31, 2022 were $105 7 million.

Christopher Anzalone: 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.

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

Christopher Anzalone: Total operating expenses for the quarter ended March 31, 2022, were $110.3 million, compared to $61 million for the quarter ended March 31, 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.

Christopher Anzalone: 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.

Thanks, Ken and thanks to all of you for joining us today.

Christopher Anzalone: We continue to estimate our operating cash burn to be $60 to $80 million per quarter in fiscal 2022. 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.

Christopher Anzalone: 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 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.

As a company have a track record of execution.

Company had the ability and commitment to continued pipeline growth.

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 RNA and the trim platform, both of which are increasingly validated clinically.

Whether addressing chronic HBV, 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 RNA against every target we're 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're 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.

Christopher Anzalone: Our common shares outstanding at March 31, 2022, were $105.7 million.

Thank you for joining us today and I'd now like to open the call to your questions operator.

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

Christopher Anzalone: Thanks, Ken, and thanks to all of you for joining us today.

Certainly as a reminder to ask a question you will need to press star one 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.

Christopher Anzalone: When markets go through cycles of intense pressure, as they are today, investors seek, value.

Christopher Anzalone: Each investor needs to define for themselves what value means, but I see value in a biotech, company through several questions.

Christopher Anzalone: Does the company have multiple potential drugs?

Hi, Thanks for taking my questions.

To ask a question on AAP, if you could talk more about the expectations for the upcoming regulatory interaction in the spring added.

Christopher Anzalone: Are those potential drugs built on a platform with known safety and activity parameters?

Christopher Anzalone: Are those drugs addressing real unmet medical needs in a unique way?

Phase III 12 month biopsy read out and how you are planning on updating investors. After the meeting is completed.

Christopher Anzalone: Does the company have sufficient capital and access to capital?

Okay everyone.

Christopher Anzalone: Does the company have a track record of execution?

Sure.

Why can with Takeda and <unk> that is leading the interaction with the FDA from now on so they will lead the next meeting which is the end of phase II meeting that we hope it within the next few months and that meeting as you know the key discussion point will be the design of the phase III study that include and pulling sample size.

Christopher Anzalone: Does the company have the ability and commitment to continued pipeline growth?

Christopher Anzalone: And is the company focused on long-term growth and getting drugs to patients?

Christopher Anzalone: These may seem simple and straightforward, but precious few companies our size can answer, all of these questions in the affirmative.

Christopher Anzalone: I believe that we do.

Christopher Anzalone: 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.

It does.

Christopher Anzalone: I believe we have a pipeline that is substantially larger than any company our size and larger, than most companies several times our size.

Christopher Anzalone: Everything we do is built on RNAI and the TRMM platform, both of which are increasingly, validated clinically.

So that's the type of with regard to the regulatory we expect to have a decision in that one.

Christopher Anzalone: 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.

Christopher Anzalone: We have a strong balance sheet and, importantly, access to ongoing capital as our current partnerships, mature and trigger milestone payments.

Christopher Anzalone: 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.

Christopher Anzalone: 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.

Christopher Anzalone: Certainly.

Christopher Anzalone: Thank you for joining us today, and I would now like to open the call to your questions.

Christopher Anzalone: 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.

Christopher Anzalone: Operator?

The second half of this year.

This study in 2001, which looked a dose ranging study for the dose ranging component is completed and it would be part of the package.

Christopher Anzalone: Our first question comes from Maury Raycroft of Jeffrey's.

As Keith said the study will be completed in Panama. The biopsy by July of this year. So we have everything we need.

Christopher Anzalone: Your line is open.

Christopher Anzalone: Hi, thanks for taking my questions.

Christopher Anzalone: I was going to ask a question on AAT.

Who had this meeting with the FDA that Cuba is doing a pretty good till then we are collaborating very closely and so I think we will have more about this in the next call for sure and also.

To be clear.

<unk> said the the dose finding portion of that study is read out and given those data Takeda has initiated.

Christopher Anzalone: If you can, 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.

Interactions with the FDA, so that's already begun.

We expect them to have a formal meeting.

And the next.

Coming months.

And so we'll see where we're at how we'll see how that phase III as designed.

The whole.

We look forward to seeing the the biopsy data sometime this fall from from the Sequoia study that as you know is blinded. So we haven't seen anything there.

That's just that's that's a bit of a wildcard we look forward to seeing what those look like.

I think we have to focus on <unk> focus on designing the phase III right now and then and then once once we see those data from from square biopsy biopsy.

See if that if that.

Thanks.

Their actions going forward with the FDA.

Got it that's helpful and well this.

Well the upcoming out of phase II meeting will that determine what the endpoint is.

And when you get the biopsy data will the endpoint change or I guess, how should we think about that.

Yes exactly.

Phase two meeting will the goal is to have an agreement on the.

Pacific Phase III study design, which will include primary endpoint the duration the dose.

The sample size. So all the details about the phase III study and also in a phase II would include CMC. The conversations so everything needs to be in place to say that Ritchie station phase III study right after that meeting.

Got it Okay, and maybe just a quick question on <unk> four just wanted to clarify if youre seeing any signals in the healthy volunteers prior to starting part too or are you just being conservative waiting for the chronic tox data.

So if you are asking.

Ducks for that study has not yet started in the clinic yet so that's still preclinical we have not enrolled any healthy volunteers.

Given independent in the prepared remarks, and James the prepared remarks.

As you described.

We learned from from prior clinical studies.

It's difficult to measure.

<unk> four and so given that it made sense to us to maybe go a bit slower on the front end. So we can go faster on the on the later stages and so we're waiting to see what those chronic tox.

Ada might look like before we before we design the.

You know that.

The study and initiate the study.

Got it okay that makes sense, okay. Thanks for taking my questions.

You're welcome.

Our next question comes from Luca <unk> of RBC capital. Your line is open.

Hello, great. Thanks, so much for taking my question, maybe circle back Morris question earlier, maybe ask a little bit more directly.

Is there a scenario where you can file early for <unk> in the second half of the year should the biopsy data check the box given that you have breakthrough therapy designation.

There would be great.

And then maybe on hepatitis B I think we've seen J&J, obviously discontinuing to collaboration with Bavarian Nordic. So wondering if that's just one off or maybe if it reflects like lower interest interest in the space for them more broadly also any color there would be great. Thanks, so much.

Sure. So let me take ABB first.

We don't see any evidence that that J&J is losing interest in HBV to the contrary.

They are working as fast as ever and they are expanding these studies it almost seems like every day.

Different patient populations and such and so we see we see a strong interest in HBV I don't know what the.

What led them to terminate those other partnerships, but but but ours is going strong and we still feel confident about our drug and we feel confident about them as a partner and they are in their their commitment to the to the disease. So so.

We're still got into plays in there with respect to <unk>.

It's hard I don't really want to speculate on what we could do with.

With those biopsy data just because there's too many unknowns right now we indicated it together have to focus on on on negotiated with the FDA on finding common ground with the FDA on what a phase III study will look like how large study. It is what the endpoints are how long the study it is and the like we think we will get there because the FDA has been quite.

Collaborative so far and as you pointed out we do have breakthrough therapy designation. So we can have these discussions. So we're confident that we will that we will or that Takeda will design.

And enroll a bold good study that will that will.

That would be beneficial to the ultimate drug I think.

Now having said that look we look forward to seeing what those biopsy data look like and once once all of that is unblinded.

We indicated together, we'll take a look at it and it's certainly conceivable that should those should those data be be extraordinarily compelling that it could lead to two discussions with the FDA under our.

Under our designation with them. So 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.

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 youre lowering that guidance. So wondering if you can give us a little more kind of quantitative color on that that'd be great. Thanks, so much.

Yes, we are lowering our guidance on capital expenditures this year as I had mentioned in our remarks. The two major projects just recently started.

So we might expect.

Our capex to be.

Something like 25% to 50% of what we originally estimated.

And as I said those projects will move more quickly at the end of this year.

Increase our capital expenditures in fiscal 2023.

Super helpful. Thanks, So much guys.

Welcome. Thank you. Our next question comes from Matthew Kumar of Goldman Sachs. Your line is open.

Hi, This is Omar arent somebody we have a handful of questions. So first can you remind us of the cadence of news flow from the <unk> program in 2022 more.

More specifically can we expect top line data at a medical meeting and disclosure of regulatory interactions.

Christopher Anzalone: Javier, do you want to address that?

Yes.

Javier you want address that so we will present that data in 2002 are you still.

Christopher Anzalone: Sure.

At the end of June and then meeting in London, So that would be.

Christopher Anzalone: As you know, we're working with Takeda, and Takeda is leading the interaction with, the FDA from now on.

At this point the only presentation.

Made this close when we complete the 2001 analysis.

Second half of this year.

And with regards to the regulatory production when we say within the next few months we have.

Christopher Anzalone: 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.

The end of phase II meeting and the expectation is to start a phase III this year.

Christopher Anzalone: So that's the status with regard to regulatory.

So that's good.

Christopher Anzalone: We expect to have a decision and an agreement at one point in the second half of this year.

Christopher Anzalone: So we have everything we need to have this meeting with the FDA.

Christopher Anzalone: The study 2001, which was the dose-ranging study, for the dose-ranging component is completed, and it will be part of the package.

Christopher Anzalone: Takeda is doing a very good job, and we're collaborating very closely.

So.

Christopher Anzalone: As Chris said, the study will be completed in terms of the biopsy by July of this year.

Christopher Anzalone: And so I think, we will have more about this in the next call for sure.

I don't think were we don't expect to provide a blow by blow, but once we have alignment with the FDA on what that basically it looks like we'll be happy to of course disclosed that and I went up to us to say.

We're working on the amount of <unk> 2002, so.

Now preparation here too suddenly that Magnus piece, so hopefully that will be published this year.

Alright. Thank you and then just maybe jumping the gun for the pulmonary R and D day in a few weeks, but what is the clinical proof of concept looks like to you for the lead loan programs.

James you want to address that.

Sure I think we will be talking a lot more about that.

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.

Christopher Anzalone: And also, to be clear, as Javier said, the dose-finding portion of that study has read, out, and given those data, Takeda has initiated interactions with the FDA.

Christopher Anzalone: So that's already begun.

Christopher Anzalone: You know, they will, we expect them to have a formal meeting in the next coming months.

We can knockdown targets in that.

We havent good dose response, there so I think thats.

The most important thing we expect to get that phase one.

Christopher Anzalone: And so we'll see how that Phase 3 is designed.

We have circulating biomarkers there so so.

It will be much more straightforward to to look at that with rage and look obviously then it was would be neck.

And.

If I could take two more questions and then how should we think about the upcoming <unk>.

Randy and Brian .

Literally landscape and then how.

How far do you plan to take <unk> and three an arrow apoc III and cardiovascular disease is there any plan to perform Cmos.

Christopher Anzalone: The whole, you know, we look forward to seeing the biopsy data sometime this fall, you know, from the Sequoia study.

Yes, so I'll take that one first look.

Look we.

It is our plan right now to take Arrow, and three and <unk> III through to registration. We think those are potentially very important drugs and we think that they.

<unk>.

They will provide important new tools to cardiologists lipid clinics and.

Said this in the past I know it sounds I don't want to overstate it but.

It really feels like those those are important drugs.

And so we are fully committed to those and I think we're going to commercialize those.

Christopher Anzalone: That, as you know, is blinded, so we haven't seen anything there.

The first question was with respect to El Paso, Dan I don't know what else I can I can tell you is we haven't seen any data. So there's nothing I can I can I can accidentally tell you.

Christopher Anzalone: And that's just, that's, a bit of a wild card.

Christopher Anzalone: You know, 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 3 right now.

We are waiting to see what those data look like just like the rest of us just.

Just like the rest of you.

As one data were compelling.

It looks like it's a very potent.

Drug candidates.

I think that the genetic validation.

With respect to that target is clear that drug or the drug candidate appears to be doing what we wanted to do it appears to be well tolerated and so we're excited to see those data and we and to be honest, we fully expect.

Christopher Anzalone: And then once we see those data from the Sequoia biopsy, you know, we'll see if that affects their actions going forward with the FDA.

For Amgen to push that into a into a pivotal study quite quickly.

Christopher Anzalone: Got it.

Alright, thanks for taking our questions.

Youre welcome.

Christopher Anzalone: That's helpful.

Our next question comes from Ellie Merle of UBS. Your line is open.

Christopher Anzalone: And will this, will the upcoming end of Phase 2 meeting, will, that determine what the endpoint is?

Christopher Anzalone: And when you get the biopsy data, will the, could the endpoint change?

Hey, guys. Thanks for taking the question.

Christopher Anzalone: Or I guess, how should we think about that?

As a follow up on that region.

AC program I guess, if youre starting to dose patients are.

Christopher Anzalone: Yeah, exactly.

Midyear, how should we think about the timing to seeing a national circulating biomarker data just given.

Christopher Anzalone: That end of Phase 2 meeting will, the goal is to have an agreement on, the specific Phase 3 study design, which will include the primary endpoint, the duration, the dose, and the sample size. So all the details about the Phase 3 study.

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 C III program.

It seems like Youre progressing through.

The cohorts <unk> I guess, how should we think about timing to initial data there and what you are looking to see for dose selection.

Such as a particular degree or level.

Knockdown in <unk> three as you think about dose selection for patients.

Sure. This is my questions I can't give you I can't give you.

Terribly straight forward guidance on any of those.

I will say with fee three though I do expect that we will that we will have some at least top line data. This year I don't know when I don't know whats going to be in it we need to.

To finish dose escalation to healthy volunteers before we before we start to look for patients I don't know how long it'll take to to dose patient.

Patients in that in that cohort. So it's really too early to give any guidance there, but I do it.

Truly they will expect we will have some data that we can talk about this year with C. III.

That's at least in healthy volunteer so far is enrolling quite well with rage and muck.

We haven't started dosing patients yet that will be as you pointed out sometime in the middle of the year and so similarly, it's a bit too too early to too.

Two to guide when we might see some wondering might present some data I expect we'll see data this year.

But but but I don't know when we'll have enough.

To package up and something that will be digestible by the outside.

My hope is that sometime soon.

In the third quarter, we'll have a much better idea about that and I can give you more more specific guidance.

Got it and then just a follow up on FSA HD, maybe just.

In terms of the decision to sort of wait for more of that chronic GOP tox data I mean, I guess was there anything that you saw pre clinically that <unk>.

For instance decision or if you could just maybe elaborate on any sort of preclinical data points that maybe content that.

Yes sure.

The key driver of that decision is what we have described already on the call is that we.

We may not have.

Clear evidence of a PD effect.

Can see until the end of phase two really so we felt like.

It was important to derisk that that could be I mean, if you look back at the Fulcrum study and they're designed to be a longer study. So we really want is to make sure that.

The Tox profile would support such a longer study.

Got it thanks.

Christopher Anzalone: And also the end of Phase 2 will include CMC, the conversation.

And our next question comes from Joel Beatty of Baird. Your line is open.

Christopher Anzalone: So everything needs to be in place to set the registration Phase 3 study right after that meeting.

Hi, Thanks for taking my questions. The first one is on the EAP program thinking ahead to the discussions with FDA on the phase III trial design.

The trial design can be different from Sequoia and is there any possibility that ends up looking pretty similar to what's already in sequence.

Christopher Anzalone: Got it.

Well listen this is deploy.

I don't know if you remember that we came to the sign of the Sequoia. So the initial take.

Now that the trial at this time.

To be a registration study is no longer in play we amended the protocol. We may then specific dose finding study, we enrolled 40 patients and feed those levels or.

Christopher Anzalone: Okay.

Christopher Anzalone: And maybe just a quick question on DUX4.

Placebo.

Is a double blind study we had the initial analysis looking at the ceiling Z protein up to week six.

<unk> for the selection and as we said in the call. We will have the last biopsy for the 40 patients.

And June or July of this year, so that data will be available later, so the phase III registration study will not be seen.

In Sequoia, we end up enrolling patients with cirrhosis, so no fibrosis, because that will see available on with regard to the sale and the C level of the protein for the selection, which that was the primary PV market for both selection.

So it's going to be different.

Of course, we need to get into the details later, when we had the meeting with the agency.

No that would be similar to the Sequoia study.

Got it that's helpful and then on the <unk>.

Two new lung programs entering the clinic midyear and what dose levels will you be testing and how do those dose levels compare to the dosing that was used in the previous the next study.

You've disclosed anything on starting dose.

For either of those programs at this point.

But it's a good question and what's your I assume youre getting at is.

Will we be do we expect to be using as much drug.

For these studies as we are for <unk> and.

And I think the answer is we do not given.

Given the.

The <unk>.

Duration.

Yes.

Probably looking for.

Timing interval between doses.

Got it thank you.

And our next question comes from Patrick Xu CEO of H C. Wainwright Your line is open.

Thanks.

Christopher Anzalone: Just wanted to clarify if you're, seeing any signals in the healthy volunteers prior to starting Part 2, or are you just being conservative, waiting for the chronic tox data?

Afternoon, just to follow up on the hip too on the oncology platform disc.

A discussion in the prepared remarks around the program and that clear target engagement has been demonstrated in that RNA on has a place in treating cancer that improve.

Christopher Anzalone: So if you're asking about DUX4, that study has not yet started in the clinic yet, so that's, still pre-clinical.

Christopher Anzalone: We have not enrolled any healthy volunteers.

Christopher Anzalone: Yeah, it just, given, in the prepared remarks, in James's 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.

Improvements on existing contracts needed to move forward I'm wondering if you can elaborate on this commentary specifically give us some 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 improvement specifically would be.

Christopher Anzalone: Got it.

Christopher Anzalone: Okay, that makes sense.

Christopher Anzalone: Okay, thanks for taking my questions.

Christopher Anzalone: You're welcome.

Christopher Anzalone: Our next question comes from Luca Issi of RBC Capital.

Part of this program compared to two program.

Christopher Anzalone: Your line is open.

Christopher Anzalone: Oh, great.

Would the target be the same or could we also have new targets as part of a broader oncology platform.

Christopher Anzalone: Thanks so much for taking my question.

Christopher Anzalone: Maybe circle back on Maura's question earlier, maybe ask a little bit more directly.

Sure. So first I'll take these are part of that first which is which targets it will be a different target.

Christopher Anzalone: Is there a scenario where you can file early for A118 in the second half of the year?

Christopher Anzalone: Should the biopsy data check the box, given that you have breakthrough therapy designation?

Christopher Anzalone: Again, any call there would be great.

As we mentioned.

The great news for for clear cell renal cell carcinoma patients is that is that there are now good alternatives. There are now good.

Christopher Anzalone: And then maybe on hepatitis B, I think we've seen J&J obviously discontinue their collaboration with Bavir and Nordic, so wondering if that's just one-off or maybe if it reflects, like, a lower interest in the space for them more broadly.

Good looking drugs that address the hip to alpha.

Christopher Anzalone: Also, any call there would be great.

Pathway and so so.

We will make bets in other targets, there's a lot of other targets I think that we could go after.

Christopher Anzalone: Thanks so much.

Now with respect to timing.

That's hard to know I can't give you any guidance certainly nothing this year.

Christopher Anzalone: Sure, sir.

Christopher Anzalone: So let me take HPV first.

Christopher Anzalone: We don't see any evidence that J&J is losing interest, in HPV.

Christopher Anzalone: 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.

We were encouraged by the data we are seeing knockdown, we can get into tumors. We can get knocked down in tumors. That's all good news, but.

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 and so we're trying a number of different strategies to get there.

Christopher Anzalone: And so we see, you know, we see a strong interest in HPV.

Christopher Anzalone: I don't know what, 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.

And so and so it's still a bit early 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.

At some point.

It would make sense for us to find a good partner.

For oncology, it's a difficult space.

And it would be great at some point.

We will if we can find a partner to work with them on new targets as well as on.

Possible delivery strategies. So so we're still in the first few innings of this of this game, but the good news is again as I mentioned I do believe we are on the board I think we've got a good first and then I think mixing my metaphors and then we've got a good first step.

Christopher Anzalone: So, you know, we're still guns ablaze in there.

At this at this platform.

Yeah, that's helpful and just a follow up on arches. Two program first can you discuss the level of confidence that the program will not have the same setback is north and secondly, what would be considered homerun data and arches too and when the data is reported in first half of 2023, and then lastly, just how do we think about the clinical development path forward.

Mixed dyslipidemia in phase III and potential commercial launch trajectory if the drug is approved.

Alright.

Let's see.

Christopher Anzalone: With respect to AAT, you know, it's hard, I don't really want to speculate on what we could do with, you know, with those biopsy data, just because there's too many unknowns.

With regard to the.

The COVID-19.

<unk> two program.

We only see the first vessels equation that I kind of think where our expectations.

<unk>.

Christopher Anzalone: You know, 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. You know, how large a study it is, what the endpoints are, how long a study it is, and the like.

Oh, I think I was sufficient that we're going to have a very clean safety profile.

He had a pattern of efficacy I mean, we already have a lot of data with a phase III study was over 100 patients.

Christopher Anzalone: 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 designations so we can have these discussions.

Christopher Anzalone: So we're confident that we will, or that Decatur, you know, will design, you know, an enrollable good study that will be beneficial to the ultimate drug, I think.

Christopher Anzalone: Now, having said that, you know, look, we look forward to seeing what those biopsy data look like, and once, you know, once all of that is unblinded, we and Decatur together will take a look at it, and it's certainly, you know, conceivable that, you know, should those, should those data be, you know, extraordinarily compelling, that it could lead to discussions with the FDA under our 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.

Different type of patient populations, and then a very very consistent so I don't see any.

Christopher Anzalone: Super helpful.

Christopher Anzalone: And then maybe, if I may, on capital expenditure, I think in the past you've guided $80-90, million for fiscal 2022.

Christopher Anzalone: That'd be great.

Christopher Anzalone: However, it sounds like you're lowering that guidance, so I'm wondering if you can give, us a little bit more quantitative color on that.

Possibly deploy robotic of any type.

Christopher Anzalone: 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 CapEx to be something like 25-50% of what we originally estimated. And as I said, those projects will move quickly at the end of this year, and we'll increase, our capital expenditures in fiscal 2023.

So the data is already strong enough so.

Very comfortable and confident about that.

And the phase II study is going to read the first quarter.

This coming year. So we would have the full answer.

What we're doing.

Significant detail is working internally and with Kols to really understand what is the this follow for both molecules. When do you think about mixed Dyslipidemia, we may talk about.

In more detail in the near future.

A lot of work going on to really understand who would be the patient populations that might benefit from either or these two drugs.

Both the profile.

Really different and we believe that the patient population that will uniquely benefit from either of these two tubes, but we are doing the work right now, but looking at the biology, the specific biology and ask of the Hcl biology, specifically, but also looking at data basis and made some clinical trials.

To understand where the residual risk for cardiovascular disease.

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 an end of phase II.

Need to start to look up flow company, some Seattle, so for us to think about the major cardiovascular outcome trials.

So I think we are in I guess it was doing a lot of work right now to be ready to receive the phase two data and how that plan.

To move forward going through the agency.

Long term strategy.

Sure.

Yes.

We expect to have a cardio metabolic day later this year and so I think we'll I think we'll have we'll have.

We can really kind of spread out and talk about our plans and what we see at that point.

But look.

We're going to learn a lot with all of these phase II studies over the next year, plus we're doing an awful lot of patients different populations and I think I think we're going to learn a lot about how how and versus April will address various populations, having said that at this point the way we're thinking about about these.

As follows four for Apoc III, 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.

Larger longer studies to support the use of Apoc III against severe hypercholesterolemia. We're also as you know doing studies and mixed it in mixed dyslipidemia and so that gives us optionality and maybe or maybe not do a very large.

Outcomes trial for that for that compound on the an side.

Similar we see and HOS <unk> possible.

Possibility there.

Similar to the FCS opportunity, where we can get to market relatively quickly and while we were doing larger studies, we do believe that that the.

A large outcome study would be interesting for <unk> III, given what we've seen so far in <unk>.

In the phase one study and so that's our expectation at this point.

To go after the large dyslipidemia population with that with that drug again, we'll learn a lot over the next year plus with these phase twos and so and so.

So some of those opinions may change a bit but right now that's what we're thinking.

Yep.

That's very helpful. Thanks.

Christopher Anzalone: Super helpful.

Youre welcome and our next question comes from my Yang maintaining and B Riley Securities.

Christopher Anzalone: Thanks so much, Gary.

Good afternoon team, thanks for taking our questions and congrats on the manufacturing facility and a foundation of I say actually if I could go back on this topic that Chris is that where you were commenting on <unk> can you just summarize for us.

Christopher Anzalone: You're welcome.

Christopher Anzalone: Thank you.

What is the opportunity you see in sort of improving the perception of <unk> T as a target.

And sort of obviously in light of what we've seen with other modalities.

And given the initial promise we had from the medallions.

<unk>.

As Youre thinking about the guide you metabolic day would be helpful. I think if you could comment on.

Sure.

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.

Yes.

Javier said our data were clear.

Our phase one two studies.

We dosed.

Large number of patients we saw consistent reductions in LDL. We saw we saw a good safety profile, we saw consistent reductions in triglycerides and so so whatever other 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.

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 on that pathway and on and on our drug.

Got it and then as you start working on your Phase one studies for Merck and rage and apply learnings from the enact program.

And does that study that I think is published at a conference about.

How are you thinking about the dose level versus knockdown it looks like.

You are working with some lower doses here with the newer targets and but like.

It was about 66% knockdown, but I think youre getting higher knockdown with some of these newer target so.

Can you just remind us like how much knockdown, we need with these newer targets and then just maybe how far along you out with the chronic dog studies for these two new programs.

Yes, sure. So we will be presenting data on both of those programs on privacy and range at the Ats Conference starts next week and Youre right. The.

We have previously described for <unk> about.

About 66% knockdown in the rat and we are seeing better knockdown than that.

Both.

Saturday targeting multi BC and reach in.

In rodents, but also in non human primates.

I'll be sharing some of some of those data.

Either that story is.

Not only a matter of just lower dose levels on lower overall exposure.

Less frequent dosing.

Dosing intervals as Chris alluded to before.

A really important I think for both market range.

Was there another piece of that question.

Chronic dog studies.

How long have you gone there in the preclinical model.

So the chronic tox.

Not yet started for either of those we've completed.

The IND or Cta, enabling tox and Thats complete for both Mark and reach in and let's be clear on that that's intentional.

We want to see what the durability to look like in humans before we do a chronic tox study and animals. Just so we have we have a good we have a good idea about about what sort of intervals, we should be testing.

Right.

Dosing once a month.

If we see durability to last the last 30 days that would that would.

Suggest certain kind of chronic tox study, if we are seeing durability in 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.

Great. Thank you for that clarification, and then just one final question high level.

Any exploratory work done of delivering on NII.

Right now it broadly CNS.

Are there going to be good nights have been also deployed have you guys done any work around that preclinical.

Yes, so we haven't talked about about any other cell types that we are going after internally.

But you've been around us long enough to know that debt.

That we are that we are always looking for new cell types and so we've not disclosed what our next cell type as yet.

Okay.

We do some of those disclosures and Youll pulmonary day later this month, thanks for taking my questions.

Christopher Anzalone: Our next question comes from Madhu Kumar of Goldman Sachs.

Great. Thank you.

And our next question comes from K, Nikki and sharpen your line is open.

Christopher Anzalone: Your line is open.

Christopher Anzalone: Hi.

Yeah.

Yes. Thank you for the question.

With respect to have two of them going after additional oncology targets. I guess my question is why why why do that as opposed to just under last question other targets, let's say outside the liver.

Yeah, that's a great question.

Don't mean to be flip, but work, but when we can we are more of an and company then or company and I think we've got the bandwidth to do both of those things.

I think your point is a good one we've got we've got really good leads and other cell types and so if we were if we were more bandwidth constrained than than one could argue that we should maybe slow walk the oncology a bit because we've got we got really good exciting opportunities in other places, but I think we can do both and also as I said in the prepared remarks.

<unk>.

All of the reasons that we that the oncology program was important for US is that it gave us.

Gave us a chance to to learn broadly how to deliver extra emphatically and I think that a lot that we'll still be the case. So it makes sense strategically there.

But.

The underlying point there is a strong one oncology is difficult.

And so.

We would not like to be solely an oncology company.

A risky endeavor, but it's something that I think we owe it to patients two to investigate because I think we could do it we've got a good we've got a good first step as I mentioned with our gift throughout the program and I think that just with a little bit of tweaking, we might have something that that can be usable across other tumor types.

Christopher Anzalone: This is Omari Oren from Madhu.

Okay. Thanks, Chris.

You're welcome.

And our next question comes from Manny Forehearth of SVP Securities. Your line is open.

Christopher Anzalone: We have a handful of questions.

Hey, guys. Thanks for taking my question.

Christopher Anzalone: So first, can you remind us of the cadence of news flow from the AAT program in 2022?

But you've always focused on speed into the clinic because one of your core I was wonder if your core competencies in sort of philosophy of the company.

One of the challenges there is making sure that every.

Target is appropriately embedded every market opportunity actually exist. So could you help us understand your rationale for why it is an opportunity for you and Pn H. How you think about other comparable EBITDA diseases, where all my element others with many times your resources and expertise in RNA eye or let's.

Christopher Anzalone: More specifically, can we expect top-line data at a medical meeting and disclosure of, regulatory interactions?

Christopher Anzalone: Javier, do you want to address that?

Christopher Anzalone: So we will present the data in 2002 at ESL to the end of June at the meeting in London.

Christopher Anzalone: So that will be, I think at this point, the only presentation.

Christopher Anzalone: We made this close when we completed the 2001 analysis the second half of this year.

Christopher Anzalone: And with regard to the regulatory interaction, we say within the next few months, we have, the end of phase two meeting, and the expectation is to start the phase three this year.

Christopher Anzalone: So that's...

Christopher Anzalone: Right.

Christopher Anzalone: Yeah.

Christopher Anzalone: And so, you know, I don't think we're, we don't expect you to provide a blow-by-blow, 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.

Let's say, it's a real challenges.

Christopher Anzalone: And I wanted to also say that we're working on the manuscript from 2002.

And then secondarily, how are we ever going to see the further but further safety data that we saw in terms.

That safety signal that showed up in <unk> or do you intend to sort of hold that internally about disclosing more detail. Thanks guys.

Yeah, So I'll let.

James handle the <unk> question quickly on the <unk>.

Christopher Anzalone: So we're in the final preparation here to submit that manuscript.

Christopher Anzalone: So hopefully that will be published this year.

Christopher Anzalone: All right.

Christopher Anzalone: Thank you.

We're still.

Considering our second we're still working on a second generation <unk>.

Christopher Anzalone: 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?

So I think until and unless we have that ready to go doesn't make much sense for us to focus on prior data. So so we'll hold off until we see where that where the <unk> is going to go James you want to address the Q3, yes sure so with regards to <unk> specifically.

Christopher Anzalone: James, do you want to address that?

Christopher Anzalone: Yeah, sure.

Christopher Anzalone: I think we will be talking a lot more about that at the R&D day, end of the month.

Christopher Anzalone: 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.

Christopher Anzalone: And we have circulating biomarkers there.

Christopher Anzalone: So I think that's the most important thing we expect to get out of phase one.

Christopher Anzalone: So, you know, it'll be much more straightforward to look at that with RAGE and MUC-PIVC than, it was with R&D.

Christopher Anzalone: If I could fit two more questions in, how should we think about the upcoming Lapsarandia, and Guevara Lp8 landscape?

Christopher Anzalone: And then how far do you plan to take Arrow H3 and Arrow Apo C3 in cardiovascular disease?

What interest plus there is the data out of other companies with <unk> three inhibition specifically.

There's only one <unk> three inhibitor that is out there and that is approved.

And really showed significant improvement even compared to <unk> inhibition in the <unk> population the issue with <unk> three inhibitors that it's at.

Sub Q infusion, it's given at high doses every other day or I think almost daily in some circumstances that is limiting.

At an equivalent level of <unk> three inhibition with a single subcutaneous dose with <unk> knockdown that last three months I think assuming it has the same inhibition of complement activity and assuming you get the same changes in hemoglobin I think thats pretty compelling.

That's the argument for <unk>.

Okay. That's helpful and then with the speed with which youre, adding programs to the clinic, how should we be thinking about the tempo of.

Opex.

Maturation over the next couple of years, you commented on the timing for it.

For Capex being pushed out to next year, how should we think about the scaling of opex. So it would be.

Larger proportional to the size of these studies that you're enrolling will be chunkier around the lipid study just kind of give us a sense of how we should model that between now and next two or three years.

Yes. So we gave guidance earlier this year, we expect to update that at our at our call.

Two quarters from now.

We only look forward really 12 months out of that in that forecast. So we'll have more to come on that.

Okay. Thanks, guys.

Okay.

And I'm showing no further questions I would now like to turn the call over to Chris Anzalone for closing remarks.

Christopher Anzalone: Is there any plan to perform CBOPS?

Christopher Anzalone: Yeah, so I'll take that one first.

Christopher Anzalone: So it is our plan right now to take Arrow H3 and Arrow Apo C3, you know, through to registration. We think those are potentially very important drugs, and we think that they will provide, you know, important new tools to cardiologists and lipid clinics.

Christopher Anzalone: And, you know, I've said this in the past, and, you know, it sounds, I don't want to overstate it, but it really feels like those are important drugs.

Christopher Anzalone: I will say with C3, though, I do expect that we will have some, you know, at least top-line, data this year.

Christopher Anzalone: And so we are fully committed to those, and I think we're going to commercialize those.

Christopher Anzalone: I don't know when.

Christopher Anzalone: The first question was with respect to Lapsarand, I don't know what else I can tell you on this.

Christopher Anzalone: I don't know what's going to be in it.

Thanks, everyone for joining us on our call today, and we will talk to you next quarter.

Christopher Anzalone: We haven't seen any data, so there's nothing I can accidentally tell you.

Christopher Anzalone: You know, we need to finish those escalation healthy volunteers before we start to look, for patients.

Christopher Anzalone: You know, we are waiting to see what those data look like, just like the rest of us, just like the rest of you.

Christopher Anzalone: I don't know how long it'll take to dose patients, you know, in that cohort, so it's really too, early to give any guidance there.

Christopher Anzalone: The phase one data were compelling.

Christopher Anzalone: But I do truly, though, expect that we will have some data that we can talk about this, year with C3, but that's, at least in healthy volunteers so far, is enrolling quite well.

Christopher Anzalone: That looks like it's a very potent drug candidate.

Christopher Anzalone: With RAGE and MUC, we haven't started dosing patients yet.

Christopher Anzalone: I think the genetic validation with respect to that target is clear.

Christopher Anzalone: That will be, as you point out, sometime in the middle of the year.

Christopher Anzalone: That drug candidate appears to be doing what we want it to do. It appears to be well-tolerated.

Christopher Anzalone: This concludes today's conference. You may now disconnect.

This concludes today's conference you may now disconnect.

Christopher Anzalone: And so, similarly, it's a bit too early to, you know, to guide when we might see some, – when we might present some data.

Christopher Anzalone: 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.

Christopher Anzalone: 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.

Christopher Anzalone: All right, thanks for taking our questions.

Christopher Anzalone: 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.

Christopher Anzalone: You're welcome.

Christopher Anzalone: Got it.

Christopher Anzalone: Our next question comes from Ellie Merrill of UBS.

Christopher Anzalone: 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?

Christopher Anzalone: Your line is open.

Christopher Anzalone: Or if you could just maybe elaborate on any sort of preclinical data points that maybe prompted this?

Christopher Anzalone: Hey, guys.

Christopher Anzalone: Yeah, sure.

Christopher Anzalone: Thanks for taking the question.

Christopher Anzalone: So the key driver of that decision is what we had described already on the call is that this, we may not have clear evidence of a PD effect or efficacy until the end of phase two, really.

Christopher Anzalone: 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 potential to show proof of target engagement and delivery, even albeit in small patient numbers?

Christopher Anzalone: So we felt like it was important to de-risk that.

Christopher Anzalone: And then, I guess, just in terms of the C3 program, given that it seems like you're progressing, through the cohorts and healthy youth, 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 in C3 as you think about dose selection for patients?

Christopher Anzalone: That could be, I mean, if you look back at the Fulcrum study and their design, it could be a longer study.

Christopher Anzalone: Thanks.

Christopher Anzalone: So we really wanted to make sure that the tox profile would support such a longer study.

Christopher Anzalone: Sure.

Christopher Anzalone: Got it.

Christopher Anzalone: Those are good questions.

Christopher Anzalone: Thanks.

Christopher Anzalone: I can't give you terribly straightforward guidance on any of those.

[music].

Christopher Anzalone: And our next question comes from Joel Beattie of Baird.

Christopher Anzalone: Your line is open.

Christopher Anzalone: Hi, thanks for taking the questions.

Christopher Anzalone: The first one's on the AAT program.

Christopher Anzalone: You know, thinking ahead to the discussions with FDA on the phase three trial design, how might that trial design be different from Sequoia?

Christopher Anzalone: And is there any possibility that it ends up looking pretty similar to what's already in Sequoia?

Christopher Anzalone: Well, let's revisit Sequoia.

Christopher Anzalone: I don't know if you remember that we changed the design of the Sequoia.

Christopher Anzalone: So the initial Sequoia adapted 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 7C protein up to week 16 for dose selection.

Christopher Anzalone: 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.

Christopher Anzalone: So the phase three registration study will not be similar to Sequoia.

Christopher Anzalone: In Sequoia, we end up enrolling patients with F0, so no fibrosis, because that was irrelevant with regard to the 7C level of the protein for dose selection, which that was the primary PD marker for dose selection.

Christopher Anzalone: So it's going to be different.

Christopher Anzalone: Of course, we need to get into the details later when we have a meeting with the agency.

Christopher Anzalone: But it's not going to be similar to the Sequoia study.

Christopher Anzalone: Got it.

Christopher Anzalone: That's helpful.

Christopher Anzalone: And then on the two new lung programs entering the clinic midyear, 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?

Christopher Anzalone: Have you disclosed anything on starting dose for either of those programs at this point?

Christopher Anzalone: But it's a good question, and what I assume you're getting at is, do we expect to be using as much drug for these studies as we are for ENAC?

Christopher Anzalone: And I think the answer is we do not, given the duration, the, And our next question comes from Patrick Trucchio of HC Wainwright.

Christopher Anzalone: Your line's open.

Christopher Anzalone: Thanks.

Christopher Anzalone: Good afternoon.

Christopher Anzalone: Just to follow up on the PIP-2 on the oncology platform, there was discussion in the prepared, remarks around the program and that clear target engagement has been demonstrated and that RNAi has a place in treating cancer.

Christopher Anzalone: The improvements on existing constructs are needed to move forward.

Christopher Anzalone: 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.

Christopher Anzalone: What improvements specifically would be expected to be part of this program compared to a HIP-2, program?

Christopher Anzalone: And would the target be the same or could we also have new targets as part of the broader, oncology platform?

Christopher Anzalone: Sure.

Christopher Anzalone: So first, I'll take the easier part of that first, which is targets.

Christopher Anzalone: It will be a different target.

Sure.

Christopher Anzalone: As we mentioned, the great news for clear cell renal cell carcinoma patients is that, there are now good alternatives, that there are now good looking drugs that address the, HIP-2 alpha pathway.

[music].

Christopher Anzalone: And so I think we'll make bets in other targets.

Christopher Anzalone: There's a lot of other targets I think that we could go after.

Christopher Anzalone: Now with respect to timing, you know, that's hard to know.

Christopher Anzalone: I can't give you any guidance, certainly nothing this year.

Christopher Anzalone: We were encouraged by the data.

Christopher Anzalone: You know, we are seeing knockdown.

Christopher Anzalone: We can get into tumors.

Christopher Anzalone: We can get knockdown in tumors.

Christopher Anzalone: That's all good news.

Christopher Anzalone: But I think we can do a bit better.

Christopher Anzalone: I think we can get deeper knockdown.

Christopher Anzalone: I think we can get more durable knockdown. And so we're trying a number of different strategies to get there.

Christopher Anzalone: And so it's still a bit early to give you guidance on when we think we're back into, the clinic.

Christopher Anzalone: And also, and I've said this publicly before, at some point, it would make sense for us, to find a good partner for oncology.

Yes.

Christopher Anzalone: It's a difficult space, and it'd be great, you know, at some point, if we can find a, partner to work with on new targets, as well as on, you know, possible delivery strategies.

Yes.

Christopher Anzalone: So, you know, we're still in the first few innings of this game.

Yes.

Christopher Anzalone: But the good news is, again, you know, as I mentioned, I do believe we are on the board.

Christopher Anzalone: 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.

Okay.

Christopher Anzalone: Yep.

Christopher Anzalone: That's helpful.

Yes.

Christopher Anzalone: And just to follow up on ARCH's two program, first, can you discuss level of confidence, that the program will not have the same setback as buprenorphine?

[music].

Christopher Anzalone: And secondly, what would be considered homerun data in ARCH's two, and when the data is reported, in the first half of 2023?

Christopher Anzalone: 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's approved?

Christopher Anzalone: All right.

Christopher Anzalone: Let's see.

Christopher Anzalone: All right.

Christopher Anzalone: Let's see.

Christopher Anzalone: With regard to the ARCH 2 program, Would you repeat the first part of the question that I kind of missed it?

Christopher Anzalone: What are our expectations for spupenorsin?

Christopher Anzalone: Oh, I think our expectation is that we're going to have a very clear safety profile, and a very clear pattern of efficacy.

Christopher Anzalone: I mean, we already have a lot of data.

Christopher Anzalone: Our phase one study was over a hundred patients with four different types of patients, populations, and the results are very, very consistent.

Christopher Anzalone: So, I don't see any possibility for a drawback of any type there.

Christopher Anzalone: So, the data is already strong enough.

Christopher Anzalone: So, I feel very comfortable and confident about that.

Christopher Anzalone: And the phase two study is going to read first quarter of this coming year.

Christopher Anzalone: So, we have a full answer.

All right.

Christopher Anzalone: 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.

[music].

Christopher Anzalone: We may talk about that in more detail in the near future, but 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.

Christopher Anzalone: The therapeutic profile are clearly different.

Christopher Anzalone: We believe that there are patient populations that will uniquely benefit, from either of these two drugs.

Christopher Anzalone: But we are doing the work right now by looking at the biology, the specific biology, and ask of the HDL biology specifically.

Christopher Anzalone: We're also looking at databases and major clinical trials to understand, where the residual risk for cardiovascular disease is in patients with mixed dyslipidemia.

Christopher Anzalone: And so, there is a lot of work that we want to finish by the end of this year.

Christopher Anzalone: So, we're ready for an end of phase two.

Christopher Anzalone: We're ready to start to look at four companies in Seattle, so forth, to think about the major cardiovascular outcome trials.

Christopher Anzalone: So, I think we're in, 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 end of phase two meeting.

Christopher Anzalone: So, we expect to have a cardiometabolic day later this year.

Christopher Anzalone: 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.

Christopher Anzalone: But look, we're going to learn a lot with all of these phase two studies, you know, over the next year plus.

Christopher Anzalone: 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.

Christopher Anzalone: Having said that, at this point, the way we're thinking about these is as follows.

Christopher Anzalone: For APOC3, you know, 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.

Christopher Anzalone: We're also, as you know, doing studies in mixed dyslipidemia.

Christopher Anzalone: And so, that gives us optionality to maybe, or maybe not do a very large outcomes trial for that compound.

Christopher Anzalone: On the ANG side, similar, you know, we see an HOFH possible, possibility there, similar to the FCS opportunity, where we can get to market relatively quickly.

Christopher Anzalone: And while we're 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.

Christopher Anzalone: And so that's our expectation at this point, you know, to go after the large dyslipidemia, population with that drug.

Yes.

Christopher Anzalone: Again, we'll learn a lot over the next year plus with these phase twos.

Christopher Anzalone: And so some of those opinions may change a bit, but right now, that's what we're thinking.

Okay.

Christopher Anzalone: Yeah, that's very helpful.

Christopher Anzalone: Thanks.

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Christopher Anzalone: You're welcome.

Christopher Anzalone: And our next question comes from Mayank Mamtani of B Riley Securities.

Christopher Anzalone: Good afternoon, team.

Christopher Anzalone: Thanks for taking our questions and congrats on the manufacturing, facility and the formation of ICERNA.

Christopher Anzalone: 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 ANGPTL3 as a target?

Christopher Anzalone: 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, 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.

Christopher Anzalone: And then I have a follow-up question on the lung programs.

Christopher Anzalone: Yeah, so as Xavier said, you know, our data were clear, you know, in our phase one, two studies. You know, we dosed a large number of patients. We saw consistent reductions in LDL.

Yes.

Christopher Anzalone: We saw good safety profile. We saw consistent reductions in triglycerides.

Yes.

Christopher Anzalone: And so whatever other folks saw with their drugs, you know, it's interesting to look at, I suppose.

Christopher Anzalone: But I think our take-home message is that our data were strong, and we expect that to continue.

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Christopher Anzalone: Now, you know, 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.

Christopher Anzalone: Got it.

Christopher Anzalone: And then as you start working on your phase one studies for Merck and Rage and deploy learnings from the ENAC program, and then, you know, just the RAD study that I think is published at a conference about, you know, how are you thinking about the dose level versus knockdown?

Christopher Anzalone: You know, it looks like you're working with some lower doses here with the newer targets, but like with the ENAC, it was about 66 percent knockdown, but I think you're getting higher knockdown with some of these newer targets.

Christopher Anzalone: 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?

Yes.

Christopher Anzalone: Yeah, sure.

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Christopher Anzalone: So we will be presenting data on both of those programs on Merck, Privacy, and Rage at the ATS conference that starts next week.

Christopher Anzalone: And you're right, we previously described for ENAC about 66 percent knockdown in the RAD, and we are seeing better knockdown than that with both sRNA targeting 5AC and Rage in rodents, but also in non-human primates, and we'll be sharing some of some of those data and the key to that story is it's not only a matter just lower dose levels but lower overall exposure so that the less frequent dosing intervals as Chris alluded to before are really important I think for both muck and rage but was there another piece of that question um chronic talk studies how long have you gone there in the preclinical model the chronic talks has not yet started for either of those we've completed the the IND or CTA enabling talks and that that's complete for both muck and rage 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 talk study in animals just so we we have we have a good we have a good idea about 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 the last 30 days that would would suggest you know a certain kind of crime talks study, if we are seeing durability 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 great thank you for that clarification and then just one final question high high level has there any exploratory work done of delivering RNA I to the you know retina or broadly CNS as as you know oligonucleotides have, been also deployed as have you guys done any work around that preclinical are we yeah so so we haven't talked about about any other cell types that we we are going after internally but you've been around us long enough to know that that that that we are that we are always looking for new cell types and so we've not disclosed what our next cell type is yet okay look forward to some of those disclosures and and your pulmonary day later this month thanks for taking our questions great thank you and our next question comes from K Nikki of Chardon your lines open yes thank you for the question with respect to hip to and going after additional oncology targets I guess my question is why why why do that as opposed to you know just on your last question other targets let's say outside deliver yeah you know that's a great question we're I don't mean to be flip but we're but when we can we are we 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 we've got really good leads and and other cell types and so if we were if we were more bandwidth constrained then then one could argue that that we should maybe slow walk the the oncology a bit because we've got we've got really good exciting opportunities in other places but I think we can do both and also as I said in the prepared remarks you know look one of the reasons that we that the oncology program was important for us is that it gave us it gave us the chance to to learn broadly how to deliver extra epatically and I think that will that will still be the case so it makes sense strategically there but you know you're you're the underlying point there is a strong one oncology is difficult and so it's it's it's we would not like to be solely an oncology company that's that that's a risky endeavor but it's something that I think we owe it to patients to it to investigate because I think we could do it you know we've got a good we've got a good first step as I mentioned but there gives two alpha program and I think that just with a little bit of tweaking we might have something that that you know that could be usable across other two, Mani Foroohar of SVP Securities, your line is open.

Christopher Anzalone: Hey guys, thanks for taking the question.

Christopher Anzalone: You've always focused on speed into the clinic as one of your core competencies and sort of philosophy of the company.

Christopher Anzalone: One of the challenges there is making sure that every target is appropriately vetted, every market opportunity actually exists.

Christopher Anzalone: So could you help us understand your rationale for why this is an opportunity for you in PNH, how you think about other complicated diseases where Alnylam and others with many times your resources and expertise in RDI have faced real challenges.

Christopher Anzalone: And then secondarily, are we ever going to see 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?

Christopher Anzalone: Thanks, guys.

Christopher Anzalone: Yeah, so I'll let James handle the PNH question quickly on the ENAC.

Sure.

Christopher Anzalone: So we're still considering a second, or we're still working on a second generation ENAC.

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Christopher Anzalone: 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.

Christopher Anzalone: So we'll hold off until we see where the ENAC 2 is going to go.

Christopher Anzalone: James, you want to address C3?

Christopher Anzalone: Yeah, sure.

Christopher Anzalone: So with regards to PNH specifically, what interests us there is the data out of other companies with C3 inhibition specifically.

Christopher Anzalone: 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.

Christopher Anzalone: 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.

Christopher Anzalone: So that is limiting.

Christopher Anzalone: 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.

Christopher Anzalone: Okay, that's helpful.

Yes.

Christopher Anzalone: And with the speed with which you're adding programs to the clinic, how should we be thinking about the tempo of OPEX moderation over the next couple of years?

Christopher Anzalone: You commented on timing for CAPEX being pushed out to next year.

Yes.

Christopher Anzalone: How do we think about the scaling of OPEX?

Christopher Anzalone: Should it be largely proportional to the size of these studies that you're enrolling?

Christopher Anzalone: Will it be chunkier around the lipid studies?

Okay.

Christopher Anzalone: Just kind of give us a sense of how we should model that between now and say the next two or three years.

Christopher Anzalone: Yeah, so we gave guidance earlier in this year.

Good morning.

Christopher Anzalone: We expect to update that at our call two quarters from now.

Christopher Anzalone: We only look forward really 12 months on that forecast, so we'll have more to come on that.

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Christopher Anzalone: Okay.

Christopher Anzalone: Thanks, guys.

Christopher Anzalone: And I'm showing no further questions.

Christopher Anzalone: I would, now like to turn the call over to Chris Anzalone for closing remarks.

Christopher Anzalone: Thanks, everyone, for joining us on the call today, and we'll talk to you next quarter.

Okay.

Sure.

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Sure.

Okay.

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