Q2 2021 Ionis Pharmaceuticals Inc Earnings Call

Please go ahead.

[music].

Good morning, and welcome to eye on it from.

Operator: Good morning, and welcome to Ionis Pharmaceuticals' Second Quarter 2021 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Dave Nacasona, Investor Relations, to lead off the call. Please begin.

Masuda calls second quarter 2021 financial results conference call. As a reminder, this call is being recorded.

At this time I would like to turn the call over to Dave Nakasone.

That's your relations to lead off the call. Please begin.

Dave Nacasona: Thank you, Debbie. Before we begin, I encourage everyone to go to the investor section of the IONUS website and find the press release and related financial tables, including a reconciliation of the gap to non-gap financial measures that we will discuss today. We believe in non-gap financial results that represent the economics of our business and how we manage our, We've also posted slides on our website that accompany our discussion. With me on today's call are Brett Monia, Chief Executive Officer; Beth Howigan, Chief Financial Officer; and Richard Geary, Executive Vice President of Development.

Thank you Debbie before we begin I encourage everyone to go to the investors section of <unk> website on the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures, we will discuss today.

We believe non-GAAP financial results better represent the economics of our business and how we manage our business.

We've also posted slides on our website that accompany our discussion today.

With me on today's call are Brent ammonia, Chief Executive Officer, Beth Hougen, Chief Financial Officer.

And Richard Geary Executive Vice President of development.

Dave Nacasona: Joining us for Q&A are Juaniza Katare, Chief Corporate Development and Commercial Officer, and Eric Swayzie, Executive Vice President of Research. I would like to draw your attention to slide three, which contains our forward-looking language. We will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially.

Joining us for Q&A on Asia category, Chief Corporate development, and commercial officer, and Eric Swayze Executive Vice President of research.

I would like to draw your attention to slide 3 which contains our forward looking language.

We will be making forward looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties and our actual results may differ materially.

I encourage you to consult the risk factors discussed in our SEC filings for additional detail.

Dave Nacasona: I encourage you to consult the risk factors discussed in our SEC filings for additional, Thanks, Dave. Good morning, and thank you for joining us on today's call. Last year, when I took on my new role as CEO of IONIS, I put forth a plan intended to bring substantially greater success to Ionis and substantially greater value for all stakeholders. This plan was to leverage our well-established foundation of scientific innovation by focusing on three strategic objectives. First, to evolve our business model to include commercializing products of our own. This includes building the necessary capabilities to prepare for multiple I-owner commercial launches.

With that I'll turn the call over to book.

Thanks, David.

Good morning, and thank you for joining us on today's call.

Last year when I took on my new role as CEO of eye on it I put forth a plan intended to bring substantially and greater success to eye on it.

And substantially greater value for all stakeholders.

This plan was to leverage our well established foundation of scientific innovation by focusing on 3 strategic objectives first to evolve our business model to include commercializing products of our own.

This includes building the necessary capabilities to prepare for multiple eye on its commercial launches second to expand our drug discovery capabilities through new initiatives to enhance our technology and third to significantly advance our late stage pipeline to ensure for a substantial increase in the number of new products to market.

Brett P. Monia: Second, to expand our drug discovery capabilities through new initiatives to enhance our technology. And third, to significantly advance our late stage pipeline to ensure a substantial increase in the number of new products reaching the market in the near and longer term. So now let's see how we're progressing against these three strategic goals for this year. The Ionis Holyone pipeline is advancing on track and growing significantly. Last week, we reached full enrollment in the neurotransformed study of Epontersin for the treatment of patients with polyneropycephythine.

Near and longer term.

So now let's see how we're progressing against these 3 strategic goals for this year.

The other 1 is wholly owned pipeline is advancing on track and growing significantly.

Last week, we reached full enrollment in the neuro transform study of F on tariffs and for the treatment of patients with Polyneuropathy.

With this study now fully enrolled and on track for data by mid 2022. This medicine is 1 important step closer to reaching the market.

Brett P. Monia: With this study now fully enrolled and on track for data by mid-22, this medicine is one important step closer to reaching the market. We are also developing Epontherison for the treatment of cardiomyopathy in the Phase 3 Cardiotransform study, which continues to enroll well. Our phase three study involving our APLC3 Lyca medicine in patients with SCS is enrolling on schedule, and our second phase three study for APOC3 Lyca is on track to begin later this year in patients with severe hypertroglyceridemia, a much larger patient population. Our phase three study for Ion 363 in patients with the genetic form of ALS due to mutations in the fuss gene is also progressing well.

We are also developing <unk> for the treatment of cardiomyopathy from the phase III cardio transform study, which continues to enroll well.

Our phase III study involving our apoc III like a medicine in patients with FCS is enrolling in schedule and our plant in our second phase III study for Apoc III is.

We are on track to begin later this year in patients with severe hybrid triglycerides EMEA.

Much larger patient population.

Our phase III study for ion $3.63 in patients with a genetic form of ALS due to mutations from the Prost G is also progressing well.

Brett P. Monia: Furthermore, we look forward to initiating a phase three study for our PKK Lyca medicine in patients with hereditary angioedema late this year or early next year. And as our wholly-owned pipeline advances, we're also making great progress in building out our commercial capabilities and our strategy. Our acquisition of XEA was a key step in advancing our commercial strategy in building these capabilities, and we've now completed the integration of XE with Ionis.

The more we look forward to initiating a phase III study for our PKK like a medicine in patients with hereditary angioedema.

Late this year or early next year.

And as our wholly owned pipeline advances, we're also making great progress on building out our commercial capabilities and our strategy our acquisition of X gene was a key step in advancing our commercial strategy in building these capabilities.

We've now completed the integration of <unk> with an eye on it.

We're pleased with the progress being made in our solar partnership for the distribution of X steady and way Libre in Europe, and North America.

Brett P. Monia: We're pleased with the progress being made in our Sobe partnership for the distribution of Texetti and Wei Livera in Europe and North America. As a reminder, we established this partnership to continue providing these important medicines, while we focus on Eval Kirsten and APA, We've also made significant additional progress this year against our strategic objective to expand the reach of our drug discovery capabilities through new investments to enhance our technology. Our efforts include broadening our internal technology initiatives, as well as licensing new technology, We recently announced a new partnership with Bicycle Therapeutics for exclusive access to Bicycle's proprietary platform chemistry for Ologanucle Droglytide Drugs, focused primarily on targeted delivery to skeletal and cardiac muscle This collaboration complements our significant internal effort, as well as the progress we're making under our ARO therapeutics and Genuity Sciences collaboration, all of which potentially enables us to significantly expand the reach of our technology.

Minor we established this partnership to continue providing these important medicines to patients while we focus on net 1 person and apoc III Micah.

We have also made significant additional progress this year against our strategic objective to expand the reach of our drug discovery capabilities through new investments to enhance our technology.

Our efforts include broadening our internal technology initiatives as well as in licensing new technologies.

We recently announced a new partnership with lifecycle therapeutics for exclusive access to buy cycles proprietary platform chemistry per organically by drugs focused primarily on targeted delivery to skeletal and cardiac muscle.

This collaboration complements our significant internal efforts as well as the progress, we're making under our Aerotherapeutics ingenuity sciences collaborate collaborations all of which.

Essentially enables us to significantly expand the reach of our technology.

And lastly, we're making great progress this year on achieving our third strategic objective.

Brett P. Monia: And lastly, we're making great progress here in achieving our third strategic objective, to have 12 or more marketed products in 2026. In addition to completing enrollment in the Epontherosome Neurotransformed study, we have recently achieved key phase three milestones with Toferson and Pelicarson.

They have 12 or more marketed products in 2026. In addition to completing enrollment in the Apollo Pearson Neuro <unk> transform study. We also recently achieved key phase III milestones with <unk> and pellet cars.

All 3 of these significant milestones from these programs closer to reaching the market and highlight the excellent progress, we're making across our late stage pipeline.

Brett P. Monia: All three of these significant milestones move these programs closer to reaching the market and highlight the excellent progress we are making across our late stage pipeline. Biogen completed the placebo control treatment portion of the Phase 3 Valor study of Toverson, with data expected by this fall, and is now offering Toverson to Sod 1 ALS patients on an individual compassionate use basis if the Pays 3 results are successful. Sopherson could become the first ever disease-modifying therapy for a genetic cause of AOS and our next commercial product. And this week, we announced achievement of a key enrollment milestone in the LP L.P. Little A Horizon, phase three study for Pellicarsin in patients with LP. Little A-driven cardiovascular.

Biogen and completed the placebo controlled treatment portion of the phase III <unk> studies overseeing day to expected by this fall and is now offering <unk> ALS patients on an individual compassionate use basis, if the phase 3 valor results were successful.

<unk> could become the first ever disease modifying therapy for a genetic causes of ALS and our next commercial product.

And this week, we announced achievement of a key enrollment milestone in the LP Little a horizon phase III study from <unk> in.

In patients with LP little a driven cardiovascular disease.

As we announced we have now achieved enrollment of nearly 4000 patients from its cardiovascular outcome trial, representing 50% of our target enrollment goal for the study.

Brett P. Monia: As we announced, we have now achieved enrollment of nearly 4,000 patients in this cardiovascular outcome trial, representing 50% of our target enrollment goal for the study. This achievement, along with the substantial progress we're making across all of our mid and late stage LICA programs, demonstrates that consistently attracts the profile for all our LICA medicines and development today. So in wrapping up my opening comments, we are very pleased with the progress we're making to achieve all our strategic projects. We've made great progress this year, and we are looking forward to an exciting second half of the year as we focus further on executing on our strategy and achieving the goals that lie ahead.

This achievement along with the substantial progress, we're making across all of our mid and late stage like programs demonstrates a consistently attractive profile for all our like medicines in development today.

So in wrapping up my opening comments, we are very pleased with the progress were making to achieve our strategic objectives.

<unk> made great progress this year and we're looking forward to an exciting second half of the year as we focus further on executing on our strategy and achieving the goals that lie ahead, and importantly, we are well positioned for growth with the people and the financial strength to achieve all of this and more.

Brett P. Monia: And importantly, we are well positioned for growth with the people and the financial strength to achieve all this and more. And with that, I'll now turn the call over to Beth to discuss your financial results. Then Richard will discuss recent pipeline updates and preview key pipeline catalysts expected for the remainder of the year. After Richard, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.

And with that I'll now turn the call over to Beth to review, our financial results and Richard will discuss recent pipeline updates and preview key pipeline catalysts expected for the remainder of the year.

After Richard I'll wrap up our prepared remarks before taking your questions now over to Beth.

Thank you Pat.

Elizabeth L. Hougen: Thank you, Brad. Our financial results for the first half of this year reflect our commitment to investing to drive future growth. We earned nearly $240 million in revenue and recognized $312 million in non-gap operating expenses, resulting in a non-gap net loss of $81 million. These results are in line with our expectations and reflect the multiple steps we have already taken this year in support of our strategic objectives. We've completed the integration of AXIA, entered into distribution arrangements with Sobe, and restructured our commercial operations.

Our financial results first cancer this year.

Our commitment to invest to drive future growth.

We are nearly $240 million in revenue and recognized $312 million in non-GAAP operating expenses, resulting in a non-GAAP net loss of $81 million.

These results were in line with our expectations and reflect the multiple steps we have already taken this year in support of our strategic objectives.

We've completed the integration of FCA entered distribution arrangements with Dolby and restructured our commercial operations.

And our first quarter earnings call, we projected realizing substantial savings from the xdr and cerave transaction.

Elizabeth L. Hougen: In our first quarter earnings call, we projected realizing substantial savings from the XIA and SOB transaction. I'm pleased to say we are on track to realize more than $50 million of savings this year. We are putting these savings to work by reinvesting them to drive future growth.

I am pleased to say, we are on track to realize more than $50 million of savings this year.

We are putting these savings to work by reinvesting to drive future growth.

Elizabeth L. Hougen: That means investing in three key areas, advancing and expanding our wholly-owned pipeline, building our commercial capabilities, and enhancing our technology. I'll provide more details about the investments we've made so far this year when I talk about our operating expenses. But first, I'll provide additional details on our revenue. In the first half of this year, Finra continued its blockbuster performance, achieving over $1 billion in global sales.

That means investing in 3 key areas advancing and expanding our wholly owned pipeline building, our commercial capabilities and enhancing our technology.

I'll provide more details about the investments we've made so far that share when I talk about our operating expenses, but first I'll provide additional detail on our revenue.

In the first half of this year and reflect continued its blockbuster performance achieving over $1 billion in global down.

Elizabeth L. Hougen: We earned over $130 million in royalty revenue, virtually all falling to our bottom line as profit. And based on Spinra's net sales, we reached the highest royalty tier in the second quarter. We are pleased with Bion's continued efforts to build upon SpinRod's proven profile of long-term safety and efficacy in SMA patients of all ages. Bajin recently reported new data reinforcing the potential for improved outcomes in patients treated with a higher dose of Spinraza, which is being evaluated in the Devote study.

Earned over $130 million in royalty revenue virtually all falling to our bottom line as profit and based on <unk> net sales, we reached the highest royalty tier in the second quarter.

We are pleased that Biogen continued efforts to build upon spin.

Proven profile of long term safety and efficacy in SMA patients of all ages.

Biogen recently reported new data reinforcing the potential for improved outcomes in patients treated with a higher dose of <unk>.

It is being evaluated in the balance.

And in the response.

Elizabeth L. Hougen: And in the response study, Bidin is continuing to evaluate Spinraza's potential to benefit patients previously treated with gene therapy. Together with the substantial and growing body of evidence supporting SpinRaz's proven profile and over 60,000 SMA patients, we believe Finrasa will continue to be the market-leading treatment for SMA patients of all ages. In the first half of this year, take SETI, and we liver generated revenues of $31 million.

IGN is continuing to evaluate <unk> potential to benefit patients previously treated with gene therapy.

Together with the substantial and growing body of evidence supporting spin rises proven profile.

And over 60000 SMA patients, we believe <unk> will continue to be the market leading treatment for SMA patients of all ages.

In the first half of this year take steady and we leveraged generated revenues of $31 million.

And also in the first half we completed the transition of our commercial operations to Toby and recognized our first full quarter of Chegg study and when they ever revenues from distribution fee based on net sales.

Elizabeth L. Hougen: And also in the first half, we completed the transition of our commercial operations to Sobe and recognized our first full quarter of Ticcetti, and we derived revenues from distribution fees based on net sale. As a reminder, we included this shift in revenue in our 2021 revenue guidance. We also earn nearly $70 million in R&D revenues in the first half, including $10 million from biogen for advancing ion 541, which is in development for patients with ALS with no known genetic history of the disease.

As a reminder, we included this shifts in revenue in our 2021 revenue guidance.

We also earned nearly nearly $70 million and R&D revenues in the first half, including $10 million from buying from Biogen for advancing and by far 1 which is in development for patients with ALS.

With no known genetic history of the disease.

More than 85% of our R&D revenue was from medicines, and our leading cardio metabolic and neurology franchises.

Elizabeth L. Hougen: More than 85% of our R&D revenue was from medicines in our leading cardiometabolic and neurology franchise. Our R&D revenues included revenue from numerous partners, as together we advanced more than 10 programs. Our ability to generate revenue from numerous diverse sources is a key element of our financial strength. We reported non-gap operating expenses of $312 million in the first half of this year.

Our R&D revenues included revenue from numerous partners as together, we advance more than 10 programs our ability to generate revenue from numerous diverse sources is a key element of our financial strength.

We reported non-GAAP operating expenses of $312 million in the first half of this year.

This was a slight increase compared to last year on was inline with our expectations.

Elizabeth L. Hougen: This was a slight increase compared to last year and was in line with our expectations. R&E expenses increased by 20% compared to last year, driven primarily by the Appon-Turson and APOC3-LICA of phase three studies and costs associated with our wholly owned program. We also incurred expenses associated with our Genuity collaboration to identify novel targets. These increases reflect two of our key areas of investment: our wholly owned pipeline and our technology. As GNA expenses decreased by approximately 25% compared to last year due to cost efficiencies realized from integrating AXIA and restructuring our commercial operations, based on our first half results and our projection for increased R&D revenues from our advancing partnered program in the second half of this year, we are reaffirming our 2021 revenue guidance of more than $600 million.

R&D expenses increased by 20% compared to last year, driven primarily by the F..1 person in April seems to be like a phase III study.

And costs associated with our wholly owned programs.

We also on credit expenses associated with our Genuity collaborations to identify novel targets.

These increases reflect 2 of our key areas of investment are wholly on pipeline and our technology.

SG&A expenses decreased by approximately 25% compared to last year due to cost efficiencies realized from integrating <unk> and restructuring our commercial operations.

Based on our first half results and our projections for increased R&D revenues from our advancing partnered program in the second half of the book here.

We are reaffirming our 2021 revenue guidance at more than $600 million.

Already in the third quarter, we have earned a $25 million milestone payment from Novartis for achieving 50% enrollment in the phase III study of Pellekar to them.

Elizabeth L. Hougen: Already in the third quarter, we earned a $25 million milestone payment from Novartas for achieving 50% enrollment in the phase three study of Pelacarcy. We expect our operating expenses to continue to increase in the second half of this year as we advance our ongoing phase three studies for Applun-Turson, IONAS APO-C-3 Lyca, and our FUS ALS. Our operating expenses will also increase as we get the phase three study underway for APOC3 LICA in patients with severe high triglycerides and potentially start the phase three study for PKK Lyca, and we are investing As Brett mentioned, we recently entered into a license agreement with Bicycle Therapeutics for a $45 million upfront payment. We did not include this license fee in our original financial guide.

We expect our operating expenses to continue to increase in the second half of this year as we advance our ongoing phase 3 studies are up on person I on this April <unk> and our first ALS medicine.

Our operating expenses will also increase as we get the phase III study underway for April it would be like in patients with severe high triglyceride and potentially start the phase III study for PKK linker.

And we are investing to enhance our technology, ensuring that our platform remain innovative and competitive.

As Brett mentioned, we recently entered into a license agreement with bicycle therapeutic for a $45 million upfront payment.

We did not include this license fee in our original financial guidance.

And for that reason alone we are revising our 2021 operating expenses and net loss guidance.

Elizabeth L. Hougen: And for that reason alone, we are revising our 2021 operating expense and net loss guidance. We now project operating expenses in the range of $710 million to $750 million and a net loss of less than $110 million, assuming the low end of expenses and all on a non-gap basis. And because of our projected increasing R&D revenue in the second half of this year, we expect our net loss will be lower in the second half of this year compared to the first half.

We now project operating expenses in the range of $710 million to $750 million and.

And a net loss of less than $110 million, assuming the low end of expenses and all on a non-GAAP basis.

And because of our projected increase in R&D revenue in the second half of this year, we expect our net loss will be lower in the second half of this year compared to the first cash.

With the important steps, we have already taken this year and more than $2 billion of cash and investments.

Elizabeth L. Hougen: With the important steps we have already taken this year and more than $2 billion of cash and investments, we believe we are well positioned for accelerated growth. We look forward to continuing to invest in our pipeline and technology and to moving more medicines towards the market to achieve our goal of 12 or more marketed products in 2020. And with that, I'll turn the call over to Richard. Thank you, Beth.

We believe we are well positioned for accelerated growth.

Forward to continuing to invest in our pipeline and technology and to moving more medicines toward the market to achieve our goal of 12 or more marketed products in 2020.

And with that I'll turn the call over to Richard.

Thank you Matt.

As Brent described earlier, we are certainly pleased with the excellent performance across our pipeline in the first half of this year.

Richard S. Geary: As Brett described earlier, we're certainly pleased with the excellent performance across our pipeline in the first half of this year, with the achievement of Key Phase 3 catalysts with Toferson, Eplomtersson, and Pella Carson. These medicines are now closer to reaching the market. These catalysts also position us well to deliver our regular cadence phase three data redouts, beginning with Toferson, expected by this fall. Toferson is now one step closer to becoming the first genetically targeted therapy for the treatment of ALS and to becoming Iona's next commercial product. Biogen recently began offering Toferson to Sard 1 AOS patients on an individual compassionate use basis, with plans to broaden this access once the data are reported.

With the achievement of key phase III catalysts with tougher upon person and pellet Carson.

These medicines are now closer to reaching the market.

These catalysts also position us well.

To deliver a regular cadence of phase III data readouts, beginning with <unk>.

Expected by this fall, 12% is now 1 step closer to becoming the first genetically targeted therapy for the treatment of AOS.

And to be coming I on this next commercial product.

Biogen recently began offering til person to Shaoguan AOS patients on an individual compassionate use basis with.

With plans to broaden this access once the data on a reported.

Richard S. Geary: Biogen is also conducting the Atlas study to investigate Toferson's potential to prevent or delay disease onset in pre-symthomatic Sond1 ALS patients. The rationale for Atlas is similar to SpinRosa Nurture Study, which has enabled infants who began treatment prior to SMA symptom onset to develop more like non-smah After Toferson, the next program on track to read out is the NeuroT Trans With enrollment in this study now complete, we expect data by the middle of next week, next year.

Biogen is also conducting Atlas study to investigate <unk> potential to prevent or delay disease onset in pre symptomatic Shawn 1 AOS patients.

Chanel for Atlas dissimilar to spin Roz the nurture study.

Which has enabled infants who began treatment prior to SMA symptom onset to.

To develop more like non SMA children.

After <unk>. The next program on track to read out is the neuro <unk> transform study on Epsilon person for the treatment of GTR Polyneuropathy.

With enrollment in this study now complete.

We expect data by the middle of next week and next year.

Nice.

As a result, we are positioned to file for marketing authorization for Epsilon church on that patients with GTR polyneuropathy by the end of next year, assuming the data are positive.

Richard S. Geary: As a result, we're positioned to file for marketing authorization for Eplon Terson and patients with TTR Polyneropathy by the end of next year, assuming the data are positive. Up next, we expect the balance study of Iona's AC3 Lyca in patients with FCS to read out in 2023. We're on track to initiate a second phase three study of Iona sapo C3 Lyca in patients with severe high triglycerides in the second half of this year, which positions this program for data in 2024.

Up next we expect balance the balance study on <unk> in patients with FCS to readout in 2023.

We're on track to initiate a second phase III study of <unk> in patients with severe high triglycerides in the second half of this year, which positions. This program for data in 2024.

Also on 2024, we anticipate phase III data from the LPGA horizon.

Richard S. Geary: Also in 2024, we anticipate phase three data from the LPA Horizon outcome study of Pell Carson, the Cardio T Transforms study of Eflon Terson, and the pivotal study in patients with FUS AOLF. In addition to our deep, late-stage pipeline, we have a large mid-stage pipeline that we expect to continue to support additional phase three starts. Many of these mid-stage programs have read out data recently or have upcoming data readouts that, if positive, position these medicines to move into the next stage of development.

On the study of powered Carson Cardio T transform study of Epsilon person and the pivotal study in patients with ALS.

In addition to our deep late stage pipeline, we have a large mid stage pipeline that we expect to continue to support additional phase III starts. Many of these mid stage programs have for read out data recently or have upcoming data readouts that if positive position. These medicines then move into the next.

Stage of development.

Data, we presented at AAN last week demonstrated that monthly and quarterly dosing with I honest map T Rx.

Richard S. Geary: Data we presented at AAIC last week demonstrated that monthly and quarterly dosing with IONASMAP TRX achieved substantial, durable, and dose-dependent reductions in all forms of CSF TAL with generally favorable safety and tolerability in Alzheimer's disease patients.

Achieved substantial durable and dose dependent reductions in all forms of CSF Tau.

With generally favorable safety and Tolerability and all timers disease patients.

Based on these results Biogen plans to advance I on this map T Rx into a larger phase II study tomorrow fully test our antisense medicine as a treatment for Alzheimers disease.

Richard S. Geary: Based on these results, Biogen plans to advance Ionis map TRX into a larger phase two study to more fully test our antisense medicine as a treatment for Alzheimer's disease. Coming up in the second half of this year, we expect data from a buprenorsin phase 2B study in patients with dyslipidemia and cardiovascular disease. We look forward to starting our phase one study of ion 582 for the treatment of patients with Angle

Coming up on the second half of this year, we expect data from <unk> phase <unk> study in patients with Dyslipidemia and cardiovascular disease.

We look forward to starting our phase 1.2 study of ion $5.82 for the treatment of patients with Angelman syndrome.

And later this year, we look forward to reporting additional data from the phase II study.

My honest PKK Leica in patients with hereditary angioedema. We also look forward to initiating our phase III study with this medicine, which is on track late this year early next year.

Richard S. Geary: And later this year, we look forward to reporting additional data from the phase two study of Iona's PKK-K-LICA in patients with hereditary angioidema. We also look forward to initiating our phase three study with this medicine, which is on track late this year or early next year. And our partner Bayer is continuing to make good progress in the phase 2B study of Ionis Factor 11 LRX in patients with end-stage renal disease, putting this study on track for data in the first half of next year.

And our partner Bayer is continuing to make good progress in the phase <unk> study of Iona Spectre <unk> <unk> L. Rx in patients with end stage renal disease, putting this study on track for data in the first half of next year.

As the year unfolds, we look forward to providing future updates as the pipeline continues to advance and we achieve additional catalysts from across the pipeline, which together move us closer to achieving our goal of 12 or more marketed medicines in 2026.

Richard S. Geary: As the year unfolds, we look forward to providing future updates as the pipeline continues to advance and we achieve additional catalysts from across the pipeline, which together move us closer to achieving our goal of 12 or more marketed medicines in 2026. And with that, I'll turn the call over to Brett to close this portion of our call. Thank you, Richard.

And with that I'll turn the call over to Brett to close this portion of our call.

Thank you Richard.

In the first half of the year, we continued to successfully advance all our key strategic objectives and have made great progress in evolving our business model building, our commercial capabilities and preparing for multiple aon as commercial launches we've made significant progress on advancing our technology to expand our drug discovery capabilities.

Brett P. Monia: In the first half of the year, we continue to successfully advance all our key strategic objectives. We've made great progress in evolving our business model, building our commercial capabilities, and preparing for multiple Hyonis commercial launches. It made significant progress in advancing our technology to expand our drug discovery capabilities and with the progress we've made across our pipeline, including achieving key phase three milestones, which moved Topherson, Epponterson, and Pellarston closer to the market.

And with the progress we've made across our pipeline, including achieving key phase III milestones, which moved <unk> <unk> and <unk> closer to the market.

We are very well positioned to achieve our goal of delivering a substantial number of new products to the market in the near and the long term.

In the second half of the year is shaping up to be even more successful with several new key clinical trial initiations and clinical readouts, including results of the phase III <unk> study in patients with Saab on Pos by this fall.

And importantly, we have the resources and people we need to invest in all our strategic priorities positioning us for accelerated growth and to help ensure great success rate on this for many years to come.

Brett P. Monia: Thank you. We are very well positioned to achieve our goal of delivering a substantial number of new products to the market in the near and long term, and the second half of the year shaping up to be even more successful with several new key clinical trial initiations and clinical redouts, including results of the Phase 3 Valor study in patients with SAD1 ALS by this fall. And importantly, we have the resources and people we need to invest in all our strategic priorities, positioning us for accelerated growth and to help ensure great success for I owners for many years to come.

And with that I'll now open open the call up for questions.

We will now begin the question and answer session.

To ask a question you May press Star then 1 on your telephone keypad. If you are using a speaker phone. Please pick up your handset before pressing the keys.

To withdraw your question. Please press Star then 2.

At this time, we will pause momentarily to assemble our roster our roster.

Brett P. Monia: And with that, I'll now open the call for questions. We will now begin the question and answer session. To ask a question, you may press star, then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys.

The first question comes from Jason <unk> with Bank of America. Please go ahead.

Hey, Thanks for taking my questions.

A couple from me just maybe can you help set the expectation into the phase <unk>.

Operator: To withdraw your question, please press star then to. At this time, we will pause momentarily to assemble our roster. The first question comes from Jason Gerbery with Bank of America. Please go ahead. Hey, uh, thank you for my questions. A couple for me, just maybe, can you help set the expectation in the Bay for buprenorsin?

Sort of curious the high unmet need subgroup of patients with more severe triglyceride levels. Just wondering your thoughts in terms of the ability to read across from this study to that patient population and then I guess secondarily.

Have you given any thought to huntington's disease, and essentially next steps to revisiting that as a category just curious your latest thoughts on huntington's. Thanks.

Jason Gerberry: Just sort of curious, you know, the high-end men need a subgroup of patients with more severe triglyceride levels; just wondering your thoughts in terms of the ability to read across from this study to that patient population. And then, I guess, just secondarily, you know, have you given any thought to Huntington's disease and potentially next steps to revisiting that? As a category, just curious about your latest thoughts on Huntington's. Jason, thanks for the question.

Sure Jason Thanks for the question so.

For <unk>, the phase II, B study, which is <unk>.

Pfizer has said that they plan to have topline data announced this year.

As a reminder, as in patients with <unk>.

Hi, non HDL cholesterol and high triglycerides and this is the patient population there.

If they move to phase III, which is the plan there.

We're getting for phase III.

Brett P. Monia: For Bupin, the phase 2B study, which Pfizer has said that they plan to have top-line data announced this year, is in patients with high non-h-DL cholesterol and high triglycerides. And this is the patient population that if they move to phase three, which is the plan, that they're targeting for a phase three program. The unmet medical need for remin cholesterol combined with high triglycerides, mixed distilidididias, if you will, is a very significant, very large patient population.

Perfect for a phase III program.

On the unmet medical need for <unk>.

Remnant cholesterol combined with high triglycerides mixed Dyslipidemia has if you will is very significant.

On a large patient population.

And.

And 1 that positions. This book nursing targeted mixed as EMEA was quite nicely.

There were also in addition to move the northern we're very excited about our apoc III like a drug that we're moving into phase III for severe hyperhidrosis rides as well.

Brett P. Monia: And one that positions us to target mixed epidemia is quite nice. You know, we're also, in addition to Lupin, we're very excited about our APLC3 Lyca drug that we're moving into phase three for severe high triglytes as well. We think that this mechanism is the best mechanism, the best in-class strategy for patients suffering purely from high trigly surrogate diseases, which affects millions of people.

We think that this mechanism is the best mechanism best in class strategy for patient suffering purely from high triglyceride related diseases, which affects millions of people. So.

I raised that because it's important to realize that moving north and our April seems to be like a medicine are targeting very large patient populations and distinct populations that have some overlap, but there really are quite distinct.

Brett P. Monia: So I raised that because it's important to realize that Bupinorsin and our APOCE 3, like medicine, are targeting very large patient populations and distinct populations that have some overlap, but they really are quite distinct for that. And I could touch on Huntington, but first I'd like to just see if Richard wanted to add anything to what I said. No, I think you've covered it well, Brett.

For that and I can touch on Huntington, but first I would like.

Just see if Richard wanted to add anything to what I said.

No I think you covered it well.

Thank you Richard.

As far as.

Huntington as Roche has said Jason.

They are continuing to analyze all the data in there and they've promised a on update on the day results.

The study as they go from more data as well as next steps by the end of the year, we're working very closely with.

Richard S. Geary: Okay, thank you, Richard. As for Huntington, as Roches said, Jason, they continue to analyze all the data, and they've promised an update on the results of the study as they go through more data as well as the next steps by the end of the year. We're working very closely with the results of the study as they go through more data as well as next steps by the end of the year.

With Roche on this.

And so stay tuned for sure in the second half a day here for an update.

Alright, great. Thanks.

The next question is from Luca <unk> with RBC. Please go ahead.

Hello Fantastic. Thanks, so much for taking my question and congrats on all the progress 2 quick 1 on the pipeline. So maybe the first on GTR Richard.

Richard S. Geary: with Roche on this. And so stay tuned for the second half of the year for an update. All right, great, thanks. The next question is from Luca Isse with RBC. Please go ahead. Oh, fantastic. Thanks so much for taking my question.

Can you expand a little bit more on the interim analysis in your planning for GTR like mid 2022 fully neuropathy. It looks to me that the interim analysis is almost 8 months. So it's actually 8 months ahead of the primary endpoint. So wondering what gives you confidence that with such a short follow up you are going to be able to see a separation of the curves and on the second question is on <unk>.

Luca Issi: Congrats on all the progress. Two quick ones on the pipeline. So maybe the first on TTR, Richard.

Richard S. Geary: Can you expand a little bit more on the interim analysis that you're planning for TTR-LICA in mid-2020 in mid-2020 for polyneuropathy? It looks to me that the interim analysis is almost eight months, actually. It's actually eight months ahead of the primary endpoint.

<unk> wondering if you could provide any update there with Steve Arrowhead also running into safety issues. There. So any thoughts on what are the safety issues that they have had are similar to the 1 that you saw and maybe bigger picture. If you could comment on what's next for the respiratory franchise.

Yes. Thanks.

Luca Issi: So wondering what gives you confidence with such a short follow-up; you're going to be able to see a separation of the curves. And then the second question is on ENAC; wondering if you can provide any update there? We've seen Arrowhead also running into safety issues there.

Ill take that Epsilon <unk> question for you first our confidence of course derives from the first.

Polyneuropathy study, we ran with Chegg study.

Same mechanism of action.

We believe we have a.

A much safer drug and a much well tolerated drug with once monthly administration.

Luca Issi: So any thoughts on whether the safety issues that they have had are similar to the one that you saw and, maybe, the bigger picture, if you can comment on what's next for the respiratory franchise? Thanks. Yeah, thanks.

But at 8 months with tech steady in that trial, we had statistically significant improvements in our endpoints.

Richard S. Geary: I'll take that Eplon-Derson question for you first. Our confidence, of course, derives from the first polyneuropathy study we ran with Tegcetti, its mechanism of action. We believe we have a much safer drug and a much more popular drug with once monthly administration. But at eight months with TECETI in that trial, we had statistically significant improvement in our endpoint. And so it was already separating from placebo quite nicely at that time point, so we believe that that gives us the kind of confidence that we need in going into this interim analysis. In fact, it's quite high.

And so it was already separating from placebo quite nicely.

At that time point, so we believe that that gives us.

That kind of confidence that we need in going into this interim analysis effect, it's quite high.

I think the second question that you had.

We.

I can't even speak to what might be happening with the competition.

We had a preclinical issue.

We're working through that and we're very confident that we'll be able to.

We have to finish Brian, yes, and if I could just add.

To what Richard said, Thank you Richard.

Brett P. Monia: I think the second question that you had, you know, I can't even speak to what might be happening with the competition because we had a preclinical issue. We're working through that, and we're very confident that we'll be able to. If the finish line, yeah, and if I could just add to what Richard said, thank you, Richard, is on Epon-Terson. Also, what gives us great confidence is not only the fact that TXETI showed a significant benefit in the same primary endpoints in the phase three study that was conducted for that drug at eight months, but F1-Turson is showing even greater TQR reductions.

On F on tariffs.

Total book.

As us great confidence not only the fact that <unk> showed statistically significant benefit in the same primary endpoints in the phase III study that was conducted for that drug at 8 months.

On Thursday, showing even greater GTR reductions were.

We're right around 90% reductions based on the dose ranging in phase III.

With excellent safety and Tolerability is right for all of our like US as Richard mentioned, so we're very confident in that outcome and we also have a.

We're very comfortable with the regulatory path forward as well.

And just to add on the pulmonary were working.

Really good progress pre clinically in looking at new designs, new molecules that can.

Brett P. Monia: We're at around 90% reductions based on the dose for using in phase three with excellent safety and tolerability, as with all of our Likas, as Richard mentioned. So we're very confident in that outcome. And we also have a, we're very comfortable with the regulatory path forward as well. And just to add on the pulmonary, we're working and making really good progress preclinically and looking at new designs, new molecules that can move the pulmonary program back to development in the future. So stay tuned for that. We'll talk more about that, maybe at the end of the year or next year. Super

Moving to pulmonary program back to development in the future. So stay tuned for that we'll talk more about that maybe the end of the year or next year.

Super Thanks, so much.

The next question is from.

Thank you our in wearable with Cowen.

Cowen.

Please go ahead.

Hi, congrats to the team on all the progress thanks for taking the questions. This is brendan on for your own.

Couple of quick ones from Us. So I know you mentioned that Youre looking to initiate the phase III <unk> study by the end of the year or early next year.

Just wanted to see what steps are left there if you already have alignment with FDA on the study design on that kind of just logistics and getting it set up at this point or you're still finalizing the study.

Operator: The next question is from Yaron Werber with Cowan. Please go ahead. Hi, congratulations to Tema on the progress. Thanks for taking the questions. This is Brendan on for your own.

And then really quickly for Angelman I wanted to see if we might get any preclinical data from that at any point this year.

Yaron Benjamin Werber: Just a couple quick ones from us. So I know you mentioned that you're looking to initiate the Phase 3 HAE study by the end of the year or early next year. Kind of just wanted to see what steps are left there. If you already have alignment with FDA on the study design, and it's kind of just logistics and getting it set up at this point, or are you still finalizing this study?

And what you might be able to tell us about timing and maybe trial design from the phase 1 too.

Thanks very much.

Sure thing I'll take a J and then.

I'll ask Eric to talk a little bit about what we.

Presented and published on in the Angelman program after them so.

Pre clinically so for HCA, we're putting final touches on the phase III study design, we're having very good.

Yaron Benjamin Werber: And then really quickly for Angelman, wanted to see if we might get any pre-clinical data from that at any point this year and what you might be able to tell us about timing and maybe trial design for Phase 1, too. Thanks very much.

Discussions with regulators really it's mostly logistics Brendan.

<unk>.

We're getting.

Drug made we're getting from preparing for the phase III design getting cash.

Selecting our sites moving forward per activation of sites, it's just blocking and tackling honestly at this point.

To get that study up and running we're hoping it's a stretch goal to get it done and initiated by the end of the year.

Brett P. Monia: Sure thing. I'll take the HAA, and then I'll ask Eric to talk a little bit about what we presented and published in the Enjuman program after that. So, preclinical.

But certainly we see it happening no later than the first quarter of next year and.

When we flow share the full dataset.

In the second half of the year for our Phase II study, we also plan to share our strategy our development strategy.

Brett P. Monia: So for H.A.E., we're putting the final touches on the phase three study design. We're having very good discussions with regulators. Really, it's mostly logistics, Brendan.

Our phase III design looks like and why we are why we think it will position PKK Micah.

Brett P. Monia: You know, we're getting drug made. We're getting for preparing for the phase three design phase, selecting our sites moving forward for activation sites. It's just blocking and tackling, honestly, at this point.

Yes. It is the best in class molecule for <unk>, Inc.

So stay tuned for that in the second half.

A lot of momentum going into the second half of the year on a lot of exciting news coming out we think in the second half.

Eric We published on Angelman, we hope were actually.

Brett P. Monia: To get that study up and running, we're hoping it's a stretch goal to get it done and initiated by the end of the year, but certainly, we see it happening no later than the first quarter of next year. When we share the full data set in the second half of the year for our phase two study, we also plan to share our strategy, our development strategy, what our phase three design looks like, and why we think it will position PKK potentially as the best in class molecule for HAE. Stay tuned for that in the second half.

The first to elucidate the mechanism in collaboration with our academic colleagues inhibits in essence transcript up regulate <unk>, which is the deficient.

Protein in Angelman syndrome.

Then we spent a good amount of time trying to optimize the drug and find the ideal keeping development candidate.

So just a little bit longer than I'd hoped but.

We've got a great looking molecule and are looking forward to getting that started in the first in human study later this year.

[noise] took everything we learned about how to.

Great neurology drugs from our extensive experience and tried to make a molecule with leader we're hopeful be best in class in this space and provide a great benefit to patients with Andrew.

Brett P. Monia: We've got a lot of momentum going into the second half of the year and a lot of exciting news coming out, as we think in the second half. Eric, we've published on Angelman. Yeah, we have.

And the.

First in patient study of the Phase <unk> study will be focused obviously on safety tolerability dose escalation select dose.

Eric E. Swayze: We were actually the first to elucidate the mechanism in collaboration with our academic colleagues that you can inhibit an anticsense transcript and upregulate EBE3A, which is the deficient protein in Angelman syndrome. Then we spent a good amount of time trying to optimize the drug and find the ideal human development candidate. It took us a little bit longer than I'd hoped, but we've got a great looking molecule and are looking forward to getting that started in the first human study later this year. We took everything we learned about how to make great neurology drugs from our extensive experience and tried to make a molecule that we're hopeful will be best in class in this space and provide a great benefit to patients with angelic.

Based on biomarker readouts for a potentially.

Potentially for a phase III study default.

Got it thanks guys.

The next question is from me in on 2 with Wells Fargo.

Go ahead.

Great. Thanks for taking my questions and congrats on the progress a lot of.

Things going on.

I have 1 question on the technology platform upfront, which really.

Part 2 bicycle collaboration.

So have you compared their buy side.

Cyclic peptides.

Approach targeting.

The transferrin receptor.

<unk>.

Eric E. Swayze: And the first inpatient study, the phase-1 study will be focused obviously on safety tolerability, dose escalation, and select dose based on biomarker readouts for potentially a Bayes study to follow. Got it. Thanks, guys. The next question is from Yanon Zoo with Wells Fargo. Please go ahead. Great, thanks for taking my questions and congrats on the progress; there are a lot of things going on. I have one question on the technology platform front with regard to bicycle collaboration.

The approaches.

Using either.

On the Corona antibodies or antibody fabs.

And.

Also given your.

Prior experience with my Atonic dystrophy in clinical studies.

When you look at the data.

When you were doing your diligence.

You feel there is enough fold increase in muscle at the exposure.

Compared with our on label the antisense that gave you confidence that you could.

Eric E. Swayze: So have you compared their cyclic peptide approach targeting and transferring receptor with the approaches of using either monoclonal antibodies or antibody fabs, and Also, given your prior experience with myatonic dystrophy in clinical studies, when you look at the date when you were doing your diligence, do you feel there is enough fold increase in muscle exposure compared with unlabeled antisense that gives you confidence that gives you confidence that you could perhaps research restart the myotonic dystrophy program and have an accelerated path.

Perhaps the restart the marathon dystrophy program and have accelerated.

Path.

Yeah. So so that's the first question.

Thanks, Yes, we're really excited about the advancements we're making in targeted delivery across the board including bicycle.

Eric.

The answer is yes, we've done from Paris quite a bit of comparative work prior to.

Completing the bicycle deal Eric.

Eric.

On web.

That effort with his team and so I'll turn it over to him.

Why we are so excited about bicycle on what are how we believe we differentiate from other approaches yes sure. Thanks, Brian.

Yanon Zoo: Yeah, so that's the first question. Thanks.

So we absolutely have comparative with other transferrin receptor ligand. So we were involved in this space on a reasonably early on in that extensively looked at how monoclonal antibodies in fabs.

Brett P. Monia: Thanks, and we're really excited about the advances we're making and targeted delivery across the board, including BISIC. Eric, and the answer is yes, we've done comparatives, quite a bit of comparative work prior to completing the bicycle deal. Eric's left, joined that effort with his team, and so I'll turn it over to him to tell you why we're so excited about bicycles and what we are, how we believe we differentiate from other approaches. Yeah, sure, thanks, Brett.

Target transferrin receptor 1 can deliver cargoes to the muscle.

We definitely demonstrated that that can happen and we're interested in trying to find better laggards that we thought would make better drugs in the yen and that ultimately led us to buy cycle, which has these very unique by cyclic peptides that have been able to we would have been able to develop high affinity ligands for multiple protein.

Eric E. Swayze: So we absolutely have compared it with other transparent receptor ligands. So we, we, we, We were involved in this space recently early on, and it extensively looked at how monoclonal antibodies and fabs that target transfer receptor one can deliver cargoes to the muscle. And we definitely demonstrated that that can happen, and we were interested in trying to find better ligates that we thought would make better drugs in the end. And that ultimately led us to bicycle, which has these very unique bicycly peptides that have been able to where they've been able to develop hypheny ligands for multiple proteins and transparent receptor one in particular.

And transparent receptor 1 in particular.

We absolutely prepared by cycle oligo conjugated to the Fabs and found them to be essentially identical in terms of the potency of based on the oligonucleotide nucleotide to be delivered in the key advantage here is the size Monica.

Monoclonal antibodies or big buy cyclic peptides are small there is probably a 50 to 75 fold difference in weight.

And that translates directly to less total drug that would have to be administered a few scaled up to a human dose projection because all of those are reasonably small and the price cycles are smaller and so we think that'll be a large advantage with this technology, we can make it work and make hopefully best in class muscle and cardiac targeting.

Eric E. Swayze: We absolutely compared the bicycle oligoconjugates to the fabs and found them to be essentially identical in terms of the potency based on the oligonucle amount of liganuclidid that would be delivered. And the key advantage here is the size.

In essence drugs.

As to the programs.

You alluded to <unk>, yes, we do have more potency on that program and this is what the bicyclic transferrin receptor 1 targeting technology does force.

Eric E. Swayze: Monoclo Antibers are big, bicyclic peptides are small. There's probably a 50 to 75 percent difference in weight, and that translates directly to less total drug that would have to be administered if you scaled it up to a human dose projection because all of those are reasonably small and the bicycles are smaller. And so we think that'll be a large advantage with this technology if we can make it work and achieve, hopefully, best in class muscle and cardiac targeting.

We think that it certainly has the potency enhancements to.

To get us in the range of what we need clinically and.

And then beyond that we're not really prepared to comment exactly on what targets, we will advance the timing, but we have a whole host of neuromuscular and cardio cardiac targets lined up that we think are great for this technology and are anxious to get it moving.

Great. Thanks for all of those color.

Eric E. Swayze: of the antitense drugs. As to the programs, you alluded to DMPK and DM1, yes, we needed more potency in that program. And this is what the bicyc transfer inhibitor one targeting technology does for us. We think that it certainly has the potency enhancement to get us in the range of what we need clinically. And beyond that, we're not really prepared to comment exactly on what targets will advance for the timing, but we have a whole host of neuromuscular and cardio cardiac targets lined up that we think are great for this technology and are anxious to get it moving. Great, thanks for all the color.

And then a quick question on Tau lowering or the map.

T program.

You showed us some.

Very impressive reductions of how how should we think about this approach.

Compared with for example, antibody approach targeting Tau.

And <unk>.

Could there be.

On a a biomarker.

Forward.

This is the <unk>.

Given the recent development with a beta approach.

Yanon Zoo: And then a quick question on TAL lowering all the MAPT programs. You showed us some very impressive reductions of TAL. How should we think about this approach, compared with, for example, antibody approaches targeting TAL? And could there be a kind of biomarker path forward with this approach given the recent development with the A-Bata approach?

Yes, so as to the path forward buys from us that they plan to advance this into a larger phase II study.

To more fully test the.

Clinical outcomes and clinical benefits associated with Tau lowering.

So that's the strategy.

As far as a comparison of the antisense approach to an antibody approach.

I really think there is no comparison.

Brett P. Monia: Thanks. Yeah, so as to the path forward, Bayesian said they plan to advance this into a larger phase two study to more fully test the clinical outcomes and clinical benefits associated with Tau lowering. So that's the strategy clinically. As far as a comparison of the antistence approach to an antibody approach, I really think there is no comparison.

<unk> is an intracellular protein, it's known to accumulate aggregate inside the cells and Thats, where our growth work. So they turn off the.

Translation and creation and synthesis of the Tau protein by binding to integrating the RNA. So we turn off all forms of Tau and that's what we demonstrated on a trial that all forms of tower reduced.

To reduce tau in the CSF scanner.

Brett P. Monia: Tau is an intracellular protein. It's known to accumulate and aggregate inside cells, and that's where our drugs work. So they turn off the translation and creation and synthesis of the tau protein by binding to and degrading the RNA. So we turn off all forms of tau, and that's what we demonstrated in the clinical trial, that all forms of tau are reduced. To reduce tau in the CSS, by our mechanism, it has to be reduced inside the cell because that's where it comes from.

By our mechanism it has to be reduced in size itself, because that's where it comes from whereas antibodies.

You have a macro molecule that has a small penetration into the into the CNS space and in the CSF. It binds to the Tau protein and reduces it only in CSF and we don't think those antibodies can engage productively inside of itself, which is what our drugs are doing and we think thats where the <unk>.

<unk> of towers occurring.

But you need to lower Tau throughout the brain and also population.

We're very encouraged about our drug we think it's good.

1 of the key things to test the Tau lowering hypothesis in AAV and we think it's a great..1 of the test and are excited that Biogen has taken on forward to do exactly that.

Brett P. Monia: Whereas antibodies, you have a macro molecule that has a small penetration into the CNS space, and in the CSF, it binds to the tau protein and reduces it only in the CSF. And we don't think those antibodies can engage tau productively inside of a cell, which is what our drugs are doing, and we think that's where the key pathology of tau is occurring. and that you need to lower tau throughout the brain in all cell populations.

Great very helpful. Thanks for the color.

Thanks, Ken.

The next question is from Paul <unk> with Stifel.

Stifel. Please go ahead.

Hey, Thanks for taking our question. This is Alex on for Paul actually a follow up on on map T. I was wondering from the phase 1.2 if you could comment on the relative ASO doses versus.

And tell me nursing phase III, and then secondarily curious if if there are any.

Brett P. Monia: And we're very encouraged about our drug, and we think it's one of the key things to test the, the, the, the, the, the, the, the, the, the, the, the tower-lowering hypothesis in AD. And we think it's a great one to test and are excited that biogen is taking it forward to do exactly that. Great, very helpful. Thanks for all the color.

Biomarkers are via MRI sort of measures in this study and if you could comment on that or if you expect that to sort of get published or presented in the future. Thanks.

Sure.

Those werent disclosed in that poster we are working on getting our phase 1 data published in and so stay tuned for that and hopefully we can share more information about it I will say that.

Operator: Thank you. The next question is from Paul Matase with, Stiffle. Please go ahead. Hey, thanks for taking our question. This is Alex on behalf of Paul.

This is a pretty good oligos and we've been working hard on making advances in how.

How we design and identify all of those subtle tweaks to the chemistry on the design of the compounds and so we've been able to make them more and more potent over the years and I think our PK PD modelers have done a fantastic job predicting the human doses and we.

Paul Matteis: Actually, a follow-up on MAPT. I was wondering from phase one, two, if you could comment on the relative ASO doses versus in Toma Nursing phase three. And then secondarily, curious if there were any biomarkers or any other VMRI sort of measures in this study and if you could comment on that or if you expect that this would get published or presented in the future. Thanks. Sure, you know, the doses weren't disclosed in that poster.

We think this is this represents 1 of the 1 of the better molecules. We've made it performed as expected so.

Hopefully we can share more data in a publication soon.

And can you just say whether or not there were biomarker data taken in this study or is that not something that was done.

Yeah.

<unk>.

We had a range of Biomarkers and outcomes in the study I can't comment beyond what we reported in terms of <unk>.

Richard S. Geary: We are working on getting our phase one data published, and so stay tuned for that, and hopefully we can share more information about it. I will say that this is a pretty good oligo, and we've been working hard on making advances in how we design and identify oligos, subtle tweaks to the chemistry and the design of the compounds and so we've been able to make them more and more potent over the years and I think our PKPD modelers have done a fantastic job predicting the human doses and we think this is this represents one of the one of the better molecules we made and it performed as expected so hopefully we can share more data in a publication soon, And can you just say whether or not there were biomarker data taken in this study, or is that not something that was done? Beyond the- Well, we had a range of biomarkers and outcomes in the study. I can't comment beyond what we reported in terms of MAPT-LAR. All right. Good. Great. Thanks.

Okay, great. Thanks.

Okay.

The next question is from Yale Jen with Laidlaw <unk> company.

Please go ahead.

Good morning, and thanks for taking the questions just maybe a little before were looking on debt.

But in terms of loans.

Loans or sudden.

You get a proof maybe in 2023.

The question is that after you.

Integrate day.

Infrastructure operations, what's the future sort of commercial infrastructure.

Infrastructure.

Strategy out.

Should that be the case and that this will be your net.

Product to launch.

Thanks, Neil I'll ask <unk> to talk to.

To talk about our bunkers from program why we're so excited about it not just for the Polyneuropathy free but also why we're excited about this program as a potential best in class for cardiomyopathy as well on a value on.

Richard S. Geary: The next question is from Yale Jen with Laidlo and Company. Please go ahead. Good morning, and thanks for taking the questions. This may be a little bit forward looking, but in terms of Apple Lonesome, if you get a proof, maybe in 20203, the question is that after you integrate AXIA operations, what's the future sort of commercial infrastructure or strategy you have, should that be the future commercial infrastructure or strategy you have?

I am.

Yes, happy to talk about our program and our commercial launches. So we are absolutely building the capabilities to prepare markets for eye on its commercial launches and Youre right. This would be 1 of the first ones that we would bring to market.

It is as Brett said.

A foundational treatment best in class from both Pn and cardiomyopathy.

We expect to see proven benefit in neuropathy and quality of life.

Richard S. Geary: Should that be the case and that this will be your next product to loan. Thank you, Yale. I'll ask Naysa to talk a little about our Epon-Person program, why we're so excited about it, not just for the polyneropathy in 23, but also why we're excited about this program as a potential best in class for cardiomyopathy as well. Anayna, you on?

Very favorable safety profile and optimal self administration and at home dosing.

So we're very excited about moving this program forward. There is a brand team that's been formed around it and they're preparing the market for launches as well on cardiomyopathy as well as the second indication. It is important to remember that is where we have the largest trial and see them.

Have about 750 patients from a recruiting and we are conducting this trial to generate just a robust set of clinical data.

Yale Jen: I am. Yes, happy to talk about our program and our commercial launches. So we are absolutely building the capabilities to prepare markets for IONIS commercial launches. And you are right; this would be one of the first ones that we would market. It is, as Brett said, foundational treatment best in class for both PN and cardiomyopathy. We expect to see proven benefit in neuropathy, quality of life, a very favorable safety profile, and optimal self-administration and adharmament, and at. So we're very excited about moving this program forward.

We're excited about this program as the second indication for <unk>, 1 person because it's going to be really the breadth of data on the diversity of data that is going to provide for clinicians on how if 1 person can be used in a very dynamic market right with or without standard of care.

It's going to be really.

An advantageous place for every 1 person overall so low.

I'm good I'm good program, great indications and again looking for foundational treatment is best in class per month, Pn and see them.

Okay, Great. That's very helpful. Maybe just 1 more question here, which is that you will have to outgrow <unk> data readout.

Second half of this year could.

Could you recap a little bit of this program and what sort of expectation.

Yale Jen: There is a brand team that's been formed around it, on cardiomyopathy as well as the second indication. Remember, that is where we have the largest trial in CM. We have about and we are conducting this trial with a big set of clinical data. We're excited about this program as the second indication for Appalachichers. Really, the breadth of data and the diversity of data that is going to provide how it in a very dynamic market, with or without standard of care, is going to be really an advocate. So really good program, great, Okay, great, that's very helpful.

You guys may have.

Sure thing, yes so.

We are.

As you said, we're planning to share the results of the phase 2.

On study for our growth hormone receptor <unk> medicine in acromegaly patients who are poorly controlled on top on it.

By the fact that the ticket somatostatin analogs and this was on top of Smiths then.

In that study and the data that we share.

Is.

In the second half of the year will include also open label extension day, which we think is important to characterize the long term profile for growth hormone receptor like it.

Yale Jen: Maybe just one more question here, which is that you will have the Accumegaly data read out in the second half of this year. Could you recap a little bit of this program and what sort of expectations you guys may have? And thanks. Sure thing, Yale.

In this patient population so.

We will be presenting data on target engagement drove a non binding.

Brett P. Monia: So we're, as you said, planning to share the results of the phase two study for our growth hormone receptor Lycom Medicine and Acrimagin patients who are poorly controlled on top, despite the fact that they're taking somatostatin analogs, so this is on top of somatocetan analogs in that study, and the data that we've managed to share is in the second half of the year will also include open-label extension data So we will be presenting data on target engagement, growth hormone binding, safety tolerability, impact on IGF1, and also patient-reported outcomes and other measures of how patients are feeling with this disease in this readout. You know, we haven't identified the venue or the way in which we'll present the data or get the data out in the second half of the year.

Safety and Tolerability.

Impact on IGF, 1 and also patient reported outcomes and other measures of of how patients are feeling.

With this disease.

And this readout.

We're we haven't identified the venue.

Or the.

The way in which we'll present the data organs stayed out in the second half of the year, we're still working on that but we will get it out from second half of the year, we're still analyzing quite a bit on the open label extension data.

They said Hey, we think that's quite important to include.

And as a reminder, this is 1 study of <unk>.

Program.

On this drug we also have the.

Phase III study per PHR like Oh.

Patients frontline monotherapy in patients with acromegaly and that study is expected to readout next year. So we're positioning this drug potentially as a treatment for patients who are poorly controlled on standard of care as well as potentially frontline depending on how the data reads out.

Brett P. Monia: We're still working on that, but we will get it out in the second half of the year. We're still analyzing quite a bit of the open label extension data. And as I said, we think that's quite important to include. And as a reminder, this is just one study of a program for this drug. We also have the phase two study for GHR, like in patients frontline monotherapy in patients with acromegaly, and that study is expected to read out next year.

Okay, Great that's very helpful and congrats on the other provinces.

Thanks you.

The next question is from Jessica Fye with Jpmorgan. Please go ahead.

Hey, guys.

2 quick question on tow person.

What you read across to the rest of it here on neuro pipeline do you think investors can and cannot make based on the upcoming phase III results.

And second 1 is related to that product.

Brett P. Monia: So we're positioning this drug potentially as a treatment for patients who are poorly controlled with standard of care as well as potentially frontline, depending on how the data results turn out. Okay, great, that's very helpful and congratulations on all the progress. Thank you. The next question is from Jessica Fye with J. Morgan. Please go ahead. Hey guys, two quick questions on Toperson.

Can you talk about the reason why the compassionate use is currently restricted to those patients with the most rapidly progressing disease.

Yeah.

Sure thing just back from your question so.

We're very much looking forward as well.

As you know from the phase III readout for October sitting inside of on Nols as we said in the.

Our presentation.

The potential to be the very first disease modifying treatment per genetic cause of AOS any thoughts of AOS fairly when you look at it.

Jessica Fye: What read across to the rest of your neural pipeline? Do you think investors can and cannot, based on the upcoming phase three results and the second one related to that product? Can you talk about the reason why compassionate use is currently restricted to those patients with the most rapidly progressing disease? Sure thing, Jess.

So we're excited about it.

The read through is significant.

Positive.

It will be another demonstration.

Of.

What we believe is the leading platform for the treatment of Neurodegenerative diseases.

Brett P. Monia: Thanks for the question. So we're very much looking forward, as you know, to the face three readout for Topperson and Sarlan analysis. We said in our presentation that this has the potential to be the very first disease-modifying treatment for genetic costs of ALS, really any course of ALS, really when you look at it. So we're excited about it. The read-through is significant, if positive. It will be another demonstration of, you know, what we believe is the leading platform for the treatment of neurodegenerate diseases of any. When you look at the size of our pipeline, it will be a further confirmation.

If any when you look at the size of our pipeline and it will be a further confirmation and not only.

Can we engage targets that cause that are at the root cause of these diseases and neuro as we've done per over 6.7 programs to date that we can hit these targets well at the safety and Tolerability.

As attractive and that we can provide clinical benefit.

And patients Neurodegenerative diseases. So we think that this has significant read through.

In 2 ways 1.

To the rest of our AOS platform right.

It will demonstrate that this platform on our strategy to target AOS works.

Brett P. Monia: And not only can we engage targets that cause, that are at the root cause of these diseases in neuro, as we've done for over 6, 7, 8 programs to date, but we can hit these targets well, that the safety, the tolerability is attractive, and that we can provide clinical benefit in patients' nerve generative diseases. So we think that this has significant read-through into the rest of our ALS platform in two ways, right?

And it bodes very well for 2 other genetic because forms of AOS, our C&I on ORF program, which is due to read out phase III readout next year and our first generic generic pass through to force mutations.

Which is in phase III development.

And we believe it also has significant read through to the broad AOS population that has no known genetic cause our.

Brett P. Monia: It will demonstrate that this platform, our strategy to target ALS, works, and it bodes very well for two other genetically caused forms of ALS. Our C9-Norf program, which is due to readout, days two, read out next year, and our FUS genetic ALS due to the FUS mutation, which is in phase redeveloping. And we believe it also has significant read-through to the broad ALS population that has no known genetic cause, our ATACTS II program.

Our <unk> 2 program.

And also beyond that for neuro and general I mean, it demonstrates we can all the things I already said about target engagement and Tolerability and also that we can penetrate key regions within the CNS.

And provide meaningful hopefully meaningful clinical benefit.

From patients.

As for our compassionate use that's really question for Biogen I really would not want to get ahead of what statements. They've made on this as you know there's been a lot of pressure on biogen to maintenance.

Brett P. Monia: And also, beyond that, for Neurone in general, I mean, it demonstrates we can do all the things I already said about target engagement and tolerability and also that we can penetrate key regions within the CMS and provide meaningful, hopefully meaningful, clinical benefit to patients. As for compassionate use, that's really a question for biogen. I really don't want to get ahead of what statements they've made on this.

Available to patients with Saab on AOS.

Because of the devastating nature of the rapidly progressive natrium seized.

I mean.

We put they believe that this drug will be available to all patients with <unk>. That's the hope of course.

Brett P. Monia: As you know, there's been a lot of pressure on biogen to make this drug available to patients with Sod1 AOS because of the devastating nature and the rapidly progressive nature of the disease. I mean, simply put, they believe that this drug will be available to all patients with Side 1 ALS. That's the hope, of course, in the near future.

In the near future. So they are focused on those were rapidly progressing from some disease because those patients may not make it to the time in which this drug institute available for all patients from the cycle on AOS.

Quite simply I think thats thats the rationale behind it.

Brett P. Monia: So they focused on those with rapidly progressing forms of disease because those patients may not make it to the time when this drug is available for all patients with Side 1 ALS. And quite simply, I think that's the rationale behind it. Great, thank you. The next question is from Manny Furrah with SBB Lerink. Please go ahead. Hey guys, thanks for the question. A couple quick ones. I know it's been danced around on this call and others.

Great. Thank you.

Okay.

The next question is from Manny for Ferrara with S&P BBB Leerink. Please go ahead.

Hey, guys. Thanks for the question a couple of quick ones.

Deaths out on this call and others can you layout for us without we could expect potential exploratory cardiac measures from the neuro <unk> transform study 1 of your competitors.

Discussed at length exploratory cardiac measures from their partner on this study.

Manny Forrah: Can you lay out for us whether or not we could expect potential exploratory cardiac measures from the NeuroTDR Transforms Study? One of your competitors discussed at length exploratory cardiac measures from their pornography study. And failing that from the cardiomyopsy side, do you give us a sense of what you are seeing in the market? as opposed to what we're seeing in a clinical trial execution setting around the use of thephematists alongside oligotherapy in patients with combined neuropathy and cardiomyopathy and cardiomyopathy.

And failing and failing that from.

On the claim up besides could you give us a sense of what you are seeing in the marketplace as opposed to are you seeing any clinical trial execution setting around use of <unk> along side all of the growth therapy on pace.

Patients with combined with combined neuropathy and cardiomyopathy symptoms.

Sure Manny.

Take the first 1 on I'll ask him.

Manny Forrah: Sure, I'll take the first one and I'll ask Naysa to talk a little bit about how we see the market playing out right now with RNA targeted therapies and contaminism, but we're really, probably more importantly, how we see it playing out in the future. Yes, indeed, we have cardiac measures in the polyneopathy, Sepontersin Phase 3 study. These are secondary endpoints and maybe some exploratory endpoints as well. All the classic endpoints will be looked at for those patients with mixed phenotypes who have cardiac involvement.

Nathan ill talk a little bit about how we see the market playing out right now.

On a targeted therapies and contaminants and but we're really probably more importantly, how we see it playing out in the future.

Yes, Indeed, we have cardiac measures in the Polyneuropathy.

Stefan <unk> from Phase III study.

These are secondary endpoints are and maybe some exploratory endpoints as well while the classic endpoints will be looked at for those patients with mixed phenotype.

On with cardiac involvement.

Brett P. Monia: That'll be, that'll include, you know, the ventricular load and build up in the heart, markers such as NP Pro B&P and other markers in that study as we did in the TXET, Phase 3 study. So be on the lookout for that next year when the data is released, as well as, of course, the primary endpoints, which is MIS plus 7. And for the next eight months, it's also TTR reductions, right, Richard?

That'll be that'll include.

Drinking with load and we build up into our.

Markers such as empty pro BNP.

And other markers.

In that study as we did in the <unk> study.

Phase III study.

So maybe on what would go from there.

Next year when the data reads out as well as of course, the primary endpoints, which is on this plus 7.

And for the 8 months and social PTR reductions right Richard.

Brett P. Monia: Yeah. And then as we bring this study to its completion at 15 months, we'll also have quality of life as a primary implant. I think Onea might be the best one to comment on the market for stabilizers that aren't targeted therapists. Yeah, happy to. Hi, Mani. How are you?

And then as we bring this study to its completion of 15 months or so.

Quality of life as a primary endpoint indefinitely.

I think on Asia that might be the best 1 to comment on the market.

On stabilizers and on a targeted therapies, yeah happy to hi money how are you.

Thanks for the question too.

Onaiza Cadoret: Thanks for the questions. So, yeah, we are seeing, so really your question is, like, it's a geographical answer, so in the U.S., some, you know, a fair amount of use, and you know, and, you know, again, they're doing a really good job of, you know, We've done some good work with KOLs, you know, good market research with clinicians who prescribed this, as well as payers, sense we're getting from them is that, you know, this isn't really really need care and that they could see a world where use the silencer and stabilizer together, and I think, you know, it would have been nice to have the silence But, you know, that's not how the order of, out, but the market is large, diverse.

We are seeing so really your question is like it did.

Geographical answer so in the U S. We're seeing.

So a fair amount of use of <unk>.

And again, they're doing a really good job of diagnosing and getting patients treated.

We've done.

Some good work with Kols and just good market research with clinicians, who prescribe this as well as payers and the <unk>.

We're getting from them is that this isn't really sick.

These patients actually.

Really need care and.

That they could see a world where.

We can easily use a silencer and stabilizer together.

And I think Mechanistically of course, it would have been nice to have the silencer honest first.

But you know that.

That's not how the order of entry really worked out but the market is large it's Doug.

It's dynamic and again, what I really again go back to what I like what we're doing is we're actually looking at.

Onaiza Cadoret: And what I really, again, go back to what I like, what we're doing is we're actually looking at the world and how it's evolving, and we will have From a payer perspective also, we've seen Villeenao products alone or in combination as well. Again, going back, Thanks, Anasia. Bonnie did it.

The future World and how it's evolving and we will have a set of data for clinicians where they want to use this with or without a day.

Families and a wide and diverse patient population from.

On a per perspective also we've seen really no hesitation to use these products alone or in combination as well again going back to this is a very sick population and we need to do what's right for the patient here.

Thanks Nathan.

Bonnie.

Brett P. Monia: Good. Thanks. I have a quick follow-up. Yeah, I have one quick follow-up. There's been a lot of discussion around the role of the six-minute walk as an approval endpoint in cardiopathy. It was a little different in the experience that Tasaminis Vindekal and Alvindamax had. What's the, in your sort of commercial as well as clinical trial experience, what's the state of feedback you're getting from clinicians regarding their receptiveness to using therapy is approved on a six So how do you, how do you execute on that when you're launching against an asset and all assets that have a survival benefit?

Okay. Thanks.

A follow up.

Yes, I have 1 quick follow up there's been a lot of discussion around the role of 6 minute walk.

On the approvable endpoint in cardiomyopathy was a little different from the experience that <unk>.

<unk> had on what's.

Whats the in Europe in Euro so on commercial as well as clinical trial experience, what's the state of feedback youre getting from clinicians regarding their receptiveness to use therapies approved on a 6 minute walk, but with out but without survival data in hand, and so how do you. How do you how do you execute on that when youre launching against.

When asked that all asset that does have a survival benefit.

Okay and anything you're on a run with that.

Onaiza Cadoret: Anay, you want to run with that? Sure. Yeah, listen. I think, you know, again, you have to look at where the market is, and the market has survival data in there, so I think it's going to be really important to deliver that.

Yeah listen I think you know again.

You have to look at where the market is and the market have survival data in there. So I think it's going to be really important to be able to deliver that.

Onaiza Cadoret: Sure, yeah, listen, I think, you know, again, you have to look at where the market market has to effectively find a place for that new therapy that's coming out. Credit vass. So I think it's going to be, and is claimed as, very important for making a decision. That being said, you know, we have, as our secondary endpoint in our studies, functional improvements, yeah, they're important for the market, that as well as how the effect on patients because these patients do progress, and those Yeah, and just to add to that, Mani, as you know, for the mixed phenotypes, the hereditary penitaphs, cardiobascular, cardiomyopathy, and polyneuropathy, those six So if you're improving polyneuropathy in the feet, you may be able to improve the six-minute walk test since it has nothing to do with improvements in cardiomyopathy.

On to effectively find a place for that new therapy, that's coming on place in terms on what is the.

On cardiovascular risk reduction.

It can be I'm going to be and is claimed as a very important.

Factor from making a decision for these patients.

That being said you know we have is our secondary endpoint in our studies it.

Functional improvement so yeah. They are important for patients and 6 minute walk as a good functional improvement but again.

The market, where things are already established with CVR I think it's going to be about that as well as how quickly you actually see.

The effect on patients because these patients do progress and those are the 2 things that are coming up it's really important for us.

And just to add to that non as you know for the mixed phenotypes that hereditary cardiovascular cardiomyopathy and polyneuropathy.

On 6 minute walk test or a little complicated because of the polyneuropathy component the disease Sofia improving partner apathy.

And the fee.

You may be able to improve 6 minute walk distance has nothing to do with.

Improvements in cardiomyopathy, so it's a little complicated.

Brett P. Monia: So it's a little complicated. We believe in how, We believe the outcome data will drive the greatest number of sales by far thousands for these drugs when they go when that's demonstrated. Great, thank you, guys. The next question is from Miles Mintar with William Blair. Please go ahead. Hi, everyone.

We absolutely believe in.

We believe the outcome data.

We will do.

The greatest but far value for these drugs.

When they went from that demonstrates.

Great. Thanks, taking my question guys.

The next question is from Myles Minter on with William Blair. Please go ahead.

However on a just a quick question on the map day data right.

Myles Minter: Just a quick question on the map key data at AIC. I noticed that particularly on the total tail level session, they keep decreasing even though these patients have been off four months of drugs or been off drugs for four months. So I'm just wondering how you think or how Bidgen made me think about dosing frequency in that particular indication as you move into a better powered phase two. And in the publication, will that include CDI, some of the boxes, you know, followed up for this long-term extension, but thanks.

Okay.

I noticed that particularly on the total level session that take day pricing, even though those patients obtained after 4 months of drug.

Or paying off drug for 4 months, sorry, I'm, just wondering how youre thinking on <unk> may be thinking about dosing frequency in that particular indication as you move into a better powered phase 2 and in the publication will that include a city on some of the boxes.

And I followed up for this long term extension part thanks.

Myles Minter: Yeah, so this is, as I said earlier, we think this is a great drug, and duration of action is one of the things that we've been working hard on. So I think that continued tau reduction and expansion is evidence of that. And we hope to expand on that with the publication as we share more data on the program and really demonstrate that this is an outstanding looking molecule.

Yes. So this is as I said earlier, we think this is a great drug and duration of action is 1 of the things that we've been working hard on it.

And on our.

So I think that continued <unk> reduction that's mentioned.

As evidence of that.

We hope to expand on that with the publication as low as we share more data on the program.

And really demonstrate that this was an outstanding looking molecule.

Eric E. Swayze: And of course, we'll design our studies to support the optimal dosing schedule. And if you're doing intrapecal injections, fewer injections less frequently are a good thing. And the durability really is remarkable for the drug.

Of course, we will design our studies to support the optimal dosing schedule and if youre doing interest equal injection fewer injections frequently are a good thing.

And the durability really is from model.

Drug.

On.

Brett P. Monia: You know, it probably supports bi-annual dosing potentially. Not that that is necessarily the dosing regimen for the phase-2 study, but certainly the data supports that. And as Eric said, it's a reflection of the continued improvements we're making, not just in the drugs we identify in neuro, but across the board. And then just was the CDR, some of the boxes, something that will be included in the publication, or was that only measuring its baseline to screen these patients?

It probably is.

Ports biannual dosing potentially.

That is necessary.

Necessarily the dosing regimen for the phase III study, but certainly the data.

Towards that.

As Eric said, it's a reflection of the continued improvements we're making not just in the drugs, we identify neuro, but across the board.

And then just with the city outside of the box is that something that will be included in the publication all of us that finally measured at baseline to screen these patients yet.

Brett P. Monia: I don't think we have visibility yet whether or not the long-term extension will be in the publication. Typically, when we publish first in patient studies, it's just the randomized portion of the study, and then the long-term extensions will be presented at medical meetings to follow and those sorts of things, and maybe publications as well. I don't have a definitive answer for that question, Miles. No worries.

<unk>.

I don't think we have visibility, we know yet whether or not the long term extension of the beam and the publication typically when we published first an inpatient studies. It's just the randomized portion of the study and then the long term extensions will be.

Presented at medical meetings to follow and those sorts of things and maybe publications as well.

I don't have a definitive answer for that question Myles.

Thanks for the questions.

Myles Minter: Thanks for the questions. The next question is from Esther Roja Vallou with UBS. Please go ahead. Hey, good morning.

Okay.

The next question is from Elster Roger is on Lu with UBS. Please go ahead.

Hey, good morning, and thank you for taking my question.

Esther Roja Vallou: Thank you for taking my question. On Fuse ALS, can you help us understand some of the trial design considerations for this space three that you're starting to enroll compared to Fersen? And then I have a follow-up on another topic. Richard, do you want to take them?

On fused AOS can you help us understand some of the trial design considerations for this phase 2 but we are starting to enroll comport Coca wholesome.

And then I have a follow up on another call.

Richard do you want to take them.

I'll share this is <unk>, yes.

Richard S. Geary: This is Foss. Yes. So, similar in terms of the design and the regimen. And so it is a phase three registrational study, so it's not. It's moving directly from what has been an open-label, single patient, or a few patients being treated to a full registration with all the health authority input with the design, etc. So in terms of where we are with FUS, we're very confident that the design that we put together is one that will be supportive of this, again, a very good drug moving into phase three.

So.

It's similar in terms of the design.

And the regimen and so it is a phase III Registrational studies. So it is not.

It's moving directly from.

What has been on open label.

Single patient or a few patients being treated to a full registration with all the health authority endpoint.

With the design et cetera.

I think in terms of where we are with <unk>.

Confident that the design that we've put together is 1 that.

That will be supportive of this again, a very good drug.

In 2 phase III and we're excited on program has started and patients are enrolling.

Richard S. Geary: And we're excited the program is starting and patients are enrolling. And to add to that, Esther, the primary endpoint is the same as the Toperson, so there's a direct link there, the ALS functional rating scale. Obviously, we have the ability to measure target engagement in patients too, like we did with the Topherson study. So it's quite similar.

And to add to that after the primary endpoint is the same as the 12%. So there is a direct link there the ALS functional rating scale.

Obviously, we have the ability to measure.

On target engagement and patients do I begin with the <unk> study.

And.

Brett P. Monia: It's a longer study than six-months for some studies, like 250, almost a year, I think, treatment, right? Right. I think it's two seven or two days or something. So is it the longer duration of treatment that is, is that specific to this patient phenotype, or what's the talk behind that? ALS is a rapidly progressing or gender-specific disease, but there are certain forms of ALS that are more rapidly progressing than others.

Okay. So it's quite similar to it's a longer study.

And then 6 months dosing studies by 250, almost a year I think treatment right.

Yes.

Alright, I think thats kicked on okay.

So is it the longer duration of treatment that is is that specific to the patient phenotype or what.

What's the thought behind that.

ALS is a rapidly progressing neurodegenerative diseases, but there are certain forms of iOS that are more rapidly progressing day message buses.

Brett P. Monia: Fuss is a sort of your normal, if you will, if you want to use that word, progressing patient population for ALS. So it takes a little longer, and therefore the study is longer. Got it.

Is it sort of your.

On your normal if you will go on.

Use that word from.

Breastfeeding patient population per hour, so it takes a little longer and.

And therefore the study longer.

Got it okay. Thank you and then a quick follow up on the 10th and the second question that was asked earlier.

Esther Roja Vallou: Okay, thank you. And then a quick follow-up on the transparent receptor question that was asked earlier. You referred to cardiac indications, but can you maybe help us understand whether you're referring to cardiomebabolic indications or more tied to the structural issues in the heart? Oh, we're focused on diseases like heart failure, targeting cardiac myocytes directly, not metabolic or those sorts of things. We're going after well-validated targets based on genetics as well as validation, validated targets based on preclinical data that we've generated and others have generated, and others have generated, targeting directly cardiac myocytes. So different forms of heart failure are our primary focus. I understand. Thank you very much. The next question is from David Lieberwitz of Morgan Stanley.

Hard to cardiac applications, but can you maybe help us.

I understand why that you're referring to cardio metabolic indications are more tight.

Tied to the structural issues and the high.

Oh, we're focused on.

Diseases like heart failure.

Targeting cardiac myocyte directly not not metabolic or are those sorts of things.

We're going after.

Well validated.

Targets based on genetics as well as on validation Val.

Validated targets based on preclinical data that we've generated.

And others have generated.

Moving directly carty.

Cardiac myocyte, so different forms of heart failure.

As our primary focus there.

Understood. Thank you very much.

The next question is from David Leibowitz with.

David Lebowitz: Thank you very much for taking my question. When you look forward to the SIG 1 readout, could you just run us through what we could expect to see in that readout, and what you think needs to be achieved as far as being able to exceed regulatory thresholds? That would be very helpful.

Morgan Stanley. Please go ahead.

Thank you very much for taking my question. When you look forward to the side 1 weighted out could you just run us through what we could expect to see in that readout.

What you think needs can be achieved.

As far as.

Being able to exceed regulatory thresholds.

That would be very helpful. Thank you.

Sure David So.

Brett P. Monia: Sure, David. So obviously, this is a randomized placebo-controlled six-month trial, Topherson Fasebo versus Pacebo, primary endpoint AOLF functional rating scale, and the sort of focus is to demonstrate statistically significant clinical benefit to patients on the drug versus placebo. There will also be quite a bit of supportive long-term extension data from that study as well. However, we do not believe that side one reduction, the biomarker, will be sufficient for an approval by itself. With that said, there is an enormous outcry.

Obviously this was a randomized placebo controlled.

Month trial placebo versus placebo.

Primary endpoint AOS functional rating scale, that's where the focus is to demonstrate statistically significant clinical benefit to patients on drug versus placebo.

They will also be quite a bit of <unk>.

For the long term extension data from that study as well.

We do not believe that aside 1 reduction the biomarker will be sufficient.

For an approval by itself with that said, there's enormous outcry from these drug today.

Brett P. Monia: for this drug today by the ALS community. This is a very active patient community that has cried out for, as we touched on earlier, in the compassion that you studied at, Biogen opened up, cried out for this drug a long time ago to get access to it. There are no treatments for this disease, and it's a severe, it's a severe neurodegener disease, as you know. So, you know, that's what we're looking for. That's what we're feeling confident about based on phase two data, and we're targeting the genetically known cause of this disease. But there are no treatments for this disease.

AOS community.

This is a.

Very active.

On patient.

<unk>.

That has.

Right out for as we touched on earlier on the compassionate use study data Biogen opened up quite out for this drug long time ago to get access to it there are no treatments for this disease is a severely.

Ordinary share because as you know so.

That's where we're looking for that's what we're feeling confident about based on the phase III data and the fact that we're targeting to genetics the known cause of this disease.

But.

There are no treatments for this disease. So you know.

I do believe the regulators will be open minded on trying to deliver a drug like this to patients as rapidly as possible.

Brett P. Monia: I do believe that regulators will be open-minded to trying to deliver a drug like this to patients as rapidly as possible. Thank you very much for your attention. Thank you, David. And I think that that's our last question. So, with that, I'd like to thank everybody who joined us on our call today. We have a lot of momentum going into the second half of the year, and as the year unfolds, we're really looking forward to providing further updates as we continue to execute on all of our goals. Until then, thanks for joining us today, and have a great day. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

Thank you very much for taking on.

Thank you, David and I think that that's our last question.

So with that I'd like to thank everybody, who joined us on our call today, we have a lot of momentum going into the second half of the year and as the year unfolds. We're really looking forward on providing further updates as we continue to execute on on all of our goals until then thanks for joining us today and have a great day.

The conference has now concluded. Thank you for attending today's presentation you may now disconnect.

Yeah.