Q1 2022 Ionis Pharmaceuticals Inc Earnings Call

Unknown Executive: Before we begin, I encourage everyone to go to the investor section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financial results. We believe non-GAAP financial results better represent the economics of our business and how we manage our business.

I encourage everyone to go to the investors section of <unk> website.

Yes release and related financial tables can be will be discussing today.

Including a reconciliation of GAAP to non-GAAP financial.

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

Brett Monia: We have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Eugene Schneider, Chief Clinical Development Officer. And joining us for the Q&A portion of the call are Eric Swayze, Executive Vice President of Research, and Onaiza Cadoret, Chief Product Strategy and Operations Officer. I would like to draw your attention to slide three, which contains our forward-looking statement.

<unk> also posted slides on our website that accompany today's call.

With me this morning are Brent <unk> chief of staff.

Officer, Beth Hougen, Chief Financial Officer, and Eugene Schneider, Chief Clinical development Officer.

Joining us for the Q&A portion of the call are Eric Swayze Executive Vice President of research and Nathan Countering Chief product strategy and operations Officer.

I would like to draw your attention to slide three which contains our forward looking statements. During this call we will be making forward looking language statement that are based on our current expectations and beliefs.

Brett Monia: During this call, we will be making forward-looking language statements that 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 contained in our SEC filings for additional details. With that, I'll turn the call over to Brett.

These statements are subject to certain risks and uncertainties and our actual results may differ materially.

I encourage you to consult the risk factors contained in our SEC filings for additional detail with that I'll turn the call over to Brent.

Thanks Julien.

Brett Monia: Thank you, Julie. Good morning, everyone, and thanks for joining us on today's call. This year, we are already off to a very strong start. We continue making excellent progress in building our commercial organizations, advancing and expanding our technology, and moving towards delivering an abundance of new medicines to the market. This includes the great progress we're making with our near-term commercial opportunities at Wuntersen, Olazarsen, and Donnie DeLorsen. The Phase III neurotransform study of epinephrine in patients with PTR polyneuropathy remains on track for a date of mid-year, and working hand-in-hand with AstraZeneca, we're preparing to file for regulatory approval by the end of the year, assuming positive data.

Good morning, everyone and thanks for joining us on today's call.

This year, we are already off to a very strong start.

We continue making excellent progress building, our commercial organization, advancing and expanding our technology and moving towards delivering an abundance of new medicines to the market.

This includes the great progress, we're making with our near term commercial opportunities at.

That one person or resource.

Turning to <unk>.

The phase III neuro <unk> transform study <unk> in patients with <unk> Polyneuropathy remains on track for data mid year.

And hand in hand with Astrazeneca, we are preparing for the regulatory approved by the end of the year and assuming positive data.

At the same time, we're also advancing our go to market preparations.

Brett Monia: At the same time, we're also jointly advancing our go-to-market preparation. We recently achieved our original enrollment goal in our CardioTransform study for patients with ADTR cardiomyopathy. And last week, we announced that we took a bold step by increasing the size and duration of our study. As a result, we expect to generate even more robust data, better positioning us to successfully compete in this dynamic market estimated to grow to well in excess of $10 billion.

We recently achieved our original enrollment goal cardio transform study for patients with <unk> cardiomyopathy.

Last week, we announced that we took a bold step by increasing the size and duration of our study.

And in doing so.

We expect to generate even more robust data better positioning us to successfully compete in this dynamic market estimated to grow well in excess of $10 billion.

Based on these updates in our current brisk enrollment rate, we expect a modest shift in our timeline with data reading out shifts with data readout shifting from late 2020 for the first half of 2025.

Brett Monia: Based on these updates and our current brisk enrollment rate, we expect a modest shift in our timeline with data readout shifting from late 2024 to the first half of 2025. We also continue to advance our olfdarsen phase 3 program in patients with high triglycerides. The BALM study of patients with familial carbomyokinemia syndrome, or SCS, remains on track for data next year. And the core study in patients with severe hypertriglyceridemia, SHTG, continues to progress, with data expected in 2024. Severely elevated triglycerides is a key independent cardiovascular disease risk factor for which current standard of care therapies are ineffective.

We also continued to advance our <unk> phase III program in patients with high triglycerides the.

The balance study for patients with familial private from academia syndrome, or FCS remains on track for data next year.

And the core study in patients with severe hyper triglycerides EMEA <unk> continues to progress with data expected in 2024.

Severely elevated triglycerides as a key independent cardiovascular risk factor for which current standard of care therapies are ineffective.

With over 3 million patients in the U S severe hypertrichosis leukemia, and our first mover advantage, we believe <unk> represents a blockbuster opportunity for <unk>.

Brett Monia: With over 3 million patients in the U.S. with severe hypertrichosterolemia and our first-mover advantage, we believe Olazarsen represents a blockbuster opportunity for Ionis. Ionis Pharmaceuticals Inc., Our Phase III Oasis HAE study with Donovores in patients with hereditary angioedema also continued to progress well, with data expected in 2024. We believe Donovan-Lewison has the potential to be a best-in-class prophylactic treatment for HAE patients.

<unk>.

Our phase III Oasis Hae's study of <unk> in patients with hereditary Angioedema also continued to progress well with data expected in 2024.

We believe done the Brewers and has the potential to be a best in class prophylactic treatment for HAE patients.

Brett Monia: And as a result, Donna Dolores represents a significant opportunity for us, given the significant unmet medical need of these patients in this growing billion-dollar-plus market. We have also made excellent progress across our rich mid-stage pipeline. AstraZeneca presented positive phase 2B data in ACC in April from the adhesion study of IM449 or PGSK9 medicine in patients who are at high risk for cardiovascular disease with hypercholesterolemia. The study met its primary and secondary endpoints, showed good safety and tolerability, and ION449 demonstrated a potential best-in-class profile. With more than 10 million patients in the U.S. who remain above their LDL-C goal despite maximum statin and acetamide therapy, we believe IM-449 could be a significant opportunity for us.

And as a result of the worst represent significant opportunity for us given the significant unmet medical need of these patients and is growing 1 billion dollar plus market.

We also made excellent progress across our rich mid stage pipeline.

Astrazeneca presented positive phase II data.

ACC in April from the <unk> study of INO, four nine or <unk> medicine in patients who are at high risk for cardiovascular disease with hypercholesterolemia.

The study met its primary and secondary endpoints include safety and Tolerability and <unk>.

Four nine demonstrated a potential best in class profile.

With more than 10 million patients in the U S remained above their LDL goal despite maximum statin.

Therapy, we believe <unk> could be a significant opportunity for us.

Additionally, we reached full enrollment in the phase <unk> study of <unk> in patients with treatment resistant hypertension with data expected in the second half of this year.

Brett Monia: Additionally, we reached full enrollment in the Phase 2B study of Ionis AGT-LRX in patients with treatment-resistant hypertension, with data expected in the second half of this year. We're also evaluating Ionis HT-LRX in a Phase II study in patients with chronic heart failure with reduced ejection fraction. These indications combined represent over 15 million patients in the U.S. alone. Despite advances in therapy, a significant need remains for more effective treatments to address treatment-resistant hypertension and heart failure.

We're also evaluating <unk> in a phase II.

<unk> hundred study in patients with chronic heart failure with reduced ejection fraction.

Indications combined represent over 15 million patients in the U S alone.

Despite advances in therapy is a significant need remains true.

Treatments to address treatment resistant hypertension.

Our failure.

Looking ahead, we expect numerous additional catalysts highlighted by the phase III <unk> data readout midyear and our planned regulatory filing by year end. We also expect to be more phase <unk> data readout with several key study initiations and updates on important technology advances and with that.

Beth Hougen: Looking ahead, we expect numerous additional catalysts highlighted by the Phase 3 of Montersey data readout mid-year and our planned regulatory filing by year-end. We also expect three more Phase 2b data readouts, several key study initiations, and updates on important technology advances. And with that, I'll turn the call over to Beth to review our first quarter financial results, and Eugene will discuss our recent key pipeline updates and preview upcoming catalysts for the rest of the year. After Eugene, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.

I will turn the call over to Beth to review, our first quarter financial results and Eugene will discuss our recent key pipeline updates and previewed upcoming catalysts through the rest of the year.

After using our wrap up our prepared remarks before taking your questions now over to Beth.

Beth Hougen: Thank you, Brett. Our first quarter financial results clearly demonstrate a key element of our financial strength. That is our ability to consistently generate substantial revenue and cash from numerous diverse sources. Our revenues increased more than 25% year-over-year to more than $140 million and were split approximately 50-50 between commercial and R&D revenues. Our operating expenses and net loss, both on a non-gap basis, were in line with our expectations, and we ended March with a healthy balance sheet, including cash and investments of $2.1 billion.

Thank you, Brian our first quarter financial results clearly demonstrate a key element of our financial strength.

It is our ability to consistently generate substantial revenue and cash numerous thanks Ernie.

Our revenues increased more than 25% year over year to more than $140 million.

And were split approximately 50 50 between commercial and R&D revenues.

Our operating expenses and net loss both on a non-GAAP basis were in line with our expectation.

And we ended March with a healthy balance sheet, including cash and investments of $2 $1 billion.

Beth Hougen: These results keep us on track to meet our 2022 financial guidance. We earned $72 million in the first quarter in revenue from our marketed products, with the majority coming from Spinraza. Finranza's global sales were $473 million, increasing more than 7% compared to the previous quarter.

These results keep us on track to meet our 2022 financial guidance.

We earned <unk> $72 million in the first quarter in revenue from our marketed products with the majority coming from Cinryze.

And Ron just global sales were $473 million, increasing more than 7% compared to last quarter.

Beth Hougen: As a result, we earned $54 million in royalty revenue. Just as a reminder, our royalty rates recess at the beginning of each year, and as in prior years, we expect to quickly move through the royalty tiers and reach the highest tier by mid-year. Spinraza revenue increased in both the U.S. and ex-U.S. in the first quarter compared to the fourth quarter last year. In the U.S., new patient starts for Spironza reached a two-year high, while discontinuations continued to decrease. Outside the U.S., the increase in Finraza revenue was driven by strong initial uptake in China.

As a result, we earned $54 million in royalty revenues.

Just as a reminder, our royalty rate recess.

Beginning of each year and as in prior years, we expect to quickly move through the royalty tiers and reached the highest share by midyear.

Okay.

And on the revenue increase to both the U S and X U S. In the first quarter compared to the fourth quarter last year.

In the U S. New patient starts for <unk> at least a two year high above discontinued.

Discontinuation continued to decrease.

Outside of the U S. The increases around the revenue was driven by strong initial uptake in China.

I can recently presented updates from me, it's been an arm study in patients previously treated with competitive products.

Beth Hougen: BITIN recently presented updates from the ASCEND and RESPOND studies in patients previously treated with competitive products. Biden also presented new results from the NURTURE pre-symptomatic study, which continues to show that patients receiving early and sustained Spiroza treatment achieve and maintain motor milestones consistent with normal development. Based on these results and Spinraza's attractive profile, we continue to see a bright future for Spinraza. We earned our new revenue of $70 million, which more than doubled compared to the same quarter last year.

I can also presented new results from the nurture pre symptomatic study.

It's continued to show that patients receiving early and sustained and rod the treatment achieved and maintained motor milestones consistent with normal development.

Based on these results and 10 Ross's attractive profile, we continue to see a bright future.

We earned R&D revenue of $70 million, which more than doubled compared to the same quarter last year.

Beth Hougen: We earned R&D revenue from several different partners for advancing 15 programs, and revenue from our strategic collaboration with Biogen was the largest contributor. We earned $40 million in the first quarter from Biogen for advancing numerous neurological programs. Our R&D revenue also included $20 million in cost-sharing payments from AstraZeneca for their 55% of Epsilon-Turksen's first quarter development costs. We reported non-GAAP operating expenses of $173 million, which was a 9% increase compared to the same period last year.

We earned R&D revenue from several different partners for advancing the <unk> program.

And revenue from our strategic collaboration with Biogen was the largest contributor.

Earned $40 million in the first quarter from Biogen for advancing numerous neurological program.

Our R&D revenue also included $20 million.

In payments cost sharing payments from astrazeneca for their 55% upon.

First quarter about Macau.

We reported non-GAAP operating expenses of $173 million, which was a 9% increase compared with the same period last year.

R&D expenses increased by more than 25% driven in large part.

Beth Hougen: Are the expenses increased by more than 25% driven in large part by the six phase three studies we are currently conducting? Our R&D expenses also included increased spending for CMC and medical affairs activities to support our near-term commercial opportunity. SG&A expenses decreased year over year by about 40%.

Six phase III studies, we are currently conducting.

Our R&D expenses also included increased spending for PMT and medical affairs activities to support our near term commercial opportunity.

SG&A expenses decreased year over year by about 40%. This was largely due to the substantial savings from the FCA.

Beth Hougen: This was largely due to the substantial savings from the Axia Immigration and Sobe Transaction. However, these savings were offset in part by the investments we are making in our go-to-market preparation for Eflon Thurston, Ola Darson, and Donita Larson. Looking forward, we expect our revenues in Q2 to be similar to Q1. We also anticipate that second half revenues will be more weighted toward the back end of the year. We project operating expenses to increase in Q2 and over the course of this year.

Integration and <unk> transactions.

These savings were offset in part by the investments, we're making in our go to market preparation for F. One person.

Duston.

<unk>.

Looking forward, we expect our revenues Q2 to be similar to Q1, and we also anticipate the second half revenues will be more weighted towards the backend of this year.

We project operating expenses to increase in Q2 and over the course of this year.

Beth Hougen: Consistent with our guidance, we expect R&D expenses to increase between 25% and 30% this year compared to last year, as our Phase 3 studies continue to progress. We project our SG&A expenses to be in line with last year, even while we increase our investment in preparing to bring Athlon Terneson, Ola Zarsan, and Donita Larson to the market. With $2.1 billion in cash and investments at the end of March, combined with our ability to generate substantial revenue from many diverse sources,

Consistent with our guidance, we expect R&D expenses to increase between 25%, 30% this year compared to last year.

As our phase III study continues to progress.

We protect our SG&A expenses to be in line with last year, even while we increased our investment in preparing to bring Apple and <unk> and the needle or sent to the market.

With $2 $1 billion in cash and investments at the end of March combined with our ability to generate substantial revenue for many diverse sources.

Eugene Schneider: We have the financial strength to underwrite the investments we are making to drive significant future growth. And with that, I'll turn the call over to Eugene. Thank you, Beth.

Have the financial strength to underwrite investments, we're making to drive significant future growth.

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

Thank you Bob.

I'm pleased to report on the continued pipeline progress we made during the first quarter.

Eugene Schneider: I'm pleased to report on the continued pipeline progress we made during the first quarter. Our Phase 3 programs are progressing well, with the most advanced being that one person, with data from the Phase 3 Neuron Transform Study expected next week. And, as Brett said, we're preparing to file for regulatory approval in the second half of this year. Summarizing positive data.

Our phase III programs are progressing well.

Both of them is up one person.

Data from the phase III neuro transform study expected mid year.

And as Brent said, we're preparing to file for regulatory approval in the second half of this year assuming positive data.

Additionally, we're looking forward to presenting the baseline characteristics from the neuro transform study of the peripheral nerve Society Congress later this month.

Eugene Schneider: Additionally, we're looking forward to presenting baseline characteristics from the Neurotransform study at the Peripheral Nerve Society Congress later this month. Last week, we announced that we achieved our original enrollment goal in the One Person Phase 3 Cardiac Transplant Study. We also announced an important amendment to our study. The amendment included expanding enrollment to approximately 1,000 patients from 750 patients and extending the blinded dosing period to 140 weeks from 120 weeks. The CardioTransform study is the largest study in patients with ATTR cardiomyopathy.

Last week, we announced that we achieved the original enrollment goal.

Two phase III cardiac transplant study.

We also announced an important amendments are subject the amendment included.

Expanding enrollment to approximately.

Patients from 750 patients.

And extending the blinded dosing period to 140 weeks from 120.

The cardio transform study the largest study in patients with <unk> cardiomyopathy.

Eugene Schneider: It was designed to generate clinical evidence about lung cancer's benefits when administered alone or in combination with stabilizers. This should enable physicians and payers to make the most informed decisions. By increasing the size and duration of the study, our aim is to ensure a highly positive study outcome and to generate even more of a, in a broad patient population to successfully compete in this growing and dynamic industry. The timing is right to implement these changes now because enrollment is occurring at a very high rate.

Designed to generate clinical evidence.

When administered alone or in combination with stabilizes.

This should enable physicians and payors to make the most important decisions.

By increasing the size and duration of the study our aim is to ensure a highly positive study outcome.

And to generate an even more robust data.

In a broad patient population to successfully compete in this growing and dynamic market.

The timing is right to implement these changes now because enrollment is occurring at a very high rates with.

Eugene Schneider: We have accumulated a substantial amount of baseline demographic and clinical data, and our first patients are nearing entry into the open label. Based on our current rate of enrollment, together with the updates to the study that I just outlined, we're projecting a modest shift in our timeline, with data redoubts moving from late 2024 to the first half of 2025. Our broad Allis-Arsen development program also continues to advance and remains the leading program targeting ApoC3 currently in clinical development.

We have accumulated a substantial amount of baseline demographic clinical data.

Our first patients are metering entry into the open label extension.

Based on our current rate of enrollment.

Together with the update to the study.

We're projecting a modest shift our timeline.

With data readout moving from late 2024th to first half of 2025.

Our broad <unk> development program also continues to advance and remains the leading program targeting <unk> three currently in clinical development.

We designed the <unk> development program to fully realize the potential of this medicine.

Eugene Schneider: We designed the Olazarsan development program to fully realize the potential of this medicine, including moving it towards the market in two indications, FCS and severe hypertriglycerides. We have two ongoing Phase 3 studies, the BALANCE-SCS study, which is on track for data next year, and the CORE-SHTG study, with data planned for 2024. In phase 2, we demonstrated robust reduction in triglycerides and APC3 with a monthly 50 mg dose.

Moving it towards the market in two indications Fcs and severe high triglycerides email.

We have two ongoing phase III studies, the balance FCS study, which is on track for data next year.

And the core phase III studies.

With data plan for 'twenty to 'twenty four.

In Fayetteville, we demonstrated robust reductions in triglycerides, apoc III with monthly 50 milligram dose.

Eugene Schneider: In our two phase 2 studies, in addition to evaluating the 50 mg monthly dose, we're also assessing an 80 mg monthly dose, which we expect to result in even greater triglycerides. The Dunning-Dunlop-Doloresan Phase III OASIS-AGE study is also progressing and remains on track for data in 2024. Earlier this year, we reported additional data from the Donald L. Oreson Phase II study demonstrating clinically meaningful and sustained improvements in quality of life in patients with HVAC. Coming up later this year, we plan to report data from the ongoing Phase 2 Open Label Extension Study. Including data from the monthly and bimonthly doses.

Two phase III studies in addition to evaluating 50 milligram monthly dose.

So assessing the 80 milligram monthly dose, which we expect to result in even greater triglyceride reductions.

The Donlin gold silver some phase III <unk> study is also progressing and remains on track for data in 2024.

Earlier this year, we reported additional data from goods on Dolores and phase II studies, demonstrating clinically meaningful and sustained improvements in quality of life in patients with <unk>.

Coming out later this year, we plan to report data from the ongoing phase II open label extension study.

Including data from the monthly and bimonthly dose groups.

In June Biogen plans to present, new integrated so for some data from <unk> and the ongoing.

Eugene Schneider: In June, BiJun plans to present new integrated Chilferson data from Valor and the ongoing NOAA leak in patients with SADL1 ALS who were treated for up to one year. Additionally, Biogen remains engaged with regulators to identify a potential path forward. We also have a wrench from N Stage 5, which we expect to continue to deliver.

Patients with <unk>.

So were treated for up to one year.

Additionally, biogen remains engaged with regulators to identify potential or took us.

We also have the rich midstage pipeline.

We expect to continue to deliver some of the recent highlights.

Eugene Schneider: Here are some of the recent highlights. We're pleased with the positive case-to-be data from the adhesion study for ION449 or PCSK9-like hematocytes in patients who are at high risk of cardiovascular disease. The study met its primary and secondary endpoints. Ion-449 demonstrated dose-dependent reductions in mean LDL cholesterol levels by up to 79% and PTFK-9 levels by up to 94%.

We're pleased with the positive phase III data from the infusion study for ion four nine Bcf to nine <unk> and.

In addition score high risk of cardiovascular disease with hypercholesterolemia.

The study met its primary and secondary endpoints.

<unk> hundred 40, <unk> demonstrated dose dependent reductions in mean LDL cholesterol levels by up to 79% and Tcf to nine levels by up to 90 folks.

The positive results from the infusion study gives us confidence that pound for nine could change the current standard of care for patients affected by hypercholesterolemia.

Eugene Schneider: The positive results from the adhesion study give us confidence that ION449 could change the current standard of care for patients affected by hypercholesterolemia who have cardiovascular disease. Additionally, the Solana Phase 2B study of ION 449, designed to confirm, We believe that AstraZeneca will make a decision on further development later this year, based on the Euteasian and Solanus study results. We also recently completed enrollment in our PACE-2B study of Ionis PGT-LRX, our medicine to treat patients with treatment-resistant hypertension, keeping us on track for data in the second half of the year.

Cardiovascular disease.

Additionally, the Salon, a phase <unk> study of iron ore.

I wanted to confirm.

Phase III is ongoing.

We believe that Astrazeneca will make a decision on further development later this year.

On the infusion onslaught of study results.

We also recently completed enrollment in our phase III study of <unk>, our medicine to treat patients with treatment resistant hypertension, keeping us on track for data in the second half of this year.

We're also advancing <unk> <unk> and a phase two study in patients with chronic heart failure with reduced ejection fraction, which we expect to read out next year.

Eugene Schneider: We're also advancing Ionis, EGT, and LRX in a phase 2 study in patients with chronic heart failure with reduced ejection fraction, which we expect to double. In addition to the programs I already mentioned, we expect several more data readouts to appear, including GSK reporting data from the Phase 2D study of our hepatitis B drug, and Bayer reporting data from our Phase IIb study of fesamercin or Factor XI lichen medicine in patients with men's atria.

In addition to the programs I already mentioned, we expect several more data readouts, including.

Including GSK to report data from the Phase <unk> study in <unk>.

Our hepatitis B drug.

And Bayer to report data from our phase <unk> study of customers.

After 11 like a medicine to patients with end stage renal.

Because I just summarized we have a number of important minimum with Fitch programs progressed.

Eugene Schneider: As I just summarized, we have a number of important mid- and late-stage programs progressing. As the year unfolds, we're looking forward to a steady cadence of data rebounds. And with that, I'll turn the call back over to Brett to close this portion of the call. Thanks, Eugene. We're off to an excellent start this year.

As the year unfolds, we're looking forward to a steady cadence of data readouts.

I will turn the call back over to Fred to close a portion of the call.

Thank you Jim.

Brett Monia: We continue to execute on our three strategic priorities that I believe will drive substantial growth for Ionis. Building the Ionis commercial pipeline, including rapidly advancing our three near-term commercial opportunities at Von Thurston, Olazarsen, and Donahue-Horst toward the market, and making great progress in building out our commercial organization for these important medicines. We're also continuing to build on the substantial progress we made last year in expanding and diversifying our technology, including advancing our follow-on medicine, Spinraza, that we announced earlier this year, as well as making other important technological advances.

Off to an excellent start this year.

To execute on our three strategic priorities that I believe will drive substantial growth for Ireland.

Building the island as commercial pipeline, including rapidly advancing our three near term commercial opportunities upon <unk> and done towards the market and making great progress in building out our commercial organization for these important medicines.

We're also continuing to build on the substantial progress we made last year in expanding and diversifying our technology, including advancing our follow on medicine to spin rouser that we announced earlier this year as well as making other important technology patches.

Brett Monia: I look forward to sharing further details on these advancements later this year. And our third strategic priority, delivering an abundance of new medicines to the market in the near term and in the longer term, starting with our planned launch of Eplanters for patients with TTR polyneuropathy as early as late next year. Additionally, we are well capitalized with the resources we need to continue executing on all our priorities.

Forward to sharing further details on these expansions later this year.

Our third strategic priority delivering an abundance of new medicines to the market in the near term and the longer term starting with our planned launch of <unk> for patients with <unk> Polyneuropathy is earliest.

Late next year.

Additionally, we're well capitalized with the resources, we need to continue executing on our priorities.

Without the seven key data Readouts expected from our mid and late stage pipeline before year end. The remainder of 2022 looks to be highly productive and eventful and with that I'll now open up the call for questions.

Operator: With up to seven key data readouts expected from our mid- and late-stage pipeline before year-end, the remainder of 2022 looks to be highly productive and eventful. Operator.

Later.

Operator: Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone.

Thank you we will now begin the question and answer session to ask a question you May Press Star then one on your Touchtone phone.

Yanon Zhu: If you're using a speakerphone, please pick up your handset before pressing the key. To withdraw your question, please press star then two. And at this time, we'll pause momentarily to assemble our roster. And the first question will come from Yannon Zhu with Wells Fargo. Please go ahead.

We're using a speakerphone please pick up your handset before pressing the keys to withdraw your question. Please press Star then two and at this time, we'll pause momentarily to assemble our roster.

Yes.

And the first question will come from Yanan, Zhu with Wells Fargo. Please go ahead.

Hi, Thanks for taking my questions and congrats.

Yanon Zhu: Hi, thanks. Thank you for taking my questions and congrats on the progress in the quarter. So I hope you could elaborate a little bit more on the protocol change to the cardio transform study. I'm going to bring things into context a little bit more for us. I think you probably have been monitoring.

Progress has progressed during the quarter.

I hope you could elaborate a little bit more.

The protocol change to the cardio transform study.

Put some things into context, a little bit more for us.

I think you probably have.

Have the monitoring of.

Yanon Zhu: The cardiovascular event rate and probably also are looking at the overall patient mix in terms of disease severity. Transcripts provided by Transcription Outsourcing, LLC, the observation bin during these monitoring. How does that lead to the decision to expand?

The carnival.

Escalators that rate and.

Probably you also are looking at the patient overall patient mix in terms of a disease severity.

The pharma does to us and all of that to what happened.

The observation.

During those monitoring.

And how does that lead to the decision to expand the study and also lastly.

Brett Monia: and also. I'm curious, have you also looked at the six-minute walk data, and how does that compare with some of the... Thank you for the question. I appreciate it.

Just curious have you also looked at the six minute walk data.

And how does that compare with some of the data that we have seen from other companies. Thank you.

Thank you for the question I appreciate it.

Brett Monia: And I'll address that and ask Eugene to expand on it. So, you know, as we've been saying for quite some time now, We have been right from the onset of this study, from the get-go, monitoring the enrollment and the demographics for this study. Demographics that relate to, for example, the severity of how sick the patients are, New York Health Class Association 1, 2, 3, for example, or how much defaminants are used in the study versus naive patients. The balance between hereditary and wild-type patients.

Yes.

We are addressing and are seeking to expand on it.

So.

As we've been saying.

For quite some time now.

We have been recommended onset of this study from the get go.

Monitoring the enrollment and the demographics for this study.

Demographics that relate to for example, the severity of how patients are doing.

Glass Association 123 for example.

Much defamatory usages in this study <unk> naive patients the balance between hereditary and wild type patients. Those are the primary things that we're looking at all along we are.

Brett Monia: Those are the primary things that we're looking at. And all along, we were projecting that we would possibly make adjustments to the study to ensure that the study readout was as successful as possible in a really big market, in a growingly competitive market. And that's exactly what we did. There were no firearms that went off or anything like that.

Projected that we would possibly make adjustments to the study to insure.

But the study readout was successful.

<unk>.

Really big market.

Growingly competitive market and Thats exactly what we did there were no firearms.

Or anything like that or doing something and pull the trigger on something that we were planning to potentially do.

Brett Monia: We're doing something and pulling the trigger on something that we were planning to potentially do all along. It's really less about event rate. It's relatively early on in the study. Yonin, those events really start accumulating in the second half of a cardiovascular outcome trial. Sure, we're looking at events, but it's really driven by the demographics and the type and the patient populations that we want to have in our study that really ensures a successful, highly successful outcome. We're not looking at a six-minute walk test. That has nothing to do with this decision.

Overall.

It's really less about the event rate it's relatively early on in the study Jonathan those events really start accumulating in the second half of the cardiovascular outcome trial sure we're looking at events.

It's really driven by the demographics and the tightened the patient population that we want to have in our study.

That really insurance for successful a highly successful outcome, we're not looking at six minute walk test.

With this decision. This is all about making sure we have the right patients in this study.

Brett Monia: This is all about making sure we have the right patients in the study. And then the last thing I'll say before I ask you, Eugene, if you have anything you'd like to expand on is the fact that this is the right time to do that in this study. This is the perfect time.

And then the last thing I'll say before asking you Kevin.

You might expand on is the.

Fact that this is the right time to do that.

Is the perfect time.

Brett Monia: We're early on in the study, so we are well-positioned to be able to make that decision without having a significant, really a significant impact on the study timing. It's a modest delay, and the expense and the investments are small.

Our early on in the study we are well positioned to be able to make that decision without having a significant really a significant impact on the on the on the study timing.

It's a modest delay.

And the expense and the investments are small.

We measure that up against a.

Brett Monia: You measure that up against the upside that this provides in allowing us to have a very positive outcome, you know, is very, very important, very significant. Enrollment is going very fast. We're very strong.

The upside is providing.

Willingness to have a very positive outcome.

<unk> is very very important very significant enrollment is going very fast.

It's very strong. So this is the right time to do the studies done by making an adjustment like this this is the time to do it and it's all for good reasons Eugene anything to add.

Brett Monia: So this is the right time to do the study. There's no point in making an adjustment like this and waiting to study. This is the time to do it. And it's all for good reasons.

Eugene Schneider: Yep. Eugene, anything to add to that? That was really, really well characterized.

No.

Really really well characterized only also.

This change also gives us maximize our ability to look at important subgroups within the study, which is also going to be critical for informing.

Practice patterns and providing a meaningful dataset for.

Stakeholders when the study reads out.

That's super.

Eugene Schneider: I would only also add that this change also maximizes our ability to look at important subgroups within the study, which is also going to be critical for informing Practice Patterns and Providing a Meaningful Dataset for Stakeholders, one of the study results. That's super helpful. Thank you for that answer. If I may ask, about the mid-year aplankerson polyneuropathy data readout? Can you, would you be able to share any color on what stage you are currently in in terms of, you know, locking the database, data analysis, and all that, and any additional color on what that will be around what time?

Helpful. Thank you.

Answer if I may.

May I ask about the midyear I applaud person Polyneuropathy data readout.

Thank you.

Would you be able to share any color on what stage are you. Currently currently in in terms of locking the database data analysis and all of that and.

Any additional color on what.

Around what time quickly see potentially see the data. Thank you.

Eugene Schneider: Um, yeah, so as we've been saying, John, and we're right on track to achieve, we've been saying mid-year this year, we're expecting the top-line data from the up-on-surface polyneuropathy-based study, and we're really not providing much more color than that. What I can add to that is that in parallel with, you know, the study coming to completion, we're preparing for the filing, regulatory filing, as we said in our prepared remarks, and we're also planning for the launch. And maybe I could ask you to maybe provide some color on the preparations we're doing for the launch with our partner AstraZeneca. Yeah, sure.

Yes.

So as we've been saying John .

And we're right on track.

To achieve we've been saying mid year. This year, we're expecting the top line data from the <unk> neuropathy phase III study in but really not providing much more color than what I can add to that.

In parallel with the <unk>.

Coming to completion, we're preparing for.

The filing regulatory filing as we said in.

In our prepared remarks.

And we're also planning.

Two.

For the launch and maybe I could ask Nathan.

Provide some color on the preparations we're doing on.

For the launch with our with our partner Astrazeneca.

Brett Monia: Diane, and you know, launch preparation takes a lot of effort across a lot of team members. And I'm pleased to say the team just had a pretty robust launch readiness meeting last week with AstraZeneca at their offices on the East Coast, with really everybody from clinical. Thank you all for the overall launch preparedness. They are in great shape.

Yes sure Dan.

Diana <unk>.

Launched preparation.

It takes a lot of effort across a lot of team members and I am pleased to say the teams just had.

Actually.

Pretty robust launch readiness meeting last week.

Astrazeneca and their offices on the East Coast, and we had really everybody from clinical to CMC and obviously, the marketing teams as well as the customer facing teams and medical affairs to kind of thanks to the overall launch preparedness they are in great shape.

Brett Monia: It's a collaboration that builds on each other. Our knowledge of amyloidosis and being in the..., about a decade and a rare disease along. So, we're in really good shape. Sarah Wollins. Thank you.

It's a collaboration that is really building on each other strengths, our knowledge of amyloidosis and being in the market for about a decade and rare disease, along with kind of the broad reach and expertise is really a really great complementary collaborations.

<unk> may even have been I would say so.

Really good shape and I would say well ahead of the curve for getting this product launched next year I'm.

Assuming everything goes well and we are expecting to file by the end of the year as well. So the teams are ready to go.

Thank you that's great to hear.

The next question will come from your own Werber with Cowen. Please go ahead.

Euron Werber: Thank you. The next question will come from Euron Werber with Cowen. Please go ahead. Hi, this is Brendan. I'm afraid you're wrong. Congratulations on the quarter, guys, and thanks for taking the questions. Just a couple quick ones from us.

Hi, This is brendon on for you Ron Congrats on the quarter guys and thanks for taking the questions. Just a couple quick ones from us first and not resistant hypertension can you maybe just remind us what the phase two readout is going to look like they're maybe in terms of the number of patients and what kind of data we can expect.

Eugene Schneider: First, in treatment-resistant hypertension, can you maybe just remind us what the phase two readout is gonna look like there, maybe in terms of the number of patients and what kind of data we can expect? And really, in that same program, I guess, as you're looking ahead to a potential phase three, is there like a threshold, or what are you really looking for in terms of efficacy, target engagement there that would give you confidence to move forward with the drug? Excuse me, thanks very much. Eugenia Wang, would you like to take this?

And really in that same program I guess as Youre looking ahead to a potential phase III.

Is there like a threshold or what are you really looking for in terms of efficacy target engagement. There that would give you confidence to move forward with the drug.

Thank you very much.

I would like to take that.

Sure.

Eugene Schneider: Sure. Yeah, so phase two, Current beta, is in patients with treatment-resistant hypertension. We're hoping basically to see consistent effects with what the earlier, smaller study demonstrated, which range in the order of 10 to 15 millimeter mercury, but again, in a larger study, of course. With greater variability, what we're hoping to see, of course, are highly significant changes. The study is appropriately sized for this type of exploration. It's in 150, approximately 150 patients. So really, that's all I could tell you at this point. And if I could just expand on that a little bit. Thanks, Eugene.

Yes.

Thank you.

Data cut.

Current data.

In patients with treatment resistant hypertension.

Or.

We're hoping basically to see.

Consistent effects with.

What the earlier smaller studies that demonstrated.

Which.

Range in the order of 10 to 15 millimeter of.

Mercury, but again in a larger study of course.

With greater variability quarter to quarter.

Hoping to see of course are.

With significant changes.

B.

So study is appropriately sized for us.

<unk>.

Type of exploration is in.

150.

Proximately 150 patients.

So really there is.

That's all I can tell you that.

At this point.

If I could just expand on that a little bit.

Thank you gene.

Just a reminder, Brandon.

Brett Monia: Just a reminder, Brendan, we have a pretty comprehensive program ongoing for AGT right now. In addition to that readout for the phase 2B study later this year in crack reactor hypertension, we have an ongoing study with that drug in patients with heart failure. We're looking for that to read out next year. And then coming up behind our lead drug is a new molecule, our Gen 2.5 AGT molecule that completed phase 1 very successfully. Now we're trying to start phase 2.

We have a pretty comprehensive program.

For ADT.

Right now.

In addition to that readout.

For the Phase <unk> study later this year in refractory hypertension, we have an ongoing study with that drug in patients with heart failure, and we're looking for that to read out next year.

And then coming up behind our lead drug is a new molecule. Our gen. Two five <unk> molecule has completed phase one very successfully now for phase III.

Brett Monia: And sometime next year, we plan to look at all the data, the lead molecule, the follow-on molecule, heart failure, and refractory hypertension, and we will make a decision on what's the best molecule and what's the next step for phase 3. But, you know, what we're looking to see is what Eugene said, confirmation of the proof of concept we already achieved in refractory hypertension in a bigger patient population and also with good safety, of course. And when I say safety, I mean on target safety.

Next year, we plan to look at all the data lead molecule follow on molecule.

Heart failure refractory hypertension, and we will make a decision on whats the best molecule. What's the next step for phase III, but what we're looking to see what you just said is confirmed.

Formation of the proof of concept, we already achieved the refractory hypertension in a bigger patient population and also with good safety of course, and when I say safety.

Safety continues to be very.

Brett Monia: We need to be very, you know, aware of the fact that inhibition of this pathway, the RAS pathway in the kidney, can cause kidney issues. And we haven't, we never, we haven't seen it in our phase 2 studies. We don't expect to see it. It's the lichen that targets the liver, not the kidney.

Aware of the fact that inhibition of this pathway the Ras pathway in the kidney.

Of course, these issues and we never said we haven't seen it.

Phase III studies, we don't expect to see it.

<unk>, which targets to deliver in the kidney but.

Brett Monia: But we need to confirm that, and once we look at all the safety and the efficacy of the study, we'll make a call on the next step, potentially phase 3. All right, great. Thanks so much.

But we need to confirm that.

Once we look at all the safety and.

Efficacy study will make a call on.

Your next step for <unk>.

Potentially phase III.

Alright, great. Thanks, so much.

Thanks Brendan.

The next question will come from Luke.

Luca Issi: Thanks, Brendan. The next question will come from Luca Issi with RBC. Please go ahead. Well, great. Thanks so much for taking my question. Congratulations on all the progress here. So maybe on TTR polyneuropathy, I think the primary endpoint is actually at nine months. Will that be sufficient for filing both in the U.S. and in the EU, or will you need to wait for the 18-month data point to file in the EU, similar to what has happened to adenylone? And then maybe on TCSK9, a pretty impressive knockdown.

<unk> <unk> with RBC. Please go ahead.

Great. Thanks.

Thanks, So much for taking my question Congrats on all the progress here.

Thank you Dr. Paul Neuropathy, I think the primary end point is actually at nine months.

Would that be sufficient for filing both in the U S and in the EU or when do you need to wait 18 months data point to filing the EU similar to what has happened to us in Ireland.

Maybe on pieces canine I think pretty impressive knockdown whoever we did see four patients at the high dose experiences. Some A&P elevations two of them I think would discontinue the drug. So I'm wondering how you think about that in the context of being closer at least I'm not aware of that signal and then finally any update on the pulmonary franchise posted <unk>. Please continue.

Luca Issi: However, we did see four patients at the high dose experiencing some ALT elevations. Two of them, I think, discontinued the drug. So I'm wondering how you're thinking about that in the context of Inclisiren. At least, I'm not aware of that signal.

Brett Monia: And then finally, any update on the pulmonary franchise post the ENAC discontinuation? Thanks so much, guys. Thanks Luca, you've squeezed a lot in there.

Thanks, so much guidance.

Thanks, Luca you squeeze a lot in there.

Brett Monia: I'm happy to do our best in addressing all three of those questions. So yeah, we're very excited, very pleased with the data readout on IN449, our PCSK9 drug that was presented to ACC. You know, there's such an enormous need for more effective LDL-lowering drugs for patients at high risk for cardiovascular disease and continued hypercholesterolemia despite being on statins, methamide, despite being on monoclonal antibodies for PCOS-9, and despite being on inquisirine.

You too.

To our best in dressing or Fritos question. So yeah, we're very excited and very pleased with the data readout on our end.

449.

Arc is shifting on drug it was presented at ACC.

There is such an enormous need.

For more effective LDL lowering drugs for patients at high risk for cardiovascular disease and continued hypercholesterolemia despite being on statin.

Brett Monia: This molecule looks to be the most potent, efficacious PCOS-9-lowering drug and LDL-C-lowering drug of any that's been, or has come out to date. And that is why AstraZeneca is so enthusiastic about this program. It could be a real game changer for the millions of people suffering from hypercholesterolemia and CBD. The phase 2B adhesion study was a dose-ranging study, and we achieved reductions of LDL-C greater than well over 70% and in the 90% range at doses where there were no signals on ALTs.

Despite being on monoclonal antibodies for Pcs, despite being on <unk>.

This molecule looks to be the most.

Potent efficacious PCA skin and lowering drug ldlc lowering drug.

Any that's been.

That has come out.

And that is why Astrazeneca is so because you asked me about this program.

So we think could be a real game changer for the millions of people suffering from hypercholesterolemia in CBD.

The phase <unk> study with a dose ranging study.

We achieved.

<unk> of ldlc greater than well over 70% and it just came right in the 90% range at doses, where there were no safety signals around <unk>.

Brett Monia: That was a 50 mg monthly dose in that study, and a 90 mg dose where we saw, I think, for patients with mild ALT elevations, a couple of things worth noting. One is that they're mild to, and two of the patients continue dosing, and ALT returns to baseline, or towards baseline.

50 Mig.

Monthly dose in that study.

And the 90 milligram dose, where we saw I think for patients with mild.

ALC elevations.

Full of things worth, noting one is that there are more.

<unk> two is that two of the patients continue dosing and.

In terms of baseline reports baseline so this isn't.

Brett Monia: So, you know, this isn't all toxicity, it's an ALT observation in a very small number of patients at 90, but more importantly, it's an ALT observation in a very small number of patients at 90. The Phase 3 doses are going to be in the range of 50 or so in that range because that's what we're achieving our LDL targets there. And there's an ongoing study called Solano that AC is conducting to further confirm the Phase 3 dose, and that study is looking very good, and they're preparing for Phase 3 development.

The toxicity is.

LP observation and a very small number of patients but.

More importantly.

Basically does the phase III doses are going to be in the range of 50 or so.

In that range, because thats, what were achieving our LVL mark targets there.

And there's an ongoing study called Solana that Acs conducting to further confirm the phase II dose and that study is looking very good and they are preparing for phase III.

Element so the drug looks very good very safe and.

Brett Monia: So the drug looks very good, very safe, and we haven't seen any bumps in the road. With respect to glycerin, I prefer not to comment on competition, except what I already said. There's a need for more effective LDLs to help patients get to their targets. And so a drug like ION449 is needed in this patient. Community.

We haven't seen any any bumps in the road.

With respect to <unk>.

Prefer not to comment on competition makes up what I already said there is a need for more effective LDL C. Lowering agents patients are not getting to their target.

And so a drug right.

<unk> needed.

And those patients.

Immunity.

Eric Swayze: Ed Sheer, Ed Sheer, Ed Sheer, Ed Sheer. You want to talk about lung cancer a little bit, Eric? Um, sure. So what we're doing in pulmonary is taking a hard look at some of our chemical class, and the hope there is that we can find some molecules that overcome some of the clinical issues we saw with inflammatory effects in non-human primates. And in Here, we're thinking of some of the new backbone chemistries that we've talked about that allow us to tinker with the properties of the molecule and reduce the baseline potential for inflammatory effects.

You also have a pulmonary little bit Eric.

Sure so.

What we're doing in pulmonary is picking out of our book.

Our chemical class.

The hope there is we can find molecules that overcome some of the clinical issues, we saw within inflammatory effects of nonhuman primates.

Here, we are thinking of some of the new backbone chemistry that we've talked about that allow us to tinker with the properties of the molecule reduced.

The baseline potential for inflammatory effects.

Eric Swayze: And we've seen really good data on some of these compounds across multiple programs and are working hard to try and get some data in the relevant species in the not too distant future to both advance new chemistries and also potentially, We've moved them into some pulmonary diseases where we think there are lots of potential applications with lots of unmet medical need, and we're making solid progress in the areas that Erik said, Luca, and we're very encouraged that I didn't answer your question about polyneuropathy. I apologize; I kind of went out of order.

Really good data on some of these compounds across multiple programs and are working hard to try and get some data in the relevant species in the not too distant future to two.

Both advanced new Chemistries and also potentially.

Move them into some pulmonary diseases, where we think there's lots of potential applications with lots of unmet medical need and we're making solid progress.

In the areas of Eric.

We're encouraged we're very encouraged that the pulmonary programs.

To be reactivated.

On the development side.

I didn't answer your question about the.

I apologize I kind of went out of order.

Brett Monia: So, we're planning to file the NDA this year on F1-3 and polyneuropathy. I should point out that you mentioned 18-month data; remember our full data set was completed in 15 months, not 18, in the neurotransform study. But what you're highlighting is the fact that XUS, European regulators, have set a higher bar for approval, and they have signaled that they would like to see the full data set. With that said, we haven't ruled out another U.S. filing, and we're keeping that option open, but we're focused right now on the NDA. Super helpful.

So.

We're planning to file the NDA this year on that.

One person in Polyneuropathy.

I should point out that you mentioned the 18 month data remember are our full dataset 15 months now.

In the neuro <unk> transform study.

But what you're highlighting is the fact that.

Ex U S European regulators have set a higher bar.

For approval.

And they have signaled that they would like to see.

The full dataset.

With that said, we havent ruled out ex U S filing and we're keeping that option open.

But we're focused right now on the NDA.

Super helpful. Thanks, So much guys.

Got it.

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

Jessica Fye: Thanks so much, guys. The next question will come from Jessica Fye with J.P. Morgan. Please go ahead. Hey guys, good afternoon.

Hey, guys. Good afternoon. Thanks for taking my questions I wanted to follow up on a prior question about the changes to cardio transform.

Jessica Fye: Thanks for taking my questions. I wanted to follow up on a prior question about the changes to cardio transform. You talked about them being driven by patient demographics. Are you changing any of the inclusion or exclusion criteria or the regions you'll focus on for further recruitment in addition to just increasing the sample size and treatment duration? Thanks for your question, Jessica. So no, we're keeping the eligibility criteria the same. We are, however, looking into geographies with the fairly specific intention of, again, as Brett said, ensuring that the population we enroll is, number one, representative of the current landscape of patients with ATTR, the full landscape, but also, importantly, enables us to make some inferences about drug effects in important subgroups of patients. And that could involve prioritizing certain geographies and territories for your sector.

You talked about them being driven by patient demographics are you changing any of the inclusion or exclusion criteria and northern regions Youll focus on for further recruitment. In addition to just increasing the sample size and treatment duration.

Thanks for your question Jessica.

So now were keeping the eligibility criteria. The same we are however looking into.

Sort of geographies.

With.

Fairly specific intention of again as Brad said, ensuring the population we enrolled.

Is number one representative.

The current landscape of patients with ADT or the full landscape, but also importantly enables us to make some inferences.

Forward, a drug effect and important subgroups of patients.

And that could involve.

Jeff that could involve prioritizing certain geographies and territories to your second point.

Okay.

Eugene Schneider: Okay, so I guess I should say it will, it will involve it. Yeah, because in the past, you've talked about your expectation for maybe a 50-50 split between patients who are on background defamitists and those who are not, even though you're not limiting, background to pamphlet, is, so is that still your expectation that that'll be the next one? What we've said, Jess, is we want the naive versus the fantasy to be very well-balanced. So, you know, 50-50 would be perfect, but, you know, we're looking for a well-balanced naive versus the fantasy.

Well I should say it will.

It will involve.

Yeah, because I think in the past you've talked about your expectations for maybe a 50 50 split between patients who are on background to feminists and those who are not.

Even though youre not limiting.

Background parameters. So is that still your expectation that that will be the mix.

With what we said Jeff as well.

We want the Bayou first Tennessee seems to be very well balanced so.

Because it would be perfect but.

We're looking for.

Well balanced menu versus to Massachusetts.

Okay, and I guess last one on this topic, where these changes to cardio transform prompted by a recommendation from the F&B or where they made without.

Jessica Fye: Okay, and I guess last question on this topic: were these changes to CardioTransform prompted by a recommendation from the DSMB, or were they made without DSMB input? And has there been an interim analysis in the trial at this point? There's been no interim analysis. We still have the option to conduct an interim analysis after patients, you know, at the appropriate time, but we haven't done any interim analysis at this stage. This was driven entirely by Ionis.

The F&B input and has there been an interim analysis in the trial at this point.

Theres been no interim analysis, we still have an option to conduct an interim analysis after patients.

Brett Monia: This has nothing to do with a safety oversight committee or AstraZeneca. We put this forward, as I said earlier in the call. This was always an option, this was always part of the plan, not necessarily to do it, but to potentially do it, and we're now triggering that option that we have, and we're in an excellent position. I think the first episode of Media Management for the Next 20 Years is the final decision. Okay, great, thank you. Thank you. The next question will come from Paul Mateus with Stiefel. Please go ahead. Hey, thanks for taking our questions. This is Alexander, for Paul.

Yes.

At the appropriate time, but we have done no interim analysis.

At this stage this was driven entirely by August .

We have nothing to do with a safety oversight committee.

That's even astrazeneca, we put this for as I said earlier in the call.

So as an option. This was always part of the plan not necessarily do it but to potentially to it and which now triggering that option that we have.

And we're in excellent position.

Timelines and enrolling wise it will trigger this day.

Course, we engage astrazeneca and fully support the decision and were working.

And in hand with them on <unk>.

No this was entirely driven by items.

Okay, great. Thank you.

Thank you.

The next question will come from Paul Matteis with Stifel. Please go ahead.

Alexander: Just one eplantersin polyneuropathy question and then one neuro question. So for eplantersin, can you remind us, is there a pre-specified cardiac subgroup within the polyneuropathy study? And if so, do you expect to have any exploratory biomarker imaging data either at this readout or the full readout? And then on neuro, given that Biogen announced their pipeline prioritization, have you thought at all about reacquiring any rights to your neuro programs in collaboration with Biogen? Thanks.

Hey, Thanks for taking our question. This is Alex on for Paul just one <unk> point out for the question and then one neuro question so for Epsilon person.

Can you remind us is there a pre specified cardiac subgroup within the Polyneuropathy study and if so do you expect to have any exploratory biomarker imaging data either at this readout or the full readout and then on neuro given that Biogen announced that their pipeline prioritization have you thought at all about <unk>.

We acquiring any rights to your neuro programs in collaboration Biogen. Thanks.

I'll take the first one on the cardio subgroups in neuro.

Eugene Schneider: You want to take the first one in the cardio subgroups in the room? Yeah, thanks for your question. So yes, there will be an analysis, a look at specific subgroups predefined in the cardiac subgroup in a polyneuropathy study, neurotransform study. It's again, just to remind you, it's not exactly the same population for cardio transform. These patients don't have symptomatic heart failure, they're largely polyneuropathy patients with mixed phenotype and have some evidence of cardiac disease. So I think that's an important distinction. But yes, there will be an important subgroup. Yeah, now that it's a CUMMED, let me just take a step back.

Yes.

Thanks for the question so yes, there wont be.

And analysis.

Look at specific subgroup predefined look.

In the cardiac.

Subgroup.

I think neuro <unk> transform study.

Again just to remind.

It's not exactly the same population to cardio transform these patients don't have symptomatic heart failure.

We found neuropathy.

Patients with mixed phenotype, and having some evidence of cardiac I think thats, an important distinction, but yes, there will be an important subgroups.

Yes.

Yeah.

Let me just take a step back for Biogen we have.

Brett Monia: We have a very strong partnership and relationship with Biogen that spans 10 plus years now. And, you know, it started with Spinraza and has grown and got stronger and stronger over the years. Their relationships are strong at all levels in the partnership.

Very strong partnership and relationship with Biogen that spans 10 plus years now.

And.

Start with Roger.

And got stronger and stronger over the years the relationships are strong at all levels.

Brett Monia: We've gone through management changes before at the top with Biogen and without a bump in the road, without any setbacks or anything like that. I actually think that the Ionis pipeline of drugs that we're working on with Biogen will become an even higher priority for Biogen. I don't think they're going to be willing to give those up easily.

In the partnership we've gone through the management changes at the top with Biogen and without a bump in the road.

Any setbacks or anything like that.

I actually think that the <unk> pipeline of drugs that we're working on with Biogen have become will become an even higher priority Biogen I don't think they're going to be willing to give those up.

Easily.

Brett Monia: It's, you know, they're going to be turning the page, and they're going to be looking at the drugs like MAPT, the follow-on with Spironaz, and everything else that we're working on with them. I think these will continue to be very high, but I think they might be even higher priorities with Biogen. With that said, we're very pleased with our neuropipeline of drugs that we are growing here at Ionis, that whole new Ionis neurology pipeline.

They're going to be turning the page and they're going to be looking at drugs like map T.

The follow on whats been Ross and everything else that we're working on with them I think these will.

Continue to be very high, but I think as it might be.

The higher priority with Biogen.

That said, we're very pleased with our neuro pipeline.

Of drugs.

Bad debt that we are growing <unk> wholly owned Aon as neurological neurology pipeline.

And one example of that.

Brett Monia: And one example of that is we're very much looking forward to starting our studies in prion disease in the second half of this year as one of our lead programs, not our only program, but one of the key programs that we've highlighted as a key study initiation. So no, I don't think we're going to be requiring assets from Biogen as a result of the change in management that they announced yesterday. Thanks, and just one clarification: do you expect any of the cardiac data at the top line mid-year or not until later? Thanks. No, so the top line will be data on the full, full population, and all of the subgroups will be reported at a later time.

We're very much looking forward to starting with <unk>.

Our studies in <unk> in the second half of this year.

One of our lead programs that are only program, but one of the key programs there.

We've highlighted as a key study initiation this year. So no I don't think were going to be.

Acquiring assets from Biogen as a result of the change management.

Yesterday.

Okay. Thanks, and just one clarification do you expect any of the cardiac data get them at the top line mid year or not until later thanks.

No so the top line.

<unk> will be data on before.

Population all of the subgroups will be reported at a later time point.

The next question will come from Gary Nachman with BMO capital markets. Please go ahead.

Gary Nachman: The next question will come from Gary Nachman with BMO Capital Markets. Please go ahead. Hi, thanks. First, just another follow-up on epilontericin and adding more patients to the cardiomyopathy study. So, why didn't you wait until the PN data came in before making the decision since the data are coming soon? And it sounds like, you know, we will have some cardio data in there for some of the patients, and it potentially could have been informative in your decision.

No.

Alright. Thanks, So first just another follow up on Epsilon, Charleston, and adding more patients to the cardiomyopathy study. So why didn't you wait until the pn data before making decision since that data are coming soon.

It sounds like.

We will have some cardio data in there for.

For some of the patients in a potentially it could have been informative to your decision.

So that's one and then also for Beth.

Gary Nachman: That's one. And then also for Beth, the $20 million that you got from AZ for Eplontourism development costs, is that the kind of number we should expect on a quarterly basis? Or is there some upfront load, and And then lastly, just what are the next steps for 449, the PCSK9 program?

$20 million that you got from AZ for outbound tourist and development cost is that the kind of number we should expect on a quarterly basis or is there some upfront loading in there.

And then lastly, just what are the next steps for 449.

PCF canine program do you have an idea what types of dyslipidemia patients Youll target in the next phase based on the phase <unk> data that read out. Thank you.

Eugene Schneider: Do you have an idea what types of dyslipidemic patients you'll target in the next phase based on the phase 2b data that has been read out? Thank you. Sure. I'll take the first question.

Alright.

Beth Hougen: So related to the timing of this amendment, as Brett said, again, we've been mulling this over for quite some time, and the timing was one of the key considerations, and we felt that the timing now was really kind of ideal for implementing a change such as this one. Why not wait until NeuroTransform? Well, firstly, it's just a very different patient population that we enrolled in NeuroTransform, so we just don't see how this would inform us.

Sure.

Take the first question.

So related to timing of this.

Amendment that those spreads again, we've been.

We've been modeling the silver for quite some time and the timing of course.

One of the key considerations and we felt that the timing now.

Was really kind of ideal for implementing change such as this one.

Why not wait until neuro transform bolt firstly.

Just a very different patient population that we enrolled in neuro transform so we just don't see how this would inform us.

Beth Hougen: Whatever on what we're going to cardio transform. Secondly, the cardio transform changes will be driven by. There are intentional desires for a particular sort of balance in the population characteristics that Brett had outlined. Sure, so on the $20 million, the way to think about that is it's 55% of our, call it fully loaded, F1 person, broad phase 3 development expenses for the first quarter. So when I say fully loaded, that means external expenses, internal FTE expenses, and DMC expenses.

Whatsoever on what Theyre going to cardio transform secondly, the cardiac transplant change was really driven by.

Sort of a potential.

Desires for a particular answer.

Balance and the population characteristics that Brad.

Outline.

So on the $20 million.

The way to think about that is it.

55% of our customers.

Fully loaded.

<unk> drive phase III development expenses in the first quarter. So when I say fully blended Daphne external expenses internal FTE expenses and CMC expenses.

Beth Hougen: So that $20 million is essentially 55% of what we incurred in that phase 3 program in the first quarter. And as we continue to see those expenses grow over the course of the remainder of the time, particularly with the cardiomyopathy study, and as we get closer to that data readout and to launching the drug, those expenses in that broad phase 3 program are going to continue to grow. And so the 55% that AstraZeneca is responsible for will also grow, and you'll see that each quarter. And it's the same amount, let me say this differently: the development expenses and the 55% of revenue are for the same quarter. So there's no offset, there's no loading, and there's no lag with that.

So that $20 million is essentially 55% of what we incurred in.

That phase III program in the first quarter. So as we continue to see those expenses grow over the course of the.

Remainder of the.

The time, particularly with the cardiomyopathy study and as we get closer to that date of readout and too.

To launching the drug those expenses in that broad phase two program, we're going to continue to grow and so the 55% that astrazeneca is responsible who I will also proud.

Youll see that each quarter and it is.

True.

The same amount.

Let me say that differently.

The development expenses and a 55% of revenue for the same corner. So there is no offset there is no loading.

Black their narrow mines, so as expenses grow each quarter.

Beth Hougen: They're aligned. So as expenses grow each quarter, so will the 55% of revenue under the F1 person joint collaboration revenue line. And regarding PCSK9, if you think about it like that, it's the same patient population that was treated in adhesion. That's why that study is so, so important. It's actually the same five patient population, patients that have cardiovascular disease. So they've had an event in their life, and have high high LDL cholesterol on moderate to maximum doses of statins and Zetia that can't get to their LDL target.

So will the 55%.

Of revenue under the dapple interest in joining <unk>.

Collaboration revenue line.

And again, we're very Mpc's canine.

Think about it like that.

It's the same patient population that was true.

<unk> <unk> that's why.

That study is so so important.

It's actually the same patient population of patients that have cardiovascular disease. So they've had an event.

No Mike.

Hi, LDL cholesterol on moderates to maximum doses of <unk>.

That can't get their LDL targets.

Beth Hougen: And that would be the phase three patient population. Okay, great. And when is that study going to start? I may have missed it.

And that would be the phase III.

Patient population.

Okay, great and when is that study going to start.

I missed it I jumped on late.

Beth Hougen: I jumped on late. No problem. The actual study start date hasn't been disclosed, but what has been disclosed is that AstraZeneca will make a decision on phase three development in the second half of next year. Remember, there's an ongoing study. There is a study ongoing to confirm the base three dose, and so that's not necessarily the same dose I was going to teach, right? They're looking to really solidify the phase 3 dose in Solano. That study is wrapping up, it's really coming to a completion, so we'll, and that's the basis of the delay in making it. Okay, great, thank you. The next question will come from Manny Ferreira with Please go ahead.

No problem.

Actual study start hasnt been disclosed but what.

Has been is that Astrazeneca will make a decision on phase III development in the second half of the year.

Remember this is a study ongoing <unk> study.

I'm going to confirm the phase III dose.

And to that not necessarily the same dose that was in the <unk> right, they're looking to really solidify the phase III dose.

That study is.

Wrapping up.

It's really coming to a completion, so and that's the basis.

And making a decision.

Okay, great. Thank you.

Got it.

The next question.

<unk> will come from Manny Forever with SBB Securities. Please go ahead.

Thanks for taking my question.

Manny Ferreira: Thanks for taking my question. Not to beat an entirely dead horse, but I want to talk a little bit about the commercial opportunity and strategy around your approach to TGR cardiomyopathy. There's a clear avenue for you guys to have the closest thing to a true add-on label for combination therapy on top of a stabilizer. How do you think about pricing strategy? Should you be approved with a label that has data that supports that use? And how do we think about the pricing opportunity prior to and then after perfeminist genericization in the U.S. versus the EU market? Hey Joe, would you like to take that? Sure. Hi Moni. How are you?

Not to beat them entirely dead horse.

But I want to talk a lot about the commercial opportunity and strategy around your approach to <unk> cardiomyopathy.

Clear Avenue for you guys to have the closest thing to a true add on label for combination therapy on top of a stabilizer. How do you think about pricing strategy should you be approved with a label that has data that support that use.

And how does how do we think where the pricing opportunity prior to.

And then asks her to Samad as generic sedation.

In the U S versus EU markets.

And so would you like to take that sure.

Sure Hi, Mike how are you.

So you have great thinking over here in terms of the upland Tristan strategy I'll kind of start off with I think you know the amendment that we filed here is to really accelerate our leadership position to TR from early to late stage disease, We're looking at about 300000 patients and cardiomyopathy.

Onaiza Cadoret: So yeah, great thinking over here in terms of the upline person strategy. I'll kind of start off with, and the amendment that we filed. The data set that we're going to get, for all players, including payers. We've gone out in the marketplace and, you know, really tested out the Target Product Profile.

The dataset that we're gonna go does he Jean said is really important for all of all players, including payers as well as clinician. So as we've gone out in the marketplace and real.

Really tested out the target product profile. It is extremely important to generate data that's on top of that dominance as well as naive because we're going to have.

Onaiza Cadoret: It is extremely important to generate data that's on top of defamatory as well as naive because we're going to have Mary Dyna, Mark, and a set of patients that are going to be naive to therapy or, you know, a lot, and they're going to look for what is your clinical evidence, for the... How do I actually treat them as the audience? [inaudible] The payer strategy, and what we've learned from payer stuff, is that they view this patient population this way. That's a very sick patient population. , you know, and in the terminal, They are not going to... Ionis Pharmaceuticals Inc., Transcripts provided by Transcription Outsourcing, LLC. Transcription by CastingWords. That's what they're and not this.

In this very dynamic market a set of patients that are going to be.

I used to therapy or.

Particularly in the U S treated onto cabinets and Theyre going to look for what is your clinical evidence.

For these patients and how to actually treat them. They already understand this and how do I treat them at their naive and we will have both data sets to be able to do that.

Bayer.

Strategy and what we've learned from payers. Thus far is that debuted this patient population.

That's a very sick patient population.

And a terminal disease and they are not going to manage it actively to say what what the position should do if you're early on and other standard of care or you're in combination to that if the physician requires a combination therapy.

What they are looking to approve and not necessarily have stepped in the situation, which is one of the questions. Obviously we had.

Onaiza Cadoret: So we're expecting actually a relatively open environment, and Ionis. Spective, obviously they all go through prior on prior. Owners.

So we're expecting actually a relatively open.

Garment four four from a payer perspective, obviously, they all go through a prior odds, but nothing onerous in terms of you know.

Q2 requirements or steps with therapies as well.

Onaiza Cadoret: There are huge requirements and or steps with therapies as well, so we'll price accordingly to where the clinical trial is. Great. That's really helpful.

So we'll price accordingly to where the clinical value proposition is coming out which it can be a very robust.

Set of.

Clinical evidence.

Great. That's very helpful. Thank you.

Thanks Ben.

Joseph Stringer: Thank you. Thanks, Ben. The next question will come from Joseph Stringer with Needleman Company. Please go ahead.

The next question will come from Joseph Stringer with Needham <unk> Company. Please go ahead.

Hi, Thanks for taking my question a quick one from us on soon to lessen in acromegaly phase two readout.

Eugene Schneider: Hi, thanks for taking our question. A quick one from us on syndalursin and acromegaly, the phase 2 readout, excuse me, second half of this year, monotherapy, what reduction in IGF-1 or perhaps a percent of patients that have normalized IGF-1 would you be looking for or that would give you confidence in this program going forward? Thank you. Eugene Grady, Sure.

It gives me the second half of this year.

Monotherapy what reduction.

IGF, one or perhaps percent of patients that have normalized IGF. One would you be looking for or that would give you confidence in this program going forward. Thank you.

I'll take that.

Sure.

Eugene Schneider: So really, the remaining need here is being able to achieve normalization of IGF-1. And that's really the bar that we set for this drug, both in a monotherapy setting as well as in the add-on setting. So outside of that, I can't really speculate what the...

So really the remaining.

Need here is being able to achieve normalization of IGF, one and thats really the goal.

We said before for this drug both in the.

Monotherapy setting as well.

And then the add ons settings.

Outside of that.

I can't really speculate what the.

Eugene Schneider: The threshold in terms of responder rate would get us really, really excited. But we're obviously planning for a very positive readout in terms of IGF-1 normalization. I would just add here that both sets of data on monotherapy and in addition to SSAs are going to be really important here, and we'll have, and their people are still seeing good breakthroughs. The next question will come from Salveen Richter with Goldman Sachs. Please go ahead. Hey, thanks. This is Matt Alford-Salvin.

The threshold in terms of responder rate that.

Would get us really really excited about.

Sure.

We've been planning for a very positive readout.

IGF one normalization.

Yes, I would just add here that both sets of data on monarch monotherapy and in addition to associates are going to be really important here from a market perspective.

And we'll have boats.

And there are people are still seeing good.

Our breakthrough attacks over here, so I do think that the IGF normalization as key goal, but having such a data as monotherapy as well as in combination will.

It will be very important.

Yeah.

The next question will come from Selvey enriched <unk> with Goldman Sachs. Please go ahead.

Salveen Richter: Just going back to 449, could you guys discuss your thoughts on market strategy or pricing? And then separately, could you give us an update on your ALS programs? In particular, when should we expect Phase I-II data for 541? Thanks a lot.

Hey, Thanks, This is Matt on for solving.

Going back to 449 could you guys discuss your thoughts on market strategy or pricing.

And then separately could you give us an update on your AOS programs in particular when should we expect phase one two data for 541, thanks a lot.

Brett Monia: So, for 541, that's our Ataxia 2 drug, and sporadic or non-genetic ALS, Biogen is running that study, and they have disclosed the timing, but I would, you know, look towards next year for that data readout. And, of course, we're very much looking forward to that, and that could go to phase three based on, you know, positive results. Onaiza, would you like to talk a little bit about, you know, commercial opportunities? And I don't want to really touch on pricing much for PCSK9, but why don't you go for it?

So.

For 541, Thats, our apex two trial.

And sporadic or non genetic AOS Biogen is running that study and they haven't disclosed timing, but I would I would.

Look towards next year.

For that data readout.

And of course.

Very much looking forward to that.

And that could go to phase III based on the results.

Yes.

<unk> would you like to talk a little bit about the.

The commercial opportunity and none of them really touch on price do much for Ccs canine, but once you go over.

Onaiza Cadoret: Yeah, sure. Really large market, you know, about 11 to 16 million patients, so a very large population that's still uncontrolled on maximally tolerated statins. The guidelines are really getting aggressive here because of the cardiovascular risk for these patients, particularly secondary, Transcripts provided by Transcription Outsourcing, LLC. U.S. in 55. Medical Medicare for Desolate are out.

Yeah sure really large market you know about 11 to 16 million patients.

So a very large population thats still uncontrolled on maximally tolerated statin.

The guidelines are really creating aggressive here because of the cardiovascular risk.

For these patients, particularly the secondary.

Prevention and they are leading to about 70 milligrams per deciliter in the U S and 55 actually milligrams per deciliter outside of the U S. So really good.

Onaiza Cadoret: So really good momentum, in terms of aggressive guidance. Itazian showed you some tremendous LDL-C reduction. All right, all right. Mabs have shown, and also well above what Inclusiran. Victoria, so just to put this into contact.

Good momentum I would say in terms of our aggressive guidelines to treat which I think will help this entire market growth substantially.

At TVN showed you some tremendous ldlc reduction, which is well above what the maps have shown and also well above what <unk> has shown in this area. So just to put into context, we're looking at about the 50% range.

Onaiza Cadoret: 3% range, you know, you know, for... Alec Vio, Ed Sheerl, and really substantially lowers the LDL, and we expect with all the models. That positioning is what will drive the value out of the pricing strategy and also which level of, you know, area.

For for.

<unk> about the <unk> for the maps and we're looking at in the seventies four for RPC S canine, which is going to be.

Really substantial improvement in LDL, lowering and we expect with all the modeling. This will also translate into really good mix.

<unk> as well that positioning is what will drive the value proposition and kind of the pricing strategy and also which level.

Area that we actually want to go into in terms of the reimbursement as well, so it's really well positioned to do well, but the efficacy profile. The best in class efficacy is what's going to kind of drive.

Onaiza Cadoret: Ionis Pharmaceuticals Inc. So it's really well-positioned to do well, but, you know... Profile.

Onaiza Cadoret: The best in class efficacy is what's going to kind of drive the next question. The next question will come from Myles Minter with William Blear. Please go ahead, questions, just in your prepared remarks on 9. You did say... Second half, but the commentary on the call today seems to be like, well and truly going ahead. So Brett, can you just clarify what preparation Ray Develle, Phase II trials done? Or have you seen a protocol?

Go to market strategy for this agent.

Next question.

Myles Minter: And then Beth, can you talk to the miles? Ideal if phase three is started up in the second half. The last one.

The next question will come from Myles Minter with William Blair. Please go ahead.

Taking the questions just in your prepared remarks on four nine you did say astrazeneca is going to make a formal decision on the size and the second half, but the commentary on the call today. It seems to be like that's well and truly going ahead, sorry, Brett can you just clarify what prepping for phase three development actually means.

Not just getting these phase III trials done.

Or have you seen a protocol.

And then Beth can you talk to the milestone structure, if anything on that deal. If a phase III is started up in the second half and my last one is just on the muscle locker program.

I need to take a single asset into IND, enabling studies. There I know you have multiple collaborations in programs there or would you take multiple programs into the annoying.

Tox studies, thanks, Thanks miles.

Brett Monia: Transcript by Rev.com Page of Ionis Pharmaceuticals Inc., or would you take multiple... Thanks, Miles. Yeah, this is AstraZeneca is planning to start phase three development from, you know, a stop position. After the ongoing salons data reach out, they're, they're very much preparing for phase three now. That includes making the drug, getting the drug ready, and then that's on its way. The protocol, sure, protocols are being developed, and they're preparing for another phase two meeting, so you know, and we're working very closely with them on this program, so all that is in motion, all that is happening. We're really just waiting on finalizing protocols and getting ready for regulatory interaction. You know, obviously we've had regulatory interactions previously, So yeah, all those wheels are in motion, and as far as the economics of that, Beth.

Yes. This is astrazeneca is planning to start.

Phase II development from.

From us from a stock position after the ongoing slot data rich out there. They are very much preparing for phase III now that includes making the drug and the drug ready and demand.

Brian The protocol sure protocols being developed and they are preparing for an end of phase II meeting.

So we're.

And we're working very closely with them on those programs. So all that is in motion all that is happening.

We're really just waiting on finalizing protocols.

Getting ready for a regulatory interactions.

Obviously, we've had a frame for David David have regulatory interactions previously been announced the end of phase II interactions.

Are you getting drug right. So yes.

Those deals are in motion.

And as far as the economics.

Sure.

Beth Hougen: Sure. So now as we look forward to the next steps, there aren't any milestones associated with Phase 3, but there are, you know, a substantial number of milestones for sort of common regulatory type events and then a very significant number of commercial milestones that add to our tiered royalties that go up into the teams. Muscle Lincoln, Eric?

Already earned a substantial amount.

Revenue from this program.

So now the SD.

Look forward to.

The next steps there arent any milestones associated with <unk>.

With phase III.

Sure.

Substantial amount of milestones or sort of common regulatory.

Type event, and then a very significant amount.

Commercial milestones.

That add to our tiered royalties.

Welcome to the <unk>.

James.

Muscle Lincoln.

Eric Swayze: Yeah, sure. So, what we've stated is we have an objective to advance one muscle lica into development this year. As you know, we have lots of programs; we have to start one first before we get to many, I think. And there are lots of great opportunities there.

Yes sure so.

And what we've stated is we're haven't objected to advanced one muscle like.

The development this year.

As you know we have lots of programs we have to start one first before we get too many.

Yes.

There's lots of great opportunities there, we have lots of preclinical programs.

You plan to be aggressive in.

Eric Swayze: We have lots of preclinical programs, and we plan to be aggressive in picking off the best clinical opportunities in the fourth semester of post-unmet needs and moving those programs forward. Yeah, I mean we're, just to put a fine point on that, Miles, Eric, under pressure to move several muscle glycogen development because the data is really looking great. I also want to remind you that we have our own muscle glycode programs, Ionis, Holyong. We are also working on neuromuscular diseases with Biogen, and we also have an excellent partnership with AstraZeneca in cardiovascular diseases, aka cardio. So we have a lot of, you know, balls here.

Picking off the best clinical opportunities and whether it's domestic postponement.

And moving those programs forward.

I mean.

Just to put a final point on that Myles.

Eric.

Under pressure to move several of them.

You get the data is really looking great.

Remind you that we have our own muscle.

Programs I own this wholly owned.

Also we're working on neuromuscular diseases with Biogen and we also have an excellent partnership with Astrazeneca in cardiovascular disease.

Brett Monia: And, and, and things are moving forward both, you know. What will be first is less important than I think the gist of your question, which is that we're expecting to have a rich pipeline of muscle mycotropes in development in the future. Thanks again to all of you. Thank you guys. The next question will come from Yale Jen with Laidlaw and Company. Please go ahead. Thanks for taking the questions and congratulations on the progress. Just two quick ones.

Cardiac so we have a lot of it.

Pause here and things are moving forward.

What will be first is that's important and I think the gist of your question, which is we expect to have a rich pipeline of muscle like trucks and development.

In the future.

Fair enough, thanks, again to all of us.

Got it.

The next question will come from Yale Jen with Laidlaw <unk> Company. Please go ahead.

Thanks for taking the questions and congrats on the progress just two quick ones. The first one just wanted to clarify that in terms of the cardio.

Yale Jen: The first one, I just want to clarify that in terms of the cardio-transformed trials, does that include any patient with a mixed phenotype? In other words, with the polyneuropathy patients, or simply purely all in cardiopsy? Yeah, no, this very much includes some patients that have mixed phenotypes. We are certainly aware of how significant of an overlap there is between the two sort of, Um... Edges of the spectrum, if you will, that used to be considered very separate diseases but really are manifestations of the same pathology in different organ systems.

<unk> trials.

Does that include any patient with a mixed phenotype in other words with the polyneuropathy patients or simply period.

Cardio site.

Yes, no very much includes some patients Mexican in fact, we are certainly aware of how significant of an overlap.

There is between the two.

Sure.

As of the spectrum, if you will that used to be considered very separate diseases, but really are manifestations of the same pathology.

In different organ systems, so yes, we.

Yale Jen: So, yeah, we are looking at neurological endpoints appropriate for the patient population. And you know, Yale, it's, it's an interesting question. There's more and more attention in this field being paid to neural neuropathy symptoms that patients with wild-type cardiomyopathy have.

We are looking at.

Neurological endpoints are appropriate for the patient population.

And all that.

Eugene Schneider: So it's a very relevant question and something we are paying very close attention to, and it will be something we're assessing in the cardio transform study. Like Eugene said, so, thanks for the question, Yale. Unfortunately, we're over time, so we're going to have to close the call. I really do want to thank everybody for joining us. Today and on the call, you know, we're making great progress at Ionis. We're very happy about the first quarter, and we're very excited about the rest of the year ahead. And we look forward to providing additional updates throughout the rest of the year. So, until then, thanks very much, and everybody have a great day. Goodbye.

It's an interesting question theres more and more attention in this field.

In page two neuro neuropathy symptoms that patients with wild type cardiomyopathy.

So it's a very relevant question and something we are paying very close attention to and it will be something we're assessing in the cardio transform study rate like Eugene said so.

So thanks for the question Yale.

Unfortunately, we're over time, so we're going to have to close the call I really do want to thank everybody for joining.

Today and participating on the call.

Great progress that icon is we're very happy about the first quarter and we're very excited about the rest of the year ahead, and we look forward to providing additional updates throughout the rest of the year. So until then thanks very much and everybody have a great day.

Goodbye.