Q3 2021 Ionis Pharmaceuticals Inc Earnings Call

Okay.

Operator: Good day and welcome to the Ionis Pharmaceuticals third quarter 2021 Financials Conference Call. As a reminder, this call is being recorded. And at this time, I would now like to turn the call over to Jennifer Capazella. Please go ahead.

Good day and welcome to the Ion It's Pharmaceuticals third quarter 2021 financial results Conference call. As a reminder, this call is being recorded.

And at this time I would now like to turn the call over to Jennifer <unk>. Please go ahead.

Unknown Executive: Thank you, Tom. 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 gaps to non-gap financials. We believe non-capitalized financial results better represent the economics of our business and how we manage your business. We've also posted slides on our website that accompany today's call. With me on this call this morning, our Brett Monia, Chief Executive Officer, Beth Hagen, Chief Financial Officer, and Richard Geary, Executive Vice President of Development. And joining us for the Q&A portion of the call are Richard, sorry, Eric Swaye, Executive Vice President of Research, and Anaza Catteray, Chief Corporate Development and Commercial Officer.

Thank you Tom.

We began I encourage everyone to go to the investors section of the IR website to view the press release and related financial tables, you'll be discussing today.

A reconciliation of GAAP to non-GAAP financials.

We believe non-GAAP financial results.

Better represent the economics of our business and how we manage our business.

We have also posted slides on our website that accompany today's call.

With me on this call. This morning are Brent non-GAAP.

Sure.

Beth Hougen, Chief Financial Officer, and Richard Geary Executive Vice President of development.

And joining us for the Q&A portion of the call are Richard.

Sorry, Eric Swayze Executive Vice President of research and Theres, a cat or a chief corporate development and commercial officer.

Unknown Executive: I'd now like to draw your attention to slide three, which contains our forward-looking statements. During this call, we will be making forward-looking 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 detail. And with that, I'll turn the call over to Brett.

I'd now like to draw your attention to slide three which contains our forward looking statements.

During this call you'll be making forward looking statements that are based on our current expectations beliefs.

These statements are subject to certain risks and uncertainties.

Our actual results may differ materially.

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

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

Brett P. Monia: Thanks, Jen. Good morning, everybody, and thanks for joining us on today's call. In the second half of 2021, Ionis has made important progress on several fronts. We expanded our late stage pipeline, and started our phase three core study of old Zarsin, which we previously referred to as IONASAPO C3 LRX. This study will evaluate Olazarsin in patients with severe hypertricidemia, an indication with an estimated 3 million patients or more in the United States.

Yeah.

Thanks Jen.

Everybody and thanks for joining us on today's call.

In the second half of 2021, I understand important progress on several fronts.

We expanded our late stage pipeline start of our phase III core study of <unk>, which we previously referred to as I honest Apoc III LR X.

This study will evaluate <unk> in patients with severe hypertension, but for EMEA and indications with an estimated 3 million patients or more in the United States.

Brett P. Monia: We completed enrollment in the phase three neurotransformed study of Epilem Kyrson in patients with QTRPolyneuropathy, putting us on track for data in mid-2020, and we are on track to initiate our phase three study of Doninth Dilerson, which we previously referred to as IONISPKLRX in patients with hereditary angioidema before the end of this year. We will also advance our commercial strategy and go-to-market initiatives in anticipation of phase three data, readouts, and potential commercial launches of these programs.

We completed enrollment in the phase III neuro <unk> transform study of F. One person.

Person in patients with <unk> polyneuropathy, putting us on track for data in mid 2022.

And we are on track to initiate our phase III study of Donuts Tillerson, which we previously referred to as Iowans PKK LR X in patients with hereditary angioedema before the end of this year.

We also advanced our commercial strategy and go to market initiatives in anticipation of phase III data readouts and potential commercial launches of these programs.

Brett P. Monia: Additionally, we further increased investments in our LICA platform for our transaction with bicycle therapeutics. While Toferson missed the primary endpoint in the placebo-based Vowler study in patients with Sard 1 ALS, we are encouraged by the totality of evidence from Valor and the open label extension, which showed signs of slowing disease progression in these patients.

Additionally, we further increased investments in our like our platform through our transaction with bicycle therapeutics.

October <unk> missed the primary endpoint in a placebo controlled phase III <unk> study and patients decide when AOS. We are encouraged by the totality of evidence valor and the open label extension, which showed signs of slowing disease progression in these patients.

Brett P. Monia: Importantly, Biogen is now actively engaged with regulators and other key stakeholders to determine the next steps for this program. Bayogen also plans to expand its early access program to the broader population of people living with Saad 1 ALS. And given the importance of treating patients early in their disease as reinforced by top-line data from Valor and the OLE, we are pleased that the Atlas study in pre-symptomatic patients continues as originally planned.

Importantly, Biogen is now actively engaged with regulators and other key stakeholders.

To determine the next steps for this program.

Biogen also plans to expand its early access program to the broader population of people living with type one AOS.

And given the importance of treating patients early in their disease is reinforced by topline data from valor and the OE. We are pleased that the Atlas study pre symptomatic side when airlines patients continues as originally planned.

Brett P. Monia: Coming up in the next 12 months, we're looking forward to a number of key catalysts, including our presentation summarizing the phase two results for Dona Doloreson in patients with head hereditary endu edema at the ACAAAI annual meeting on Sunday. And at our Virtual Investor Day event on December 9th, we look forward to sharing our strategy, plans, and progress, bringing our most advanced programs to market and achieving commercial success. Importantly, we remain financially strong, on track to achieve our financial guidance, and have the resources to meet our strategic objectives.

Coming up in the next 12 months looking forward to a number of key catalysts, including our presentation summarizing the phase II results for <unk> in patients with hereditary angioedema and the AC AI annual meeting on Sunday.

And that our virtual Investor day event on December nine we look forward to sharing our strategy plans and progress bring our most advanced programs to market.

<unk> commercial success.

Importantly, we remain financially strong on track to achieve our financial guidance and have the resources to meet our strategic objectives.

Brett P. Monia: And with that, I'll turn the call over to Beth to review our financial results, and Richard will discuss recent pipeline updates and upcoming pipeline catalysts. After Richard, I'll wrap up our prepared remarks for taking your questions. Now over to you.

And with that I'll turn the call over to Beth to review, our financial results and Richard will discuss recent pipeline updates.

Upcoming upcoming pipeline catalysts after Richard I'll wrap up our prepared remarks before taking your questions.

Now over to Beth.

Elizabeth L. Hougen: Thank you, Brad. During the first nine months of this year, Ionis earned $370 million in revenue and recognized $499 million in non-GAP operating expenses, reflecting our commitment to advancing our wholly owned pipeline and our technology. This resulted in a non-GAAP net loss of $131 million.

Thank you Brad.

In the first nine months of this year I honest three.

$370 million in revenue and recognized $499 million in non-GAAP operating expenses.

Reflecting our commitment to advancing our wholly owned pipeline and our technology.

This resulted in a non-GAAP net loss of $131 million.

Elizabeth L. Hougen: Spinraza's global sales in the first nine months of this year were $1.5 billion, and we earned nearly $200 million in royalty revenue from Spinraza, virtually all falling to our bottom line as profit. We are pleased with Biogen's ongoing work to further inform SMA treatment and address the remaining unmet needs of SMA patients of all ages. Bayigen recently announced plans to initiate the Ascend study to evaluate the potential of high-dose binrazha to benefit patients previously treated with RISDA.

It's been Ross's global sales in the first nine months of this year were $1 $5 billion and we earned nearly $200 million in royalty revenues from spin Raza virtually all falling into our bottom line as profit.

We are pleased with biogen's ongoing work to further inform SMA treatment and address the remaining unmet needs of SMA patients of all ages.

Biogen recently announced plans to initiate the ascend study to evaluate the potential of high dose has been rather to benefit patients previously treated with rates at the plant.

Elizabeth L. Hougen: The DeVote study is evaluating the potential of high dose bin rasa to demonstrate even greater benefit compared to the currently approved dose, and the response study is evaluating SpinRods' potential to benefit patients who have had a suboptimal response to gene therapy. Together with the substantial and growing body of evidence supporting Spinraz's proven profile, and over 60,000 SMA patients in markets where Viagin has a commercial presence, we believe Spinraz Tegcetti and Weiliver generated nearly $50 million in revenue in the first nine months of this year.

The devote study is evaluating the potential of high dose.

<unk> demonstrated even greater benefit compared to the currently approved dose.

And the response study is evaluating <unk>.

Potential to benefit patients, who had a suboptimal response to gene therapy.

Together with the substantial and growing body of evidence supporting <unk> proven profile.

And over 60000, SMA patients in markets, where Biogen has a commercial presence we.

We believe spin RASM will continue to be the market leading treatment for SMA patients of all ages and types.

Chegg study and we leveraged generated nearly $50 million of revenue in the first nine months of this year.

Elizabeth L. Hougen: And as discussed on our last quarterly call, during the second quarter, we completed the transition of our commercial operations for these medicines to Sobe. As a result, our revenues from Texcet and Wei are now comprised of distribution fees based on that sale. Importantly, both medicines continue to make advances in new markets. Takedi recently achieved innovative drug pricing in Brazil, reflecting the significant unmet medical need and prevalence of TTR polyneuropathy in that country.

And as discussed on our last quarterly call during the second quarter, we completed the transition of our commercial operations for these medicines just obi.

As a result, our revenues from Chegg study and we lever are now comprised of distribution fee based on net sales.

Importantly, both medicines continued to make advances into new markets.

<unk> recently achieved innovative drug pricing in Brazil, reflecting the significant unmet medical need and prevalence of GTR polyneuropathy in that country.

Elizabeth L. Hougen: Tegedi's categorization as an innovative treatment is a key milestone toward optimizing its value in Latin America, and Wai Libra was approved in Brazil as the first and only treatment for patients with FCS, which triggered a $4 million milestone payment from PTC in the third quarter. We earned $115 million in R&D revenue in the first nine months of this year by advancing more than 15 programs within our cardiometabolist and neurology franchise. This included a $25 million milestone payment from Novartas for achieving 50% enrollment in the phase 3 outcome study of Calicarsan. Our ability to generate revenue from numerous diverse sources continues to be a key element of our financial strength. We reported non-gap operating expenses of $49 million in the first nine months of this year.

Take steady categorization as an innovative treatment is a key milestone towards optimizing its value in Latin America.

And we believe we live where it was approved in Brazil at the first and only treatment for patients with FCS, which triggered a $4 million milestone payment from PTC in the third quarter.

We earned $115 million in R&D revenue in the first nine months of this year from advancing more than 15 programs within our cardio metabolic and neurology franchises.

This included a $25 million milestone payment from Novartis for achieving 50% enrollment in the phase III outcome study Pellekar spin.

Our ability to generate revenue from numerous diverse sources continues to be a key element of our financial strength.

We reported non-GAAP operating expenses of $499 million in the first nine months of this year.

Elizabeth L. Hougen: This was a 10% increase compared with last year and was in line with our expectations. R&D expenses increased by nearly 35% compared with last year. This increase was driven primarily by expenses related to our phase three pipeline, including the ongoing studies of Applanstersson and start-up costs associated with the phase three Ola-Sarsson core study. We also recognized $35 million of R&D expense in Q3 because of our license agreement with bicycle therapeutics. SGNA expenses decreased by nearly 35% compared with last year, driven by the substantial savings we realized from the exeat integration and so be transaction.

This was a 10% increase compared with last year and was in line with our expectation.

R&D expenses increased by nearly 35% compared with last year.

This increase was driven primarily by expenses related to our phase III pipeline, including the ongoing study is about one person and startup costs associated with the phase III OLED <unk> core study.

We also recognized $35 million of R&D expense in Q3, because of our license agreement with bicycle therapeutics.

SG&A expenses decreased by nearly 35% compared with last year driven by the substantial savings we realized from the <unk> integration and sobey transaction.

Richard S. Geary: As planned, these transactions unlocked substantial cost savings that we are now reinvesting to drive future revenue growth. This includes funding our go-to-market initiative for our late stage pipeline. Based on our results for the first nine months of this year, today we are reaffirming our 2021 financial guidance, which calls for revenue of more than $600 million, operating expenses in the range of $710 to $750 million, and a net loss of less than $102 million, assuming the low end of our expenses and all on a non-gap basis. We are projecting higher R&D revenue in the fourth quarter from our advancing

As planned these transactions unlocked substantial cost savings that we are now reinvesting to drive future revenue growth.

This includes funding our go to market initiative for our late stage pipeline.

Based on our results for the first nine months of this year today, we are reaffirming our 2021 financial guidance, which calls for revenue of more than $600 million operating expenses in the range of $710 million to $750 million.

And a net loss of less than $102 million, assuming the low end of our expenses and all on a non-GAAP basis.

We are projecting higher R&D revenue in the fourth quarter from our advancing partnered programs.

Richard S. Geary: Looking to our collaborations with Biogen and AstraZeneca, we have a deep pipeline of programs that provide us with several opportunities to achieve significant milestone payments this year. In addition, we expect operating expenses to increase in the fourth quarter as our Olasen and Dona Lorson phase three studies get underway. With $2 billion in cash, we believe we are well positioned to continue investing in our pipeline, our technology, and the go-to-market activities for our most advanced medicines. And with that, I'll turn the call over to Richard. Thank you, Beth.

Looking to our collaboration with Biogen and Astrazeneca, we have a deep pipeline of programs that provide us with several opportunities to achieve significant milestone payments this year.

Further we expect operating expenses to increase in the fourth quarter.

As our <unk> and <unk> phase III study get underway.

With $2 billion of cash we believe we are well positioned to continue investing in our pipeline our technology and the go to market activities for our most advanced medicine and with that I'll turn the call over to Richard.

Thank you Beth.

Richard S. Geary: We continue to be pleased with the overall performance of our pipeline. Already this year, we've achieved numerous milestones and look forward to more over the next 12 months. Looking first at our late stage pipeline, Eplonterson is progressing well. We completed enrollment in the phase three Neuro Transform study in patients with TTRPolyneuropathy, putting us on track for data mid-next year and an NDA filing by the end of next year, assuming positive data. The Cardio T-T Transform study also continues to progress, as does our Pelkarsin and Fuss ALS study.

We continue to be pleased with the overall performance of our pipeline.

Already this year, we've achieved numerous milestones and look forward to more over the next 12 months.

Looking first at our late stage pipeline Epsilon person is progressing well, we completed enrollment in the phase III neuro <unk> transform study in patients with <unk> Polyneuropathy.

US on track for data mid next year, and an NDA filing by the end of next year, assuming positive data.

Cardio T. Transform study also continues to progress as do our pellet Carson and phosphate Lf studies.

Richard S. Geary: We expect data from all three of these phase three studies in 2024, continuing the regular cadence of data readout from our late stage registration studies. We're also pleased with the progress we're making with OlaSAR. The balanced SCS study remains on track for data in 2023. And just this week, we announced the initiation of the Phase 3 core study in patients with severe hypertriclycerdemia, triglycerides, over 500 milligrams per decil. As Brett mentioned, SHTG, or severe high triglycerides, represents a substantial opportunity with more than 3 million patients in the U.S. alone.

We expect data from all three of these phase III studies in 2020 for continuing the regular cadence of data Readouts from our late stage registration.

Studies, we're also pleased with the progress, we're making with <unk>.

Our balance FCS study remains on track for data in 2023.

And just this week, we announced initiation of the phase III core study in patients with severe hypercholesterolemia triglycerides over 500 milligrams per deciliter.

As Brett mentioned S. H T J, our severe high triglycerides.

<unk> represents a substantial opportunity with more than 3 million patients in the U S alone.

Richard S. Geary: Core is the second study in our comprehensive Ola Sarsen development program, which we designed to fully realize this medicine's potential to address a broad range of patients at risk for triglyceride-driven disease who today have limited treatment options. And as our seventh phase three study now underway, Core further expands our rich late stage pipeline. We've also made great progress with our Donita Lorson development program for the treatment of her hereditary angio We look forward to presenting additional data from the Doniglorson Phase 2 study at the ACAAI annual meeting coming up on Sunday.

Of course, the second study and our comprehensive <unk> development program, which we designed to fully realize this medicines potential to address a broad range of patients at risk for triglyceride, driven disease, who today have limited treatment options.

And as our seventh Phase III study now underway core further expands our rich <unk> late stage pipeline.

We've also made great progress with our <unk> development program for the treatment of hereditary angioedema.

We look forward to presenting additional data from the Donegal horse in phase two study at the ACC.

My annual meeting coming up on Sunday.

Richard S. Geary: These data will further demonstrate why we believe this medicine has the potential to be the best in-class treatment for people with H-E. We're also on track to start the Donie Lawson Phase 3 study before the end of this year. We have moved with urgency to begin this very important phase three program, putting us on track to get up and running well ahead of our plan. The start of the study will further expand our deep phase three pipeline to six medicines over eight indications. However, we were disappointed that the phase three Valor study in patients with SAD 1 ALS didn't reach statistical significance in the primary endpoint.

These data will further demonstrate why we believe this medicine has the potential to be the best in class treatment for people with HIV.

We're also on track to start the Danita Louis in Phase III study before the end of this year.

We have moved with urgency to begin this very important phase III program, putting us on track to get up and running well ahead of our plan.

The start of the study will further expand our deep phase III pipeline to six medicines over eight indications.

We were disappointed that the phase III valor study in patients with sod one AOS didnt reach statistical significance in the primary endpoint.

Richard S. Geary: We're encouraged, however, that trends favoring Tuferson are seen across multiple measures of biologic activity and clinical function, including motor function, respiratory function, and quality of life compared with placebo. Additionally, the totality of data from Valor and the ongoing OLE reinforced these findings and showed that patients who started Tuferson earlier experience better outcomes, further suggesting a positive clinical effect. As Brett mentioned, we're encouraged that Biogen is now actively engaged with regulators and plans to expand its Tocers and expanded access program to all patients with SAD1ALS.

We're encouraged however that trends favoring tow person.

As seen across multiple measures of biologic activity and clinical function, including motor function respiratory function and quality of life compared with placebo.

Additionally, the totality of data from valor and the ongoing OLED reinforced these findings and showed that patients who started <unk>.

Earlier experience better outcomes further, suggesting a positive clinical effect.

As Brent mentioned, we are encouraged to Biogen is now actively engaged with regulators and plans to expand its <unk> expanded access program to all patients with <unk> ALS.

Richard S. Geary: And as we and Viogen continue to analyze these data, we look forward to applying the learnings from Valor and the OLE to further optimize the development of other programs in our AOS franchise. Now, let's turn to the steady progress we're making within our mid-stage pipeline. We reported that Ionis MAP TRX achieved the primary endpoint of safety and tolerability and its complete phase 1-2 study in patients with Alzheimer's. Ionismab TRX also offered the first clinical demonstration of anti-sense mediated CSF, tau protein suppression and achieved substantial, durable, dose-dependent reductions of CSF, total tau, and phospho-tow.

And as we and Biogen continue to analyze these data we look forward to applying the learnings from valor and the OLED to further optimize development of other programs in our AOS franchise.

Now, let's turn to the steady progress, we're making within our mid stage pipeline, we reported that I honest map T. Rx achieved the primary endpoint is safety and Tolerability and its completed phase one two study in patients with Alzheimer's disease.

My honest <unk> also offered the first clinical demonstration of antisense mediated CSF Tau protein suppression and achieved substantial durable and dose dependent reductions of CSF total Tau and Foster hotel.

Richard S. Geary: Based on these promising results, Biogen is actively planning, a longer phase two study of IonisMap TRX in Alzheimer's disease patients. With chief proof mechanism and a strong indication of proof of concept in our phase two study of Simdler, previously referred to as Ionis, GHR, LR, and Acromegalate patients uncontrolled on standard of care therapy. While the phase two study was no longer powered to assess the primary endpoint due to COVID-related enrollment difficulties, results from this study, and a preliminary assessment of the ongoing open label extension study, showed significant reductions in growth hormone binding protein, a measure of target engagement with no associated increase in growth hormone, a reduction in integrated IGF1 response, and good safety and patient and patients treated with Syndalersen, all supportive of its continued development in patients with acromic, In addition to our ongoing open label extension study, we are studying Simdherson in a monotherapy study.

Based on these promising results Biogen is actively planning a longer phase II study of <unk> in Alzheimers disease patients.

We achieve proof of mechanism and a strong indication of proof of concept in our phase II study of similar some <unk>.

Previously referred to as <unk> G HR L Rx and acromegaly patients uncontrolled on standard of care therapy.

While the phase II study was no longer powered to assess the primary endpoint due to COVID-19 related enrollment difficulties.

<unk> from this study in a preliminary assessment of the ongoing open label extension study.

Significant reductions in broker hormone binding protein a measure of target engagement.

With no associated increase in growth hormone.

A reduction in integrated IGF one response.

And good safety and Tolerability in patients treated with <unk>.

All supportive of its continued development in patients with acromegaly.

In addition to our ongoing open label extension study, we are studying <unk> in our monotherapy study.

Richard S. Geary: Both of these studies are progressing on track with data expected next year. Ion 449, targeting PCSK9, is progressing on track. And we're looking forward to data readout from the multiply sending dose studies in individuals with high cholesterol at the American Heart Association annual meeting later this month. Lupin is also on track for Phase 2B data redoubt end patients with dyslipidemia and cardiovascular disease by the end of this year. Enrollments in the phase 2B end-stage renal disease study of phasomerson, previously referred to as Zionist Factor 11 LRX, are now complete, putting this study on track for data readout in the first half of next year.

Both of these studies are progressing on track with data expected next year.

Ireland 449 targeting Pcf's canine is progressing on track.

And we're looking forward to a data readout from the multiple ascending dose studies in individuals with high cholesterol at the American Heart Association annual meeting later this month.

<unk> is also on track for phase II data readout in patients with Dyslipidemia and cardiovascular disease by the end of this year.

Enrollment in the phase two b end stage renal disease study of <unk> <unk>.

Previously referred to as ion This factor 11 L. Rx is now complete putting this study on track for data readout in the first half of next year.

Brett P. Monia: And finally, our phase one study of Ion 582 in patients with Angelman syndrome is also on track to start by year end. As I've just summarized, we're rapidly advancing and expanding our phase three pipeline with potential for new phase three programs. We also look forward to a steady cadence of data readouts as we move into next year from our late stage pipeline, beginning with Eplontersen, NTTR, and polyneuropathy patients mid-next year. With that, I'll turn the call back over to Brett.

And finally, our phase one two study of <unk> <unk> two in patients with Angelman syndrome is also on track to start by year end.

As I've just summarized.

We're rapidly advancing and expanding our phase III pipeline with potential.

For new Phase III programs. We also look forward to a steady cadence of data readouts as we move into next year from our late stage pipeline, beginning with Epsilon person NTR Polyneuropathy patients mid next year.

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

Yes.

Thanks Richard.

Brett P. Monia: Thanks, Richard. Throughout this year, we have executed on our strategic objectives to advance our pipeline, expand the reach of our technology, and prepare to successfully commercialize our most advanced whole we own program. All three of these objectives are central to my vision to bring Ionist to greater heights of success, and as we reviewed this morning, we're well on our way. At our virtual investor day coming up on December 9th, I'll talk more about my vision and what makes me so optimistic for IONUS's future.

Throughout this year, we have executed on our strategic objectives to advance our pipeline.

Expand the reach of our technology and prepare to successfully commercialize our most advanced wholly owned programs.

All three of these objectives are central to my vision to bring Io, Mr. Greater heights of success.

And as we reviewed this morning, we're well on our way.

And our virtual Investor day coming up on December nine.

Talk more about my vision and what makes me optimistic Brian I own. This is future. You'll also hear from many other islands leaders will discuss our strategies and the progress we're making to achieve all our most important near and long term goals. We also aim to answer to your questions, including questions about our commercial strategy and go to market initiative.

<unk>.

Brett P. Monia: You will also hear from many other IONIS leaders who will discuss our strategies and the progress we're making to achieve all our most important near-long-term goals. We also aim to answer your questions, including questions about our commercial strategy and go-to-market initiatives. And while not the primary focus of our investor today, we also plan to discuss the investments we're making in our technology and how we see those investments paying off for years to come. I should be a great fan, so please watch for details in the coming weeks. And with that, I'll now open the call up for questions.

And while not the primary focus of our Investor Day. We also discussed the investments, we're making in our technology and how we see those investments paying off for years to come.

To be a great event. So reflects the details in the coming weeks and with that I will.

I'll now open the call up for questions Tom.

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

If you are using a speakerphone please pick up your handset before pressing the keys.

To withdraw your question. Please press Star then two.

And the first question comes from Yale Jen with Laidlaw <unk> co. Please go ahead.

Good morning, and thanks for taking the questions.

In terms of the Q T R studies.

My first question is that the.

He will work with the pulling the neuropathy or cardiomyopathy and crew mix type of patients.

Brett P. Monia: Thank you. We will now begin the question and answer session. To ask a question, press Star Than One on a touchtone phone; if you are using a speaker phone, please pick up your hand set before pressing the. To withdraw your question, please press star, then two.

Absolutely, yes so.

The Polyneuropathy neuro transform study.

Enroll and now due to read out by mid year next year is very similar.

Operator: And the first question comes from Yale Jen with Late Law & Co. Please go ahead. Good morning and thanks for taking the questions. In terms of the two TTR studies, my first question is, does either one for polyneuropathy or cardiomyopathy include mixed types of patients? Absolutely, absolutely, yes.

The study we did previously within of tourists in which it involves patients that have to have polyneuropathy, but a good number of those patients will also have.

Symptoms of cardiomyopathy as well.

Patients with hereditary <unk> polyneuropathy.

Hereditary.

Form of this disease.

In the Cardium cardio transform study.

Richard S. Geary: So the, The polyneuropathy Neurotransform study that's full and now due to read out by mid-year next year, is very similar to the study we did previously within a tersin, in which it involves patients that have to have polyneuropathy, but a good number of those patients will also have symptoms of cardiomyopathy as well. That is, patients with hereditary TTRoneropathy. So that's what the hereditary form of this is.

Cardiovascular cardiomyopathy outcome trial.

That will include both wild type and hereditary patients and <unk>.

Certainly the hereditary patients will also be mixed phenotype as well many of them will be mixed phenotype as well.

Okay, Great and maybe one more question.

The same thing.

Paul.

Is that what is the current sort of.

Recruitment status picking up I'm gonna status for the cardiomyopathy.

Richard S. Geary: In the Cardiotechardo Transform study, the cardiovascular cardiomy outcome trial, that will include both wild type and hereditary patients, and certainly the hereditary patients will also be of mixed phenotype as well. Many of them will be mixed phenotypes as well. Okay, great. And maybe one more question on the same line, on the same compound product, which is that what's the current recruitment status, patient recruitment status for the cardiomyopathy TDR study at the moment? Yeah, yeah, we're not providing specific details on where exactly we are in enrollment, but we are planning to complete enrollment in the first half next year. Okay, great.

TV study at the moment.

Yeah.

Yes, yes.

Not providing.

The specific details on where exactly we are in enrollment, but we are planning to complete enrollment in the first half of next year.

Okay, great. Thanks, a lot and congrats for all the progress.

Thank you.

Okay.

Yeah.

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

Oh, Hey, this is Keith on for Jason Thanks for taking my questions two from me.

First one on the Essex team Essex teaching programs you have your wholly owned ecosystem puts us on course phase Iia study.

Operator: Thanks a lot and congratulations on all the progress. Thank you. The next question comes from Jason Gerberry with Bank of America. Please go ahead. Oh, hey, this is Chian for Jason. Thanks for taking up questions. Two from me.

And you also have an S. Ppl's, where you program partnered with Pfizer with upcoming Phase III data do soon and Pfizer has some point talk about ethics, Teachey say potential indications pursued so.

Understand Brian you talk about that you know you see the two programs can coexist.

Operator: First one on the SHTG programs, you have your wholly own AEC3 position for the Phase 3 study, and you also have an HPTO3 program partner with FISA with upcoming Phase 2D data due soon. And FISA has some points to talk about SHTG as a potential indication pursuit. understand, Brett, you talk about that, you know, you see the two programs can coexist.

Yes, also with broken nurse out from what I recall iron ore at the Telesphere has the option to participate in a survey commercialization activities with Pfizer in the U S with Brooklyn nurse and so.

Ultimately long winded question, but curious how and to what extent I and our suppliers to maximize.

Brett P. Monia: And also, you know, with Vipanuris, from what I recall, I don't know, IACA or Atatomac Sea or has the option to participate in certain commercialization activities with FISA in the U.S. with Burpen Nersen. So ultimately, long-winded question, but curious, how and to what extent does IANNs plans to maximize the value of the two assets, perhaps some overlap between them?

The value of what the true asset given perhaps some overlap between them dots I honest up any input to their opening out of some coal plants in terms of the direction of development following phase III data.

Second question sort of one or the ATT curious do you have a.

Tiny Gwen the phase two might.

Brett P. Monia: Does IONAs have any input to the Lupinoran programs in terms of the direction of development following Phase-2 data? Second question, shorter one on the AGT. Curious, do you have a sense of timing when the Phase 2 might be reading out? Can we expect data in 2022 with the HET program? Thanks. Yeah, great questions, Gian.

Mikey leading out can we expect data in 2022 with the HGTV program. Thanks.

Yeah.

Great questions John.

So I'll ask Richard to talk a little bit about how we see.

Andrew putting like freedom of nurse in the Aoc three of those are some differentiating in the market. We're very excited about both drugs.

And we're glad that you know we are we are you know.

We are developing and commercializing <unk> and ourselves and we have a great partner adviser nordson.

Richard S. Geary: So I'll ask Richard to talk a little about how we see Andrew Fweeten, like 3, Movenorson, and APOC3, Volazar, differentiating in the market. We're very excited about both of these drugs. And we're glad that, you know, we are, you know, we are, you know, we're developing and commercializing it all as ours and ourselves, and we have a great partner advisor, which they do differentiate, and Richard Rang can take us through that. So I think the best way to think about this, Giannis, is that Ola Sarsen is strictly a triglyceride player and is a very strong triglyceride lowering agent in severe high triglycerides and active in FCS.

But they do differentiate.

Richard why don't you take us through that.

So I think the best way to think about this John is is that <unk> is strictly a triglyceride play and is very strong triglyceride lowering agents in in severe high triglycerides and active in Fcs.

And it will differentiate.

From Angiopoietin like three and that Angiopoietin like three is very much focused on.

Our mixed Dyslipidemia pop.

Population that also suffers from increases in or increased and uncontrolled cholesterol and so I think youll see differentiation. It's also a very large population and so youre going to be.

Onaiza Cadoret: And it'll differentiate from angiopoietin-like-3, and that angiopoietin-like 3 is very much focused on a mixed dyslipidemic population that also suffers from increases in or increased and uncontrolled cholesterol. And so I think you'll see differentiation. It's also a very large population.

Working in a place where really there's nothing else there.

Today that substantially lowers triglycerides in patients with these severe high.

Richard S. Geary: And so you're going to be working in a place where really there's nothing else there today that substantially lowers triglycerides in patients with these severe high measures of triglycerides. So I see the differentiation. I'm not speaking to the positioning on the market necessarily, but you can see from the biology that they will differentiate. Yeah, and maybe Anazza could also talk a little bit about that a little bit more, but specifically with a view to the market opportunity for Olazars. Yeah, sure, be happy to. You know, as everyone's already said on the call, this is a really large population.

Measures.

That's right so I see the differentiation I'm not speaking to the.

Positioning.

On the market necessarily but you can see from the biology that they will differentiate.

And may be amazed that could also talk a little bit about that.

That felt a little bit more but specifically with a view towards the market opportunity for <unk>.

Yeah sure I'd be happy to.

As everyone's already said on the call. This is it.

Two really large population severe hypo triglyceride demeo greater than 500 or so.

Onaiza Cadoret: Severe hypertroglyceridemia greater than 500 is a well thought out indication that's being studied, right? It's an adjunct diet to reduce TG levels, greater than 500. As we look at the market of this over 3 million patients in the U, that clinicians already have, mind and I think that's where some of the positioning will eventually play when we do actually launch these two two products in the marketplace, Vicer, Vuponorsen, and Ionis on Olaz And as Richard said, you know, where we see this really playing out for Ola's arson is that it is best, both at risk for cardiomemetabolic disease and acute pancreatitis, right, due to the yellow So we're seeing that emerge really nicely.

It's a well thought out indication that's being studied right. It's a it's an adjunct to diet to reduce teacher levels in <unk>.

Patients over.

Greater than 500, as we look at the market of this over 3 million patients in the U S. We see that clinicians already have like a segmentation in their mind and I think that's where some of the positioning will eventually play when we do actually launch. These two two products in the marketplace, Pfizer blueprint or send an io.

Yes.

On Oh is that person.

And as Richard said.

No.

We see this really playing out for <unk> is that it is best in class therapy to reduce triglycerides in patients both at with poor cardio metabolic disease and acute pancreatitis right due to the elevation of the trig levels as well so.

We're seeing that emerge really nicely there might be a bit of event diagram, but we do see lupin northern positioning.

Onaiza Cadoret: There might be a bit of a Venn diagram, but we do see the loop, themselves very So we are seeing some distinct segments actually emerging right now, and as everyone has said very well, Thanks, Anayza, and just to add to that, Olizarson is substantially more potent, will produce much more potent reductions in triglycerides compared to both in buprenorsin, too. So it's a much more effective triglyceride reducereide, if you will.

Themselves very nicely and in.

Patients with mixed Dyslipidemia with elevated remnant cholesterol.

So.

We are seeing some distinct segments actually emerging right now and does everyone has said very large market and really great opportunity.

Thanks, Nathan just to add to that.

<unk> substantially.

Substantially more potent.

We will produce more much more potent reductions in triglycerides convertible.

The nordson.

A much more effective triglyceride.

<unk>.

Brett P. Monia: Regarding the angiolitan-like-3, yes, where data is expected out next year for both refractory hypertension as well as the exploratory heart failure study. Thank you. The next question comes from Janon Ju with Wells Fargo. Please go ahead. Hi, thanks for taking my questions and congrats on the progress. A few questions, again, on the Olysarsen program in ShtG.

Regarding the NDA.

<unk>, Yes, we're data is expected out next year for both refractory hypertension as well as the exploratory heart failure study.

Thank you.

Okay.

Okay.

The next question comes from Jan on June with Wells Fargo. Please go ahead.

Hi, Thanks for taking my questions and congrats on the progress a few questions.

Again on the <unk>.

Artisan program P N S H T G.

Operator: So, of course, congratulations on initiating the Phase 3 core study. I have a few questions about the overall development program. Given the large indication size, I think probably more studies are needed. So just curious, how many studies are needed for the registration of this product, and how many patient years of exposure is needed for the safety database? And also, the data for Core is expected in 2024, as you have previously mentioned. What about the data for the overall program and the timeline for approval? Thanks. Will you let me take that?

Congrats on initiating the phase III core study.

I have a few questions on the overall development program.

Given the large indication size.

Hum.

Think of probably a more studies are needed. So just curious how many.

Studies are needed for the rich the registration of this product.

How many patient year exposure or.

Is needed for the safety database.

And also the data for for core is expected 2024, I think you previously have mentioned what about the the data for the overall program and the timeline.

Two approval.

Thanks.

Yes.

Want me to take that.

Richard S. Geary: Yep. So we've got quite a number of studies planned. I don't think we've specified the number, but certainly more than 1,500 patients will be included in this database. So stay tuned. We've got a few more to start next year.

So we've got quite a number of studies planned I don't think we specified the number but certainly more than 500 patients will be exposed in this database.

So stay tuned we've got a few more to start next year.

Richard S. Geary: That will be supportive, particularly for the severe high triglyceride larger population. Will this be, sorry, go ahead, sorry, Brad. I was going to say in the beta readout was talking about 2024 would be to support registration. Right. Yeah, so it all comes together around that time.

That will be supportive, particularly for the severe high triglyceride larger population.

Is this the I'm.

I'm sorry go ahead, sorry, Brett.

I was going to say.

The data readout.

So it would be to support registration right, yes, so it all come together around that time.

Okay.

Great that's great and maybe a quick follow up on that.

The core study.

Richard S. Geary: Great, that's great. And maybe a quick follow-up on the core study. The primary endpoint is triglyceride reduction. Is that acceptable?

The primary endpoint is the triglyceride triglyceride reduction.

Is that a registry.

Provable.

Richard S. Geary: Do you need the acute pancreatitis event rate event rate to secure the product? Thank you. Right. The answer is yes; triglycerides are approvable alone.

Do you need the pancreatitis acute pancreatitis.

Right.

For to secure the approval.

Thank you.

So.

The answer is yes, triglycerides are approvable alone.

Richard S. Geary: The pancreatitis, of course, we believe, will be a profile-enhancing component for this drug, but only the triglyceride level is required for approval for this indication. Got it. Thank you. That's very helpful. The next question comes from Esther Raja Vali of UBS. Please go ahead. Hey, thank you for taking my question. I have a couple. I'll start off with the Angelman's program.

Titus of course, we believe will be a profile enhancing <unk>.

<unk> for this drug.

But only the triglyceride level is required for approval for.

For this indication.

Got it. Thank you that's very helpful.

The next question comes from Esther <unk> with UBS. Please go ahead.

Hey, Thank you for taking my question.

I have a couple of I'll start off with the Angelman program can you talk about that.

Operator: Can you talk about that program and give it some color on how your molecule is perhaps different from some of the others in the clinic, and anything you can share on the route of administration or other considerations as you're planning your trial and enrollment would be helpful. And then have a couple quick follow-up questions. Sure, I'll ask Eric to talk earlier about what we know about how our molecules are different. We're very excited to get the study up and running by the end of this year.

Graham and give us some color on how your molecule is perhaps different from some of the others in the clinic and maybe anything you can share on the radically administration or other considerations that you are putting your trial and enrollment would be helpful.

A couple of quick follow ups.

Sure I'll ask Eric to talk a little about what we know about how our molecule is different.

We're very excited to get the study of running by the end of this year.

Operator: And as, you know, we dose most of our drugs for neurological diseases, our drug will be dosed interestingly. And Eric Bunch talked a little about what we know about how we are different. Yeah, sure. So the mechanism that we're utilizing is the same as some of the other innocence molecules in the clinic. This is a mechanism that we pioneered along with our academic collaborators in lowering the ice transcript and increasing the expression of UBE pre-A, different deficits of which are causal for Injel syndrome.

And as you know we dose for most of our drug for neurological diseases, our drug will be dose interests equally.

And.

And Eric Bunched up a little bit about what we know about how we are different.

Yes sure.

The mechanism.

Utilizing is the same as some of the other <unk> molecules in the clinic.

This is a mechanism.

Pioneered along with our academic collaborators and lowering the highest since transcript and increasing expression of <unk>.

Eric E. Swayze: And we spent a fair amount of time optimizing our molecule and trying to find the most potent and best tolerated and safest molecule we could find, and we obviously have a different molecule than our competitors in the space. The chemistry and technology we use is the same as our other neurology drugs, the same chemical modification that's in Spirasa, and we're optimistic that the profile of our drug will look like our MAPTA, which we released some data on early this year and has been performing great. So hopefully, we'll have a best in class molecule that can address this disease. I got it.

Deficits are which are causal for instruments syndrome, and we spent a fair amount of time optimizing our molecule trying to find the most potent and best tolerated and safest molecule, we could find and obviously have a different molecule than our competitors in the space.

The chemistry and technology, we use is the same as our other neurology drugs.

Same chemical modification that same spirit spin rosin.

Domestic is the profile of our drug will look like.

<unk>, which we released some data on earlier this year and it's been performing great. So hopefully we will have a best in class molecule that can address this disease.

Got it.

Brett P. Monia: And then on the personal FDA discussions, can you share your expectations on the timing for an update and what a realistic outcome could be from these discussions? Yeah, Esther, I wish I could, but I can't because Bayigen has not stated any point in time at which they plan to provide an update on the next step. You know, I can just, what I'll do is just remind you that what we have said, what June has said, and Ionis has said, is that we're still, we remain very encouraged.

And then on the pet person FDA discussions can you share your expectations on the timing for an update and what are realistic.

Some could be from this discussion.

Yes, Sir.

I wish I could but I cant because.

Biogen has not stated any point in time in which they plan to provide an update on the next steps.

I can just what I'll do is just remind you there.

What we have said what Biogen has said and <unk> said is that we're still we remain very encouraged as we said in our opening remarks by the totality of the data.

Brett P. Monia: As we said in our opening remarks, by the totality of the data, they continue to engage regulators to review the data, discuss potential next steps, and they're planning to open up the expanded access program to all sideline AILA's patients based on the high-end medical need in the safety prophecy.

They continue to engage regulators on.

To review the data discuss potential next steps and they are planning to open up the expanded access program to all side one else patients based on the high unmet medical need and the safety profile and the totality of the data, but there is no specific point in time in which I'm updates have been stated.

Brett P. Monia: But there is no specific point in time at which updates have been stated as of yet. Got it, thank you. And then lastly, if you can give us any color on the Flamingo Agreement that was in the press release this morning and what sort of milestones that could be that should be on our radar. Yeah, let me just provide very briefly the strategy here.

As of yet.

Got it. Thank you and then lastly, if you can give us any color on the Flamingo agreement that was in the press release this morning.

What.

Set of milestones.

Could be that should be on our radar.

Yeah.

Let me let me just provide for very briefly the strategy here.

Brett P. Monia: You know, we have a rich pipeline, as you know, and what we are moving towards doing as a very high priority is to focus in those areas where we think have the potential to bring the greatest value to IONIS and all stakeholders. And those areas are in cardiovascular disease, and in certain indications like heredoridema where we think we have a best in-class molecule disease, neurology, and in certain indications like hereditary angioidema, where we think we have a best in-class molecule, oncology, although we've had a long history in oncology, and we've made great progress there, and we are enthusiastic about the drugs that moved over to Fomingo.

No.

We have a rich pipeline as you know.

<unk>.

What we're what we are moving towards doing is a very high priority is to focus in those areas, where we thank him for his attention to bring the greatest value to our owners.

To all stakeholders.

And in those areas are in cardiovascular disease, neurology and in certain indications like hereditary angioedema or we think we have a best in class smaller.

Oncology.

Though we've had a long history in oncology and we've made great progress there and we are enthusiastic about the trucks have moved over to Flamingo.

Brett P. Monia: Oncology drug development requires substantial investment and laser focus to give those drugs the best chance to win. Based on our commitment to focus on those therapeutic areas where we think bringing them will have the greatest success, we divested our oncology pipeline and moved it into a company that we helped create both Flamingo Therapeutics, and we're confident that Fomingo will do a very good job with the drugs that we moved over. The Flingo, we obviously have a vested interest economically and otherwise in Flemingo and in seeing those drugs go forward. And we're very much involved in the Flingo. As far as milestones in those sorts of economics are concerned, I don't know if those have been disclosed, Beth. No, they're not public.

But.

Culture drove zellner requires substantial investments and laser focus to give those drugs the best chance to win based on that.

Our commitment to focus on those therapeutic areas, where we think premiums will have.

<unk> success, we divested our oncology pipeline and moved it into a company that we help create both Flamingo therapeutics.

And we're confident definitely will do a very good job.

Drugs over the Flamingo, you, obviously have a vested interest economically.

And otherwise.

And Flamingo and see those drugs go forward.

And we're very much involved and with Flamingo.

As far as milestone.

And those sorts of economics.

Those have been disclosed.

No they are not public.

Elizabeth L. Hougen: And just to maybe amplify what Brett said, what we're, when you think about the economics in this transaction, the real value, in our view, is the ability of Flamingo to fund and advance these medicines for a variety of different cancers and to move them forward, you know, with a sole focus on oncology, which I think really helps us internally focus our energies in cardiometabolic and neurology in particular. And so the economics, I think, are, you know, really less about the milestones and more about the long-term value of those medicines and the long-term economics, as well as the equity investment we have in the company.

Just to maybe amplify on what Brad said, what we are.

When you think about the economics in this transaction.

The real value in our view is the ability of Flamingo to fund and advance these medicines for a variety of different cancers.

And to move them forward with that.

With a sole focus in oncology, which which I think really helps us in.

Internally focus are our energy in cardio metabolic and neurology in particular.

And so the economics I think are.

Really less about the milestones and more about the long term value of those medicines in the long term longer term economics as well as the equity investment we have in the company.

Elizabeth L. Hougen: Got it. So should we be thinking about this as an Axia model where it's spun out from an R&D standpoint, and then eventually, you'll decide whether to bring it back into the IONIS fold? No, not at all.

Got it so should we be thinking about this as an ex via model, where it's spun out from an R&D standpoint, and then eventually you'll decide whether to bring it back into the eye on this phone.

Elizabeth L. Hougen: So Mingo is an independent company. We have equity ownership, but it's, you know, less than 20%. So I would not. This is not an Anexian model, and that's not a model we intend to follow going forward. The next question comes from Yara and Werber with Cowan. Please go ahead. Hi, thanks for taking the questions. This is Brendan on for your own.

No not at all so Nico as an independent company, we have an equity ownership, but it's a it's less than 20%. So I would not this is not a.

And <unk> modeling and that's not a model we intend to follow going forward.

Yes.

Understood. Thank you very much.

Okay.

Yeah.

The next question comes from Yaron Werber with Cowen. Please go ahead.

Yeah.

Hi, Thanks for taking the question. This is Brendan on for your on just I think a couple quick ones from US first mostly in AG actually.

Operator: Just, I think, a couple quick ones from us. First, mostly in H.A.E., actually. I was wondering what you might be able to tell us about the design of phase three. I know this is kind of an increasingly crowded space at this point, and I guess we're also kind of wondering where you really see the bar on advocacy for phase three, not really just for approval, but maybe more so to really kind of differentiate yourself from some of these other stage and commercialized assets. Sure.

I was wondering what you might be able to tell us that the design of the phase III I know this is kind of a increasingly crowded space at this point and I guess, we're also kind of wondering where you really see the bar on efficacy for the phase Iia not really just for approval, but maybe.

Maybe more so is it really kind of differentiate yourself from some of these other late stage and commercialize that.

Sure I'll ask Richard to talk little bit about the phase III design and also in Asia on what we expect to get out of this study to win on the market with this potential best in class target again.

Richard S. Geary: I'll ask Richard to talk a little bit about the phase three design and also an Aesda on what we expect to get out of the study to win on the market with this potential best-in-class drug. Again, a lot of the data, and a significant amount of new data, will be presented this weekend at a medical meeting. And I think that data will demonstrate why we're so excited about Doni DeLarsen as a potential best-in-class medicine that we think will be the best treatment for H.A.E. What can we share on phase three design, Richard? Yeah, so the phase three design is really patterned fairly closely after phase two.

The data.

A lot of the data.

A significant amount of new data will be presented this weekend at.

At a medical meeting and I think that data will demonstrate why we're so excited about.

Don't need to Larsen.

A potential.

Potential best in class Medicine that we think will be the best treatment for <unk>.

Look we share on phase III design Richard.

Yeah. So the phase III design is really patterned fairly closely after the phase two.

Richard S. Geary: These are going to be patients that are treated who have frequent attacks; it'll be placebo control of court, and patients will then get the treatment, and we'll be looking at the percent of patients that go completely attack-free. One of the reasons we think this drug has really demonstrated in phase two that it is, in fact, potentially best in class is that nearly all the patients went completely attack-free. And now they've rolled over into open label and gone long-term attack-free, which is very different from the current standard of care in the industry for prophylaxis.

Is it going to be patients that are treated who have frequent attacks.

It'll be placebo controlled of course.

And patients will then.

Get the treatment and we'll be looking at.

Percent of patients that go to completely attack free one of the reasons. We think this drug has really demonstrated in phase two that it is in fact potentially best in class is that nearly all of the patients went to attack free and now they are.

Rolled over into open label and have gone long term attack free, which which is very different from the current standard of care.

In the industry and prophylaxis.

So we're excited about it the design of the study if you follow.

Richard S. Geary: So excited about it, the design of the study, if you follow a little bit more the data that's going to be released this coming weekend, you'll see the design of that study and the endpoints very, very soon. Thanks for Triton. Oneesa?

A little bit more of the data that's going to be released this coming weekend youll see the design of that study and the endpoints are very very similar.

Thanks Julien.

Onaiza Cadoret: What are you looking for to win on the market? Yeah, it's a winning profile from what we've seen from the phase two data, as Richard just expressed. We've done some really thoughtful work in understanding kind of where the unmet need is, given the market and where kind of the uptake has been. You know, I think there are three dimensions that are really emerging, and we actually meet all of them. The first one is that, you know, when you're looking, the name of the game is zero attack rates, and the sooner, more confident they are, and the less anxiety that's putting on the patient

What are you looking forward to win on the market.

Yeah, it's a it's a winning profile from what we've seen from the phase II data as Richard just expressed we've done some really thoughtful work in understanding kind of where the unmet need is given the prophylactic treatments currently on market and where kind of the.

Uptake has been and.

There is three dimensions that are really emerging and we actually meet all of those three dimensions. The first one is that.

When youre looking at is the name of the game is zero Tac rates and the sooner you can get patients to a zero tax rate obviously, the more confident they are and the less anxiety, that's putting on the patient and we just do that.

Onaiza Cadoret: And we just do that, you know, really well at the onset of We also show really great data on a tax rate of 92% in weeks 5 to 17, which is also going to be very important in terms of adoption. And then lastly, this is a market that has injections that are two to four weeks, high injection site reactions, and do think that the convenience is really valuable. Very exciting product. Thanks, Nasea.

You know really well in our phase III as we get to Max clinical onset of efficacy better than than the other agents that are out there and we hope to replicate that in the phase threes.

We also as Richard said show a really great data.

Attack free 92% in weeks five to 17, which is also.

Going to be very important in terms of adoption and then lastly.

Market that has you know injections that are two to four weeks are highly viscous and.

And injection site reactions and do you think that the convenient profile that this offers in addition to the efficacy is can be really valuable in terms of adoption of our agent out there so very exciting product.

Looking forward to moving this forward.

Thanks, Nathan we're also looking forward to sharing in more detail the phase III design and our go to market strategy.

Brett P. Monia: We're also looking forward to sharing in more detail the phase three design and our go-to-market strategy at our investor day in December. So stay tuned for that. All right, great. Thanks very much.

Our Investor day in December so stay tuned for that.

Alright, great. Thank you very much.

Operator: The next question comes from Josh Schimmer with Evercore ISI. Please go ahead. Thanks for taking the question, Beth. I just want to clarify the operating expense guidance for the rest of the year. I guess it assumes a pretty significant step-up quarter over quarter, especially if we adjust for the bicycle payment in the third quarter. I know you said you were starting up some trials, but it's still a pretty sizable jump. Maybe you can elaborate on the driver's comment. Sure, happy to.

The next question comes from Josh Shanker with Evercore ISI. Please go ahead.

Great. Thanks for taking my question I just wanted to clarify.

Operating expense guidance for the rest of the year I guess, it assumes a pretty significant step up quarter over quarter, especially if we adjust for the for the bicycle payment in the third quarter. I know you said youre starting up some some trials, but it's still a pretty sizeable jump maybe you can elaborate on the drivers for that.

Sure happy to.

I think youre right focus on our late stage pipeline on the fact that the that the phase III.

Elizabeth L. Hougen: I think you're right, focus on our late stage pipeline and the fact that the phase three pipeline has continued to grow and continue to mature. So if we start with Terson, the polyneuropathy study is fully enrolled now. We announced that in our second quarter earnings call.

<unk> has continued to grow and continue to mature. So if we start with that one first in Polyneuropathy study is fully enrolled now we announced that.

In our second quarter earnings call. So that is that its most expensive phase with data expected mid next year.

Elizabeth L. Hougen: So that is at its most expensive phase with data expected mid-next year. The cardiomy study continues to enroll nicely, and as you heard, Brett said, with complete enrollment next year.

The cardiomyopathy study continues to enroll nicely and as you heard Brett say with <unk>.

Complete enrollment next year. So again, that's bad expenses is growing.

Elizabeth L. Hougen: So again, that expenses are growing pretty sizably, particularly given that that is the largest outcome study in that patient population ever conducted. It's 750 patients. And then as you think about olizarcin, we've got the FCS phase three study ongoing and continuing to enroll patients. Severe high triglycerides is getting up and running in that core phase three study. And when we start a study, we tend to have a bolus of expenses just to get the study up and running, and then those expenses grow as we enroll more and more patients. And then, of course, PKK, phase three, will be getting.

Pretty sizable, particularly given that that is the largest outcome study in that patient population ever conducted at 750 patients and then as you think about all this arson.

We've got the FCS phase III study ongoing and continuing to two enrolled patients.

Severe high triglycerides is getting up and running that core phase III study and when we started the study.

We tend to have a bolus of expenses.

To get the study up and running and then those expenses grow as we as we enroll more and more patients.

Then of course, PKK phase III will be getting underway.

Elizabeth L. Hougen: underway here very shortly, and again we'll have those startup expenses that will be a bolus in the fourth quarter. So as you can see, just a lot of study starts and late stage studies, which are all, you know, quite expensive. And then as we move into next year, we're going to continue to build on that as the studies continue to enroll, and as we have new studies, particularly related to Ola-Barsen, and we build out that phase-free program. So that's why we see continued growth into the fourth quarter and beyond in R&D. The next question comes from Gary Knockman with BMO Capital Markets. Please go ahead.

Here very shortly and as and again, we'll have those startup expenses that will be a bolus.

In the fourth quarter.

So as you can see just a lot of study starts and late stage studies, which are all quite quite expensive and then as we move into next year, we're going to continue to build on that as the studies.

Continue to enroll.

And as we add new studies, particularly related to <unk> and we built out that phase III program.

So that's why we see continued growth into the fourth quarter and beyond that in R&D.

Okay. Thank you.

Sure.

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

Operator: Hi, thanks for taking the questions. So first on Eplonterson for TTRPN, depending on the data from phase three mid-next year, how do you expect it to be used in that market? How much could it potentially expand addressable patients relative to Tegsetti? And how will you promote it? Will you rebuild your infrastructure there?

Hi, Thanks for taking the questions. So first on Epsilon person for TCR T and depending on the data in the phase III mid next year, how do you expect it'll be used in that market how much could it.

Potentially expand addressable patients relative to Chegg study and how will you promote it will you rebuild your infrastructure there.

Operator: And then on SpinRaza, just how long do you think it'll take for biogen to run the Ascente study? Is that something that could potentially update the label? And are physicians currently using higher doses on their own for RISD failures to the extent that you're aware of that? So I'll ask Amaze, as a comment, a little bit about why we think we have the opportunity to win on the market. And if I could take the liberty, I would like to talk not just about polyneuropathy but also about my opportunity with that von deris.

Then.

On spin Ross just how long you think it'll take for Biogen to run. The offense study is that something that could potentially update the label and our physicians currently using higher dose thing on their own for risky failures to the extent that youre aware of that.

So.

Our.

S Amazes would come out a little bit why we.

How do we think we have the opportunity to win on the market and take the Liberty I would like to talk about not just about polyneuropathy, but also.

We've got one person, but I will remind I want to remind you first that this is.

Operator: But I will remind you first that this is a LICA medicine that has all the advantages, has the highly attractive profile of all of our LICA medicines. There's very infrequent once-monthly, up to low volume, injections, at home, with an auto injector, with a pristine, excellent safety profile.

Leica.

Madison.

It has all the advantages.

Highly attractive profile of all of our like a medicine says it very infrequently once a months of Q low volume <unk>.

Jackson at home with an auto injector.

Pristine excellent safety profile.

Brett P. Monia: And as I mentioned, as we've seen with all of our drugs, in our phase one study, we were getting TTR reductions on the order of up to 90%. In the phase one study, that you can compare to about 70, 75% in the Turson Tech study. And we think it's a profile that will translate into even greater efficacy. So we're excited about the profile, and we're also excited about the market, and we're working on our plans to move into the market with Bonterson. And I'd like an Ane who could maybe talk a little bit about our strategy there.

And as I mentioned as we've seen with all of our drugs in our phase one study, we're getting ctr reductions on the order of up to 90% in the phase one study.

You can compare to about 70, 75% for in the <unk> study and we think that will translate into even greater efficacy. So we're excited about the profile and we're also excited about the market and we're working on our plans to.

The move into the market.

If one person.

Maybe talk a little bit about our strategy there.

Onaiza Cadoret: Yeah, I'd be happy to. So, you know, as we think about launching with the initial, really important to know that kind of advancing their thinking about that will emerge a lot in our market as well. And there's increasing recognition that the whole burden and prevalence of Polyneuropros mixed fetus, also really critical to address. So if you think about that, you know, overall you've got 40,000 patients initially, both in heredity, are that Currently, I think only 10 to 15% of these patients are receiving treatment, so they're, And, you know, as to your question, last generation and second generation, we know that, you know, the first generation silencers just didn't really have the ability to kind of seamlessly integrate into a patient's lifestyle, and this will be well above and beyond that.

Yeah, I'd be happy too so you know.

As the as we think about launching with the initial indication it's really important to know the market is really kind of advancing their thinking about this disease is a systemic disease and we've seen that a lot in our market research and just talking to our kols as well.

And there is increasing recognition that the whole burden and prevalence of Polyneuropathy mixed phenotype patients is also really are critical to address so if you think about that overall, you've got 40000 patients initially both in hereditary H T T R.

We will be focusing in on currently I think only 10% to 15% of these patients are receiving treatment.

There continues to be a lot of opportunity and unmet need.

And you know as to your questions in last last generation and second generation. We know that you know the the first generation silencer as just didn't really have the ability to kind of seamlessly integrate into a patient's lifestyle and.

This will be well above and beyond that so I think that's a very exciting place to be in terms of how we're looking forward to being on the marketplace. In addition, you know the.

The broad part of the market is and wild type cardiomyopathy.

Onaiza Cadoret: So I think that's very important. In addition, you know, the broad part of the market is in wild-type cardiomyopathy. We are well positioned to win in the marketplace because of our clinical trial and the ability to generate clinical data with and without standard of care, and we think that will help physicians if they actually have patients who are naive. We'll have the data for that. They have patients who are already on stabilizing medication.

There we are.

Well positioned to.

A win in the marketplace because of our clinical trial and the ability to generate clinical data with and without standard of care and we think that will broadly position.

Person.

For physicians, if they actually have patients who are naive we will have the data for that they have patients who are already on on on a stabilizer will have the data for that so they can make the right decision for their patients. So I'm really looking forward to that plant or some getting into the marketplace.

And.

Regarding ascend Gary so.

Onaiza Cadoret: And regarding a send, Gary, We are not aware of any patients, I estimate patients that have been treated with higher doses that have been on the sand, that have been on risk of plan previously. I would know that if that would happen.

I'm not we are not aware of any.

Patients SMA patients that had been treated with higher dose that have been on this thing that had been on risk defined previously advised you would know that if that were to happen I doubt very much with that because the devote study is just it's in process, which is examining the higher dose of spin around so in a controlled study.

Brett P. Monia: I doubt very much what happened because the dedicated study is just, you know, it's in process, which is examining the higher dose of Stenrasa in the controlled study. And as a reminder, this is a study of the higher dose of Spinraza, I think it's 28 noograms, and in patients that were on reciproplanned who have chosen to be washed out of the transplant and go on to a higher The assumption, of course, is that patients feel like they need better control of their disease.

And as a reminder, ascend is a study of the higher doses and Raj I think it's 28 milligrams.

In patients that are on or is the plan to have chosen to.

It'd be washed out or is the plan to go on to a higher dose that's been roster.

The assumption of course is that patients feel like.

They need better control of their disease, so they're moving on to <unk>.

Brett P. Monia: So they're moving on to Spinraza, and we'll try the higher dose study, which has already cleared the dose escalation portion of the devote study showing safety, and now it's the randomized portion of the study. And then in addition to vote and ascend, we also have the response study in patients that are ongoing with bygents conducting in patients that have run gene therapy, they had a subal response, and then went on to Spenraza at the commercial dose. Okay, that's helpful. Thank you. The next question comes from Jessica Fye with J. Morgan. Please go ahead. Hey guys, good morning.

Tried to higher dose study, which has already been cleared the dose escalation portion of the devote study shown safety and that was in the randomized portion of the study.

And then in addition.

To devote and sand. We also have the response study in patients that are that's ongoing with Biogen is conducting in patients that were on gene therapy to have a suboptimal response, and then went on to spin Rosa at the commercially and had the commercial doses.

Right.

Okay. That's helpful. Thank you.

Yes.

Next question comes from Jessica Fye with Jpmorgan. Please go ahead.

Hey, guys. Good morning, Thanks for taking my questions. Just two first how should we interpret the IGF one AUC data for similar Sun in Acromegaly can you talk about how these patients IGF one levels look relative to the upper limit of normal after treatment and then on Pts canine.

Operator: Thanks for taking my questions. First, how should we interpret the IGF1 AUC data for Simdilerson in Akramegaly? Can you talk about how these patients' IGF1 levels looked relative to the upper limit of normal after treatment? And then on PCSK9, thinking beyond the subcutaneous version to an oral, are you still eager to pursue that path, or is it still too early to say? and assuming you'll eventually need an outcome study for either agent, would you envision ultimately developing both sub-Q and oral in parallel or choosing one over the other? Thanks. Let me try it, thanks, Jess.

Thinking beyond the sub Q version, two and oral are you still eager to pursue that path or is it still too early to say.

I'm, assuming you'll eventually need an outcome study for either agent would you envision ultimately developing both sub Q and oral in parallel or choose one over the other thanks.

Let me thanks, Jeff I'll take that Tcf's canine and I'll ask Richard to comment on and provide a more fulsome sort of summary of.

Brett P. Monia: I'll take PCSK9, and I'll ask Richard to comment on and provide a more fulsome sort of summary of the acromegaly data with HRL. So for PCSK9, as we said in the script, that Astrosendigo Plans will give an update in a couple of weeks on the days one study in patients with high cholesterol. They're very excited about this study, and the other two studies are essentially complete now as well. They're trying to share results from phase two next year. This is the subcube formulation once a month.

The acromegaly.

Data with THR out so.

Tcs canine.

As we said in the script there.

Astrazeneca, perhaps quite up the a J a couple of weeks on the phase one study in patients with high Quest are all very excited about this study the phase III studies are essentially complete now as well I have to share results from the phase two next year. This is the <unk> formulation once a month favorably.

Brett P. Monia: They believe that this is, and we believe, based on all the data we've seen, that this is a, this has the high potential to be the best in-class PCSK-9 inhibitor of anything that is out there today. They do plan to conduct, are planning to conduct several phase three studies, including a cardiovascular outcome trial. And they are actually building a comprehensive program to win in this market.

And we believe based on all the data we've seen.

This is a.

This has the potential to be the best in class pieces canine inhibitor of any thing you guys out there today.

They do plan to conduct.

Our planning to conduct several phase III studies, including a cardiovascular outcome trial.

And they actually are building a comprehensive program.

To win in this market because they do think that this drug has the best lower.

Brett P. Monia: They do think that this drug is the best lower, a lowering agent for PCSK9, and that will correspond to the best LDL lower effects, too, which we're seeing in patients and in normals. Regarding oral, it's not part of the PCSK9 program today. They're, they're, uh, is a.

Lowering agent for Pcs canine and.

Will correspond to the best LDL lowering effects to which we're seeing in patients.

Normals.

Regarding oral.

It's not part of the <unk> program today is there.

There is 100% committed in the sub Q formulation today with that said, we and Astrazeneca.

Brett P. Monia: Z is 100% committed to the subcQ formulation today. With that said, we in AstraZeneca are working on oral delivery as a platform play, not necessarily a PCSK9 play, but a platform play. As you know, we have several drugs in development and research with AstraZeneca, and we continue to work on oral delivery, and we're somewhat optimistic about the progress we're making with different oral. But it's not specific to PCSK9.

Our working on oral delivery as a platform play not necessarily a <unk> play, but a platform play as you know we have a we have several drugs in development and research with Astrazeneca.

And we continue to work on oral delivery and we're somewhat optimistic on the progress we're making your floor, but it's not a specific feature and they believe that this subdued drugs is a winner on the market and that's what they're focused on specifically of course any learnings for moral you always think about for the future of the desktop or focus.

Brett P. Monia: They believe that this subcutaneous drug is a winner on the market, and that's what they're focused on specifically. Of course, any learnings from oral can always be thought about for the future, but that's not Go. Okay, Simda Larson.

Okay <unk>, let me just take you through a few things.

Richard S. Geary: Let me just take you through a few things. I think it's very important to look at the data that we were able to achieve significant growth hormone lowering. So look at growth hormone binding protein, which is a surrogate measure for the target itself, with no changing growth hormone. So that's a very significant thing.

Yeah, I think it's very important looking at the data that we were able to achieve.

Significant growth hormone lowering so look growth hormone binding protein, which is a surrogate measure for the targeted cell.

With no change in growth hormone. So that's a very significant thing these patients.

Richard S. Geary: These patients, to get to your question, were uncontrolled on some antistatants. So they were resistant to or recalcitrant to standard of care treatment. Their levels of IGF1 were two to threefold higher than the upper limit of normal. As you probably know, getting them below 1.

To get to your question.

We are uncontrolled on somatostatin, so they were resistant to or recalcitrant to standard of care treatment.

Their levels of IGF, one where two to three fold higher than upper limit of normal.

As you probably know getting them below one five X upper limit of normal is kind of the goal.

Richard S. Geary: And so we looked at AUCR integration of IGF1. What that shows is that you're getting a lowering of IGF1 that was actually significant at the highest dose compared to placebo, and placebo is going up. So these patients who are recalcitrant to somatosatin analogs continue to get worse, and on our drug, we're getting better. So the drug is lowering IGF1. The levels that they came in at were like 400 nanograms per milliliter, if you're familiar with the levels of IGF1, normal would be 200, and I'm generalizing because the levels are determined by sex and age, so they can be different for each individual.

And so the we looked at AUC or integration of IGF, one what that shows is that youre getting.

Lower ring of IGF one.

That was actually significant at the highest dose.

Compared to placebo and placebo is going up so these patients who are recalcitrant to somatostatin analogs.

Continue to get worse.

And on our drug we're getting better there.

The drug was lowering IGF one.

The levels that they came in.

We're like.

400, nanogram per Mil, if you're familiar with the levels of IGF, one normal would be 200.

And I'm.

Generalizing because the the levels are.

Determined by sex and age so it can be different for each individual but around 200 would be normal.

Richard S. Geary: But around 200 would be normal. 1.5 would be 300. Most of these patients came in around 400. So you really want to get these patients under 300, and you want to be able to lower their IGF1, and in this case, intercalcitrant patients. We were able to do that, and I think it's very encouraging, in the hardest-to-treat patients. Of course, it's not the end of the story.

The 1.5 would be 300 most of these patients came in around 400.

So you really want to get these patients under 300.

And you want to be able to lower their IGF, one and in this case and recalcitrant patients.

We were able to show that and I think it's very encouraging.

In the hardest to treat patients of course, it's not the end of the story, we have the OLED, where we're extending treatment.

Richard S. Geary: We have the OLE where we're extending treatment in these patients, as well as looking at naive patients or patients who are not on somatosan analogs, which is another population. Many who have either failed somatistan analogs are no longer on treatment or are naive coming in and just having their surgery but still being IGF1 uncontrolled. Yeah, thanks, Richard. I'll just add a couple of things, it might work while adding a couple other things.

Treatment in these patients as well as looking at.

<unk> naive patients or patients who are not on somatostatin analogs.

Which is another.

Population, many who have either failed somatostatin analogs no longer on treatment or are nave coming in and just having having their surgery, but still being IGF one uncontrolled.

Yeah, Thanks, Richard and I will just add in government it might be worthwhile, adding couple of other things one.

Brett P. Monia: To our knowledge, no one's ever studied a drug to get IGF1 under control in this recalcitrant patient population. So, you know, in somatos fat and failure. So we're really, you know, pioneering a new patient population here. So, you know, any IGF1 lowering, let alone getting some patients in the normal range, is a huge benefit. We're also seeing signs of improving quality of life that will continue to focus on as we go through the Open Label extension. And, very importantly, we didn't see any increases in growth hormone as a consequence of inhibiting the growth hormone receptor.

To our knowledge no one's ever studied a drug.

IGF one other controlling this in this recalcitrant patient population so.

Matt a statin failures. So we're really pioneering a new patient population here so.

Any idea of when lowering let alone getting some patients in the normal range.

Abuse benefits.

We're also seeing signs of improvement in quality of life that will keep we will continue to focus on as we go through the open label extension and very importantly, we didn't see any increases in growth hormone is a consequence of inhibiting the growth hormone receptor and that's very important because elevation of growth hormone.

Brett P. Monia: And that's very important because elevation of growth hormone can contribute to tumor growth. And that's the last thing we want to do, and we didn't see it, so we were very pleased about that. Thank you. The next question comes from Joseph Stringer with Needam and Co. Please go ahead. Hi everyone, thanks for taking our questions. Just a quick follow-up on phase three HEE. Just curious about your thoughts on potential enrollment rates and when that trial could potentially be fully enrolled. Thank you. Which study was that, Joey? Oh, the AJE. Yeah, the AGEE.

Can contribute to tumor growth.

And that's the last thing we want to do and we didn't see it. So we're very pleased about that.

Thank you.

Thanks Jess.

Yeah.

The next question comes from Joseph Stringer with Needham <unk> co. Please go ahead.

Hi, everyone. Thanks for taking my questions just a quick follow up on the.

Phase III <unk> just curious in your thoughts on.

Potential enrollment.

Enrolment rates and when that trial could could potentially be.

Thank you.

Which I think was that Tony.

Hey, a J E T.

Thank you.

Operator: Yeah, you know, I don't think we put that out yet, Joe, on when we expect to complete enrollment in that study. I think we have said, potential launch in the 2024 timeframe. I think it was on our, yeah, I think we've said that, but we haven't put out without specific timing on completion of enrollment and so on. So, sorry, I just can't give you that level of detail.

Yeah.

Sure.

I don't think we've put that out yet.

On when we expect to complete enrollment in that study.

I think we have said.

The launch in the 2024 timeframe.

Think it was on our yeah, I think we've said that but we haven't put a specific timing on completion of enrollment and so on.

So.

Sorry, I, just couldn't get to you that level of detail but.

Brett P. Monia: But as you know, we're getting that study started this year, and we were very successful in enrolling that study very expeditiously, the Phase II study, very expeditiously. As Richard said, there's a lot of enthusiasm for this profile with this drug. And also, I'd like to remind you, you know, probably something else we should mention is that we continue the open-label extension, evaluation of patients from the open-label extension of the phase two study that will be, the full phase two study we presented on Sunday.

As you know, we're just getting that study started this year.

And we were very successful enrolling that study very expeditiously the phase II study very expeditiously and us.

But you said, there's a lot of enthusiasm for this profile.

For this drug.

Also remind you.

Probably something else, we should mention that we continue the open label extension evaluation of patients from the open label extension from the Phase two study that will be.

Before the phase II study will be presented on Sunday.

Brett P. Monia: But the open label extension will continue to follow from that. We have excellent, excellent participation in that OLE. People want this drug. And we're looking forward to sharing more data next year in the first half and next year of medical Congress as well, safety, quality of life, and other data to complement what we're going to present on Sunday. It really looks like a winner.

But the open label extension, we are continuing to follow up on that with excellent excellent participation in that oily people want this drug and we're looking forward to sharing more data next year in the first half of next year of medical Congress as well OE quality of life and other data to complement what we're gonna presented.

Sunday really looks like a winner.

Operator: Great. Thanks for taking our question. Thank you. The next question comes from Luca EC with RBC. Please go ahead. Oh, great. Thanks so much for excusing me. I have three questions, all pretty quick.

Great. Thanks for taking my question.

Thank you.

Okay.

Okay.

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

Oh, great. Thanks, so much for squeezing me in I have three questions all pretty quick wondering if we'll see three the other one on acromegaly and get them out on the Faas last so April C. Three obviously greater just starting to phase III study on patients that have triglycerides above 500 milligrams per deciliter is there a future plan to start a trial also in patient.

Operator: One on APOC3, the other one on Acromegroly, and the other one on Fuzzy ALS. So APOC3, obviously, great if you're starting to phase three study on patients that have triglycerides above 500 milligram per decid. Is there a future plan to start a trial also in patients with triglycerides above 150 milligram per deciliter? And if so, are you planning to run a cardiovascular outcome trial there similar to what the SEPA has done? Maybe on acromegaly, you know, an exciting early signal.

With triglycerides above 150 milligram per deciliter, and if so are you planning to run a cardiovascular outcome trial there similar to what Vascepa has been made.

Acromegaly exciting early signal however, it doesn't sound like you're ready to commit to a phase three study quite yet wondering if you can comment on that and maybe what's gating for a go no go decision there and lastly for phosphate I'll ask I know the program is wholly owned and you're already recruiting patients in phase III in light of the toll free.

Operator: However, it doesn't sound like you're ready to commit to a phase three study quite yet. Wondering if you can comment on that and maybe what's gating for a go-no-go decision there. And lastly, for FOSALS, I know the program is wholly owned and you're already recruiting patients in phase three. In light of this Toferson data, are you planning any protocol amendment to maybe increase the problem of the success of that trial? Thanks so much.

<unk> data are you planning any protocol amendments to maybe increase the probability of a successful trial. Thanks so much.

Operator: Thanks, Luca, for your many questions. I'll ask Richard to comment on, you know, other patient populations that will explore both 150 and outcome trials for proposed arson in a minute. Meanwhile, let me touch on acromegaly and the fuzz.

Thanks, Luca Oh, great questions I'll ask Richard to comment on.

Other patient populations that will explore about $1 50, an outcome trials for our resource and in a minute, let me touch on the acromegaly.

Brett P. Monia: So for acromegaly, as we said, we're going to continue to follow the open label extension together as much data in the refractory patient population as we possibly can through next year. In addition, next year, the monotherapy. data I would view it as front line but some of those patients as Richard said failed on somatostatin and then come in washed out so it's a monotherapy trial that data will read out next year and the next steps are to look at the totality of the data the data the somatostatin failure study the open label from that study and then the monotherapy and decide on the next step with that program, which would be a phase three trial.

So for acromegaly.

<unk>.

As we said we're going to continue to follow the open label extension to gather as much data in the refractory patient population.

What we can through next year.

In addition next year the monotherapy data.

I would view it as frontline, but some of those patients as Richard said failed on somatostatin and then come in.

<unk> now so it's a monotherapy trial that.

That data will read out next year.

And the next steps are to look at the totality of the data.

The somatostatin failure study open label from that study in the monotherapy and decide on.

The next step for that program, which would be a phase III trial, what's the right patient population. So I guess in a nutshell you can add you can expect an answer to your question on are we go into phase III.

Brett P. Monia: So I guess, in a nutshell, you can ask and you can expect an answer to the question, "Are we going to phase three with Cindy Learson next year?" And if so, what's our strategy?

With sinter Larrison next year and if so what's our strategy.

Brett P. Monia: The monotherapy population is the most attractive opportunity over the refractory population, but we'll see. We'll see what the data looks like. Regarding FUS ALS, absolutely, we've already learned so much from the Toferson trial that's going to help and inform us on the design of our ALS clinical trials in the future to further optimize them. I'd just be very clear in our view.

Monotherapy population is the most attractive opportunities.

Over the refractory population, but we will see we'll see what the data looks like.

Regarding.

Plus AOS are absolutely we've already learned so much from the October some trial, that's going to read.

And inform us on the design of <unk>.

Our ALS clinical trials in the future to further optimize them I'd just be very clear in our view. We believe the drug did everything that was supposed to do what we need to do is figure out how best to prove the efficacy of <unk> in all of our AOS drugs by designing an optimal or more optimal clinical trial.

Brett P. Monia: We believe the drug did everything it was supposed to do. Now, we need to figure out how best to prove the efficacy of Toferson and all of our ALS drugs by designing an optimal, a more optimal clinical trial. We're exploring brand new areas here, and we're learning a great deal. Some of the things that we've learned from the Toferson trial are this: One, the longer you treat, the better.

We're exploring brand new areas here and we're learning a great deal some of the things that we've learned from the <unk> trial or this one the longer you treat the better number to the earlier treatment and disease progression earlier symptom earlier disease stage is the better off you are and thirdly nerve.

Brett P. Monia: Number two, the earlier treatments in disease progression, the earlier symptoms, the earlier disease states, the better off you are. And thirdly, neurofilament light chain is a better predictor of progression regression rates for fast progressors versus regular progressors. And we're applying all those learnings to all of our ALS trials. And yes, since the bus ALS tri, ataxon 2, the sporadic ALS, and the C9 studies are in phase two. So we have the opportunity to apply those lessons to phase three.

Filament light chain is a better predictor of progression rates for SaaS progressing versus regular progresses, and we're applying all of those learnings to all of our AOS trials and yes since the bus AOS try ataxia too.

Braddock AOS and the C. Nine studies are in phase two so we have the opportunity to apply those to phase III for the plus AOS work still early on in the trial and that gives us.

Brett P. Monia: For the FUS AOS AOS, we're still early on in the trial, and that gives us, and certainly we're planning to make some protocol amendments to incorporate the learning that I just sort of outline for you to maximize my potential for success from that.

Certainly we are planning to make some protocol amendment to incorporate the learnings that I just.

Sort of outline where you maximize potential for success.

For that study.

Good Thank you Brett.

Brett P. Monia: Good. Thank you, Brett. One node on triglyceride lowering and cardiovascular disease at greater than 150 and looking at all the trials that have been done with triglyceride lowering agents, there have been a lot of failures in cardiovascular. Just stated simply, we have no plans to go into a cardiovascular outcome trial with our APOC3 drug. What we know is that remnant cholesterol is a very important component, and it may be that we'll learn something from our phase three programs in this regard that gives us more input on this particular question.

One note on triglyceride lowering and.

Cardiovascular.

Disease at the greater than 150, and looking at all of the trials that have been done with triglyceride.

Triglyceride lowering agents.

Been a lot of failures in cardiovascular.

Yeah.

To state it simply we have no plans to go into a cardiovascular outcome trial with.

With our Apoc III drug.

What we know is that.

Remnant cholesterol is a very important component.

And it may be that we will learn something from our phase III programs in this regard that.

Give us a more input on this particular question.

Brett P. Monia: But right now, that's not where we're going. Lupinoracin, which is both a triglyceride and a cholesterol-lowering agent in mixed dyslipidemia, seems like the best play in that market for actually impacting remnant cholesterol-lowering agents in mixed dyslipidemia. It seems like the best play in that market for actually impacting remnant cholesterol, where we think the bad actor is.

But right now that's not where we're going <unk>.

<unk>, which is both a triglyceride Ana cholesterol lowering agent in mixed Dyslipidemia.

Seems like the best play in that in that market for actually impacting remnant.

Remnant cholesterol, where where we think the bad actor is.

Richard S. Geary: Hope that's helped you. It was super helpful. Very clear. Thanks so much. Thanks, Luca. And I'd like to thank everybody who joined us and participated in the call today. We're looking forward to seeing you again at our virtual Investor Day in December, where we'll discuss, as I said earlier, our commercial plans for several of our most exciting late-stage programs and much more detail. Until then, thanks again for joining us and have a great day. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.

Hope that's helpful.

Super helpful very clear thanks, so much super helpful.

Thanks Luca.

And I'd like to thank everybody, who joined us in participating on the call today, we look forward to seeing you again at our virtual Investor day in December.

<unk> will discuss as I said earlier, our commercial plans for several several of our most exciting.

Late stage programs much more detail.

Until then thanks again for joining and have a great day.

Okay.

Okay.

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

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