Q1 2023 Ionis Pharmaceuticals Inc Earnings Call

So do you need assistance. Please signal a conference specialist by pressing Star then zero. After today's presentation, there will be an opportunity to ask questions to ask a question. You May Press Star then one on a touchtone phone to withdraw your question. Please press Star then two as a reminder, this call is being recorded at this time I would like to.

I'll turn the call over to Wade Walke Senior Vice President of Investor Relations to lead off the call. Please begin sir.

Thank you before we begin I encourage everyone to go to the investors section of the <unk> website to view the press release and related financial tables, we will be discussing today, including 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've also posed.

The slides on our website that accompany today's call.

With me. This morning are Brent Maya Chief Executive Officer, Richard Geary, Chief Development Officer, and Beth Hougen, Chief Financial Officer.

Swayze Executive Vice President of research Eugene Schneider, Chief Clinical development Officer, and <unk>, Chief Global product strategy and operations Officer will also join us for the Q&A portion of the call.

I would like to draw your attention to slide three which contains our forward looking statements. During this call we will be making forward looking language 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.

All over to Brett.

Thanks Wade.

Good morning, everyone and thanks for joining us today.

This year is off to a strong start with several important achievements already especially from our neurology franchise.

Last week, the FDA granted <unk> accelerated approval for the treatment of sod one AOS.

This approval represents a major scientific breakthrough Saudi is the first and only approved treatment to target a genetic form of AOS.

With this approval <unk>, Saudi joined <unk> as our newest product to reach the market for patients with a devastating neurological disease.

In addition to being a tremendous advance for the ALS community. This approval further validates our RNA targeted therapeutic platform to treat neurological diseases that today includes 12 medicines in clinical development.

We also just reported positive data from the phase three neuro transform study of <unk> in patients with <unk> Polyneuropathy.

In this study <unk> was shown to halt neuropathy disease progression with approximately half of patients experiencing improvement in the co primary efficacy endpoints in this plus seven and Norfolk quality of life.

<unk> also demonstrated favorable safety and Tolerability.

Based on the totality of the data we are confident in <unk> strong product profile and has potential to be an important treatment for the largely untapped hereditary <unk> polyneuropathy population.

With these data, we and our partner Astrazeneca are working towards additional regulatory submissions in countries outside the U S.

Of course is in addition to our NDA, which is under review with a <unk> date of December 22nd of this year.

And his amazing discussed during our webcast last week, we're working hand in hand with Astrazeneca to bring this important medicine to the market as quickly as possible.

Our two other near term commercial opportunities our resource and Donegal worsen are also progressing very well.

With <unk>, we remain on track for data from the Phase III balanced study in FCS in the second half of this year.

And we're preparing for our first independent commercial launch in this rare disease indication.

We also continue to make really good progress in our pivotal <unk> studies of <unk>.

With Donegal worsen or on track to complete enrollment in the phase II Oasis study.

Studies soon keeping us on track for data in the first half of next year.

Additionally, our robust late stage pipeline continues to expand now at seven programs advancing nine separate indications with the initiation of phase III development of <unk> in chronic HBV.

Our expanding late stage pipeline sets us up for a steady and growing cadence of data readouts over the next few years, increasing the potential for a substantial number of new <unk> medicines to reach the market.

And importantly, we remain on track to accomplish our key strategic goals across the business and achieve our 2023 financial guidance.

With that I'll turn the call over to Richard to discuss our recent pipeline progress and preview our upcoming key events.

Next Beth will review, our first quarter financial results and then I'll wrap up our prepared remarks before taking your questions.

Richard.

Thank you Brad.

Brett just mentioned we have Matt.

<unk> of goals and key programs already this year, we believe that the positive data we reported from the neuro <unk> transform study demonstrate epsilon persons potential to substantially improve outcomes in patients with <unk> Polyneuropathy Epsilon.

<unk> met all primary and all secondary efficacy endpoints.

Remonstrated consistent benefit for <unk> polyneuropathy patients across a range of important neuropathy and quality of life measures.

<unk> demonstrated robust and sustained reductions in serum <unk> and significant improvements in measures of neuropathy and quality of life with a substantial number of patients demonstrating improvement at both week 35, and <unk> 66.

<unk> also showed statistically significant and clinically meaningful benefit across all four secondary endpoints and continued to demonstrate a favorable safety and Tolerability profile. In addition to publishing results from this study were set to present additional data at upcoming medical conferences.

We and our partner Astrazeneca remain on track for a potential approval in the U S. In December and are preparing regulatory submissions in additional markets around the world for later this year and next year.

The positive efficacy and safety results, we've seen from the neuro <unk> transform study.

Give us even greater confidence for the performance of our <unk> and our ongoing cardio transform study in patients with <unk> cardiomyopathy.

Cardio T transform is the longest and largest study in this indication to date.

Designed to demonstrate benefit in a broad set of patients.

That represents the current treatment landscape, we anticipate completing enrollment mid year.

Our broad <unk> development program for two indications characterized by severely elevated triglycerides FCS and severe hcg is also continuing to progress well the phase III balanced the FCS study is fully enrolled and ring and we remain.

On track for data in the second half of this year.

And our multi study phase III program designed to evaluate <unk> in the broader <unk> indication is also continuing to progress.

Additionally, our Donna Dolores and development program remains on track and we expect to fully enroll the phase III Oasis Hae's study shortly which keeps us on schedule for data in the first half of next year. During the first quarter, we reported additional positive longer term data from the Dod or since.

<unk> open label extension study in patients treated for one year reinforcing its potential competitive profile, which included rapid onset of action with clinically meaningful improvements in quality of life.

<unk> attack protection, and a continued favorable safety and Tolerability profile.

Our neurology franchise includes 12 medicines in development, including two in Phase III studies and eight in phase II I would like to spend a couple of minutes highlighting two of these medicines.

Important recent updates.

As Brett mentioned.

We are pleased that the FDA recently approved <unk>, making it the first and only approved treatment to target a genetic form of ALS.

This is a monumental breakthrough for the AOS community.

<unk> approval was based on the reduction in plasma neuro filament light chain, our NFL a marker of neuronal damage that correlates with disease progression in ALS.

POS patients the approval was supported by the 12 months integrated results from the Phase III <unk> study and the open label extension.

The integrated results showed patients who started treatment earlier experienced a slowing decline in measures of clinical function as well as respiratory and muscle strength.

Additionally, <unk> demonstrated a favorable safety profile.

<unk> is under review in the EU and Additionally, the ongoing phase III Atlas study in pre symptomatic <unk> ALS study patients is also progressing nicely.

We are encouraged by the recent data Biogen presented at the <unk> Conference and published in nature Medicine from the <unk> Phase <unk> study.

Our map T medicine also known as bid the 80.

Is our medicine aimed at reducing the production an aggregation of tau protein associated with disease progression in patients with Alzheimer's disease.

Results in early 80 patients treated for up to 100 weeks showed a rapid substantial and sustained reduction in Tampa pathology.

As measured by both CSF levels.

And Tau pet imaging.

In fact, our map T drug is the first to demonstrate this magnitude of a reduction of Tau pathology across important brain regions today.

Biogen is advancing the phase two study in patients with early AAD.

Which includes two different dose cohorts dosed every six months and one dose cohort dosed every three months.

Our map T. Drug is just one example of advances we are making with our technology to potentially extend duration and reduced dosing frequency for CNS diseases.

And even more broadly.

Our late stage pipeline expanded this year to seven drugs advancing in a total of nine separate indications with the startup of pivotal program for the payer version in patients with chronic HBV.

We expect our late stage pipeline to expand further this year when Roche advances <unk> into a phase III study for Iga nephropathy.

We recently took steps to further focused our R&D efforts and prioritize our pipeline with the discontinuation of two programs Similarly in acromegaly, and <unk> and beta thalassemia.

With both drugs, we saw evidence of good target engagement and favorable safety and Tolerability.

But efficacy results in the mid stage studies did not meet our minimum target product profile to justify further development.

We continued to advance the phase III study of <unk> in for Polycythemia, Vera and we plan to share data from this study as it becomes available.

We remain on track for a number of key events, including regulatory decisions in late stage pipeline achievements. These include USF on person approval and phase III data for <unk>, our next potential medicine to launch after implantation.

We will keep you updated on our progress on these events and more throughout the year.

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

Thank you Richard.

Our first quarter financial results reflect our ability to generate meaningful revenue, while making investments in key growth opportunities across our business.

We earned revenues of $131 million for the first quarter with approximately half from our commercial products and half from numerous partnered programs.

Our operating expenses and operating loss for the first quarter increased over the same period last year.

We advanced our commercial readiness activities and advanced our pipeline, especially our late stage programs.

We ended March with substantial cash and investments of $2 $3 billion, enabling us to continue making investments to create future growth opportunities.

We earned $50 million in spin royalty revenue based on global product sales of $443 million in the first quarter.

Our spin Mazda royalties reset annually and based on our revenue expectations, we anticipate reaching the highest royalty tier by mid year. Additionally, we continue to record a 100% of our spin rather royalties as commercial revenue under our royalty pharma transaction.

Boston RASM product sales were slightly lower in the first quarter compared to last year, we and Biogen continued to see signs of stabilization in Biogen patient base.

Importantly, biogen remains focused on expanding into new markets and expanding existing markets. While also generating important efficacy data from its robust lifecycle management program.

Based on all of these efforts, we and Biogen believe FINMA Arthur can return to growth.

We earned R&D revenue of $63 million in the first quarter for advancing numerous program partnered with Biogen and Astrazeneca among others.

Already in the second quarter, we earned <unk> $16 million milestone payment for calcified EU asset profile.

Our non-GAAP operating expenses increased in the first quarter compared to the same period last year.

As we advanced our robust pipeline our steady cost.

Increased at most of our ongoing phase III studies were either fully enrolled are approaching full enrollment, which resulted in higher higher R&D expenses.

Additionally, as we continue to prepare to launch upon testing Elisa <unk> and Danny to alert them. Our SG&A expenses also increased modestly year over year.

We bolstered our working capital by adding $500 million from royalty pharma in exchange for a minority share of our spin Martha and potential pellet Carson royalties.

As a result, we recorded a long term liability, which we will reduce when we make payments to royalty pharma.

Additionally, we will recognize imputed non cash interest expense, which for the first quarter of 2023 was $16 million.

Looking ahead, we expect our revenues in Q2 to be modestly higher compared to Q1.

We also anticipate that second half revenues will be weighted toward the back end of the year.

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

Consistent with our guidance, which includes expenses related to our capital intensive phase III studies.

We estimate our full year R&D expenses will increase between 20% and 25% year over year.

Excluding the managed to Gnome upfront payment, we made last year.

We also project our full year SG&A expenses to increase in the range of about $35 million year over year from our investments in our commercial preparations for alpine Creston <unk> and Danny to learn.

For the next few years, we are planning to continue to be in a period of investment as we advance our late stage clinical program.

And prepare to independently commercialize our medicines.

As a result, we project our operating expenses to grow modestly.

Additionally, I keeping more programs for ourselves.

We anticipate a greater proportion.

Of commercial revenues compared to R&D revenue.

And as we add increasing commercial revenues on top of our substantial and sustained base of R&D revenue.

We project, our commercial revenues to be the primary driver of future revenue growth.

With our goal to continue to build our.

Our <unk> owned pipeline, we expect our investments today and into the future to drive greater value Fry for ion and our shareholders and with that I'll turn the call back over to Brad.

Thank you Beth.

We anticipate continuing our positive momentum as we advance our key priorities with additional important regulatory and late stage pipeline events silicone this year.

Well on our way to achieving our goal of delivering an abundance of new genetic medicines to the market.

We just added <unk> to our commercial portfolio and with a December <unk> date, we could also add up one person late this year.

With our rich late stage pipeline, we are well positioned to bring additional medicines to the market on a steady cadence over the next several years.

Additionally, with the progress we're making in all of our pre commercial activities. Our first planned launch of <unk> with Astrazeneca in patients with <unk> neuropathy is in sight.

With our independent launches for <unk> and Donny Tourism also clearly in view.

We continue to make innovative technological advancements for future medicines and finally, our strong financial foundation enables us to invest in areas with the greatest potential to drive growth and drive value.

We look forward to sharing our progress as we build on our recent achievements and accomplish our important objectives and with that we will.

I'll now open it up for questions.

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

The speakerphone, please pick up your handset before pressing the keys.

If at any time. Your question has been addressed and you would like to withdraw your question. Please press Star then two.

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

Our first question comes from Joseph Stringer with Needham and company. Please go ahead.

Hi, Thanks for taking our questions.

Just wanted to get any.

Additional color on the trade program disk.

Discontinuation. Thanks.

It didn't fit your target product profile, but just curious.

Is it sort of efficacy threshold that didn't need or are there any safety signals of any additional color on that would be helpful. Thank you.

Sure Joey happy too.

So.

No safety issues at all.

The safety profile for <unk>.

Beta thalassemia, intermedia and symbol Ericsson and acromegaly clean.

Christine.

Was all about efficacy.

Both of these cases these two drugs were being tested in a.

In a scenario for the first time north of our targeted focusing first on acromegaly to your question.

Growth hormone receptor.

On hepatocytes to block IGF one production.

Acromegaly is caused by excess of GH pro hormone and our hypothesis was that if we block the receptor on the Paris site, we can lower IGF one levels.

Substantially that it could be a competitive.

Treatment for acromegaly.

We tested in refractory.

And we've reported that data last year and this was the monotherapy data.

It didn't meet our minimum target product profile for IGF one reductions.

We saw some reductions but wasn't good enough and considering the richness of our pipeline adjusted clear the bar. So we're moving on from Acromegaly.

<unk>.

As more interesting in my view.

<unk> we are developing.

Four.

Multiple indications.

The first was a beta thalassemia intermedia.

As a reminder, we showed that separate burson targeting timber six a gallon.

Targeting strategy should really quite remarkable.

Signs of efficacy in our target engagement I should say in our phase one normal volunteer study, we reported that a couple of years ago. We showed a very significant elevations in upside in levels, which is what we're trying to achieve with targeting <unk>.

And and <unk>.

Expected predicted changes in iron metabolism, exactly as we had predicted in normal volunteers.

And polycythemia Im sorry in beta thalassemia intermedia.

We didn't see those changes.

As a reminder, temporary fixes a pathway.

Pathway targeted Jeanette.

Genetically validated target and keep that in mind and.

And we didn't see the biology translate from preclinical to clinical in that setting.

With that said so it didn't need the product profile with.

That said.

In parallel we advanced into part of Polycythemia Vera and.

I'm very pleased to say that we're very encouraged by some of the initial data we are seeing in PV PV seems to biology seems to be very different.

By target.

With targeting timber six.

Versus beta thalassemia intermedia, so it's all about biology.

We're laser focused on ensuring that the drugs that we invest in our pipeline meet a minimum target product profile.

So we can focus our attention on the drugs that are going to bring the greatest value and.

That drug for acromegaly in that indication for <unk> did not meet the bar.

Great. That's very helpful and thank you for taking my question.

Youre welcome.

The next question comes from Jessica Fye with JP Morgan. Please go ahead.

Thanks for taking my question.

One one person.

First with the IRS changes to part D. Can you talk about how you think about the annual out of pocket costs. That's one person for Medicare patients in 2024, and 2025 and beyond.

How that compares to the out of pocket costs.

So your competitor product reimbursed through part B.

And then also related to F. One person I'm curious what youll be watching for when the ACA reminisce attribute data readout. This summer. Thanks.

Thank you Jeff Great question, and as you would take the IRA you Jean maybe you could talk a little bit about.

Data readouts from competitive programs in <unk> sure sure Hi, Jeff.

No.

First of all it's important to understand the payer mix as we're going into the marketplace. So we're estimating about a third of the patients.

In Polyneuropathy or <unk>.

Medicare.

Third will be commercial so will they will not be subjected to.

Objected to Medicare part B design, you are talking about they will go through the normal.

Hopefully tier two tier three co pays which will.

Which we obviously will offer some level of co pay relief the copay card shipments manufacturers too.

On specifically the <unk>.

Key paths for <unk> for the <unk>.

Third of the patients.

We are patient out of pocket cost starting in 2024.

Our Medicare part D recipients will be capped at $2000. As you know currently it goes into until it gets to Kevin traffic here.

It ranges in the 20000 thats going to come down 10 folds for these patients which is a huge.

Positive change for patients in Medicare part D. And then I would say that we still expect to provide.

Access for these patients to the foundations for.

For for for the disease for GTR disease diseases. As is currently being used for first generation silencer since Bob for stabilizers.

In terms of the part B I think that's a very different dynamic in terms of what is happening for the patients. They still have to think about depending on their coverage what level of co insurance they would be paying if they don't have supplemental then that could be actually really high for them and then the office costs have to be.

<unk> as well because you know you really have some.

And I'm curious what youll be watching for when the <unk> attribute data reads out this summer.

Some dynamics there in terms of increasing the.

The number of staff you have onboard for those particular offices to make sure. They have the ability to administer our patients that are coming in.

Thank you Jeff Great question, and as you would think the IRA Eugene maybe you could talk a little bit about.

Data readouts from competitive programs and see I'm sure sure Hi, Jeff.

And then I would just characterize our our benefit of self administration at home it really reduces the burden on both the patient as well as the physician, particularly if youre not cluster Center excellence, it's really our drive for many of these patients as well and that ability to self administer at home.

<unk>.

First of all it's important to understand the payer mix as we're going into the marketplace. So we're estimating about a third of the patients.

In Polyneuropathy or <unk>.

Medicare.

<unk> will be commercial so will they will not be subjected to.

Is it really continues to be a really big.

Driver a preference travel on Carson.

Objected to a Medicare part B design, you are talking about they will go through the normal.

Eugene what are you looking for what's most interesting in the upcoming Echo reminisce Brito.

Hopefully tier two tier three co pays which will.

Well the most interesting.

Which we obviously will offer some level of co pay relief with copay cards with most manufacturers to.

Thank you me would certainly be the fact that we see on outcomes.

And trial and by modern I mean, the trial, but really.

On specifically the.

Part D paths for <unk> for the third of the patients that go through at their.

Was conducted post to some of the sort of the.

Within the last couple of years relative to what was seen in the past them.

Patient out of pocket costs, starting in 2024.

For all Medicare part D recipients will be capped at $2000.

I think the most interesting but for me it would be.

Two.

Currently it goes into until it gets to Kevin traffic care. It ranges in the 20, thousands thats going to come down 10 fold for these patients which is a huge.

To see the background rate in placebo arm not even.

The active arm although of course, we're all focused on.

Positive change for patients in Medicare part D. And then I would say that we still expect to provide.

And also seeing the treatment effect this is stu.

Study now.

Was followed followed these patients over.

<unk>.

A number of years so.

Access for these patients to the foundations for <unk>.

Is going to be the first readout as I said for the for the population, which we believe is more reflective of what the current population of newly diagnosed patients may look like.

For for for the disease for GTR disease diseases. As is currently being used for first generation <unk> as well for stabilized.

In terms of the part B I think that's a very different dynamic in terms of what is happening for those patients. They still have to think about depending on their coverage what level of co insurance they would be paying if they don't have supplemental then that could be actually really high for them and then the office costs have to be considered.

So okay.

Whether or not the patients indeed are more mild than what they were in the placebo group compared to the attract study and it will also be interesting to see how a stabilizer.

It looks up it matches up to some of the early data we've seen with the silencer as well that would be interesting.

<unk> as well because you really have some.

Some dynamics there in terms of increasing.

Next question.

The number of staff you have onboard for those particular offices to make sure. They have the ability to administer patients that are coming in.

The next question comes from Yanan, Zhu with Wells Fargo. Please go ahead.

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

And then I would just characterize our our benefit of self administration at home it really reduces the burden on both the patient as well as the physician, particularly if youre not close to our centre of excellence, it's really our drive for many of these patients as well and that ability to self administer at home.

Our upfront person maybe two questions here, maybe want to follow up.

What you were just talking about about cardiomyopathy study.

What to look out for from the competitor study I was wondering with your.

Cardio transform study.

Is it really continues to be a really big.

<unk> completion of enrollment.

Could you provide an update on our mix of <unk> versus the <unk> naive patients in kind of the proportions.

Driver a preference for a blood test.

Eugene what are you looking for what's most interesting in the upcoming ACA reminisce Brito.

And any.

Any update on the ongoing on a blinded event rate and also with we'd be able to learn about the baseline characteristics of these patients are.

The most interesting.

Thank you me would certainly be the fact that we see on outcomes and a modern trial and by modern.

Trial early.

Les you complete enrollment before you readout the data so that we could as you suggested.

Was conducted post to some of those sort of.

Within the last couple of years relative to what was seen in the past them.

Okay.

Studies.

Just the pace of the event rate.

I think the most interesting but for me would be.

With a more than a comparable comparator and lastly, our ethicon trust in Polyneuropathy wondering about your pricing strategy that you and Astrazeneca.

Two.

To see the background rate in placebo arm not even.

The active arm although of course, we're all focused on.

I assume we're working on.

Whether it would be a parody strategy it was competitive rux or whether it could be.

I would also say the treatment effect. This is the study now.

Competitive price. Thank you.

It was followed followed these patients over.

Thanks, Ian all great questions. So we when we upsize the study the cardio transform study we had several objectives that we sought to achieve one was to ensure that we had to.

The size of the study to support the powering that was necessary for a patient population that has.

Become more mild due to earlier diagnosis and in detection and awareness of disease.

The second was to ensure that we had about a 50 50 well balanced.

Usage in the study of <unk> versus naive patients.

And then thirdly to increase the percentage of patients better bearings versus wild type.

And then thirdly to increase the percentage of patients better bearings versus wild type.

Obviously, we're coming close to completing the study and we're very good.

Confidence in our decision to upsize the study to around 14 patients and really wrapping up enrollment very soon.

So we're well on our way there of course, but.

We're also very pleased that.

Our objectives for.

Good balance between the feminists and nave as well as increasing the percentage of.

Variant patients in the <unk> study.

Is is we're achieving and we're well on our way to achieving all of our goals there so thats well in hand.

As far as the blinded event rates were monitoring those very carefully and that too is.

<unk> is doing it is performing very well as we had hoped it would when we.

Upsize the study.

<unk> prioritized sites when we upsize the study.

Where.

We think patients would be.

We would be would be sicker.

We didn't have such.

Such a high percentage of mild disease. So that's working very well too we're seeing what we want to see in the blinded event rates with respect to publishing demographics.

I don't have that plan in front of me I don't think this is a very competitive space.

We will publish or present that data at the right time, but I don't think we're going to be rushing to do that and as far as pricing strategy on Asia would you like to comment on that.

Thanks, Shannon all great questions. So we when we upsize the study the cardio transform study we had several objectives that we sought to achieve one was to ensure that we have.

Yes, yes.

Then really simply we're going to price.

According to where we believe we're going to get the best and strong access and coverage for our future.

The size of the study to support the powering that was necessary for a patient population that has.

That work is ongoing right now with Astrazeneca.

<unk> become more mild due to earlier diagnosis and detection and awareness with disease.

And in terms of your comment on parity pricing. It's just a reminder, that we're launching in multiple markets outside of the U S.

Second was to ensure that we had about a 50 50 well balanced.

Where we will be first so we will be setting setting the price in those markets as well. So those are both going into consideration.

Usage in this study of <unk> versus naive patients.

And again the goal is to get access for these 40000 patients both mixed phenotype as well as in Polyneuropathy and make sure we have products and coverage.

And then thirdly to increase the percentage of patients better variance versus wild type.

Obviously, we're coming close to completing the study and we're very.

Great very helpful. Thank you.

Okay.

Confidence in our decision to upsize the study to around 14 on our patients and we're gonna be wrapping up enrollment very soon.

The next question comes from Mike <unk> with Morgan Stanley . Please go ahead.

So we're well on our way there of course, but we.

Yeah, Hey, guys. Thanks for taking the question, maybe just a quick follow up on <unk> specifically in PV.

We're also very pleased that.

Our objectives for a good balance between two families of naive as well as increasing the percentage of.

I guess do you anticipate any read through to PV from from the beta cell study. It sounds like you don't based on some biology, but maybe you could just explain why the biology may be different in those two different indications.

<unk> variant patients in the <unk> study.

And we're.

We're achieving and we're well on our way to achieving all of our goals there so thats well in hand.

As far as the blinded event rates were monitoring those very carefully and that too is.

We we thought thanks very good question.

We thought that there could be some read through for.

It is doing it is performing very well as we had hoped it would when we upsized the study.

<unk> Val.

Two PV.

<unk>.

Because in boats in our objectives for both studies was to elevate.

And prioritize sites when we upsize the study where we.

Upside in production and a disease that is really caused by very low or nonexistent <unk> levels.

We think patients would be.

It would be would be sicker.

Sure.

But we didn't see the read through we are not seeing the read through we are seeing very encouraging.

We didn't have.

Such a high percentage of mild disease. So that's working very well too we're seeing what we want to see in the blinded event rates with respect to publishing demographics.

Early signs in polycythemia, Vera and that the biology in beta thalassemia intermedia.

Ism.

I don't have that plan in front of me I don't think this is a very competitive space. We will we will publish or present that data at the right time, but I don't think we're going to be rushing to do that and as far as pricing strategy on Asia would you like to comment on that.

Reading through.

And we think this bodes really well for other indications that we're thinking up for <unk>.

Our separate person Super six drug.

I wish I had an answer for why the biology is different we don't what was really surprising was the preclinical data in beta thalassemia intermedia, which we published on extensively and models that we thought were predictive.

Yes, yes.

And then really simply we're going to price them.

Accordingly to where we believe we're going to get the best and strong access and coverage for our <unk>.

Beta thalassemia intermedia I mean, they had all the right signs.

And that work is ongoing right now with Astrazeneca.

Yeah.

Profiles in those animal models was very strongly similar to the human condition.

In terms of your comment on parity pricing. It's just a reminder, that we're launching in multiple markets outside of the U S.

It didn't happen so we were surprised.

Where we will be first so we will be setting setting the price in those markets as well. So those are both going into consideration.

I really wish we knew the biology, what was going on there more.

What I can tell you is that in data that we did not get the upside and the increases that we expect it to get that we got in normal volunteers and then we're seeing elsewhere. So it's just something more complex about that that patient population.

And again the goal is to get access for these 40000 patients both mixed phenotype as well as in Polyneuropathy and make sure we have broad access and coverage.

Completely agree.

Great very helpful. Thank you.

But there is no read through on the efficacy, but on the safety I wouldn't say, it's reading through very very nicely and that means we're not seeing any safety issues and in fact, the sensitivity on the PV patients at least in the early look.

Okay.

The next question comes from Mike <unk> with Morgan Stanley . Please go ahead.

Yeah, Hey, guys. Thanks for taking the question, maybe just a quick follow up on <unk> specifically in PV.

Seems to think we may be driving doses even lower.

So big margins, yes, yes.

I guess do you anticipate any read through to PV from from the beta cell study. It sounds like you don't based on some biology, but maybe you could just explain why the biology may be different in those two different indications. Thanks.

Great point Richard if.

I can expand on your expanding Amit.

We've really pushed the dose in beta thal and.

And we created a long time, because we expected to see.

Effects in beta Thal.

We we thought thanks very good question.

And as Richard said, even though we push the dose the safety was pristine and we came into another indication we realized that we didn't need that dose.

We thought that there could be some read through for from.

From beta Thal.

Two PV.

So we're doing we're looking at so the doses can be lower than what we pushed in beta thal and that just further gives us confidence in it.

<unk>.

Because in both in both of our objectives for both studies was to elevate.

Upside in production and a disease that is really caused by very low or nonexistent herbicide and levels.

Why we chose this target and why we pursued it.

For various indications it looks like it's going to be.

So we didn't see the read through we are not seeing the read through we are seeing very encouraging.

Low dose.

Treatment for indications we develop.

Early signs in polycythemia, Vera and that the biology in beta thalassemia intermedia.

Got it very helpful. Thank you.

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

Reading through.

And we think the disposal really well for other indications that we're thinking up for our <unk> drug.

Good morning, and thanks for taking the question.

I wish I had an answer for why the biology is different we don't what was really surprising was the preclinical data in beta thalassemia intermedia, which we published on extensively and models that we thought were predictive.

My first question.

Ill zoster.

Yes.

I know that data will be presented later this year I'm just curious what you guys have learned from the prior experience from we live in.

Beta thalassemia intermedia I mean, they had all the right signs.

In terms of the future.

That will.

We will.

Yes.

Further sort of improve the.

Profile. So in those animal models was very strongly similar to the human condition.

Commercial outlook.

Aspect of this drug.

Follow up.

It didn't happen so we were surprised.

Rich.

Yes.

I really wish we knew the biology, what was going on there more.

That's a great question and looking back at our.

What I can tell you is that in data that we did not get the herbicide and the increases that we expect it to get that we got in normal volunteers and then we're seeing elsewhere. So it's just something more complex about that that patient population.

Not only previous but current experience, what's the right way Libra.

We have really nice growth in the commercial space and I think what's really driving that are not only the significant triglyceride lowering activity of.

Completely agree.

But there is no read through on the efficacy, but on the safety I would.

This approach a policy three inhibition, but what appears to be a very strong connection to the.

I'd say its reading through very very nicely and that means we're not seeing any safety issues and in fact, the sensitivity in the PV patients at least in the early look.

The down downstream events of pancreatitis.

We may be driving doses, even lower.

And so patients are feeling better.

And so big margins.

<unk> better and so all of these things drive obviously.

Yes.

Great point Richard.

If I could expand on your expanding Amit.

Hopefully.

Commercial so that's the that's the learning I think that we've gotten.

We've really pushed the dosing data bell and.

And the learnings that we have even today from our way Libre experience yes.

And we created a long time, because we expected to see.

FX in beta Thal.

Add to that Richard that.

And as Richard said, even though we pushed the dose the safety was pristine and we came into another indication we realized that we didn't need that dose.

<unk> is a more potent molecule and we expect even deeper reductions in <unk> III in triglycerides than we saw with the early generation of.

So we're doing we're looking at so the doses can be lower than what we pushed in beta thal and that just further gives us confidence in.

Of course with us for the pristine safety profile like we're seeing for our all of our like us.

And why we chose this target why we pursued it for various indications it's it looks like it's going to be.

Date.

And the other thing is that we're going to be paying attention to is in addition to patients which is feeling better productions potentially strong trends hopefully in pancreatitis productions.

Low dose.

Treatment for <unk>.

The indications we develop.

With my liver, we saw reductions in liver fat.

Got it very helpful. Thank you.

And that's important to them and we'll be looking at that as well because again, we're seeing.

Okay.

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

Greater reductions in April three in and we're going to be very good.

Good morning, and thanks for taking the question.

We're going to want to replicate that.

And then you had another question Yale.

My first question.

Austin.

Yes.

Yes.

Yes.

In terms of those tougher for us.

I know that data will be presented later this year I'm just curious what you guys have learned from the prior experience from we live in.

NPV are first of all is that data will be recorded.

Later, this year and secondly that.

In terms of the future.

In terms of.

That's that will.

If those were positive.

Paul.

Further sort of improve the.

The pivotal study what are you seeing.

Commercial outlook.

Approvable endpoint will be used or contemplate.

Aspect of this drug and I have another follow up.

Rich.

Thanks.

Yes.

So maybe.

That's a great question and looking back at our.

Eugene.

Little bit about <unk>.

Not only previous but current experience with the right way Libra.

Approvable endpoint would be.

For PV, we don't know if were going to have.

We have really nice growth in the commercial space and I think what's really driving that are not only the significant triglyceride lowering activity.

Sufficient data this year yield to report.

On the TV.

Again in dose ranging.

I wouldn't rule it out, but we certainly are not promising.

This approach a policy three inhibition, but what appears to be a very strong connection to the.

At this point, we're just going to have to.

Really figure out the dose and cyclical with the profile of it and so.

I'll leave it at that and where do you where.

Down downstream events of pancreatitis.

When you look at it.

It's a good question.

And so patients are feeling better.

Are things, we're going to explore and early proof of concept studies. Obviously the goal is to maintain these patients hematocrit level within the range.

Functioning better and so all of these things drive obviously.

Hopefully.

Commercial so that's the that's the learning I think that we've gotten.

It doesn't require phlebotomy.

And the learnings that we have even today from our way Libre experience yes.

The main.

Clinically significant endpoint, but theres a number of other.

Add to that Richard that.

Exploratory endpoints, we are examining these patients.

<unk> is a more potent molecule and we expect even deeper reductions in <unk> III in triglycerides than we saw with the early generation.

Experienced pretty pretty low quality of life related to their PV symptoms such as fatigue.

We're obviously going to explore the impact of improving there.

Of course with us for the pristine safety profile like received for all of our like us.

To date.

Tom.

We're in a matter of birth control.

And the other thing is that we're going to be paying attention to is in addition to patients with just feeling better productions potentially strong trends hopefully in pancreatitis event reductions.

And being phlebotomy free, but also weather impact translates into.

Into them actually experiencing better quality of life.

Anything you want to add to that yes.

We saw reductions in liver fat.

I'll just add that it's a really attractive commercial opportunity theres a significant addressable population both in the U S as well as outside of the U S. And in addition to what Eugene said in terms of.

And Thats important too and we'll be looking at that as well because again, we're seeing great.

Greater reductions in April three and and we're going be very we're going to want to replicate that.

And then you had another question Yale.

When do think phlebotomy bottoming free there is also a significant portion of this market that's at high risk.

Yes.

Yes.

In terms of those tougher for us.

NPV are first of all is that data will be recorded.

Thrombotic events, so we do believe that.

Later this year.

Both things are going to be really.

Secondly that.

In terms of occupancy.

Okay.

Positive.

Yes.

Paul.

What he is that.

Pivotal study what do you think.

Does this signal post first line or second line.

Approvable end point will be used or contemplate.

Alright.

I think that's going to be a bit I think it would be first line. If there were no payers inbound.

Thanks.

So maybe.

Eugenia.

Payers and while we do.

Little bit about <unk>.

Approvable endpoint would be.

And we're doing some work on this that they may have to step through.

For PV, we don't know if were going to have the <unk>.

Step through some of the generic certainly not.

Sufficient data this year Yale to report.

At two.

On the TV.

Too restrictive, but there may be a step to Brendan.

We're getting dose ranging.

Okay, great. Thanks.

I wouldn't rule it out, but we certainly are not promising.

Appreciate it and congrats.

At this point, we're just going to have to.

The next question comes from Arun.

Really figure out the dose in cyclical with the profile of it.

However, with TD Cowen. Please go ahead.

I'll leave it at that and.

When you look at it.

Hi, guys. This is Brendan on for you around thanks for taking the question just a couple of quick ones from us early.

It's a good question.

Number of things, we're going to explore an early proof of concept studies. Obviously the goal is to maintain these patients hematocrit level within the range.

On <unk> here.

Can you just remind us are you prepared to file in the U S. Next year, if the data hits in the first half so we could potentially see $8 billion in sales maybe starting in 2025.

It doesn't require phlebotomy.

And then I'll, let me just wondering if you have any new or additional feedback from some of these physicians on how you think the drug.

The main.

Clinically significant endpoint, but theres a number of other.

We fit into the existing paradigm, and maybe where you're seeing kind of the high unmet need and lowest hanging fruit that you think you could most quickly and move into an HIV launch. Thanks.

Exploratory endpoints, we're examining these patients.

Experienced pretty pretty low quality of life related to their PV symptoms such as fatigue.

Yeah. The first question. The second question I'll ask on Asia to address.

We're obviously going to explore the impact of improving there.

The first question is easy answer we're expecting data readout early next year filing next year launch in 'twenty five.

We're in a matter of birth control and being phlebotomy free but also weather impact translates into.

But very much getting ready to do that yeah. We are where the teams are working very diligently on and launch preparations over here.

Into them actually experiencing better quality of life.

Maybe you want to add to that yes.

We continue to do research in the marketplace and our best in class profile holds true on a couple of very important parameters that will be important for switch.

Yes, I'll just add that it's a really attractive commercial opportunity there.

Significant addressable population both in the U S as well as outside of the U S. And in addition to what Eugene said in terms of.

Switch and or uptake in new patients.

But the.

<unk>.

When do you think phlebotomy Homogamy free.

Our our data in terms of the mean reduction in HAE attacks is really by far the most compelling point for physicians and for patients that really want to have virtually as many as there are taxes that can rate in a given year.

Also a significant portion of this market that's at high risk.

And we do believe that.

Both things are going to be really important.

Okay.

Yes.

Also haven't really strong quality of life data that emerged if you took a look at our our early data, which is also in testing reading out really well.

<unk> does this deal.

Speaking of post first line or second line, Okay got it.

I think that's going to be a bit.

An important point on duration of activity and.

It would be first line, if there were no payers and bond.

Rapid onset.

Tara payers and while we do.

All of those are really important asset.

And we're doing some work on this that they may have to step through.

Best in class profile features and of course, our Q1 monthly.

Captured some of the generic certainly not.

Kind of what standard of care is right now in the marketplace, which is Q2 weeks.

At.

Too restrictive, but there may be an establishment.

Thanks Nathan.

Okay, great. Thanks.

Appreciate it and congrats.

Thanks.

The next question comes from Celgene Richter with Goldman Sachs. Please go ahead.

The next question comes from.

Robert with TD Cowen. Please go ahead.

Thanks for taking a question congrats on the progress. This is Tommy on for <unk>. So now that we've seen positive data from two phase III. Alzheimer's studies, how are you thinking about the abd and any read through and more broadly on the cardio portfolio as you start to advance these programs in larger markets. How do you go through the process.

Hi, guys. This is Brendan on for you Ron and thanks for taking the question just a couple quick ones from us really on HLA here.

Can you just remind us are you prepared to file in the U S. Next year at the data hits in the first half so we could potentially $8 billion in sales maybe starting in 2025.

And then just wondering if you have any new or additional feedback from some of these physicians on how you think the drug.

Thinking about reimbursement access dynamics or models here for longer acting treatments and these indications where oral treatments merit be available. Thank you.

They fit into the existing paradigm, and maybe where you're seeing kind of the highest unmet need and lowest hanging fruit that you think you could most quickly move into an <unk> launch. Thanks.

Sure Eric do you want to comment on.

But what we're doing in dementia and how the recent successes.

Yeah. The firsthand question. The second question I'll ask <unk> to address.

Well I think so certainly for patients.

Positive data is fantastic to see and so.

The first question is easy answer we're expecting data readout early next year filing next year launch in 'twenty five.

Clearly there are obviously different mechanisms right. So.

And we're very much getting ready to do that yeah. We are.

Therapies with positive data and the one from early this morning was.

Sure.

The teams are working very diligently on and launch preparations over here.

In amyloid, reducing antibody, which is affecting one of the pathologies involved in alzheimers disease.

We continue to do research in the marketplace and our best in class profile holds true on couple of very important parameters that will be important for switch.

Key pathology is the accumulation of Tau.

And Thats, what <unk> addresses so we think there.

We're nicely positioned to be the first drug that can really test the tau hypothesis in Alzheimer's disease, and lower pathogenic Tau accumulation and Thats. The data that was shown by <unk>.

Switch and or uptake in new patients.

But the.

Our data in terms of the mean reduction in HAE attacks is really by far the most compelling point for physicians and for patients that really wanted to have virtually as many of their taxes. They can rate in a given year.

Biogen from the open label extension at the recent <unk> meeting, where by Tau Pet where you can actually visualize the accumulation of pathogenic Tau inside the brain, we were able to reduce that with the.

Also have really strong quality of life data that emerged if you took a look at our our early data, which is also in testing reading out really well.

Map T drug debating that generated lots of enthusiasm and that has prompted biogen to take that forward into a pretty large phase <unk> study, where they're looking at six.

It's an important point on duration of activity and.

Six month dosing in form of those.

Rapid onset.

Importantly, dosing intervals of two different doses of the drug to see if it really makes a difference and lowering that tau pathology can make a difference in clinical outcomes. So certainly.

All of those are really important asset.

Best in class profile features and of course, our Q1 monthly.

Kind of what standard of care is right now in the marketplace, which is Q2 weeks.

I think that you can make the fact that.

Improvements have been seen with other drugs is encouraging and we look forward to testing with hypothesis I think it's a great program, yet the intracellular Tau hypothesis, which hasnt been tested before.

Thanks Nathan.

Thanks.

The next question comes from <unk> Richter with Goldman Sachs. Please go ahead.

And we have a great living drug and debate.

Thanks for taking our question and congrats on the progress. This is Tommy on for <unk>. So now that we've seen positive data from two phase III. Alzheimer's studies, how are you thinking about the abd and any read through and more broadly on the cardio portfolio as you start to advance these programs in larger markets. How do you go through the process.

The other thing is just too.

Expand on that a bit more.

We have several programs rich program in dementia.

Programs intervention.

That are that are coming behind Chow.

So stay tuned for those in the future it's not at all.

Our whole Beth is not on just how although we're very excited about it as does Biogen and then Tommy can you repeat your second question.

Thinking about reimbursement access dynamics or models here for longer acting treatments and these indications where oral treatments merit be available. Thank you.

I'm sorry.

Great It was.

Sure Eric do you want to comment on.

Some of the cardio programs and generally more prevalent markets. How do you think about reimbursement and access for longer acting treatments, whereas oral merit be available because we've seen some headwinds here with other programs.

But what we're doing in dementia and how the recent successes.

Well I think so certainly for patients.

Positive data is fantastic to see and so.

Yes.

Yeah.

It's a it's a really good question I mean, I go back to kind of basics on this I think you have to really think about what the continued unmet need is in the marketplace and what your products, bringing in terms of its profile of <unk> delivered on that when we take that combination and say, okay. What's the value proposition we're bringing.

Clearly there are obviously different mechanisms right. So the <unk>.

Therapies with positive data and the one from Lilly This morning was.

And amyloid, reducing antibody, which is affecting one of the pathologies involved in Alzheimer's disease. The other key pathology is the accumulation of Tau.

Through this particular disease, David unmet need and then price accordingly to that.

And Thats, what <unk> addresses so we think there.

We're nicely positioned to be the first drug that can really test the tau hypothesis in Alzheimer's disease, and lower pathogenic Tau accumulation and Thats. The data that was shown by <unk>.

So.

We have done some really good work, if youre talking battle with arson.

The broader prevalent <unk> market, and we and we do see really good pricing potential in the kind.

Biogen from the open label extension at the recent <unk> meeting, where by Tau Pet where you can actually visualize the accumulation of pathogenic Tau inside the brain, we were able to reduce that with the.

Kind of higher premium cardiovascular product ranges.

Which again, we are triglyceride reduction is like three X the magnitude, but the oils are right now. So we really do believe we have a very compelling value proposition to price in that and that our CV premium range.

Map T drug debating that generated lots of enthusiasm and that is prone to biogen to take that forward into a pretty large phase <unk> study, where they're looking at six.

Thanks, Tommy Thanks Nathan.

Six month dosing and foremost.

Importantly, dosing intervals of two different doses of the drug to see if it really makes a difference and lowering that has helped US hold you can make a difference in clinical outcomes. So certainly.

The next question comes from Paul Davis with Stifel. Please go ahead.

Hi, This is James on for Paul Thanks for taking a question.

I think that you can make the fact that.

Maybe just a kind of broader high level question.

Improvements have been seen with other drugs is encouraging and we look forward to testing with hypothesis I think it's a great program, yet the intracellular Tau hypothesis, which hasnt been tested before.

Assuming <unk> Hudson S HDD and done on Dolores and hits NHI, what do you think <unk> looks like in 2025 2026.

And we have a great lift in drug and debate.

Specifically with respect to what your sales force could look like and what type of synergy there would be between <unk>.

The other thing is just too.

Expand on that a bit more.

We have several programs rich program in dementia.

For those two assets if at all any thoughts there would be great. Thanks.

Programs and pension.

That are that are coming behind Tao.

Well I'll just start out as an agent to address there.

So stay tuned for those in the future.

Sort of vision for the build of our commercial organization.

Our whole debt is not on just how although we're very excited about it as does Biogen and then Tommy can you repeat your second question.

We work with we're obviously working on and preparing for launches in the near term.

I'm sorry.

<unk>.

Great.

But we're expecting a half dozen or so new drugs on the market in that timeframe.

On some of the cardio programs and generally more prevalent markets. How do you think about reimbursement and access for longer acting treatments, whereas oral merit be available because we've seen some headwinds here with other programs.

James.

That includes of course wholly owned drugs, we commercialized as long as our partner.

We're pretty confident in that.

Yes, Jeff on Asia Yeah.

But in Asia, we're going to talk a little bit about the the growth yeah. It looks really exciting I mean, we have to to cross functional teams planning from both launches and they're not overlapping I will just say that behind the scenes of all of the commercial infrastructure that you need there are a lot of synergies right. So what we are.

It's a really good question I mean, I go back to kind of basics on this I think you have to really think about what the continued unmet need is in the marketplace and what your products, bringing in terms of its profile to deliver on that when we take that combination and say, okay. What's the value proposition we're bringing.

<unk> four <unk>.

To this particular disease state unmet need and then price accordingly to that.

Even for Epsilon terse, and with our patient services and hubs and where we have our field medical team, we're thinking about how we bring them forward to our next independent launches and then all the systems that go behind it as well and we will see lots of synergy there, but where we will see differences is obviously in our sales.

So.

We have done some really good work, if you're talking about <unk> and the broader prevalent <unk> market and we and we do see really good pricing potential in the kind.

And a higher premium cardiovascular product ranges.

Teens eventually for these two products and they will be different they are different call points.

Which again, we are triglyceride reduction is like three X the magnitude of what the Orange are right. Now. So we really do believe we have a very compelling value proposition to price in that and that arent CV premium range.

And for <unk>, we know, it's a large opportunity, but we're really honing in on two specialties, which is cardiology and endocrinology.

And these are very severely elevated triglycerides. So this is not a place where a lot of PCP or GPS are are are actually prescribing, they're referring out to the specialties where we're.

Thanks, Tommy Thanks Nathan.

The next question comes from Paul <unk> with Stifel. Please go ahead.

We're working on the sizing of that team.

Hi, This is James on for Paul Thanks for taking our question maybe.

And then for Don it alerts and its allergists and comparing very concentrated 50% of the docs actually prescribed <unk>, 80% of the prescriptions and you can bench it really easily to where the market later Takeda is and they have about 50 50 reps or so that are going after that opportunity and very well concentrated in <unk>.

Maybe just a kind of broader high level question.

Assuming <unk> hits and S HDD and Donald Lorestan hits NHI, what do you think <unk> looks like in 2025 2026.

Specifically with respect to what your sales force could look like and what type of synergy there would be between <unk>.

So it is different but they are they are really good ways that we're thinking about it he touring that the teams at the focus that they need and are calling on the right docs with the most efficient model.

For those two assets if at all any thoughts there would be great. Thanks.

Well I'll just start out as an agent to address sort of vision for the build of our commercial organization.

Thank you.

Thanks James.

The next question comes from cost Us <unk> <unk> with BMO capital markets. Please go ahead.

Something we work with we're obviously working on and preparing for launches in the near term.

Hello, everyone. Thanks for taking our questions and congrats on the progress a couple of questions from us the first one on a day.

<unk>.

We're expecting a half dozen or so new drugs on the market in that timeframe.

James and.

Given the relatively small size of the market. There how are you thinking about the competitive gene editing therapies or gene therapies, which is they are really one and done they can sit in the market size had been tested and then I have a follow on follow up.

That includes of course wholly owned drugs, we commercialized as long as our partner.

We're pretty confident in that.

In Asia, we're going to talk a little bit about the growth, yes. It looks really exciting I mean, we have to to cross functional teams.

Lanning from both launches and they're not overlapping I will just say that behind the scenes of all of the commercial infrastructure that you need there are a lot of synergies right. So what we are building for four even for Epsilon terse, and with our patient services and hubs and where we have our field medical team we're thinking about.

Well I'll start announced SMA, she wants to expand in that but.

H a patient population well first let me start here.

Everything is still very early on there's a lot to prove with respect to all aspects of the pharmacology.

That includes.

The safety of your off target potential.

How we bring them forward to our next independent launches and then all the systems that go behind it as well and we will see lots of synergy there, but where we will see differences is obviously in our sales teams. Eventually for these two products and they will be different they are different call points.

To potentially permanently.

Edit DNA.

And.

Unplanned manner and a non preferred manner.

As well as the durability is it really one and done we've heard that for gene therapy.

And for <unk>, we know, it's a large opportunity, but we're really honing in on two specialties, which is cardiology and endocrinology.

And the team can truly be won and done as well and then if it's not can you re dose.

So much to learn here for DNA editing. The second thing is when you start getting into these younger patient populations.

And these are very severely elevated triglycerides. So this is not a place where a lot of PCP or GPS are are are actually prescribing, they're referring out to the specialties.

Which <unk> largely is this is a disease that is getting diagnosed earlier and earlier.

On the.

<unk>.

The interest.

We're working on the sizing of that team.

There's real concerns by from patients about.

And then for Diana to loosen its allergists and preparing very concentrated 50% of the docs actually prescribed <unk>, 80% of the prescriptions and you can bench it really easily to where the market later Takeda is and they have about 50 50 reps or so that are going after that opportunity and very well concentrated in <unk>.

Their DNA to be blunt.

At an early at such an early age.

When they are thinking about building families and those sorts of things. So theres a lot of headwind on DNA anything specifically for a J.

As you know cost this we are investing in DNA editing.

So it is different but they are they are really good ways that we're thinking about ensuring that the teams get the focus that they need and are calling on the right docs with the most efficient model.

We have a different strategy for target identification and drug development.

We're trying to address those types of concerns as we bring our molecules forward, it's still early days, but.

Thank you.

Thanks James.

We believe in our investment in DNA editing, but we don't think HCA is going to be the right place for this approach what do you think right now I think you summarized it well I would say in addition to kind of the long term safety that still needs to be demonstrated this patient population is appetite for actually taking.

The next question comes from cost Us <unk> <unk> with BMO capital markets. Please go ahead.

Hello, everyone. Thanks for taking our questions and congrats on the progress a couple of questions from us the first one on a day.

Given the relatively small size of the market. There how are you thinking about the competitive gene editing therapies or gene therapies, which is they are really one and done they can sit in the market size. Even further and then I have a follow up follow up.

A DNA and it's so early in their in their lives and not knowing what the long term consequences are a major and then I'll add a third I think the third one is what will be the continued remaining unmet need in <unk>. Because we are really kind of fulfilling that we have a great product and.

Well I'll start announced SMA, she wants to expand on that but.

Hey, Jay pipe patient population well first let me start here.

Again it is.

And I think it's going to be fully satisfied by the time of day.

Everything is still very early on there's a lot to prove with respect to all aspects of the pharmacology.

Okay.

And then you had a second question costs, yes.

And the second quick one on <unk>, how are you thinking about that.

That includes.

The safety of your off target potential.

The pie sync because you are potentially launching into different markets, where the size of the.

To potentially permanently.

At a DNA.

Population is different how are you thinking about pricing that it needs to be some populations and I would assume that the drug would be exactly the same in terms of dozing in northeast.

Okay.

Unplanned manner.

Preferred manner.

As well as the durability is it really one and done we've heard that for gene therapy.

Thank you.

Team truly be one and done as well and then if it's not can you re dose. There's so much to learn here for DNA <unk> second thing is when you start getting into these younger patient populations.

Yeah, Yeah. It's a good question, we know that we have a rare disease population with FCS and then.

A more prevalent broader with S. Https. So we don't expect the rare disease pricing, obviously for the broader population. We are working through the pricing strategy in terms of what our launch pricing will be.

<unk> <unk> largely is this is a disease that is getting diagnosed earlier and earlier.

The.

They tune, where we're thinking through a lot of like different strategic ways too.

The interest.

There's real concerns from patients about.

To get at it but you should know if you're looking at the broader population that we don't expect that obviously to be in rare disease pricing range at all again.

Their DNA to be blunt.

At an early at such an early age.

When you're thinking about building families and those sorts of things. So theres a lot of headwind on DNA anything specifically for a J.

As I said earlier will be in the cardiovascular kind of premium pricing range that you see for more prevalent.

Thank you very much medical.

As you know cost this we are investing in DNA editing.

Thank you.

The next question comes from Gena Wang with Barclays. Please go ahead.

We have a different strategy for target identification and drug development.

Thank you.

We're trying to address those types of concerns as we bring our molecules forward, it's still early days, but.

Very quick questions.

One more question regarding the Itchy program already.

I already described quite a lot of sense.

We believe our investment in DNA editing, but we don't think HCA is going to be the right place for this approach what do you think right now I think you summarized it well I would say in addition to kind of the long term safety that still needs to be demonstrated this patient population is appetite for actually taking.

Clinical profiles Youre looking for.

You also consider once every two months dosing as a typical choice to become more competitive.

My second question quick question is regarding the <unk> program, what is the expected timing for data update.

Safety signals you will have seen so far.

A DNA and it's so early in their in their lives and not knowing what the long term consequences of major and then I'll add a third I think the third one is what will be the continued remaining unmet need in <unk>. Because we are really kind of fulfilling that we have a great product and.

Lastly, very quickly on commercial readiness for FY <unk>.

Is astrazeneca, taking full charge and what is the marketing strategy given that you're already in the market.

Thanks, Gino quite thorough.

And again it is.

Three very different topics are very good questions. So I'll, let <unk> handle the HLA two month dosing and the commercial readiness for <unk>.

I think it's going to be fully satisfied by the time they.

Okay.

And then you had a second question costs, yes.

And the second quick one on all as I've said, how are you thinking about that.

Because but I will take the Angel and just as a quick answer.

The pie sync because you are potentially launching into different markets, where the size of the.

There's no nothing new to report on timing the enrollment is going well.

Population is different how are you thinking about pricing that it needs to be some populations and I would assume that the drug would be exactly the same in terms of dosing and all these.

And.

The study is going very well and we're very pleased with the safety profile that we're seeing to date.

No no concerns for the Angelman program.

Thank you.

Yeah, Yeah. It's a good question, we know that we have a rare disease population with FCS and then.

Bi monthly dosing Ajay.

The readiness.

Hi.

A more prevalent broader with <unk>. So we don't expect the rare disease pricing, obviously for the broader population. We are working through the pricing strategy in terms of what our launch pricing will be.

Hey, our competitive profile is so strong that we actually don't really need the two month dosing as a way to differentiate in the marketplace.

We'll wait for the phase III data, but certainly it's an option for us to make that available for physicians and for patients if need be but it will all be data dependent.

They tune, where we're thinking through a lot of like different strategic ways too.

To get at it but you should know if you're looking at the broader population that we don't expect that obviously to be in rare disease pricing range at all again.

For <unk> commercial readiness and lots of work going on as you can imagine we're right in that.

As I said earlier will be in the cardiovascular kind of premium pricing range that you see for more prevalent.

El minus X months as our window over here.

And.

We're going at it in a very strong way.

Thank you very hypothetical.

Thank you.

We do believe that this is a market where there is a lot of growth because of the number of patients who haven't been identify diagnosed or treated yet and we're planning for that approach in terms of really understanding where the centers of excellence currently are and where they could be in the future and really trying to hit.

The next question comes from Gena Wang with Barclays. Please go ahead.

Thank you.

Very quick questions.

One more question regarding the Itchy program already.

I already described quite a lot of sense.

Our clinical profile you're looking for.

You also consider once every two months dosing is it to go choice to become more competitive.

Both.

It's an end of our system or for us and we have the ability to do that with the scale of Astrazeneca and then I would say.

My second question quick question is regarding the <unk> program, what is the expected timing for data update.

No.

<unk>.

The clinical data in and of itself speaks for itself. So it has a really nice strong profile and then lastly, I'll add it is important to note that even though we're coming in second.

Safety signals you will have seen so far.

Lastly, very quickly on commercial readiness for FY <unk>.

Is astrazeneca, taking full charge and what is the marketing strategy given <unk> already in the market.

In the U S. That's not necessarily the order of entry that you should expect outside of the U S. In many many markets as well of course.

Some European markets will be second, but there are a lot of European markets.

Thanks, Jim.

Quite thorough.

Three very different topics, but very good questions. So I'll, let <unk> handle the HLA two month dosing and the commercial readiness for <unk>.

Eastern Europe , and China, and Japan, where we expect to be first.

Thanks Gena.

Because but I will take the Angel and just as a quick answer.

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

There is no nothing new to report on timing the enrollment is going well.

Oh, great. Thanks, so much for taking my questions I have two quick ones maybe Brett.

And.

Can you just talk about how your relationship with Biogen has evolved now that Theres, a new leadership team in place sounds like Viehbacher is pretty focused on actually containing cost and obviously, we've seen them discontinue your collaboration with tax and three so just wondering if the bar for progressing quarter molecule is now higher given their folk.

The study is going very well and we're very pleased with the safety profile that we're seeing to date no. There are no concerns for the Angelman program.

Bimonthly dosing AJ.

Lunch readiness.

Hi.

Our competitive profile is so strong that we actually don't really need the two months.

On cost again any color there would be much appreciated and then maybe on apoc III circling back to the final question can you remind us what your commercial plan ex U S. Sorry policy three was your partner to Rice will you use a distributor like so when you have your own sales force on the ground again any color much appreciate it. Thanks so much.

<unk> as a way to differentiate in the marketplace.

We will wait for the phase III data, but certainly it's an option for us to make that available for physicians and for patients if need be but it'll all be data dependent right now.

For <unk> commercial readiness.

Second question for our names on the first one Luca Thank you for the questions.

Lots of work going on as you can imagine our rank in that.

Our.

Al minus X months as our window over here.

Our relationship with Biogen is as strong as it has ever been and it's a great relationship.

And we're.

We're going at it in a very strong way.

We do believe that this is a market where there is a lot of growth because of the number of patients who haven't been identified diagnosed or treated yet and we're planning for that approach in terms of really understanding where the centers of excellence currently are and where they could be in the future and really trying to hit.

We're very pleased by the fact that.

<unk> is prioritizing.

Very highly.

We're working with other programs like the <unk> program to Eric commented on before it really exciting program to them very important is getting all the resources.

You can imagine that as needed as they are the Angelman program as well we just.

Both.

It's an end of our system or for us and we have the ability to do that with the scale of Astrazeneca and then I would say.

They did a great job in bringing <unk> to the through the finish line and onto the market and it's already launched so they are totally ready to launch that drug.

No.

<unk>.

The clinical data in and of itself speaks for itself. So it has a really nice strong profile and then lastly, I'll add it is important to note that even though we are coming in second.

And several of the other mid stage and research programs are progressing and going very well.

Absolutely Biogen I'm, not saying anything is not hasnt been in the public they are focusing their efforts on programs that they are going to bring the greatest value to their company.

In the U S. That's not necessarily the order of entry that you should expect outside of the U S. In many many markets as well of course.

And we are a large part of that pipeline. So we are a top priority for them relationship with futures is growing very well.

Some European markets will be second, but there are a lot of ERP and markets Easter.

Eastern Europe , and China, and Japan, where we expect to be first.

As far as the tax and three.

A bit of a kind of like a ultra rare disease, if you will.

Thanks Gena.

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

Clearly it was a portfolio prioritization exercise.

That was communicated directly to me as the.

Oh, great. Thanks, so much for taking my questions I have two quick ones maybe Brett.

It was the.

It was the reason behind the drug being return program being returned to our owners that.

Can you just talk about how your relationship with Biogen has evolved now that there is a new leadership team in place sounds like Viehbacher is pretty focused on actually containing cost and obviously, we've seen them discontinue your collaboration with tax and three so just wondering if the bar for progressing quarter molecule is now higher given their phone.

That's not surprising.

As it's probably not if we know it's not in their sweet spot, where the areas that they want to focus on.

We are evaluating what to do with that program today, whether to keep it or to re partner, we have a rich neuro pipeline that's growing that's wholly owned by.

On cost again any color there would be much appreciated and then maybe on a policy three circling back to the prior question can you remind us what your commercial plan ex U S. Policy three was your partner to Rice will you use a distributor like so when you have your own sales force on the ground again any color much appreciate it. Thanks so much.

I own this and we will emphasize this pipeline growing forward and we will expand on it.

As well. So this also bodes well for I one is to build out our wholly owned pipeline drugs that we're interested in commercializing come back from from Biogen, but the relationship is very strong.

Second question for <unk> on the first one Luca thank you for the questions.

We are absolutely have no concerns about.

Our.

Any programs that are returned to owners because.

Our relationship with Biogen is as strong as it has ever been and it's a great relationship.

For the most most of them would love to have them back end.

And if we don't keep them ourselves.

We're very pleased by the fact that.

<unk> III partner.

Apoc III ex U S commercialization, that's an interesting question.

<unk> is prioritizing.

Very highly.

Something we haven't been talking about.

We are working with other programs like the <unk> program to Eric commented on before it really exciting program to them very important is getting all the resources.

Thanks Luca.

I'd say listen first of all we are getting very ready for launch readiness in the U S for both indications for FCS and first of year hyper triglycerides EMEA.

You can imagine as needed as they are the Angelman program as well we just.

Our plans current plans O U S is to look for a partner.

They did a great job in bringing Kal Saudi to the through the finish line and onto the market and it's already launched so there are totally ready to launch that drug.

The type of partnership is where youre going for has not yet been determined but its important to note like we are going to look for a really good quality partner that can reach as many patients as possible in a swift manner, and that's going to be a really important right.

And several of the other mid stage and research programs are progressing and going very well.

We're still working on it.

Absolutely Biogen I'm, not saying anything is not hasnt been in the public they are focusing their efforts on programs that they are going to bring the greatest value to their company.

Our systems.

Stay tuned thanks, and I think we have time for one last question for wrapping up yes. Our last question for today comes from Myles Minter with William Blair. Please go ahead.

And we are a large part of that pipeline. So we are a top priority for them relationship with Duke is growing very well.

Thanks for sneaking me in again on all of those Austin just wanted your updated thoughts on the <unk>.

As far as the tax and three.

A bit of a kind of like a ultra rare disease, if you will.

Potential Navy if any for a cardiovascular outcome study in severe hot that triglycerides Emile.

Clearly it was a portfolio prioritization exercise.

Maybe not so much for regulatory approval, but certainly for reimbursement just given the comments that it seems like youre trying to take a slot premium pricing range for that product relative yes.

That was communicated directly to me as the.

It would be.

And behind the drug being return program being returned to our owners.

Not surprising.

As it's probably not if we know it's not in their sweet spot, where the areas that they want to focus on.

Since it's focused on reimbursement and I'll ask <unk> to take that as well.

Yeah. It's a good question, we actually tested that hypothesis pretty early in the program and we continue to.

We are evaluating what to do with that program today, whether to keep it or to re partner, we have a rich neuro pipeline that's growing that's wholly owned by <unk>.

For all sorts of payers as you can imagine the 500 plus population it as.

I own this and we will emphasize this pipeline going forward and we will expand on it.

It's severely elevated has a clear regulatory path as you said without a <unk> study.

As well. So this also bodes well for I, one is to build out our wholly owned pipeline drugs.

Given the unmet need and the fact that this is really a different population.

That we're interested in commercializing come back from from Biogen, but the relationship is garnering strong in <unk>.

And you were looking for different risks for many of these patients such as acute pancreatitis risk. This is this is not a place where even payers are are one king are expecting a <unk> from a reimbursement perspective so.

And we're absolutely have no concerns about.

Any programs that are returned to owners because for.

For the most most of them would love to have them back end.

It's going in and right in line with where the unmet need is and the value proposition of what we bring again the three X magnitude of what's currently available for triglyceride reduction for these severely elevated trick patients with high risk for acute pancreatitis is where where the payer focuses so.

And if we don't keep them ourselves.

<unk> III partner.

Apoc III ex U S commercialization, that's an interesting question.

We have been talking about.

Thanks Luca.

I'd say listen first of all we are getting very ready for launch readiness in the U S for both indications for FCS and first of year hyper triglycerides EMEA.

In there without without a cardiovascular outcome studies.

Thanks, Myles and thanks, everybody for joining us on our call today looking ahead and plan to continue our momentum by delivering additional key updates progress against our objectives on the commercial front the pipeline and our technology.

Our plans current plans or use is to look for a partner.

The type of partnership is where youre going for has not yet been determined but its important to note like we are going to look for a really good quality partner that can reach as many patients as possible in a swift manner, and that's going to be a really important right.

We will provide updates throughout the second half of the year with very much looking forward to it so with that we'll close and thank you again and have a great day everybody.

We're still working on it.

So stay tuned and I think we have time for one last question for wrapping up.

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

Our last question for today comes from Myles Minter with William Blair. Please go ahead.

Thanks for sneaking me in again on all of those Austin just wanted your updated thoughts on that.

Potential need if any for a cardiovascular outcome study.

The Hartford Triglycerides Emile.

Maybe not so much for regulatory approval, but certainly for reimbursement just given the comments that it seems like youre trying to take a slight premium pricing range for that product relative.

Since it is focused on reimbursement and I'll ask <unk> to take that as well.

Yes, Doug.

Good question, we actually tested that hypothesis pretty early in the program and we continue to.

For all sorts of payers as you can imagine.

500, plus population it as severe.

As severely elevated has a clear regulatory path as you said without a <unk> study.

Given the unmet need and the fact that this is really a different population.

And you were looking for a different risk for many of these patients such as acute pancreatitis risk. This is this is not a place where even payers are are one king are expecting a CEVA from a reimbursement perspective so.

It's going in and right in line with where the unmet need is and the value proposition of what we bring again the <unk> III <unk> magnitude of what's currently available for triglyceride reduction for these severely elevated treat patients with high risk for acute pancreatitis is where the payer focuses so.

In there without without a cardiovascular outcome study it's definitely.

Thanks, Myles and thanks, everybody for joining us on our call today looking ahead and plan to continue our momentum by delivering additional key updates progress against our objectives on the commercial front the pipeline and our technology.

And we can provide updates throughout the second half of the year with very much looking forward to it so with that we'll close and thank you again and have a great day everybody.

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

Okay.

Sure.