Q2 2020 Ionis Pharmaceuticals Inc Earnings Call

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Good morning, and welcome to Ioannis Pharmaceuticals, second quarter 2020 financial results Conference call I.

Operator: Good morning, and welcome to Ionis Pharmaceuticals' second quarter 2020 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Vice President, Investor Relations, to lead off the call. Please begin.

As a reminder, this call is being recorded at this time I would like to turn the call over to Wade Walke, Vice President Investor Relations to lead off the call. Please begin.

Thank you Andy before we begin I encourage everyone to go to the investors section of the honest website to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today.

Wade Walke: Thank you, Ivy. Before we begin, I encourage everyone to go to the investor section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial measures better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development. Additionally, joining us for Q&A are Onaiza Cadoret, Chief Corporate Development and Commercial Officer, and Eric Swayze, Executive Vice President of Research. I'd like to draw your attention to slide three, which contains our forward-looking language statement.

Believe non-GAAP financial measures <unk>, better, but represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany our discussion today.

With me on todays call or Britain, Sonia Chief Executive Officer, Beth Hougen, Chief Financial Officer, and Richard Gary Executive Vice President of development.

Additionally, joining us for today are on days, a category Chief corporate development, and commercial officer, and Eric Swayze Executive Vice President of research.

I'd like to draw your attention to slide three which contains our forward looking language statement, we will begin by making forward looking like we would be making forward looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties and our actual results may differ materially I encourage you to consult the risk factors discussed in our FCC filings for.

Wade Walke: We will begin by 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 discussed in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Additional detail.

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

Thanks Wade good morning, Thank you for joining us on todays call.

Brett P. Monia: Thanks, Wade. Good morning, and thank you for joining us on today's call. The first half of this year was marked by numerous important achievements that position us well for success this year and in the future. This has been a remarkable year for many reasons, but in particular for the tremendous strength and dedication demonstrated by the Ionis team. Our hard work has enabled us to remain on track to meet our key 2020 goals and achieve great success for years to come. And as we enter the second half of this year, I believe we are stronger than ever.

The first half of this year was marked by numerous important achievements that position us well for success this year and in the future.

This has been a remarkable year for many reasons, but in particular for the tremendous strength in dedication demonstrated by the Io and his team [noise].

Our hardware has enabled us to remain on track to meet our key 2020 goals and achieve great success for years to come.

And as we entered the second half of this year I believe we are stronger than ever our phase three programs are on track to five studies in progress into additional registration studies expected to start this year, our mid and early stage medicines are making excellent progress with additional proof of concept theater for several programs. Due later this year.

Brett P. Monia: Our phase three programs are on track with five studies in progress and two additional registration studies expected to start this year. Our mid and early stage medicines are making excellent progress, with additional proof of concept data for several programs due later this year. We continue to make growth; we continue to grow and expand the scope of our clinical pipeline with new medicines advancing rapidly to treat many new diseases for which effective treatments are lacking. We also continue to grow the IonisZone pipeline, while in parallel developing our commercialization strategy in support of this pipeline, and we continue to advance and expand the reach of our technology at a record pace. Looking ahead, we remain on track to achieve our 2020 financial guidance, and we have the financial resources, the people, and the commitment to execute on our agenda.

We continue to make growth, we continue to grow and expanded scope of our clinical pipeline with new medicines advancing rapidly to treat many new disease for which effective treatments are lacking we also continue to grow the eye on its own pipeline, while in parallel developing our commercialization strategy in support of this pipeline and we continue to advance.

Hansen expand the reach of our technology at a record pace looking ahead, we remain on track to achieve our 2020 financial guidance and we have the financial resources to people and the commitment to execute on our agenda.

My vision for Ioannis is to lead our industry in bringing transformative medicines to patients suffering with devastating diseases consistent with this goal, we anticipate and are on track to deliver 10 or more marketing applications for a range of devastating disease through the end of 2025, which we expect to result in it.

Elizabeth L. Hougen: My vision for Ionis is to lead our industry in bringing transformative medicines to patients suffering from devastating diseases. Consistent with this goal, we anticipate and are on track to deliver 10 or more marketing applications for a range of devastating diseases through the end of 2025, which we expect will result in a number of new commercial medicines. Our recent accomplishments, including those made this year, position us well to achieve our goals. I'll now turn the call over to Beth to review our financial performance, followed by Richard to discuss our pipeline progress, and then I'll open the call up for questions after brief closing remarks. Thank you, Brett.

Number of new commercial medicines, our recent accomplishments, including those made this year position us well to achieve our goals.

I'll now turn the call over to bet to review our financial performance, followed by Richard will discuss our pipeline progress and then I'll open the call up for questions. After brief closing remarks Ed.

Thank you Brad.

Elizabeth L. Hougen: We ended the second quarter with net income on a non-gap basis, and we continue to be well capitalized with cash and investments of more than $2.3 billion at the end of June. We remain financially strong as we enter the second half of this year, with substantial resources to execute on our ambitious agenda. As we noted last quarter, we are projecting increased revenue and earnings in the second half of this year. Based on our first half results and our forecast for the second half, we are reaffirming our financial guidance for this year. As we look at our commercialized medicines, Finraza remains a foundation of care for patients with all types of FMA. At the end of June, there were over 11,000 patients on Spinraza treatment worldwide, a substantial increase over last year. New patient growth was driven by markets across all major regions and led to global sales of $495 million in the second quarter. Spinraza's second quarter sales resulted in $72 million in royalty revenue to us.

We ended the second quarter with net income on a non-GAAP basic and we continue to be well capitalize the cash and investments of more than $2.3 billion at the end of Chan.

We remain financially strong as we entered the second half a bit here, let's substantial resources to execute on our ambitious agenda.

As we noted last quarter, we are projecting increased revenue and earnings in the second half of this year.

What their first half results on our forecast for the second half we are reaffirming our financial guidance for this year.

As we look at our commercialized medicine Spinraza remain a foundation of care for patients with all types of estimate.

At the end of June there were over 11000 patients on Spinraza treatment worldwide, a substantial increase over last year.

New patient growth is driven by market across all major region and led to global sales of $495 million in the second quarter.

Spinraza second quarter sales resulted in $72 million in royalty revenues flat.

Looking ahead, we invite agency opportunity for continued Spinraza growth in estimate patients have all ages and across many established and emerging markets.

Elizabeth L. Hougen: Looking ahead, we see the opportunity for continued Spinraza growth in SMA patients of all ages and across many established and emerging markets. Biogen now estimates that there are over 60,000 SMA patients in markets where it has a commercial presence, a nearly 35% increase from previous estimates of 45,000 patients. Additionally, new data continue to be generated that supports Benraza's substantial benefit in SMA patients of all ages. In the U.S., the Spinraza label was recently expanded to include new nurture data demonstrating unprecedented survival benefit in patients treated pre-symptomatically, with some patients treated for up to nearly five years. And in several EU markets, new, independent, real-world data demonstrating substantial and clinically meaningful benefit in adult and teen SMA patients is supporting broader reimbursement.

Hi to now estimate that there are over 60000 estimate hasten in markets, where buys and has a commercial presence.

Nearly 35% increase of previous estimates of playback thousand patients.

Additionally, new data continues to be generated that support spinraza substantial benefit an estimate patients about agent.

In the U.S. Spinraza label was recently expanded to include new nurture data demonstrating unprecedented survival benefit in patients treated pre symptomatically with some patients treated for absent nearly five years.

And in several EU market, new independent real world data demonstrated substantial and clinically meaningful benefit an adult and team estimate patience is supporting broader reimbursement.

Additionally, bison plans to initiate the response post marketing studies early next year, which will evaluate spinraza benefit in patients with a suboptimal clinical response to sell Jennifer.

Elizabeth L. Hougen: Additionally, Biogen plans to initiate the RESPOND post-marketing study early next year, which will evaluate Spinraza's benefits in patients with a suboptimal clinical response to Zolgensis. Biogen is also conducting the DEVOTE study of a higher dose of Spinraza, which has the potential to bring even greater benefit across SMA patients of all ages. Now, turning to Teghzadi and Wade Lebowitz.

Hi. This is also conducting the devote study of a higher doses been hot Spinraza, which has the potential to bring even greater benefit across estimate patients about agent.

Now turning to take steady and we've ever.

Elizabeth L. Hougen: We are pleased to report that these medicines delivered another quarter of growth, with product sales increasing to $16 million in the second quarter, a substantial increase compared to last year. Today, TxETI is commercially available in 15 countries, and the U.S. takes advantage as an at-home subcutaneous injection with further amplify, as new patients continue to initiate treatment, and existing patients were able to remain on treatment without disruption. We attribute this success to a number of factors, including AXSIA's world-class patient support program, AXSIA Connect. Xe is continuing to broaden reimbursement in the U.S. Additionally, 2,000 physicians have used Xe's genetic testing program to date, resulting in a growing number of patients being diagnosed with HATTR.

We're pleased to report that these medicines delivered another quarter of growth with product sales increasing to $60 million in the second quarter, a substantial increase compared to last year.

Today takes that is commercially available at 15 country.

In the U.S. take that is advantage as an at home subcutaneous injection was further amplified.

As new patients continue to initiate treatment and existing patients were able to remain on treatment without disruption.

We attribute this success to a number of factors, including at Sea is world class patient support program Akcea connect.

Akcea is continuing to broaden reimbursement in the U.S.

And Additionally, 2000 physicians have used akcea genetic testing program to date, resulting in a growing number of patients being diagnosed with H.A. TTR.

Akcea is also making solid progress broadening take steady access outside the United States.

Elizabeth L. Hougen: XE is also making solid progress broadening tech study access outside the United States. They have recently secured reimbursement in several new European markets, including Portugal, which is strategically important due to its endemic PTR amyloidosis population. In Canada, multiple private payer agreements are now in place, and government reimbursement negotiations are progressing well, and in Latin America, PTC Therapeutics is working to expand tech study access into new countries and to secure pricing in Brazil. We anticipate that expansion into even more new countries will help drive Tech City growth this year. Now, turning to Waylibra.

They have recently secured reimbursement in several new European markets, including particle which is strategically important due to its endemic TTR amyloidosis population.

In Canada multiple private payer agreements are now in place and government reimbursement negotiated negotiations are progressing well.

And in Latin America, PTC Therapeutics is working to expand take steady access into new countries and to secure pricing in Brazil.

We anticipate that expansion into even more new countries will help drive takes any growth this year.

Now turning to a lever we liver is on the market in Austria, Germany, Greece and in France through its HQ a reimbursed early access program.

Elizabeth L. Hougen: Waylibra is on the market in Austria, Germany, Greece, and France through its ATU, a reimbursed early access program. In Latin America, PTC recently filed for marketing authorization for WeLibra in Brazil and is working to expand access in other Latin American markets. AXSIA plans to launch in additional EU countries this year, and we are preparing to refile with the FDA. We're pleased with the performance of our commercial medicines and continue to see opportunities for growth as each of these transformational medicines reaches more patients in new and existing markets. Our partnered programs across each of our therapeutic franchises remain a substantial and sustainable source of revenue for us, with continued opportunities for growth. Many of our partnered programs achieved important catalysts this year, which is reflected in the more than $55 million in R&D revenue we earned in the second quarter. This amount included over $25 billion from our neurological disease franchise, including several programs under our Biogen collaboration; $14 million from our oncology franchise, including a licensee from AstraZeneca for Ion-7 free sex, and more than $10 million from our Cardiorenal Disease franchise, including programs with AstraZeneca and Pfizer.

In Latin America, PTC recently filed for marketing authorization for we live in Brazil, and is working to expand access and other Latin American market.

Axiom plans to launch an additional EU countries. This year and we are preparing to re file with the FDA.

We're pleased with the performance of our commercial medicine and continue to see opportunities for growth as each of these transformational medicines reach more patients in new and existing market.

Our partnered program across each of our therapeutic franchises remain a substantial and sustainable source of revenue for us.

With continued opportunities for growth.

Many of our partner programs achieved important catalyst this year, which is reflected in the more than $55 million in R&D revenue, we earned in the second quarter.

This amount included over $25 billion from our neurological disease franchise, including several programs under our eyes in collaboration.

$14 million from our oncology franchise, including a license fee from Astrazeneca for ion 73 cents.

And more than $10 million from our cardio renal disease franchise, including partner programs with Astrazeneca and Pfizer.

We remain on track for significantly higher R&D revenue in the second half of this year compared to the first half.

Elizabeth L. Hougen: We remain on track for significantly higher R&D revenue in the second half of this year compared to the first. And we have already generated $35 million in milestone payments in the third quarter, including payments from Biogen for progress with Ionis MAP-TRX and the initiation of a Phase I-II study of ION464 in patients with multiple system atrophy. Driven by our Phase III program for Axia TTR-LRX and the progress of other medicines in our Ionis-owned pipeline, our Q2 non-GAAP operating expenses were slightly higher compared to last year. With these results, we achieved net income of $8 million for the quarter on a non-GAAP basis, an increase compared to our first quarter results.

And we have a heavy generated $35 million in milestone payments in the third quarter.

Including payments from Biogen for progress for progress with Ioannis map Trx.

And the initiation of the phase one two steady if I add or six four in patients with multiple system atrophy.

Driven by our phase three program for Akcea, TTR Dash LR Act and the progress of other medicine in our Ioannis pipeline. Our Q2, non-GAAP operating expenses were slightly higher compared to last year.

With these results we achieved net income of $8 million for the quarter on a non-GAAP basis, an increase compared to our first quarter results.

Elizabeth L. Hougen: Our first half results and projections for the rest of this year enable us to reaffirm our 2020 financial guidance. In the second half of this year, we project increasing revenues with numerous opportunities to earn significant R&D revenue on top of our strong commercial revenues, and we continue to execute on our strategic objectives for this year. We expect higher non-GAAP operating expenses compared to the first half of this year.

Our first half results and projections for the rest of this year enable us to reaffirm our 2020 financial guidance.

In the second half of this year, we project, increasing revenues with numerous opportunities to and significant R&D revenue on top of our strong commercial revenues.

And we continue to execute on our strategic objectives for this year.

We expect higher non-GAAP operating expenses compared to the first half of this year.

Richard S. Geary: Our financial strength is a fundamental pillar enabling broad success across our business. With more than $2.3 billion in cash and investments, we have the financial resources to execute on our near and longer-term strategic priorities. And with that, I'll turn the call over to Richard to provide an update on our pipeline. Thank you, Beth.

Our financial strength as a fundamental pillar, enabling broad success across our business.

With more than 2.3 billion in cash and investments we have the financial resources to execute on our near and longer term strategic priority.

And with that ill turn the call over to Richards provide an update on our pipeline.

Thank you Beth.

Our pipeline of over 40 medicines targeting a broad range of diseases achieved numerous catalysts in the first half of this year.

Richard S. Geary: Our pipeline of over 40 medicines targeting a broad range of diseases achieved numerous catalysts in the first half of this year, and we're looking forward to a significant number of additional catalysts in the coming months. I'll start with highlights from our world-class neurological disease franchise. As we highlighted in our recent neurological disease pipeline webcast, this is a robust and growing franchise with 15 programs in development and many more in various stages of research. With so many programs today, I'll focus only on those with recent highlights.

And we're looking forward to a significant number of additional catalysts in the coming months.

Ill start with highlights from our World class neurological disease franchise.

As we highlighted in our recent neurological disease pipeline webcast. This is a robust and growing franchise with 15 programs in development and many more in various stages research.

With so many programs today I'll focus only on those with recent highlights.

Richard S. Geary: But I urge anyone who missed our Neuro webcast to listen to the replay to learn more about these exciting programs. Tillman Urson and Tofferson, our late-stage neurological disease programs, are positioned to be our next commercial medicines. The Pneumonurse in a Phase III study in patients with Huntington's disease is fully enrolled and on track for data and potential regulatory filing in 2022. The Toperson in a phase III study in patients with SOD1 ALS is on track for data late next year. Data from a Toperson Phase 1-2 study in patients with STOD1-ALS were recently published in the New England Journal of Medicine.

But I urge anyone who missed our neuro webcast to listen to the replay to learn more about these exciting programs.

From an arsenal tow person all our late stage neurological disease programs, our position to be our next commercial medicines that some winners in phase three study in patients with Huntingtons disease is fully enrolled and on track for data and potential regulatory filing in 2022.

The tougher sense phase three study in patients with side one LLS is on track for data late next year.

Data from 12% Phase one two study in patients with side, one ill ask where recently published in the New England Journal as.

Richard S. Geary: These data demonstrated promising signs of efficacy after only three months of treatment, providing hope for patients with this devastating disease. Results from the Phase 1-2 study also support the potential for a growing ALS franchise, which today includes medicines in development to treat all forms of ALS. Ion 541, our first medicine for the treatment of sporadic ALS, which accounts for approximately 90% of the ALS patient population, is expected to enter a Phase I-II study soon. Ion 5-4-1 is a potent inhibitor of Ataxin-2, designed to modulate toxicity resulting from inappropriate localization of the TDP-43 protein, which is thought to contribute to motor neuron toxicity.

These data demonstrated promising signs of efficacy after only three months of treatment, providing hope for patients with this devastating disease.

Results from the Phase one two study also support the potential for a growing aeolus franchise.

Which today includes medicines and development to treat all forms of the allowance.

Yeah on five four won our first medicine in the treatment of sporadic kls, which accounts for approximately 90% of the last patient population.

Is expected to enter a phase one two studies soon.

I on 541, as a potent inhibitor of attacks and to designed them onto a toxicity, resulting from inappropriate localization of the GBP 43 protein, which is thought to contribute to motor neuron toxicity.

And we recently added eye on three Sixthree, our first Ioannis owned a aaos medicine in the pipeline.

Yeah on 306, three is designed to treat Foss aeolus another familial form of this disease caused by mutations in the bus gene.

Richard S. Geary: And we recently added ION363, our first Ionis-owned ALS medicine in the pipeline. Ion 363 is designed to treat FUS ALS, another familial form of this disease caused by mutations in the FUS gene. This program could have a rapid path to the market going directly into a registration study later this year or early next year. Biogen also recently initiated a Phase 1-2 study of ION-464, our medicine targeting alpha-synuclein for the treatment of multiple system atrophy, a rapidly progressing neurodegenerative disease with no therapeutic options. And importantly, our Ionis-owned medicines for the treatment of Alexander's, Lephora, and prion diseases continue to progress well and remain on track to enter clinical studies in patients late this year and next year. Turning to our Cardiorenal and Metabolic Disease Friends

This program could have a rapid path to the market going directly into registration study.

Later this year or early next year.

Biogen also recently initiated a phase one two study of ion for six for our medicine targeting Alpha Synuclein for the treatment of multiple system atrophy.

A rapidly progressing neurodegenerative disease with no therapeutic options.

And importantly, our I honestly don't medicines for the treatment of Alexander's before.

And for non diseases continue to progress well and remain on track to enter clinical studies in patients late this year and next year.

Turning to our cardio renal and metabolic disease franchises.

The phase three study of Akcea April literally lrx is progressing well and the trial readout is expected in 2024.

Richard S. Geary: The Phase 3 study of Axia Apolital A LRX is progressing well, and the trial readout is expected in 2024. LRX was recently granted fast-track designation by the FDA, underscoring the significant risk for cardiovascular events in the millions of patients with LPA-driven cardiovascular disease. Additionally, our Phase 3 studies of Axia TPR-LRX, both Neurotransform and Cardiotransform, are progressing well, with data expected in 20 Coming up, we look forward to providing a comprehensive update from our Cardiorenal Disease Franchise. We plan to present the full positive Phase 2 dataset for our Leica Medicines Xeia ApoC3 LRX and Buprenoracin, our medicine targeting EngPTL, and a medical conference later this month. And next month, we plan to host an investor webcast to provide an update on these two programs and a number of other programs in our cardio renal franchise. Please stay tuned for details and timing for these events.

Ixia April literally Lrx was recently granted fast track designation by the FDA underscoring the significant risk for cardiovascular events in the millions of patients with Lpa driven cardiovascular disease.

Additionally, our phase three studies of Akcea TTR Lrx.

Both neuro transform and cardio transform are progressing well with data expected in 2023.

And coming up we look forward to providing a comprehensive update from our cardio renal disease franchise, we plan to present the full positive phase two data set for like a medicines Ixia April C. Lrx and open the Morrison, our medicine targeting and PD L. Three.

At a medical conference later this month and next month, we plan to host an investor webcast to provide an update on these two programs and a number of other programs in our cardio renal franchise.

Please stay tuned for details and timing for these events.

We continue to make significant progress with a number of programs partnered with Astra Zeneca. This collaboration continues to be very productive with numerous cardio renal metabolic and oncology programs underway.

Richard S. Geary: We continue to make significant progress with a number of programs partnered with AstraZeneca. This collaboration continues to be very productive, with numerous cardiorenal, metabolic, and oncology programs underway. Later this year, we at AstraZeneca look forward to providing an update on Ionis AZ-4 2.5 LRX, our program for the treatment of cardiovascular disease, which includes both subcutaneous and oral formulations.

Later this year, we had Astra zeneca look forward to providing an update on Ioannis AC for 2.5 Lrx our program for the treatment of cardiovascular disease, which includes both subcutaneous and oral formulations.

Astrazenecas also making good progress with the ongoing phase one studies with an eye on a tree nine are getting be NPL athree for the treatment of Nash.

And I on 532 targeting April one for the treatment of chronic kidney disease.

Turning to our oncology programs Astra Zeneca recently returned our stand three inhibitor Denver tiers.

Richard S. Geary: AstraZeneca is also making good progress with the ongoing Phase 1 studies with Ion 839 targeting PN-PLA3 for the treatment of NASH, and Ion 532 targeting ApoL1 for the treatment of chronic kidney disease. Turning to our oncology program, AstraZeneca recently returned our STAT3 inhibitor to Amputeer.

We are reviewing data from the them the Trc clinical program and forming our plans.

For the continued development of this medicine for the treatment of cancer.

And we're pleased that Astra Zeneca recently licensed eye on 736 are in a sense medicine net targets Fox P. Three.

Yeah on 76 is our first and I sense medicine, working purely through an immuno oncology mechanism of action. We look forward for this program entering clinical studies inpatient shortly.

Richard S. Geary: We are reviewing data from the Dan Van Teersen Clinical Program and forming our plans for the continued development of this medicine for the treatment of cancer. And we're pleased that AstraZeneca recently licensed Ion 736, our antisense medicine that targets FOXP3. Ion 736 is our first antisense medicine working purely through an immuno-oncology mechanism of action.

We're looking forward to providing updates from our advancing and expanding pulmonary franchise as well later this year. We plan to report pulmonary delivery proof of concept results from the healthy volunteer cohort from our Ioannis Nx 2.5, Rx phase one two study.

In early next year, we expect to have data from the fully enrolled cystic fibrosis patient cohort from the phase one two study.

Richard S. Geary: We look forward to this program entering clinical studies in patient short, we're looking forward to providing updates from our advancing and expanding pulmonary franchise as well. Later this year, we plan to report pulmonary delivery proof-of-concept results from the Healthy Volunteer Cohort from our Ionis ENAC 2.5Rx Phase 1-2 study. Early next year, we expect to have data from the fully enrolled Cystic Fibrosis patient cohort from the Phase 1-2 study. Also later this year, we look forward to initiating a Phase 2 study of Ionis ENAC 2.5 RX in patients with COPD. This study both broadens the ENAC development program and further expands our pulmonary franchise to diseases beyond cystic fibrosis.

Also later this year, we look forward to initiating a phase two study of Iona Cnf 2.5, Rx in patients with Seo TV.

This study both broadens the enact development program and further expands our pulmonary franchise to diseases beyond cystic fibrosis.

Along with high on US Even act 2.5, Rx, we have ion six sixthree and development and development today for an undisclosed pulmonary indication with multiple additional new drugs to follow in the near future.

Also coming up in the second half.

Plan to report proof of concept results from our AG.

Dramatically and hypertension programs, we look forward to initiating registration studies with Akcea April C. Lrx in patients with FCS and with an eye on 363 in patients with fossil assets.

And we plan to initiate a phase one two study of our eye on its own cancer medicine targeting IRS for ion 251 to be evaluated first in patients with multiple myeloma.

Richard S. Geary: Along with Ionis ENAC 2.5RX, we have ION663 in development today for an undisclosed pulmonary indication, with multiple additional new drugs to follow in the near future. Also, coming up in the second half, we plan to report proof-of-concept results from our HAE, acromegaly, and hypertension programs. We look forward to initiating registration studies with XeA-C3-LRX in patients with FCS and with Ion-363 in patients with FusAOX.

I'm extremely pleased with the progress we are achieving with our pipeline today and look forward to providing further updates as the year progresses.

I want to take the opportunity to acknowledge that continued trust and commitment of the patients families investigators and medical staff participating in our studies. During this time and I want to point out that it is because of the hard work of our dedicated and resilient employees.

Brett P. Monia: And we plan to initiate a Phase I-II study of our Ionis-owned cancer medicine targeting IRF4, Ion 251, to be evaluated first in patients with multiple myeloma. I'm extremely pleased with the progress we are achieving with our pipeline today and look forward to providing further updates as the year progresses. I want to take this opportunity to acknowledge the continued trust and commitment of the patients, families, investigators, and medical staff participating in our studies during this time. And I want to point out that it is because of the hard work of our dedicated and resilient employees. And we have continued to successfully adapt to the evolving global pandemic and continue to execute on our goal to deliver transformational medicines to patients in need. And with that, I'll turn the call back over to Brett to close this portion of the call.

And we have continued to successfully adapt to the evolving global pandemic and continued to execute on our goal to deliver transformational medicines to patients and indeed.

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

Thanks Richard.

Our business today is stronger than ever thanks to the dedication and hard work of everyone Ioannis as best discussed we remain financially strong with the resources and people we need to continue executing on our very ambitious agenda.

As Richard just highlighted our pipeline continues to advance and expand in new and exciting ways, keeping us on track to deliver 10 or more marketing applications for a range of devastating diseases through the into 2025, which we expect to result in a number of new commercial medicines.

I'm very excited about the progress I see for the rest of this year, including advancing our phase three studies and starting to additional registration studies for patients with FCS and Alice.

Reporting clinical proof of concept results for several programs.

Operator: Thanks, Richard. Our business today is stronger than ever thanks to the dedication and hard work of everyone at Ionis. As Beth discussed, we remain financially strong with the resources and people we need to continue executing on our very ambitious agenda. And, as Richard just highlighted, our pipeline continues to advance and expand in new and exciting ways, keeping us on track to deliver 10 or more marketing applications for a range of devastating diseases through the end of 2025, which we expect will result in a number of new commercial medicines. I'm very excited about the progress I see for the rest of this year, including advancing our Phase III studies and starting two additional registration studies for patients with STS and ALS, reporting clinical proof of concept results for several programs, and expanding and advancing the ionosome pipeline with the expectation to initiate clinical development for several new ionosome medicines this year.

Expanding in advancing the onus on pipeline with the expectation to initiate clinical development for several new Ioannis on medicines this year.

Building, our commercial capabilities and strategy and broadening the reach of our technology, which is advancing at a record pace.

As we achieved these and the multiple additional goals and objectives that make up our ambitious agenda, we move closer to becoming the leader in delivering transformational medicines to patients need and aspiration that with our pipeline technology people and financial resources, we're well on our way to making a reality.

And with that I'd like to open the call for some questions.

We will now begin question answer session I ask the question you May Press Star then one on your Touchtone phone. If you are using speakerphone. Please pick up your handset before prices keno.

Similar to your question. Please press Star then Q.

Our first question will come from Jim Birchenough with Wells Fargo.

Hi, guys. Congrats on all the progress a few questions I guess first just on the inhaled program.

Maybe you could give us a sense of what level of knocked down you're targeting in the normal volunteer part of the study and what gives you confidence that you can overcome the physical barriers to.

Operator: Building our commercial capabilities and strategy and broadening the reach of our technology, which is advancing at a record pace. As we achieve these and the multiple additional goals and objectives that make up our ambitious agenda, we move closer to becoming the leader in delivering transformational medicines to patients in need, an aspiration that, with our pipeline, technology, people, and financial resources, we are well on our way to making a reality. And with that, I'd like to open the call to questions. We will now begin the question and answer session. To ask a question, you may press star and then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys.

Getting adequate drug penetration in patients with CF opt to start with and then on the oral just.

Assuming success towards year end, how quickly could you move some of your other programs forward in an oral formulation.

Thanks, Jim for the for the questions.

So.

As you know.

Each pulmonary program each each disease areas.

We'll be unique in the level of knockdown of a specific target that will produce benefit.

Patients specifically for our Aonec program, which is the program we're going to readout.

From our pulmonary franchise later this year the phase one normal volunteer study and will provide an update on the CF study as well.

Unknown Executive: To withdraw your question, please press star, then two. Our first question will come from Jim Bertinoff with Wells Fargo. Hi guys, congrats on all the progress. A few questions, I guess first on the Inhaled program: maybe you could give us a sense of what level of knockdown you're targeting in the normal volunteer part of the study and what gives you confidence that you can overcome the physical barriers to getting adequate drug penetration in patients with CF to start with? And then on the oral, just assuming success towards year end, how quickly could you move some of your other programs forward in an oral formulation? Thanks, Jim, for the questions.

We have demonstrated in preclinical models that as little as 50% reduction in the next aren't at messenger on a in protein produces actual reversal.

Of disease in models of cystic fibrosis and other models of.

Yes, mucus related pulmonary diseases.

So that's our target.

That's our that's our target for the clinical studies, we're confident we'll probably go beyond that.

Greater reductions in target expression for in there.

We are we're quite confident in our ability to penetrate.

The unusual architecture of although both.

Cystic fibrosis long for example, or CRPD loan, which can have become weakest linings.

Unknown Executive: So, as you know, each pulmonary program, each disease area will be unique in the level of knockdown of a specific target that will produce benefit in patients. Specifically, for our ENAC program, which is the program we're going to read out from our pulmonary franchise later this year from the phase one normal volunteer study, and we'll provide an update on the CF study as well. We have demonstrated in preclinical models that as little as 50% reduction in the ENAC RNA, messenger RNA, and protein produces actual reversal of disease in models of cystic fibrosis and other models of mucus-related pulmonary disease. So, you know, that's our target.

Over in the appealing we've generated quite a bit of data preclinically in models.

And type of cystic fibrosis, and we have shown really good excellent are attractive uptake into into cells in the Brazilian broadly throughout the along with with with knocked down thats really comparable to that and normal lungs, and Weaver and we've also replicated in CF models, but normal.

Monkeys.

Similar knockdowns falling integration of our index over our drug and for other programs for other drugs as well in our pulmonary program. So.

And these these this deliveries and simple sailing solutions were not give you sort of delivery vehicle to penetrate the OEM.

Unknown Executive: That's our target for the clinical studies, but we're confident we'll probably go beyond that and get even greater reductions in target expression for ENAC. We're quite confident in our ability to penetrate, you know, the unusual architecture of a cystic fibrosis lung, for example, or a CLPD lung, which can have, you know, thick mucous linings covering the epithelium. We've generated quite a bit of data preclinically in models that replicate a type of cystic fibrosis, and we've shown really good, excellent, attractive uptake And we've also replicated it, not in CF models, but in normal monkeys. Similar knockdowns following inhalation of our e-neck of our drug and for other programs for other drugs as well in our pulmonary program. And this delivery is in a simple saline solution, so we're not using any sort of delivery vehicle to penetrate the epithelium.

Regarding.

The oral program Yeah, we're looking forward.

In sharing an update on our.

On this program, both subcutaneous formulation and the oral formulation later this year with our partner Astra Zeneca.

And as we're moving other programs forward, we're already doing that.

We're confident.

In.

In the oil platform and we're not sitting still we're continuing to develop new formulations. Even go beyond what we have in the clinic or ready today.

And we already moving forward several programs Preclinically and we're prioritizing those programs that will to move into the clinic orally.

Based on.

Based on where we think it would have the greatest impact so stay tuned for that and hopefully we'll provide an update at that time.

We provide an update on the current or a programmable move you have a peek into what else coming later this year.

And Brett maybe if you allow me one more just quickly for for Bath, when we think about the uptick in R&D revenue in the second half of the year, how should we think about that as as a run rate for.

Longer term do you have enough visibility in terms of future milestones in the cadence of various partner programs.

To give us some sense of whether thats, a sustainable level of R&D revenue or how do we think about modeling that going forward.

Unknown Executive: [inaudible] The Oral Program. Yeah, we're looking forward to sharing an update on this program, both the subcutaneous formulation and the oral formulation later this year with our partner AstraZeneca. And as we're moving other programs forward, we're already doing that. We're confident in the oral platform, and we're not sitting still.

That's a great question, Jim Thank you so.

I think is you've seen over the over the last quite a few years with the company. We have continued to increase our research and development revenues.

Elizabeth L. Hougen: We're continuing to develop new formulations to even go beyond what we have in the clinic already today, and we're already moving forward several programs pre-clinically, and we're prioritizing those programs that will move into the clinic early based on, you know, where we think they would have the greatest effect. So stay tuned for that, and hopefully we'll provide an update at that time. When we provide an update on the current oral program, we'll give a peek into what else is coming later. And Brett, maybe if you'll allow me one more just quickly for Beth, when we think about the uptick in R&D revenue in the second half of the year, how should we think about that as a run rate for, you know, longer term? Do you have enough visibility in terms of future milestones and the cadence of various partner programs to give us some sense of whether that's a sustainable level of R&D revenue? Or how do we think about modeling that going forward? That's a great question, Jim.

And build on top of that obviously very strong base of commercial revenues and when I see as I look out into the future are a number of factors that I think continued to sustain and potentially grow our R&D revenues and that is fine.

The strength of our existing partnerships.

On the sheer number of partnered programs under those partnerships and the fact that those partnered programs will continue to increase particularly as you think about the biogen collaboration.

As a very productive relationship that we have just the number of medicines that we are continuing to bring forward in the neurological stays working with Biogen.

And then as all of those medicines advance in development.

When you see greater and greater.

Dollar values of milestone payments licensing fees, reflecting the increase value that we are creating as our medicines advanced development. So I think those factors together give us.

Elizabeth L. Hougen: Thank you. So, you know, I think, as you've seen over the last quite a few years with the company, we have continued to increase our research and development revenues and built on top of that, obviously, a very strong base of commercial revenues. And what I see as I look out into the future are a number of factors that I think could continue to sustain and potentially grow our R&D revenues. And that is, first, just the strength of our existing partnerships, the sheer number of partnered programs under those partnerships and the fact that those partnered programs will continue to increase, particularly as you think about the Biogen collaboration and the very productive relationship that we have, just the number of medicines that we are continuing to bring forward in the neurological space working with Biogen.

Our confidence in the ability to sustain a potentially grow our R&D revenues into the future.

Great. Thanks for taking the questions guys.

Thanks.

Our next question comes from L.A. Merrill Lynch Cantor Fitzgerald.

Hi, Thanks, so much for taking the question.

Okay, all the update on.

And a broader strategic one have you guys with so many in the pipeline. How are you thinking about you know you've done sort of the akcea.

Ladies and SAP, how are you thinking about long term potentially strategic vision as view about franchises and focused and area with neurology and cardiovascular and various okay.

[music].

Thanks for the question Alley.

No we have such a prolific drug discovery engine here that we validated here at Aon is established.

Elizabeth L. Hougen: And then as all of those medicines advance in development, you see greater and greater dollar values of milestone payments and licensing fees reflecting the increased value that we are creating as our medicines advance in development. So I think those factors together give us real confidence in the ability to sustain and potentially grow our R&D revenues into the future. Great, thanks for taking the questions, guys.

We.

It sets us up very well.

Many different options to maximize the value of each of our medicines for ioannis shareholders for patients.

Uses and taking advantage of you know this engine as drug discovery engine.

We will continue to partner strategically where it makes sense in the future that one way to think about that is for your broad large indications like we did with Pfizer last year for large cardiovascular indication with our nursing program or like we do it LT little a with Novartis.

Brett P. Monia: Our next question comes from Ellie Merle with Cantor Fitzgerald. Hey guys, thanks so much for taking the question, and I appreciate all the updates. Just a broader strategic one, as you guys have so many assets in the pipeline, how are you thinking about, you know, you've done sort of the Axia relationship, how are you thinking about long-term, potentially strategic visions as you, you know, develop franchises and focus on areas such as neurology, you know, cardiovascular, and, you know, various focuses there? Thanks.

We will hold onto those drugs longer to command, even greater economic upside for Ioannis.

Not partner so early.

And that will continue.

In addition to that we are.

Prioritizing certain assets certain franchises within the cornerstone pipeline and building our commercialization strategy alongside the next year.

Strategy.

And.

And we're prioritizing the pipe one one area that were particularly.

Brett P. Monia: Thanks for the question, Ellie. We have such a prolific drug discovery engine here that we've validated here at Ionis and established. It sets us up very well with many different options to maximize the value of each of our medicines for Ionis shareholders and for patients. Taking advantage of this engine, this drug discovery engine, we will continue to partner strategically where it makes sense. For example, like we did with Pfizer last year for a large cardiovascular indication with our Rupa Narsan program, or like we did with Lp-a with Novartis, we will hold on to those drugs longer to command even greater economic upside for Ionis, not partner so early, and that will continue. In addition to that, we are prioritizing certain assets, certain franchises within Ionis' own pipeline and building our commercialization strategy alongside the Axia strategy. And we're prioritizing the pipeline; one area that we're particularly focused on to bring through phase three into the market is our rare neurological disease pipeline. We think that this brings great value.

Focused on.

To bring through phase three into the market. Our is on rare neuro neurological disease pipeline, we think that that brings great value, we already have fiber or more drugs in the onus on neuro pipeline.

We touched on the bus sale as program meridians webcast, but also drugs like Alexander's disease, and probably on seasonal or disease, and others are coming and I think that this this will be a priority for ioannis.

To bring through the finish line ourselves, so you're going to see a balance of.

We continue to see a balance of strategic partnering.

Driving.

Attractive economics to the company.

While we also build our own pipeline.

It's amazing the joint.

At all about our neuro pipeline in how we see them, but we see the value in that segment of the finish line sure.

So you know a inspection said we are investing in that business on pipeline in comparing our business strategy and among the many rare diseases in the portfolio. We have prioritizing urology isn't initial against its a very complementary conserve leveraging really the deep neural expert in drug discovery and development and then complementing.

Now with building out the commercial capabilities needed to bring our where newer products to patients.

Brett P. Monia: We already have five or more drugs in the Ionis One Neural Pipeline. We touched on the FUST-ALS program already in this webcast, but also drugs like Alexander's disease and prions disease and LaFord disease and others are coming. And I think that this will be a priority for Ionis to bring through the finish line themselves.

So it's really important also noted the products we have deliver on significant unmet needs that they get to root causes disease and have the potential to stabilize reverse and prevent.

So we're very excited on that and as Brent already alluded to we have not chest.

Onaiza Cadoret: I'm driving attractive economics for the company while we also build our own pipeline. Onaiza, do you want to talk at all about our neural pipeline and how we see, what we see the value in that, take it to the finish line? Sure.

Faster and last but we also have chief app for Alexander's to be than high on Tvs and these are kind of.

Building upon each other relatively rapidly over the next year and getting into the clinic and we expect a really strong accelerated path towards.

Onaiza Cadoret: So, you know, as Brett just said, we are investing in Ionis' own pipeline and preparing our business strategy. And among the many rare diseases in the portfolio, we have prioritized neurology as an initial focus. It's very complementary because we're leveraging deep neuroscience expertise in drug discovery and development and then complementing that with building up the commercial capabilities needed to bring our rare neuro products to patients. So it's really important to also know that the products we have deliver on significant unmet needs if they get to the root cause of the disease, and they have the potential to stabilize, reverse, and or prevent disease. So, we're very excited about that, and as Brett already alluded to, we have not just FUS for ALS, but we also have GFAP for Alexander's disease and prion disease, and these are kind of, you know, building upon each other relatively rapidly over the next year, getting into the clinic, and we expect a really strong accelerated path to, So it gives us a good, good portfolio to start with. And importantly So based on that, you know, it's an exciting time, and we're really building out the capabilities commensurate with the clinical data readouts for commercial residents. Got it. Very helpful.

And it gets that's a good good portfolio to start with Ben and importantly, we also see other products in ran euro.

That are beyond the several fueled the business strategy not just for.

For the initial period Thats really for sustainable growth.

Based on that in an exciting time, and we're really building out the capabilities commensurate with the clinical data read outs for commercial readiness.

Very helpful and maybe just oh opt in on that the more directly and maybe for that just from kind of corporate restructuring.

Financial relationship perspective, I guess, what are the pros and cons the kind of keeping all of these assets in ioannis itself versus potentially forming additional new subsidiaries.

Yes.

That area I think I, certainly have a very very light pipeline.

The only thing.

At this point, we are in the early stages of looking at.

And looking at our Ioannis on pipeline looking at the narrow assets.

I think we're making excellent progress along that path and I think an ace and her team working with the rest of let's say to any great job.

But as far as what exactly structure, we would put in place I think it's just really too early to to say I think whats important is the key takeaway here is we're prioritizing our ioannis owns pipeline.

Elizabeth L. Hougen: And maybe just to ask in perhaps a more direct way, maybe for Beth, just from kind of a corporate structuring financial relationship perspective, what are the pros and cons of kind of keeping all of these assets in Ionis itself versus potentially forming additional new subsidiaries, such as, you know, a neuro subsidiary, as you guys certainly have a very, very large pipeline. So I think, you know, at this point, we are in the early stages of looking at our Ionison pipeline, looking at the neural assets. I think we're making excellent progress along that path. And I think Onaiza and her team, working with the rest of us, are doing a great job.

And our intention is to retain substantial commercial value from our eye on this on pipeline.

Got it thanks.

Thanks.

Our next question comes from cabin Messer Needham and company.

Great. Thanks for taking my questions and congrats on all the progress.

Maybe a little bit a follow up to the to the prior kind of strategic question.

You guys founded Akcea I know at the time a lot of the dialogue along around the rationale was it enabled you to retain better economic develops who commercial capabilities, but kind of silo off.

Sort of a culture of that sort of R&D culture that has helped create that fantastic.

Elizabeth L. Hougen: But as far as what exactly structure we would put in place, I think it's just really too early to say. I think what's important is the key takeaway here is that we're prioritizing our Ionison pipeline, and our intention is to retain substantial commercial value from our Ionison pipeline. You got it. Thanks so much.

Discovery and development engine.

Appreciating that you know over time, you strategy sorta had to evolve and adapt just wondering how report.

Chad Messer: Thanks, y'all. Our next question comes from Chad Messer with Medium Income. Great. Thanks for taking my questions and congratulations on all the progress. Maybe a little bit of a follow-up to the prior kind of strategic question.

You view that today as you are growing your wholly owned pipeline.

Particularly in Europe in other areas as well.

Great question Chad.

The word Evelyn evolve that you use is a great words, a thing to think about this.

R&D innovation scientific innovation will always be the core of islands, we think were among the leaders.

Brett P. Monia: When you guys founded Axia, I know at the time a lot of the dialogue around the rationale was it enabled you to retain better economics, develop some commercial capabilities, but kind of silo off the culture of the sort of R&D culture that has helped create this fantastic discovery and development engine. Appreciating that over time your strategy sort of had to evolve and adapt, just wondering how important you view that today as you're growing your wholly-owned pipeline, particularly in Nero but other areas as well. Great question, Chad. The word evolved that you use is a great word to think about this.

And innovation in our into biotech industry.

Today.

By offices.

And that will always be priority.

However evolution.

And the company is in a very strong position culturally today and very importantly, we've now proven the technology improvement in so many different ways. We were we're in a different place we found that akcea for five years ago and it was is it was a good strategy as I was very good strategy at the time to maximize the commercial.

Value of certain AFE rare disease assets in the pipeline, while preserving the innovation that is at our core at Ioannis and proving invalidating the technology not just clinically, but also commercially which we've now done when a different place today and I think that the culture can endure.

Brett P. Monia: You know, R&D, innovation, scientific innovation will always be the core of IONS. We think that we're among the leaders in innovation in the biotech industry. Today, Ionis, and that will always be a priority, however, evolution happens, and the company is in a very strong position culturally today, and very importantly, we've now proven the technology, we've proven it in so many different ways, we were in a different place when we founded Axia four or five years ago, and it was a good strategy at the time, it was a very good strategy at the time to maximize the commercial value of certain rare disease assets in the pipeline, while preserving the innovation that is at our core at Ionis, and proving and validating the technology, not just clinically, but also commercially, which we've, We're in a different place today, and I think that the culture can endure and work and actually synergize with the creating of our own pipeline and building commercial capabilities to maximize the value of that. Thanks, and congrats again.

Work and actually synergize with the creating of our of our own pipeline and building commercial capabilities to maximize the value of that quickly.

Great Thanks, and congrats again.

Thanks, Ken.

Our next question comes from Paul Nonsense clip Stifel.

Hey, Thanks for taking the question is Alex on for Paul I'd, just curious as you're thinking about a year PKK assets for AG.

How you're thinking about that market sort of the the place right and so in what is relatively a competitive market.

With some major drugs, they're going generic just curious your thoughts there. Thanks.

Yeah, maybe I'll ask laser touch on this the she's been thinking hard about.

This is another ioannis owned asset for rare diseases.

Elizabeth L. Hougen: Thanks, Jeff. Our next question comes from Paul Mathis with Stiefel. Hey, thanks for taking the question. This is Alex on behalf of Paul.

We're very excited about the pre telecom program, we're looking forward to share results.

In patients with a JV later this year.

Unknown Executive: I'm just curious, you know, as you're thinking about your PKK asset for HAE, how you're thinking about that market, sort of the place for an ASO in what is relatively a competitive market, with some major drugs there going generic. Just curious about your thoughts there. Thanks. Yeah, maybe I'll ask Onaiza to touch on this, because she's been thinking hard about it. You know, this is another Ionis-owned asset for rare diseases. We're very excited about the pre-CALICRAN program, and we're looking forward to sharing results in patients with HAE later this year. Onaiza?

Yes, sure, yes, you're right that's actually a exit competitive market, we feel like we haven't really strong kind of product on we've done some early market research and we still think there is opportunity and boom for more players in here.

I think we've heard that they want prophylactic treatment the better more defined prevent attacks rather than simply kind of tree.

Uh huh.

HM E and we're seeing some room in there because they are feeling that with the current products that they are still breakthrough symptoms that are happening. We think we have differentiation there.

And certainly we have differentiation from.

Onaiza Cadoret: Yeah, sure. Yeah, you're right. It's actually a competitive market, but we feel like we have a really strong competitive product. We've done some early market research, and we still think there's opportunity and room for more players here. I think we've heard that they want prophylactic treatments that are more designed to prevent attacks rather than simply kind of treat acute episodes of HAE. And we're seeing some room in there because they feel that with the current products, there are still breakthrough symptoms that are happening. So we think we have differentiation going on there.

And dusting perspective is I'll Miss injectable administration.

No QVC acumen.

Yes, well.

Those are some really great area that would have announced premium that competitive differentiation and I'll just add add to that Alex.

In addition to monthly or or even less frequent dosing.

This this is another program that has the potential to develop an oral formulation, which would be a very competitive.

Meaningful competitive advantage. So our first focus is to demonstrate no tax or.

Unknown Executive: And certainly, we have differentiation from a dosing perspective as well, with injectable administration, with, you know, QE or Q bi-monthly as well as a possibility. So those are some really great areas that we're focusing on to bring about competitive differentiation. And I'll just add to that, Alex, that, you know, in addition to monthly or even less frequent dosing, this is another program that has the potential to develop an oral formulation, which would be a very meaningful competitive advantage. So our first focus is to demonstrate no attacks or an attack rate in patients that's comparable to, you know, what drugs on the market are beating, and then think about what would be more convenient for patients and how patients would value All right, great, thanks. Our next question comes from Tyler Van Buren with Piper Sandler. Hey guys, good morning.

Tack rates to patients that's comparable to.

With drugs on the market.

We're beat it.

And then think about what the what would be more more creative for patients where patients with value a product like this.

Unfold.

Great. Thanks.

Our next question comes from Tyler Van Buren with Piper Sandler.

Hey, guys. Good morning notes a follow up question on the Enac program, which you touched on earlier so the phase two.

Study can you.

Or the phase II study in patients already with data early next year, you just outline exactly what type of data will be getting.

Getting us who view on an exacerbation them sweat chloride data and as we think about comparing it to another business that are another product.

What product on market would be most appropriate.

Well maybe.

It's Richard to just touch on the clinical study and what we're expecting to come out of it.

Unknown Executive: I just have a follow-up question on the ENAC program, which you touched on earlier. So, the Phase II study, can you, or the Phase I-II study in CF patients started with data early next year. Can you just outline exactly what type of data we'll be getting? We'll be getting FEV1 and exacerbation and sweat chloride data. And as we think about comparing it to another data set or another product, what product on the market would be most appropriate?

The net pro when I can talk a little bit about the second part of that question.

Sure.

Yes, we're excited about it so the the phase one two study of course is a short term proof of concept.

And it really that focuses on the enac knockdown in other words, the pharmacodynamics of delivering the pulmonary drug and the pharmacodynamics within the law.

Both in a normal long initially and then in the cystic fibrosis spot.

Richard S. Geary: Well, maybe I'll ask Richard to just touch on the clinical study and what we're expecting to come out of it for the ENET program. And I could talk a little bit about the second part of that question. Sure. Yeah, we're excited about it. So the Phase 1-2 study, of course, is a short-term proof of concept, and really the focus is on the ENAC knockdown. In other words, the pharmacodynamics of delivering the pulmonary drug and the pharmacodynamics within the loft, both in a normal lung initially and then in the cystic fibrosis lung.

So it's going to be PD, PK safety and Tolerability.

Which would then position us for further development.

So that's the that's the clinical program and that should be the expectation of the the data coming out of that.

Relatively short term six week dosing regimen.

Okay. Okay. Thanks, Richard and then.

Visioning wise.

Dina has potential to work in CF patients.

Richard S. Geary: So it's going to be PD, decay, safety, and tolerability, which would then position us for further development. So that's the clinical program, and that should be the expectation of the data coming out of that. You know, relatively short-term, six-week dosing regimen. Okay, okay. Thanks Richard. And then, you know, positioning wise.

For all mutation sites so it's.

It's not.

Linked to any particular mutation obviously based on its mechanism of action. So we see this drug working in combination with CF GR modulators.

There are already approved.

And there on the market today, but even greater bet patients with with cystic fibrosis. In addition.

We also believe.

Unknown Executive: DNAC has the potential to work in CF patients for all mutations, so it's not linked to any particular mutation, obviously, based on its mechanism of action. So we see this drug working in combination with CFTR modulators, which are already approved, and they're on the market today to provide even greater benefits to patients with cystic fibrosis. In addition, we also feel very good about the potential of this target for other indications, pulmonary indications. We're planning to start the Phase II study in COPD later this year, and we're exploring other indications, too, so it's quite a versatile target that has a lot of upside for various types of indications. Okay, great.

Feel very good about the potential of this target for other indications pulmonary indications we're planning to start the phase two study and Geo PD.

Later this year, we're exploring other indications too so it's quite a versatile targeted that has a lot of upside on very per various types of indications.

Okay, great. Thanks for taking the questions.

Sure. Thanks.

Our next question comes from Joel Beatty with Citi.

Hi, Tim Thanks for taking my questions. The first wanted to the follow up to that last question on the Enac program.

He took a little bit more about how you would actually be testing for knockdown in along for Metro.

Yeah, we're going to be looking directly at Teaneck Arnie.

Unknown Executive: Thanks for taking the question. Our next question comes from Joel Beattie with Citi. Hi team, thanks for taking the questions. The first one is a follow-up to that last question on the ENAC program.

In.

In the large fluids is taken from patients that were that are treated with the next year. So.

Terrific and then maybe another question on the oral liquid program.

Unknown Executive: Can you tell us a little bit more about how you would actually be testing for knockdown in the lungs in that trial? Yeah, we're going to be looking directly at ENAC RNA in the blivage fluid taken from patients that are treated with the ENAC ASL. Terrific. And then maybe another question about the oral lipid program. Could you help characterize what level of knockdown would be a success?

Could you help characterize what level of knocked down would be a success and is the bar. The same as it is for a subcutaneously delivered drug or is that most of our different for the oral approach.

Yeah.

We haven't.

Really we can't comment on the level of knockdown.

That were.

Targeting in that program.

Unknown Executive: And is the bar the same as it is for a subcutaneously delivered drug? Or is the bar different for the oral approach? Yeah, we haven't, We really can't comment on the level of knockdown that we're targeting in that program, but the second part of your question is important. We can achieve that with oral, based on our preclinical data. And remember, this is a Gen 2.5 like. Uh, so it's a, that knockdown is substantial.

But the second part of your question is important we're targeting the same level and subcutaneous and we feel good about that based on the preclinical data at the level and knock down that we're getting.

Subcutaneous. The is is we see them, we can achieve that with oral based on our preclinical data and remember this is a gen 2.5 like.

So it's a that knockdown a substantial.

Unknown Executive: Great, thanks a lot. Our next question comes from Jason Gerberry with Bank of America. Hey guys, thank you for taking my questions. Just a couple on anti-TLA-3 and the decision to go to Phase 2B versus doing a straight jump to Phase 3. What are you expecting to learn incrementally through the Phase 2B? Is it an issue of trying to figure out what your lowest effective dose is here as you look to go to a Phase 2B as opposed to the pivotal testing step? And then secondly, can you help us think a little bit about positioning anti-TLA-3 versus Lp-a with Novartis? How do you see the therapies positioned differently? Are they competitive?

[noise] critical.

Got it.

Our next question comes from Jason Gerberry with Bank of America.

Hey, guys. Thank you for taking my questions. Just just a couple on quanta and sequelae three and the decision to go to phase to be versus doing a straight jump phase three what are you expecting to learn incremental through the pace to be it is it an issue of trying to figure out.

What's your lowest effective dose here.

As you look at to go through a phase to be as opposed to the pivotal.

Testing stuff and then secondly can you help us think a little bit about positioning of ASP delay three versus LP Little later with Novartis, how you see that therapies positioned differently.

Are they competitive is it more of them multiple shots on goal for you or do you think that they'll ultimately operate within segments of the market based on genetic background. Thanks.

Richard S. Geary: Is it more of a multiple shots at goal for you, or do you think that they'll ultimately operate within segments of the market based on genetic background? Thanks. Richard, do you want to take that?

Sure thing Richard I'll take them, yeah. So two parts to that question I'll start with the.

Richard S. Geary: Yeah, so there are two parts to that question. I'll start with the Phase 2B approach. The Phase 2B, because the Phase 2 study was not actually conducted in the patients that we intend to go into, there was a desire to make sure that we had the right dose before we went into 8,000 to 10,000 patients. I think that makes sense.

Phase to be approach the phase to be because the phase two study was not actually conducted in the patients that we intend to go into.

There was a desire to make sure that we had the right dose before we went into a 10000 patients I think that makes sense and and so there is additional work looking at dosing dose regimens.

Richard S. Geary: And so there's additional work looking at dose and dose regimen, um, going into that going into that program, it can be done very quickly uh because they've already set up the organization and the structure to do a very large phase three program that was already in place. So this just goes very quickly into phase 2B and can be enrolled rapidly. So that's the front end of your question. The second part of your question..., which has to do with differentiating between LP and little a as they are completely different populations.

Going into that going into that program. It can be done very quickly.

Because they've already set up.

The organization and the structure to do a very large phase three program that was already in place. This just goes.

You know very quickly into a phase to be and can be enrolled rapidly. So that's the the front end of your question as the second part of your question.

Which has to do with differentiating with LP than like they are completely different populations.

Richard S. Geary: LPA, in general, the patient population that has elevated LP, little A, and cardiovascular disease are patients that have an LPA driven cardiovascular issue, and most of these patients, it turns out, when you look epidemiologically, do not have elevated triglycerides, so they don't have a triglyceride problem. Lupinorsin is targeting the triglyceride issue as or perhaps more significantly, the remnant cholesterol There are patients who have elevated triglycerides, not super high, but greater than 150, greater than the upper limit of normal for triglycerides.

Okay in general the pipe the patient population that have elevated LP literally and cardiovascular disease, our patients that have an lpa driven cardiovascular issue.

And most of these patients it turns out when you look epidemiologically do not have elevated triglycerides. So they don't have a triglyceride problem Lupin arsone is targeting the triglyceride issue as our or perhaps more significantly the remnant cholesterol component.

Of.

The high triglyceride patient population. So these are enriched with diabetics there are patients who have elevated triglycerides, not super high but greater than 150 greater than the upper limit of normal for triglycerides and the intent is to drive down.

Richard S. Geary: And the intent is to drive down Triglycerides and Residue Cholesterol, and that's what buprenorphine does very well. It's a pan dyslipidemic drug that really takes down the lipids that are elevated in a dyslipidemic patient population like the patient population targeted here. These are generally not ILPA patients, so there's a clear differentiation they're different patients, with this Thanks, Jason.

Triglycerides in remnant cholesterol and that's what loop Norcen does very well, it's a pan dyslipidemia drug that really takes down.

The limits that are elevated in a dyslipidemia patient population.

Like the patient population targeted here. These are generally not hi, lpa patients. So there's a clear differentiation there different patients.

With this residual risk that's very real in both of these populations.

Great. Thank you that accurately thanks, Jason.

Our next question comes from the our own Weber with Kelly.

Unknown Executive: Our next question comes from Yaron Werber with Cohen. Yeah, hi Kim, thanks for taking my question. I have a couple of questions.

Yeah, Hi, Tim Thanks for taking my my question of a couple of questions. The first one is just a follow up on the in that program for them. It sounds like you're you're moving toward a phase two in fuel could be oh, what you're still waiting for the phase one two in CF. So it almost appears that they're slightly more conviction to move to face to answer.

Unknown Executive: The first one is just to follow up on the ENAC program. But I mean, it sounds like you're moving toward phase two in COPD, but you're still waiting for phase one and phase two in CF. So it almost appears that there's slightly more conviction to move to phase two in COPD than in CF, and maybe just a little bit of an understanding of how you're thinking about that. And then secondly, for acromegaly, maybe again, the same set of questions: what's the target knockdown do you need?

We've had been in CF, and maybe just a little bit of an understanding kind of how you're thinking about that and then secondly for acromegaly, maybe again the same sort of question what target knock down do you need.

Unknown Executive: And what are some of the PD markers that we can expect from phase one and phase two? Thank you. Thanks for the question, Yaron. So, we feel very good about our ENAC program. We're very confident in our pulmonary franchise overall.

And what are some of the duty markers that we can expect from the phase one two thank you.

Thanks for the question your own so.

We feel very good about our you that program, we're very confident in our preliminary franchise overall.

Unknown Executive: Again, ENAC is the first of several pulmonary drugs that are in development or marching or getting close to development, with new clinical studies for other targets expected soon. We don't believe that the CF study is, the outcome of the phase 2 study in CF patients is gating for us to move into COPD. We've already seen enough that gives us confidence that, as a platform, we can achieve our goals of target engagement, and we believe in the target.

He Mac is the first of several pulmonary drugs that are and develop in or margin or getting close to development with new clinical studies for other targets expected soon.

We don't believe that the CF study is is the outcome of the phase two study in CF patients to skating pressed to move into CRPD, we've already seen.

No.

That gives us confidence that.

That.

As a platform.

We can achieve our goals of target engagement.

And.

And we believe in a target so we're moving on to other indications.

Unknown Executive: So we're moving on to other indications, and um, uh, so it's not CF, the CF study is not gaining, we've seen enough As for acromegaly, you know, there's a proven, validated biomarker that can be used for approval as an IGF-1 model. And our objective is to normalize IGF-1 or get close to normalization for IGF-1. I don't know, based on our preclinical data, what level of knockdown of the growth hormone receptor is needed to achieve that ratio. You have that on your. No, I don't.

And.

So it's nice to see if the CF study is not gaining we've seen enough.

Yes, we're acromegaly.

There is a proven.

Theres a.

Validated biomarker that that is.

Can be used for approval as I get one levels in our objective is to normalize idea at Warner get close to normalization Pride you want I don't know based on preclinical data what level of knockdown of growth hormone receptor is needed to achieve that Richard.

Do you have that on your.

No I don't.

Unknown Executive: The pre-clinical model, I mean. Because you don't really have an elevated IGF-1 model, it's not something you can really directly look at. You don't have acrobatically models to go directly into that, but that is our focus. IGF-1 is the biomarker, and, In addition, we're looking at measures of how patients feel, quality of life. We are also examining, you know, growth deformities like ring size in patients in the study as well. In addition, we are also carefully looking at additional options. This is a study in patients that are not well controlled on somatostatin analog.

The preclinical model I mean.

Because you don't really have an elevated idea of one model.

It's not something you can really.

Directly.

Look at Novak from equity models to go directly into that but that is our that is our focus is designed you. If one is the biomarker and.

In addition, we're looking at measures of how patients feel quality of life. We are also examining growth deformities like brings size in patients in this study as well.

In addition.

We are also.

Carefully looking at additional options. This is a study.

Patients that are not well controlled on smart stacking the analog.

Unknown Executive: And we're also considering the possibility of initiating a study as a monopoly. Transcripts by Transcription Outsourcing, LLC. The only thing I would add to that is that on ENAC, going back to that, we've been able to move forward with COPD because we're very confident with the data that we're getting from the Phase 1-2, but that doesn't mean we're leaving CF behind. CF will continue, and we hope to be able to move into other mutations that don't have good drugs to control their CF and move into those quickly And for the acromegaly program, have you, if I remember correctly, the preclinical data showed about a 60% knockdown. Is that sort of what you're expecting in the human study? And if I remember correctly, this is a LICA program.

And we're also considering the possibility of initiating a study as a monotherapy.

In patients with Acromegaly, we think that the populations are quite unique there are different and one may not be game for the other.

The only thing I would add to that is that on enact going back to that we've been able to move forward with CRPD, because we're very confident with the data that we're getting from the phase one too.

But that doesn't mean, we're leaving see a behind CF, Gary will continue and we hope to be able to move into even.

Other mutations that don't have good.

Drugs to control their CF.

And move into those quickly.

Okay and for the economically program have you if I remember quickly the preclinical data showed about a 60% takedown is that sort of what you're expecting in the in the human study and if I remember correctly. This is a like a program is that correct them because a fix some of the power Antelope, one like all right. Thank you.

Unknown Executive: Is that correct? Because I think some of the prior analogs weren't LICAs, Yes, that's correct, it is Leica, and you bring up the previous analogs. We do have data that shows that 50-60% reduction begins to bring down IGF-1, but this is going to be with Leica, infrequent dosing, again, low volume once a month, and bring forward, I think, a very good product. Terrific, thank you.

Yes, that's correct is like.

And you bring up the previous analog so we do have data that that shows that 50, 60% reduction begins to bring down the idea of one but this is this is going to be with alike.

Infrequent dosing again low volume once a month and bring forward I think a very good product.

Terrific. Thank you.

Thanks for the questions.

Our next question comes from jail, Kim with laid lifestyle.

Unknown Executive: Thanks for the questions. Our next question comes from Yale Jin with Laidlaw & Co. Good afternoon and thanks for taking the course. You guys are going to move the Apple C3 Leica into Phase 3, so could you guys provide some timeline in terms of the sort of development of this program? Would that be of a similar timeline to the development time before? So, thanks, Yale.

Oh, good up into and thanks for taking the questions.

You must go to move to oppose the lead light could take two phase three so could you guys. So climb long into consulted source development of this pro blends or would that be up a similar pines online.

Ladies.

Well I'll give out in time before.

So thanks Yale.

So we are.

Planning.

And are on track to initiate phase three study.

Unknown Executive: So we are planning and are on track to initiate the phase three study for ApoC3 Leica in FCS patients this year. We're also looking at other potential opportunities to develop this drug for other disease indications involving high triglycerides, and also other aspects related to broader populations with cardiac disease suffering from cardiovascular disease. But the SCS study is due to read out this year.

For April C like.

And.

FCS patients this year.

We're also looking at other potential opportunities to develop this drug.

For other.

Disease indications involving high triglycerides.

And also other aspects.

Related to broader populations with card suffered from cardiovascular disease, but the FCS studies due to.

Read out this year.

Unknown Executive: We're hoping that we can achieve a, you know, our objective is to get in, to get to the filing for Wai Libra and potentially market it next year. I mean, it depends on the regulatory time of regulatory review and the timing for all that and their acceptance of our data set. So, you know, Wai Libra, if things work out, Wai Libra will be commercially available in the U.S. as we launch it in Latin America by PPC and as well as the ongoing EU launch several years ahead of the likelihood.

We're hoping that we can achieve a our objective is to get into.

As to get to the filing for way live wrong and potentially market next year.

I mean, it depends on the regulatory to time of regulatory review and the timing for all of them.

In their acceptance of our dataset.

So you know Laila Rowe, if things work out way Liberal will be commercially available in the U.S. as we launch and you in glass some.

In America, but could you see in as well as ongoing you launch.

Several years ahead.

The like.

Yes.

Okay, Great maybe one more question again, the builders deep strategic site that in our own to that Oh, you guys still today to be seeking pool.

Unknown Executive: Okay, great. Maybe one more question. I don't know about the strategic side, but let me narrow it down to that. Are you guys still potentially seeking a DD collaboration with some of the large pharma? I don't know who is still left at this point.

BD collaboration with some of that the large bottom I don't know who is still left at this point, that's not necessarily something you offices going forward.

Unknown Executive: Or that's not necessarily something you are pursuing going forward? So, um, Yale, uh, we have so much interest, uh, externally in our, in our technology, by pharma companies and so on. We're very selective in the types of partnerships we do today because we feel that they really have to bring strategic value. We don't do deals anymore just for the money. It's really what strategic value they bring to Ionis, what expertise they bring, whether they have the resources to develop the drugs and commercialize them for very large populations, and so on. So we will continue to partner strategically as we build the Ionis-owned pipeline in parallel. We have the luxury of having, if you will, our cake and eat it too. We're developing our own pipeline, and we have the ability to partner strategically when and where it makes sense. Those could be licensing transactions after we bring drugs through phase two proof of concept or through some level of proof of concept, as we did with Pfizer last year. So we're planning to do all of that. Okay, great.

So Yale a we has so much interest externally in our in our technology by both pharma companies and so on.

We're very selective.

And the types of partnerships, we do today.

We feel that they really have to bring strategic value. We don't do deals any more just for the.

Money.

It's really what strategic value they bring to maintenance what expertise they bring whether they can they have the resources to develop the drugs and commercialize them for very large populations.

And so on.

So.

We will continue.

To.

Partner strategically as we build the ioannis on pipeline in parallel we have the luxury of having people are taking you too.

Our own pipeline and we have the ability to partner strategically where and when and where it makes makes sense those could be licensing transactions f., we bring drugs through phase two proof of concept or through some level of proof of concept as we didnt Pfizer last year.

Or they could be you know potentially strategic relationships in areas like we've done with Biogen if they if they if they make sense to do.

Unknown Executive: Thanks a lot and congratulations on the pretty good progress so far. Thank you. Our next question comes from Luca Issi with RBC. Oh, terrific.

So will the brunt, we're planning to do.

All of that.

Okay.

Okay, great. Thanks, Congrats for critical programs.

Thank you.

Our next question comes from Luca if he with RBC.

Unknown Executive: Thanks for taking my question, Luca Issi from RBC Capital. Congratulations on all the progress. Two quick questions here.

Oh terrific. Thanks for taking my question, Okay see from RBC capital Congrats on all the progress two quick questions here why many isn't read the plan I think the PDUFA date is actually two weeks from Monday. So it was actually curious you can hear what's your latest thinking on the label in term of what could be like a base case to their downside case scenario.

Unknown Executive: One is on the RISD plan. I think the PDUFA date is actually two weeks from Monday. So I was actually curious if you could share what's your latest thinking on the label in terms of what could be like a base case scenario, a downside case scenario, and an upside case. And maybe, I think you already alluded to it, but I'd love to add a finer point here on APOC3. I think your competitor recently pivoted from a monogenic disease like FCS to a polygenic disease like MCM, given that the indication is actually 10 times larger than FCS. Are you planning to do the same? And if not, maybe why not?

And they upside case, and maybe the I think you're already alluded to it I love to add a finer point here on April see three I think your competitor recently pivoted from an monogenic disease like FCS to a polyjet disease like MCN given that indication is actually 10 times larger than Sts.

Like are you planning to the same and if not me maybe why thank you.

Unknown Executive: Thank you. Thanks for the questions, Luca. You know, it's not appropriate for us to comment on our competitors and what we, you know, our projections or what we see as what would be in their labels or what their strategies are and so on.

Thanks to the questions Luca you know.

It's not appropriate for us to comment on our competitors.

And what we are.

Our projections or what we see is as what would be under label or whether strategies are so on what I can say is right. We're very excited about the future spinraza.

Unknown Executive: What I can say is we're very excited about the future of Spinraza. Spinraza is now in more than 11,000 patients around the world. The prevalence of SMA is much larger than was originally anticipated, and Biogen continues to do extremely well in bringing this drug to patients around the world. And we don't see that change.

Spinraza is now in more than 11000 patients around the globe prevalence of SDMA is much larger than was originally anticipated and Vijay continues to do extremely well in bringing this drug to patients around the globe and we don't see that change we see continued growth for spinraza.

Unknown Executive: We see continued growth for Spinraza. Despite the pandemic, despite the complications, and no one, nobody, Ionis Biogen is sitting still, as Beth talked about in her in her in her readings today. Ionis has launched the DeVoe post-commercialization study to show even greater, They're about to initiate, they announced, and they will start a clinical study soon to treat patients who are not getting adequate treatment, suboptimal treatment in gene therapy with Zol And in addition to all of that, we're working on follow-on medicines for SMA that we think can get us to every nine-month dosing or every 12-month dosing, single intradenal administration. So, you know, and with the pristine safety profile that Spironza offers, that is what enables us to be able to go to higher doses to demonstrate that.

Despite the pandemic despite the competition.

And Ah Noah Nobody Ioannis, Biogen sitting still as Jeff talked about in her.

In there in her ratings today. The Biogen is wants to devote post commercialization study to show even greater efficacy prescribers are about to initiate they announced and they will start as clinical study soon to treat patients who are not getting adequate treatment of suboptimal treatment.

Gene therapy, which will generate.

And in addition to all of that we're working on following medicines for estimate that we think can get us to every nine months dosing or every 12 months dosing single Intraductal administration.

Or.

So you know and with a pristine safety profile. This draws offers that as well it enables us to be able to go to higher dose demonstrate efficacy all that is what other competitors are gonna have to prove.

Unknown Executive: All that is what other competitors are going to have to... um... to compete with SpinRod. Same for the competition on ApoC3 Lyca. I prefer not to comment on what competitors are doing as followers to us, and they are following us, but I did mention earlier that, in addition to FCS, we are looking at other indications involving triglycerides, patients with high triglycerides. You referred to that as

To compete what's been Rossum.

Same for the competition I think we'll see three like.

Not to comment on what competitors are doing as followers to us they are following us.

But I did mentioned earlier the in addition to FCS we are looking at other indications involving triglyceride pocket patient should hydrate was right. So you referred you referred to that as Mcs. We're we're very familiar with the indication and we're building strategies around other other trade.

Unknown Executive: We're very familiar with the indication, and we're building strategies around other triglyceride indications, such as MCS and others. And we're also not only looking at those indications, which are really metabolic indications; we're also looking at cardiovascular. I'm going to go through a couple of large indications where we can reduce the risk of cardiovascular events in patients, such as heart attacks and strokes.

Thats right indications, such as Mcs and others.

And we're also not only looking at those indications, which are really metabolic indications, both who can't cardiovascular indications so large indications in which we can reduce the.

Which our goal would be to reduce.

The risk of cardiovascular events to patients heart attacks the credit basket rate related debt all of that is on our agenda. FCS is just the first.

Unknown Executive: All of that is on our agenda. FCS is just the first. Terrific. Thank you. Our next question comes from Vincent Chin with Bernstein. Thank you very much for taking the question. Maybe just one on the oral program.

Terrific. Thank you.

Yes.

Our next question comes from Vincent Ken with Bernstein.

Thank you very much for taking the question.

Let me just one or the oral program. So thinking about the World program you have some sense for the bioavailability with oral dosing, which will further reinforced with the upcoming data and you will have experienced with what dose levels necessary for for different indications for for the Subcu.

Unknown Executive: So thinking about the oral program, you have some sense of bioavailability with oral dosing, which you'll further reinforce with the upcoming data. And you have a lot of experience with what dose level is necessary for different indications in the sub-Q. Do you have a sense for what portion of your currently marketed drugs or pipeline programs may actually be amenable to oral dosing? Is there some dose level, for example, some sub-Q dose level you could point to and say, I think that anything that's dosed at this level or below is probably feasible for conversion to oral dosing? And maybe in a couple of particular examples, if I think about things like the Tegceti follow-on PCR LRX or your LP little A program, are these indications that you might be able to switch to oral dosing? Thanks Vince.

So for what portion of your currently marketed drugs or pipeline Brugos, maybe indeed amenable to oral dosing is there is there some dose level. For example is there some sub acute dose level you could 0.2, and say I think that anything doesn't dose at this level or below is probably feasible for for conversion to oral dosing and maybe in a couple of particular.

For example, if I think what things like the take said a follow on PVR lrx or your LP literally program.

These indications that you Michael switch oral dosing.

Thanks Vince.

We we believe that.

Unknown Executive: We believe that a substantial portion of the pipeline, particularly our liver, um... would be amenable to an oral strategy once we crack commercial, Viable Oral Dose. The program we're working on in the clinic right now, we want substantial reductions so that we're not talking about 20, 30, 40 percent reductions that would make this a commercially viable product. We're looking at large reductions that we want to achieve. So that would be applicable to anything in the pipeline, whether it be PTR, or LKa, or angiopoietin-like-3, or ApoC-3-like. I can go on.

A substantial portion of the pipeline, particularly our liver targets.

Would be minimal to an oral strategy once we cracked commercial.

Viable oral dosing.

The program, we're working on the clinic right now we want substantial reductions so that we're not talking about 2030, 40% reductions would make this a commercially viable product. We're looking at large reductions that we want to achieve.

So that would be flick with anything in the five and whether it'd be TTR, elk, a little a or or angiopoietin like three or able seem to be like I can go on.

And and as I mentioned I think earlier, we're not sitting still we're re prioritizing.

Unknown Executive: And as I mentioned earlier, we're not sitting still. We're already prioritizing drugs for... that we think would benefit you greatly from an oral sort of opportunity for them, and we're moving those forward. The chemistry is Gen 2.5 chemistry coupled with Leica, and it's the potency that this combination brings to us that we think it's getting, having somewhere around 10% oral bioavailability in humans, which we've already demonstrated previously with Gen 2 chemistry, could get us to commercially viable oral delivery. So we're not talking, you know; our objective is not to show a small impact on target.

Drugs for.

That we think would benefit Ukraine is.

From an oral sort of opportunity.

For them and we're moving us forward.

Chemistry is gen 2.5, chemistry, coupled with like that and it's the potency that this combination brings to us that we think it's getting it having somewhere around a 10% oral bioavailability humans, which we've already demonstrated previously which end to chemistry.

Could get us to commercially viable oral delivery so.

When I talk them you know our objective about shows more.

Impact on target.

Unknown Executive: Our objective is to, and when we refer to commercial viability, we're speaking about reductions that are comparable to some of our best sub-Q drugs today. When might we expect to see some additional oral candidates move into, I guess, yeah, when might we expect to see some insight into what's going to be the next oral candidate? And when will it move into the clinic? And what's the gating factor on that?

Our objective is to.

And when we refer to commercial viability were.

We're speaking about reductions that are comparable to some of our best Subcu drugs today that would show.

When might we expect to see if some additional oral candidates move into I guess, when maybe expect to see.

It's some insight into what's going to be the next oral candidate one doesn't move into the clinic and what's the what's the gating factor on that as it just a matter of waiting for the current data than just clarifying checking the box. This look do flick similar or.

Unknown Executive: Is it just a matter of waiting for the current data and just verifying, checking the box, "These look similar?" Or, yeah, what else needs to happen before you say, here, before you come out and say, here's the next thing we're moving, we're switching over to an oral platform? Um, so, um, we, as I said earlier, we're not sitting still; we are screening now for certain targets, some programs for the Gen 2.5 chemistry with Leica, and we're just going through that process. Obviously, there's going to be some gating factor.

What else needs to happen before you say here, but where you can say here here's the next things were moving were switching over to an oral platform.

So.

We as I said earlier, we're not sitting still we are screening now for certain probate for certain targets some programs.

For the Gen 2.5, chemistry with like and we're just going through that process. So there is.

Obviously, there's going to be some gating factor would want to see the data, but we're not wholly routes, we're not sitting still waiting for that data with these are moving forward.

Unknown Executive: We're going to want to see the data, but we're not sitting still waiting for that data. Things are moving forward. This year, we want to provide an update on the oral strategy overall, not just the clinical study, but what is the rationale for our oral program? Where do we think the opportunities, the biggest opportunities, could be for current molecules as well as future molecules?

This year, we want to provide an update on the oral strategy overall, not just a clinical study, but what is the rationale for oral program, where do we think the opportunities. The these opportunities could be.

For the for current molecules as well as future molecules and I think we're going to do that probably at Investor day. This year, if not sooner.

Unknown Executive: And I think we're going to do that probably at Investor Day this year, if not, Great, thanks for taking questions and congratulations on all the progress. OK, well, I think that's our last question. I want to thank everybody again for joining us today. Before we close today, I would like to take this opportunity to remind you of our Investor Webcast focused on our Cardiorenal Franchise next month, as well as our Investor Day, which I just referred to earlier, planned for December. We plan to provide details for these events soon, so stay tuned for all the details.

Great. Thanks for taking your questions and congrats a little progress.

Okay, well I think thats, our less last.

Question.

Want to thank thank everybody again for joining us today.

Before we closed today I would like to take this opportunity to remind you of our investor webcast focused on our cardio renal franchise next month.

As well as our Investor day, which I just referred to earlier plan for December we plan to provide details for these events soon so stay tuned for all the details. Thank you again and have a great Dane.

Unknown Executive: Thank you again, and have a great day. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect. Goodbye.

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

Good bye.