Q3 2020 Ionis Pharmaceuticals Inc Earnings Call

[music].

Good morning, and welcome to the Ionis Pharmaceuticals third quarter 2020 financial results Conference call.

Operator: Good morning, and welcome to the Ionis Pharmaceuticals 3rd Quarter 2020 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to call Wade Walke, Vice President, Investor Relations, to lead off the call. Please go ahead. Thank you, Brandon.

As a reminder, this call is being recorded.

At this time I would like to call over Wade Walke, Vice President Investor Relations to lead off the call. Please go ahead.

Thank you Brandon.

Wade Walke: 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 the reconciliation of GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, our Chief Executive Officer; Beth Hougen, our Chief Financial Officer; Onaiza Cadoret, our Chief Corporate Development and Commercial Officer; and Richard Geary, Executive Vice President of Development. And joining us for Q&A are Eric Swayze, Executive Vice President of Research, and Kyle Janais, Chief Commercial Officer of Axia.

Before we begin I encourage everyone to go to the investors section of the honest website and the press release and related financial tables, including a reconciliation of GAAP to non-GAAP financial measures that we'll discuss today.

We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website to accompany our discussion today.

With me on today's call are Brett more young our Chief Executive Officer, Hougen, Chief Financial Officer Laser category, our Chief corporate development and commercial officer, Richard Geary Executive Vice President of development and joining us for Q and Hey, we had Eric's Wavier executive Vice President of research in College, and a chief commercial officer next year.

I would like to draw your attention to slide three which contains our forward looking language well be making forward looking statements, which are based on our current expectations and beliefs. These.

Wade Walke: I would like to draw your attention to slide three, which contains our forward-looking language. We'll be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional details. And with that, I'll turn the call over to Brett.

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

Encouraged to consult the risk factors discussed in our SEC filings for additional detail.

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

Thanks, Wade and good morning, and thank you for joining us on today's call.

Brett P. Monia: Thanks, Wade. And good morning, and thank you for joining us on today's call. As we near the end of 2020, we are well positioned to achieve our next stage of growth. Since our last update, we took the very important step of acquiring Axia. We believe that together as one company, we're stronger and more efficient with an even greater ability to achieve success today and well into the future.

As we near the end of 2020, we are well position to achieve our next stage of growth.

Since our last update we took a very important step of acquiring akcea.

Believed that together as one company for stronger and more efficient even greater ability to achieve success today and well into the future.

This transaction also represents a significant step forward in the evolution in execution of our commercial strategy by combining ex U.S commercial capabilities with the eye on its own pipeline.

Brett P. Monia: This transaction also represents a significant step forward in the evolution and execution of our commercial strategy. Combining Axia's commercial capability with the IonisOwn pipeline, we move closer to fully maximizing the value of these medicines. And we're very pleased with the excellent progress we're making across our ionosome pipeline and our pipeline overall. Our five ongoing Phase 3 studies continue to progress well. We also remain on track to begin our sixth Phase 3 study when we initiate phase 3 testing of ApoC3 LRX in FCS patients later this year.

Closer to probably maximizing the value of these medicines.

And we're very pleased with the excellent progress, we're making across our eye on some pipeline and our pipeline overall.

Five ongoing phase three studies continue to progress well. We also remain on track to begin our six phase three study when we initiate phase three testing are able to see three L.R.S. in FCS patients later this year.

We're also evaluating larger indications for this medicine with an additional pivotal study potentially starting next year.

Brett P. Monia: We're also evaluating larger indications for this medicine, with an additional pivotal study potentially starting next. Beyond our Phase III pipeline, we continue to make excellent progress with our medicines in mid-stage development. The Ionis ENAC 2.5Rx data we recorded last month provided additional support for our rapidly expanding platform of inhaled anti-sense medicines. Luca Norson, Ionis Factor XI LRX, and Ionis HPV RX all advanced further in development, with each medicine entering a Phase 2B study. Ion 541, one of our four ALS medicines in development, entered a Phase I-II study in patients with nearly all forms of ALS regardless of family history.

Beyond their phase three pipeline, we continue to make excellent progress with our medicines in mid stage development.

Honest enact two point Fived Rx data, we reported last month, providing additional support for our rapidly expanding platform of inhaled anti sense medicines.

Moving north and Ionis factor 11, Lrx and I honest HBV, our ex all advance further in element each medicine entering phase to be studies.

I and five for one one of our four LS Medicine development entered a phase one two study in patients with nearly all forms of Aon west regardless of family history.

I always PKK LR X has completed enrollment in a phase two study in patients with rent Terry and your DEMA, which is due to read out next year and is also under evaluation in a phase two investigator study.

Brett P. Monia: Ionis PKK-LRX has completed enrollment in a Phase II study in patients with hereditary angioedema, which is due to read out next year, and is also under evaluation in a Phase II investigator study in hospitalized patients with severe COVID-19 complications in Brazil. And we further extended the reach of our technology this past quarter through a collaboration with Genuity Science, whose unique approach to new target identification is expected to enhance our already robust drug discovery and development capabilities. With these achievements, we are closer than ever to reaching our goal of 10 or more marketing applications through 2025, which should result in a large number of new medicines. Importantly, we remain financially strong and on track to achieve our 2020 guidance. Coming up on December 7, we will be hosting our Virtual Investor Day.

In hospitalized patients with severe koby Nike complications in Brazil.

We further extended the reach of our technology. This past quarter through a collaboration with Genuity science is unique approach for new target identification is expected to enhance our already robust drug discovery and development capabilities.

With these achievements are closer than ever to reaching our goal of 10 or more marketing applications through 2025.

It should result in a large number of new marketing products.

Importantly, we remain financially strong and on track to achieve our 2020 guidance.

Coming up on December seven we will be hosting our virtual investor day. During the presentation. We look forward to sharing our commercial plans provide several development program updates and highlight some of the great progress, we're making that is extending the reach of our technology.

Brett P. Monia: During the presentation, we look forward to sharing our commercial plans, providing several development program updates, andhighlighting some of the great progress we're making that is extending the reach of our technology. More information about this event will be released soon. And with that, I'll hand the call over to Beth to take us through our Q3 financial results. Onaiza will then talk about the Axia integration, and Richard will review our recent pipeline achievement. After Richard finishes, I'll wrap up our prepared remarks before taking your questions. Now, over to Beth.

More more information about this event will be really soon and with that I'll hand, the call over to Beth take us through our Q3 financial results on Ace and will then talk about the Akcea integration and Richard will review, our recent pipeline achievements after Richard I'll wrap up our prepared remarks before taking your questions.

Now over to Beth.

Thank you Pat.

Elizabeth L. Hougen: Thank you, Brad. As we approach year end, we remain financially strong and well capitalized with the resources to achieve our goal of significant growth. Our acquisition of Axia is one of the steps we have taken this year to achieve this goal. By integrating the two companies into one, our business is further strengthened in numerous ways, including improving our already strong financial position.

Prior to year end, meaning any actually shot and well capitalized.

The resources to achieve our goal a significant crowd.

Our acquisition of Akcea is one of the App being taken this year to achieve all.

By integrating the two companies into one I business is further strengthened in numerous ways, including.

Including improving our already strong financial position.

Elizabeth L. Hougen: We now retain more value from Axia's rich pipeline and commercial products. Additionally, we can use AXA's current cash and future cash flows to advance our strategic priorities. And beginning next year, we expect to realize meaningful cost synergies from our integration activities. We delivered strong financial results in the third quarter, with revenues increasing by 10% compared to the prior quarter, and we earned operating income and net income both on a non-gap basis. Spinraza generated global sales of $495 million in the third quarter, resulting in $74 million in royalty revenue for Ionis.

We now retain more value from Akcea is rich pipeline and commercial products.

Additionally, we can use that its current cash and future cash flows to advance our strategic priority.

And beginning next year, we expect to realize meaningful cost synergies from our integration activity.

We delivered strong financial results in the third quarter with revenues, increasing by 10% compared to the prior quarter and we earned operating income and net income.

Non-GAAP basis.

[noise] Spinraza generated global sales of $495 million in the third quarter, resulting in $74 million and royalty revenue try on it.

Elizabeth L. Hougen: At the end of September, there were over 11,000 patients on Spirazza treatment worldwide, with growth driven by markets outside the United States, and with a significant number of untreated SMA patients across numerous established and emerging markets. Together with SpinRod's proven efficacy and safety profile, we at Biogen continue to see opportunity for growth. Biogen's DEVOTE study is progressing well. This study is evaluating the potential for higher doses of Spinraza to deliver even greater benefit to SMA patients of all ages.

At the end of September there were over 11000 patients on spend lots of cheap worldwide with growth driven by markets outside the United States.

But the significant number of untreated estimate patients across numerous established and emerging market.

Together, what's behind this proven efficacy and safety profile, we imagine continue to see opportunity for growth.

I just didn't study is progressing well. This study is evaluating the potential for higher doses of spinraza to deliver even greater benefit at the main patients of all ages.

Enrollment in the open label safety Copart is now complete with enrollment in the randomized pivotal cohort to follow next.

Elizabeth L. Hougen: Enrollment in the Open Label Safety Cohort is now complete, with enrollment in the Randomized Pivotal Cohort to follow next. And early next year, Biogen plans to initiate a response study to evaluate Spinraza's benefit in patients with a suboptimal clinical response to gene therapy. Peccetti and Wade-Liver continued to deliver growth in the third quarter. Product sales were $19 million, an increase of more than 15% compared to the previous quarter and a nearly 60% increase over last year.

And early next year Biogen plans to initiate the response study to evaluate the not just the benefit in patients with a suboptimal clinical response to gene therapy.

Hey, setting and went live I continued to deliver growth in the third quarter try.

Product sales were $19 million, an increase of more than 15% compared to last quarter and a nearly 60% increase over last year.

We continue to see growth in the number of patients on tech savvy across North America and Europe.

Elizabeth L. Hougen: We continue to see growth in the number of patients on TxETI across North America and Europe. We believe patients and physicians are choosing Tecfeti in part due to its subcutaneous self-injection, enabling patients to take their therapy at home. This is one of the important benefits of TxETI, which has been especially important during the ongoing pandemic. In the United States, patients are starting and remaining on therapy, thanks in part to the excellent service provided by AXSIA's patient support program, AXSIA Connect. We continue to see growth with Axia's genetic testing program, with over 2200 physicians and an increasing number of tests conducted to date. In Europe, we successfully achieved reimbursement and recognized revenue from multiple new markets, including Portugal, home to a large endemic HATTR patient population. And in Canada, TxEDI reimbursement is in place in the largest provinces and through multiple private payers.

We believe patients and physicians are choosing to Eddie impart due to its subcutaneous self injection, enabling patients to take their therapy at home.

This is one of the important benefits of Tech city, which has been especially important during the ongoing endemic.

In the United States patients are starting and remaining on therapy. Thanks in part to the excellent service provided by Axiall patient Department aircraft Akcea connect.

We continue to see growth with Akcea genetic testing program with over 2200 physician and an increasing number of tests conducted to date.

In Europe, we successfully achieved reimbursement and recognized revenue from multiple new markets, including Portugal home to a large endemic ha TTR patient population.

And in Canada takes any reimbursement is in place and the largest provinces and through multiple private payers.

We also moved closer to achieving public reimbursement for all patients in Canada.

In Latin America, PTC Therapeutics is focused on new patient finding while continuing to negotiate pricing in Brazil.

Now turning to aim at Pratt, where we are generating revenue from a growing number at the market.

Elizabeth L. Hougen: We also moved closer to achieving public reimbursement for all tick study patients in Canada. In Latin America, PTC Therapeutics is focused on new patient findings while continuing to negotiate pricing in Brazil. Now turning to Alibra, where we are generating revenue from a growing number of EU markets. In the UK, Axia finalized pricing and reimbursement with Nice, and in Latin America, PTC filed for marketing authorization in Brazil earlier this year and is working to expand access in other Latin American markets, and in the United States, we plan to reapply with the FDA next year. During the third quarter, we earned R&D revenues of $65 million.

In the UK akcea finalized pricing and reimbursement was nine and.

And in Latin America, PTC filed for marketing authorization in Brazil earlier, this year and is working to expand access in other Latin American markets.

And in the United States, We plan to re file at the FDA next year.

During the third quarter, we earned R&D revenues.

<unk> million dollars. This revenue included over $50 million from our neurological disease franchise, primarily driven by several Biogen partnered program.

We expect a substantial increase in R&D revenue in the fourth quarter, including the $75 million milestone payment from Pfizer.

Additionally, we recently obtained a favorable award in our arbitration proceeding with <unk> El Nio.

This route award for teams to fees arising from L. Nylons agreement withstand a fee related to the two strands and its TTR prior.

Elizabeth L. Hougen: This revenue included over $50 million from our neurological disease franchise, primarily driven by several Biogen-partnered programs. We expect a substantial increase in R&D revenue in the fourth quarter, including the $75 million milestone payment from Pfizer. Additionally, we recently obtained a favorable award in our arbitration proceeding with Alnyla. This award concerns fees arising from El Nylon's agreement with Sanofi related to Fetuceran and its TTR products. The final judgment has not been determined, but we expect it will add meaningful revenue in the fourth quarter. Our non-GAAP operating expenses in the third quarter increased compared to last year, primarily driven by our Phase III program for Xea, TTR-LRX, and progress with our other Ionis-owned medicine. With these results, we achieved operating income of $9 million and net income of $5 million for the third quarter, both on a non-gap basis. Early last month, we used our strong balance sheet to successfully complete our acquisition of Axia. Following the acquisition, we remain in a strong financial position with an estimated pro forma cash balance of $1.8 billion.

The final judgment has not been determined but we expect it will add meaningful revenue in the fourth quarter.

Our non-GAAP operating expenses in the third quarter increased compared to last year, primarily driven by our phase three program for Akcea TTR Dash Lrx and progress with our other Ionis owns medicine.

With these results we achieved operating income of $9 million and net income of $5 million for the third quarter of <unk> on a non-GAAP basis.

Early last month, we used our strong balance sheet to successfully complete our acquisition of Akcea.

Following the acquisition, we remain in a strong financial position with an estimated pro forma cash balance of $1.8 billion in.

Importantly, our entire cash balance is now available to us to advance I honest, its strategic priorities and to build value for our patients and our shareholders.

We also anticipate achieving meaningful cost synergies as we progressed the integration activity.

And our financial statements will be much simpler for example, beginning next year, we will no longer include a non controlling interest adjustment on our p. now our balance sheet.

Elizabeth L. Hougen: Importantly, our entire cash balance is now available to us to advance Ionis' strategic priorities and to build value for our patients and our shareholders. We also anticipate achieving meaningful cost synergies as we progress the integration activity. And our financial statements will be much simpler. For example, beginning next year, we will no longer include a non-controlling interest adjustment on our P&L or balance sheet.

With our third quarter results and our projections for increased revenues in the fourth quarter. We are on track to achieve our 2020 financial guidance as.

Meaningful profitability.

Our financial strength, including our substantial cash position enabled us to continue to invest in areas that we believe will accelerate growth.

And with that I'll turn the call over to Anita to provide an update on the akcea integration and progress with our commercial strategy.

Onaiza Cadoret: With our third-quarter results and our projections for increased revenues in the fourth quarter, we are on track to achieve our 2020 financial guidance of meaningful profitability. Our financial strength, including our substantial cash position, enables us to continue to invest in areas that we believe will accelerate growth. And with that, I'll turn the call over to Onaiza to provide an update on the Axia integration and progress with our commercial strategy. Thank you, Beth.

Great. Thank you Bob.

The acquisition of Akcea now closed our process to merge the two companies into one is well underway.

The transition team, which is made up of cross functional leadership from both companies is following an established playbook to achieve full integration well focusing on three primary goals.

Our highest priority is to ensure our patients continue to receive tech study and we live without interruption and with a high level of personalized support.

Onaiza Cadoret: With the acquisition of Axia now closed, our process to merge the two companies into one is well under way. The transition team, which is made up of cross-functional leadership, is following an established playbook to achieve full integration while focusing on three primary areas. Our highest priority is to ensure our Unknown Executive, Huidong Wang, James Condulis, Sam Tsimikas, William Pickering, Sam Tsimikas, with a high level of personal. Second, we are focused on ensuring our employees remain highly engaged.

Second we are focused on ensuring our employees remain highly engaged and productive.

And finally, we are looking to advance our commercial plans for the Ionis on pipeline with the addition of Akcea is commercial capabilities.

As we integrate the two companies we are carefully reviewing all aspects of our business processes to ensure we are driving the greatest value for patients and shareholders.

No Akcea, we now have access to pay or health economics, and outcomes research Medical affairs and other capabilities to support our eye on its own to pipeline. We look forward to adopting these capabilities and accelerating our go to market strategies as our medicines advancing towards the market.

Onaiza Cadoret: And finally, we are looking to advance our commercial plans for Ionis. As we integrate, We are carefully reviewing all aspects of our business. Through Alexia, we now have Payer, Health Economics and Outcomes Research, Medical Affairs, and other reports such as R.I.O.N.I.S. We look forward to accelerating these capabilities and accelerating our go-to-market strategies as our... At our Investor Day next month, I look forward to- And with that, I'll turn the call over to Rick. Thank you, Onaiza.

At our Investor Day next month, I look forward to discussing our commercial plans for neurological and other rare disease programs as well as TTR like any proceeds we like.

And with that I'll turn the call over to Richard to discuss our key pipeline highlights.

Thank you and nice.

As Bret said, we've continued to advance our pipeline in the third quarter with significant achievements cross or neurological pulmonary and cardiovascular disease franchises.

Starting with the neuro pipeline the Thoma nursing phase three study in patients with Huntington's disease remains on track for data and potential regulatory filing in 2022.

Richard S. Geary: As Brett said, we've continued to advance our pipeline in the third quarter with significant achievements across our neurological, pulmonary, and cardiovascular disease franchises. Starting with the neuropipeline, the TomaNursen Phase III study in patients with Huntington's disease remains on track for data and potential regulatory filing in 2022. Ahead of the Phase 3 data, our partner Roche plans to provide an update from the Phase 1-2 Open Label Extension and Natural History Studies next year. A phase 3 study of Xea TTRL-Rx in patients with TTR polyneuropathy also continues to progress.

Ahead of the phase three data our partner Roche plans to provide an update from the phase one two open label extension and natural history studies next year.

The phase three study of Akcea TTR lrx in patients.

With TTR Polyneuropathy also continues to progress.

Our AOL program has continued to grow with four medicines now in our pipeline.

For the treatment of they allowed.

The phase one two study of eye on five or one or purchase medicine designed to address nearly all forms of a last regardless of family history is underway. The phase three study of co person in patients with sod one real last is progressing with data expected in the second half of next year.

Richard S. Geary: Our ALS program has continued to grow, with four medicines now in our pipeline for the treatment of ALS. The Phase I-II study of ION541, our first medicine designed to address nearly all forms of ALS, regardless of family history, is now underway. The Phase III study of TOFERSEN in patients with SOD1-ALS is progressing with data expected in the second half of next year. Also next year, Biogen plans to initiate a study of dofersin in pre-symptomatic SOD1 ALS patients, with the potential to delay or prevent disease onset.

Also next year.

Biogen plans to initiate a study oh person in Presymptomatic sod, one airwatch patients with the potential to delay or prevent disease onset.

The phase one two study of Ionis see nine Rx in patients with Cnine Aon last remains on track for data next year.

And I on 363, our first Ionis owned Aeolus medicine for the treatment of Aeolus patients with mutations in the bus gene.

Remains on track to enter a Registrational study next year.

Richard S. Geary: The Phase 1-2 study of Ionis C9-Rx in patients with C9-ALS remains on track for data next year, and ION363, our first Ionis-owned ALS medicine for the treatment of ALS patients with mutations in the FUS gene, remains on track to enter a registrational study next year. Looking beyond these programs, we continue to advance multiple earlier stage programs for the treatment of ALS. Now, from our growing pulmonary franchise, we recently reported positive Ionis ENAC 2.5 Rx healthy volunteer data demonstrating significant and substantial reductions in ENAC levels in the lung with attractive safety and tolerability. Importantly, these data also support inhalation as a viable route of delivery for antisense medicines more broadly, giving us greater confidence for positive results in our ongoing study in cystic fibrosis patients, and opens a path for us to broaden our pulmonary franchise to numerous new diseases of the lung, representing a significant opportunity for growth.

Looking beyond these programs, we continue to advance multiple earlier stage programs for the treatment of Aon watch.

Now from our growing pulmonary franchise, we recently reported positive I want to see next 2.5, Rx healthy volunteer data demonstrating significant and substantial reductions in enac levels, and along with attractive safety and Tolerability.

Importantly, these data also support innovation as a viable route of delivery for antisense medicines more broadly gives.

Gives us greater confidence for positive results in our ongoing study in cystic fibrosis patients.

And opens a path for us to broaden our pulmonary franchise to numerous new diseases of the lung representing a significant opportunity for growth. In fact, we look forward to initiating a study of I honestly in that 2.5 Rx in patients with C. O P. D. Later this year.

We also made significant progress in the development of my honest Teekay KRX any.

Enrollment in the phase two study in patients with hereditary angioedema or H E is now complete with data expected next year.

Earlier this year results from a compassionate use study with our PK program were published in the New England Journal Medicine.

Richard S. Geary: In fact, we look forward to initiating a study of Ionazine Act 2.5 Rx in patients with COPD later this year. We have also made significant progress in the development of Ionis PKK-LRX. Enrollment in the Phase 2 study in patients with hereditary angioedema, or HAE, is now complete, with data expected next year.

Demonstrating its potentially reduce the frequency of attacks in patients with HIV.

I on the Speaker KRX also recently advanced into an investigator study in patients hospitalized with severe cold was 19 complications in Brazil.

Richard S. Geary: Earlier this year, results from a compassionate use study with our PKK program were published in the New England Journal of Medicine, demonstrating its potential to reduce the frequency of attacks in patients with HAE. Ionis PKK LRX has also recently advanced into an investigator study in patients hospitalized with severe COVID-19 complications in Brazil. Designed to prevent the formation of bradykinin, this medicine has the potential to significantly reduce a cause of the Severe Complications Characteristic of the COVID-19 virus. Turning now to our cardiovascular disease franchise. The Phase III study of pelicarsin in patients with LPA-driven cardiovascular disease continues to progress, with data expected in 2024. Our Phase 3 study of Xeo-TTR-LRX in patients with TTR cardiomyopathy also continues to progress.

[noise] designed to prevent the formation of Brady Keinan. This medicine has the potential to significantly reduce a cause of the severe complications characteristic of the COVID-19 virus.

Turning now to our cardiovascular disease franchise.

The phase three study of pellet Carson in patients with Lpa driven cardiovascular disease.

Continues to progress with data expected in 2024.

Our phase three study of Ixia TTR Rx in patients with TTR Cardiome IOP. Buffy also continues to progress.

We also made excellent progress with our mid stage cardiovascular disease pipeline Pfizer rigs recently initiated a phase twob dose finding study a blueprint Orson which is expected to read out in the second half of next year. This study is being conducted in patients with dyslipidemia despite stable LDL lowering.

And treatment.

Which is representative of its planned phase three program focused on the over 6 million patients in the U.S. at high risk for cardiovascular disease. Despite despite a maximum LDL C lowering therapy.

Brett P. Monia: We also made excellent progress with our mid-stage cardiovascular disease pipeline. Pfizer recently initiated a phase 2b dose finding study of buprenorphine, which is expected to read out in the second half of next year. This study is being conducted in patients with dyslipidemia despite stable LDL-lowering treatment, which is representative of its planned phase three program focused on the over six million patients in the U.S. at high risk for cardiovascular disease despite maximum LDL-C lowering therapy. To support this strategy, Pfizer is planning three phase three studies of, including a large cardiovascular outcome study and studies in patients with elevated triglycerides and severe hypertrigly We expect all three of these studies to get underway in 2022. We at AstraZeneca look forward to providing an update on progress with our medicine targeting PCSK9 for the treatment of cardiovascular disease at the AHA later this month.

To support this strategy Pfizer is planning three phase three studies of the group and Morrison, including a large cardiovascular outcome study and studies in patients with elevated triglycerides and severe hypertriglyceridemia.

We expect all three of these studies to get underway and 2022.

We and Astrazeneca look forward to providing an update on progress our medicine targeting Tcs canine for the treatment of cardiovascular disease at the A.J. Later this month as these presentation at A.J. will include updates from both the subcutaneous and oral form.

Relations of this action.

And before the end of the year, we look forward to initiating a phase three study of Akcea April C. L. Rx in patients with EPS, yes.

These achievements move us closer to 10 or more marketing applications through 2025.

And with that I will turn the call back over to Brad to close this portion of the call.

Thank you Richard.

In closing I'm pleased to say that I own is stronger than ever.

Brett P. Monia: AZ's presentation at AHA will include updates on both the subcutaneous and oral formulations of this activity. And before the end of the year, we look forward to initiating a phase three study of Axia Apleseq 3 LRX in patients with S. These achievements move us closer to 10 or more marketing applications through 2025. And with that, I'll turn the call back over to Brett to close this portion of the call.

We are financially strong and has taken several important steps recently to further strengthen our financial position.

Yes see acquisition now complete we are one company with one leadership team in one set of strategic goals position positioning us well for the future.

We are achieving a great deal of success across the business, our pipeline continues to advance well and deliver value for patients and investors.

Brett P. Monia: Thank you, Richard. In closing, I'm pleased to say that Ionis is stronger than ever. We are financially strong and have taken several important steps recently to further strengthen our financial position. With the XE acquisition now complete, we are one company with one leadership team and one set of strategic goals positioning us well for the future. We are achieving a great deal of success across the business. Our pipeline continues to advance well and deliver value for patients and investors. Our five phase three studies are advancing, with a sixth expected to start by year's end. Furthermore, we look forward to numerous value-driving catalysts in the remaining months of this year and next year, including data from the Phase III study of Tilpersen in patients with SOD1 ALS in 2021. We believe that Doverson has the potential to be the first disease-modifying medicine approved for patients with ALS. We have also made excellent progress in our mid-stage pipelines.

Our five phase three studies are advancing with a six expected start by years end.

Furthermore, we look forward to numerous value driving catalysts in the remaining months of this year and next year.

Including data from the Phase three study of 12% in patients with sub one day less in 2021.

We believe that FFO person has the potential to be the first disease modifying medicine approved for patients with LSW.

We have also made excellent progress in our mid stage pipeline.

Successfully completed several important phase two studies.

Advance inhaled delivery and initiated several important phase two studies.

Our success this year puts us in an even better position to achieve our goal of 10 or more marketing applications through 2025.

We expect all result in a large number of new marketed products.

We're also very proud of fixed setting, meaning the pre galleon USA Award for best Biotechnology project in 2020.

Our vision in the discovery and development Tech study was to improve the lives of patients living with devastating effects of TTR amyloidosis, a rare genetic disease that greatly impacts the lives of families over generations.

Brett P. Monia: We successfully completed several important Phase II studies, including Advanced Inhale Delivery, and initiated several important Phase II studies. Our success this year puts us in an even better position to achieve our goal of 10 or more marketing applications through 2025, which we expect will result in a large number of new marketed products. We are also very proud of Pixeti, winning the Pre-Galleon USA Award for Best Biotechnology Project in 2020.

This is ioannis his second transformational medicines when the prestigious award.

As being Spinraza, which transform the treatment landscape for estimate leading genetic cause of in depth.

This award is a testament to the hard work and dedication of our employees work tirelessly to improve the lives of patients suffering with serious diseases.

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

We will now begin the question and answer session.

To ask a question you May Press Star then one on your Touchtone phone.

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

Brett P. Monia: Our vision in the discovery and development of TXETI was to improve the lives of patients living with the devastating effects of PTRM leukdosis, a rare genetic disease that greatly impacts the lives of families over generations. This is Ionis' second transformational medicine to win the prestigious award, the first being Spinraza, which transformed the treatment landscape for SMA, the leading genetic cause of infant death.

To withdraw your question. Please press Star then too but.

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

Our first question comes from Doe, Kim with BMO capital markets. Please go ahead.

Hi, Thanks for taking my questions a question on the Enac inhibitor EPS. So the phase one data.

Just wanted to get your thoughts on how how the PK data tracked with the reduction of inactive M&A as.

As a dose escalated do you think you saw a dose response and whether you had any thoughts on why the highest dose at three times weekly didn't show much a reduction.

Brett P. Monia: This award is a testament to the hard work and dedication of our employees who work tirelessly to improve the lives of patients suffering from serious conditions. With that, I'll open the call for questions. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys.

So though of uptick in thanks. Thanks for the question first of all I'll take a step down and I'll toss it over to Richard to expand so our phase one data in which we in normal volunteers in which we demonstrated.

Excellent safety Tolerability in normal volunteers with dose dependent reduction in that was very consistent with what we expected based on our wealth of preclinical data.

Operator: To withdraw your question, please press star then 2. At this time, we will pause momentarily to assemble our roster. Our first question comes from Dokim with BMO Capital Markets. Please go ahead. Hi, thanks for taking my questions. A question on the ENAC inhaled ASO, the phase one data. Just wanted to get your thoughts on how the PK data tracked with the reduction of ENAC mRNA as the dose escalated. Do you think you saw a dose response? And whether you have any thoughts on why the highest dose at three times weekly didn't show much of a reduction?

The the effects as I said were dose dependent and we achieved significant statistically significant reductions in enact that are well beyond the reductions that we expected.

That we expect to produce efficacy based on preclinical data we've generated so far now as you said as Richard highlighted we are now in a phase two study in patients with CF to demonstrate clinical benefit, which which we hope to share next year.

Richard you want to get into the PK relationships with more detail.

Brett P. Monia: So, I'll take a stab at that, and I'll toss it over to Richard to expand. So, our Phase 1 data, in which we demonstrated excellent safety and tolerability in normal volunteers with dose-dependent reductions in ENAC, was very consistent with what we expected based on a wealth of preclinical data. The effects, as I said, were dose-dependent, and we achieved statistically significant reductions in ENAC that are well beyond the reductions that we expected to produce efficacy based on the preclinical data we've generated so Now, as we've said, as Richard highlighted, we're now in a phase two study in patients with CF to demonstrate clinical benefit, which we hope to share next year. Richard, do you want to get into the PKA relationship a little bit more in detail?

Yes, so we saw the dose dependent.

Reductions in AG and that didn't track with our pharmacokinetics and the highest all as dose which was given less frequently them at lower doses given more frequently.

Didn't track PK didn't track with with the effect, we saw and I think that that is what has given us confidence as we move forward and the CF population and also.

On the verge of initiating the CLP side.

Yes.

Great. That's very helpful and just a quick question on.

The high on five for one for most types of Pls.

Do you think that that therapy will also be effective in the familial.

Lastly, coghlan and see United for and would you consider a strategy whereby there because their strategy for a combo with the specific therapy.

The I'm 541 is targeting a texan too.

Richard S. Geary: Yeah, so we saw dose-dependent production in ENAG, and that did track with our Pharmacokinetics, and the highest bolus, which was given less frequently than lower doses given more frequently, did track, PK, did track with the effect we saw. And I think that is what has given us confidence as we've moved forward in the CF population and also are on the verge of initiating COPD. Great, that's very helpful.

And for all forms potentially of LLS and yes, we there is strong rationale for for that for this target.

By knocking it down which would drive toward five were one to show efficacy in genetic forms.

Or hereditary forms of LSW as well as sporadic Eric we're.

More on that.

Yeah sure.

So the mechanism of action of this drug is ship modulators, GDP 43 pathology by down regulating by reducing the levels the tax and two which has been shown to be important to methodology and most forms of the Alaskan bulk some pathology of GDP 43, so we'd expect that drug to work in any form of Dale EPS.

Eric E. Swayze: And just a quick question on ION541 for most types of ALS. Do you think that that therapy will also be effective in familial ALS like SOD1 and C9-ORF? And would you consider a strategy, or would Biden consider a strategy for a combo with the mutant specific therapy? The Ion 541 is targeting Ataxin-2 and all forms potentially of ALS, and yes, there is strong rationale for this target by knocking it down with 541 to show efficacy in genetic forms. There are more hereditary forms of ALS as well as sporadic.

That has that type of pathology.

Treat most all forms of analysts and your question about combination yeah.

They radically you can you can envision a scenario in which combining a sod one where the may tax through too.

Inhibitor, which provide even greater benefit for us.

C.

How the data shakes out in the clinic I mean sod one we think is going to show great interest in the clinic and we'll see how much better we can achieve beyond that in those particular patients but from a mechanistic standpoint, you can see the rationale for added benefit yet.

Great Congrats on the progress and thanks for taking my questions.

Eric E. Swayze: Erik, more on that? Yeah, sure. So the mechanism of action of this drug is it modulates TDP-43 pathology by downregulating, or reducing the levels of Ataxin-2, which has been shown to be important in that pathology. And most forms of ALS involve some pathology of TDP-43. So we'd expect that drug to work in any form of ALS that has that type of pathology, in most forms available.

So.

Our next question comes from Chad Messer with Needham and company. Please go ahead.

Hello, everyone. This is bill on for Sad and thank you for taking our questions sort of it of a more general question. So.

As to the Ixia platform and the new commercial capabilities, how transferable are they too across indications in.

But could you envision this platform being used for example to promote no.

Trucks in a logical indications.

That's a great great question, we're very excited about three acquisition.

Eric E. Swayze: And your question about combination therapy, yeah, theoretically, you can imagine a scenario in which combining a SOD1 with an ataxin-2 inhibitor would provide an even greater benefit. We'll have to see, you know, how the data shakes out in the clinic. I mean, SOD1, we think, is going to show great efficacy in the clinic, and we'll see how much better we can achieve beyond that in these. But from a mechanistic standpoint, you can see the rationale for added benefit, yeah. Great, congrats on the progress and thanks for taking my questions. Thanks, Joe.

Of Akcea, because as amazes said in their.

A discussion earlier it really accelerates one of our top priorities is to build out our commercial capabilities and we think that you know and we are building our strategy for that and as she said she got plenty to share. Some details on that strategy in December at Investor Day, and we do believe it will be broadly applicable.

These capabilities to areas that we want to investing including neurological I'm amazed that.

We'd like to expand on that.

I'm sure Yeah. Great question, you know in any building out any kind of a weird. These capabilities that are some that are transferable and and leveraged across therapeutic areas Ray we think about these things as our health economics capabilities, the payer space our access hub as it is.

Operator: Our next question comes from Chad Messer with Needham and Company. Please go ahead. Hello, everyone.

Onaiza Cadoret: This is Gilan for chat. And thank you for taking our questions. Maybe a bit of a more general question. So, as to the Axia platform and the new commercial capabilities, how transferable are they to a cross indication? Could you imagine this platform being used, for example, to promote drugs and neurological indications? That's a great question.

GAAP did to the therapeutic area or areas, where we see that the capabilities can be applied and really build a very customized approach to urology as well as to the Olympic cardiology space that the team has been.

Onaiza Cadoret: We're very excited about the reacquisition of Axia because, as Onaiza said in her discussion earlier, it really accelerates one of our top priorities is to build out our commercial capabilities, and we think that, you know, and we're building our strategy for that. And as she said, she's planning to share some details on that strategy in December at Investor Day, and we do believe it'll be broadly applicable these capabilities to areas that we want to Onaiza, would you like to expand on that? Sure. Yeah, a great question.

But you know as you know that you know when you look at more of the marketing and sales people that will obviously be based on kind of customer types and we wouldn't see a lot of overlap there with polyneuropathy as well as going into into our urology portfolio were looking to see whether we're finding some good customer facing.

Synergies there as well.

Well that is a good flavor.

Thank you that's very helpful.

A question for Richard on the NAFTA combine with US is there something special and the Enac HM catalyst for further so that makes it more absorbable and the long.

Just a little bit of color on that.

So.

Onaiza Cadoret: You know, building out any kind of, you know, rare disease capabilities that are some that are transferable and leveraged across therapeutic areas. Our health economics capabilities, the payer space, our access hub as it is adapted to the therapeutic area. The capabilities can be applied and really build a very customized cardiology space, uh... but you know if you know that when you look at uh... more of the marketing and sales people that will deal with polyneuropathy as well as go into our neurology. Thank you. Thank you, that's very helpful. And maybe a question for Richard on ENAC, just to remind us, is there something special in the ENAC agent chemistry for the ASO that makes it more absorbable? And along with that, just a little bit of color on that.

As far as sell uptake oligonucleotides delivered to the long.

By aerosol are well taken up and multiple cell types. So the general state of sell off take Theres nothing really special about.

The chemistry for uptake however, the Enac has a 2.5 or a c. at.

Buyside quick sugar model.

Modification, which makes it very much more potent than the two brammo modifications and so we've increased potency and we have the similar distribution within the law.

All right excellent and just one last question from me so.

You mentioned the post marketing study with Spinraza in gene therapy failures, though.

Richard S. Geary: So as far as cell uptake is concerned, oligonucleotides delivered to the lung by aerosol are well taken up in multiple cell types. So the general state of cell uptake, there's nothing really special about it. The chemistry for uptake, however, ENAC is a 2.5 or a SEAT. We have increased potency, and we have a similar distribution within the line. All right, excellent. And just one last question from me. So, you mentioned the post-marketing study with Spenraza in gene therapy failures. I'm assuming this is taking forward the idea of a label expansion.

Assuming the Super ticking forward of a label expansion is that a right way to look at it.

You know Biogen has not talked about how assuming a positive outcome in the.

In response study with impact a label change or that sort of thing. So you know we don't we don't want to get too far ahead.

On that but.

We are feeling pretty confident that.

EPS and Roger will demonstrate.

A benefit significant benefit to patients who are performing suboptimally on.

On gene therapy, as as long as I'm sure you're aware Guild, there is anecdotal quite a bit of anecdotal.

Brett P. Monia: Is that the right way to look at it? You know, Biogen has not talked about how assuming a positive outcome in the response study would impact a label, you know, change or that sort of thing. So, you know, we don't want to get too far ahead on that, but we are feeling pretty confident that Spinraza will demonstrate a benefit, a significant benefit to patients who are performing suboptimally. On gene therapy, as I'm sure you're aware, Gail, there is, you know, anecdotal, quite a bit of anecdotal evidence, www.pharmacist.com. He moved on to Spinraza. And what Biogen wants to do is take that anecdotal information and turn it into a controlled trial so that they can prove it. And obviously, they're doing that to enhance the value of Spimraza to patients and to the community as a shareholder. So, you know, I wouldn't put that outside the realm of possibility, but I don't want to get too far ahead. I very much appreciate the color and congratulations on all the progress.

News information out there.

On patients.

Don't perform well as wells desired on gene therapy.

Moving on to Spinraza.

And nobody wants to do is take that anecdotal information and turn it into a.

Well controlled trial, so the improvement.

And obviously they are doing that to enhance the.

Are you Oh spinraza to patients and to.

The shareholders so.

I would put that outside of their own profitability, but I don't want to get too far ahead.

Hi, I much appreciate the color and congratulations on all the progress. Thank you.

Okay.

Our next question comes from Jim Birch enough with Wells Fargo. Please go ahead.

Yeah, Hi, guys. Congrats on all the progress and thanks for taking my question I guess the first question is just related to the integration of back the a and the synergies and how you see that affecting your ability to remain sustainably profitable and cash flow positive and then I have.

A couple of questions on the pipeline. Thanks.

Oh.

I'll take the first one Jim.

Hey, Dan good morning.

Thank you.

[laughter] the way I would think about the Akcea integration is isn't absolutely moves us down the path of others.

Operator: Our next question comes from Jim Birchenoff with Wells Fargo. Please go ahead. Yeah, hi guys, congrats on all the progress. I guess the first question is just related to the integration of Axia and the synergies and how you see that affecting your ability to remain sustainably profitable and cash flow positive, and then I have a couple of questions on the pipeline. I'll let, I'll let Beth take the first one, Jim. Hey, Tim.

In closer to commercializing our other some pipeline I felt that because you know that pipeline continues to expand and advanced in its been a key focus of ours and.

Certainly throughout this year and will continue to be as we go into the future years, we will see meaningful synergies cost synergies from the integration certainly putting two public companies together. There is some obviously hanging fruit in that we won't have to sustain cost structures for two public companies going for.

Elizabeth L. Hougen: Good morning. So, the way I would think about the Axia integration is that it absolutely moves us down the path of being closer to commercializing our IOSM pipeline ourselves. Of course, you know that the pipeline continues to expand and advance, and it's been a key focus of ours certainly throughout this year and will continue to be as we go into the future years. We will see meaningful synergies, cost synergies, from the integration, certainly putting two public companies together. There's some obvious low-hanging fruit in that we won't have to sustain cost structures for two public companies going forward.

Great and then as far as so.

The same profitability.

Our focus is really on our eye on it so the pipeline and building this building that pipeline expanding that pipeline building. These commercial capabilities offers the.

The capex combined with the capabilities that we've now hired wholly from Akcea and also looking for ways to invest to expand or extend the reach of the technology and so there that's our highest priority profitability is still important.

Elizabeth L. Hougen: And then as far as sustained profitability is concerned, our focus is really on our Ionis pipeline and building that pipeline, expanding that pipeline, building these commercial capabilities off of the – combined with the capabilities that we've now acquired wholly from Axia. And also looking for ways to invest to extend the reach of the technology. And so, that's our highest priority. Profitability is still important to us, but it is not our first and top priority. I got it.

To us, but it is not our first and top priority.

Got it that's very helpful. And then maybe just on ion for nine and the ha.

Dictation I know its embargoed, but.

But how should we think about what youre, hoping to show these would be the.

Brett P. Monia: That's very helpful. And then maybe just on ION449 and the AHA presentation, I know it's embargoed, but how should we think about what you're hoping to show vis-à-vis the Sub-Q and then if you've got a successful oral approach? So what other candidates make most sense for the technology? Yeah, you're referring to the, thanks Jim, you're referring to the PGSK-9 programs.

Thank you and then if you've got a successful oral approach what other candidates make most sense for the technology.

Yeah, you're referring to the thanks, Jim you're referring to the biggest canine programs right and and we have.

Oh.

Formulation.

And the other is the oral program both in.

Brett P. Monia: Right. And we have... formulation, and the other is the oral program, both in. Clinical Testing, as I said. At the AHA, we're going to have data, clinical data on, you know, the subcube program showing reductions in PCSK9, and LDL cholesterol. We are very excited about that, and we think it has the potential to really differentiate this drug from all other drugs that are in development or on the market today as a potential best-in-class medicine. The Oral Program will also be updated at the American Heart Meeting.

Clinton and clinical testing as I said.

Yeah, Jay we are we're going to we're going to have data clinical data on you know the the Subcu program showing reductions in gcs canine LDL cholesterol back.

We are very excited about that we think have the potential to really differentiate this drug from all other drugs that are in development or on the market today as a potential best in class medicine.

The oral program will also be updated at American heart meeting.

Brett P. Monia: We'll principally focus on the rationale, the strategy, and the preclinical data supporting the clinical testing in which the conclusion from that Oral Program will be that we've solved commercially viable oral delivery as a once-a-day tablet that will drive reductions in target in the liver by PCSK9 through leveled copper holes in the sub-Q program I just referred to. There may also be some clinical data from the oral program, but in the abstract, it's focused entirely on the preclinical data so far. But I also want to expand on that a little, Jim.

Well principally focused on the rationale the strategy the preclinical data supporting the clinical testing in which the conclusion from that oral.

Program will be that we can believe we've solved commercially viable OSV deliveries and once they tablet thatll drive reductions in target in the liver like pcsknine to levels comparable to the Subcu for program I just referred to there maybe also some clinical data from the oil program, but in the abstract is focused.

Entirely on the preclinical data so far but.

I just want to expand on that a little Jim in addition to the Pcsknine program for oral we have prioritized several programs here at Ionis for oral development that we think will provide a significant advantage differentiating or ability to differentiate from competition and we're spending on touching on the eye on its own or programs a little bit at.

Brett P. Monia: In addition to the PCSK9 program for oral, we have prioritized several programs here at Ionis for oral development that we think will provide a significant advantage, differentiating our ability to differentiate from competition. And we're planning on touching on the Ionis donor programs a little bit at Investor Day. Great, thanks for taking that question. I guess the final question is just on timeline. Neuro Rare, Programs. What's the earliest we could see

Investor Day.

Great. Thanks for taking that question I guess the final question is just on timelines for the neuro rare disease programs. What's the earliest we could see data from one of those mindedly before.

Alexandra disease is that more of a 2022 right.

Brett P. Monia: Data from, you know, one of those client diseases before Alexander disease. Is that more of a 2022? Dynamic, or could we see some data? So we're excited about starting several of those clinical trials next year. They're really, some of them in the first half, early next year.

Dynamic or could we see some data from that next year.

So we're excited about starting several of those clinical trials next year, they're really some of them in the first half early next year.

And and as you know because they are rare diseases in severe diseases. We are expecting a very fast clinical development path. Some of them just one study.

Brett P. Monia: And as you know, because they are rare and severe diseases, we are expecting a very fast clinical development path, some of them just one study. So we'll be providing an update on the initiation of those studies and our development strategy next year, early on. But I would expect the timeframe that you're thinking of is about right for clinical trials. Great.

So we will be providing an update on the initiation and those studies and our development strategy next year early on.

But I would expect the timeframe that you're thinking of is about right preclinical data.

Great. Thanks for taking the question guys.

Thanks, Jeff.

Our next question comes from Joel Beatty with Citi. Please go ahead.

Operator: Thanks for taking the question, guys. Our next question comes from Joel Beattie with Citi. Please go ahead.

Operator: Hi, thanks for taking the question. This is a follow-up to the last question on oral PCSK9. Just to clarify, for the biomarker data on PCSK9 and LDL lowering for the oral molecule, is there potential for that to come at age A? Or, if not, how much later could that come?

Hi, Thanks for taking my question. This is a follow up to the last question on on the oral Pcsknine just to clarify I prefer the biomarker data on like Pcsknine and LDL lowering for the oral molecule, but is there a potential for that to come Ah ha.

Or how or if not how much later that come.

The.

Brett P. Monia: The oral, as I said, we will be presenting with AstraZeneca an update on both programs, subcutaneous and oral. The subcube will have pharmacodynamic data on PCSK9 and LDL lowering. These are in patients on top of statins. And whereas the oral program will principally focus on preclinical data that will set up, you know, that will really provide the strategy, the justification for developing this platform for oral delivery. That will certainly include PD data on preclinical models, but the clinical data will stay until next year for oral. Okay, I got it.

The oral Dave we will as I said, we will be presenting with Astra zeneca, an update on both programs subcutaneous an oral the book the Subcu will will have pharmacodynamic data on Pcsknine LDL lowering these are on patients.

On top of statins, and whereas the oral program were principally focused on preclinical data that will that will set up you know that will really provide that strategy. The justification for developing this this platform for delivering.

That will certainly include PD data on preclinical models, but the clinical data were saved for next year.

For oral.

Okay got it and then thinking about the potential for all the technology more broadly in your pipeline could you could you talk little bit about how broadly applicable the oral pcsknine data would be for other agents and then also how how quickly that could be applied to other agents in your pipeline.

Brett P. Monia: And then thinking about the potential for oral technology more broadly in your pipeline, could you could you talk a little bit about how, you know, broadly applicable the oral PCSK9 data would be for other agents and also how quick that could be applied to other agents in your pipeline? Yeah, it's, you know, what we've engineered for oral delivery, again, this is what we're looking at is a once a day tablet that will achieve target reductions comparable to any of our substitute programs that we've developed or are in development today, and it focuses on Gen 2.5 chemistry with like a chemistry so we get the potency of the two chemistries that really we think solves commercially viable oral delivery we're advancing forward several programs from the ion zone pipeline now we've prioritized them we'll talk about them soon and at best today and we're expecting to move one or two of these drugs into development next year for oral delivery, Great. Thanks for the update. Yeah. In addition to PCSK9.

Yeah. Its Oh, you know what we've engineered for oral delivery to Genesis yeah. So once they tablet.

That we'll achieve target reductions comparable to any of our subcu programs that we've developed or in development today.

Our focus is on Gen 2.5, chemistry with like a chemistry. So we get the potency of the two chemistries that really we think solves commercially viable oral delivery I'm. We're advancing forward several programs from the islands on pipeline now and we prioritize them, we'll talk about them soon that investor day, and we're expecting to move.

One or two of these drugs into development next year oral delivery.

Great. Thanks for the update it Yeah. In addition to Tcs cannot thanks Joel.

Our next question comes.

Some chief along with Bank of America. Please go ahead.

Brett P. Monia: Thanks. Our next question comes from Chi Fong with Bank of America. Please go ahead. Oh, hey, this is Chéon for Jason Gerberry from Bank of America.

Oh, Hey, this is chip on for Jason Gerberry with Bank of America, except thank for taking my questions. I guess another follow up on Tcs Kenai looks like Iron has has already had some early.

Brett P. Monia: Thanks for taking my questions. I guess another follow up on PCSK9. It looks like Ionis has already had some early PKPD data with the oral formulation. Curious if you have a chance to review that with AstraZeneca and what kind of feedback you've heard from the collaborator. And, you know, curious if there's any sort of initial conversation about advancing the oral formulation. Sorry, Jay, I need to get a clarification on your question about the first question. What data are you referring to?

[laughter] data with the oral formulation curious if you have a chance we'll be viewed that way best for Seneca and what kind of feedback you've heard from the cooperate and.

Curious if that's any sort of initial conversation about advancing the oral formulation to a further in development or maybe perhaps sometime next year.

And then I have a couple of follow up after that thanks.

Sorry, Gee I need to get a clarification on your question about the first question. What data are you referring to Oh, we haven't shared data on our latest oral platform.

Brett P. Monia: We haven't shared data on our latest oral platform outside of what has been submitted to the American Heart by Ionis and AZ so far. Can you clarify? I'm curious if you have seen any human PK and PD data with the oral formulation that would not be part of the AHA, like internally, whether you and a partner at AstraZeneca can review that, what's the initial feedback you've heard from partners, and whether there's a thought of advancing the oral formulation in further development, perhaps sometime next year, even though you're not presenting the data ahead of time It's just a question of whether or not that study will be completed in time to share at the American Heart.

Outside of what has been submitted to the American heart I I honestly don't see so far can you clarify.

Ah curious if you have seen any human PK PD data with Delstar on Malaysian that will not be part of the 8-K like internally whether you are now part of Astrazeneca had we view that what the initial feedback you've heard from partner and whether there's a thought of advancing the or formally.

And is it fair to development, perhaps sometime next year.

Even even though you're not pretending a data ahead of time.

Absolutely, yes. It sure we have PK data from Europe program from from clinics in the clinic are ready and we are encouraged by it's just a question of whether or not that study will be completed in time to share the African heart and the abstract for Smith you know earlier this year. So it really focused on the strategy.

Brett P. Monia: And the abstracts were submitted, you know, earlier this year, so they really focused on the strategy, the rationale, the justification for commercially viable oral delivery, focused on preclinical data. But yeah, we've seen, we have clinical data on the oral program, and we have more clinical data on the SubQ program, which is why there'll be more data at the American Heart Association on the SubQ. And as for, I think your other question was really related to other programs.

The rationale and the justification for commercially viable deliberate focus on preclinical data, but yeah, we've seen.

We have clinical data on the oral program and we have more clinical data on the Subcu program, which is why were.

So we more data at the American heart So Q.

And as for I think your other question was really related to other programs that we're advancing forward.

Additional programs using oral delivery as the route of administration.

Focusing on the eye on its own pipeline and and will provide an update on those programs soon and we expect one or more of those drugs to ridge development next year. The other thing I'll just add to that is that we continue to invest in research and new Chemistries and new formulations to further enhance.

Brett P. Monia: Yeah, we're advancing additional programs using oral delivery as the route of administration, focusing on the ionosome pipeline. And we'll provide an update on those programs soon. And we expect one or more of those drugs to reach development next year. The other thing I'll just add to that is that we continue to invest in research and new chemistries and new formulations to further enhance oral delivery. So this isn't sort of our only stab at validating commercially viable oral delivery. We continue to prioritize this in our research. Awesome. I guess my follow up on my another question would be on Spim Brasa. I'm curious.

So this isn't this isn't sort of our only Stan.

Validated commercially viable or will the route we continue to prioritize this and our research group.

Awesome I guess my follow up on my another question would be on same rasa I'm curious.

I think between gross and Biogen earnings call I Kinda elect you may be about 200 patients.

Initially switched from so Ross are too risky.

Do you think that's more reflective of pent up demand or do you think thats, how dark like the rate of attrition that we might see for the next couple of quarters going forward.

Elizabeth L. Hougen: I think between Brose and Biogen's earnings call, kind of allude to maybe about 200 patients initially switched from Spinarasa to RISD. Do you think that's more reflective of the pace of demand? Or do you think that's sort of like the rate of attrition that we might see for the next couple of quarters going forward?

I guess a lot of part of the question would be you know do you and Biogen.

How companies like you with teeth and Rotce up profile do you expect a loss that you have yield for your growth for 2021% 2020.

Well I would I would say as far as Q3, but those are concerned.

Elizabeth L. Hougen: And I guess another part of the question would be, you know, you and Biogen, how confident are you with the Spinarasa group profile? Do you expect Spinarasa to have year over year growth in 2021? So I would say as far as Q3 results are concerned, I would re-envisage and believe that those patients were really a function of pent-up demand. We don't anticipate seeing that as a trend on a go-forward basis. I think the way to think about growth on a year-over-year basis with SPINRASA is to think about the efficacy profile and the safety profile that SPINRASA has demonstrated in, right now, more than 11,000 patients in the real world, in a commercial setting, as well as in the clinic.

I wouldn't we invite you to believe that those patients were really a function of pent up demand and we don't anticipate seeing you know that that as a trend on a go forward basis I think the way to think about growth on a year over year basis.

With Spinraza is to think about the you know the efficacy profile as a CPT code.

Rasa has demonstrated in right now 11 more than 11000 patients.

In the real world in a commercial setting as well as in the clinic and the fact that the that's.

That does have to get the date that efficacy and safety profile has been well established across all types in ages of Esa nave patients.

Elizabeth L. Hougen: And the fact that the efficacy and safety profile has been well-established across all types and ages of SMA patients and for many, many years. You know, we've been studying SPINRASA in the clinic, and it's been on the market now for... So we've got lots and lots of data that supports the profile, and I think as you think about it, there's limited data in the competition right now, particularly oral, and that data suggests that its benefit is limited to really younger patients. As you get older and your weight increases, you have less ability to take the medicine and see the benefits.

And over many many years, we've been we've been studying spinraza into clinic in its been on the market now combined for.

Tina eight plus years, so we've got lots and lots of data that supports the profile and I think as you as you think about it.

Theres limited data in the competition right now, particularly the oral and that data suggests notch.

Its benefits is limited in she's to relieve the younger patients as you get older and and your rate increases you have less ability to to take take the medicine and do that so we're really focused on the fact that.

Elizabeth L. Hougen: So we're really focused on the fact that Spinraz's efficacy and safety set the bar, frankly. It sets a very high bar, and that, combined with the fact that there are more than 60,000 patients worldwide with SMA, and most of those patients are outside the United States and in markets where Viagin has a commercial presence. So, you know, we think all of those factors bode well for Spinraz's growth trajectory in the coming years, including next year. And just to add to that, as Beth highlighted earlier on the call, we also think that the studies that are in progress or planned for spina borasa bode well for spina borasa in the future, too, including the ongoing DEVOTE study in patients that have had suboptimal performance on gene So there's a lot going on to further enhance the potential growth of spina borasa. Thanks. The next question comes from Luca Issi with RBC. Please go ahead.

Ross this activity and safety sets the bar frankly, that's a very high bar and that combined with the fact that there are you know us.

More than 60000 patients worldwide with estimate and and most of those patients outside the United States and in markets, where Biden has the commercial presence. So we think all of those factors bode well for certain losses browse project trajectory.

In a in coming years, including next year.

And just to add to that as Beth highlighted earlier on the call.

Also we also think that the studies that are in progress are planned for Spinraza bode well for spinraza in the future to including the ongoing devote study in patients.

I have a suboptimal performance on gene therapy.

Which is start next year and respond studies, both the boat study in progress looking at higher doses are summarized demonstrate even greater efficacy. So there's a lot going on further enhance the potential growth of spinraza.

Awesome. Thanks.

Got it.

Our next question comes from Luca Issi with RBC. Please go ahead.

Oh terrific. Thank you for taking my questions.

Operator: Oh, terrific. Thank you for taking my questions. Two questions, one on the strategy and two on the competitive landscape, maybe.

Two questions one on the strategy and two on the competitive landscape maybe someone to strategy can you just talk maybe high level of how the acquisition of Akcea and the $1.8 billion pro forma cash position changes your BD strategy and two on the competitive landscape I think we'll see novartis receiving orphan drug designation for <unk>.

Brett P. Monia: So on the strategy, can you just talk maybe at a high level about how the acquisition of Axia and the $1.8 billion Proforma cash position changes your BD strategy? And two, on the competitive landscape, I think we've seen Novartis receiving orphan drug designation for their oral splicing modulator for Huntington. Wondering if you have any thoughts on that approach and maybe what are some of the implications for your program?

Oral twice the modulator for Huntington wondering if you have any thoughts on that approach and maybe what are some duplication through your program. Thank you.

Brett P. Monia: Thank you. Yeah, I'll take a stab at the first one, and I'll probably ask Beth or somebody to help me with that, too. And then, Eric, maybe you can talk about the Huntington Program. So, you know, the acquisition of Axia is, as we highlighted, right in line with our strategy to build our pipeline and build our commercial strategy for the future, and this acquisition accelerates our path toward that.

[noise], Yeah, I'll take a stab at the first one and plus there's some [laughter] openly with that too and then there every circuit program.

So you know the acquisition of Akcea is is as we highlighted.

Is right in line.

With our strategy to build our to prioritize videos on pipeline and build our commercial.

Our strategy for the future.

And this ex acquisition is it accelerates our path towards that.

Brett P. Monia: Onaiza, and Ionis in general, will talk about that strategy in more detail at Investor Day in December, but it will focus on rare diseases, at least to start. And we'll talk about the types of rare diseases and which ones we're going to prioritize to bring those forward. The Ionis platform, our technology, is incredibly prolific. We continue to bring many new drugs into development each year. Some of those drugs will not necessarily conform necessarily to the commercial strategy that we're planning to initiate that we're implementing, I should say now. So we will continue to partner. Business development will continue to be a very important aspect of Ionis to maximize the value of our pipeline, our technology, and maximize growth. We're a hybrid species.

Our NATO will and illness in general we'll talk about that strategy in more detail at Investor day in December but.

But it will focus on rare diseases at least to start with and.

And we'll talk about the types of rare diseases, and which ones, we're going to prioritize to bring those forward.

The Ionis platform to our technology is incredibly prolific.

We continue to bring many new drugs into development each year some of those drugs will not conform necessarily.

To the commercial strategy that we're planning to initiate that we're implementing I should say now so.

We will continue to partner business development will continue to be a very important aspects of of eye on is to maximize the value of our pipeline or technology maximize growth for the company were hybrid were commercial organization and we're partnering organization and we think the best the best strategy for me.

Brett P. Monia: We're a commercial organization, and we're a partner organization, and we think that that's the best strategy for maximizing value for all of our, all of our stakeholders. And we'll continue to do so. So I guess I would say that the acquisition of Xea and building our commercial capabilities and strategy will force us to partner less in rare diseases, but we'll still continue to partner in those areas that make the most sense to us. I assume you're talking about Branaplam with the Novartis orphan designation. That's an older drug, it's been around a while, it's in the face of, I'll let you draw I like our drug, Taminersan is in the lead in the Huntington's space, it's in the phase 3 trial, as you know, scheduled to read out in 2022, lowering Huntington directly I think is the best strategy to deal with Huntington's disease, and I'm perfectly comfortable and happy with our strategy with Taminersan and Rutger. Super helpful.

Maximizing the value to all of our.

All of our stakeholders and we'll continue to do so.

I guess I would say the SPX acquisition of Akcea and building, our commercial capabilities and strategy will.

Force us to partner less in rare diseases, but whats the spoken to your partner in those areas that make.

Make more sense to like owners.

Eric you want to take the Huntington, Yes, I assume you're talking about brand apply them and with the Novartis orphan designation.

That's an older drugs, it's been around a while its been phase.

Two trials for us. It may also so I'll, let you draw your conclusions about something that modifies the splicing of two different genes.

I like our drug to medicines in the lead in the Huntington spaces in the phase three trial as you know it's going to be to read out in 2022 lowering on Zixone directly I think is the best strategy to deal with allegiance disease, and perfectly comfortable and happy with our strategy with diminished and then rich.

Super helpful. Thanks, guys.

Thanks Lou.

Our next question comes from Paul Metis with Stifel. Please go ahead.

Eric E. Swayze: Thanks, guys. Our next question comes from Paul Mattis with Stiefel. Please go ahead. Hi, this is Katie on behalf of Paul.

Hi, This is Katie on for Paul and I just had a quick question as we wait for the H. A result, what do you mainly looking for on whether it be reduction in attack rate or to extend treatment duration looked like a and also if you could clarify the updated timing, it's all that will be.

Operator: I've had a quick question as we wait for the HAE results. What are you mainly looking for, whether it be reductions in attack rates or to extend treatment duration with LICA? And also, if you could clarify the updated timing as well, that would be super helpful, thanks. Yeah, Richard, why don't you take that one?

Super helpful. Thanks.

Yeah, Richard why did you take that one sure well of course the endpoint is.

Richard S. Geary: Sure. Well, of course, the end point is going to be attack rate focused, and it's also going to be breakthrough in terms of, you know, attacks that occur while on treatment, which is one of the confounding issues with some of the existing products. So what we expect to see is a best-in-class response.

There's going to be attack rate focus.

And it's also going to be on breakthrough in terms of.

Ill attacks that occur while on treatment.

Which is one of the one of the.

Confounding issues with some of the existing.

Products. So what we what we expect to see is a best in class response pets.

Richard S. Geary: That's the approach we're taking, and the study is designed to evaluate that in addition to the question that you asked, which is to extend the frequency of dosing, one of the issues with some of the existing platforms is that if they spread their frequency out to more than two weeks or one month, they begin to have these breakthrough issues. So in our Open Label Program, we'll be looking at the ability for this medicine, with its long half-life and long PD component, to be able to be administered at even more..., frequent or less frequent, more applicable kind of and competitive. Administration.

That's that's the approach we're taking and the study is designed to to evaluate that in addition to the question that you asked which is to extend a you know a frequency of dosing one of the issues with.

Some of the existing platforms is that if they.

Broaden their their frequency.

Now to more than down two weeks or one month say they begin to have these breakthrough issues. So in our open label program, we'll be looking at the the ability for this this medicine with its long half life and long TV.

Component to be able to be administered at even more.

Frequent or less frequent more.

More applicable kind of and competitive.

Administration range.

Richard S. Geary: Okay, I agree. Thank you. You got it. Thank you. Yeah. Our next question comes from Yaron Werber with Cowan. Please go ahead.

Okay I heard your question.

You got it thank you yep.

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

Operator: Yeah, hi, and thanks for taking the time. I have a couple of questions. The first one is maybe just a follow-on to the last one. Maybe on PKK, is Tequisro, do you view that to be sort of the most relevant competition because of potency and less frequent dosing? Or do you feel that there are other compounds that are, you know, kind of bigger competitors for you? And then I have a quick follow-up. No, I think you nailed it.

Hi, and thanks for taking up I have a couple of questions. The first one is maybe just a follow on to the last one maybe on PKK is took his role or do you view that to be sort of the most relevant competition, because the potency and less frequent dosing or do you feel that there's other compounds that golar.

You know kind of bigger competitors too and then I have a quick follow up.

No I think you nailed it that's what steps are.

Richard S. Geary: That's what, that's our hurdle to beat. And that's what we're aiming for, and the design of the study allows us to evaluate that. Yeah, and can you think you can dose it every month? I mean, it sounds like monthly, potentially certainly doable. What about less frequently, like every two months?

That's our hurdle to beat.

And that's where we're at that's what we're aiming for and the design of the study allows us to evaluate that.

Yes. They can you do think you couldn't doses every I mean, it sounds like monthly potentially certainly doable what about less frequently like every two months or is that a stretch based on what you see in PD.

Richard S. Geary: Or is that a stretch based on what you see in PD? Now the PKPD actually supports every two months, and then it's just a matter of starting to get some experience with that regimen. Yeah, and whether, obviously, whether a bimonthly versus monthly regimen from a marketing standpoint actually represents an advantage for patients. But as Richard said, if we feel it does, we have the ability to move there.

Now the PK PD actually supports every two months and then it's just a matter of Oh, Oh, starting to get some experience with that regimen.

And when and whether obviously, whether a bimonthly versus monthly regimen from a marketing standpoint is.

This is actually represents an advantage for patients, but as Richard said it.

If we feel it does we have do you have the ability to move there.

Richard S. Geary: Yeah. Okay. Great. And the final question: I'm just moving to GHR LRX.

Okay, Great and final question on just moving to G.H.R. Lrx.

Richard S. Geary: If I remember correctly, that phase two data, we should see that soon, Necromegaly, that is looking at some of our naive patients, right? I don't think you're enrolling failures. Correct me if I'm wrong. And then what does that mean for potentially the phase three program? Would it be naives, or can you also go for some of our failures?

If I remember correctly that phase two data, we should see that soon that chrome ugly that he's looking at so somewhat worth nave patients right.

I don't think you're enrolling failures correct me if I'm wrong, and then what does that mean for potentially though the phase three program would be would be naive or can you also go for the somewhat horse failures. Thank you.

Richard S. Geary: Thank you. Yeah, so the initial studies that we've conducted are on somovert failures, you can call it that; it's patients who are on somovert and uncontrolled biochemically. And then we have the second study that actually will report out next year in the NIEEP. We're covering the entire spectrum, starting with some of our... Uncontrolled Patients. Did that answer your question?

Yes, so the the initial studies that we've conducted are on some of our.

Failures, you could call it that its patients who are also covered and uncontrolled.

Biochemically.

And then we have the second study that actually will report out next year.

In the night.

We're covering that we're covering the entire spectrum starting with the silver.

Uncontrolled patients.

Did that answer your question.

Richard S. Geary: Yeah, so the data, right, so this is going to be the second study, and that's in the naive segment. And then based on that, the thought, you know, assuming, you know, based on the prior data, we're expecting positive results in this phase two, the thought then, in phase three, to do sort of a head to head against some of our failures, maybe within a single arm design or, or go to the naive. I mean, there's sort of two ways you can go there. The teams are still working out the designs, and the regulatory interactions are still ahead of us, so it would be, I think, premature. I'm giving you a design of the Okay, great, thank you.

Yes, so that for the data right. So this is going to be the second study that's in the <unk> segment and then based on that is is the thought you know assuming you know based on the pro data we're expecting positive results from this phase two is the thought that in phase three to do sort of a head to head against him or her to go through the failures, maybe with them since.

Alarm design or or go to the naive them into sort of two ways you can go there.

Yeah. The teams are still working out the designs and the regulatory interactions are yet for us. So I would be I think premature and giving you a design at this point.

Okay, great. Thank you.

Thanks here. Our next question comes from Vincent Chen with Bernstein. Please go ahead.

Operator: Our next question comes from Vincent Chen with Burns. Please go ahead. Congratulations on your progress, and thanks for taking my questions. A couple of quick ones on the oral program and oral delivery of ASOs. I guess the first would simply be, I'm curious, how would bioavailability for one of your ligand conjugated ASOs differ from another one if they were dosed orally? I guess what I'm thinking about is, would you expect bioavailability to probably look pretty similar between different types of like a drug, or would there be meaningful differences?

Congrats on Reuters and thanks for taking my question is on a couple of quick ones on the oral program is oral delivery of eight of those deals. The first is simply be.

Here's how would bioavailability for one of your life and conjugate if those differ from another one.

If there are dosed orally I guess thinking about would you expect bioavailability, probably looks pretty similar between different like a like a drugs or would there be meaningful differences and I guess the second related would be you mentioned earlier your continue to do research on new formulations, and new chemistry too.

Richard S. Geary: And I guess the second related question would be, you mentioned earlier, you're continuing to do research on new formulations and new chemistries to enhance oral delivery. Asbury, could you provide some color on what are some of the things you can do with formulation or chemistry to try to boost oral bioavailability? So, you know, Thanks for your questions, Vince, but I'll pass them on to Richard, who's one of the experts in oral delivery of all of these types anywhere.

Enhance oral delivery I was wondering could you provide some color on what are some of the things you can do on formulation or chemistry to try to boost oral bioavailability.

So you know I'll.

Starting in the first and thanks for your questions, Vince and but I'll pass it on to Richard.

One of the experts in oral delivery of Oregon tides anywhere.

But recently, yeah, we have shown that the oral delivery or oral bioavailability that we get or like a drugs is very similar to our non like a drugs.

Richard S. Geary: But we believe, you know, we have shown that the oral delivery or oral bioavailability that we get with our Lyca drugs is very similar to our non-Lyca drugs. And what was very important to demonstrate was the ability to be that, to be comparable to what we've shown previously with non-lycan drugs, but also to be stable and be, you know, effective in target reduction in the liver. And we've also shown that this is transferable across several, many different anti-sense drugs with Gen 2.5 chemistry and Leica. So it is directly transferable. And Richard, maybe you can talk a little bit about what we expect on first pass and that sort of thing with the Leica drug and the like of drugs. I mean, it really all comes down to public.

And and is and what was very important to demonstrate was that the.

That that by availability to be done to be comparable to what weve shown previously I'm like Android, but also to be stable.

And be you know effective in target reduction in liver.

And we've shown also that this is transferable across several many different antisense drugs with Gen 3.5 chemistry in like US. So it is it is directly transferable and Richard maybe you could talk a little about what we expect on first pass and that sort of thing.

With like a drugs.

Well I can drive I mean, it's it really all comes down to potency.

Brett P. Monia: And that's why the sub-Q data that you're gonna see is so important. It starts to give the justification for why a molecule that gives you 10% bioavailability or something like that can be a very clinically relevant dosage form. So it comes down to cost of goods and potency. You asked the question about, you know, what a different like of a different chemistry gives you different bioavailability. Actually, across our platform, the oligonucleotide bioavailability is fairly comparable across the chemistry types.

And that's why the Subcu data that you're going to see is so important that starts to give the justification for why a molecule that gives you, 10% bioavailability or something like that can be.

I'm very.

Clinically relevant dose.

Dosage formulation.

So it comes down to cost of goods and potency.

You asked the question about you know what a different like kind of a different chemistry give you different bioavailability actually across our.

Platform.

The older nucleotide bioavailability is fairly comparable.

Across the chemistry types the difference with the like is that you present.

Richard S. Geary: The difference with the lica is that you present it to the liver first, versus a subcube. So you get a bit of a bang for your buck, if you will, by presenting it first to the liver and allowing the liver to see the drug at low concentrations first, with millions of copies of the GalNac receptor on the hepatocytes scooping up the drug as it passes through the liver first. So that gives you that extra something extra over and above what you would get with an unconjugated oligonucleotide. Is that helpful?

To deliver first.

Versus the Subcu, so you get a bit of.

Have a bang for your Buck if you will by presenting first to deliver and allowing the liver to see the drugs.

At low concentrations first with millions of copies of the Galnac receptor on their path sites scooping up the drug as it passes through the look first so that gives you that extra.

Over and above what you would get with an unconscious located.

Only going to be tied.

Is that helpful.

And I'll just add to that also the fact that these drugs are so stable and so long acting allows us to have can they accumulate in the parasite. So but you know 10% by availability for a drug to Atish has has a half life of 24 hours or less is not very commercially viable.

Brett P. Monia: And I would also add to that also, the fact that these drugs are so stable and so long-acting allows us to have them accumulate in the hepatocyte. So, you know, 10% bioavailability for a drug that has a half-life of 24 hours or less is not very commercially viable because of the fluctuations you're going to get in bioavailability and all kinds of things. But the fact that our drugs are so long-lasting allows that availability to be very significant and very important and justify oral delivery with our platform. So that's a very important thing to also remember.

Because of the fluctuation you're going to get viability in all kinds of things, but the fact that our drugs are so long lasting.

Allows that by bill ability to be very significant and very important and justified oral delivery.

With our platform. So that's that's a very important things also remember.

Brett P. Monia: As for the work we're doing on new formulations, stay tuned Vince. We have a lot of work in progress, a lot of irons in the fire, we're not sharing our strategies there, but obviously, we've tackled stability with our drugs, so we're really focused on penetration, getting more of the drug into the bloodstream. I see. Well, I'll stay tuned then.

As far as the work we're doing on the formulations stay tuned and you know we have a lot of work in progress our arms of the fire were not you know sharing our strategies there, but you know obviously, we set we've tackled stability.

With our drugs I'm. So we're really focused on penetration I'm getting getting more drug into the blood.

Hi, as a follow up.

If you then thanks for taking the question to appreciate it appreciate the insights and congrats again on a little broke all the progress.

Operator: Thanks for taking the question, and I appreciate the insights and congratulations again on all the progress. Our next question comes from Annie Stogovar with SBB Lead Rank. Please go ahead. Hi, this is Rick Diling in Fermani.

Thanks Vince.

Our next question comes from Manny the lower with SVB Leerink. Please go ahead.

Hi, This is Rick dialing in for money, thanks for taking our questions.

Operator: Thanks for taking our questions. First, moving back to ENAC, could you maybe broadly discuss what lessons were learned from the ENAC readout? You know, there seems to have been good target engagement in the lungs.

First turning back to Enac could you maybe broadly discuss what lessons were learned from the Enac read out.

I mean are there seems to have been good target engagement in a longer. So we were wondering you know what the main takeaways were and how you're thinking about target selection for any other and held at those that may be in development.

Richard S. Geary: So we were wondering, you know, what the main takeaways were and how you're thinking about target selection for any other inhaled ASOs that may be in development. I would say that the key lessons learned are that our Gen 2.5 chemistry is outperforming our Gen 2 chemistry for aerosol delivery. Based on the potencies that we get with that drug that Richard referred to earlier, it's really the first time we've shown statistically significant and substantial reductions in target with an aerosol antisensory nucleotide in humans. So that's a huge lesson learned, and we think that, and that gives us confidence that in our emerging pulmonary pipeline overall, we have several other drugs in development for pulmonary disease. One of, at least one of which we expect to reach development next year, or in development, potentially clinical, well, clinical testing next year, the second drug. So, and of course, safety and tolerability are a very important lesson learned. The third is, you know, the doses that we're seeing these effects give us confidence that the preclinical data is predicting what we expect to see in humans very, very, very well. Very important.

I would say that the key lessons learned are there. Our gen 2.5, chemistry is outperforming or gender tend to chemistry for airseal delivering alone based on the potency that we get with that drug that Richard referred to earlier.

It's really the first time, we've shown statistically significant and substantial reductions in target with an aerosol antisense oligonucleotides in humans.

So that's a huge lesson learned and we think that in that gives us confidence that in our emerging pulmonary pipeline overall, we have several other drugs in development for pulmonary disease.

One of at least one of which we expect to reach development next year.

Or in developing potentially clinical clinical testing next year or the second drug.

So and of course, the safety and Tolerability is a very important lesson learned the third as you know the doses that we are seeing these effects or give us confidence that the preclinical data.

Is predicting.

What were what we expected to see in humans, I'm very very very well, which is very important.

Okay.

Got it thanks for that.

Second question or just something to see if there is any update on the status of recruitment into the phase three studies for TTR like us they.

Richard S. Geary: Thanks for that. Second question, just looking to see if there's any update on the status of recruitment into the phase 3 studies for TTR-Lica. Just are there any trends you've been seeing in enrollment over the last quarter and how you're currently thinking about time to data for polyneuropathy and cardiomyopathy? So, studies are enrolling, sites are being activated for both the polyneuropathy and the cardiomyopathy phase three studies, and they're moving well. We've had some impact with COVID-19 in getting sites activated and so on, but overall, we're not providing details. It's obviously a competitive situation that we're in, but we're pleased.

Just are there any trends you've been seeing in enrollment over the last quarter and how you're currently thinking about time to data for Polyneuropathy and cardio man biopsy.

So where were the studies are enrolling.

Sites are being activated for both on are up in the Cardium out with the phase three studies and there you know they are moving well we've had some some impact of CODI 19 in getting sites activated and so on but overall that you know.

We're not providing details it's obviously a competitive situation that we're in but we.

We're pleased with.

Please within a roaming that we're seeing so far.

In both phase three studies and we like we like our clinical trial designs, which are are we think are enhancing enrollment.

No changes to what we said publicly aircard am I off but the data room second data read.

Brett P. Monia: We're pleased with the enrollment that we're seeing so far in both Phase 3 studies, and we like our clinical trial designs, which we think are enhancing enrollment. There are no changes to what we've said publicly, our cardiomyopathy data, we're expecting data readout from the phase 3 study in the 24-time frame, and the polyneuropathy data in the 23-time frame for the full data set, and we also have an interim analysis baked into the polyneuropathy study, and that data is due to come out in 2022. All right, perfect.

Readout from the Phase two study in 24 time frame and the all in our opinion 23 timeframe for the full dataset and we also have an interim analysis baked into the Polyneuropathy study and if we.

And that data is due to come out in 2022.

All right perfect. Thanks for taking my questions.

Got it.

Our next question comes from Yale Jen with Laidlaw and company. Please go ahead.

Hi, good afternoon, thanks for taking the question so.

The first was in Asia regarding the willpower no listen.

Phase two after that the phase Twob study by Pfizer, what could you elaborate more in terms of by the plans for the pivotal study.

Operator: Thanks for taking our questions. Our next question comes from Yale Gen with Laidlaw & Company. Please go ahead.

Richard S. Geary: Good afternoon, and thanks for taking the questions. The first one is regarding Pan-Northern Phase 2, after the Phase 2B study by Pfizer, what's the, could you elaborate more in terms of Pfizer's plans for the pivotal studies? You mentioned three studies, but maybe a little bit more color on that. That's a perfect pitch for Richard. Knock it out. Yeah, good question. So the phase 2B study is in dyslipidemic patients with cardiovascular disease, high risk. Profile, and it's in, direct Preparation for a Phase 3 program that includes a cardiovascular outcome trial. Much will be learned because these patients are hypertriglyceridemic as well. Much will also be learned about dose selection for the severe hypertriglyceridemic platform.

Three studies, but maybe a little bit more color on that.

Yeah. So.

Perfect fit for Richard.

I'm not going out [laughter] yeah.

Good question.

So the phase Twob study isn't just a gimmick patients with a cardiovascular disease high risk.

Our profile and its in June.

Darex.

Preparations for phase three program that includes cardiovascular outcome trial much won't be learned because these patients are hypertriglyceridemia as well I told you learned about dose selection also or the severe triglyceride deeming.

Platform and so it's it is a.

Richard S. Geary: And so it's a dose range finding study that will set up the finalization of protocols for those two programs and those two populations. And is there a third one, which is you will use the cardiovascular outcome as an end point and in the color zone, that the cardiovascular outcome trial is one trial, and then the severe hypertriglyceridemic population, there's planned a couple of phase threes for that. Okay, great. That's very helpful. One more question. In terms of SDR, at this point, I know you will give them more color at investor day, but any other thoughts, at least on the 10,000 foot angle, in terms of any additional, all of these elements or changes need to be added after this presentation. Not really, Yale.

A dose range finding study that will set set up the finalization of protocols.

For those two programs and those two populations.

And is there a third one which is a you will use the cardiovascular outcome or endpoint in the in the colors on that study.

Yes, cardiovascular outcome trial is one one trial and then the severe hypertriglyceridemia.

Valuation.

Is there as planned a couple of phase threes for that.

Okay, Great. That's very helpful. I'm, sorry, one more question.

One more question.

In terms of the.

A position at this point I know you will give them a little color at the Investor day, but any other thoughts.

On the 10000 foot angle in total.

Is there any additional additional.

Element or changes on the animal.

Thats need to be added up to this oh position.

Brett P. Monia: We'll talk more about it. As mentioned at Investor Day, this is a key step towards building our commercial strategy for the future. But really, I wouldn't say that there are any additional elements than what we've said today or what we put out when we announced the closer closing of the acquisition. We're very excited about this. We think this is a very important strategic step in the growth of Ionis for many reasons that we've highlighted that are both financial as well as based on efficiencies and building our commercial plans for the future. You know, that's a lot right there.

I'm not really yet we'll talk more about it as mentioned at Investor Day, a how is how this is a key step towards our building our commercial strategy for the future.

But really I wouldn't say that theres any additional elements than what we've said today or what we put out when we announced the closer closing of the.

The acquisition.

We're very excited about this we think this is a very important strategic step and the growth of Ionis for many reasons that we've highlighted that both financial as well as based on efficiencies and based on building our commercial.

Plans for the future so.

That's a lot right there and we're and we'll talk more about it in.

Brett P. Monia: And, you know, we'll talk more about it in December. I really can't expand more on your question. Okay, great. Thanks, Larry. I appreciate it.

In December I really cant expenses more than that.

On your question.

Okay, great. Thanks, a lot appreciate it and congrats on the others.

Operator: And congratulations on the talk. Thank you. Our next question comes from Jessica Fye with J.P. Morgan. Please go ahead.

Thanks you.

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

Operator: Hey guys, good morning. Thanks for taking my question. Another one on buprenorphine. It looks like the doses being studied in Phase 2B are generally higher than what was studied in Phase 2A. So thinking about the non-very high triglyceride population, kind of the broader high CV risk group, I'm just curious, when you look at those higher doses, how much more efficacy are you hoping to achieve relative to the Phase 2A endpoints like LBL? Yeah, a great question.

Hi, guys. Good morning, Thanks for taking my question. Another one on just an arson it looks like the dose is being studied in pay TV are generally higher than what was studied into Q and a.

So thinking about the.

The non very high triglyceride population kind of in the broader high CV risk group.

I'm just curious when you when you look at those higher doses, how much more efficacy, you're hoping to achieve relative to the C. N on endpoints like LDL C.

Yeah, Great question I'm really be the primary endpoint is non HDL C.

Richard S. Geary: Really, the primary endpoint is non-HDLC, which is a group of lipid particles that are involved in atherosclerosis. So the increase is a combination of an increase in triglycerides, an increase in VLDL-C, and LDL. So it's not a single component look.

Which is a a group.

With the particles that are involved in Africa.

Atherosclerosis. So the increase is a combination of an increase on triglycerides.

Increase on V LDL C and LDL. So it's not a single component look it's it's basically the remnant cholesterol that remains in the circulation in patients with elevated triglycerides.

Richard S. Geary: It's basically the remnant cholesterol that remains in the circulation in patients with elevated triglycerides and Cardiovascular Disease. So, I don't know if that answers your question. It's a dose range finding study, and the doses are now being tested in patients with dyslipidemia and cardiovascular risk, which is a different population than the population we studied in our Phase 2a study. Yeah, I think that's the key, Jess, that it is a different patient population than the Phase 2 study, so Pfizer wants to get the dose right. For the Phase 3, for the several Phase 3 studies that Richard mentioned that they're planning to initiate, because it is a different patient population, and the doses could be different, and they want an optimal dose.

And cardiovascular disease.

So I don't know if that answers your question the the dose range finding study and the doses are.

Are now being tested in patients with Dyslipidemia and cardiovascular risk return is a different population than.

The population we studied in our phase two study yeah I think that's the kick aegis is that it is a different patient population in the phase two study so pfizer wants to get those right for phase three for several several phase three studies that Richard mentioned that they're planning to initiate because it is a different vision pop.

Relation and the dose could be different and they want an optimal dose so I'm going to higher doses just part of that strategy.

Richard S. Geary: So going to higher doses is just part of that strategy. Okay, makes sense. And just kind of sticking with this product. And, you know, recognizing the lack of support for benefit in drugs that increase HDL, what do you think of the declines observed with this product in HDL? Again, yeah, so we've looked at this very carefully, and you know that there is actually a genetic population that has a knockout of ANG-PTL3. And in that population, they have extremely low HDL, extremely low LDL, and Triglycerides, and they have no cardiovascular disease, and they have a very long, you know, bunch of very long-lived individuals. Now this is a small population in the hill country of Italy.

Okay. It makes sense.

And just kind of sticking with this product and you know recognizing the lack of support for benefit in drugs that increase Hcl, what do you make of the declines observed with this product in each DLC.

Let me take that Weve, yeah. So we've looked at this very carefully and you know that there is actually a.

Genetic.

Population that has a knock out of Anj PPL three.

And in that population they have extremely low HDL extremely low LDL.

And triglycerides and they have no cardiovascular diseases have a bearing on a bunch of.

Very long lived individuals now this is a small population.

In the.

Hill country of Italy.

Brett P. Monia: So now we're studying this in populations where we're actually knocking it down, not from birth, but in a selected population. So I guess what I would say is when we think about HDL. HDL, as always, has to be taken into consideration, along with all the other atherogenic lipids. What's been shown is that HDL alone does not, you know, by raising HDL, does not apparently, you know, improve the cardiovascular outcomes of patients. But what we know is that if you take down cholesterol, if you take down remnant cholesterol, you do improve the cardiovascular health of patients. Thank you. Thanks, Jess. We're running late.

So now we're studying this and.

Populations.

Where we're actually knocking it down not how on Earth Buddy.

But in a.

Yes, hi student population.

Population.

So I guess, what I would say is when we think about HDL.

Each deal is always has to be taken into consideration.

Along with all the other atherogenic lipids.

What's been shown is that HDL alone does not you know by raising HDL does not apparently no improves the cardiovascular outcomes of patients, but what we know is if you take down cholesterol. If you take down remnant cholesterol that you do.

Improve cardiovascular health of patients.

Got it thank you.

Thanks, Jeff maybe running.

Operator: We'll take one more question and then we'll have to close. Our last question comes from Miles Mintar with William Blair Company. Please go ahead.

We're running long, we'll take one more question and they won't have to close.

Our last question comes from Myles mentor with William Blair <unk> Company. Please go ahead.

Hi, Thanks for taking the questions just maybe one on something we haven't talked about the tempress six assets or beta Sal I'm, just wondering why am I going to say phase two data next year, whether you've got clarity on that.

Operator: Oh hey, thanks for taking the questions. Just maybe one on something we haven't talked about, the Tempora-6 asset for beta-thal. Just wondering when we're going to see phase 2 data next year, whether you've got any clarity on that. And just in terms of the primary endpoint, can you maybe explain the clinical meaningfulness of a 1 gram per deciliter increase in hemoglobin in this patient population and not the transfusion-dependent population? Just trying to understand how to interpret that moving forward if this does go into a pivotal trial of some sort. Thanks.

And just in terms of the primary endpoint can you maybe explain the clinically.

The clinical meaningfulness, so by a one gram per deciliter increase in hemoglobin in this patient population and not the transfusion dependent population just trying to understand how to interpret that.

That moving forward. If this does go into a pivotal trial the subsalt. Thanks.

Yeah, I'll take a stab at that maybe Richard can expand on anything worth highlighting the on this so we're very excited about this program.

Brett P. Monia: I'll take a stab at that, and maybe Richard can expand on anything worth highlighting beyond that. So we're very excited about this program. We think the opportunity in beta-thal intermediate, as well as other indications that are plagued by low hepcidin levels, are also very relevant for our Tempor6 inhibitors. As you know, Miles, in Phase 1, we not only showed good safety and tolerability, but we showed significant increases in hepcidin levels and changes exactly in the direction based on preclinical data that that data would predict in iron and transparent saturation. In the intermediate patient population, there are two goals, right? One is to increase, to deal with anemia, and to increase hemoglobin to the extent that you highlighted, which is very meaningful.

We think the opportunity in data Sal intermediates as well as other indications where that are plagued by low have cited levels are also very relevant for our tempur syk inhibitor as you know miles in phase one we not only showed good safety and Tolerability, we showed significant increase.

So I didn't levels and in changes exactly in the direction based on our preclinical data would that data would predict in iron and transparent saturation.

Into the intermediate patient population.

There's two goals right one is to increase just to deal with the India and to increase.

Moving to the extent that you highlighted which is very meaningful endpoint in these patients is potential approvable endpoint in the intermediate patient population, but with this drug can also do is.

Brett P. Monia: Unknown Executive, Huidong Wang, James Condulis, Yaron Werber, Elizabeth Hougen, Gary Nachman, is reduced iron load in the liver and in the heart and reduces toxicities associated with iron overload in those organs and other organs as well. So this is a very unique drug, potentially, that has the ability to not only affect the anvil and improve and normalize, potentially, the anemia but also the devastating effects We have a wealth of preclinical data published in real good models of beta-thalassemia.

His reduce iron load in liver and heart and reduce toxicities associated with iron overload in those organs and other organs as well. So this is.

Very unique drug potentially that has the ability to not only affect it.

Handle and improve.

Improve and normalize potentially be in EMEA, but also the devastating effects of iron overload in various organs and we have a wealth of preclinical data published in real good models, a beta cells immune. We're also exploring additional indications for this drug that are related to as I said.

Brett P. Monia: We're also exploring additional indications for this drug that are related, as I said, to, you know, dysfunctional management of iron due to low Timing for the study, I don't think we've disclosed that to date for the Phase 2 study that's in progress. It is a novel design that we can share data, potentially next year, from the study, but I don't think we can. I can't come out on that yet, so when exactly that date will be. Okay, cool, that's helpful. I was just going to add to Brett's point that we just, and Iron Overload.

MS. This functioning dysfunctional management of iron due to low.

Timing for the study or even a I think we've disclosed that to date for the phase two study that's in progress.

It is a novel design that we can share data.

As.

Potentially next year.

On the study but.

We've come out on that yet, they're going exactly that they will read out Myles.

Okay Cool that's helpful.

Jennifer I was I was just going to add to Brett the point that we just actually completed the market Research survey and it shows that you know just from a clinicians perspective that the dual benefit of managing both EMEA and iron overload you know with the single each and every time.

Richard S. Geary: So we've got that 85% of clinicians out there are looking for it. understood. Last quick one from me, and I may be wrong here, but is there any reason why, for the chronic hepatitis B program that GSK is running, why they would have taken a non-lica conjugated product in phase two as opposed to a lica product? Yeah, I mean, the reason there is that the reductions in the antigens that were shown in the trial were not really different from the likelihood and that the parent molecule was actually performing very well. And the next question you'll ask me is why that is, and the answer is truthfully, we really don't know why that is. It's one of the programs where we haven't seen that, but the specifics of that program are that the This is the only LICA where we have not seen a significant increase in potency with LICA versus non-LICA.

You know we've gotten that 85%.

Clinicians out there are looking for an iron controlling product aside from the Ironkey, leading agents and the deal benefited continues to be a really.

<unk>.

Understood last.

Last quick one from me and I may be wrong here, but is there any reason why for the chronic hepatitis b.

They program that GSK is running why that would have taken a non lockett conjugated product in a fight so as opposed to a lot of products.

There but.

Yes, I mean, the the reason there is that the.

The reductions in the antigens that were shown in the trial, we're not really different with the like.

And the parent molecule was actually performing very well and then the next question. You asked me is why that is and dancers truthfully. We really don't know why that is one of the it's the only program, where we haven't seen that but the.

The specifics of that program is the parent molecule is performing.

Better than loved unlike in the like it didnt get an advantage.

Yes. This.

This is the only like it where we have not seen a significant.

Increased potency with a like versus a month.

Works, where we're trying to understand it but GSK.

Richard S. Geary: We're trying to understand it, but GSK is very excited about the drug that they licensed from us, as are we, and they think that this has the potential to be an HPV cure. Fair enough, thanks for squeezing me in; I appreciate it. Thank you, Miles, and thank everybody. So with that, I want to thank everybody for participating in today's call, and remind you again of our upcoming Investor Day on December 7th, where we're really excited about some of the progress, a lot of the progress that we're making, we'll be sharing in more detail. And then, finally, we wish all of you a great day. Thank you. The conference is now concluded. Thank you for attending today's presentation. Goodbye. You may now disconnect.

It's very excited about the drug that they license from us as we are to they think that this is a potential as a potential for HBV cure.

In future Myles.

Fair enough. Thanks for squeezing me in I appreciate it.

Thank you miles and thank everybody so with that.

I want to I want to thank everybody for participating on today's call remind you again of our upcoming Investor day on December 7th where we're really excited about limited progress a lot of the progress that we're making will be sharing more detail.

And then finally with all of you a great day. Thank you.

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

Hmm.

[music].

Oh.