Q2 2019 Earnings Call

Unknown Executive: I would like to turn the call over to Wade Walke, Vice President of Investor Relations, to lead off the call. Please begin.

As a reminder, this call is being recorded.

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

Wade Walke: Thank you, Nicole. Before we begin, I encourage everyone to go to the Investor section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP non-GAAP financials to the measures that we'll discuss today.

Thank you Nicole.

Before we begin I encourage everyone to go to the investors section of the honest website find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financials.

Ah the measures that we'll discuss today, we believe the non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our web sites accompany our discussion today.

Wade Walke: We believe the non-gap financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website to accompany our discussion today. With me on today's call are Stan Crook, Chairman of the Board and Chief Executive Officer, Beth Haugen, Chief Financial Officer, Brett Monia, Chief Operating Officer, and Damien McDevitt, Chief Business Officer, who will join us for Q&A.

With me on today's call are Stan Crooke, Chairman and Chief Executive Officer.

Hougen, Chief Financial Officer, Bret ammonia, Chief operating officer, and Jamie Mcdevitt, Chief business Officer will join us for today.

Wade Walke: I would like to draw your attention to slide 3, which contains our forward-looking language statement. We will be making forward-looking statements that are based on current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. With that, I'll turn the call over to Sam.

I would like to draw your attention to slide three which contains our forward looking language statement you will be making forward looking statements, which are based on current expectations and beliefs. 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 with that I'll turn the colors.

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

Stan Crook: Thanks, Wade, and good morning, everyone. Thank you for joining us on today's call.

Stan Crook: In the first half of 2019, we achieved a substantial number of value-driving successes across our business, further strengthening our financial position as we enter the second half of this year. We finished the first half of the year with revenues of $460 million.

In the first half of 2019, we achieved a substantial number of value driving successes across our business.

A further strengthening our financial position as we enter the second half of this year.

We finished the first half of the year.

Revenues of $460 million.

This is an increase of more than 75%.

Stan Crook: This is an increase of more than 75% compared to last year, putting us on track to deliver our fourth consecutive year of operating income and our third consecutive year of net income. We achieved these strong financial results while continuing to invest as aggressively as it makes sense broadly across our entire business, including commercializing medicines and advancing our pipeline of technology. Spinraza's blockbuster performance continued into the first half of this year. It remains the worldwide standard of care and the only therapy approved for the treatment of SMA patients of all ages and all SMA types. I have now treated some SMA patients with Spinraza for approximately seven years.

Compared to last year.

Putting us on track to deliver our fourth consecutive year of operating income and our third consecutive year of net income.

We achieved these strong financial results, while continuing to invest as aggressively as it makes sense.

Oh broadly across our entire business, including commercializing too.

Two medicines.

And advancing our pipeline technology.

Spinraza blockbuster performance continued into the first half of this year.

Spinraza remains the worldwide standard of care and the only therapy approved for the treatment of SDMA patients of all ages and all that so many types.

Having now treated some estimate patients with spinraza for or for approximately seven years.

Stan Crook: We now have patients who began treatment as adolescents and are now young adults. I'm particularly gratified to think about these young adults who, before Spinraza, would have faced a life of progressive weakness and increasing dependence. Today, they are able to live longer, more independent, and more productive lives. And that's just the beginning.

We now have patients who began treatment as adolescents and are now young adults.

I'm, particularly gratified to think about these young adults who before spinraza.

I would just say still alive for progressive weakness and increasing dependence today.

They are able to live.

Longer.

More independent and more productive lives.

And that's just the beginning babies with estimate are now being treated before becoming symptomatic and the vast majority of those babies.

Stan Crook: Babies with SMA are now being treated before becoming symptomatic, and the vast majority of those babies... are maturing like normal healthy children and can look forward to a life of independence and productivity. Our Commercial Affiliate, Axia, has now completed the first two quarters of the tech-savvy launch and a reported $10 million in product sales in the second full quarter of launch. That is a 40% increase compared to last quarter. While it is still early in the launch, we are

Our maturing like normal healthy children, you can look forward to a life of independence from productivity.

Our commercial affiliate Akcea has now completed the first two quarters of the tech savvy launch.

And reported a $10 million in product sales in the second full quarter of launch.

That is 40% increase compared to last quarter.

While it is still early in the launch we are receiving positive feedback from each from TTR patients and from physicians about the positive benefits. Its et said he is having on patients lives. We libra is the only approved medicine for the treatment of patients with severe triglyceride disorder Fcs.

Stan Crook: WeLibra is the only approved medicine for the treatment of patients with the severe triglyceride disorder, FCS. We're launching WeLibra in Europe. This quarter through AXSIA, and we are looking forward to expanding into the Latin American market through PTC Therapeutics later this year. In the U.S., we in AXSIA are encouraged by our recent productive discussions with the FDA to clarify a path to patients in the U.S. Additionally, we recently completed the broader study in Boyle-Lieber in patients with FPL.

We're launching the Libra.

In Europe .

This quarter through Akcea and looking forward to expanding into the Latin American market to PTC Therapeutics later this year.

In the us.

We and Akcea ahead are encouraged by.

Our recent productive discussions with the FDA to clarify a path.

To patients in the U.S.

Acxiom Lee.

We recently completed the broader study and we lever in patients who have FPL.

Another rare triglyceride disorder characterized by metabolic abnormalities, including very high triglycerides and in the plasma and liver and extreme insulin resistance.

Stan Crook: Another rare triglyceride disorder characterized by metabolic abnormalities, including very high triglycerides in the plasma and liver, and extreme insulin resistance, as well as an abnormal distribution of body fat. In the broad study, where liver achieved its primary endpoint dramatically and statistically significantly reducing plasma triglyceride levels, liver also achieved an important secondary endpoint with the reduction of liver fat, along with good safety and tolerability observed in the We look forward to presenting the detailed data from this study at a future medical meeting and in a publication.

As as well as abnormal distribution of body fat and the broader study we leveraged achieved its primary endpoint dramatically.

And statistically significantly reducing plasma triglyceride levels really were also achieved.

An important secondary endpoint with the reduction of.

Liver fat along with good safety and Tolerability observed in the study.

We look forward to presenting the detailed data from this study at a future medical meeting in in a publication.

Now lets look.

Briefly.

Hi, Ed.

At more recent value driving catalyst from our pipeline.

Stan Crook: and more recent value-driving catalysts from our pipeline. Our late-stage pipeline of Phase III and near-Phase III programs is advancing as planned. Our Phase III medicines for Huntington's disease and SOD1-ALS are in Phase III studies, both with the potential for rapid paths to patients. Our two late-stage Leica medicines, one to treat patients with LPA-driven cardiovascular disease and the other to treat patients with all forms of TTR amyloidosis, are on track to begin phase III studies this year, and our mid-stage pipeline is advancing on schedule as well. Our partner GSK reported that our HBV program achieved positive results. We are completing our Phase II study of Ionis Factor XI-RX in patients with end-stage renal disease, as well as the Phase I study of Lycaform of Factor XI-RX.

Our late stage pipeline of phase three in near Phase three programs is advancing as planned.

Our phase three medicines for Huntingtons disease, and Esselte, one alias Payless are in phase III studies, both with the potential for rapid test to patients. Our two late stage life come at us.

One.

To treat patients with Lpa, driven cardiovascular disease and the other to treat patients with all forms of TTR amyloidosis.

We are on track to begin phase III studies this year.

And our mid stage pipeline is advancing on schedule as well.

Our partner GSK reported that our HBV program achieved positive results.

We are completing our phase two study of Ionis factor 11, Rx in patients with end stage renal disease as well as the phase one study of the like a form.

Of of factor 11 Rx.

Stan Crook: And we believe that at the completion of this study, we'll set the stage to rapidly advance both of these medicines into later stage development. We're pleased with what we are seeing in these studies, and we look forward to presenting the results of these studies after they're fully completed and analyzed. Additionally, we recently initiated two Phase II programs. We initiated the first Phase II study of Ionis Vector D-LRX for the treatment of people with complement-related or mediated diseases, with studies in additional complement-mediated disease indications planned as well. We have also initiated a Phase II study of Ionis PKK-LRX for the treatment of patients with hereditary angioedema and plan to move forward with regard to additional indications involving abnormalities of the PKK pathway.

And we believe that the as the completion of this study will set the stage to rapidly advance one or both of these medicines into later stage development.

We're pleased.

With what we are seeing in these studies and we look forward to presenting the results of these studies after they're fully completed and analyze additionally.

We recently initiated two phase II programs, we initiated the first phase two study of Ionis factor the lrx for the treatment of people with complement related or mediated diseases.

With studies in additional.

Complement mediated diseases disease indications plan as well.

We also initiated a phase two study of Ionis PKK Lrx.

For the treatment of patients with hereditary angioedema and plan to move forward.

In additional.

With regard to into additional indications involving abnormalities PKK pathway.

We are the leader in R&D targeted drug discovery and development I am pleased to tell you that the technology continues to advance and an ever increasing pace. Our pipeline is full of potentially transformative medicines that are advancing rapidly and we're doing all of this while continuing to achieve sustainable profitability now I'll turn the call over to Beth to provide.

Elizabeth L. Hougen: Discovery and Development. I'm pleased to tell you that the technology continues to advance at an ever-increasing pace. Our pipeline is full of potentially transformative medicines that are advancing rapidly, and we're doing all of this while continuing to achieve sustainable profitability. Now I'll turn the call over to Beth to provide our financial updates, followed by Brett, who will update you on our pipeline progress.

Our financial update.

Followed by Brett who will update you on our pipeline progress.

Thank you Stan.

Elizabeth L. Hougen: Thank you, Stan. Our financial results for the first half of this year continue to build on our multi-year growth trajectory. We ended the first half with total revenues of more than $460 million, a more than 75% increase over the same period last year, driven by growth in both commercial and R&D revenues. Our significant revenues resulted in continued growing profitability, with operating income of $190 million and net income of $162 million for the first half of this year, both on a non-gap basis. We also maintained our substantial cash position by ending the quarter with $2.3 billion, even while investing broadly across our business.

Our financial results for the first half of this year continue to build on our multi year growth trajectory.

We ended the first half with total revenues of more than $460 million.

More than 75% increase over the same period last year driven by growth in both commercial and R&D revenues.

Our significant revenues resulted in continued growing profitability with operating income of $190 million and net income of $162 million for the first half of this year, both on a non-GAAP basis.

We also maintained our substantial cash position by ending the quarter with $2.3 billion, even while investing broadly across our business.

In the first half of 2019, spinraza generated over $1 billion and worldwide net sales, a nearly 30% increase compared to 2018.

Elizabeth L. Hougen: In the first half of 2019, Spinraza generated over $1 billion in worldwide net sales, a nearly 30% increase compared to 2018. These strong results put Spinraza well on track to significantly exceed 2018 revenue. Reflecting Spinrad's strong performance, our royalty revenue also increased by more than 30% to $130 million. Notably, in the second quarter, we reached the highest royalty rate.

These strong results put spinraza well on track to significantly exceed 2018 revenue.

Reflecting spinraza strong performance.

Royalty revenue also increased by more than 30% to $130 million.

Notably in the second quarter, we reached the highest royalty rate.

The number of Spinraza patients on treatment worldwide increased by approximately 12% compared to last quarter and now approximately 8400 patients are being treated with spinraza.

Elizabeth L. Hougen: The number of Spinraza patients on treatment worldwide increased by approximately 12% compared to last quarter, and now approximately 8,400 patients are being treated with Spinraza in the U.S. Adult patients, which make up the largest patient segment, continue to be a significant driver of growth in the second quarter.

In the you asked a number of patients on spinraza increased compared to last quarter.

Adult patients, which make up the largest patient segment continued to be a significant driver of growth in the second quarter.

Outside the us the number of patients on Spinraza also increased.

Elizabeth L. Hougen: Outside the U.S., the number of patients on Spinraza also increased, in this case by approximately 17% compared to last quarter. This growth was driven by new patients in larger, mature markets, along with rapid uptake in more recently launched markets, including in Asia and Latin America. Biden continued to increase reimbursement for Spinraza around the world in the second quarter. Formal reimbursement is now in place in over 35 countries with the addition of the UK, Ireland, Brazil, and Argentina.

In this case by approximately 17% compared to last quarter.

This growth was driven by new patients in larger mature markets, along with rapid uptake and more recently launched markets, including in Asia and Latin America.

Formal reimbursement is now in place in over 35 countries with the addition of the UK, Ireland, Brazil, and Argentina in the second quarter.

We believe that Spinraza thorough clinical development program and its continued outstanding performance with long term treatment account for Spinraza broad acceptance by payers around the globe.

Elizabeth L. Hougen: We believe that Spinraza's thorough clinical development program and its continued outstanding performance with long-term treatment account for Spinraza's broad acceptance by payers around the globe. Biogen now estimates that the global opportunity for Spinraza is much larger than initial estimates, with more than 45,000 patients in markets where Biogen has a direct presence. With new patient growth expected to continue, we believe Spinraza will remain a global foundation of care for the treatment of patients with FMA. We earned $10 million in commercial sales from TegCeti in the second quarter, a more than 40% increase over the first quarter. And as you would expect with a rare disease medicine, Axia continues to focus on disease education and patient identification, with particular investment in community centers where HATTR patients can benefit from TegCeti treatment close to their home on their schedule. Outside the U.S., we look forward to the launch of TXETI in additional EU countries, as well as the potential approval and launch of TXETI in Brazil through PTC Therapeutics. XE is launching WeLibre this quarter, beginning in Germany, with additional EU country launches planned for next year.

Five to now.

Global Foundation of care for the treatment of patients with Fms.

We earned $10 million in commercial sales from take Sandy in the second quarter of more than 40% increase over the first quarter.

And as you would expect with a rare disease medicine Akcea continues to focus on disease education and patient identification.

With particular investment in community centers, where.

Our patients can benefit from take steady treatment close to their home on their schedule.

Outside the US we look forward to the launch of tech savvy in additional EU countries as well as the potential approval and launch of take study in Brazil through PTC therapeutics.

Akcea is launching we live this quarter beginning in Germany with additional EU country launches planned for next year.

In recognition of way liver the EU approval, we earned $6 million from PTC.

Elizabeth L. Hougen: In recognition of Wayne Liburd's EU approval, we earn $6 million from PTC. PTC is actively preparing to provide Raylibra to patients in Latin America. R&D revenue in the first half of this year nearly doubled compared to 2018, to more than $300 million. This growth demonstrates that R&D is a significant and sustainable source of revenue for us. R&D revenue we earned in the first half of this year was primarily driven by the following significant components. $75 million dollars from the amortization of upfront payments. $52 million in milestone payments from our partners as our medicines advance. That included more than $13 million in amortization of milestone payments we received from Biogen for neurology programs we're advancing, and $35 million from Roche for advancing Ionis HTT-Rx.

PTC is actively preparing to provide way liver to patients in Latin America.

R&D revenue in the first half of this year nearly doubled compared to 2018 to more than $300 million.

This growth demonstrates that R&D revenue is a significant and sustainable source of revenue for us.

R&D revenue we earned in the first half of this year was primarily driven by the following significant components.

$75 million from amortization of upfront payments.

$52 million in milestone payments from our partners as our medicines advanced.

That included more than $13 million and amortization of milestone payments, we received from Biogen for neurology programs were advancing and $35 million from Roche for advancing Ionis HCT Rx.

And the third component $173 million in license fees, which included $20 million for Meld Island, when they license our technology to regeneron.

Elizabeth L. Hougen: And the third component, $173 million in license fees, which included $20 million from El Nilem when they licensed our technology to Regeneron. To date, Alnylam has paid us nearly $100 million, which includes royalties on commercial product sales, and we expect this amount to grow as medicines based on our technology advance; and $150 million from Novartis for licensing XEA 808-LRX in the first quarter.

To date Alnylam is paid it's nearly $100 million, which includes royalties on commercial product sales and we expect this amount to grow as medicines based on our technology advance.

And $150 million from Novartis for licensing Ixia April a dash lrx in the first quarter.

Our non-GAAP operating expenses in the first half of this year were $271 million.

Elizabeth L. Hougen: Our non-GAAP operating expenses in the first half of this year were $271 million, an increase compared to last year. We are investing broadly across our business, including investing in commercializing TXETI globally and preparing to launch Waylivra in the EU. We also recognized $24 million of income tax expense during the first half of this year.

An increase compared to last year.

We are investing broadly across our business, including investing in commercializing take sandy globally and preparing to launch we liver in the EU.

We also recognize $24 million of income tax expense during the first half of this year.

We are incurring income tax expense, because we project that we will generate us federal and state taxable income this year.

Elizabeth L. Hougen: We are incurring income tax expense because we project that we will generate U.S. federal and state taxable income this year. During the second half of this year, we anticipate earning significant commercial revenue and R&D revenue. If we do not achieve another large revenue item, like the $150 million license fee we earned from Novartis in the first quarter, we are projecting our revenues in the second half of the year to be generally in line with the first half of this year. We also anticipate higher operating expenses in the second half of this year due to our continued investments in commercializing Tegceti and Longyue Libre and continuing to advance our pipeline. In particular, we are on track to initiate the Phase 3 program for Axia, TTR, Leica, and Rx before the end of this year, which we expect will increase our development expenses.

During the second half of this year, we anticipate earning significant commercial revenue and R&D revenue.

If we do not achieve another large revenue item like the $150 million license fee. We earned from Novartis in the first quarter.

We are projecting our revenues in the second half of the year to be generally in line with the first half of this year.

We also anticipate higher operating expenses in the second half of this year due to our continued investments in commercializing take sandy.

Lunch human liver.

And continuing to advance our pipeline.

In particular, we are on track to initiate the phase three program for Acxiom TTR like our acts before the end of this year, which we expect will increase our development expenses.

With all of that we are on track to meet or improve upon our financial guidance for this year.

Elizabeth L. Hougen: With all of that, we are on track to meet or improve upon our financial guidance for this year. We are also on track to achieve our fourth consecutive year of operating income and our third consecutive year of netting, both on a non-gap basis. Our strong results are a testament to the productivity and efficiency of our platform technology coupled with our novel business model. Looking to the remainder of this year and into the future, we have confidence that we can continue to deliver sustained financial strength while maintaining our focus on increasing innovation to drive value to patients in need. And with that, I'll turn the call over to Brett to provide an update on our pipeline.

We are also on track to achieve our fourth consecutive year of operating income.

And our third consecutive year of net income both on a non-GAAP basis.

Our strong results are a testament to the productivity and efficiency of our platform technology, coupled with our novel business model.

Looking to the remainder of this year and into the future. We have confidence that we can continue to deliver sustained financial strength, while maintaining our focus on increasing innovation to drive value to patients in need and with that I'll turn the call over to breadth to provide an update on our pipeline.

Thanks Beth.

Brett P. Monia: Thanks, Beth. Today we have three recently approved medicines in a pipeline of over 40 medicines advancing through development. In the first half of 2019, we achieved numerous pipeline successes, and through the remainder of this year and into next year, we look forward to additional programs achieving significant value-driving catalysts. Spenraza is the worldwide standard of care in the treatment of SMA patients of all ages and all SMA types, and emerging data from longer-term Spenraza treatment continue to demonstrate even better performance. We continue to see that infants treated before symptom onset develop like normal, healthy kids. This is demonstrated again in new data from the ongoing NURTURE study in patients treated for up to 45 months, and supported by new long-term data showing continued improvement in over 300 patients treated for up to 5 years. The Spinraza label has recently expanded into Europe.

Today, we have three recently approved medicines and a pipeline of over 40 medicines advancing through development.

In the first half of 2019, we achieved numerous pipeline successes and through the remainder of this year and into next year. We look forward through additional programmes achieving significant value driving Cavaliers spinraza is a worldwide standard care in the treatment of estimate patients of all ages annual estimate tires and emerging data from longer term spinraza treatment continues to demonstrate even better performance.

We continue to see the infants treated before symptom onset developed with normal healthy cues. This is demonstrated again in new data from the ongoing nurture study in patients treated for up to 45 months and supported by new long term data showing continued improvement in over 300 patients treated for up to five years. The spinraza labels recently expanded in Europe .

What is difficult to improve although its typical improvements from roses efficacy and safety profile, we embark in or pursuing a follow on this medicine with potential for reducing dosing frequency to once or twice per year, and we look forward to advancing the following those into development potentially late this year or early next year.

Brett P. Monia: What is difficult to improve, although it's difficult to improve Ponson-Mraz's efficacy and safety profile, we in Biogen are pursuing a follow-on antisense medicine with the potential for reducing dosing frequency to once or twice per year, and we look forward to advancing a follow-on medicine into development potentially late this year or early next year. As part of the ongoing launch of TxETI, we and Xeia continue to present data supporting the benefit HATTR patients are experiencing with TxETI treatment. Earlier this month, we presented new data from the NeuroTTR Open Label Extension Study demonstrating durable and substantial efficacy with long-term ticstudy treatment in patients with HATTR polyneuropathy, with no new safety issues identified.

As part of the ongoing launch it takes say, we and Akcea continue to present data supporting the benefit HD TTR patients are experiencing with access to treatment.

Earlier this month, we presented new data from the neuro TTR open label extension study, demonstrating durable and substantial efficacy with long term fix any treatment in patients with HCR polyneuropathy with no new safety issues identified.

Moving onto a liver in the us we and Akcea continue to recognize the unmet medical need of FCS patients for a safe and effective medicine for this rare and debilitating disease and we're encouraged by our recent productive interactions with the FDA to clarify a path forward for way with growth in Fcs.

Brett P. Monia: Moving on to whey livera, in the U.S., we at AXSIA continue to recognize the unmet medical need of FTS patients for a safe and effective medicine for this rare and debilitating disease. And we're encouraged by our recent productive interactions with the FDA to clarify a path forward for weight libera in FCS. A second indication we're evaluating with weight libera is familial partial lipodystrophy, or FPL. FPL is a rare lipid disorder characterized by an inability to store fat or triglycerides normally, with excess fat settling in the liver, muscle, and at very high levels in the bloodstream. This leads to a range of metabolic abnormalities, including an increased risk of acute pancreatitis, premature cardiovascular disease, and liver disease, which can result in cirrhosis.

The second indication, we're evaluating with liver is familial partial lipodystrophy or appeal.

FPL is a rare with the disorder characterized by an inability to store fat or triglycerides normally with excess fat settling in the liver muscle and a very high levels in the bloodstream, leading to a range of metabolic abnormalities, including an increased risk of acute pancreatitis premature cardiovascular disease and liver disease, which can result in cirrhosis.

Ixia and we recently completed the broadened study with the brand patients with SPL.

Brett P. Monia: Axia, and we recently completed the Broaden Study of Oiliberin Patients with FPL. We're pleased to report that we have achieved both the primary end point of reductions in triglyceride levels and the key secondary end point of reduction in liver fat. We were also encouraged by the safety profile of whey liver in this study. The most common adverse events were mild or moderate in severity, and no serious or severe decreases in platelets were observed.

We're pleased to report that we liver achieved both the primary endpoint of reductions in triglyceride levels and this the key secondary endpoint of reduction in liver fat.

We were also encouraged by the safety profile of re lever in this study the most common adverse events were mild or moderate in severity and no serious or severe decreases in platelets were observed.

We're continuing to review these results in discussing them with key experts in the field, which will help us determine the next steps for this indication.

We look forward to presenting these data at a future scientific conferences and publications.

Brett P. Monia: We're continuing to review these results and discussing them with key experts in the field, which will help us determine the next steps for this indication. We look forward to presenting these data at a future scientific conference and through publication. Moving now to our pipeline.

Turning now to our pipeline.

Our late stage pipeline of phase three in their phase three programs continue to advance with the potential for significant value driving catalysts in the near term.

The phase three generation HD study Leo's HD Trx also known as RG six zero for two in patients with Huntington's disease is progressing well with our partner Roche.

In addition to the phase three study the broad and robust HD clinical program includes the open label extension study of Ionis Ttrx in Huntingtons patients along with an ongoing natural history study.

Brett P. Monia: Our late-stage pipeline of Phase III and near-Phase III programs continues to advance with the potential for significant value-driving catalysts in the near term. For example, the Phase III Generation HD Study of Ionis HD-TRX, also known as RG6042 in patients with Huntington's disease, is progressing well with our partner Roche. In addition to the Phase III study, the broad and robust HD clinical program includes the Open Label Extension Study of Ionis HD-TRX in Huntington's patients, along with an ongoing natural history study. Both studies are nearing completion, and we look forward to these data being presented at a future medical meeting. These studies are part of a comprehensive clinical program Roche is conducting to potentially provide this medicine to patients as rapidly as possible. The Phase III study of Tofersen is also progressing very well. As a reminder, Biogen recently reported data from the Phase I-II study of Tofersen in patients with SOD1 ALS, demonstrating a positive safety profile and marked reductions in SOD1 protein, which were associated with clinical benefit in measures of ALS disease progression after only three months of treatment.

Both studies are nearing completion, and we look forward to this data to be presented at a future medical meeting.

These studies are part of a comprehensive clinical program roche's conducting to potentially provide this medicine to patients as rapidly as possible.

So the phase three study of tow person is also progressing very well as a reminder, biogenerative recently reported data from the phase one study of total person in patients with someone LSW, demonstrating a positive safety profile and market reductions and saw one protein.

Which were associated with clinical benefit in measures of aeolus disease progression after only three months of treatment.

Based on these data buys and initiate a phase three study of the overseas, which is expected to provide results in 2021.

Our late stage like a medicines targeting LP little a driven cardiovascular disease and Pcrm late doses are on track to start phase three studies before the end of the year.

Akcea April Lrx, our most advance like a medicine has a potential to transform the treatment of the millions of people worldwide suffer from LP Little a driven cardiovascular disease and is representative of the potential of our technology to treat a broad range of diseases, both rare and common our partner Novartis recently shared design of the phase three study. The study will enroll approximately 770 500 patients with elevated LP little a levels of 70 milligrams per deciliter or higher with cardiovascular disease.

We also continued to make important progress with our like a fall in medicine to fix SETI Akcea Akcea, TTR, Lrx, which we're developing for the treatment of patients with all forms of TTR amyloidosis.

Brett P. Monia: Based on these data, Biogen initiated a Phase III study of Tofersen, which is expected to provide results in 2021. Additionally, our late-stage Leica medicines targeting Lp-a-driven cardiovascular disease and TCRM leidosis are on track to start Phase III studies before the end of the year. Axia ApoA-LRX, our most advanced Leica medicine, has the potential to transform the treatment of millions of people worldwide suffering from Lp-a-driven cardiovascular disease and is representative of the potential of our technology to treat a broad range of diseases, both rare and common. Our partner, Novartis, recently shared the design of the Phase III study. The study will enroll approximately 7,500 patients with elevated alpha-little-a levels of 70 mg per deciliter or higher who have cardiovascular disease.

We are nearing completion of our phase one study of Akcea TTR Lrx and we look forward to sharing these data to conferences. This of the September the European meeting for 80 journalists doses in Berlin, and then again at the Heart failure Society of America annual meeting in Philadelphia.

And looking ahead, we remain on track to initiate a phase three program with Akcea Ttrx this year.

This program will include two phase three studies, including a study in patients with hereditary TTR Polyneuropathy and a study in patients with wild type and hereditary TTR cardiomyopathy.

In addition to the great progress, we're making in our late stage pipeline, our mid and early stage pipeline also continues to perform very well.

We're pleased with the progress being made in our hepatitis B development program.

Effecting over 200 million people worldwide chronic hepatitis b is a potentially fatal liver disease, which can significantly increase a person's risk of cirrhosis liver failure and liver cancer.

Unlike currently marketed medicines that inhibit viral replication without clearing the virus, our HBV medicine as a potential to also clear the virus, which can provide patients with a functional cure.

Brett P. Monia: We also continue to make important progress with our LycoFollow medicine to TXETI, XeA-TTR-LRX, which we're developing for the treatment of patients with all forms of TTR mellitosis. We're nearing completion of our Phase 1 study of XeA-TTR-LRX, and we look forward to sharing these data at two conferences this September, the European meeting for ATTR And looking ahead, we remain on track to initiate a phase 3 program with Xe-TTR-LRX this year. This program will include two phase 3 studies, including a study in patients with hereditary TTR polyneuropathy and a study in patients with wild type and hereditary TTR cardiomyopathy. In addition to the great progress we're making in our late-stage pipeline, our mid- and early-stage pipeline also continues to perform very well. We're pleased with the progress being made in our Hepatitis B development program. Affecting over 200 million people worldwide, chronic hepatitis B is a potentially fatal liver disease that can significantly increase a person's risk of cirrhosis, liver failure, and liver cancer.

GSK recently reported that this program achieve positive clinical results, which we and GSK look forward to presenting at a future medical meeting.

We also look forward to GSK decision regarding licensing. This program later this year, particularly given our enthusiasm for its potential value.

Ionis factor 11, Rx currently in a phase two study in patients with end stage renal disease and Ionis factor 11 L. Rx currently in phase one are nearing completion and we are very enthusiastic about the data we're seeing in both studies.

Hi owners factor 11, Rx is the first antithrombotic medicines prevent thrombosis without a significant risk in bleeding. This conclusion was demonstrated in the study of over 300 patients undergoing total knee replacement surgery, which was published in the journal Medicine.

Based on our data from earlier studies, we believe our medicines targeting factor live and have the potential to be used broadly in patients at risk for thrombosis, especially those patient populations with additional risks for bleeding.

We and our partner bear look forward to sharing results from both these studies at a future medical meeting.

We're also looking forward to bear his decision later this year to advance one or both of these programs further into development.

We recently initiated a phase two study in our program to develop Ionis FPL Rx for the treatment of a broad range of complement mediated diseases under our collaboration with Roche in earlier clinical trials, we demonstrated robust dose dependent target reductions and the positive safety profile.

Brett P. Monia: Unlike currently marketed medicines that inhibit viral replication without clearing the virus, our HPV medicine has the potential to also clear the virus, which can provide patients with a functional cure. GSK recently reported that this program achieved positive clinical results, which we at GSK look forward to presenting at a future medical meeting. We also look forward to GSK's decision regarding licensing this program later this year, particularly given our enthusiasm for its potential value. Ionis Factor XI-RX, currently in a Phase II study in patients with end-stage renal disease, and Ionis Factor XI-L-RX, currently in Phase I, are nearing completion, and we're very enthusiastic about the data we're seeing in both studies. Ionis Factor XI RX is the first anti-thrombotic medicine to prevent thrombosis without a significant risk of bleeding. This conclusion was demonstrated in a study of over 300 patients undergoing total knee replacement surgery, which was published in the New England Journal of Medicine.

The phase two study of Ionis FPL Rx will evaluate we'll evaluate multiple dose levels and approximately 300 patients with geographic atrophy secondary to age related macular degeneration. The first indication we erosion pursuing into development program.

Patients will be treated for one year on our global Phase two study and in addition, we're gearing up to initiate a phase two study evaluating ionis FPL Rx in a second indication.

As you can see from this slide we have numerous value driving events expected within the next six to 12 months, including.

Both study initiation and data readout.

We're looking forward to discussing these with you more throughout the year and with that I'll turn the call back over to Stan.

Thanks, Rick.

We've built illness on a foundation of our efficient technology at home through supporting maximum innovation in the business model.

That enables us to maximize the value of each of our medicines in our pipeline and are being commercialized.

Brett P. Monia: Based on our data from earlier studies, we believe our medicines targeting Factor XI have the potential to be used broadly in patients at risk for thrombosis, especially those patient populations with additional risks for bleeding. We and our partner, Bayer, look forward to sharing results from both these studies at a future medical meeting. We're also looking forward to Bayer's decision later this year to advance one or both of these programs further into development. We recently initiated a Phase II study in our program to develop Ionis FBL-Rx for the treatment of a broad range of complement-mediated diseases in our collaboration with Roche. In earlier clinical trials, we demonstrated robust dose-dependent target reductions and a positive safety profile. The Phase II study of Ionis FBL-Rx will evaluate multiple dose levels in approximately 300 patients with geographic atrophy secondary to age-related macular degeneration, the first indication we and Roche are pursuing in the development program.

Our business strategy is succeeding and today, we are sustainably profitable and iOS is delivering more value to patients shareholders every day.

With the approval of way Libra, we now have three medicines approved in the last two years or so.

Our medicines continue.

To advance in late stage development.

We are on track to achieve our goal of four phase three studies underway by the end of this year.

And our mid stage pipeline continues to advance as demonstrated by the numerous phase two readout since study initiation has already accomplished this year.

Our technology continues to advance as well.

And advancing at an even more rapid pace, we look forward.

Giving you a glimpse of our exciting progress.

And Adam.

In the technology and a webcast focused on our technology later this year.

We have more than we have more and more illness owned programs and that we are developing.

Brett P. Monia: Patients will be treated for one year in our global Phase II study. And, in addition, we're gearing up to initiate a Phase II study evaluating Ionis FBL-RX in a second indication. As you can see from this slide, we have numerous value-driving events expected within the next 6 to 12 months, including both study initiations and data readout. We're looking forward to discussing these with you more throughout the year. And with that, I'll turn the call back over to Stan.

For our own account.

And.

We are continuing to maximize the value of our medicines by identifying the optimal commercialization path and retaining more economic value.

The business success.

And financial strength, we've built gives us confidence that we will continue to develop value for our patients and our shareholders.

In the short term and for years to come I look forward to updating you on our continued achievements throughout the rest of this year.

Stan Crook: Thanks, Brett. We've built Ionis on the foundation of our efficient technology, a culture supporting maximum innovation, and a business model that enables us to maximize the value of each of our medicines in our pipeline and that are being commercialized. Our business strategy is succeeding, and today we are sustainably profitable, and Ionis is delivering more value to patients and shareholders every day. With the approval of WayLibre, we now have three medicines approved in the last two years or so. Our medicines continue to advance in late stage development. We are on track to achieve our goal of four Phase III studies underway by the end of this year, and our mid-stage pipeline continues to advance, as demonstrated by the numerous Phase II readouts and study initiations already accomplished this year.

And with that we will open up the call for questions. So if I recall, you can set us up for questions I'd appreciate it.

Thank you.

We will now begin the question and answer session.

To ask a question you May press Star then one on your telephone keypad.

If you are using a speakerphone please pick up your handset before Preston Mckee.

Anytime your question has been addressed and you would like to withdraw your question. Please press Star then too.

Our first question comes from Tyler Van Buren.

Piper Jaffray. Please go ahead.

Hey, guys. Good morning, and congrats on the progress with risk and the positive broaden study results and with respect to where you live.

Can you remind us of the opportunity in the PEO and the prevalence and the patient breakdown as we think about adding that on top of the existing Fcs indication.

Stan Crook: Our technology continues to advance as well, and it's advancing at an even more rapid pace. We look forward to giving you a glimpse of our exciting progress in the technology at a webcast focused on our technology later this year. We have more and more Ionis-owned programs that we are developing on our own account, and we are continuing to maximize the value of our medicines by identifying the optimal commercialization path and retaining more economic value. The business success and financial strength we've built give us confidence that we will continue to develop value for our patients and our shareholders in the short term and for years to come. I look forward to updating you on our continued achievements throughout the rest of this year. And with that, we will open up the call for questions, so if, Nicole, you can set us up for questions, I'd appreciate it.

Yes. Thanks.

Pls is rare indication of course and the size of the field population of fiery call correctly is about.

Similar to FCS may be around 3000 patients or thereabouts.

So.

We think of the opportunity is being roughly.

Similar to the FCS opportunity and we believe that the combination of the two will will will will be an important contributor to the to our to our future revenues.

Okay. That's helpful and then with respect to the phase one two TTR lrx update in September .

Could you give us maybe a glimpse of what additional information we will see at that meeting that could be meaningful for the pathway forward and then as a follow up to that.

What have you seen so far that gives you confidence that it could have a potential follow on product thats dose once or twice a year.

Unknown Executive: Thank you. We will now begin the question and answer session. If you have a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the key.

Sure Tyler ill take that this is Brent.

So.

Yes, we're looking forward to sharing the results of our phase one study on TTR like.

We're very encouraged by the results so far our TTR like is performing like all of our light goods with excellent potency pristine safety.

Unknown Executive: If at any time your question has been addressed and you would like to withdraw your question, press star then. Then, our first question comes from Tyler Van Buren of Piper Jaffray. Please go ahead. Hey guys, good morning and congratulations on the progress and the positive widened study results. And with respect to Wey-Livre, can you remind us of the opportunity in FPL and the prevalence and the patient breakdown as we think about adding that on top of the existing FCS indication?

In durability, and we'll share that data will share the pharmacodynamic that TTR lowering data and we'll show the safety data will also give you a probably a glimpse of what our phase three designs are going to look like.

And partner up the Carty Myopically since we're getting we're gearing up to start those studies.

We can dose the free good we can utilize we have lots of options for dosing frequency for like its strategies. We can go.

Monthly easily like we're doing for most of our programs. We can go quarterly or even less frequent if we choose to we're settling on the exact and thats based on the wealth of data we have with all of our license just the durability of efficacy that we see.

Wade Walke: Yeah, thanks. FPL is a rare indication, of course, and the size of the FPL population, if I recall correctly, is similar to FCS, maybe around 3,000 patients or thereabouts. So, we think of the opportunity as being roughly similar to the FCS opportunity, and we believe that the combination of the two will be an important contributor to our future revenues.

They're all saying.

We're settling on the dose frequency right now the truth is Tyler we don't see a significant advantage to going less frequent than monthly from a patient convenience standpoint, and we think there are advantages to actually going to monthly as well and we talk more detail about that maybe in the presentation, but we have the ops, we have options monthly quarterly where we want to do but.

Brett P. Monia: Okay, that's helpful. And then, with respect to the Phase 1, 2, 2TR LRX update in September, could you give us maybe a glimpse of what additional information we'll see at that meeting that could be meaningful for the pathway forward, and then as a follow-up to that, what have you seen so far that gives you confidence that you could have a potential follow-on product that's dosed once or twice a year?

I think we're settling on monthly right now so Tyler the question that you asked about.

Luxury class year may have been related to the follow on SDMA.

Into two spinraza.

In that case, obviously.

And Intrathecal administration.

For most of our Intrathecal drugs, we give them a quarterly or a little less frequently and.

Brett P. Monia: Sure, Tyler. I'll take that. This is Brett.

Across the board, we're working on on on new molecules that we think will allow us.

Brett P. Monia: So, yeah, we're looking forward to sharing the results of our Phase I study on TTR Leica. You know, we're very encouraged by the results so far. Our TTR Leica is performing like all of our Leicas, with excellent potency, pristine safety, and durability.

We'll support for much less frequent dosing there I think there's real value in in in maximizing the space between doses because it's obviously a procedure that that requires.

Meaningful effort.

Brett P. Monia: And we'll share that data. We'll share the pharmacodynamic, the TTR lowering data, and we'll show the safety data. And we'll also give you a glimpse of what our Phase III designs are going to look like in polyneuropathy and cardiomyopathy, since we're gearing up to start those studies.

So.

The way I think of it is that for systemic administration, we're in position to provide the patient dose frequency that makes sense.

We've looked through.

Our pipeline and we've talked to patients with talking to providers and our conclusion is that by and large monthly dosing is easiest thing for patients providers to work with.

Brett P. Monia: We can dose, we can utilize, we have lots of options for dosing frequency for our Likens strategies. We can go monthly, easily, like we're doing for most of our programs. We can go quarterly or even less frequently if we choose to. We're settling on the exact frequency, and that's based on the wealth of data we have with all of our Likens, just the durability of efficacy that we see. They're all the same.

For Intrathecal administration.

Our intention is to have have drugs, there that can be dosed as infrequently as possible and we're making great progress there.

Thanks for that question.

Yes, but I wouldn't want people to confuse.

We are not seeking to make annual dosing systemically, we don't think that's the best or even semi yearly we don't think thats. The best solution for most patients very different from intrinsic.

Thanks again.

Stan Crook: You know, we're settling on the dose frequency right now. The truth is, Tyler, we don't see a significant advantage to going less frequent than monthly from a patient convenience standpoint, and we think there are advantages to actually going to monthly as well. We could talk more in detail about that maybe in the presentation, but we have options for monthly, quarterly, what we want to do. I think we're settling on monthly right now.

Our next question comes from Jim Birchenough.

Wells Fargo. Please go ahead.

Hi, guys congratulations on all the progress.

Couple of questions here. The first one is just on Huntingtons, that's becoming a very high profile.

Program.

Theres been some attention on neuro filament light chain increases that appear transient and ventricular volume increase and a bit of speculative backfill on it may be being related to wild type knock down or.

Stan Crook: So Tyler, the question that you asked about once or twice a year may have been related to the follow-on to SMA and to Spinraza. In that case, obviously, intrathecal administration. For most of our intrathecal drugs, we give them quarterly or a little less frequently, and across the board, we're working on new molecules that we think will allow us to do much less frequent dosing. In that case, I think there's real value in maximizing the space between doses because it's obviously a procedure that requires, you know, meaningful effort. So... The way I think of it is that for systemic administration, we're in a position to provide the patient with a dose frequency that makes sense. We've looked through our pipeline and we've talked to patients, we've talked to providers, and our conclusion is that, by and large, monthly dosing is the easiest thing for patients and providers. For intrathecal administration, our intention is to have drugs there that can be dosed as infrequently as possible, and we're making great progress.

So in general and so could you, perhaps address that directly and more meaningfully address.

Whether and maybe just address this directly whether roche's extension to every four months dosing had anything to do with either of those phenomenon I think it'd be helpful. Just to have you speak to that.

Jim I'll take that this is Brad again so.

The intention enthusiasm for our Huntington program with Roche is is warranted for sure I mean this is a true.

Very exciting program patients are in desperate need for this medicine and Roshe is doing a great job in developing this drug and we're looking forward to continuing.

Presenting data on the open label extension this year or early next year.

So regarding the.

The data that was presented and earlier this year and published in New England Journal of Medicine as you indicated.

With continued dosing of our Huntington medicine.

We saw.

A transient increase in NFL and the country color volume that was coming back down to baseline and was essentially a baseline with continued dosing and with that continued dosing of course Huntington levels are continuing to be driven down.

Further, which which which that data by itself indicates that has nothing to do with Huntington reductions be as you would expect the if it was related to that that there would be continued increases in neuro filament, but we don't see that so it's clearly not really to Huntington reduction.

Stan Crook: Thanks for taking the time.

Stan Crook: Yeah, but I wouldn't want people to confuse us with annual dosing systemically; we don't think that's the best, or even semi-yearly; we don't think that's the best solution for most patients. Very different from intrathecal.

In the sense of a toxicity.

With respect to.

The.

Dosing frequency in the changes to that.

Early on in the phase three.

Study.

We had just begun the phase three study with data was coming out from the open label extension looking at Huntington reductions by both monthly and bi monthly dosing and what was clear in the.

Unknown Executive: Thanks again. Our next question comes from Jim Bertinoff of Wells Fargo. Please go ahead.

Brett P. Monia: Hi guys, congratulations on all the progress. I have a couple of questions. I guess the first one is just on Huntington's, that's becoming a very high-profile program. There's been some attention on neurofilament light chain increases that appear transient and ventricular volume increase, and a bit of speculation on it maybe being related to wild type knockdown or to ASOs in general. So could you perhaps address that directly and more meaningfully address whether, and maybe just address this directly, whether Roche's extension to every four months of dosing had anything to do with either of those phenomena? I think it would be helpful just to have you speak to that.

Open label data was that the bi monthly dosing and even potentially a tri annual dosing was getting us well below the threshold that was necessary for huntington reductions to produce potential benefit based on all the preclinical data we had since Roche had just begun that study they wanted to offer greater convenience to patients.

With by monthly or and Tri annual dosing.

Considering the drugs being administered injured equally so they made that decision and it really had very little impact on.

The the phase three study, including one the expected readout is expected.

But in no way was that related to any adverse events or as a ease that we were seeing.

And that correlated in any way with the transition.

Brett P. Monia: Jim, I'll take that. This is Brett again. So, the attention and enthusiasm for our Huntington program with Roche is warranted for sure. I mean, this is a very exciting program. Patients are in desperate need of this medicine, and Roche is doing a great job of developing this drug, and we're looking forward to continuing to present data on the Open Label Extension this year or early next year. So, regarding the data that was presented to AAN earlier this year and published in the New England Journal of Medicine, as you indicated, with continued dosing of our Huntington medicine, we saw a transient increase in NFL and left ventricular volume that was coming back down to baseline and was essentially at baseline with continued dosing.

NFL changes that we saw or particular volume that weve changes that we saw in this study.

Simplification is the decision was consistent with our goal to maximize the time between Intrathecal injections.

And once we had data that told us that we could do that we did it.

With regard to the question of whether it's.

Related to his shows them in general.

Let me say that Ioannis, we have more experience with Intrathecal administration of army targeted therapies and the rest of the world combined and multiply by 10.

And we are very confident and ASEAN administered intrinsically.

Our safe and well tolerated.

Brett P. Monia: And with that continued dosing, of course, Huntington levels are continuing to be driven down further, which that data by itself indicates that has nothing to do with Huntington reductions, because you would expect, if it was related to that, that there would be continued increases in neurofilament, but we don't see that. So, it's clearly not related to Huntington reduction in the sense of a toxicity. With respect to the dosing frequency, the changes to that, you know, early on in the Phase 3 study, we had just begun the Phase 3 study when data was coming out from the Open Label Extension looking at Huntington Reductions by both monthly and bimonthly dosing, and what was clear in the Open Label data was that the bimonthly dosing and even potentially a triannual dosing was getting us well below the threshold that was necessary for Huntington Reductions to produce potential benefit based on all the preclinical data we had.

And I am sure.

Investors are as well they have to do is look at seven years of experience with Spinraza.

That's helpful.

Standard Brett just following up on the factor 11 opportunity in the data update that will get.

I guess, just if you could remind us what the if there is an opt in milestone payable at fair moves forward with one or both of those and.

Maybe comment on your level of confidence that.

That they will move forward with the factor 11 directive antisense approach.

Jim Yes, there is a milestone payment for their decision to move forward in the development and right now.

There is reviewing.

With us the data from both the phase one like a drug as well as the phase two study in end stage renal disease patients and in that in that study of course, we have.

Safety Tolerability factor level productions.

Evidence of prevention from both us as well as bleeding.

Brett P. Monia: Since Roche had just begun that study, they wanted to offer greater convenience to patients with bimonthly and triannual dosing, considering the drug was being administered intravenously. So they made that decision, and it really had very little impact on the Phase 3 study, including when the expected readout is expected. But in no way was it related to any adverse events or SAEs that we were seeing that correlated in any way with the transient NFL changes that we saw or left ventricular volume changes that we saw in the study.

The bear is very excited about factor 11, as a program and our antisense medicine in particular, they made a strong commitment to this pathway into factor 11, specifically and im feeling.

Very good about.

They are they're likely going to moving forward with this program based on all the enthusiasm that they've shown I mean the data.

That we have seen so far is very encouraging as has been the data that we presented previously from our knee replacement study in published in New England Journal of Medicine.

It's a very exciting program and it's again.

Stan Crook: The simple explanation is that the decision was consistent with our goal to maximize the time between intrathecal injections, and once we had data that told us that we could do that, we did it.

It's a program that has the potential to treat millions of patients at risk for thrombosis, who are also at risk for fleeting.

Everything we see from these drugs teachers that.

Stan Crook: With regard to the question of whether it's related to ASOs in general, let me say that at Ionis, we have more experience with intrathecal administration of RNA-targeted therapies than the rest of the world combined and multiplied by 10, and we are very confident that ASOs administered intrathecally are safe and well tolerated. And I'm sure investors are as well. All they have to do is look at seven years of experience with Spinraza.

That.

That they are really important assets in our pipeline. So speaking not for buyer, but for US. We are really excited about these products.

And we'll we'll be developing them.

Through Bayer or other ways.

But I'm entirely in agreement with Brad Pitt.

We are optimistic that there will move forward rapidly with these agents.

Next ray thanks for taking the questions.

Brett P. Monia: That's helpful, Stan and Brett. Just following up on the Factor XI opportunity and the data update that we'll get. I guess just if you could remind us if there's an opt-in milestone payable if Bayer moves forward with one or both of those, and maybe comment on your level of confidence that they will move forward with a Factor XI directed anti-sense approach.

You bet.

Our next question comes from Paul Mccain of Stifel. Please go ahead.

Hi, guys. This is David on for Paul Thanks for taking the question congratulations the way lever data and I hear you on the positive interactions with the FDA for FCS and if you can provide any details there that would be great but.

I'm, assuming you're limited there.

And could you touch on the regulatory path, specifically for FPL and the U.S. and then just the overall your strategy there.

Brett P. Monia: Jim, yes, there's a milestone payment for their decision to move forward in the development, and right now, you know, VAER is reviewing with us the data from both the Phase I Leica study and the Phase II study in end-stage renal disease patients. And in that study, of course, we have safety, tolerability, factor-11 reductions, evidence of prevention of thrombosis, as well as bleeding. VAER is very excited about Factor XI as a program and our antisense medicine in particular. They've made a strong commitment to this pathway, and to Factor XI specifically, and I'm feeling very good about their likelihood of moving forward with this program, based on all the enthusiasm that they've shown. It's a very exciting program, and again, it's a program that has the potential to treat millions of patients at risk for thrombosis who are also at risk for bleeding.

Thanks.

Well, you're right is we can't add any.

Comments further to what we said.

About our interactions with the FDA and I'm hesitant today to get into details on FPL, because we just have the data and and and so what we're going to need to do is finished the analysis of the study it's actually fairly complicated analysis of lots of different kinds of data.

And then.

Take the opportunity to sit down with regulators and and and.

See what what sorts of of criteria, they're going to want us to be to achieve.

A path to commercial.

Opportunities with FPL.

Given this the again the rare size. This disease population. So I think I'm just going to have it gives us a little time.

To get.

We get more information from regulators about the process.

Stan Crook: Everything we see from these drugs teaches us that they are really important assets in our pipeline. So speaking not for Bayer, but for us, we are.

Got you that makes sense and then maybe just one more on the earlier stage pipeline could you could you touch on the odd to phase two units shaded for the pre Calligan program and ha.

Stan Crook: I'm really excited about these products, and we'll be developing them through Bayer or other ways. But I'm entirely in agreement with Brad that we're optimistic that Bayer will move forward rapidly with these agents. Great, thanks for taking the question.

Sure happy to.

So its is a like a drug.

And PKK like.

And we are.

And it's performing.

Like all of our like a drugs with excellent potency Tolerability safety.

Unknown Executive: You bet!

Unknown Executive: Our next question comes from Paul Matteis of Stiefel. Please go ahead.

Durability.

We are actually pursuing multiple indications for our for PKK like a drug the first drug.

Stan Crook: Hey guys, this is Nadon for Paul. Thanks for taking the question. Congratulations on the way you leveraged data. And I hear you on the positive interactions with the FDA for FCS. And if you can provide any details there, that would be great. But I'm assuming you're limited there.

Which is in a competitive environment hereditary angioedema and we're starting that study in HCV patients now.

And.

We're looking forward to providing benefit in as measured by reducing frequency of attacks AG attacks and these patients. This is a this has the potential to be a very convenient drug for these patients have very effective drug. We know, we can reduce PKK reduction or levels and reduce the activity of the kallikrein pathway substantially.

Stan Crook: And could you touch on the regulatory path specifically for FPL in the U.S. and then just the overall U.S. strategy?

Stan Crook: Well, you're right. We can't add any comments further to what we've said about our interactions with the FDA. And I'm hesitant today to get into details on FPL because we just have the data. And so what we're going to need to do is finish the analysis of the study. And then take the opportunity to sit down with regulators and see what sorts of criteria they're going to want us to meet to achieve a path to commercial opportunities with the FPL, given, again, the small size of this disease population. So I think you're just going to have to give us a little time to get... more information from regulators about the process.

80, 90% range or so and we think that that based on everything we've seen is going to really have a positive impact. In addition, we haven't disclosed the indication yet, but we're also now.

Exploring multiple other indications that are relevant to the kallikrein pathway and one in particular will share. Some information on maybe later this year early next year.

An indication that we think.

Is even broader than for HIV and news on that will be coming soon.

It's a competitive area and so we're we're not willing today to discuss the various indications that were pursuing or considering to pursue but we're excited about the product.

Thanks for the thanks again guys.

Brett P. Monia: Gotcha. That makes sense. And then maybe just one more on the earlier stage pipeline. Could you touch on the Phase 2 you initiated for the pre-Calican program in HIE?

You bet.

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

Great. Thanks for taking my question and congrats on both the clinical and financial results.

Brett P. Monia: Sure, happy to. So, this is a LICA drug, PKK-LICA, and we are very pleased with its performance, like all of our LICA drugs, with excellent potency, tolerability, safety, and durability. We are actually pursuing multiple indications for our PKK-LICA drug. The first indication is in a competitive environment, hereditary angioedema, and we're starting that study in H.A.E. patients now, and we're looking forward to providing benefit as measured by reducing the frequency of attacks, and H.A.E. attacks in these patients. This has the potential to be a very convenient drug for these patients, a very effective drug. We know we can reduce PKK levels and reduce the activity of the calocrine pathway substantially, you know, the 80-90% range or so, and we think that, based on everything we've seen, is going to really have a positive impact on H.A.E. In addition, we haven't disclosed the indication yet, but we're also now exploring multiple other indications that are relevant to the calocrine pathway, and one in particular we'll share some information on maybe later this year or early next year, an indication that we think is even broader than for H.A.E., and news on that will be coming soon.

For factor 11, you mentioned you even barely deciding to take one.

Or both of those.

The like and.

And the older School antisense.

Forward can you describe the situation and when it sort of a scenario, which bringing both forward would make sense.

Well in principle.

It will generally relate to timing.

In the case of the.

Parent.

We already have a very significant phase two experience.

Very positive data in the total knee replacement in earlier data in patients with end stage renal disease. This study is really a confirmatory study.

In those patients a larger study.

So.

I think the.

The.

The equation that needs to be written in all these cases, where we are where we have the like of form and as well as the parent debt and being developed.

Really boils down to timing and dollars.

And April C.

Yes exactly.

Analogous and in there of course, we went ahead and developed we lever because it was close to the market and we thought it could provide benefit to patients who at rare diseases and now we're following up with the April C. Lika and of course, we're tremendously excited about that because of its being a like an expressive utility.

Stan Crook: It's a competitive area, and so we're not willing today to discuss the various indications that we're pursuing or considering to pursue, but we're excited about the product.

Unknown Executive: Thanks for the info, guys.

Unknown Executive: Our next question comes from Chad Messer of Needham & Company. Please go ahead.

Stan Crook: Great, thanks for taking my question and congratulations on both the clinical and financial results. For Factor XI, you mentioned you and Beryl would be deciding to take one or both of the Leica and the older school antisense forward. Can you describe a situation, sort of a scenario, in which bringing both forward would make sense?

So.

We'll sit down with a with Bayer and we will write that equation.

Look at the at the value and and and make of a financially and patient centered decision that makes sense.

Stan Crook: Well, in principle, it will generally relate to timing. In the case of the parent, we already have a very significant phase 2 experience. Well, given the very positive data on total knee replacement and earlier data in patients with end-stage renal disease, this study is really a confirmatory study in those patients. It's a larger study. I think the equation that needs to be written in all of these cases where we have a LICA form as well as the parent that are being developed really boils down to timing and dollars, and ApoC-3 is exactly analogous, and there, we went ahead and developed Oilever because it was close to the market and we thought it could provide benefit to patients who had rare diseases, and now we're following up with the Apo So we'll sit down with Bayer, and we will write that equation and look at the value and make a financially and patient-centered decision that makes sense.

All right yes.

It makes sense to me.

And then just one more.

Paul just kind of can't help myself here because.

Really excited about this.

I understand we may be getting an oral antisense into the clinic soon and probably have to wait to get a lot of details on that but can you share. What you can about that now and maybe talk about what sort of technical.

Advances made that possible.

Well.

I am not sure where you have heard that.

But.

Before before I get too.

A comment about that.

I do want to return to this interesting challenge that we face and have faced I think fairly successfully and then is that the technology is not static it's constantly evolving.

And in our technology with cash I hope, we get a chance to demonstrate to use the breadth of advances that are that are taking place and as those advances.

Take place, we see improvements in drug performance.

Stan Crook: Yeah, that makes sense to me. And then just one more. Apologies, I kind of can't help myself here because I'm really excited about this. I understand we may be getting an oral antisense into the clinic soon and probably have to wait to get a lot of details on that, but can you share what you can about that now and maybe talk about what sort of technical advances may be

And so.

The way, we manage the conversion of.

Generation to generation to five the conversion of both of those to like.

That is a pathway that we will be pursuing.

In the coming years as these new advances come forward.

And and yes. It is an interesting challenge to manage but it's it is it's a great problem to have to be constantly making better and better drugs. So we're excited about it.

Stan Crook: Well, I'm not sure where you heard that, but... Before I get to... a comment about that. I do want to return to this interesting challenge that we face, and have faced, and I think fairly successfully, and that is that technology is not static; it's constantly evolving, and in our technology webcast, I hope we get a chance to demonstrate to you the breadth of advances that are taking place, and as those advances take place, we see improvements in drug performance. And so the way we have managed the conversion of Generation 2 to Generation 2.5, the conversion of both And yeah, it is an interesting challenge to manage, but it's a great problem to have, to constantly make better and better drugs. So we're excited about it. With regard to oral, these are the things I'm prepared to say today.

With regard to oral.

These are the things I'm prepared to say today. If you go back and look at can Nam ROE we showed in human beings in a phase one study that week, we got.

Sufficient below by the ability to reduce it will be 100 and reduce LDL.

So.

The that demonstrated that.

It's it's really more of an engineering issue and the challenge there is to find a solution we have enough drug.

That the size of the pills and the cost of the therapy and all of those things are reasonable.

So just as we've been making advances everywhere else.

We've been working steadily on taking that basic observation that we can do this and now making a commercially attractive opportunity.

And.

And.

We discuss advances in our technology lead we think they are ready to be incorporated into drugs and when we have absolute conviction that were right.

Stan Crook: If you go back and look at Conamryl, we showed in human beings in a phase one study that we got sufficient oral bioavailability to reduce ApoB100 and reduce LDL. That demonstrated that it's really more of an engineering issue and the challenge there is to find a solution where you have a potent enough drug, that the size of the pills and the cost of the therapy and all of those things are reasonable. So, just as we've been making advances everywhere else, we've been working steadily on taking that basic observation that we can do this and now making it a commercially attractive opportunity, and we discuss advances in our technology And so we will follow that course with ORL. You will hear from us as soon as we're confident that we have achieved what we meant to achieve. We hope that that can be in the near future.

And.

So we will.

Follow that course with oral.

You will hear from us as soon as we're confident we have achieved what we meant to achieve.

We hope that that can be in the near future.

All right well certainly stay tuned on that that's very very again, a lot of words to say nothing I know, but okay.

[laughter].

Yes.

Obviously very.

Game changing in terms of the indications that would allow you to consider so we'll stay as it is you know and his team has actually the last frontier for initiatives.

We now have.

Demonstrated that we can get these medicines by every single route of administration, it's ever been tried I believe including enema.

For for local Poland disease.

And so oral really is the lash hill to climb.

And.

We've been climbing it and we look forward to.

Stan Crook: All right, well, certainly stay tuned on that. That's very, very exciting. Yeah, that's a lot of words to say nothing, I know, but okay.

Getting to the top.

Okay, great. Thanks.

You bet. Thanks, Chad.

Our next question comes from Ritu Baral Cowen. Please go ahead.

Stan Crook: Yeah, and anyway, obviously very game-changing in terms of the indications it would allow you to consider. It is, you know, and it's the, it's actually the last frontier for Anacin.

Hi, guys. Thanks for taking the question as we look forward to the.

Like a TTR phase one two data release.

What what level.

TTR knockdown.

Are you guys targeting.

Stan Crook: We now have demonstrated that we can give these medicines by every single route of administration that's ever been tried, I believe, including enema for local colon disease, and so oral really is the last hill to climb. And, you know, we've been climbing it, and we look forward to getting to the top.

What would make you happy I understand thats, a dose ranging study how should we how should we think about that dose ranging data and.

What.

What do you guys feel you need to move the needle on to get a clinical benefit and then if you think about that phase three program in Japan, you wanted to.

Unknown Executive: [inaudible] Our next question comes from Ritu Bharel of Cowan. Please go ahead.

You will get more detail later, but should we be thinking about it significantly differently then.

Unknown Executive: Hi guys, thanks for taking the question. As we look forward to the Leica TTR Phase 1-2 data release, what level of TTR knockdown are you guys targeting? What would make you happy?

Then the retreat to Rand Healios program.

Actually I think you used a was allowed to use the control group from.

Stan Crook: I understand that's a dose-ranging study. How should we think about that dose-ranging data and what do you guys feel you need to move the needle on to get a clinical benefit? And then as you think about that Phase 3 program, Brett, I understand you wanted to, you'll give more detail later, but should we be thinking about it significantly differently from the Brutusaran Helios programs? Especially, I think Helios A was allowed to use the control group from the original technology Apollo study. Are there sort of creative ways around long, extended studies for the potential, like a TTR Phase 3?

The original technology Apollo study.

Are there sort of creative ways around long extended studies for the potential like a TTR phase three.

With regard to the first question really I think you just should refer to April whaler action all the other.

Like.

Bottom line is that we can dial in pretty much whatever reduction by one.

And and and so we have the ability to.

Make that choice just thinking of the dose.

Brett P. Monia: With regard to the first question, I think you should refer to APOA, LRX, and all the other BICAs. The bottom line is that we can dial in pretty much whatever reduction we want, and and so we have the ability to make that choice just by picking the dose. And we already know the level of reduction that gives us the kinds of results we've gotten with Tec-Ceti, and we have a very clear idea of the level of reduction we want out of the Leica so that it's maximally competitive, and then we're going to leave it With regard to the phase 3 trials for polyneuropathy and for the cardiac indication, I'll turn that over to Brett. Sure, Stan.

And we already know the level of reduction that gives us the kinds of results we've done with with.

Take setting.

And we have a very clear idea level reduction we want out of life, so that its maximally competitive and I'm going to leave it there.

With regard to the phase III trials for Polyneuropathy Polyneuropathy and.

And for the cardiac indication I'll turn that over to Brad.

Sure Stan.

Hey, Rick.

Stan Crook: Hey Rick, Hey. Hey, Hey.

So.

Yes.

Brett P. Monia: Yeah, we have had very productive and recently completed our discussions with regulatory agencies and are settling on the final design of the studies. I mean, let's face it; we all talk to the same regulators, the same divisions, and we have the option to do the type of study you referred to for polyneuropathy if we choose to. We're thinking through that to think if we can be even more creative and bring this drug to patients as rapidly as possible, but that's certainly an option, the open-label type of study that you referred to for polyneuropathy. For cardiomyopathy, our discussions have also gone very well with regulators. You know, Pfizer has done an outstanding job with tefamidus in the study they conducted, and the outcome of t So that will certainly be an important component of our cardiac study, but we're also thinking creatively about ways that we can bring this medicine even faster to patients, and I think we'll share some of that data in September at the

We have had very productive and recently completed our discussions with radio with regulatory agencies and are settling on the final design of the studies.

I mean, let's face it we all talk to the same regulators the same divisions and.

And we have the option to do.

The type of study you referred to for Polyneuropathy. If we chose to we're thinking through that I think if we can be even more creative and to bring his patient this drug to patients as rapidly as possible, but thats certainly an option. The open label type of study that you referred to for Polyneuropathy.

Regarding my apathy, our discussions have also gone very well with regulators.

Pfizer has done an outstanding job with the families and the.

In the study they conducted and the outcome of the feminist for patients in desperate need, particularly the wild type cardiac patients they set the bar I mean.

To me.

An outcome study is not just important for approval.

But I think an outcome study is important for payers and.

For patients want to get the drug.

So that will certainly be at OKE of important component to our cardiac study, but we're also thinking of creatively.

On ways that we could bring this medicine, even faster to patients and I think we'll share some of that data in September at the analyst meeting.

Got it that is questionable.

Go ahead.

Oh, sorry. Thanks. My next question was on the the complement program.

What could we expect the geographical.

Atrophy.

Brett P. Monia: Got it. Next question.

Program, sorry trial data and how are you thinking about the next indication.

Unknown Executive: Oh, sorry, thanks. My next question was on the complement program. When can we expect the geographical atrophy program, sorry, trial data? And how are you thinking about the next indication and the different markets? Do you guys prefer to go into sort of the more competitive complement space, the less competitive space? How are you thinking about potential differential pricing or differential profiles as you look across the complement disease landscape?

And the different markets.

Pete you guys prefer to go into service the more competitive complement space.

The less competitive space and how are you thinking about potential differential pricing or differential.

Profile.

As you look across the complement disease landscape.

Well, we're at we're reducing complement b.

And what we what we believe is that.

That is an ex that is a really valuable way to alter the complement pathways in general.

Stan Crook: Well, you know, where would Reduction Complement be? And what we believe is that that is a really valuable way to alter the complement pathways in general. And we're very confident that, as a LICO, the overall performance of the drug will match up against anything out there that reduces complement system activity. So we look at the opportunity as very broad, and we're planning to enter some interesting indications as well as those that have been well-trod and are competitive. We think we've got a winner.

And we're very confident that as of.

As a like to add that the.

The overall performance of the drug will will will match up against anything out there.

That reduces complement system activity.

So we look at the opportunity as very broad.

And were planning to enter.

Some interesting indications as well as those that have been well trodden and our competitive we think we've done a winner.

The the.

The study in the API is a large longer term study.

Stan Crook: The study in the eye is a large, longer-term study. It's just getting underway, so it's going to be a while before we're able to talk about the data. And I'd like to see how the enrollment goes for a bit more and how the overall study appears to be performing before I start handicapping on a date when we're going to have some information about that.

It's just getting underway so it's going to be a while before we will be able to talk about those data and I'd like to.

See how the enrollment goals for a bit more and and how the overall study appears to be performing before right.

Start handicapping, what on a date when we're going to have some information about that.

Got it and when do you think you might announce the next indication for for FBR.

Stan Crook: Got it. When do you think you might announce the next indication for FBLRx?

Once again.

Stan Crook: Once again, given the breadth of interest in the complement pathway, and the number of companies involved, and the number of drugs, we think the clinical plan that we have is a competitive advantage, and so we're going to be fairly precious about what we're willing to tell people. And we're very precious today; I'm not willing to tell you anything.

Given the breadth of interest in the complement pathway in a number of companies involved in a number of drugs.

We think the clinical plan that we have is a competitive advantage and so we're going to be fairly precious about what we what we are willing to tell people and.

We're very precious day I'm not willing to tell you anything.

[laughter].

Fair enough thanks for the color.

Stan Crook: Fair enough. Thanks for the color. Thank you, Beth.

You bet.

Our next question comes from Yale Jen of way Boston Company. Please go ahead.

Unknown Executive: Our next question comes from Yael Jen of Leyblon Company. Please go ahead.

Thanks for taking the question again add my congrats for the progression so far.

Unknown Executive: Thanks for taking the question again and my congratulations for the progression so far. Maybe just have two quick ones.

Maybe just have two quick ones first one is that.

Brett P. Monia: First one is that HPV program you have with GSK. I know you have some data reports earlier by GSK. Could you give us a little bit more detail in terms of what the target is? And also, you also have a Leica version of that. And what should we anticipate from these two programs going forward?

TV program you have with the GSK I know you have some data report earlier by GSK.

Could you give us a little bit more detail in terms of what the target and also you also have a light covers and all of that and.

Well, we anticipate from these two programs going forward.

Brett P. Monia: Hi Yale, this is Brett. As we mentioned in the webcast, we're very excited about this program, as is GSK, and GSK will be presenting data with us later this year at a medical meeting.

Hey, Alan this is Brad.

Yes, as we mentioned in the web cast we're very excited about this program as GSK and GSK will be presenting.

Data with US later this year.

Medical meeting.

Stan Crook: As you know, one of the things that hinders current medicines, nucleoside analogs, that target HPV, is that they can block polymerase and replication of the virus, but they don't eliminate the virus, and that causes, turns the disease into a chronic disease that causes, that still causes many important problems for patients. Our strategy, using an anti-sense mechanism, is to be able to target all the transcripts that are produced from the HPV circular DNA, which there are basically four transcripts, right, there's the polymerase, there's the core protein, there's the S-antigen, and our mechanism targets all those transcripts. And that gives us a significant advantage because it potentially allows us to not just block the replication but to eliminate the virus entirely, essentially causing a functional cure. We have to prove that, of course, but so far, the data is very encouraging. More on how we're targeting the transcript, we're gonna keep that to ourselves for a little while.

You know as you know one of the things that hinders current medicines nucleoside analogs that target HPV.

Is that they can block polymerase and replication of the buyers, but they don't eliminate the virus and that causes turns the disease into a chronic disease that causes that still.

Causes problems for many important promise for patients.

Our strategy using in antisense mechanism is to be able to target all the transcripts that are produced from major from the HBV.

Circular DNA.

Which basically for transcripts right theres the polymerase, there's the core protein theres the S antigen and.

Our our mechanism targets for all those all those.

Transcripts.

And that gives us a significant advantage because that potentially allows us to not just block the replication.

But to.

Eliminate the virus entirely.

Essentially causing a functional cure.

Prove that of course.

But so far the data is very encouraging more on how we're targeting the transcript.

We're going to keep that to ourselves for a little while.

And on the like.

And parent where we're just we're collecting data on both the Paredis more advance of course and so it's another one of those situations towards like April C.

Stan Crook: And on the like and parent, we're just collecting data on both. The parent is more advanced, of course, and so it's another one of those situations, sort of like ApoC3, like Factor 11, in which we'll look at the performance of both, and we'll look at the time advantage of one versus the other. And in this case, GSK will make all those decisions. Obviously, we are optimistic that GSK will choose to move forward with the program, but we would be delighted to have it back, and if it were our choice, we'd use the same sort of equation that we've written for these other drugs.

Like a factor 11.

In which we'll look at the performance in FFO and we'll look at the time advantage of one versus the other.

And in this case GSK will make all those decisions.

Obviously, if we are optimistic that GSK will choose to move forward with with the program.

But we would be delighted to have the Bakken and and if it were our choice than we used the same sort of equation that we've written for these other drugs as well.

Stan Crook: Okay, great. Maybe just one follow-up question here. You mentioned that you have great expertise in intrathecal injections and that the sort of next-gen product basically is even less frequent dosing. Just in general, without revealing your trade secrets, what are the sort of typical sort of either formulation or other aspects to enable this type of even less frequent dosing potential?

Okay, Great maybe just one follow up questions. Here, you mentioned that you will have a great expertise and the interest veeco injection into the sort of next gen product basically is even more or less frequent dosing.

Just in general without revealing your trade secrets, what are the sort of typical either formulation or other aspect.

To enable these type of.

Even less frequent dosing so to.

Potentials.

Stan Crook: It's not a change in formulation. I mean, these medicines, like all of our medicines, except for oral, are just basically formulated in saline. It's a change in the chemistry, and that supports longer duration and also higher doses if we choose to go there. So it's a fairly straightforward sort of engineering challenge, and the art form here is to make sure that we've got a molecule that's going to give us at least every six months of dosing but really hope for much longer than that. I think we're almost there, and so we look forward to moving that forward, and obviously, as that experience teaches us how to do it, as we learn how to do it, then that is something that we can apply to all of our intrathecal programs, just as the Leica program and Generation 2.5 can be applied to all of our systemic programs. Think of it in an entirely analogous way to what we've done in the rest of the body, you

It's not a change in formulation.

I mean, these medicines like all of our medicines, except for oral are just basically formulated in sailing.

It should change in chemistry and it supports then.

Longer duration, and and also higher dosing if we choose to go there.

So its fairly straightforward.

Sort of engineering challenge.

And then the art form here is to.

Is to make sure that we've got a molecule that is going to give us at least every six months dosing, but really hope for much longer than that.

I think we're almost there and.

And so we look forward to.

Moving that forward and obviously as debt.

Stan experience teaches us how to do it as we learn how to do it and that is something that we can apply to all of our interest vehicle programs just as like a program and generation two five can be applied to all of our systemic programs. So think of it in an entirely analogous way to what we've done in the rest of the body.

So ultimately you could have ballpoint since most of you all antisense product maybe a few years in almost in yearly boasting possibility if thats the best.

Stan Crook: So ultimately, you could have, for instance, most of your antisense product, maybe in a few years, at almost yearly dosing possibility, if that's the best treatment paradigm for specific indications.

Hello.

Given the treatment paradigm for specific indications.

Stan Crook: Well, I certainly am not ready to say we're going to have all that accomplished in the next couple of years, but we are making very good progress toward far less frequent dosing in the central nervous system, and we're optimistic that we're going to be able to bring that to the clinic here and improve what we've seen in animals to what we can see in humans. And once we have that, obviously, we'll be converting our intrathecal administrations to those kinds of forms going forward. So stay tuned. I think we're going to be excited about what we're able to share with you.

Well.

I certainly have not ready to say, we're going to have all that accomplished in the next couple of years, but we are making very good progress toward far or less frequent dosing in the central nervous system and and we are optimistic that we're going to be able to bring that to the clinic here and improve but what we've seen in animals.

We can see in humans.

And once we have that obviously, then we'll we'll be converting our Intrathecal administration those kinds of forms going forward.

So stay tuned.

But I think I think we are going to be excited about what we're able to share with you.

Unknown Executive: Great. Thanks a lot. I appreciate it. UBIT

Great Thank thought and predicted.

You bet.

Unknown Executive: Our next question comes from David Lebowitz of Morgan Stanley. Please go ahead.

Our next question comes from David Lebowitz of Morgan Stanley . Please go ahead.

Unknown Executive: Thanks for taking my question. Quick question on TegCeti. At this point, after several quarters on the market, is there a specific profile of patient that typically chooses TegCeti versus the other options out there at this point?

Hi, Thanks for taking my question.

Quick question on Tech study.

To this point after several quarters on the market is there specific profile of patient that.

Typically chooses tug study.

Versus the other options out there at this point.

Not not that we have yet.

Stan Crook: Not that we haven't yet. And our hope is, of course, that patients of a wide range of types can take CETI because of its convenience of administration and the freedom from, you know, the freeing up of the limitations of the disease. But I think it's too early to make judgments about that today.

And our hope is of course, the patience of the wide range of types tick tick setting.

Because of his convenience of administration and the freedom from.

The freeing up of the limitations of the disease that makes too early to make judgments about that today.

Unknown Executive: Fair enough. And an understanding that it's approved for a differing and educated indication. Is there any feedback or commentary or hearing anything on tefamidus from the doctors?

Fair enough and.

Understanding that its approved for a differing and educate indication.

Is there any.

Feedback or commentary or hearing anything on on to permit us from the doctors.

Damien McDevitt: Damien, or do you want to go?

Damian entitlement oded are Brent.

Unknown Executive: We haven't seen much of an impact. We're still getting increases in prescriptions from cardiologists, neurologists, and hematologists. We saw a 50% increase overall in prescriptions in the U.S. in the last quarter. As you heard during the call, earnings were $10 million, which is a 40% increase over the first quarter. It's early still, but we haven't really seen much of an impact. Thanks for taking my questions.

So we are we in terms of impact on Tech savvy. I mean, we were still we haven't seen much of an impact were still getting increases in prescriptions from cardiologists neurologists and hematology is we have a 50% increase overall prescriptions in the us in the last quarter as you heard during the during the call that the earnings earnings was 10 million, which is 40% increase over the first quarter. So we haven't it's early still but we haven't really seen much of an impact.

Thanks for taking my questions.

Our next question comes from Jessica Fye.

Unknown Executive: Our next question comes from Jessica Fye of J.P. Morgan. Please go ahead.

P. Morgan. Please go ahead.

Unknown Executive: Hey guys, good afternoon. Following up on the earlier question on Huntington's, what do you expect physicians will be focused on when that OLE data is presented?

Hey, guys good afternoon.

Following up on the earlier question on Huntington's.

What do you expect physicians will be focused on when that only data is presented.

Brett P. Monia: Well, Jess, I think the physicians will be focused on lots of things. I mean, they're certainly going to be focused on the durability of mutant Huntington reductions in the OLE, which will be up to, it'll be 15 months or longer. Patients will be on the drug. And the, you know, and how the patients are getting on with their, the dosing, safety, and tolerability. And, you know, we don't know for sure yet what's going to be presented, but I think we would expect that, considering there'll be 15 months of data with natural history in parallel and published natural history data, I think you'll, we'll expect to see some signs of clinical endpoints, some aspects of clinical results in that update as well. And I think that's what, you know, that's what physicians will be looking for

Well, Jeff I think the physicians will be focused on.

Lots of things I mean.

They're going to certainly be focused on the durability of mutant Huntington reductions.

In the OE, which will be.

Up to it will be 50 months or longer patients will be on drug and the.

How the patients are getting on with their with their.

They are the dosing the safety Tolerability.

And.

And.

We don't know for sure yes.

What's going to be presented but I think.

We would expect that considering that would be 15 months of data with natural history in parallel and published natural history data I think you will expect to see some signs of.

Clinical endpoints some aspects of clinical.

Our results.

In that update as well.

I think that's what that's what the physicians we looking for we've described the endpoints that are going to be measured for efficacy and that is the huntington.

Stan Crook: We've described the endpoints that are going to be measured for efficacy in the hunting... of Endpoint. So. And so.

Endpoints yet so.

It will be it will be analyzing the data of.

Unknown Executive: I mean, we'll be analyzing the data with regard to those endpoints and safety, tolerability, and all that. Next question, please.

With regard to those endpoints of safety Tolerability and all that.

Next question please.

Jim Birchinoff: Our next question comes from Jim Birchinoff of Wells Fargo. Please go ahead. Hi guys, just a couple of follow-ups. I guess, Scan, just maybe, at a high level, you've had tremendous revenue growth, and you've had several years of profitability. Just from a financial perspective, are you at the point where we should start focusing on earnings growth, or is the goal here to continue to grow the top line, reinvest in the business, and stay cash flow positive, but not necessarily get people too focused on earnings growth, or are we at that point?

Our next question comes from Jim Birchenough of Wells Fargo. Please go ahead.

Yeah, Hi, guys. Just a couple of follow ups I guess scan just maybe at a high level you've had tremendous revenue growth and you've had several years of profitability just from a financial perspective are you at the point, where we should start focusing on earnings growth or is the goal here to continue to grow the top line reinvest in the business and and stay cash flow positive, but not necessarily get people to focused on earnings growth or are we at that point.

Well first of all Jim. Thank you because for all this is sitting next to me.

Stan Crook: Well, first of all, Jim, thank you because poor old Beth is sitting next to me, and she's about to go to sleep.

If you go to sleep.

[laughter].

And.

Elizabeth L. Hougen: I'll give you my answer, and then Beth will give you the correct answer if that's necessary. We're excited about where we are financially. And we see continued growth in revenues and continued growth in earnings and continued increase in investment while we do all that. And for us, that's just a start.

I'll I'll give you.

My answer and then Beth will give you the correct answer.

That's necessary.

We're excited about where we are financially and we see continued growth in revenues and continued growth in earnings and continued increasing investment while we do all that.

And for US that's just to.

Stan Crook: Just a really exciting moment. So, I would say focus on earnings growth. We are an earnings story today and have been, with an extraordinary pipeline and an opportunity to create value that's stochastically increasing as the pipeline advances. Exciting for us, and we welcome that kind of focus. I completely agree. That's the first time.

Just a really exciting moment.

So I would say you focus on earnings growth.

We are an earnings story today and have been.

With an extraordinary pipeline and an opportunity to create value. This.

Yes, that's that's stochastic.

We.

Increasing as the pipeline advances.

Signing exciting to us and we win we welcome that.

That kind of focus.

Completely agree.

Unknown Executive: Okay. With that, and Jim, thanks for asking a financial question. I really do mean that. With that, I think we've completed the Q&A. I want to thank everyone for your thoughtful attention and excellent questions. We look forward to keeping you apprised of progress. We expect, as the year progresses, to continue to report financial successes as well as pipeline and commercial successes, and that puts us at an extraordinarily exciting moment in our history, and we look forward to sharing it with you. Thank you.

That's the first time.

[laughter] okay.

So with that and Jim Thanks for asking a financial question I really do mean Ed.

With that I think.

We've completed the culinary I want to thank everyone for your thoughtful attention and excellent questions.

We look forward to keeping you apprised of progress.

We expect.

As the year progresses to continue to report financial success.

Pipeline and commercial successes and that puts you said.

Extraordinarily exciting moment in our history, and we look forward to sharing it with you.

Thank you.

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

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