Good morning, and welcome to Ionis' Second Quarter 2023 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin..

Thank you, MJ. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials.

We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, our Chief Executive Officer; Richard Geary, Chief Development Officer; and Beth Hougen, our Chief Financial Officer.

Eric Swayze, Executive Vice President of Research; Eugene Schneider, Chief Clinical Development Officer; and Onaiza Cadoret, Chief Global Product Strategy and Operations Officer, will also join us for the Q&A portion of the call. I would like to draw your attention to Slide 3, which contains our forward-looking statement.

During this call, we will be making forward-looking language statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail.

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

Thanks, Wade. Good morning, everybody, and thanks for joining us today. We achieved a great deal in the first half of 2023 as we continued to focus on our most important strategic priorities. We advanced our pipeline in many important ways. We made great progress in building our commercial capabilities.

We are writing the next chapter for Ionis as we transform Ionis into a highly successful, fully integrated biopharma, focusing on delivering an abundance of new medicines to patients. Launch preparations for our three near-term commercial opportunities, eplontersen, olezarsen and donidalorsen are right on track.

Eplontersen is currently under regulatory review for ATTR polyneuropathy in the U.S. and we're on track to submit additional filings outside the U.S. before the end of the year. We and AstraZeneca share the goal of bringing eplontersen to ATTR patients globally, who today have limited treatment options.

We are also pleased with the longer term week 85 data for eplontersen from the Phase 3 NEURO-TTRansform study that we reported last month. These longer term data showed continued improvements from baseline out to 19 months, highlighting eplontersen's durable efficacy and contributing further to its overall attractive profile.

And in a few minutes Richard will dive deeper into the importance of these data. And just last week we reported that our landmark CARDIO-TTRansform study of eplontersen in patients with ATTR cardiomyopathy completed full enrollment with more than 1,400 patients. This is the largest study ever conducted in this patient population.

Our next major late stage milestone is the top line readout of the olezarsen Phase 3 BALANCE study in FCS in the second half of this year. We expect olezarsen in FCS to be the first independent commercial launch for Ionis and we're well prepared.

In parallel, we're advancing our olezarsen Phase 3 pivotal studies in the much larger patient population, severe hypertriglyceridemia, or SHTG, which we're also well prepared for. We also completed enrollment in the Phase 3 OASIS-HAE study of donidalorsen earlier this year.

This important milestone keeps us on track for data in the first half in next year. We continue to be encouraged by the efficacy data donidalorsen has generated to date.

We recently announced two-year open-label extension data that showed consistent and sustained protection against HAE attacks in line with what we previously reported from our randomized Phase 2 study and our open label extension study at one year.

I also want to highlight the continued success we've achieved developing medicines for patients with neurological diseases. SPINRAZA continues to be the global market leader for the treatment of all types of SMA.

And just recently, SPINRAZA's proven strong efficacy was reinforced further with highly encouraging new data from the ongoing RESPOND study in SMA patients who had a suboptimal response to gene therapy. And with their recent approval of QALSODY in the U.S.

we now have two breakthrough commercial medicines on the market to treat two severe neurodegenerative diseases. The FDA has accelerated approval of QALSODY, brings hope and a breakthrough treatment to people with SOD1-ALS and their families. And QALSODY's approval further validates our capabilities to treat intractable neurological diseases.

Today, we have 12 medicines in clinical development for neurological diseases, including treatments for other forms of ALS, dementias, neurodevelopmental diseases, and much more. Our industry-leading neurology research team is also making remarkable achievements to further advance our leadership in neurology therapeutics.

With a track record of driving innovation, we are focused in making great progress in advancing new cutting edge medicines into development to address severe neurological diseases for patients in need. Additionally, for the second quarter in a row, our robust late stage Phase 3 pipeline has expanded.

Roche recently initiated Phase 3 development of IONIS-FB-LRx in IgA nephropathy, increasing our late stage Phase 3 pipeline to eight drugs being developed for 10 separate indications.

Our robust late stage pipeline sets us up for a steady cadence of Phase 3 data readouts over the next few years, positioning Ionis to deliver many new important transformational products to the market for years to come.

And just last week we were pleased to announce our expanded collaboration with Novartis, demonstrating their confidence in Ionis' capabilities to create a next generation compound targeting Lp(a) as a potential follow-on to pelacarsen utilizing our latest cutting edge technologies.

As a reminder, pelacarsen is in an ongoing Phase 3 cardiovascular outcome study called Lp(a) HORIZON, which is fully enrolled with more than 8,000 patients. The HORIZON study is progressing well with data and a potential filing plan for 2025.

We also recently expanded our cardiovascular franchise when we advanced our first cardiac muscle like a drug into preclinical development. This muscle targeting drug is our first to enter into development utilizing our in-license Bicycle technology.

This achievement further highlights the potential for us to expand our drug discovery capabilities for cardiovascular and neuromuscular diseases. And importantly, we remain on track to accomplish our other key strategic goals across the business, including achieving our 2023 financial guidance.

With that, I'll turn the call over to Richard to discuss our recent pipeline progress and preview of coming key events. Next, Beth, will review our second quarter and first half financial results and then I'll wrap things up before taking your questions.

Richard?.

Thank you, Brett. Well, as Brett just mentioned, we've made important pipeline progress in the first half of this year, bringing us even closer to our goal to deliver an abundance of new medicines to patients and to the market.

We believe that the positive data we have reported to date from the NEURO-TTRansform study demonstrate eplontersen's potential to provide substantial benefit for patients with ATTR polyneuropathy. The recent 85 week data further strengthened our confidence in eplontersen's competitive profile.

Through 85 weeks, eplontersen continued to demonstrate a sustained and substantial reduction in CM-TTR concentration base compared to baseline. As you can see from both the mNIS+7 and Norfolk Quality of Life graphs, the changes from baseline through 85 weeks of treatment are very encouraging.

Importantly, a substantial number of patients treated with eplontersen continue to demonstrate improvement in neuropathy impairment and quality of life through the 85 weeks of treatment. These data further add to the totality of data supporting eplontersen's differentiated profile.

We plan to report the full data set at a medical conference later this year. Eplontersen is currently under review in the U.S. with additional filings outside the U.S., including the EU planned for the end of this year.

We and AstraZeneca, recently expanded our agreement to include Latin America, further underscoring our and AstraZeneca's commitment to bringing eplontersen to patients around the world. Positive efficacy and safety results we've seen from NEURO-TTRansform study also support our confidence in eplontersen for ATTR cardiomyopathy.

Notably, we recently completed enrollment in our Phase 3 CARDIO-TTRansform study. With more than 1,400 patients, this is the largest study ever conducted in this indication. We designed the study to demonstrate benefit on cardiovascular outcomes in a broad set of patients.

Now that enrollment is complete in CARDIO-TTRansform, we expect to report data as early in the first half of 2025. As with most outcome trials, our timelines are based on a variety of factors including event rates and the evolving clinical landscape.

Following eplontersen, olezarsen is the next drug we expect to bring to the market and is the first we will commercialize ourselves. We are developing olezarsen for two indications, FCS, and SHTG.

And while FCS is a rare indication and SHTG represents a much broader population, both indications are characterized by severely elevated triglycerides, which can lead to fatal pancreatitis and atherosclerosis, and both are poorly managed by the current standard of care.

We remain on track to report data from the Phase 3 BALANCE FCS study in the second half of this year. Our development program to support the broader SHTG indication is also progressing well. With over 3 million patients in the U.S.

with severe hypertriglyceridemia and first mover advantage, we believe olezarsen represents a blockbuster opportunity for Ionis. Following closely behind olezarsen is our next wholly-owned medicine, donidalorsen to treat patients with hereditary angioedema.

We recently completed enrollment in the Phase 3 OASIS-HAE study for donidalorsen keeping us on track for data in the first half of next year.

In June, we reported top line two year results on the Phase 2 open-label extension study of donidalorsen showing an overall sustained mean reduction in HAE attack rates of 96% from baseline through two years across dosing groups. We plan to present these data at a medical conference later this year.

Based on the totality of the data generated to date, donidalorsen continues to demonstrate sustained protection in preventing potentially fatal HAE attacks. As a result, we are confident in donidalorsen's competitive profile, providing us with a meaningful commercial opportunity.

Our industry-leading neurology franchise continues to deliver groundbreaking medicines. In April, the FDA approved QALSODY for patients with SOD1-ALS, making it the first approved treatment to target a genetic cause of ALS.

In addition, we have 12 medicines in clinical development to treat neurological diseases, including two in Phase 3 studies and eight in Phase 2. One of our highest priorities is to expand our wholly-owned franchises in neurology and cardiology. We currently have several wholly-owned medicines that are moving quickly to the clinic.

Our world-class neurology research team is working to turn great science into great medicines that we plan to develop and commercialize ourselves.

As a result, we expect a steady cadence of new clinical study starts over the next several years, ensuring our neurology franchise continues to lead in innovation and positioning us to deliver a growing number of new medicines to patients and the market for years to come.

Now, I would like to briefly touch on the recent positive interim results from the RESPOND study of SPINRAZA. RESPOND is an ongoing two year Phase 4 open-label study evaluating SPINRAZA in SMA infants and toddlers with suboptimal response to gene therapy.

Results from the interim analysis showed that most patients improved in measures of motor function with SPINRAZA treatment. SPINRAZA also continued to demonstrate a favorable safety profile on these patients previously treated with gene therapy. These data add to the extensive body of evidence demonstrating SPINRAZA's benefit for SMA patient.

And that includes treating more than 14,000 patients with a well-established safety profile based on data in patients treated up to eight years. In addition to RESPOND, Biogen is conducting the ASCEND and DEVOTE studies that together aim to address remaining unmet need and inform treatment decisions for the SMA community.

Our late-stage pipeline expanded for the second consecutive quarter with the start of a pivotal program for IONIS-FB-LRx in patients with IgA nephropathy. We now have eight drugs in late stage development advancing in a total of 10 separate indications.

GSK recently presented new data for bepirovirsen in chronic HBV patients, our other medicine that started a robust Phase 3 development program earlier this year. The data presented at EASL showed that bepirovirsen treatment resulted in a durable response in responders from the B-Clear Phase 2b study.

GSK plans to present new data later this year from the B-Together study, which is evaluating bepirovirsen in combination with pegylated interferon. In totality, we have had an eventful first half with many important positive data events and clinical advancements.

In the second half of this year, we remain on track for a number of key additional events, including U.S. eplontersen approval and regulatory filings outside the U.S. as well as Phase 3 data for olezarsen in FCS, our next potential medicine to launch after eplontersen.

We will keep you updated on our progress on these events and more throughout the rest of the year. And with that, I'll turn the call over to Beth. .

Thank you, Richard. In the second quarter, we continued to make progress on our goal to further strengthen our financial foundation in support of our strategic priorities. Our financial results for the second quarter reflect our ability to generate meaningful revenue to fund investments in key growth opportunities across our business.

We earned revenues of $188 million and $319 million for the second quarter and first half of this year respectively. Our revenues increased 40% for the quarter and 16% year-to-date over the same periods last year, driven by significant partner payments.

As anticipated, our operating expenses and operating loss for the second quarter and first half of this year increased over the same periods last year as we advanced our commercial readiness activities and our pipeline, especially our late stage programs.

We remain well capitalized with $2.4 billion in cash and investments at the end of June, enabling us to continue deploying our financial resources to bring transformational medicines to the market. In the second quarter, we opportunistically refinanced our 2024 convertible notes and were able to accomplish all our objectives.

We retained our cash to continue making key value driving investments in our pipeline. We extended the maturity of our 2024 notes to 2028 while maintaining a low coupon. And importantly, we retained the flexibility to repay the new notes with cash, equity or a combination of the two, enabling us to mitigate potential equity dilution.

We retired approximately 80% of the 2024 convertible notes. And as a result, our cash balance at the end of June included approximately $115 million we have earmarked to address the remaining 2024 notes. SPINRAZA's global sales were $437 million for the second quarter and $880 million year-to-date.

As a result, we earned $61 million and $111 million in royalty revenue for the corresponding period. SPINRAZA's global sales were essentially flat compared to the same periods last year, reflecting SPINRAZA's resilience against emerging competition in the U.S. and abroad.

By working to expand existing markets while also generating important efficacy data from SPINRAZA's robust Life Cycle Management Program, Biogen is making good progress on their goal of returning SPINRAZA to consistent growth.

We earned R&D revenue of $110 million in the second quarter and $173 million year-to-date, both of which increased substantially compared to the same periods last year. Our significant R&D revenue reflects the value Ionis' technology is creating as numerous partnered programs advance.

Notable payments earned in the second quarter included $40 million from AstraZeneca for eplontersen, which included development cost sharing payments, and the $20 million license fee for Latin America rights.

$20 million also from AstraZeneca for advancing ION839 into a Phase 2b study for NASH and a $16 million milestone payment from Biogen for QALSODY U.S. approval.

As planned and aligned with our goal to invest for revenue growth, our non-GAAP operating expenses increased in the second quarter and year-to-date compared to last year, as most of our ongoing Phase 3 studies are either fully enrolled or approaching full enrollment.

As you would expect, our clinical study costs increased, which resulted in higher R&D expenses. Additionally, as we prepared to launch eplontersen, olezarsen and donidalorsen, our SG&A expenses also increased modestly year-over-year.

Our results for the first half of this year keep us on track to meet our 2023 financial guidance, including our P&L and cash guidance. Looking ahead, with many partnered programs advancing, we continue to have numerous opportunities to earn additional R&D revenue.

We anticipate revenue in the second half will be weighted towards the back end of the year. For example, we are eligible to earn a $50 million milestone payment for the U.S. approval of eplontersen, and we expect to recognize additional amortization revenue from our recently expanded collaboration with Novartis.

We project operating expenses to continue to gradually increase over the course of this year. Consistent with our guidance, which includes expenses related to our capital intensive Phase 3 studies, we estimate our full year R&D expenses will increase between 20% and 25% year-over-year, excluding the Metagenomi upfront payment from last year.

We also continue to project our full year SG&A expenses to increase approximately $35 million year-over-year as we prepare to bring eplontersen, olezarsen and donidalorsen to the market.

For example, as we move closer to launching eplontersen, assuming an approval in late December, our SG&A expenses will include our share of the cost to build out the eplontersen sales force as well as additional launch readiness expenses. Over the next few years, we are poised to launch several medicines. As a result, we are in a period of investment.

We project our operating expenses to grow modestly and importantly, by keeping more programs for ourselves, we are positioned to deliver significant revenue growth. Additionally, we continue to expect our substantial base of R&D revenues to contribute meaningfully to our overall revenue as our partners continue to advance numerous programs.

And with three near-term commercial opportunities that have a combined multibillion-dollar peak sales potential and a steady cadence of medicines poised to follow closely behind, we are well positioned to drive substantial revenue growth and long-term value for shareholders. And with that, I'll turn the call back over to Brett. .

Thanks, Beth. Looking forward to the rest of this year, we're laser focused on advancing our key priorities with additional important regulatory and late-stage pipeline events planned for the second half. We're well on our way to achieving our goal of delivering an abundance of new medicines to patients.

We now have two breakthrough medicines to treat devastating neurological diseases on the market. And with the December PDUFA date, we could also add eplontersen to our commercial portfolio late this year. We're on track with our go-to-market activities for each of our near-term commercial opportunities.

Our first planned launch of eplontersen with AstraZeneca in patients with ATTR polyneuropathy is quickly approaching with our independent launches for olezarsen and donidalorsen following closely behind. And with our rich late-stage pipeline, we're well positioned to bring additional medicines to patients for many years to come.

We also continue to make innovative technological advancements to enhance our leadership position in RNA therapeutics, positioning us to add to our steady cadence of new transformational medicines well into the future. And our strong financial foundation enables us to invest in areas with the greatest potential to drive increasing value.

We look forward to sharing our progress as we advance our priorities. And with that, we'll now open it up for questions.

Operator?.

[Operator Instructions] Today's first question comes from Myles Minter with William Blair. .

Congrats on the quarters. First one is olezarsen. And I know that your stance in the severe hypertriglyceridemia trials is that you wouldn't need to conduct an outcome study or not looking to.

There's been some language put out there from one of the peer companies developing in the space as well that they would be doing an outcome study? Has that language sort of changed your viewpoint on the need to conduct an outcome study in that population?.

Thanks, Myles. Absolutely not. We're focused on patients with severely elevated triglyceride to genetically caused FCS for -- severely elevated triglyceride where there's no known genetic cause of disease.

These are patients that suffer from severe metabolic diseases, particularly acute pancreatitis that can evolve to chronic pancreatitis, diabetes and all kinds of other morbidities.

There is also a cardiovascular component to severely elevate triglyceride, but our focus is on getting patients out of harm's way in the -- to have -- are suffering from severely elevated triglycerides. We've done a lot of research. We're preparing the market, and we're ready to -- we're preparing for launching olezarsen for FCS and SHTG.

And I'd like to just maybe Onaiza to expand on Myles' question. .

Sure. Myles, yes, as we've spoken before, we see a great unmet need for severely elevated triglycerides in the marketplace, over 500. This is a market where we have over 3.5 million patients.

The standard of care is just not sufficient to actually meet the goals that these patients are required to meet or the medical guidelines, which is to get them below 500 or as close to 500 is possible to get them out of harm's way for the risks that Brett just highlighted, particularly acute pancreatitis risk.

So we have -- we're really looking forward to getting the drug on market for that, both for the rare disease, genetically defined as FCS. We expect to see the BALANCE data by the end of the year and then looking forward to launching into that and then -- and ultimately, into the severe hypertriglyceridemia space. .

And second question is just on the week 85 data for ATTR polyneuropathy. I do also understand that there was vitamin A deficiency related ocular events that were discovered in that trial. Obviously, reduction that you get FDA deficiency and you can supplement that.

But my question is, have you submitted that data to the FDA just for safety purposes only.

I don't think you've submitted it with the efficacy data, but will they see that safety data?.

Eugene?.

Yes. Thanks for your question, Myles. So we submitted all of the comprehensive safety information, including the information that was routine with a day 120 update as part of the NDA. So all of the safety data that was available at the time as well as the updates related to the day 120 update were submitted to the FDA and are under review. .

Everything on track, right, Eugene?.

Everything on track, absolutely. .

The next question comes from Debjit Chattopadhyay with Guggenheim Securities. .

This is Robert on for Debjit. How does Ionis and AZN plan to compete against siRNA options in the ATTR-PN market.

And does AZN's presence potentially allow eplontersen to be first approval to any significant markets?.

Thanks, Robert.

Onaiza, do you want to...?.

Yes, sure, Robert. We're very excited with the data that we're seeing. The week 85 data was very encouraging. We saw a duration of effect sustained TTR suppression for TTR and then obviously, halting disease progression and seeing improvement in a substantial number of patients in both mNIS+7 and Norfolk Quality of Life.

So we've got a really great efficacy data package. We have from all of the research we've done, the more preferred administration profile with self-administration at home, allows patients to be empowered in taking control of their disease and taking the medication wherever they are with them, not relying on going into the HCP's office.

The efficacy combined with this self-administration profile gives us a really strong way to end the marketplace. As I've said before, this is a market where we still have 40,000 patients and less than 20% of those patients have been either identified, diagnosed and treated for polyneuropathy, including mixed phenotype.

So our ability to get to where these patients are identify them and get to the offices outside of the centers of excellence where they're presenting is going to be really important. And those are some of the strategies we're working on with AstraZeneca. And then as to your question on whether we will be first in many global markets, yes.

That is the goal. We are planning to file in different markets outside of the U.S. in the second half of the year, particularly in Europe. But as you know, we're also looking at expanding into markets such as Eastern Europe, Russia, China, Japan.

And again, these are places where AstraZeneca's global scale will bring the ability to really penetrate and get these patients in care where there is needed. .

And as you know, Robert, we're very pleased that AstraZeneca also enthusiastically license Latin America rights for eplontersen for, of course, all indications, neuropathy as well as cardiomyopathy. It demonstrates the their enthusiasm for eplontersen, our partnership and enthusiasm for the data that has been generated to date..

The next question comes from Kostas Biliouris with BMO. .

One on pelacarsen follow-on molecule that you recently announced.

Can you discuss the potential technologies that you could leverage there to improve the efficacy and the dosing frequency of the first-generation molecule? And approximately how many years did you expect this follow-on molecule to enter the clinic after -- to enter the market, sorry, after pelacarsen?.

Sure, Kostas. Thanks. Very excited that Novartis came to us with a proposal to work on with them a follow-on strategy, follow-on program for pelacarsen. Let me just say right from the outset that pelacarsen -- the pelacarsen Phase 3 program is going well, very well on track, and is on track for data readout and potential filing in 2025.

The fact that Novartis came to us really demonstrates their enthusiasm, their added enthusiasm for this -- there's opportunity for Lp(a) cardiovascular disease. They expect to be a semi-approval for pelacarsen the first on the market and to have a substantial global reach.

And the follow-on form is to extend that reach the purpose is to reach more and more patients with the follow-on program. Novartis recognizes our expanded and vast capabilities in RNA-targeted therapeutics. And we're bringing our full arsenal to the table, and they appreciate that -- that's why they partnered with us on this.

That includes all the great work that our research organization has been doing over the last few years in expanding our medicinal chemistry capabilities, including NspA backbone that we have talked a lot about in the past and other chemistries as well as our rapidly emerging capabilities in RNAi technology and combinations of both.

We can utilize chemistries that we utilize in ASO technology as well as for RNAi platforms. It's tough to beat the efficacy that pelacarsen has demonstrated in Phase 2 Kostas. I mean, with 98%, 99% of patients with CBD due to high Lp(a). We were able to get their Lp(a) levels down below the threshold associated with CBD.

So really, we want to maintain that efficacy. We want to reproduce that efficacy and a potential follow molecule, but what we're really focused on is pelacarsen. We're very confident in our ability to deliver a molecule with semiannual dosing to be annual dosing, utilizing a mixture of our technology capabilities, and that is the focus with Novartis.

And we're going to be working hand in hand with them to bring the best molecules forward to follow on pelacarsen. .

Sorry.

No, I was going to ask approximately how many behind is the follow-on molecule compared to pelacarsen?.

Yes. We haven't stated -- discussed that publicly Kostas about what the timelines are. And obviously we're still in research phase. So it would be a little risky to actually speculate on that right now. .

The next question comes from Mike Ulz with Morgan Stanley. .

Just on eplontersen in cardiomyopathy, maybe you can comment on the recent Bridge data and sort of how that impacts your thinking in terms of the CARDIO-TTRansform study? And then maybe secondly to that, is there a potential for you to maybe stop the study earlier? Or is the thinking still to go through sort of the full results there?.

Sure, Mike. So BridgeBio data, obviously, good patience to have another potential option for TTR cardiomyopathy. To state the obvious, we need a lot more data. We need to see more data. We're looking forward to seeing more detailed data and I think they're planning to present later this year.

The demographics of the studies supports our trial design, reinforces our trial design, gives us even greater confidence in our expanded trial design, which we're going to -- which we're going to have -- we have now as we have completed enrollment, a very good balance between tafamidis patients [indiscernible] as well as naive patients.

So it supports that. CV mortality -- overall mortality is very important in this population. And maybe I'll ask Onaiza to just really expand as on the importance of this from a physician standpoint, from a payer perspective. .

Yes. So as you know, eplontersen Michael, that we love the breadth of our trial. We believe we're going to -- it's a landmark trial. It's going to generate the significant amount of data to really go in and arm the physicians with the data that they need to actually treat these patients.

This means anything from EHA Class I, II and III, so mild to severe hereditary and wild-type naive to silence or therapy naive to cardiomyopathy therapies and TTR as well as on top of standard of care tafamidis as well. We really love our endpoints.

We have done a fair amount of work in recent times to really understand the difference in terms of how physicians view mortality versus cardiovascular death.

And that is actually a more meaningful cardiovascular endpoint, along with the richness of cardiovascular hospitalizations and then some of our secondary endpoints, obviously, in 6-minute walk and other measures that are going to be at play. But the endpoint is just actually really meaningful.

So all in all, we are really excited about our data set, our trial design and looking forward to seeing the output of that in the coming times. .

And Michael, we -- there's no plans to change our -- there's no changes to our plans for when the study will complete based on any new emerging data that has come out recently. We love our trial design. There are several factors that will impact when we read the study out. The first, of course, was to complete enrollment.

We've now achieved that, and we've achieved it very successfully. We have the demographics in the study that we intended to have for -- to actually have the greatest data set when the study reads out. We'll also be looking at changing competitive landscape, new data as it emerges that could potentially affect the time we read the study out.

We don't think the Bridge trial data is going to impact that, but there may be other data that comes out.

And thirdly, our blinded event rates will be very important for us to continue to monitor as we decide when it's beast, but there's no change in the -- currently, there's no change in the timing of when that study is -- our CARDIO-TTRansform study is due to read out. .

Let me just address one other question, which was on the payer reimbursement that I missed. So just to make sure that we've done a fair amount of testing with payers on the trial design.

And again, if we show the cardiovascular risk reduction on top of tafamidis, there is clinical meaningfulness in that for physicians, and they are not going to be kind of standing in the way in terms of reimbursing a combo product here.

Again, the data will bear out, and they're very favorable in making sure these patients who are highly at risk, it's a terminal disease or getting the best medication and care possible.

So we're really pleased to see them thinking about the disease and the patients is way and thinking about the landscape of reimbursement as either mono or combo in the space. .

The next question comes from Yanan Zhu with Wells Fargo. .

I was wondering if you could share your thoughts on some recent development in Angelman syndrome field where Roche decided not to move their ASO program into the next stage of clinical development. And wondering if you could share any update from your Angelman syndrome clinical study that is ongoing.

And any thoughts around the programs or the product candidates, efficacy and safety profile. And also, if you could also talk about for ATXN2 program, and its ongoing study, that will be great. I think the data are expected around the same time as the Angelman syndrome program. .

Sure. Thanks for the question. So the Angelman's program -- the Ionis Biogen Angelman program is going very well. We're operationalizing the Phase 1/2 study, and we're continuing to enroll patients in this study. We are -- with Biogen are planning to have data around midyear next year from the Angelman's program.

And as I said, it's going very well so far. We haven't disclosed our -- we really don't have any insights into the reasoning behind why Roche ended their study. I think obviously, I've said that it wasn't a safety issue. They said they didn't meet their minimum target product profile or minimum criteria. I assume on efficacy.

We really don't have and shouldn't -- we're not disclosing anything we may think on this. So we're really focused on our program. So expect to read out from that study next year. We may be able to provide an update on the status of the program late this year.

There is a -- we have a standing invitation to an Angelman meeting called fast in which we always have a podium slot, and I'm sure we'll be present this year too. But we're not necessarily expecting data -- new data at the meeting. But we haven't decided what we're going to present at that meeting yet.

As far as ATXN2, this, of course, is another one of our ALS drugs. This drug is particularly exciting because it's targeting a sporadic ALS. So no known genetic cause of ALS -- is enrolling.

This is a study in which we're examining 4-dose cohorts with the highest dose cohort having expanded to add more patients to have the most robust data set to inform on a potential Phase 3 study if study is successful. That, as you mentioned, is also due to read out around the same time next year, around midyear -- next year.

And all indications are that it's going well. .

The next question comes from David Lebowitz with Citi. .

Given the HA data is coming up earlier next year, could you -- assuming the Phase 2 data is replicated, could you tell us what your efforts will look like for launching the therapy and trying to convince physicians to move to a new modality?.

Onaiza?.

David, yes, we're very excited about our preparations for donidalorsen launch and waiting for the Phase 3 data next year. We are thinking about the market in a variety of ways. As you know, this is going to be pretty much a switch market.

So we do actually have a switch study that's going alongside our Phase 3, which will be very informative and give confidence for physicians to switch patients as a confidence piece is going to come from the ability to make sure there are no breakthrough attacks in the process of the switch.

And given our rapid onset, we believe we will be able to demonstrate that. On the patient side, I think we can see the switching behavior already in the marketplace with Orladeyo kind of inciting more switches from Takhzyro, which is the standard of care. So we see that patients are willing to try new treatments.

And want -- they want zero attack rates, and they want more convenience, and we offer both with our profile as well. So the team is very active in understanding kind of what will drive some of the switching behavior and their go-to-market strategies alongside of that. .

And one additional question. Moving towards a potential eplontersen launch.

Do you have any thoughts on how market growth has shifted since the subcu was launched by Alnylam? And how that might apply to eplontersen and how you're thinking of the launch going forward?.

Yes. Taking a look at how AMVUTTRA's uptake is going on in the marketplace. I mean they've got a good start. And it's just important to note that they're working through a lot of ONPATTRO switches right now, right? So we're really trying to understand how much market growth there is.

As I said, this continues to be an underpenetrated marketplace, lots of patients that are still not identified, diagnosed or treated. And I think Alnylam is doing their job of getting most of their patients on to their next-generation silencer. And we have a lot of work to get new patients to just silencer therapy overall in this marketplace.

So we expect it to grow readily. This is when you have a couple of players in the marketplace, it's always a good thing for patients. We're looking forward to getting in, in January and starting to work.

And as you -- as I said earlier, we have a very exciting product profile, efficacy as well as the self-administration profile, which we believe will do very well in the market. .

The next question comes from Allison Bratzel with Piper Sandler. .

Just one for me on the Phase 2 GOLDEN trial in GA. Just curious, is there any update on your view of the geographic atrophy space and potential opportunity for a therapy targeting complement factor B, just given some of the recent safety and regulatory updates in the GA space in recent weeks.

Could you just frame what you're looking for in the Phase II readout next year to warrant further investment in that space?.

Thanks, Allison. Yes, we're -- and our partner, Roche, are very enthusiastic about our GA study, our Factor B-LRx geographic atrophy study GOLDEN. We're pleased that there's a benchmark to get drugs approved for GA. This helps set a path forward for all drugs that are being developed for GA, including ours. We like our drug. We like our profile.

So far, the GOLDEN study is a large study, around 300 patients to dose cohorts, dosing groups, in which patients are going to be treated for about 15 months. So it's a good study. And what we're looking for is the primary changes in geographic atrophy area in the study.

So it's an efficacy study, a proof-of-concept study, and that study is due to read out next year. We like this. We like to target, Factor B in the alternative play, we think is the right target for GA, we think systemic approaches to the complement pathway, particularly Factor B is the right approach for treating GA.

And we think that the overall safety profile and tolerability profile that we're going to have with Factor B-LRx is going to be a very significant advantage versus IBT drugs, which are administered directly to the eye and have side effects as a consequence to that.

We expect Factor B-LRx to have an excellent safety profile, much like the rest of our LICA platform that has eplontersen, pelacarsen, olezarsen, donidalorsen. So that -- it's in Phase 2, and we're seeking to achieve proof-of-concept for the next year.

If the data is strong or the data supports, I should say, Roche is preparing to go to Phase 3, and they're equally enthusiastic for the program as we are. .

The next question comes from Paul Matteis with Stifel. .

Congrats on all the progress. I wanted to ask about olezarsen in light of how much the cardiometabolic space has really changed since you initiated the pivotal program. Just specifically looking back at the Phase 2 baseline characteristics, I think most patients in the study had type 2 diabetes, most patients had comorbid hypertension.

BMI was overweighed on average.

I guess, how do you think about the impact of this recent WEGOVY data and more broadly, the takeoff of these weight loss drugs on the market for olezarsen? And I guess, what percent of patients with trigs above 500, would you say demographically wouldn't actually qualify for one of those drugs on label?.

Onaiza, you want to take that?.

Yes. Hi, Paul. Yes, been on it's a lot of good data for the GLP-1s recently as well. So a couple of important things to note. First of all, they're not going to be indicated, right, for triglyceride lowering. And if you looked at some of their TG -- just their TG lowering data, it's very much in line with what current standard of care is.

So they're not getting to the really high levels of TG lowering that APOC3 target can actually deliver here. So that's kind of the first thing.

If physicians do use it off-label, it's a very important reminder, and I think most of the endocrinologists know is that the GLP-1s have a warning in their label for not being used in patients with risk or a history of acute pancreatitis.

And as you know, in the 500-plus severely elevated triglycerides where olezarsen is being studied, we have many, many patients who are at risk for AP. So we do think both the magnitude of triglyceride reduction along with the risk for these patients who are over 500 for AP, we do not expect that to be a direct or an indirect competitor. .

The next question comes from Yaron Werber Cowen. .

Just on SPINRAZA, the response by the interim results are definitely encouraging.

Can you give us a sense, are these potentially label-enabling? Like how do you think about it just given your broad label? Do you need sort of label enabling? Or is this just for standard of care sort of change? And then secondly, just in terms of some of the ATXN2 program and the ATXN3 programs. I know you touched a little bit on ALS.

You also have a fast program for ALS.

Just maybe give us a little bit of a sense what's the next timing and what do you expect from the data? I know the fast ALS is a pivotal in 2025 or the other 2?.

Yaron, so is our understanding that ASCEND or RESPOND -- responding the data you're talking about verging data, patients that haven't done that well on gene therapy moved on to SPINRAZA and really showing really good strong signs of doing very well, improving muscle strength, neuromuscular function.

Not surprisingly, there's been a lot of anecdotal data out there over the years that this is the case, but it's very helpful to that biogenetically did a study just to demonstrate how the study is ongoing.

It's our understanding that these studies and patients that perform suboptimally on either gene therapy or on that a SPINRAZA will be more for publication purposes and those sorts of things and which are for certainly in line with promotion. It's the DEVOTE study that has the potential to actually expand label.

The DEVOTE study is a randomized controlled Phase 3 study looking at higher doses of SPINRAZA to demonstrate even greater efficacy in SMA patients of all kinds. So that's my understanding. So I'm getting head nods from my clinical folks here so. Eric, just reminded me, I didn't answer the ATXN2 question, Yaron.

So the ATXN2 is enrolling for dose cohorts. The top dose is an expanded cohort to have more patients in the dose that has the potential to be the dose that goes to Phase 3. That data is due to read out midyear next year, ATXN2 for non-genetic ALS. I'm sorry. .

The next question comes from Luca Issi with RBC Capital Markets. .

Maybe if I may, following up on the prior question and Brett, you may have already alluded to it, but I want to make sure was [indiscernible] in-licensed the next-generation molecule informed in any sort, form or shape by the blinded event trade that they're seeing in the cardiovascular outcome trial pelacarsen or is this just truly life cycle management? Question to maybe, Eugene, if I may, on TTR cardiomyopathy, wondering if you could comment on what statistical methodology are you using for the Phase 3 for TTR cardiomyopathy are using your Finkelstein-Schoenfeld method similar to BridgeBio and Pfizer? Or are you using the Andersen-Gill method, which is similar to Alnylam and maybe why you choose one versus the other? And then lastly, maybe on AGT, what was your reaction to Alnylam-Roche deal and how you're thinking about BD for your molecule?.

Sure, Luca. Before turning it over to Eugene, I'll take through those, and then you can talk about the statistical plan for CARDIO-TTRansform. So Lp(a) entirely life cycle management.

The pelacarsen Phase 3 study is going very well on track for data in 2025 with a potential filing in 2025 has nothing to do with any particular data from the study, except to say that the study is going very well. So that lends even greater confidence by Novartis to pursue life cycle management.

We're focused Luca on our own programs, really don't have a reaction to any competitors in the AGT space or anywhere else in partnering strategies. We -- our plans haven't changed. We are planning to share new AGT data in the second half of this year at a medical meeting.

And we've said all along that we think a drug like this for indications like hypertension and heart failure are best suited with a partner to reach as many patients globally around the world. And we haven't provided any details on the timing when we're going to partner the program, nor -- of course but stay tuned to that down the road.

Eugene, could you talk a little bit about the Luca's question about our stats plan for CARDIO-TTRansform. .

Sure. So if I understood, it was related to the analysis of the primary endpoint.

Is that right, Luca?.

That's correct. Yes, that's correct. .

Yes. So as we said, the methodology that we're utilizing or planning to utilize for that analysis is a pretty tried and true using Andersen-Gill method to look at both CV mortality and CV events, recurrent events that are listed in our SAP.

So again, there's nothing -- I think fancy about this method has been tried and done in multiple outcome studies. It's a fairly classic way of what these events. .

The next question is from Yale Jen with Laidlaw & Company. .

The first question is for eplontersen that if you get it approved later or to the end of this year in neuropathy, do you anticipate the drug will also be used for treating the mixed type patients? Then I have another follow-up. .

Absolutely, we do have provided they have deductible polyneuropathy, yes. This drug would be suitable for pure PN patients as well as mixed phenotype patients. .

Okay.

And my another question is for olezarsen that in terms of the SHTG enrollment, can you provide any color in terms of the status? And do you anticipate complete enrollment later this year?.

I missed the specific….

How we are on SHTG enrollment?.

Enrollment is going very, very well. And either very late this year or very early next year, it's kind of the guidance that we've been giving. .

The last question today comes from Joseph Stringer with Needham & Company. .

Just a quick one on olezarsen Phase 3 FCS later this year.

Can you just frame expectations on what type of outcome you need to see to be successful commercially? What type of key metrics should we be looking at beyond the primary endpoint from -- that would be important from a physician or a payer perspective?.

You want to take that, Eugene? I mean obviously, the primary endpoint is triglyceride lowering -- for triglyceride lowering compared to placebo, and that's important. And we expect what will really drive this market is substantial TG lowering in this patient population.

But Eugene and then on Onaiza, maybe to talk about the commercial also what additional endpoints we're looking to see. .

Sure. Happy to. We're obviously going to also look at responder -- a variety of responder analysis. So looking at proportions of patients that get below particular clinically meaningful thresholds, thresholds like 80 for instance, [is the classic 400, 500].

So again, achieving those reductions that are thought to be meaningful in terms of their risk for having acute pancreatitis events is something that we're -- and future prescribers will be very keen to see. We're also looking at quality of life measures.

But again, we'll indicate whether these patients are actually feeling better, they're able to function better and those, again, are included as well. .

We've -- yes. No, that's great. I think we've done obviously some good market understanding on this as well. Just a reminder, this is a rare disease population for FCS. They really have no tools at their disposal.

This is where the first-line treatment is restrictive diet and it's just not -- I mean, they just can't continue on that level of restrictive diet that they're on for a while. So there's just a huge unmet need. I really do think that this is going to be -- let's get the product that's efficacious but also really safe and easy to use.

And I think getting some of the safety tolerability and here is going to be really important versus first generation, and it's going to be a well go. A lot of lipidologist and a lot of patients are waiting. .

Thank you. Thanks, everybody, for joining us today for today's call. We're well on our way. We're planning to continue our strong momentum in the second half of this year by delivering across all of our aspects of our business, commercial pipeline, technology and so on.

Also, I want to highlight that we're looking forward to providing a comprehensive update on all the great progress we're making on at our Investor Day on October 4. We really hope that many of you can join in person for that meeting. I hope to see you there. Until then, thanks, and have a great day, everybody. .

The conference has now concluded. Thank you for your participation. You may now disconnect your lines..