Ionis Pharmaceuticals, Inc.

Good morning and welcome to the Iona second quarter 2024 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 Walk, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Danielle. Before we begin, I encourage everyone to go to the investor section of the Iona's website to view the press release and related financial tables that 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 on this morning's call are Brett Monia, our Chief Executive Officer, Richard Geary, Chief Development Officer, Kyle Genet, Chief Global Project Strategy Officer, and Beth Haugen, our Chief Financial Officer. Eric Swayze, Executive Vice President of Research, Eugene Schneider, Chief Clinical Development Officer, and Jonathan Burchell, Chief Commercial Officer, will also join us for the Q&A portion of our call. I would like to draw your attention to slide three in our presentation, which contains our forward-looking language statements. During this call, we will be making forward-looking language statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, everyone. Thanks for joining us on today's call. We've achieved a great deal during the first half of this year, delivering many significant milestones as we continue to execute on our vision to bring better futures to people with serious diseases. Today, biomes discovered and developed medicines are reaching more and more people. hosted by two recent launches, WENUA, for people with hereditary APTR polyneuropathy in the U.S., and CALSATI, the first approved treatment for a genetic cause of ALS, currently available in the U.S. and now approved and available in Europe. And with the progress we're making across our pipeline, our medicines are well-positioned to continue reaching more and more patients for years to come. The U.S. launch of our first Ionis co-branded medicine, Wenua, is progressing well with AstraZeneca, and we expect to bring Wenua to even more patients across the globe with the recent approval in Canada, an anticipated approval decision in Europe later this year, and with additional regulatory submissions completed in many other geographies with more coming. Today, we are even more confident in the potential of Wenua to address the larger ATTR cardiomyopathy population. As the largest study ever conducted in this patient group, our ongoing landmark CardioTransform trial is on track to deliver the most comprehensive and the most robust data set in this patient population. We believe Wingoa has the potential to be the treatment of choice for the global ATTR population. Our confidence is based on we knew a strong efficacy profile as demonstrated in hereditary ATTR polyneuropathy and the freedom of simple at-home self-administration, together with AstraZeneca's global cardiovascular commercialization leadership, along with our leadership in VTR amyloidosis. As the Wainoa launch accelerates, we're also preparing for the launch of Olisarcin in FCS later this year, our first independent launch of a whole-immune medicine for Ionis. Olisarcin represents one of the most meaningful opportunities in our pipeline today. as we prepare to first launch an FCS, a severe rare disease with no approved treatments in the U.S., and then to expand to the much larger SHTG patient population. Our NDA submission for olizarcin was recently accepted with priority review. Our PDUFA date is set for December 19th, and we're ready to bring this groundbreaking medicine to people with FCS. We also recently completed enrollment for our SHTG Phase III program, keeping us on track for data in the second half of next year. Based on our significant first-mover advantage and our positive results demonstrated to date, if approved, we believe Olazarsen could be the standard of care for both SCS and SHTG. We're building on the capabilities we've established for Renewal and Olazarsen in preparation for our anticipated launch of Diamond Olazarsen. for HAE prophylaxis next year. In our comprehensive clinical program, Donna Dolorsen has demonstrated strong evidence of meaningful benefit across multiple measures of disease with a favorable safety and tolerability profile. These data, together with the potential for monthly or every two months self-administration using an autoinjector, strengthen our belief that, if approved, Donna Dolorsen has the potential to advance the treatment paradigm for people living with HAE. With positive phase three data in hand, we expect to submit the MDA for Donald Olorson soon as we look to independently bring Donald Olorson to patients in the U.S. Outside the U.S., our commercial partner, Atsuka, is preparing to file for marketing approval in Europe later this year. And with our recently expanded license agreement, Atsuka is also working to bring Donald Olorson to people with HAE in the Asia-Pacific region. Following Renewal, Olorson and Donald Olorson Our next wave of wholly-owned opportunities includes our program for Angelman syndrome. Based on the positive results from the HALOS Phase 1-2 study that we presented last week, we are advancing this potentially transformational medicine into a Phase 3 study, which we anticipate will begin in the first half of next year. ION582 is positioned to become the cornerstone of our wholly-owned neurology franchise. which today includes five wholly-owned medicines and clinical development, with more to come by the end of the year. Our accomplishments so far this year and the investments we're making move us closer to achieving our goal of bringing a steady cadence of new transformational medicines to patients for years to come and generating next-level value for all Iona stakeholders. With that, I'll turn the call over to Richard to discuss our recent pipeline progress and preview key upcoming events. Next, Kyle will review the Wainua launch and our launch plans in progress for Olasarsen and Bonneville-Worson. And Beth will review our financial results. I'll then wrap up things before taking your questions. With that, over to Richard.

Thank you, Brad. We are pleased that our pipeline delivered many important achievements to date this year. With Wainua reaching more and more people with hereditary ATTR polyneuropathy, I am proud of all that our honest team has accomplished to discover and develop this important new medicine and bring it to patients in need. Recent ATTR cardiomyopathy data further reinforce our confidence in the potential of Wainua to improve cardiovascular outcomes in this estimated worldwide patient population of approximately 300,000 to 500,000. With over 1,400 patients enrolled, our ongoing CardioT Transform study is the largest and most comprehensive study ever conducted in ATTR cardiomyopathy. And as a result, we expect the data we generate will enable physicians and payers to make informed treatment decisions in this dynamic treatment landscape. In addition, as part of our phase three program, we're conducting advanced cardiac imaging sub-studies, including an MRI sub-study and a centigraphy sub-study, which will generate valuable data about the potential benefits of Waynua in cardiomyopathy patients. We were delighted that our recent Olisarcin NDA submission was accepted by the FDA for priority review, highlighting the potential of this medicine to make a profound difference in the lives of patients. Our submission was based on the positive Phase III results in FCS that we presented and published earlier this year. In the Phase III balance study in patients with FCS, olisarcin showed substantial and durable triglyceride reductions, and importantly for patients, physicians, and payers alike, olisarcin demonstrated substantial and clinically meaningful reductions in acute pancreatitis attacks a remarkable 84% reduction in hospitalizations, and a favorable safety and tolerability profile. We look forward to our upcoming December PDUPA date and, assuming approval, bringing Olisarcin to people with FCS who currently have no approved treatments in the U.S. We are also developing Olisarcin for the much larger severe triglyceride patient population We recently completed enrollment in our extensive Phase III program for SHTG with more than 2,500 patients enrolled across three studies. This puts us on track for data in the second half of next year, maintaining our multi-year first mover advantage for this wholly-owned blockbuster opportunity. Following closely behind Osarsen is Donna DeLorsen for the prophylactic treatment of hereditary angioedema. We recently presented and published in the New England Journal of Medicine positive Phase III data from OASIS-HAE, our placebo-controlled trial. Additionally, we also presented positive data from OASIS+. Our trial includes an open-label cohort for patients rolling over from the Phase III study and a separate cohort that we refer to as the SWITCH study. Dr. Dolores' treatment significantly reduced HAE attacks. The reduction in HAE attacks translated into significant and clinically meaningful improvements in quality of life across multiple validated measures and high levels of disease control in a vast majority of patients. And with longer-term treatment, patients improved further on all these measures. Additionally, as of our most recent data cutoff in February, 98% of OLE patients remain in the study. These positive data were further bolstered by the encouraging switch results. The switch study through week 17, patients showed a substantial reduction in their HAD attack rate with Donna-Dolores treatment compared to baseline on their previous treatment. Donna-Dolores treatment also resulted in improved quality of life measures and increased disease control. Importantly, more than 80% of patients surveyed reporter of preference for donodilursin over their prior prophylactic treatment. And nearly 90% of SWITCH study patients remain in the study as of the data cutoff in February. In addition to strong clinical results, donodilursin offers the potential for simple monthly or every two months self-administration via an autoinjector. Based on these data, we believe donodilursin could become a preferred prophylactic treatment or people with HAE. Our NDA, which we plan to submit soon, will include data from OASIS-HAE, OASIS+, OLE study switch, and our Phase II study. Outside the U.S., Atsuka is preparing to submit for marketing approval in Europe later this year. And with the recent expansion of our license agreement, Atsuka also plans to bring Donna Dolores into patients in the Asia-Pacific region. The rest of our rich Phase III pipeline is also advancing, positioning us to continue delivering a steady cadence of potentially transformational medicines to patients. We recently completed enrollment in the pivotal arm of our Zildjian Nurse and Study for Alexander Disease, keeping us on track for a Phase III readout next year. And GSK recently completed enrollment in the Phase III program for the peer person for chronic hepatitis B, which keeps the program on track for data in 2026. Coming right behind these programs, we have our next wave of medicines, including a number of medicines to treat both rare and broad neurological diseases, five of which are wholly owned, and we expect our wholly owned pipeline to expand later this year when two more medicines from our neurodisease franchise enter clinical development. ION582, our medicine for Angelman syndrome, has transformational potential for the tens of thousands of people living with this serious rare disorder who are in need of disease-modifying treatments. For this reason, ION582 is poised to become the cornerstone of our wholly-owned neurology pipeline. We're encouraged by the recently presented positive early results from the HALO study of ION582 and people with Angelman syndrome In the study, we demonstrated evidence of consistent and meaningful improvement on all key functional areas across multiple assessments. This includes 97% of participants showing clinically meaningful improvement in overall Angelman syndrome symptoms on the SAS CGI assessment. Improvements in measures of communication, cognition, and motor function exceeded natural history on the Bayley-4 Myelin-3, and ORCA assessments. Traditionally, we observed consistent improvements across ages and genotypes. And we saw favorable safety and tolerability at all dose levels, including no discontinuations or adverse events that were considered related to study drug. Based on these positive data, we plan to advance ION582 into a well-controlled Phase III study in the first half of next year. Alongside the positive Phase I-II data for Angeman syndrome, several recent events have also occurred in our mid-stage pipeline. We were pleased to present positive Phase II data at EASL for ION224, our medicine targeting VEF2, for the treatment of metabolic dysfunction associated steatohepatitis, or MASH. Additionally, based on the encouraging Phase I-B data from IONISMAP-TRX, also known as BID-80, that were presented late last year, Biogenic recently announced that they amended the ongoing Phase II CELIA study with the goal to accelerate a potential proof-of-concept outcome. As a result of this change, they are now projecting data in 2026. Also, we and our partners recently discontinued development for ION541, targeting Adtaxin-2 for ALS, and IONIS-FBLRX for geographic atrophy. Both programs showed good target engagement and favorable safety, but did not meet their primary efficacy endpoints. Importantly, Roche continues to advance the IONIS-FBLRX IgA Neuropathy Phase III study that they initiated last year based on positive Phase II data. Looking ahead, we have several important milestones still to come this year These include presenting new Phase II open-label extension data for Donna DeLorsen and data from the DEVOTE study, which is evaluating a higher dose of Spinraza, as well as anticipated regulatory approvals and launches for Wainoa and Nolasarcin and regulatory filings for Donny DeLorsen. And with that, I'll turn the call over to Kyle.

Thank you, Richard. We are pleased with the initial results of the way NUA launched with AstraZeneca following the U.S. approval at the end of last year, including the significant growth quarter over quarter. With an estimated 40,000 patients worldwide and fewer than 20% of patients on an approved treatment, people with hereditary ATTR polyneuropathy remain underdiagnosed and largely underserved. As a result, a high unmet need remains that we at AstraZeneca are uniquely positioned to address The combined team is working together seamlessly with a shared goal to make Wainua the preferred choice for patients with ATTR polyneuropathy. We continue to see good uptake among patients in the second quarter with an encouraging mix of new patient starts, including some who were new to this class of medicine, some switching from other treatments, and some using Wainua as an add-on treatment to their existing therapies. Prescribers and patients are recognizing Wainua's strong clinical profile and patients value the ability to easily self-administer Wainua from their home. We expect to reach a growing number of patients as we continue to educate prescribers about the value that Wainua brings. With our increased confidence and our ongoing CardioTransform study for ATTR cardiomyopathy, we and AstraZeneca are progressing our pre-commercialization activities and investments to support the potential substantial opportunity Wainoa represents. We are leveraging and building upon our efforts for the Wainoa launch to prepare for our upcoming independent launches of Olazarsson and Donny Delorsson. As Richard mentioned, we are developing Olazarsson for two indications, the rare FCS indication and the broader SHTG indication with anticipated first mover advantage in both settings. We are pleased to receive positive feedback from key opinion leaders on the Phase III SCS data that we presented at ACC. They were particularly impressed with the reduction in acute pancreatitis attacks and the substantial reductions in hospitalizations and inpatient hospital days. We expect that these data will also be important in securing access from payers. In addition, the U.S. Expanded Access Program for Olzarsson is in place. enabling patients to have access to treatment ahead of potential approval. We are putting the final touches on our independent launch plans to bring Olazarsen to patients as soon as possible after anticipated approval. Our medical affairs team has been meeting with physicians and working to improve disease awareness through disease education. Earlier this year, we hired our first illness national sales director. And now, with the December 19th PDUFA date set, we have recently hired and are now training our customer-facing team with extensive rare disease experience in preparation for the FCS launch. To bolster our field team's efforts, we are deploying a tailored omni-channel strategy to further enhance our relationships with patients and healthcare professionals. Finally, we are building a world-class patient and caregiver support team to provide a seamless customer experience to help patients initiate treatment and remain on therapy long-term. We plan to further scale our commercial capabilities as we prepare for the SHTG indication to realize the full blockbuster potential of olazarsin. Donny DeLorsen for the prophylactic treatment of HAE is our next plan launch after olazarsin. And based on the positive results we have seen in the comprehensive development program, we are excited with what Donny DeLorsen could mean for people with HAE. HAE is a well-defined patient population with an estimated 20,000 people affected in the U.S. and Europe. While prophylactic treatment in the U.S. is well accepted by patients and physicians, there continues to be a need and the market continues to grow. Outside the U.S., acute therapies have historically been the standard of care. However, prophylactic treatments are gaining ground, especially in Europe. Many people with HAE are unsatisfied with current treatments and are looking for the option that reduces frequency and severity of attacks, that also offers good tolerability and convenience. This is a disease that typically appears in childhood, so patients have to manage their disease throughout most of their life. As a result, patients have a history of switching treatments, seeking to find the best therapy for them. We believe Donny DeLorsen could be a preferred prophylactic treatment for both patients new to therapy and patients currently on available therapy. With strong clinical data, including switch data, and the simplicity of monthly or every two-month self-administration via an auto-injector, we believe Ditalorsen combines the attributes that people with HAE are looking for in a single, attractive treatment, assuming approval. Today, I'm pleased to share that we are right where we should be in preparing for our upcoming launches. Our infrastructure to support commercialization is in place. and we will be ready to begin delivering our medicines to people in need as these new therapies come to the market. Now, I'll turn it over to Beth.

Thanks, Kyle. Our results in the second quarter and first half of this year reflect the excellent progress we've made toward our goal to bring a steady cadence of medicines to the market. We continue to generate meaningful revenue while investing our capital to independently launch several new medicines over the next few years that have a combined multi-billion dollar peak sales potential. We're also investing in advancing our next wave of wholly owned medicines, which continued to make great progress in the first half of this year. In addition to our recent pipeline achievements, we delivered strong financial results, keeping us on track to achieve our financial guidance. We earned revenues of $225 million and $345 million for the second quarter and first half of this year, respectively. Spinraza remained the primary source of our commercial revenue, with $57 million and $95 million of royalties in the second quarter and year-to-date. Notably, Spinraza product sales increased 25% from the first quarter to the second quarter due to growth from both the U.S. and ex-U.S. markets. Additionally, in the second quarter of the Wayne Newell launch, Product sales were $16 million, bringing year-to-date sales to $21 million. As a result, our way newer royalty revenue increased quarter over quarter to $4 million for the second quarter and $5 million for the year-to-date period. R&D revenue also increased in the second quarter and year-to-date, reflecting the value that our pipeline and technology continue to generate. As planned, our non-GAAP operating expenses for the second quarter and year-to-date increased over the same periods last year, driven by higher SG&A expenses. Our SG&A expenses increased 46% and 31% for the second quarter and first half of this year, respectively, as we continue to make investments to prepare for our upcoming independent launches of Olasarsen and Donny-DeLarsen. Notably, we built out our commercial team, including our field organization, and they're enthusiastically preparing for our FCS launch. Our SG&A expenses also included our minority portion of WNUA U.S. launch expenses. And as planned, our R&D expenses decreased slightly for the second quarter and were flat for the first half of this year compared to the same period last year. Our results for the first half of the year keep us on track to meet our 2024 financial guidance, including revenue of more than $575 million, of which approximately $175 million will come from non-cash amortization of partner payments we received in prior years. Looking to the second half of this year, we expect our total revenue to be slightly lower compared to the first half and weighted more to Q4. We expect commercial revenue to increase as the launches ramp for Wainua and Cal State, and from higher anticipated spin rods of royalties as our tiered royalty rate increases. Additionally, we expect our R&D revenue, which often fluctuates from quarter to quarter due to the timing of achieving various collaboration milestones, to be lower in the second half of the year. Importantly, however, we still have the opportunity to earn sizable payments including a $30 million milestone payment from AstraZeneca if we knew it was approved in the EU. We continue to project our full year 2024 operating expenses to increase by a mid to high single-digit percentage compared to 2023, excluding the impact of one-time costs last year. And similar to the first half of this year, The increase will be driven primarily from sales and marketing expenses as we prepare for our back-to-back independent launches of Olasarsen and Donny Doloresen. We are on track to end the year with $1.7 billion in cash as we continue to make strategic investments in the substantial opportunities before us today, including our late-stage program and our next wave of innovative medicines. So as you can see, we delivered a strong second quarter and first half. Before I turn it back to Brett, though, I'd like to provide you with a look beyond this year to our path to revenue growth and increasing value as we deliver on our goal to bring more medicines to more people. With our strong development and regulatory progress, IONIS is at a critical inflection point. We have several near-term commercial opportunities with significant potential to help patients in need. In parallel, we are advancing our next wave of potentially transformational medicine and our technology. As a result, we plan to continue to strategically invest our capital resources to ensure we unlock the full potential of our promising near and longer-term portfolio. Our investments are focused in four key areas. First, in our go-to-market activities, enabling us to realize the full value of our medicines, which includes investing in our upcoming independent launches for olisarcin and dinodilarsin. Our expenses in this area also include our cost share with AstraZeneca for the hereditary ATTR polyneuropathy launch in the US. As we approach the anticipated olisarcin launch for the broader severe high triglyceride population, we will scale our capabilities and increase our go-to-market expenses to support the larger opportunity. And as we and AstraZeneca approach a potential ATTR cardiomyopathy launch for Whenua, our expenses will increase consistent with the much larger cardiomyopathy opportunity. Importantly, our planned investments are right-sized for the combined multibillion-dollar revenue potential that these important medicines represent. Second, we continue to advance our late stage pipeline. All of our ongoing large phase three studies are fully enrolled with more than 4,000 patients in all and are currently in the heaviest period of investment. We expect these investments to fuel our continued value generation and revenue growth as the data read out and we bring new medicines to patients over the next couple of years. Third, we are increasing our investments on our next wave of medicines. including development and pre-commercialization expenses for our growing, wholly-owned pipeline of potentially groundbreaking neurology medicines, such as ION582 for Angelman syndrome. And finally, we are investing in cutting-edge technologies to ensure we continue to deliver innovative medicines with competitive profiles well into the future. So as you can see, we are strategically investing our capital toward growth opportunities. Importantly, we expect our investments to power strong revenue growth and positive cash flow as our medicines reach more and more patients in need, positioning us to deliver next-level value for all Iona stakeholders for years to come. And with that, I'll turn the call back over to Brett.

Thank you, Beth. As just summarized, we have made great progress in the first half of this year, In the second quarter alone, we've achieved a great deal with many important successes, which include a continued strong start to the way we will launch for hereditary ATTR polyneuropathy in the United States, approval in Canada, and submissions under review in many additional territories. Positive FCS data for olizarcin, which we presented at ACC, which were the basis for our MDA submission, which was recently accepted by the FDA with priority review. Positive HAE data for Donna DeLorsen, presented at IACI. That will be the basis of our upcoming regulatory submissions. And we completed enrollment for the Phase 3 Oles Zarsen SHTG program this past quarter, keeping us on track for data next year. We also presented positive data from the HALOS Phase 1-2 study in people with Angelman syndrome. And we are well along in preparing for our end of Phase 2 meeting with the FDA scheduled for this fall. with plans to advance this important medicine phase three development next year. And we delivered solid second quarter and first half financial results, keeping us on track to achieve our 2024 financial guidance. Based on the strong progress we've made across our business this year, we are well positioned to continue building on our positive momentum as we execute towards achieving all of our strategic priorities. We've arrived where we are today by being focused on a clear vision and a clear set of strategic objectives, which include building and advancing our pipeline and delivering medicines that we conceive, discover, and develop directly to patients. Our pipeline is delivering. We achieved multiple marketing approvals and positive key data readouts over the past year, and we are poised to build on the strong momentum in the near term. We prioritize building our wholly-owned pipeline and are now advancing several of these medicines towards the market. In parallel, our partner programs are progressing on track with important phase three readouts next year and beyond. We are also focused on extending our leadership position in old and new type therapeutics by expanding and diversifying our technology, further optimizing our capabilities for existing therapeutic areas and opening up new areas for drug discovery. All of this sets us up to continue bringing a steady cadence of new medicines to patients for years to come. We're looking forward to sharing our progress as we build on our recent achievements and accomplish our strategic objectives. And with that, I'll now open the call up for questions before moving into the Q&A portion of our meeting. I just ask that our analysts please limit yourselves to a single question as we have quite a long and we'd like to get as many people into the queue and ask their questions as much as possible. So with that, Danielle, you can open it up for questions.

Thank you. We will now begin the question and answer session. To ask a question, you may press star, then 1 on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star, then 2. Again, it's star 1 to ask a question. The first question comes from Akash Tiwari from Jefferies. Please go ahead.

Hey, this is Amy. I'm for Akash. Thanks so much for taking our question. So one on ATTR-CM, there's been some debate on if you need a certain level of TTR to have a cardioprotective effect. Have you seen anything in your own data around this theory? And do you expect any differences with the silencer approach using an all-cause mortality versus a CB mortality composite primary endpoint? Finally, do you have the flexibility to change your primary endpoint if needed? Thanks so much.

Thank you, Amy. We don't believe that there's any evidence of a threshold effect for TTR lowering to achieve benefit in either polyneuropathy or in cardiomyopathy endpoints. We're very pleased with the magnitude of TTR reductions that we have seen in all of our studies for Wainui for polyneuropathy. I'm very pleased with the level of magnitude of TTR lowering we're getting. I don't believe that there's any believable evidence out there that suggests a specific threshold effect for TTR lowering to produce benefit either in polyneuropathy or in cardiomyopathy. We believe our primary endpoint is in cardiovascular mortality and hospitalizations, and that's what we're laser focused on. We also have, as secondary endpoints, specifically CV mortality as well as all-cause mortality, and we think they're both very important. Next study, or next question.

The next question comes from Miles Minter from William Blair. Please go ahead.

Hi. Just on the timing of the cardio TTR transform readout, I mean, is it fair to say that you're at least waiting for data at ASC in London that might have read through to your trial. And if that is the case, what exactly would you be looking for out of that data set to stick with the decision that you're going to read that out early or just wait until the full 140 weeks are up in that study? Thanks very much.

Thanks, Myles. So we're very pleased with the way the CardioTransform study is advancing. We are particularly pleased with the blinded events that we're continuing to evaluate, both CV hospitalizations as well as mortality. It's going very well, right on track. As the first silencer to read out in this indication, we're very much looking forward to any and all additional data that we can see, which we think will be a very nice read-through to our Cardiotransform study. As you know, we have the largest by far study ever conducted in the patient population, and we think that anything we see from other molecules in the silencer class are going to be very, very good read-throughs to what we expect to see in our study. So we're very much looking forward to any and all data that comes from future presentations on the silencer class. Next question, please.

The next question comes from Manny Fouhar from Learing Partners. Please go ahead.

Hey, guys, you have Ryan on for Monty. Thanks for taking our question. Can you just talk a little bit about any early insights from the way Newell launched and how you see that informing a potential launch strategy in cardiomyopathy? And kind of alongside that, you know, maybe what pre-commercialization activities you guys are undertaking in cardiomyopathy? Thanks.

Or I'm sorry, Jonathan. Yeah, thanks for your question. We're very pleased with the early insights we're getting with the PN launch. As Kyle referenced, we're seeing patients who are new to treatment. We're seeing patients who are switching from existing treatments. And we're seeing patients having way newer added on to their current treatment. So we're super pleased with what we're seeing. It's very early days. This is a foundation year. for the launch of Wainoa, but we think there's certainly significant opportunity here when you think through the potential patient population of both PM and CM, the number of patients who are potentially underdiagnosed, and fundamentally, the relatively small numbers today who are actually treated. What we're pleased with is that we're seeing prescribing from both neurology and cardiology and both centers of excellence as well as in the community. And that I think bodes well not just for the PM launch and that progression but also the transition obviously into future indications. Obviously when it comes to some of those future indications it's very premature to speculate as to what might happen there. We'll have to wait for future data readouts of our own pretty comprehensive programs.

Yeah, two quick things to add. First, on the payer access side of things, we're seeing payers cover Wendua very quickly. So from the prescription process to patients actually starting on drug is going very, very well. That tells us that the right types of patients are being identified, and it's also telling us that physicians are justifying the prior authorization process with a sense of urgency which tells you that these patients need treatment and they see the value in Waynua. The second thing I'll just mention is around our patient engagement team. Our PEM team is directly interacting with these patients and getting feedback on a real-time basis. Patients are extremely pleased when they start Waynua at the ability to self-inject with the auto-injector. Very well tolerated, very easy to use, very convenient for those patients, and the profile of Waynua is really playing out the way that we expected it to in the market. Next question, please.

The next question comes from Yanan Zhu from Las Fargas Securities. Please go ahead.

Great. Thanks for taking our questions. I'm wondering about what's your takeaway from Roshi's recent presentation of the Enderman Syndrome Phase 2 data at the ASF meeting, and also separately, Given the similar development timeline of your Andromeda syndrome program and Ultragenyx program, do you think FDA will want to apply the same pivotal endpoint to both programs, or is there a possibility that the agency could allow different primary endpoints based on strength of data? Thank you.

Thanks, Yann. I'll take the first question, and then I'll ask Eugene to comment on the primary endpoint and any harmonization requirements. in primary endpoints for Angelman. So we were very pleased to see the data that Roche presented on their Angelman's program, and particularly we were pleased with the fact that the data further supported our confidence in our Phase I-II data that we presented at ASF, specifically that the rank order of improvements that they reported with respect to the magnitude of improvement was exactly what we reported. The biggest magnitude that they reported was in expressive communication, followed by expressive, receptive communication, followed by cognition, followed by motor function, and so on. And that's exactly what we reported, which bolsters the further confidence that, you know, in our results to date. We were also pleased with the magnitude of benefit we're seeing compared to their program, which really looks like when you really compare apples to apples and you convert Bayley-3 to Bayley-4 outcomes, it bodes very well. We look like we have even better efficacy at lower doses compared to what LaRoche presented. But we were pleased to see what they showed because of the consistency in subdomain benefit between the two programs. Eugene?

Yeah, well, regarding those primary endpoints and conversations to be had with the agency, of course, we're looking forward to updating you after we've had our discussions. But there is, from our standpoint, this will be data-driven. We certainly do believe that the data and consistency of what we see in our Phase I-II study gives us a pretty good idea of what we would like to see in a pivotal study, but it's still to be seen what the specific primary endpoint will end up being. We'll certainly give you an update. Is there a precedence to have a slightly different or different primary endpoint? Of course. There's plenty of precedence in neurology space as well as outside. I mean, if you look at ATTR-CM, that's another example where primary endpoint is not identical for two very similar programs. So stay tuned. We will certainly be happy to provide you an update. Thanks, Yannick. Next question.

The next question comes from Jessica Fai from JPMorgan. Please go ahead.

Hey there. Thanks for taking my question. On the back of the top line heliospeed data, What's your latest expectation for whether silencers in TTR cardiomyopathy will mainly be used in combination with stabilizers versus as monotherapy? Thank you.

Yeah, I'd be happy to talk to that. This is Kyle. Thanks, Jessica. The data ultimately is going to drive this, we believe. That is a starting point. I think ultimately it will come down to physicians and patients making a decision around the profile of treatment that they want in that decision. But when we see it right now, we are seeing Wainui used in combination, obviously as an HATTR polyneuropathy indication combined with cardiomyopathy indication for the stabilizers currently. So we're seeing it happen now. We think that that will continue to progress over time. And we also believe that based on the data and the way that that data plays out will be justification for physicians to be able to justify that to the payers whenever they submit these requests and try to get the drugs approved. So I think it's ultimately data and driven by physicians and patients.

And just to add to that, as you know, Jess, we're positioned to have the richest data set across the board on primary as well as secondary and subgroups. And we're going to have a great deal of data in combination usage as well as in monotherapy, second to none. And that includes data on key endpoints, clinical endpoints, such as hospitalizations, mortality, six-minute walk tests, biomarkers, and so on, but also in imaging studies. We have several imaging studies in process, and we think that if anyone is going to be able to show really meaningful improvements in combination versus monotherapy, across the board, whether it be imaging or clinical endpoints, we're going to be in the best position to do so. And we think that that will, as Kyle said, because this is a data-driven, you know, environment, we're going to be in the best position to actually have the data to support combination usage.

Next question, please. The next question comes from Allison Bratzel from Purpose Handler.

Please go ahead. Hey, good morning, guys, and thanks for taking my question. Maybe one on Pella Carson since that phase three data and regulatory filing are coming up next year. Could you just talk to or frame what you'd like to see in that readout and maybe in broad strokes, you know, what gives you confidence in differentiation of this asset, you know, and what could be a competitive space? You know, color in that. or the NextGen program would be helpful. Thank you.

Yeah, Allison, so, you know, there's not, the only news on Pella Carson is really that the study is on track to read out as scheduled next year. Everything is going very well, and, you know, our partner Novartis is well-positioned with first-mover advantage in this first-to-market patient population, this enormous patient population. Everything we're seeing in the phase three study is very supportive of this being set up for a successful outcome. First-mover advantage is really important, and we with Novartis have substantial lead to the market. Yeah, the program that, our follow-on program to Novartis, with Novartis on the follow-on program is advancing well. Maybe I'll ask Eric Swayze to comment on how things are going. Things are going great.

We've been working closely with Novartis, looking at a variety of ways to extend the dosing interval and make a great LP lowering in a drug. And I'm sure we'll discuss it And sometimes the program advances further, but I can't really say more than that at this time. But very pleased with the progress we've been making on new technologies, siRNAs in particular, and a broad range of other things beyond what would be meantable for the LPA program.

We feel very comfortable that we're going to achieve our objectives with Novartis on a far-long molecule. Things are going very well. There's obviously a lot of benchmarks out there today. There's a lot to compare to. We're pleased. Next question, please.

The next question comes from Yaron Werber from TB Cohen. Please go ahead.

Great. Thanks for taking my question. I also have just a quick follow-up on Wainua. As you look at the Helios B data, and I'm totally obviously aware that you're probably going to be waiting for the full Helios B results, but as you think about with a much-powered... trial design, where can you potentially differentiate and how important will that combo data be, just given that overall in Butro we'll get a broad label for TTR? Thank you.

Well, thank you, Aaron. As the largest study ever conducted in this patient population by far, we think we have the opportunity to differentiate in several different areas. It'll be very interesting to see, you know, the onset of action for silencers and whether or not our onset of action is going to be similar or faster. It's going to be very interesting to see the combination data, as you alluded to just now and we touched on earlier. Combination data is going to be very important in this patient population, and despite having a broad label, which we expect to have as well, Cardiologists are data driven and they're gonna need to see data before advocating for combination usage. I think we're well positioned to have that data. You know, New York health class categories are gonna be very important to see how mild patients are doing, moderately ill patients and severely ill patients are doing. All of this, when you have a well powered study and set up to have the rich data set, you have the potential ability to differentiate across the board. Anything to add to that, Eugene?

No, not really, Brett. You characterized it. I think the power really comes from the size of the study and also an ability to look at subpopulations, which we're really well positioned to do. Thank you, Aaron.

Next question?

The next question comes from Jason Gerberry from Bank of America. Please go ahead.

Hey guys, thanks for taking my question. I wanted to come back to the CardioTransform timing question. So it sounds like we're going to get pretty detailed and granular data from Mount Nile at ESC in terms of multiple curves on overall mono and subgroups with famous background including mortality. So it seems like you'll have everything you need to know post-8 ESC on whether or not the 2025 interim is in the cards. So Is it fair for investors to get or expect maybe a clear message as of the third quarter update on which way you're going to go as the base case 2026 or whether or not you'll look to 2025 interim? Thanks.

Thanks, Jason. So Ionis and our partner AstraZeneca have been thinking – about this quite a bit. Our base case remains under 40 weeks of treatment, which brings us to mid-2026, if the study were to go to completion. But, you know, we are committed to bringing Renewit to patients as fast as possible, if it makes sense to do so. And certainly, as I mentioned earlier, you know, following up on our blinded events and following up on the studies that we're running is most important, but any new information that we get from other treatments in the same class, the silencer class, are gonna be informative on what we do. With that said, we can't get ahead of regulators. We're gonna want to get a buy-in on anything we do with respect to an earlier readout with the FDA, the EMA, before making any proclamations out there publicly. So timing is a bit uncertain right now, but rest assured that we in AstraZeneca are working on this very thoughtfully.

Thanks so much. The next question comes from Jay Olson from Oppenheimer. Please go ahead.

Oh, hey, congrats on all the progress. and thanks for taking the question. Can you talk about your launch preparation for Olazarsen in FCS and how should we expect the launch uptake and eventual opportunity in FCS and also the early access program, how many patients you have, and will those patients switch over to commercial product soon after approval? Thank you.

Yeah, thanks for your question. We're really pleased with the progress we're making and have continued to make. Obviously, our preparation started a couple of years ago with the medical affairs team. And subsequent to that, we built out all the commercial functions that you would expect, whether that's marketing, market access, patient support that Kyle referenced. We're trying to build out industry-leading support there for our patients. And to bring you right up to date, we've now started hiring and training our field teams ready to engage with customers. So the build has gone very well and is certainly on track, aligned with our regulatory progress, which with breakthrough designation has been at this point very timely. And that, we think, sets us up for a positive launch. Obviously, to your question specifically about the expanded access program, we've got patients, let's be honest, before that who've been in our pivotal registration studies that are obviously patients that at launch we hope to provide the opportunity to move on to commercial drug. And the EAP is now... in the hands of our medical team, and they're talking to customers today, and patients are progressing through the administration or the administrative side of getting access to OLSRs and through that program. So all in all, we are doing a lot of work, as you can imagine, but very much on track to be ready to launch just as soon as the FDA provides approval, fingers crossed.

Jay, next question, please.

The next question comes from Mike Holt from Morgan Stanley. Please go ahead.

Hey, guys. Thanks for taking the question. Maybe just one on the neurology pipeline with Angelman sort of emerging as your lead program. Can you maybe highlight what you view as the next key opportunity there and if there's any potential read-through from what you learned in Angelman's? Thanks.

Yeah, sure, happy to. Thanks for your question. So certainly we are delighted to have Angelman as service kind of the linchpin of the neuroscience portfolio. But it is a very rich portfolio following the Angelman Phase III program. Just to name a few that are most advanced currently, certainly the Zilver-Nersen, which is now fully enrolled in its pivotal study, as we recently announced, is the next molecule that we're super excited about. It's an ultra-rare disease. It fits very well with our neurology portfolio. The study is progressing well. There's great feedback from sites and investigators on kind of the quality of the study conduct. And behind Sogan-Narson, of course, we are delighted to have our FOSS-ALS program progressing well, our Prion program really making great strides in first-in-human experiments that we're now conducting. So we're looking forward to sharing lots of data with you over the coming months and certainly years in that rich area of research and development for us.

Our whole Neurology Pipeline, thanks Eugene, is positioned to grow and expand in addition to the programs that are in the clinic today. We expect to start two additional wholly-owned neurology programs by the end of this year and more next year for both rare as well as larger indications, more highly prevalent indications. I also want to highlight the great progress we're making to extend our leadership technologically in neurology. Our most advanced backbone chemistry, MSPA, is expected to enter clinical development and seek for a CNS indication later this year, which is focused on reducing dose frequency very meaningfully. We're also making great progress in traversing the blood-brain barrier, using subcutaneous or intravenous infrequent administration. And we're looking forward to maybe our first candidates overcoming the BBB early 2025, and we're looking forward to talking about that as well. So CNS is here now, and we're leading the space, and we continue to expect to extend our leadership position in CNS going forward. Thanks, Mike. Next question, please.

The next question comes from Gary Nachman from Raymond James. Please go ahead.

Great. Thanks, guys. For Donnie, when you submit the NDA, what indication will you be looking for on the label? And are you optimistic the switch data will actually be included on the label, which will be so important for these HAE patients? Any chance you could get a priority review, or is it likely a standard review? And when will you start building out that commercial team? How much could you fully leverage what you're doing currently with Olazarsen?

Thanks, Gary. Eugene will take the first couple of questions, and then Jonathan could touch on the build-out of the commercial team.

Yeah, with regard to the indication, of course, we're seeking a broad indication for prophylaxis of attacks in hereditary angioedema, and we're pretty comfortable with how things are progressing. Obviously, it is to be determined what the final label looks like in the indication statement. We are... Sorry, what was the second part of the sub-question? We expect to have switch data. The switch data, that's right. And yeah, along the same line, again, it's really early to speculate on what the final label is. We will do our best to, we believe our program, our pivotal program is very comprehensive and we also believe that the data that we collected in the switch populations is important for physicians to be aware of. So we'll make sure that this Data is shared broadly, whether it's publication or it ends up in the label. We can't really speculate today.

Yeah, and I'll just touch on that a little bit more, Gary. You know, the switch data is very important, we believe, from a safety standpoint, which we think bodes very well for including it in the label. I mean, these patients switch all the time, right? And actually having data that informs physicians on how to safely switch patients such that they avoid getting a gap in their protection against HAE attacks is going to be very important. And we think that will, and of course the FDA is focused on safety and protection against, you know, disease progression. So we think that that bodes very well for us to get it in the label. But as Eugene said, it's, you know, it's risky to get ahead of regulators on what a label will look like. But we think that we have a pretty good shot at that. Jonathan, how's the launch prep going?

Launch prep is going well. As you can imagine, this is coming hot on the heels of the potential Olisarsen launch that we talked about. But the launch prep on the commercial side for Donnie is well advanced. There are a lot of capabilities that we've built for Olisarsen that we can... Leverage for Donnie, whether that's the medical affairs function, first and foremost, that's been well-established for all of us, and that's now leaning in in the HAE space. We've got brand teams, access teams building out the value dossiers. Patient services is also well-advanced and ready to support patients in the HAE space. and Omnichannel as well is a capability that we feel very confident that we've built well at Ionis now and is a capability that's very applicable both to the FCS launch but also the HAE launch. So there's a lot of synergy there on the commercial side, albeit a lot of that is being appropriately built. to best serve each of those launches and the markets and the challenges that they present.

We're also very pleased with the progress Atsuka is making for submission and preparing for launch in Europe. So stay tuned for that as well. Next question, please.

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

Good morning, thanks for taking, or good afternoon, thanks for taking my question. Could you just speak to the work you're doing here on oligos with next generation backbones and the other modalities you're looking at and when these programs might enter the clinic? Thank you.

Sure. So, as Brett mentioned earlier, the first compound that incorporates our MSPA backbone We'll enter the clinic for a neurology indication later this year. And the objectives there are to try and extend the dosing interval with the enhanced stability of that backbone, which it provides. And we'll see how it performs. We also have a compound in development with a partner, AstraZeneca, that uses our bicycle program to deliver a drug to the cardiac muscle, in this case. is moving forward, and we look to start IND talks this year. And that's progressing nicely, and that's an siRNA coupled to the Bi-Cycle program. And we also have an internal siRNA program for a following indication for a liver target that we anticipate getting headed towards development this year. And then beyond that, we've been making some really nice progress in our blood-brain work, both with our Bi-Cycle collaboration And also the vectors collaboration, which we announced earlier this year very late last year. And we had some scientists from the team present some of that data at a recent times meeting with early most data in vectors collaboration. It looks fantastic and will continue to provide some more data updates and hopefully If everything goes according to plan, we can get some molecules that cross the blood-brain barrier program for our whole neuralogy pipeline into development early next year.

Thanks, Eric. And I'll just add to that. So, I mean, you can expect to see in the not-too-distant future new programs advancing towards development focused on neuromuscular diseases, skeletal muscle specifically, to further extend our leadership in neurology. And also, we're pleased with the progress we're making with metagenomy on gene editing. We have several programs there that are advancing very nicely preclinically. And I think next year could be a very informative year, very interesting year in our gene editing program with respect to new information coming out as to what our strategy is and what our first molecules will be. So stay tuned for that. We're making great progress across the board in diversifying and expanding our technological capabilities. And with that, I think we have time for one more question.

The next question comes from Costas Bilioris from BMO Capital Markets. Please go ahead.

Hello. Thanks for taking our question and congrats on the progress. Can you talk a little bit about the cardio transform and role population and specifically the differences between the geographies and the follow-up from the originally enrolled population and the population who were enrolled after the changes you made to the statistical design, and if you expect any impact from the differences between these two populations. Thank you.

Thanks, Kostas. So we, of course, haven't shared the demographics for our CardioTransforms study yet. We look forward to doing that in the future. We really are pleased with the enrollment in the study, and as we've said, we have a nice balance in this big study, the largest study we're conducting to cure cardiomyopathy. Nice balance between monotherapy patients as well as patients on combination treatment. We're also very pleased with, you know, very small percentages of drop-ins into families in the study. It's going exactly as planned. We're pleased with the percentages of patients we have with New York Health Class 1, 2, and 3 in the study. And everything we've seen that has come out in this space with respect to other people's patient demographics supports our decision to expand our study to take into account for a patient population that's been diagnosed much earlier in their disease. We couldn't be more pleased with the way the study is going, including our patient demographics. So thanks for the question, Cospis, and I think it's time to wrap things up. I really want to thank everybody who joined us today for your participation and your questions. We're very proud of everything we've accomplished this past quarter, the first half of this year, and we're planning to build on this momentum. to achieve even greater successes in the second half of this year. And we're very much looking forward to providing updates on the progress we continue to make this year as well as into next year. So thank you very much, everybody, and have a great day.

The conference is now concluded. Thank you for attending today's presentation. You may now disconnect. Goodbye.