Ionis Pharmaceuticals Inc Q2 FY2023 Earnings Call

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. 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's accelerated approval of QALSODY brings hope and a breakthrough treatment to people with SOD1-ALS and their families. 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 on 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. 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 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. 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.

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 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. 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 in these patients previously treated with gene therapy. These data add to the extensive body of evidence demonstrating SPINRAZA's benefit for SMA patients. 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 needs 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. 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. 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. 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.

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. 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. 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. 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.

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 triglycerides caused by genetically defined FCS and those with severely elevated triglycerides where there's no known genetic cause of the disease. These are patients who 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 elevated triglycerides, but our focus is on getting patients out of harm's way. We've done a lot of research. We're preparing the market, and we're ready to launch olezarsen for FCS and SHTG. I'd like to just maybe have Onaiza expand on Myles' question.

Sure. Myles, yes, as we've spoken before, we see a great unmet need for patients with 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 as possible to get them out of harm's way for the risks that Brett just highlighted, particularly acute pancreatitis risk. So we really look forward to getting the drug on the market for that, both for the rare disease genetically defined as FCS and ultimately, into the severe hypertriglyceridemia space.

And second question is just on the week 85 data for ATTR polyneuropathy. I understand that there were 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. 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? Does AZN's presence potentially allow eplontersen to be the first approved in 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 and 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, allowing patients to take control of their disease and take the medication wherever they are without relying on going into the healthcare provider's office. The efficacy combined with this self-administration profile gives us a really strong way to enter 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 identified, diagnosed, and treated for polyneuropathy, including mixed phenotype. Our ability to identify these patients and reach out to offices outside of the centers of excellence where they're presenting is going to be really important. Those are some of the strategies we're working on with AstraZeneca.

As you know, Robert, we're very pleased that AstraZeneca also enthusiastically licensed Latin America rights for eplontersen for all indications, including neuropathy as well as cardiomyopathy. It demonstrates their enthusiasm for eplontersen, our partnership, and their enthusiasm for the data 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 do you expect this follow-on molecule to enter the clinic after pelacarsen?

Sure, Kostas. Thanks. We are very excited that Novartis came to us with a proposal to work on a follow-on strategy for pelacarsen. Let me just say right from the outset that 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 and confidence in this opportunity for Lp(a) cardiovascular disease. They expect pelacarsen to become the first on the market with substantial global reach. The follow-on form is designed to extend that reach and is intended to reach more patients. Novartis recognizes our expanded and vast capabilities in RNA-targeted therapeutics. We are bringing our full arsenal to the table, and they appreciate that - that's why they partnered with us on this. This 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. It's tough to beat the efficacy that pelacarsen has demonstrated in Phase 2, with 98% to 99% of patients with cardiovascular disease due to high Lp(a). We were able to get their Lp(a) levels down below the threshold associated with cardiovascular disease. So really, we want to maintain that efficacy and reproduce it in 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 or even annual dosing while utilizing a mixture of our technology capabilities, and that is the focus with Novartis. We'll 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 years behind is the follow-on molecule compared to pelacarsen?

Yes. We haven't stated or discussed that publicly, Kostas, regarding what the timelines are. Obviously, we're still in the research phase, so it would be a little risky to 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 how that impacts your thinking in terms of the CARDIO-TTRansform study? And then, is there a potential for you to stop the study earlier, or is the thinking still to go through the full results there?

Sure, Mike. So BridgeBio data is encouraging, and it's good to see that another option is being developed for TTR cardiomyopathy. However, we need much more data. We are looking forward to seeing more detailed data, which they are planning to present later this year. The demographics of their studies support our trial design and reinforce our confidence in our expanded trial design. We have now completed enrollment, a very good balance between tafamidis patients and naive patients, which supports the demographics we're looking for. CV mortality and overall mortality are very important in this population. I’ll ask Onaiza to expand on the importance of this from both a physician standpoint and from a payer perspective.

Yes. As you know, we believe eplontersen will create a landmark trial that will generate significant data to empower physicians in treating these patients. This means anything from New York Heart Association Class I, II, and III, so mild to severe hereditary and wild-type naive to silenced or therapy-naive cardiomyopathy therapy cases. Our endpoints are well defined. We have done extensive work in recent times to understand how physicians differentiate between mortality versus cardiovascular death. That is a more meaningful cardiovascular endpoint, along with the richness of cardiovascular hospitalizations. Our secondary endpoints, including the 6-minute walk and other measures, will be important as well. Overall, we're very excited about our data set and trial design and are looking forward to the output in the upcoming times.

Michael, there are no changes to our plans regarding the completion of the study based on any recently emerging data. We have confidence in our trial design, and several factors will influence when we announce the study results. The first factor was to complete enrollment, which we have successfully achieved. We have the intended demographics in the study to ensure the best possible data set. We will also take into account the evolving competitive landscape and any new data that may affect the timing of the results. Currently, there is no change in the expected timing for when our CARDIO-TTRansform study will conclude.

Let me just address one other question, which was on payer reimbursement that I missed. To ensure that we've done a fair amount of testing with payers on the trial design, if we show cardiovascular risk reduction on top of tafamidis, there is clinical significance for physicians, and they are not going to obstruct reimbursement for a combination product. The data will verify the medication's effectiveness for patients who are at high risk, which is a terminal disease; we aim to ensure they receive the best treatment and care available.

The next question comes from Yanan Zhu with Wells Fargo.

I was wondering if you could share your thoughts on some recent developments in the Angelman syndrome field, where Roche decided not to move their ASO program into the next stage of clinical development. I wonder if you could provide any updates from your Angelman syndrome clinical study that is ongoing. Any thoughts around the programs or product candidates' efficacy and safety profile? Additionally, if you could talk about the ATXN2 program and its ongoing study, that would be great. I think the data are expected around the same time as the Angelman syndrome program.

Thank you for the question. The Ionis Biogen Angelman program is progressing well. We are currently working on the Phase 1/2 study and continue to recruit patients for this trial. We aim to have data available around mid-year next year. Everything is going smoothly so far. We haven't shared the reasons behind Roche's decision to halt their study, but it's clear that safety wasn't the issue. They mentioned they did not meet their minimum target product profile or criteria, which seems to pertain to efficacy. We cannot speculate much on that matter. Our focus is on our program, and we expect to have results from that study next year. We might provide an update on the status of the program later this year. There is an ongoing invitation to an Angelman meeting called Fast, where we typically secure a speaking slot, and we plan to attend this year as well, although we do not expect to present new data at that meeting yet. As for ATXN2, this is another one of our ALS drugs. This drug is particularly exciting because it's targeting sporadic ALS, meaning there’s no known genetic cause of ALS. The study is enrolling various dose cohorts, with the highest dose cohort having expanded its patient enrollment to build a robust data set that can inform a potential Phase 3 study if the study is successful. That data is also due to read out around mid-next year.

The next question comes from David Lebowitz with Citi.

Given the HA data is expected earlier next year, could you discuss your plans for launching the therapy and persuading physicians to adopt a new treatment approach, assuming the Phase 2 data is replicated?

Onaiza?

David, yes, we're very excited about our preparations for donidalorsen's launch, anticipating the Phase 3 data next year. We are approaching the market in several ways. As you know, this will primarily be a switch market, so we have a switch study in parallel with our Phase 3, providing valuable data to instill confidence in physicians to switch patients effectively. We hope to demonstrate that we will not have breakthrough attacks during the switch process due to our rapid onset. In addition, we see current shifting behavior within the market, with Orladeyo leading to more switches from Takhzyro, the standard of care. So we’re aware that patients are willing to explore new treatments, seek zero attack rates, and value convenience—qualities that we offer.

And one additional question. Moving towards a potential eplontersen launch. Do you have any thoughts on how market growth has shifted since the subcutaneous treatment was launched by Alnylam? How might that apply to eplontersen and your launch thinking going forward?

Yes. Looking at the uptick for AMVUTTRA in the marketplace, they had a good start. However, it's important to note that they’re working through many ONPATTRO switches right now, so we have to understand how this might impact overall growth. This remains an underpenetrated marketplace, with numerous patients still unidentified, undiagnosed, or untreated. I think Alnylam is successfully transitioning most of their patients to their next-generation silencer. We have significant work ahead to identify and transition new patients to silencer therapy overall within this marketplace. While competition is beneficial for patients when there are multiple players, we look forward to beginning our efforts in January. We have a very exciting product profile, both in efficacy and in our self-administration model, which we believe will resonate 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 Geographic Atrophy. Is there any update on your view of the geographic atrophy space and potential opportunity for a therapy targeting complement factor B? Given some of the recent safety and regulatory updates in the GA space in recent weeks, could you frame what you're looking for in the Phase II readout next year to warrant further investment in that space?

Thanks, Allison. Yes, our partner, Roche, and we are very enthusiastic about our GA study, the Factor B-LRx geographic atrophy study GOLDEN. We're pleased that there’s now a clear benchmark to get drugs approved for GA; this helps set a path forward for all drugs, including ours. We are pleased with our drug and profile so far. The GOLDEN study is a large study, around 300 patients, with two dosing cohorts where patients are treated for about 15 months. So it's a good study, and we are looking for primary changes in geographic atrophy area for its efficacy. This is a proof-of-concept study due to read out next year, and we believe that targeting Factor B in the alternative pathway is an effective approach for GA. We think our overall safety and tolerability profile will be significant advantages as they don’t require invasive admin methods.

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. 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, and the average BMI was overweight. 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? What percent of patients with triglycerides above 500, would you say demographically wouldn't actually qualify for one of those drugs on label?

Onaiza, do you want to take that?

Yes. Hi, Paul. There’s been a lot of informative data for the GLP-1s recently. A couple of critical points: First, they're not indicated for triglyceride lowering. If you analyze their TG-lowering data, it correlates with the current standard of care. Therefore, they don't achieve the high levels of triglyceride reduction that the APOC3 target can deliver. Secondly, it’s a crucial reminder—the GLP-1s have warnings about their use in patients with a history of acute pancreatitis. In patients with triglyceride levels above 500, we have many individuals at risk for acute pancreatitis, making our drug very favorable for that patient population. Hence, we don’t expect them to be direct or indirect competitors.

The next question comes from Yaron Werber with Cowen.

Just on SPINRAZA, the response by the interim results are definitely encouraging. Can you give us a sense, are these potentially label-enabling? How do you think about this given your broad label? Do you need something like label enabling? Or is this just a standard of care change? Also, in terms of ATXN2 and ATXN3 programs. I know you touched a bit on ALS. Could you give a sense of the next timing and expectations for the data? I know fast program for ALS is pivotal in 2025 or the other two?

Yaron, the interim results from RESPOND—patients performing poorly on gene therapy transitioned to SPINRAZA have done very well, showing significant improvement in muscle strength and neuromuscular function. While there have been anecdotes about this for some time, having a linked analysis by Biogen to solidify those feelings is helpful. We see these studies as more beneficial for publications; the DEVOTE study has potential for label expansion. DEVOTE will be exploring higher doses of SPINRAZA to demonstrate enhanced efficacy in SMA patients across the spectrum. I apologize for missing the ATXN2 question, Yaron. The ATXN2 is ongoing, enrolling at dose cohorts. The highest dose cohort is expanding to include more patients to strengthen the data set aimed toward a potential Phase 3 study. That data is also expected mid-next year, around mid-year.

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

Following up on the previous question, Brett may have touched on this, but has in-licensed the next-generation molecule been influenced by the blinded event trends observed in the cardiovascular outcome trial for pelacarsen? Or is this primarily about life cycle management? Eugene, if I could ask you about TTR cardiomyopathy, could you provide insights on the statistical methodology you are using for the Phase 3 trial? Are you employing the Finkelstein-Schoenfeld method like BridgeBio and Pfizer, or are you utilizing the Andersen-Gill method, similar to Alnylam? Additionally, could you explain the reasoning behind your choice of one method over the other?

Sure, Luca. Before turning it over to Eugene to address the statistical plan, I’ll clarify that the follow-on program for Lp(a) is entirely about lifecycle management. The pelacarsen Phase 3 study is progressing very well, on track for data readout in 2025, and it has nothing to do with any specific data from that study. We’re focused on our own programs and prefer not to comment on our competitors, including the AGT space. However, we plan to present AGT data in the second half of this year at a medical meeting, and we believe that a therapy for hypertension and heart failure will best reach patients through a partner on a global scale.

Sure. To clarify, the methodology the CARDIO-TTRansform study will utilize for our analysis of the primary endpoint follows the Andersen-Gill method. This approach is widely recognized and has been effectively employed in various outcome studies. It allows for the evaluation of cardiovascular mortality along with recurrent events captured in our SAP.

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

First question is for eplontersen. If you get it approved later this year for neuropathy, do you anticipate the drug will also be used for treating mixed type patients? Then I have another follow-up.

Absolutely, we do, provided they have detectable polyneuropathy. This drug would be suitable for both pure PN patients and mixed phenotype patients.

Okay. And my other question is for olezarsen. In terms of the SHTG enrollment, can you provide any color in terms of the status? Do you anticipate completing enrollment later this year?

Enrollment is going very, very well. We expect to complete it very late this year or very early next year; that's the guidance we've been providing.

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 that would be important from a physician or a payer perspective?

You want to take that, Eugene? The primary endpoint is triglyceride lowering compared to placebo, which is important, and we expect substantial lowering in this patient population to drive market demand. However, Eugene, if you want to detail on additional endpoints we might consider.

Sure. Beyond the primary endpoint, we will evaluate various responder analyses, including the proportions of patients achieving clinically meaningful thresholds—for instance, reductions of 80 or above, with classic thresholds being 400 or 500. Achieving these decreases will significantly impact their risk for acute pancreatitis events. Additionally, we'll look at quality-of-life measures to see if patients feel improved and can function better, which is also a critical aspect.

We’ve conducted solid market understanding on this as well. We feel confident that for this rare disease FCS patient population, they currently have no tools at their disposal. Their first-line treatment is a restrictive diet, which isn’t sustainable. Thus, there’s a massive unmet need for a safe and efficacious option. We believe that will heavily drive uptake for olezarsen, as lipidologists and patients are eagerly waiting for a new solution.

Thank you. Thanks, everybody, for joining us today for today's call. We're well on our way and are planning to continue our strong momentum in the second half of this year by delivering across all aspects of our business—commercial, pipeline, technology, and more. I also want to highlight that we're looking forward to providing a comprehensive update on all the progress we're making at our Investor Day on October 4. We hope many of you can join us 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.