Ionis Pharmaceuticals Inc Q2 FY2022 Earnings Call

Good morning, and welcome to the Ionis Pharmaceuticals Second Quarter 2022 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Julie Tepper, Investor Relations, to lead off the call. Please begin.

Thank you, Betsy. 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 have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Doug Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development. And joining us for the Q&A portion of the call are Eric Swayze, Executive Vice President of Research; Eugene Schneider, Chief Clinical Development Officer; and Onaiza Cadoret, Chief Global Product Strategy and Operations Officer. I would like to draw your attention to slide three, which contains our forward-looking 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. With that, I'll turn the call over to Brett.

Thanks, Julie. Good morning, everyone, and thanks for joining us today. In the first half of this year, we moved significantly closer to delivering an abundance of transformational medicines to the market. The first half was highlighted by the positive results from the Phase III NEURO-TTRansform study of eplontersen in patients with TTR polyneuropathy. Eplontersen met the co-primary and key secondary endpoints in NEURO-TTRansform, demonstrating highly statistically significant and clinically meaningful improvements in neuropathy impairment and quality of life. Based on these positive results, we're well on our way towards filing an NDA later this year. Simultaneously, we and our partner, AstraZeneca, are advancing our global go-to-market preparations to launch eplontersen for the treatment of ATTR polyneuropathy. We're also continuing to advance our ongoing CARDIO-TTRansform Phase III study, which we expect will enable us to move into a much larger market for patients with ATTR cardiomyopathy. AstraZeneca is quite confident that eplontersen is well positioned to successfully compete in this space. We're also pleased that tofersen is now under priority review with the FDA for the treatment of SOD-1 ALS. If approved, tofersen could become the first disease-modifying therapy for a genetic cause of ALS. The PDUFA date is January 25, 2023, and tofersen has the potential to be our next product on the market with eplontersen following shortly behind. Additionally, we continue to advance our late-stage pipeline, including completing enrollment in two of our Phase III studies. We have now fully enrolled the BALANCE study of olezarsen in patients with familial chylomicronemia syndrome, or FCS, making this study our next potential Phase III data readout planned for next year. Novartis also achieved full enrollment of more than 8,000 patients in the Lp(a) HORIZON cardiovascular outcome study of pelacarsen, further solidifying our first-mover advantage for this important medicine. Beyond the positive data we reported from our late-stage pipeline, we also reported positive data from six of our mid-stage programs so far this year. Based on positive Phase II study results, our partners are planning to advance two new medicines into Phase III studies next year. As a result, we expect to expand our rich Phase III pipeline to at least eight medicines across 10 different indications. In addition to advancing our pipeline, we're also making excellent progress in our go-to-market activities for our near-term product opportunities in inotersen, olezarsen, and donidalorsen. With the potential to add two new medicines to our commercial portfolio next year, along with the steady cadence of Phase III data readouts in the near and midterm, we're looking forward to bringing numerous transformational medicines to the market. All of this positions us well to maximize value for patients and shareholders. With that, I'll turn the call over to Beth to review our second-quarter financial results. Then Richard will discuss our recent key data readouts, pipeline updates, and will preview upcoming catalysts for the rest of the year. After Richard, I'll wrap up our prepared remarks before taking your questions. Now, over to Beth.

Thank you, Brett. In addition to achieving key pipeline milestones, we delivered strong financial results, earning revenues of $134 million and $276 million for the second quarter and first half of this year, respectively. Our revenues increased in the quarter and year-to-date compared to the same period last year, driven by revenue from numerous diverse sources, with just over half from our marketed products and the balance from our partnered programs. We continue to invest in advancing our rich late-stage pipeline and in our commercial readiness activity. Our operating expenses and net loss for the quarter and year-to-date reflect these important investments. Notably, we maintained our cash and investments essentially flat from Q1 to Q2 at $2 billion. SPINRAZA's global sales were $431 million for the second quarter and $904 million year-to-date. As a result, we earned $60 million and $113 million in royalty revenue for the corresponding periods. In the US, SPINRAZA sales stabilized on a year-to-date basis compared to last year. Additionally, we remain encouraged that in the US, discontinuations decreased during the quarter, a positive trend we have seen consistently for several quarters. We anticipate SPINRAZA could return to growth as the dynamics seen in the US play out across other geographies. Additionally, Biogen is executing on a robust life cycle management program that we and Biogen believe will further support SPINRAZA's return to growth. The RESPOND and ASCEND studies are evaluating SPINRAZA's potential to benefit patients who were previously treated with competitive products. The DEVOTE study, currently in the randomization phase, is evaluating the potential of higher dose SPINRAZA to provide even greater efficacy. If the data are positive, they could support filing for approval. All three of these studies are progressing well. Moreover, the future of our SMA franchise includes the follow-on medicine ION306. Based on preclinical data, ION306 may offer the potential to substantially extend dosing intervals. We earned R&D revenue of $56 million in the second quarter and $126 million year-to-date, both of which increased compared to the same period last year. We generated R&D revenue from several different partners for advancing multiple programs, demonstrating a key element of our financial strength. We earned $57 million in the first half of this year from Biogen for advancing neurological disease programs under our strategic collaboration. Additionally, we earned $37 million from AstraZeneca for their portion of tofersen development costs, and $22 million from Roche for advancing Ionis FB-L in development. In line with our goal to invest in our pipeline and commercial capabilities, our non-GAAP operating expenses increased in the second quarter and year-to-date compared to last year. The increase was driven by higher R&D expenses from advancing the six Phase III studies we are currently conducting, with eplontersen comprising our largest investment. Our R&D expenses also included increased spending for CMC and medical affairs activities to support our near-term opportunities. SG&A expenses decreased year-over-year for both periods, largely due to substantial savings from the Akcea integration and Sobi transaction last year. We are redeploying some of those savings as we invest in our go-to-market preparation for eplontersen, olezarsen, and donidalorsen. Our results for the first half of this year keep us on track to meet our 2022 financial guidance. As we look forward to the rest of the year, we anticipate our Q3 revenues to be similar to Q2. In fact, we have already earned nearly $45 million from Roche and Biogen this quarter. As our Phase III studies continue to progress, we expect our R&D expenses to increase between 25% and 30% this year compared to last year, consistent with our guidance. We project our SG&A expenses to be in line with last year, even while we increased our investments in preparing to bring our near-term opportunities to the market. With $2 billion in cash and investments at the end of June, together with the revenue and cash we generate from various diverse sources, we continue to have a strong financial foundation. By investing in our strategic priorities, including advancing our goal to deliver a steady stream of new medicines to the market, we are poised to deliver significant future growth. With that, I'll turn the call over to Richard.

Well, thank you, Beth. Our mid and late-stage pipeline continues to perform extremely well with eight positive data readouts so far this year. These achievements position us to add to our commercial products and expand our rich Phase III pipeline in the near term. Over the next few minutes, I will review the key highlights from these recent pipeline achievements and then preview the key catalysts we expect in the second half of this year. The most important event in the first half of this year was the positive data from the Phase III NEURO-TTRansform study of eplontersen in patients with ATTR polyneuropathy. As we reported in the prespecified interim analysis of 35 weeks of treatment, eplontersen met its co-primary endpoints of serum TTR concentration in mNIS+7, as well as the key secondary endpoints, Norfolk quality of life. Eplontersen demonstrated highly statistically significant and clinically meaningful changes from baseline in each of these endpoints compared to historical placebo. Importantly, a substantial number of eplontersen-treated patients showed improvement in neuropathy impairment and quality of life in the study. We're looking forward to presenting data from the interim analysis at the International Symposium on Amyloidosis or ISA in September. With these data in hand, we and AstraZeneca are finalizing the NDA and planning to file for regulatory approval for TTR polyneuropathy in the US later this year. Additionally, our CARDIO-TTRansform study, the largest and longest study to-date for patients with ATTR cardiomyopathy, also continues to progress well. Our broad olezarsen development program remains the lead medicine targeting APOCIII in clinical development to treat patients at risk for effects of triglyceride-driven disease. We recently achieved full enrollment in the BALANCE FCS study, which is on track for data next year, making this our next planned Phase 3 data readout. Our core sHTG or severe hypertriglyceridemia study, for the much larger indication with more than three million patients in the US alone, remains on track for data in 2024. Additionally, we expect to initiate a second confirmatory pivotal study of olezarsen called CORE 2 later this year, also projected to read out in 2024. Our donidalorsen OASIS Phase 3 program in patients with hereditary angioedema also continues to progress well and remains on track for data in 2024. We recently initiated OASIS+ study that includes a switch cohort for HAE patients, previously treated with other prophylactic therapies. Coming up later this year, we plan to report new longer-term data from the Phase 2 open-label extension study in HAE patients treated for one year to demonstrate long-term durable efficacy. With the differentiated efficacy, safety, dosing, and administration profile, we believe donidalorsen has the potential to be a best-in-class treatment in the attractive and growing HAE market. We are also very pleased that the NDA for tofersen is now under priority review with the FDA. This expedited review underscores the significant unmet need of patients with SOD1-ALS, and it also emphasizes the tremendous value tofersen could deliver to patients, as potentially the first disease-modifying treatment approved for a genetic cause of ALS. The filing includes new integrated data from the Phase 3 VALOR study and ongoing OLE study, which shows tofersen significantly slowed decline across multiple measures of ALS disease progression and importantly, led to robust and sustained reductions in neurofilament, a marker for neurodegeneration. With the January 25, 2023, PDUFA date, tofersen is on track to be our next product to enter the market. Additionally, we believe these new encouraging data also support the promise of our leading neurology pipeline with 11 medicines in development today to treat rare and broad neurological diseases. Our leading cardiovascular franchise comprised of medicines in development to treat major cardiovascular risk factors, also continues to progress nicely. Importantly, the safety and tolerability seen across our LICA pipeline enables us to address these broad indications. An excellent example of this is pelacarsen. Novartis recently completed enrollment in the Lp(a) HORIZON cardiovascular outcome study, enrolling more than 8,000 patients. Pelacarsen has the potential to be the first medicine on the market to address cardiovascular risk, driven by elevated LP(a). Elevated LP(a) cannot be adequately addressed with currently available treatments nor with lifestyle changes such as diet and exercise. As a result, with over 8 million people estimated to be affected worldwide who also have cardiovascular disease, pelacarsen represents a multibillion dollar opportunity. Pelacarsen is on track for data and a potential regulatory filing in 2025. We also recently reported several positive mid-stage data readouts, including from our Factor XI program, our HBV program, and for IONIS-FB-LRx in IgA nephropathy. As a result of these positive data readouts, our Phase III pipeline is poised to expand to at least eight medicines addressing 10 indications. Today, we anticipate a steady cadence of Phase III data readouts and have started this year, expanding to 2023, 2024, and 2025. As we expand our Phase III pipeline, we'll be extending the steady flow of Phase III data readouts beyond 2025. We are looking forward to building on the substantial positive pipeline progress we have delivered so far this year with additional key data readouts and program updates. In addition to eplontersen, our second half highlights include Phase IIb data from IONIS-AGT-LRx, our medicine for treatment-resistant hypertension, OLE data from donidalorsen intended to demonstrate long-term durability in HAE patients, and monotherapy data from Syndelirsen, our medicine to treat acromegaly. With that, I'll turn the call back over to Brett to close this portion of the call.

Thank you, Richard. As you've heard this morning, it's been a great year so far for Ionis. We made great progress in advancing our key priorities to grow our commercial pipeline and deliver abundant new transformational medicines to the market. We're looking forward to potentially adding eplontersen and tofersen to our commercial portfolio as early as next year. We continue to make excellent progress in advancing our other near-term opportunities, olezarsen and donidalorsen, and with multiple positive mid-stage data readouts, we're well-positioned to expand our Phase III pipeline to these eight medicines across 10 indications. In addition to all of our pipeline advances, we've been making excellent progress in expanding and diversifying our technology as well. Specifically, we are focused on advancing new chemistries, including expanding our LICA platform beyond the liver. I look forward to providing updates on these exciting advances in the future. In the second half of this year, we expect to continue our positive momentum by delivering additional key milestones highlighted by the NDA filing for eplontersen. Importantly, we have the resources needed to continue executing on our priorities to drive substantial growth and value for all stakeholders. With that, I'll now open the call up for questions. Operator, can we start the question session?

We will now begin the question-and-answer session. The first question today comes from Yanan Zhu with Wells Fargo. Please go ahead.

Great. Thanks for taking our questions and congratulations on a very productive quarter. So on eplontersen in TTR polyneuropathy, what do you hope to show at the upcoming presentation at the ISA meeting? And as we try to compare the data with existing data from approved TTR silencers, what should we focus on to get a sense of the competitiveness of eplontersen? Would it be the change in mNIS+7 from baseline, Norfolk QoL, or the proportion of patients with improvement? Any color would be helpful. Thank you.

Thank you for the question, Yanan. We are very pleased with the overall results for eplontersen. The efficacy, safety, tolerability, and target engagement have exceeded our expectations. As mentioned earlier, we are on track to submit the NDA for potential approval and prepare for the launch of eplontersen for TTR polyneuropathy next year. We look forward to sharing results from our 35-week interim analysis data at the ISA, including insights on the safety and tolerability profile, which are very promising. We will also present efficacy data on TTR lowering. The primary endpoint was co-primary at week 35, with mNIS+7 and TTR lowering, and the key secondary endpoint was Norfolk QoL-DN. In addition to safety and tolerability, we are excited to share efficacy results. TTR amyloidosis is a significant indication, and we believe comparisons with both primary and secondary endpoints, as well as exploratory endpoints for neuropathy, will be important. Furthermore, the cardiomyopathy data will be crucial for eplontersen, as we are conducting the most comprehensive trial for TTR cardiomyopathy, and we believe this will set us apart in a large market. We appreciate your interest and look forward to the presentation at ISA.

Got it. If I have a very quick follow-up on cardiomyopathy, could you share your thoughts on the top-line data and whether that changes your thinking around the powering of your cardiomyopathy study, including the recent upsizing of the study size? Thank you.

Thank you, Yanan. That's a great follow-up. We've been working in this area for nearly a decade, developing therapies for TTR amyloidosis, and we're very pleased that our new data indicates silencers could be quite effective in the cardiomyopathy disease indication. We're also very satisfied with the trial design for our cardio transform study, which is robust. We will generate data from several important patient subpopulations, including eplontersen compared to naive patients and in conjunction with tafamidis, among others. We anticipate a rich and robust data set from the cardiomyopathy study, which is a cardiovascular outcome trial. The outcome data will be crucial for facilitating uptake in this attractive market. We have not seen any data that would lead us to believe our trial design is incorrect at this stage. The study is currently enrolling well, and we are eager to reach its conclusion as planned. We are also looking forward to future data from APOLLO-B, which will provide further insights. However, for now, we do not plan to alter our trial design based on the new data released today.

Great. Thanks for all the color.

The next question comes from Paul Matteis with Stifel. Please go ahead.

Hey. This is Kathy on for Paul. Thanks so much for taking our question. I had a quick question on the tofersen recent NDA filing acceptance. I guess, would you consider filing any of your other neuro or ALS programs with NFL as a surrogate endpoint? So I guess, in other words, do you see any read-through on this acceptance onto any of your other neuro programs? Thanks so much.

Sure. I'm going to ask Richard to take a stab at that one, Kathy?

Yeah. Of course, the tofersen package is an important one, and there are many learnings from that program. One of those is that functional endpoints don't change as rapidly as some biomarkers. We can see target engagement with the target, and we can see that in a very short period of time. Following that, we saw the neurofilament decrease, very strong, and robust results. Seeing it again with the placebo patients going on to tofersen brings that whole data to light that we're having an impact on neurodegeneration through this potential biomarker. Will we be looking at the potential of filing on a biomarker alone? I think biomarker alone is probably not the play, but rather, looking at the biomarker as a good early surrogate for what can happen as we play it out. We have a robust study design with interim analysis built-in that doesn't force us to be static in the way that we look at the endpoints. We’ll be able to see when we're having good movement in functional as well as neurofilament being part of the design.

Okay. Great. Thank you.

The next question comes from Jessica Fye with JPMorgan. Please go ahead.

Hey, guys. Good morning. Thanks for taking my question. Maybe sticking with TTR and following up on the APOLLO-B question, recognizing all the details are not yet. Can you just remind me whether you plan to take an interim in cardio transform? And maybe talk about whether or how you see the APOLLO-B results affecting that decision if it is sort of up to you whether to take an interim? And then second, I think you mentioned planning additional studies for eplontersen. Can you talk in a little bit more detail about what those might include? Thank you.

Sure, Jess. Eugene, can you take that?

Yes, sure. Good question. Well, I'll start with your questions related to the early look option for cardio transform. We certainly have that option and plan to be judicious in taking that option when the timing is right. It is within our protocol to have an option for an early look into the primary endpoint, and we are using that primary endpoint, which is CV mortality and morbidity. It's important to distinguish from the current readout in APOLLO-B, which was more of an early look at functional changes. We are looking forward to seeing the full results from APOLLO-B, of course, as everyone else. It is important to look at the magnitude of these differences from placebo to understand their clinical significance, not just statistical significance.

And on the additional eplontersen trials you alluded to?

Yes. That continues to be an area of active work and discussion with our partners, and we're not prepared to start disclosing all of the life cycle management activities. I use that term broadly for this group of studies. However, there are important clinical questions that need to be answered, and we believe that we will have a profile that is highly differentiated from competitors. So stay tuned.

Yes, Jess, just stay tuned. We're working, as Eugene said, on several sets of studies, life cycle management, imaging studies, et cetera, with our partner, and those will be hitting clinical trials in the future. So we will talk more about it at that time.

Great. Thank you.

The next question comes from Do Kim with Piper Sandler. Please go ahead.

Great. Thank you for taking my question. First, as you think about and look at the data for NEURO-TTRansform, are there aspects to that or just the drug profile in general that physicians will find compelling to switch from the recently launched fitusiran, or do you think you'll be competing for just newly diagnosed patients?

I'd like to ask Onaiza to maybe address that question. Onaiza, can you take that?

Yes. Hi, Do. It's really important to know that with polyneuropathy and the mixed phenotype patients, this is a large market with the first-generation silencers. We've made only marginal progress in getting these patients diagnosed and treated. As a result, there continues to be about 40,000 patients in this population that both drugs will have access to. We expect to get a lot of new patients on. We have a very compelling product profile. Richard went through it in his prepared remarks that we have a product profile with great improvements in mNIS+7 plus Norfolk Quality of Life, which are clinically meaningful and important considerations for physicians. This is packaged with our go-to-market strategy with AstraZeneca, aiming to identify, diagnose, and treat these patients as rapidly as possible in various settings, not just in the neurologist's office. We will be able to rapidly access that broad population. So yes, we're expecting to readily find these patients and get them diagnosed and treated with eplontersen.

Just to add to that, polyneuropathy is just a start. As you know, cardiomyopathy represents a significant opportunity and addresses a major unmet medical need today. We believe eplontersen has several key differentiators. One is the study design we’ve emphasized, which we think will produce a robust and rich data set. Additionally, we have AstraZeneca, a global leader in the cardiovascular space, to maximize the delivery of eplontersen to many patients worldwide, which is another important advantage, along with the promising neuropathy data generated in NEURO-TTRansform.

Great color, Brett. We have a very strong clinical data package being generated here. I also want to remind everybody that we are backed by the longest-acting and largest study to ensure that this data is available in our label, enabling us to provide comprehensive information to physicians in a very competitive market.

Perfect. Thanks for taking my questions.

The next question comes from Gena Wang with Barclays. Please go ahead.

Thank you for taking my questions. Maybe I would just ask regarding your HBV program with your partner, GSK. Any additional color you can provide regarding the second half of this year, the data update? And then also quickly on the HAE program, Phase 2 OLE data, if you can give a little bit more color on the type of data you'll be sharing.

Yes, sure. Thanks, Brett. Gena, as I'm sure you’re aware, GSK presented some nice data at EASL on the 24-week end of treatment for Bepirovirsen, showing very remarkable data in 28% and 29% of patients either non-therapy or on therapy with nucleosides going below the limit of detection in the antigens. This has been unprecedented in monotherapy to see such a level of decline in this patient population. We think the data is very encouraging. GSK has announced their intention to conduct a Phase 3 program in the near future. The keys for that will be to see if that’s sustained in the continued B-Clear data and also in the B-Share study, which is an open-label extension with those patients. Those will be key bits of information for the program going forward.

Yes. And I think the buzz phrase is functional cures, right? Functional cures with the durability that GSK plans to present additional data in the second half of this year is to really nail down whether or not we're achieving functional cures in these patients. Regarding HAE, we look forward to presenting the open-label extension data. These will be patients who were treated for a year with donidalorsen. As you recall, Gena, the Phase 2 efficacy was remarkable, showing unprecedented reductions in HAE attacks, as well as greater than 90% of the patients were completely attack-free during that period. The objective for the presentation in the second half of the year is to show that those effects are durable. That's what we're planning to present, demonstrating the durability of the remarkable efficacy observed in Phase 2. Additionally, there will be some data for monthly and bimonthly dosing since patients were eligible to do either in the open-label extension. You'll see some analysis of how well the bimonthly holds up alongside the monthly dosing, and so on.

Thank you very much.

The next question comes from I-Eh Jen with Laidlaw & Co. Please go ahead.

Hello. Good afternoon, and thanks for taking the questions. Besides GSK, I understand that Roche also will move their program into Phase 3, the FB program. Could you elaborate a little bit more about that? And I have another follow-up.

Yes, I-Eh. We have five Phase IIb studies reading out this year. We have put out three positives, the PCSK9 Factor B that you referred to in IgA nephropathy. The results in patients with IgA nephropathy were compelling; it looks like some of the best efficacy disclosed by targeting Factor B with our LICA medicine FB-LRx. Based on the data, Roche is excited about moving into Phase 3 development, as we announced. In addition, that same drug is in a larger trial involving patients with geographic atrophy, dry AMD. That study continues to enroll today and is progressing well.

Okay, great. That's very helpful. Maybe one more question on your preclinical data. You're saying you will have a muscle LICA program readout coming this half — any elaboration on that side?

Thanks, I-Eh Jen. Eric?

Yes. We're planning on getting a muscle LICA program into preclinical development. We don’t have any more elaboration on that right now. But we're happy with the multiple technologies we've moved forward targeting the muscle, including some of the initiatives we’ve talked about, like the Bicycle collaboration with Bicycle Therapeutics, using fairly small bicyclic peptides to engage the transferrin receptor to target them to muscle. We have multiple programs progressing, and that’s one of them. We look forward to getting them started in development across multiple therapeutic areas in the not-too-distant future.

Okay, great. Thanks a lot, and congrats.

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

Hi, thanks for taking our question. This is Sonya on for Salveen. Are there any thoughts on the upcoming hypertension data, and how are you thinking about potential efficacy bars there? And then on the program in Angelman, can you help us gauge the differentiation from other potentially disease-modifying therapies in this space? And I guess provide us with an update on when we could see data from this program? Thank you.

Sure. Richard, do you want to talk through the AGT program and what we're expecting from the Phase IIb data?

Sure. For AGT, we have a Phase IIb in resistant hypertension that will read out in the second half of this year. In addition, we have a study in heart failure, a safety study, that will read out late this year or early next year.

In the hypertension study, the Phase IIb study's endpoints will be systolic blood pressure decrease compared to placebo. This is powered for two different dose groups against the control to show a significant decrease.

In the heart failure study, we’re looking at cardiovascular outcomes as well for that indication.

Eric, could you address differentiation in Angelman?

Yes, sure. I'd like to talk about Angelman a little bit. As you may be aware, all the programs I know of that are disease-modifying are using the same mechanism targeting this antisense transcript regulating the carbon gene to upregulate the gene that's deficient in Angelman syndrome. Our drug certainly does that, and we hope it is the best molecule in the space. We've invested a lot of time in identifying optimized drugs for CNS delivery and engagement of their targets. We are advancing our program into a first-in-human study, where the primary endpoint is safety. We'll monitor other clinical endpoints to see how the drug behaves. Biogen hasn't provided timing on data readout yet, but we're committed to advancing the program quickly for patients.

Thank you.

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

Great. Thanks so much for taking my question. Congrats on the quarter. Maybe on TTR cardiomyopathy. I know you have not seen the Phase 3 from Alnylam APOLLO-B. Is there a scenario where you elevate the 6-minute walk test from a secondary endpoint to a primary endpoint in your Phase 3, so you can reach the market faster? Again, I think they hit on 6-minute, a trial that is three times smaller than yours, so I wonder if you may have a good shot at hitting the stat there. So I'm wondering if that's an option. And then maybe circling back on AGT, it looks like you have a lead compound and a backup compound. Wondering if you can remind us what's the difference between the two, and why does it make sense to continue investing in both instead of pivoting to the next-gen?

Yeah, Eugene, could you address the 6-minute walk?

Sure. For cardio transform, we are looking at the 6-minute walk. However, it is our secondary endpoint; the primary endpoint focuses on current standard of care, which already provides mortality data and significant benefits on mortality and cardiovascular events. We believe this makes for a meaningful expected outcome in this indication. While there might be a theoretical faster path to market through primary endpoints, what we're really playing here is the long game. As Brett indicated, we want to assemble the most definitive data set for this indication that will be useful for physicians and patients once the drug is available. We're not trying to find shortcuts to approval, as we believe playing the long game is critical for establishing this as best-in-class therapy.

Onaiza, do you want to expand on that from a commercial perspective regarding the value a 6-minute walk endpoint would be versus the outcome data?

Absolutely. We've been preparing for our cardiomyopathy clinical data package and have been working closely with development teams as Eugene described. The most important element that physicians will want will depend on the type of patients they have—whether patients have been on tafamidis or if they're naive to therapy. They want to see cardiovascular risk reduction on top of current standard care. We believe we have to generate robust data in the clinical environment for our best-in-class profile. Payors will need assurance of clear value and clinical utility for reimbursement as well. We're positioned well across a broad set of demographics and seek to provide rich clinical data supporting our strategy.

Thanks, Onaiza. Luca, regarding AGT hypertension, Richard pointed out that we have two studies in progress with our lead molecule Gen-2 chemistry with LICA, the Phase 2b refractory hypertension study will read out by the end of this year. The heart failure study is progressing nicely too. We initiated development of another molecule—a Gen 2.5 chemistry, LICA targeting AGT. With this, we're focusing on comparing and profiling 2.5 versus 2, expecting greater potency and durability, and that study is now in Phase II in hypertension. We're waiting for data next year to help shape our strategy based on data-driven decisions.

Super helpful. Thanks a lot, guys.

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

Hi. Thanks for taking the question. The first one is just a clarification for you, Brett. You said that the IgAN data for the factor B inhibitor was the best you've seen thus far. Was that targeting just factor B, or is that relevant to the complement space more broadly? And the second question is on the GOLDEN study in geographic atrophy in clinicaltrials.gov, which has that ending in October 2022. I’m wondering whether we expect top-line data disclosure in the second half because it's not in your press release. Thanks for that.

Yeah. So thanks, Myles. The data that we've seen in IgA nephropathy to date, physicians are seeing our factor B LRx as highly competitive. We believe that based on our data generated to date, this has the potential to be the most efficacious approach for IgA nephropathy, more so than what has publicly been disclosed in this patient population. That's why Roche is pushing aggressively to move to Phase III quickly. Regarding the GOLDEN trial, we’re not planning to have a data readout from the dry AMD study this year. We haven't put a timeline on that for when it will be read out; it's a significant study with over 300 patients, and we're still enrolling. So stay tuned, but we don't have any details about when to expect data for that study.

Okay. Helpful. And just for clarification again that IgAN comment includes data from the endothelin receptor antagonist class that's inclusive of everything?

That's inclusive of everything. Yes.

Thanks, guys.

Thanks.

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

Yes, hi. I have three questions and three different drugs, if you don't mind. Just the first one on eplontersen, can you give us any insight as to when AstraZeneca is thinking about filing with EMA for polyneuropathy? And then secondly, can you confirm that you've not done an interim analysis on cardio transform before you expanded to 1,000 patients? And then just a question on ION306 or BIIB115. I don't know what you could say about it. It sounds like it's going to be of extended duration. Is it exactly the same sequence as SPINRAZA, or what's the differentiation there as well? And what's the timing for starting Phase I? Thank you.

Thanks. Actually, Rich, why don't you talk a little bit about our strategy for the EMA filing for eplontersen?

For eplontersen polyneuropathy, we will file in the US this year. Following that, we will include week 65 data as endpoint data in the EMA filing. That means the staging will be very close. So we're good. The EMA will follow the FDA filing, which will include the final endpoints at week 65.

We're preparing the European filing now, Yaron. It will be in segments. The final full filing will require the week 65 data. Regarding the decision to expand the sample size and duration for the cardio transform study, that was based on factors, including the demographics of the study. We want to ensure we have the right mix of sicker patients in the study. It wasn't driven by event rates; it was about demographics for patients coming into the study. The disease is being diagnosed early and earlier, and patients with mild disease are being diagnosed sooner. This was the basis for that; there was no look at any interim data that factored into that. Regarding the follow-on for SMA, we’re very excited about this drug. It may extend dosing intervals significantly, possibly once every nine months or once a year. We must prove that in clinical but the preclinical data is promising. Biogen has not released details on the new study's timing yet; we don’t want to get ahead of our partners on that.

Okay. Great. I have a quick question about Cimdelirsen for Acromegaly. It seems like that study is fully enrolled now. It's a monotherapy, and I understand you can enroll both treatment-naive and experienced patients. Do you have any insight into the distribution between these two patient groups? Additionally, what are your expectations for moving into Phase III? Thank you.

So the study that will read out in the second half of this year, Yaron, is monotherapy. These are not patients that are currently receiving treatment. In terms of expectations, we are looking for substantial movement and reduction in IGF-1 biomarker, which is an approvable biomarker for new treatment in Acromegaly. We hope to see a substantial number of patients reach the normal range of their IGF-1. We have to see if we can achieve that; any IGF-1 lowering that achieves normal range should meaningfully impact the quality of life for these patients. That's our objective.

Right. What I was asking is, do you expect patients to be – this is model therapy; do you expect patients to have the same therapy before with other drugs like some metasite analogs, or experienced—these patients are laser-focused on therapy post-surgery?

You're correct that the eligibility criteria will define what patients are entering the study. Some patients will have been treated before, either having not tolerated treatment for various reasons or failed to respond. Therefore, we'll monitor safety and efficacy across both these groups, which is the intent of our trial.

Thank you.

The next question comes from Joseph Stringer with Needham & Co. Please go ahead.

Hi. Thanks for taking our question. Just on the muscle LICA preclinical program, I understand from your initial preclinical data and some of the features of the targeting technology that there are indications you incline to focus on. Are you indication agnostic at this point? Thanks for taking our question.

I wouldn't call indication agnostic, but there are many indications so we are looking at both the neuromuscular space, where we've seen success, including a focus on cardiomyopathy with this class, targeting muscle, but we're also looking at various cardiovascular indications. We think it will be broadly useful in many indications, which is one reason we are excited about our current targeting approach for muscle.

Of course, Joey, heart failure is a key area where we have a lot of eagerness. We're looking for opportunities to expand in the cardiovascular space and muscle targeting. So stay tuned, and hopefully, we will have more to share by the end of the year. We may have time for one last question before wrapping up. We're a little over time.

The next question comes from Gary Nachman with BMO Capital Markets. Please go ahead.

Great. Thanks for squeezing me in. So on olezarsen, with enrollment completed in FCS, remind us about the duration of the study. Will you have data more likely in the first half or second half of next year, and what's your expectation with the data? What you're looking for? And what sort of read-through, if any, might there be for the high trig study once we see the FCS data? Then I have a couple of follow-ups.

Absolutely. We fully enrolled in June. It is a one-year study, so data readout is expected around mid-year. What we’re looking for is the primary endpoint to be triglyceride lowering. We know from WAYLIVRA, which is the same sequence, that this is our LICA medicine. What we saw in very high triglyceride patients—the FCS patients—was actually a greater response than seen in patients with lower triglyceride baseline. So we expect very robust triglyceride lowering with this APOCIII-targeted drug. Given it's a LICA, safety will be pristine, a very important aspect of this package. In secondaries, we're looking at the effects of triglycerides on patients generally suffering from abdominal pain, linked to pancreatitis, additionally evaluating quality of life improvements. We've operated in FCS for many years, and we're thrilled to see this study unfold as one of the largest study in this space.

And as far as read-through to sHTG, we expect a very strong read-through. Our Phase 2 data was in milder patients—those with less severe triglyceride elevations, and we therefore recorded reductions in triglycerides of 60% or higher at the 50 milligram monthly dosage. Our Phase 3 study will have doses of both 50 and 80 milligrams per month, and we see great safety and tolerability in several Phase 3 studies involving olezarsen. With the higher doses, we expect even greater triglyceride reduction. Overall, this is shaping up to be an excellent drug, placing us to effectively target patients with triglyceride-related diseases. Do you have a follow-up, Gary?

Yeah. On that, you're starting the second high-trig Phase 3 study. Is that going to have the same design and scope as the first one? Can you do anything to accelerate enrollment for these studies if you have the resources for that?

It's very similar. CORE 2 mirrors CORE. This is a broad indication so it requires two Phase 3 studies—a confirmatory study—understanding that's a Phase 3 study. Regarding enrollment, we are always looking for ways to enhance enrollment, but a lot of patients are involved. It takes time to enroll for all studies involving olezarsen, taking time to find the right patient size and profile. We are looking at opportunities, but it’s less about resources and more about finding the right populations. Anything to add, Eugene?

No.

Okay, and lastly, Tofersen and PN. After you file in the US, are you expecting a priority review? Additionally, maybe a few details on your collaboration with AstraZeneca concerning plans for the launch. Any insight on sizing the sales force or initial engagements with payers? If you've addressed this, I missed it—could you outline key activities you’re preparing for the launch?

For the US filings concerning polyneuropathy, we're already discussing well with regulators. Things are progressing positively for our NDA submission this year, and regarding getting priority review, that's up to the FDA. That is multifaceted, and it depends on our approach; it is essential that we wait to see once the filing is accepted and the FDA makes that decision.

Yes, it wouldn’t be appropriate for us to speak for the FDA. But maybe Onaiza could provide insights regarding our plans for the commercial launch of eplontersen with AstraZeneca, responsibilities shared, etc.

I must say, Gary, it is one of the best collaborations I've engaged in during my career. AstraZeneca is a great partner, and our teams are syncing well. We're leading the medical shares; we have been deeply engaged in this category regarding amyloidosis and maintain relationships with investigators and KOLs for over a decade. This is a core strength we are deploying in go-to-market activities. So we’re actively in the field. We're receiving great inquiries based on our top-line sharing of the Phase 3 data, and we hope ISA will enable us to present the robust profile and other indications. We have not fully sized the sales team yet, as this is actively underway. Keep in mind, patients present in various settings, so we want to ensure our promotional efforts align strategically. Additionally, we're actively preparing interaction with key stakeholders and sizing our nurse case team to ensure comprehensive launch preparation.

Okay, great.

Thank you all for joining us today on our call. It has been a great first half of the year for Ionis. We're looking forward to sharing more progress through the rest of the year. Until then, thank you again for joining, and have a wonderful day.

Goodbye.

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