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spk14: 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.
spk20: Thank you, Betsy. Before we begin, I encourage everyone to go to the investor 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, Beth Haugen, 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 Oneza Katare, Chief Global Product Strategy and Operations Officer. I would like to draw your attention to slide three, 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 SDC filings for additional detail. With that, I'll turn the call over to Brett.
spk11: 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 Neurotransform Study of Eplon-Tersen in patients with TTR polyneuropathy. Eplon-Tersen met the co-primary and key secondary endpoints in neurotransform. demonstrating highly statistically significant and clinically meaningful improvements in neuropathy impairment and in quality of life. Based on these positive results, we're well on our way towards filing an NDA later this year. And at the same time, me and our partner, AstraZeneca, are advancing our global go-to-market preparations to launch Eplon-Tersen for the treatment of ATTR polyneuropathy. We're also continuing to advance our ongoing CardioTransform phase three study, which we expect will enable us to move into this much larger market for patients with APTR cardiomyopathy. We in AstraZeneca are quite confident that Amplon-Tersen 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. could become the first disease-modifying therapy for a genetic cause of ALS. With the PDUFA date of January 25th, 2023, Tofersen has the potential to be our next product on the market, with epontericin 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 balanced study of olizarcin in patients with familial cholomycronemia syndrome, or SCS, making this study our next potential phase three data readout plan for next year. And Novartis also achieved full enrollment of more than 8,000 patients in the LP little a horizon cardiovascular outcome study of Pellicarson, 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 two study results, our partners are planning to advance two new medicines into phase three studies next year. As a result, we expect to expand our rich phase three pipeline to at least eight medicines across 10 different indications. In addition to advancing our pipeline, we're also making excellent progress in advancing our go-to-market activities for our near-term product opportunities, Eflon Tersen, Ola Zarsen, and Donnie Velorsen. With the potential to add two new medicines to our commercial portfolio next year, along with a steady cadence of phase three 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 value for 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 we'll 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.
spk13: Thank you, Brad. 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 over the same period as 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 activities. 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 period. In the U.S., Spinraza's sales stabilized on a year-to-date basis. compared to last year. Additionally, we remain encouraged that in the U.S., 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 U.S. play out across other geographies. Additionally, Biogen is executing on a robust lifecycle management program that we in Biogen believe further supports 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. As open label studies, RESPOND and ASCEND can provide Biogen with a continuous stream of data supporting Spinraza's market leader position. The DEVOTE study, which is 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. In addition, 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 periods last year. We generated R&D revenue from several different partners for advancing numerous 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. We also earned $37 million from AstraZeneca, for their portion of F1 person's 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 three studies we are currently conducting. with Applin-Turson 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. This was largely due to the substantial savings from the XCA integration and SOBE transactions last year. We are redeploying some of those savings as we invest in our go-to-market preparations for Aplon-Turcin, Olazarsson, and Donita-Laursen. 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 three 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 increase 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 numerous 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.
spk08: 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 three pipeline in the near term. And 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 NeuroT Transform study of Eplon-Tersen in patients with ATTR polyneuropathy. As we reported in the pre-specified interim analysis of 35 weeks of treatment, Eplon-Tersen met its co-primary endpoints of serum TTR concentration and MNES plus 7, as well as the key secondary endpoint, Norfolk quality of life. Eplon-Tersen demonstrated highly statistically significant and clinically meaningful changes from baseline in each of these endpoints as compared to historical placebo. Importantly, a substantial number of Eplon-Tersen-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 IASA, in September. With these data in hand, we in AstraZeneca are finalizing the NDA and planning to file for regulatory approval for TTR polyneuropathy in the U.S. later this year. Additionally, our cardio T-transform study, the largest and longest study to date for patients with ATTR cardiomyopathy, also continues to progress well. Our broad olisarcin development program remains the lead medicine targeting APA C3 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 three data readout. Our core SHTG or severe high triglyceride study for the much larger indication with more than 3 million patients in the U.S. alone remains on track for data in 2024. Additionally, we expect to initiate a second confirmatory pivotal study of oligosarcin called CORE2 later this year, also projected to read out in 2024. Our Donna Delorsen OASIS Phase III program in patients with hereditary angioedema also continues to progress well and remains on track for data in 2024. We recently initiated OASIS Plus, a 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 II open-label extension study in HAE patients treated for one year to demonstrate long-term durable efficacy. With a differentiated efficacy, safety, dosing, and administration profile, we believe Donna Dolores 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 III VALOR study, and ongoing OLE study, which shows Tofersen significantly slowed decline across multiple measures of AOS disease progression, and importantly, led to robust and sustained reductions in neurofilament, a marker for neurodegeneration. With a January 25, 2023, a DUFA 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 Leica pipeline enables us to address these broad indications. An excellent example of this is Pelocarsin. Novartis recently completed enrollment in the LP little a horizon cardiovascular outcomes study, enrolling more than 8,000 patients. Pelocarsin has the potential to be the first medicine on the market to address cardiovascular risk driven by elevated LP little a. Elevated LP little 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, pellicarsin represents a multibillion dollar opportunity. Pellicarsin 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 FBLRX 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. It has started this year. expands to 23, 2024, and 2025. And as we expand our phase three pipeline, we'll be extending the steady flow of phase three 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 Eplon-Turson, our second half highlights include Phase 2B data from Ionis AGT-LRX, our medicine for treatment of resistant hypertension. OLE data from Donna DeLorsen intended to demonstrate long-term durability in HAE patients. And monotherapy data from Cynda Learson, our medicine to treat acromegaly. With that, I'll turn the call back over to Brett to close this portion of the call.
spk11: 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 an abundance of new transformational medicines to the market. We're looking forward to potentially adding up on Tersen and Tofersen to our commercial portfolio as early as next year. We continue to make excellent progress in advancing our other near-term opportunities, Ola Sarsen and Donna DeLorsen, And with multiple positive mid-stage data readouts, we're well positioned to expand our phase three pipeline to at least 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 Lyca platform beyond liver, or providing updates on these exciting advances in the future. The second half of this year, we expect to continue our positive momentum by delivering additional key milestones highlighted by the MDA filing for Eplon-Turison. And 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?
spk14: We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed and you would like to withdraw your question, please press star then 2.
spk02: At this time, we will pause momentarily to assemble our roster. The first question today comes from Yanen Xu with Wells Fargo.
spk14: Please go ahead.
spk01: Yanen Xu Great. Thanks for taking our questions and congratulations on a very productive quarter. So 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 Eplan-Tersen? Would it be the change in MNIST plus 7 from baseline, Norfolk, QOL, or in a proportion of patients with improvement? Any color would be helpful. Thank you.
spk11: Thank you for the question. We couldn't be more pleased. As we tried to, you know, drive the message in our prepared remarks, more pleased with the overall package for Eplon-Turson, the efficacy, safety, tolerability, target engagement. There really is. We couldn't have hoped for more. And as we also said in our prepared remarks earlier, we're well on our way to submitting the NDA for potential approval and preparing for launch next year for Eplon-Turson for TTR polyneuropathy. We're very much looking forward to sharing results from our 35-week interim analysis data in polyneuropathy, ISA, and we're looking forward to sharing a lot of the results at ISA. We're certainly going to be looking forward to sharing the safety and tolerability profile. The rich and the really exciting target engagement for TTR lowering. as well as efficacy data and so on at the meeting. As you know, the primary endpoint, it was a co-primary endpoint at week 35, and we also had a key secondary endpoint. Primary endpoints were MNIST plus 7, as well as TTR lowering, and the key secondary endpoint was Norfolk Quality of Life. In addition to safety and tolerability, we're looking forward to sharing some of the efficacy results as well. And as for comparison, you know, TTR mellidosis is a big indication. And I think the comparison will be important to be looking at in the primaries and the secondary endpoints as well as the exploratory endpoints for polyneuropathy, but beyond that. It's really the cardiomyopathy data that I think is going to be incredibly important for Eplon-Tersen. You know, we're running the most robust, the richest, the largest and longest trial ever done for TTR cardiomyopathy and really believe that that is going to be a key differentiator for this very large market in the future. So stay tuned for that. and stay tuned for the presentation of ISA.
spk01: Got it. If I have a very quick follow-up on cardiomyopathy and that is could you share your thoughts on the Apollo 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.
spk11: Thanks, Yanan. Good follow-up. You know, we've been in this field for many years now, nearly a decade, I think, in developing therapies for TTR myelidosis. And we couldn't be more pleased that there's new encouraging data that shows that silencers could be very effective in the broad cardiomyopathy disease indication. And we couldn't be more pleased and happy with the trial design. for our Cardiotransform study. As I mentioned, it's very robust. We're going to be able to generate data in several different important patient subpopulations, including epontersin compared to naive, as well as on top of tefamidus and so on. It's a very rich, we're expecting a very rich, robust data set in the cardiomyopathy study, and it's a cardiovascular outcome trial. So, and we think that outcome data is absolutely essential key to driving uptake into this very attractive market. And there's no data that we've seen that is changing our assumptions, that our trial design is the right design. And it's a study that's enrolling very well now, and we're looking forward to bringing it to its conclusion as planned. We're also looking forward additional data that has come out from Apollo B in the future, which could shed additional light on things. But right now, we're not planning to change our trial design in any way based on any new data that has come out today.
spk03: Great. Thanks for all the color.
spk02: The next question comes from Paul Mattis with FEFL.
spk14: Please go ahead.
spk17: Hey, this is Katie on for Paul. Thanks so much for taking our question. I had a quick question on the Tove Fersen 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.
spk09: Sure. I'm going to ask Richard to take a stab at that one, Katie.
spk08: Yeah, of course, the Tofreson 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 of the biomarkers. And of course, we get engagement with the target. We can see that in a very short period of time. Following that, we saw the neurofilament decrease very strong, very robust. And seeing it again with the placebo patients going on to Tofersen kind of brings that whole thing home that you're actually having an impact on neurodegeneration through this potential biomarker. Will we be looking at the potential of filing on biomarker alone. I think biomarker alone is probably not the play, but rather looking at the biomarker is a very good early surrogate for what can happen as we play it out. So for FOSS, we have a robust design for our study. We have interim analysis built in that doesn't doesn't force us to be static in the way that we look at the endpoints. So we'll be able to see when we're having good movement in functional as well as, of course, neurofilament is part of the design.
spk02: Okay, great. Thank you. The next question comes from Jessica C. with J.P.
spk14: Morgan. 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 that all the details are not yet, can you just remind me whether you plan to take an interim in CardioTransform and maybe talk about whether or how you see the Apollo B results affecting that decision, if it is sort of up to you to whether to take an interim. And then second, I think you mentioned planning additional studies for Eplon-Tersen. Can you talk in a little more detail about what those might include? Thank you.
spk05: Sure, Jess. Eugene, take that. Yeah, sure. Good question. Well, I'll start in the order of your questions. Related to the early look option for Cardiotransform, we certainly have that option, and we plan to be very, judicious in taking that option when the timing is right. But it is within our protocol to have an option for an early look into the primary endpoint. And we are using primary endpoint for that, which is CV mortality and morbidity. So it's important to, again, distinguish that from the current readout in Apollo B, which really, was more of an early look at the functional changes. So having said that, we are looking forward to seeing the full results from the Apollo B, of course, as is everyone else. It is important to look at magnitude of these differences from placebo to understand their clinical significance, not just statistical significance.
spk02: And on the additional and trials you alluded to?
spk05: Yeah, that continues to be an area of active work and discussion with our partners. And we're not really prepared to start, you know, disclosing all of the lifecycle management activities. And I kind of use that term broadly for this group of studies. But there are important clinical questions that need to be, And we believe that we will have a profile that is highly differentiated from competitors. So stay tuned.
spk11: Yeah. Yeah, Jess, just stay tuned. We're working, as Eugene said, on several sets of studies, lifecycle management, imaging studies, et cetera, with our partner. And those will be hitting quintrials.gov in the future.
spk03: So we'll be able to talk more about it at that time.
spk02: Great. Thank you. The next question comes from Doe Kim with Piper Sandler.
spk14: Please go ahead.
spk00: Great. Thank you for taking my question. First, as you think about and look at the data for neurotransform, are there aspects to that or just the drug profile in general? that physicians will find compelling to switch from the recently launched Allen Islands with Tuceran, or do you think you'll be competing for just newly diagnosed patients?
spk11: I'd like to ask Tonesa to maybe address that question. Tonesa, can you take that?
spk15: Yeah. Hi, Dov. So, you know, I think it's really important to know that with polyneuropathy and the mixed phenotype patients, this is fairly a large market. With the first-generation silencers, we've only put really a marginal dent in getting these patients diagnosed and treated. So as a result, there is really still continues to be, you know, about a good 40,000 patients in this population that I think both drugs will have access to. So we do 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're going to have, you know, a product profile with great improvements of MNIST Plus 7 plus Norfolk Quality of Life, which are actually really clinically meaningful, important considerations for physicians. That packaged in with our go-to-market strategy with AstraZeneca and trying to identify, diagnose, and treat these patients as rapidly as possible in all types of settings because they do present in a variety of different settings, not just in the neurologist's office. We will be able to kind of access that population very quickly. So, yeah, we're expecting to go in and find these patients readily and get them diagnosed and treated on Eplon-Torsen.
spk09: And just to add to that, thanks, Nathan.
spk11: Just to add to that, though, of course, polyneuropathy is just a start. And as you know, cardiomyopathy is where the big population, where the big opportunity and yet biggest unmet medical need is today. And there we think we have several key differentiators for a fun person. One is the study design that we've already emphasized. We think the amount of data, the quality of the data, The details of all the data we're going to generate from that study is going to be very differentiating. Also, the fact that we have a global powerhouse in the cardiovascular space in AstraZeneca to maximize delivery of epinephrine for as many patients as possible globally is another key advantage for epinephrine, in addition to the really exciting neuropathy data that we've generated in NeuroTransform.
spk15: It's a great point, Brett. Very strong clinical data package that's being generated here, and I want to remind everybody that we are powered with the longest acting and the largest study to be able to make sure that these data are available in our label so we can provide that to all types of physicians in a very promotionally sensitive and what is turning out to be a competitive market.
spk03: Perfect. Thanks for taking my question.
spk02: The next question comes from Gina Wang with Barclays. Please go ahead. Thank you for taking my questions.
spk12: 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 also quickly on the HAE program phase two only data, if you can give a little bit more color on the type of data you'll be sharing.
spk09: Eric, do you want to take the HPV question for Gina?
spk10: Yeah, sure. Thanks, Brad. You know, Gina, as I'm sure you're aware, GSK presented some nice data at ESL on the 24-week end-of-treatment time point for papiraviricin. and showed what I think is really remarkable data in 28 and 29% of patients either not on therapy or on co-therapy with nucleosides showing going below the limit of detection in the antigens. And this has been, it's really been unprecedented in monotherapy to see that level of decline in this patient population. So We think the data is very encouraging, and as does GSK, they've announced their intention to go to a phase three program in the near future. And really the keys for that will be seeing if that's sustained in the continued Be Clear data and also in the Be Sure study, which is an open label extension. with those patients. So that'll be the key bits of information for that program.
spk11: Yeah, and I think the buzz phrase is functional cures, right? Functional cures with the durability that GSK plans to present additional data second half this year is to really nail down whether or not we're achieving functional cures in these patients. As far as HAE, yeah, we're looking forward to presenting the open label extension data. These will be Patients now treated for a year with Donna Delorsen. As you recall, Gina, the efficacy was remarkable in phase two. I mean, you know, 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 for the second half of the year is to show that those effects are durable. And that's what we're planning to present in the second half of this year is the durability of the remarkable efficacy that we showed in phase two. In addition, there'll be some data for monthly and bimonthly dosing because patients were eligible for to do either in the open label extension. So you'll see some of that as well and how well the, by month he holds up with the monthly and so on, so.
spk02: Thank you very much.
spk14: The next question comes from Yale Jen with Laidlaw and Co. Please go ahead.
spk18: Good afternoon and thanks for taking the questions. Besides the GSK, I understand that Roche also will move their program into phase three, the FBE program. Could you elaborate a little bit more about that and have another follow-up?
spk11: Yeah, Gail. You know, that's two of our partners, you know, we have four Phase IIb studies, five, I'm sorry, five Phase IIb studies reading out this year. We already have put out three positives. PCSK9 wrote a fact Factor B, that you just referred to, and IgA nephropathy, and our desimericin program, factor 11, and more coming. The results in patients with IgA nephropathy were really compelling. It looks like some of the best efficacy that's been disclosed in the by targeting factor B with our LycoMedicine FBLRX. Based on the data, Roche is really excited about moving it into phase three development, as we announced next year. In addition, that same drug is in a larger trial in patients with geographic atrophy, dry AMD. That study continues to enroll today and is progressing well.
spk18: Okay, great. That's very helpful. Maybe one more question on your preclinical data. You talk about you will have a muscle-like program, I guess, early study to come, readout to come this half. And any elaboration on that point? And thanks. Sure. Eric?
spk10: Yeah, we're planning on getting a muscle-like program into preclinical development. We don't have any more elaboration on that right now, but certainly are happy with the multiple technologies we've moved forward into targeting the muscle, including some of the things we've talked about, like the bicycle collaboration with Bicycle Therapeutics using a fairly small bicyclic peptides to engage the transfer receptor and target them to muscle. And so we have multiple programs progressing. That's one of them and look forward to getting them started in development across multiple therapeutic areas in the not too distant future.
spk03: Okay, great. Thanks a lot and congrats.
spk02: The next question comes from Salvin Richter with Goldman Sachs.
spk14: Please go ahead.
spk16: Hi, thanks for taking our question. This is Tommy on for Salveen. Ours is about the upcoming hypertension data. How are you thinking about potential efficacy bars there? And then on the program in Angelman, can you help us kind of gauge the differentiation from other potentially disease-modifying therapies in this space? And I guess provide us maybe with an update on when we could see data from this program. Thank you.
spk11: Sure. Richard, do you want to talk to the AGT program and what we're expecting from the Phase 2b data?
spk08: Sure. So for AGT Leica, we have a Phase 2b in resistant hypertension that we'll read out the second half of this year. And in addition to that, we have a study in heart failure, safety study in heart failure that we'll read out either late this year or early next year.
spk09: And in the endpoints, heart failure study. In the heart failure study.
spk08: No, I'm sorry, in the hypertension study, the ACV study. Of course, the, yeah, so the endpoints in the hypertension study are systolic blood pressure decrease compared to placebo. And this is powered two different dose groups and powered against the control. to show a significant decrease.
spk11: And Eric, can you address the differentiation in Angelman? Yeah, sure.
spk10: I can talk about Angelman a little bit. So as I'm sure you're aware, certainly all the programs I'm aware of that are disease modifying are using the same general mechanism of trying to target this antisense transcript that regulates the causal gene. then upregulates the gene that's deficient in Angelman syndrome. Our drug certainly does that. And for differentiation, we hope it's the best molecule in the space. And we spent a lot of time trying to identify the best molecule. We think we're pretty good at finding optimal drugs for CNS delivery and engagement of their targets. And we're advancing our program. And our program is a first in human studies. So the primary endpoint is safety, of course, but we're always looking for target engagement and we'll be monitoring other clinical endpoints as well to try and see how the drug behaves. And I don't believe Bison's given timing on when that readout will come out, but our goal is to advance the program as fast as we can to try and get a drug out for patients.
spk03: So that's what we're trying to do.
spk02: Thank you. The next question comes from Luca Izzi with RBC. Please go ahead.
spk19: Oh, great. Thanks so much for taking my question. Congrats to the quarter. Maybe on TTR cardiomyopathy, you know, I know you have not seen the Phase III from LALA and MAPALA-B, but is there a scenario where you elevate six-minute walk tests from a secondary endpoint to a primary endpoint in your Phase III so you can actually get to market faster? Again, I think they hit on six minutes walk on a trial that is three times smaller than yours. So I would think you may have a good shot at hitting the stats there. So wondering if that is 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 to invest on both instead of just pivoting to the next gen? Thanks so much.
spk11: Yeah, Eugene, would you address the six-minute walk? Yeah, sure. For elevation.
spk05: Sure. So for Cardiotransform, we are looking at six-minute block. However, it is our secondary endpoint, not primary, for the main reason being that the current standard of care already has mortality data and significant benefit on mortality and cardiovascular events, which we believe is really the most meaningful and expected outcome for this. certainly in terms of demonstrating a value to physicians as well as payers, importantly. So while in theory you could potentially get to the market or at least through regulatory gate faster, what we're really playing here is a long game. As Brett indicated, we are assembling the most definitive data set for this indication that will be useful for physicians and patients when this drug is on the market, not trying to kind of, you know, find a shortcut to approval. We feel that, you know, playing the long game here is critical for us to have the best in class therapy here.
spk11: You want to expand on that from a commercial perspective? value a six-minute walk standpoint would bring versus the outcome data?
spk15: Yeah, I think, you know, we've obviously been preparing for our cardiomyopathy clinical data package and really working closely with the development team, as Eugene described. And in looking out there in the marketplace across a robust set of physicians and You know, the most important element that physicians are going to want, and it depends on the type of patient that they're going to have in their office, is that what is the cardiovascular risk reduction on top of standard of care to FAMIDIS, and or if I don't have a patient on to FAMIDIS, then I'd like to see the total cardiovascular risk reduction for a patient who's naive to therapy. We believe that generating both types of data, the most robust clinical data package that we will provide need to demonstrate our best-in-class profile. In addition, I think payers will also require that, particularly as you're thinking about adding on therapies. This is a very sick population, and these patients are at risk for terminal death at the end of the day. We do not believe this is a place where physicians will be switching. And as a result, we're going to have to demonstrate the best value proposition and clinical utility on top of standard of care for payers for reimbursement as well. So, we believe we're well positioned across, you know, the broadest set of data, the broadest set of demographics, and we're really striving for label enabling data to ensure that we're very competitive.
spk11: Thanks, Annetta. Luca, regarding AGT, hypertension, so as Richard pointed out, we have two studies in progress with our lead molecule, Gen 2 chemistry with Leica. Phase 2B refractory hypertension will read out end of this year, by the end of this year, and then our heart failure studies progressing nicely. In addition, we initiated development of another molecule, a Gen 2.5 chemistry, Leica. targeting AGT. And really there we're focusing on really just comparing and profiling 2.5 versus 2. We expect greater potency. We also probably expect greater durability. And that's what we're going to be looking for. That study is now in phase two in hypertension. And we're going to look at all the data. We're going to look at the hypertension data with the 2.0. We're going to look at the heart failure data. We're going to look at the 2.5 data next year. and develop our strategy or implement our strategy accordingly based on data-driven decisions. So as far as further investments go, we made our investments, and we're going to look at which is the molecule we want to invest further in, and we'll make that decision next year.
spk03: Super helpful. Thanks so much, guys.
spk02: The next question comes from Miles Minter with William Blair.
spk14: Please go ahead.
spk21: Hey, thanks for taking the questions. The first one's just a clarification question 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. I think clinicaltrials.gov has that ending in October 2022. I'm just wondering whether we expect top-line data disclosure in the second half, because it's not in your press release. Thanks for that.
spk11: Yeah. So, thanks, Miles. The data that we've seen in IgA nephropathy to date positions our factor BLRX very competitively. We believe that based on the data we've generated to date, this has the potential to be the most efficacious approach for IgA nephropathy. bar none, not just factor B, not just complement, anything that has been publicly disclosed to date in this patient population. That's why Roche, you know, really quite aggressively pulled the trigger to move to phase three rapidly. So not just factor B, but really everything that has been laid out in the public domain to date. Regarding the golden trial, no, we're not planning to have data readout from the dry AMD study this year. We haven't really put a timeline on that for when the data will read out. It's a big study, more than 300 patients, I think, with dry AMD. And we're still enrolling the study. So stay tuned. But I, you know, we really haven't put out when any details on when to expect data from that study.
spk21: Okay, beautiful. And just a very, very quick clarification again, that IGAN comment includes data from the endothelin receptor antagonist class. That's inclusive of everything?
spk11: That's inclusive of everything. Yep, everything includes everything. Okay. Okay, okay.
spk21: Sorry, I just had to go on record. Appreciate the question. Thanks, guys. Thanks.
spk14: The next question comes from Yaron Werber with Callan. Please go ahead.
spk07: Yes, hi. I have three questions on three different drugs, if you don't mind. Just the first one on iplantersin, can you give us any insight as to when are you thinking, and AstraZeneca is thinking about filing with EMA for polyneuropathy? And then secondly, can you just confirm that you've not done an interim analysis on CardioTransform before you expanded to 1,000 patients? And then just a question also on 306 or BIB 115. I don't know what you could say about it. It sounds like it's going to be extended duration. Is it exactly the same sequence as PINRAZA, or what's the differentiation there as well? And what's timing to starting phase one? Thank you.
spk11: Yeah, thanks. So, actually, Richie, why don't you talk a little bit about our strategy?
spk08: So at Plunters and polyneuropathy, of course, we'll file in the US this year and follow with the week 65 or week 66 data as endpoint data that will be included in the EMA filing. Now, that means that the staging will be very close
spk09: But it's going to be, yeah.
spk08: So I'm getting a little bit of a signal that they're, so we're good. On EMA follows the FDA and it will include, ultimately include the final endpoint, week 65.
spk11: We're comparing the European filing now, Yaron. It's just, it'll be in segments. The final full filing will require the week 65 data to complete. As far as the decision we made to expand the sample size and the duration for the CardioTransform study, that was entirely based on a few factors. One was the demographics in the study that we wanted to make sure that we had the right mix sicker patients in patients suffering with TTR cardiomyopathy, so the right balance. It wasn't really based at all on event rates or anything like that. It was really based on what the demographics were looking like for patients coming into this study. This disease is being diagnosed earlier and earlier. Patients have milder and milder disease when they're getting diagnosed, and we're seeing that globally. We're not the only ones seeing that. So that was really the basis for that. There was no look at any data, any interim data at all that factored into that. And as far as the follow-on to SMA, very excited about this drug. This drug has the potential, you know, based on the wealth of preclinical data, it's positioned to be able to extend the dosing intervals substantially, maybe once every nine months, every 12 months or so dosing. We have to prove that in the clinic, but the preclinical data is very strong. Biogen has not put out any details on the timing for the start of the new study. So you have to stay tuned for that.
spk03: We don't want to get ahead of our partners on that one.
spk07: Okay, great. And then if you don't mind, I'm just going to throw one quickly for acromegaly, Sindelerson. So it sounds like that's fully enrolled now. It's monotherapy. I know you can enroll both naives or experienced. Do you have a sense what the split is between the two patients, and what are you expecting? What would you like to see to then move into phase three?
spk09: Thank you.
spk11: So the study that we'll read out the second half of this year, Yaron, is monotherapy. So these aren't patients that are on treatment today. If that's your question, it's a pure acromegaly. What we're looking for is, you know, substantial movement reductions in IGF-1 biomarker, provable biomarker for treatments for acromegaly. We're hoping also to get a substantial number of patients into the normal range of their IGF-1 as well. We have to see if we can achieve that. But really, any IGF-1 lowering that's achieved in these patients has been shown to have a meaningful impact on the quality of life for these patients. So that's our objective.
spk07: Right. So, Brett, I was asking, do you expect patients to be – this is a monotherapy study. Do you expect patients to have seen therapy before with other drugs, like some metastatic analogs, or be experienced? Are these naives or experienced throughout the therapy? They're all post-surgical. Yeah.
spk05: Yeah, it's – Really the eligibility criteria just define what patients are entering the study. So we, you're right, some patients will have been treated before and either not tolerated for a number of reasons or did not respond. So we'll obviously look, it's important to characterize safety and efficacy in both of these types of patients, which is what we intend to do.
spk03: But it is a monetary. Thank you.
spk02: The next question comes from Joseph Stringer with Needham & Co.
spk14: Please go ahead.
spk04: Hi. Thanks for taking our question. Just on the muscle like a preclinical program, I understand based on your initial preclinical data and some of the features of the targeting technology, are there a set of indications that you intend to focus on or would consider best fits? or are you indication agnostic at this point? Thanks for taking our question.
spk10: I can take a crack at that. I wouldn't call us indication agnostic, but there's lots of indications. So we're looking at both the neuromuscular space and because we've seen good success in getting uptake into the cardiomyocyte with this class of targeting ligand, we're also looking at various cardiovascular indications. So we think it's going to be broadly useful in multiple indications and multiple programs, which is one of the reasons why we're so enthusiastic about our current targeting approach for muscle.
spk03: Yeah.
spk11: I mean, obviously, Joey, heart failure is a key area where we have a lot of great pipeline of drugs in the cardiovascular heart failure space. And we're looking for opportunities to expand on that with a muscle like it to the heart. So stay tuned for that. Hopefully we'll have more to share by the end of the year. And maybe we have time for one last question before wrapping up. We're getting a little long on time.
spk14: The next question comes from Gary Knossman with BMO Capital Market. Please go ahead.
spk06: Great. Thanks for squeezing me in. So on Ola Zarsen, with enrollment completed in FCS, Remind us about the duration of the study. So will you have data more likely in the first half or second half of next year? And what should our expectations be with the data, what you're looking for? And what sort of read-through, if any, might there be for the high-trigs study once we see the FCS data? Then I have a couple of follow-ups.
spk09: Sure, Gary. Richard, you want to talk about the FCS study?
spk08: Absolutely. So, fully enrolled, I think we reported that in June. It is a one-year study. So, your data readout is going to be mid-year. I think what we're looking for, obviously, as primary endpoint is triglyceride lowering. And what we've seen, what we know from Weylivir, which is the same sequence, by the way. This is the Leica of Weylivir, essentially. What we saw in the very high triglyceride patients, FCS patients, was actually even a greater response than we saw in some of the lower triglyceride baseline patients. So we expect very robust triglyceride lowering with this APA C3 targeted drug. And with it being a Leica, safety is going to be, pristine, which is going to be a very important component of this package. And then in secondaries, we're looking for the effects of triglycerides on these patients generally drives abdominal pain, issues with their pancreatitis, and we're looking for reduction in some of those as well as a quality of life tool that we've developed for these patients. We've been in FCS for quite a number of years, and we're excited to see how this study rolls out. It's one of the largest FCS studies ever conducted.
spk11: Yeah. And as far as read-through to SHTG, Gary, we expect a very strong read-through. was actually in milder patients, patients with milder triglyceride elevations. And we saw there 60% or higher reductions in triglycerides. And that was at 50 milligrams per month. Our phase three study will have 50 and 80 milligrams per month. We're seeing great safety and tolerability in the various phase three studies for involving oligosarcin. But with the higher dose, we're expecting even greater TG reduction. It looks like a great drug, and we're leading the way. Naples C3 is a great target for managing patients suffering with TG-related diseases. You had a follow-up, Gary?
spk06: Yeah, first on that, so you're starting the second high-trig phase 3 study, so is that going to be the same design and scope as the first one? And, I mean, anything you can do to accelerate enrollment for these studies if you have the resources to do that? Is that a possibility?
spk11: It's very similar. CORE 2 is very similar to CORE. This is a broad indication, so it requires two phase three studies, a confirmatory study, and that's basically what this is, is a confirmatory study. As far as enrollment, we're always looking at ways to enhance enrollment. It's, you know, a lot of patience in the phase three study for all role, a study involving more than 1,000 patients across the studies. But we're always looking at opportunities to do it. It's less about more resources. It's more about just finding the right sites, finding the patients. Do you want to add to that, Eugene?
spk06: No?
spk11: Okay.
spk06: Okay. Yep. Yeah. And then just one last one. So after you file in the U.S., are you expecting a priority review? And then just maybe a few details on you and AstraZeneca just in terms of the plans for the launch. Any idea yet about sizing of the Salesforce? Any initial conversations with payers? If you said this, I missed it. I apologize. But maybe just run through some of the key activities as you're prepping for that. Thanks.
spk05: Yeah, sure. So for as far as the U.S. filings concerns for polyneuropathy, we're clearly in discussions with regulators now and things are progressing very well for the NDA filing the CR. With regard to getting priority review, that's an FDA decision. That's multifaceted. There's nothing that depends on our approach. It really is something that we need to wait once the filing is accepted and FDA decides on that.
spk04: Yeah.
spk11: It wouldn't be appropriate for us speak for the FDA at this point, Gary. But maybe one agent could talk a little bit about how our plans for commercial launch of Eplon Tersen are going and our COCO with AstraZeneca, estimate roles and responsibilities, and so on.
spk15: Yeah. You know, I have to say, Gary, it's one of the best COCO collaborations I've been a part of, and I've been part of many in my career. They're a great partner. And our teams are just sizing up really well. We're taking the lead on medical affairs. We've been in this category in amyloidosis and know the investigators and KOLs for over a decade. It's really one of our core strengths that we bring to the go-to-market activities. So we're in field. We're getting lots of great feedback. you know, request based on our top line sharing of the phase three data. And we hope after ISA, we'll be able to kind of share more of the robust safety profile and other indicators as well with these positions. We are also, you know, haven't sized up the total sales team yet, which is something we're working on pretty actively. As a reminder, and as I said I think earlier, that these patients present in a variety of different settings. So, you know, you have the neurologist, but as a reminder, AstraZeneca is already in with cardiologists with their cardiovascular agent and heart failure, the SGLT2. So, you know, just really trying to think through where all these patients present so we can make sure our promotional efforts are all in the right place. We're also actively preparing payer conversations as well as sizing up our nurse case team on the Ionis side and a whole host of other activities to make sure we're planning for a very robust and fulsome launch.
spk09: Okay, great. Thanks, Vanessa. Thanks, guys. Thanks, Gary.
spk11: And I think that wraps up our Q&A section. I'd like to thank everybody who joined us today on our call. Really a great, great first half of the year for IONAS. We're really looking forward to continuing to share the progress throughout the remainder of the year. And until then, thanks again for joining and have a great day.
spk02: Goodbye. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
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