Good morning. Welcome to Ionis Pharmaceuticals' second quarter 2021 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to David Nakasone, Investor Relations, to lead off the call. Please begin.
Thank you, Debbie. Before we begin, I encourage everyone to go to the investors section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business.
We've also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer, Beth Hougen, Chief Financial Officer, and Richard Geary, the Executive Vice President of Development. Joining us for Q&A, Onaiza Cadoret, Chief Corporate Development and Commercial Officer, and Eric Swayze, Executive Vice President of Research. I would like to draw your attention to slide three, which contains our forward-looking language statement. We will be making forward-looking statements which 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 discussed in our SEC filings for additional detail. With that, I'll turn the call over to Brett.
Thanks, Dave. Good morning, and thank you for joining us on today's call. Last year, when I took on my new role as CEO of Ionis, I put forth a plan intended to bring substantially greater success to Ionis and substantially greater value for all stakeholders. This plan was to leverage our well-established foundation of scientific innovation by focusing on three strategic objectives.
First, to evolve our business model to include commercializing products of our own. This includes building the necessary capabilities to prepare for multiple Ionis commercial launches. Second, to expand our drug discovery capabilities through new initiatives to enhance our technology. Third, to significantly advance and grow our late-stage pipeline to ensure for a substantial increase in the number of new products reaching the market in the near and longer term. Now let's see how we're progressing against these three strategic goals for this year.
The Ionis wholly owned pipeline is advancing on track and growing significantly. Last week, we reached full enrollment in the NEURO-TTRansform study of eplontersen for the treatment of patients with polyneuropathy. With this study now fully enrolled and on track for data by mid 2022, this medicine is one important step closer to reaching the market. We are also developing eplontersen for the treatment of cardiomyopathy in the phase III CARDIO-TTRansform study, which continues to enroll well.
Our phase III study involving our apoC-III LICA medicine in patients with FCS is enrolling as scheduled, and our second phase III study for apoC-III LICA is on track to begin later this year in patients with severe hypertriglyceridemia, a much larger patient population. Our phase III study for ION363 in patients with a genetic form of ALS due to mutations in the FUS gene is also progressing well.
Furthermore, we look forward to initiating a phase III study for our PKK LICA medicine in patients with hereditary angioedema late this year or early next year. As our wholly owned pipeline advances, we're also making great progress in building out our commercial capabilities and our strategy. Our acquisition of Akcea was a key step in advancing our commercial strategy in building these capabilities.
We've now completed the integration of Akcea within Ionis, and we're pleased with the progress being made in our Sobi partnership for the distribution of TEGSEDI and WAYLIVRA in Europe and North America. As a reminder, we established this partnership to continue providing these important medicines to patients while we focus on eplontersen and apoC-III LICA. We've also made significant additional progress this year against our strategic objective to expand the reach of our drug discovery capabilities through new investments to enhance our technology.
Our efforts include broadening our internal technology initiatives as well as in licensing new technologies. We recently announced a new partnership with Bicycle Therapeutics for exclusive access to Bicycle's proprietary platform chemistry for oligonucleotide drugs focused primarily on targeted delivery to skeletal and cardiac muscle. This collaboration complements our significant internal efforts as well as the progress we're making under our Arrowhead Pharmaceuticals and Genuity Science collaborations, all of which potentially enables us to significantly expand the reach of our technology. Lastly, we're making great progress this year in achieving our third strategic objective to have 12 or more marketed products in 2026. In addition to completing enrollment in the eplontersen NEURO-TTRansform study, we also recently achieved key phase III milestones with tofersen and Pelacarsen.
All three of these significant milestones move these programs closer to reaching the market and highlight the excellent progress we're making across our late-stage pipeline. Biogen completed the placebo-controlled treatment portion of the phase III VALOR study of tofersen, data expected by this fall, and is now offering tofersen to SOD1 ALS patients on an individual compassionate use basis. If the phase III VALOR results are successful, tofersen could become the first-ever disease-modifying therapy for a genetic cause of ALS and our next commercial product. This week we announced achievement of a key enrollment milestone in the Lp(a)HORIZON phase III study for Pelacarsen in patients with Lp-driven cardiovascular disease. As we announced, we have now achieved enrollment of nearly 4,000 patients in this cardiovascular outcome trial, representing 50% of our target enrollment goal for the study.
This achievement, along with the substantial progress we're making across all of our mid and late-stage LICA programs, demonstrates the consistently attractive profile for all our LICA medicines in development today. In wrapping up my opening comments, we are very pleased with the progress we're making to achieve all our strategic objectives.
We've made great progress this year, and we are looking forward to an exciting second half of the year as we focus further on executing on our strategy and achieving the goals that lie ahead. Importantly, we are well-positioned for growth with the people and the financial strength to achieve all this and more. With that, I'll now turn the call over to Beth to review our financial results. Richard will discuss recent pipeline updates and preview key pipeline catalysts expected for the remainder of the year. After Richard, I'll wrap up our prepared remarks before taking your questions. Over to Beth.
Thank you, Brett. Our financial results for the first half of this year reflect our commitment to invest to drive future growth. We earned nearly $240 million in revenue and recognized $312 million in non-GAAP operating expenses, resulting in a non-GAAP net loss of $81 million. These results were in line with our expectations and reflect the multiple steps we have already taken this year in support of our strategic objectives. We've completed the integration of Akcea, entered distribution arrangements with Sobi, and restructured our commercial operation. In our first quarter earnings call, we projected realizing substantial savings from the Akcea and Sobi transaction. I'm pleased to say we are on track to realize more than $50 million of savings this year. We are putting these savings to work by reinvesting them to drive future growth.
That means investing in three key areas: advancing and expanding our wholly owned pipeline, building our commercial capabilities, and enhancing our technology. I'll provide more details about the investments we've made so far this year when I talk about our operating expenses. First, I'll provide additional details on our revenue. In the first half of this year, SPINRAZA continued its blockbuster performance, achieving over $1 billion in global sales. We earned over $130 million in royalty revenue, virtually all falling to our bottom line as profit. Based on SPINRAZA's net sales, we reached the highest royalty tier in the second quarter.
We are pleased with Biogen's continued efforts to build upon SPINRAZA's proven profile of long-term safety and efficacy in SMA patients of all ages. Biogen recently reported new data reinforcing the potential for improved outcomes in patients treated with a higher dose of SPINRAZA, which is being evaluated in the DEVOTE study. In the RESPOND study, Biogen is continuing to evaluate SPINRAZA's potential to benefit patients previously treated with gene therapy.
Together with the substantial and growing body of evidence supporting SPINRAZA's proven profile and over 60,000 SMA patients, we believe SPINRAZA will continue to be the market-leading treatment for SMA patients of all ages. In the first half of this year, Tegsedi and Waylivra generated revenues of $31 million. Also in the first half, we completed the transition of our commercial operations to Sobi and recognized our first full quarter of Tegsedi and Waylivra revenues from distribution fees based on net sales. As a reminder, we included this shift in revenue in our 2021 revenue guidance.
We also earned nearly $70 million in R&D revenues in the first half, including $10 million from Biogen for advancing ION541, which is in development for patients with ALS with no known genetic history of the disease. More than 85% of our R&D revenue was from medicines in our leading cardiometabolic and neurology franchises. Our R&D revenues included revenue from numerous partners, as together we advanced more than 10 programs.
Our ability to generate revenue from numerous diverse sources is a key element of our financial strength. We reported non-GAAP operating expenses of $312 million in the first half of this year. This was a slight increase compared to last year and was in line with our expectations. R&D expenses increased by 20% compared to last year, driven primarily by the eplontersen and apoC-III LICA phase III studies and costs associated with our wholly owned programs.
We also incurred expenses associated with our Genuity collaboration to identify novel targets. These increases reflect two of our key areas of investment: our wholly owned pipeline and our technology. SG&A expenses decreased by approximately 25% compared to last year due to cost efficiencies realized from integrating Akcea and restructuring our commercial operations.
Based on our first-half results and our projection for increased R&D revenues from our advancing partnered programs in the second half of this year, we are reaffirming our 2021 revenue guidance of more than $600 million. Already in the third quarter, we have earned a $25 million milestone payment from Novartis for achieving 50% enrollment in the phase III study of Pelacarsen. We expect our operating expenses to continue to increase in the second half of this year as we advance our ongoing phase III studies for Eplontersen, Ionis apoC-III LICA , and our ALS medicine.
Our operating expenses will also increase as we get the phase III study underway for apoC-III LICA in patients with severe high triglycerides and potentially start the phase III study for PKK LICA. We are investing to enhance our technology, ensuring that our platform remains innovative and competitive. As Brett mentioned, we recently entered into a license agreement with Bicycle Therapeutics for a $45 million upfront payment. We did not include this license fee in our original financial guidance, and for that reason alone, we are revising our 2021 operating expense and net loss guidance. We now project operating expenses in the range of $710 million-$750 million, and a net loss of less than $110 million, assuming the low end of expenses, and all on a non-GAAP basis.
Because of our projected increasing R&D revenue in the second half of this year, we expect our net loss will be lower in the second half of this year compared to the first half. With the important steps we have already taken this year and more than $2 billion of cash and investments, we believe we are well-positioned for accelerated growth. We look forward to continuing to invest in our pipeline and technology and to moving more medicines towards the market to achieve our goal of 12 or more marketed products in 2026. With that, I'll turn the call over to Richard.
Thank you, Beth. As Brett described earlier, we are certainly pleased with the excellent performance across our pipeline in the first half of this year. With the achievement of key phase III catalysts with tofersen, Eplontersen, and Pelacarsen, these medicines are now closer to reaching the market. These catalysts also position us well to deliver a regular cadence of phase III data readouts, beginning with tofersen, expected by this fall.
Tofersen is now one step closer to becoming the first genetically targeted therapy for the treatment of ALS and to becoming Ionis' next commercial product. Biogen recently began offering tofersen to SOD1 ALS patients on an individual compassionate use basis, with plans to broaden this access once the data are reported. Biogen is also conducting the ATLAS study to investigate tofersen's potential to prevent or delay disease onset in presymptomatic SOD1 ALS patients.
The rationale for ATLAS is similar to SPINRAZA NURTURE study, which has enabled infants who began treatment prior to SMA symptom onset to develop more like non-SMA children. After tofersen, the next program on track to read out is the NEURO-TTRansform study of Eplontersen for the treatment of TTR polyneuropathy. With enrollment in this study now complete, we expect data by the middle of next year. We are positioned to file for marketing authorization for Eplontersen in patients with TTR polyneuropathy by the end of next year, assuming the data are positive. We expect the BALANCE study of Ionis apoC-III in patients with FCS to read out in 2023.
We're on track to initiate a second phase III study of Ionis apoC-III in patients with severe high triglycerides in the second half of this year, which positions this program for data in 2024. In 2024, we anticipate phase III data from the Lp(a)HORIZON outcome study of Pelacarsen, the CARDIO-TTRansform study of Eplontersen, and the pivotal study in patients with FUS ALS. In addition to our deep late-stage pipeline, we have a large mid-stage pipeline that we expect to continue to support additional phase III starts. Many of these mid-stage programs have read out data recently or have upcoming data readouts that, if positive, position these medicines to move into the next stage of development.
Data we presented at AAIC last week demonstrated that monthly and quarterly dosing with IONIS-MAPTRx achieved substantial, durable, and dose-dependent reductions in all forms of CSF tau with generally favorable safety and tolerability in Alzheimer's disease patients. Based on these results, Biogen plans to advance IONIS-MAPTRx into a larger phase II study to more fully test our antisense medicine as a treatment for Alzheimer's disease. Coming up in the second half of this year, we expect data from Vupanorsen phase II-B study in patients with dyslipidemia and cardiovascular disease. We look forward to starting our phase I, II study of ION582 for the treatment of patients with Angelman syndrome. Later this year, we look forward to reporting additional data from the phase II study of IONIS-PKK-LICA in patients with hereditary angioedema.
We also look forward to initiating our phase III study with this medicine, which is on track late this year or early next year. Our partner, Bayer, is continuing to make good progress in the phase II-B study of IONIS-FXI-LRx in patients with end-stage renal disease, putting this study on track for data in the first half of next year. As the year unfolds, we look forward to providing future updates as the pipeline continues to advance and we achieve additional catalysts from across the pipeline, which together move us closer to achieving our goal of 12 or more marketed medicines in 2026. With that, I'll turn the call over to Brett to close this portion of our call.
Thank you, Richard. In the first half of the year, we continued to successfully advance all our key strategic objectives. We have made great progress in evolving our business model, building our commercial capabilities, and preparing for multiple Ionis commercial launches. We've made significant progress in advancing our technology to expand our drug discovery capabilities.
With the progress we've made across our pipeline, including achieving key phase III milestones, which moved tofersen, Eplontersen, and Pelacarsen closer to the market, we are very well positioned to achieve our goal of delivering a substantial number of new products to the market in the near and the long term. The second half of the year is shaping up to be even more successful with several new key clinical trial initiations and clinical readouts, including results of the phase III VALOR study in patients with SOD1 ALS by this fall. Importantly, we have the resources and people we need to invest in all our strategic priorities, positioning us for accelerated growth and to help ensure great success for Ionis for many years to come. With that, I'll now open the call up for questions.
We will now begin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speaker phone, please pick up your handset, before pressing the key. To withdraw your question, please press star then two. At this time we will pause momentarily to assemble our roster. The first question comes from Jason Gerberry with Bank of America. Please go ahead.
Hey, thanks for taking my questions. A couple for me, just maybe can you help set the expectation into the phase II-B for Vupanorsen? Just curious, the high unmet need subgroup of patients with more severe triglyceride levels. Just wondering your thoughts in terms of the ability to read across from this study to that patient population. I guess just secondarily, have you given any thought to Huntington's disease and potentially next steps to revisiting that as a category? Just curious your latest thoughts on Huntington's. Thanks.
Sure, Jason, thanks for the question. For Vupanorsen, the phase II-B study, which Pfizer has said that they plan to have top-line data announced this year. As a reminder, it's in patients with high non-HDL cholesterol and high triglycerides. This is the patient population that if they move to phase III, which is the plan, that they're targeting for a phase III program. The unmet medical need for remnant cholesterol combined with high triglycerides, mixed dyslipidemias, if you will, is very significant. A very large patient population, one that positions this Vupanorsen to target mixed dyslipidemias quite nicely. We're also, in addition to Vupanorsen, we're very excited about our apoC-III drug that we're moving into phase III for severe high triglycerides as well.
We think that this mechanism is the best mechanism, best-in-class strategy for patients suffering purely from high triglyceride-related diseases, which affects millions of people. I raise that because it's important to realize that Vupanorsen and our apoC-III medicine are targeting very large patient populations and distinct populations that have some overlap, but they really are quite distinct for that. I could touch on Huntington, but first I'd like to see if Richard wanted to add anything to what I said.
No, I think you covered it well, Brett.
Okay. Thank you, Richard. As for Huntington, as Richard has said, Jason, they continue to analyze all the data, and they've promised an update on the results of the study as they go through more data, as well as next steps by the end of the year. We're working very closely with Roche on this, and so stay tuned for the second half of the year for an update.
All right, great. Thanks.
The next question is from Luca Issi with RBC. Please go ahead.
Hello. Fantastic. Thanks so much for taking my question. Congrats on all the progress. Two quick one on the pipeline. Maybe the first on TTR, Richard. Can you expand a little bit more on the interim analysis that you're planning for TTR LICA in mid-2022 for polyneuropathy? It looks to me that the interim analysis is almost eight months, actually. It's actually eight months ahead of the primary endpoint.
Wondering what gives you confidence that with such a short follow-up, you're going to be able to see a separation of the curves. The second question is on ENaC. Wondering if you can provide any update there. We've seen Arrowhead also running into safety issues there. Any thoughts on whether the safety issues that they have had are similar to the one that you saw and maybe bigger picture, if you can comment on what's next for the respiratory franchise? Thanks.
Yeah. Thanks. I'll take that Eplontersen question for you first. Our confidence, of course, derives from the first polyneuropathy study we ran with TEGSEDI. Same mechanism of action. We believe we have a much safer drug and a much well-tolerated drug with once monthly administration. At eight months with TEGSEDI in that trial, we had statistically significant improvements in our endpoints. It was already separating from placebo quite nicely at that time point. We believe that gives us the kind of confidence that we need in going into this interim analysis. In fact, it's quite high. I think the second question that you had, I can't even speak to what might be happening with the competition. We had a preclinical issue. We're working through that, and we're very confident that we'll be able to.
Yeah. The finish line. Yeah. If I could just add to what Richard said. Thank you, Richard. Is on Eplontersen, also what gives us great confidence, not only the fact that TEGSEDI showed statistically significant benefit in the same primary endpoints in the phase III study that was conducted for that drug at eight months. Eplontersen is showing even greater TTR reductions.
We're at around 90% reductions based at the dose we're using in phase III with excellent safety tolerability. It's like for all of our LICAs, as Richard mentioned. We're very confident in that outcome, and we're very comfortable with the regulatory path forward as well. Just to add on the pulmonary, we're working and making really good progress pre-clinically and looking at new designs, new molecules that can move the pulmonary program back to development in the future. Stay tuned for that. We'll talk more about that maybe at the end of the year or next year.
Super. Thanks so much.
The next question is from Yaron Werber with Cowen. Please go ahead.
Hi. Congrats to the team on all the progress. Thanks for taking the questions. This is Brendan on for Yaron. Just a couple of quick ones from us. I know you mentioned that you're looking to initiate the phase III HAE study by the end of the year or early next year. Just wanted to see what steps are left there if you already have alignment with FDA on the study design, and it's just logistics and getting it set up at this point, or are you still finalizing the study? Really quickly for Angelman, wanted to see if we might get any preclinical data from that at any point this year. What you might be able to tell us about timing and maybe trial design for the phase I, II. Thanks very much.
Sure thing. I'll take the HAE, then I'll ask Eric to talk a little bit about what we've presented and published on in the Angelman program after that preclinically. For HAE, we're putting final touches on the phase III study design. We're having very good discussions with regulators. Really, it's mostly logistics, Brendan. We're getting drug made. We're preparing for the phase III design, selecting our sites, moving forward for activation of sites. It's just blocking and tackling, honestly, at this point to get that study up and running. We're hoping it's a stretch goal to get it done and initiated by the end of the year. Certainly, we see it happening no later than the first quarter of next year.
When we share the full data set in the second half of the year for our phase II study, we also plan to share our strategy, our development strategy, what our phase redesign looks like, and why we think it will position PKK LICA potentially as the best-in-class molecule for HAE. Stay tuned for that in the second half. We got a lot of momentum going into the second half of the year and a lot of exciting news coming out as we think in the second half. Eric, we've published on Angelman's.
Yeah, we have. We were actually the first to elucidate the mechanism in collaboration with our academic colleagues that you can inhibit an antisense transcript and upregulate UBE3A, which is the deficient protein in Angelman syndrome. We spent a good amount of time trying to optimize the drug and find the ideal human development candidate. Took us a little bit longer than I'd hoped, but we've got a great-looking molecule and are looking forward to getting that started in the first human study later this year. Took everything we learned about how to make great neurology drugs from our extensive experience and tried to make a molecule that we hope will be best in class in this space and provide a great benefit to patients with Angelman.
The first in-patient study, the phase I, II study, will be focused obviously on safety tolerability, dose escalation, select dose based on biomarker readouts potentially for a phase III study to follow.
Got it. Thanks, guys.
The next question is from Yanan Zhu with Wells Fargo. Please go ahead.
Great. Thanks for taking my questions. Congrats on the progress. A lot of things going on. I have one question on the technology platform front with regard to Bicycle collaboration. Have you compared their bicyclic peptide approach targeting transferrin receptor with the approaches of using either monoclonal antibodies or antibody Fabs? Also, given your prior experience with myotonic dystrophy in clinical studies, when you were doing your diligence, do you feel there is enough fold increase in muscle exposure compared with unlabeled antisense that gives you confidence that you could perhaps restart the myotonic dystrophy program and have an accelerated path? That's the first question.
Thanks, Yanan. We're really excited about the advances we're making in targeted delivery across the board, including Bicycle. The answer is yes, we've done quite a bit of comparative work prior to completing the Bicycle deal. Eric led that effort with his team, I'll turn it over to him to tell you why we're so excited about Bicycle and how we believe we differentiate from other approaches.
Yeah, sure. Thanks, Brett. We absolutely have compared it with other transferrin receptor ligands. We were involved in this space reasonably early on and had extensively looked at how monoclonal antibodies and Fabs that target transferrin receptor 1 can deliver cargos to the muscle. We definitely demonstrated that that can happen, and we're interested in trying to find better ligands that we thought would make better drugs in the end.
That ultimately led us to Bicycle, which has these very unique bicyclic peptides where they've been able to develop high affinity ligands for multiple proteins, and transferrin receptor 1 in particular. We absolutely compared the Bicycle oligo conjugates to the Fabs and found them to be essentially identical in terms of the potency based on the oligonucleotide that we deliver. The key advantage here is the size. Monoclonal antibodies are big. Bicyclic peptides are small.
There's probably a 50 - 75 fold difference in weight, and that translates directly to less total drug that would have to be administered if you scale it up to a human dose projection because oligos are reasonably small and the bicyclics are smaller. We think that'll be a large advantage with this technology if we can make it work and make hopefully best-in-class muscle and cardiac-targeting antisense drugs.
As to the programs, you alluded to DMPK and DM1. Yes, we needed more potency in that program, and this is what the bicyclic transferrin receptor 1 targeting technology does for us. We think that it certainly has the potency enhancement to get us in the range of what we need clinically. Beyond that, we're not really prepared to comment exactly on what targets we'll advance or the timing. We have a whole host of neuromuscular and cardiac targets lined up that we think are great for this technology and are anxious to get it moving.
Great. Thanks for all those color. A quick question on tau lowering or the MAPT program. You showed us some very impressive reductions of tau. How should we think about this approach compared with, for example, antibody approach targeting tau? Could there be a kind of biomarker path forward with this approach, given the recent development with A beta approach? Thanks.
As to the path forward, Biogen said they plan to advance this into a larger phase II study to more fully test the clinical outcomes and clinical benefits associated with tau lowering. That's the strategy clinically. As far as a comparison of the antisense approach to an antibody approach, I really think there is no comparison. Tau is an intracellular protein. It's known to accumulate and aggregate inside the cells, and that's where our drugs work.
They turn off the translation and creation and synthesis of the tau protein by binding to and degrading the RNA. We turn off all forms of tau, and that's what we demonstrated in the clinical trial, that all forms of tau are reduced. To reduce tau in the CSF, by our mechanism, it has to be reduced inside the cell because that's where it comes from.
Whereas antibodies, you have a macromolecule that has a small penetration into the CNS space, and in the CSF, it binds to the tau protein and reduces it only in the CSF. We don't think those antibodies can engage tau productively inside of a cell, which is what our drugs are doing, and we think that's where the key pathology of tau is occurring. That you need to lower tau throughout the brain in all cell populations. We're very encouraged about our drug. We think it's one of the key things to test the tau-lowering hypothesis in AD, and we think it's a great one to test, and are excited that Biogen's taking it forward to do exactly that.
Great. Very helpful. Thanks for all the color.
Thanks, Yanan.
The next question is from Paul Matteis with Stifel. Please go ahead.
Hey, thanks for taking our question. This is Alex on for Paul. Actually, a follow-up on MAPT. I was wondering, from the phase I, II, if you could comment on the relative ASO doses versus inotersen phase III. Secondarily, curious if there were any biomarkers or vMRI sort of measures in this study, and if you could comment on that, or if you expect that this will get published or presented in the future. Thanks.
Sure. The doses weren't disclosed in that poster. We are working on getting our phase I data published, and so stay tuned for that, and hopefully we can share more information about it. I will say that this is a pretty good oligo, and we've been working hard on making advances in how we design and identify oligos and subtle tweaks to the chemistry and the design of the compounds. We've been able to make them more and more potent over the years. I think our PK, PD modelers have done a fantastic job predicting the human doses, and we think this represents one of the better molecules we've made, and it performed as expected. Hopefully we can share more data in a publication soon.
Can you just say whether or not there were biomarker data taken in this study, or is that not something that was done?
Well, we had a range of biomarkers and outcomes in the study. I can't comment beyond what we reported in terms of MAPTR lowering.
Okay, great. Thanks.
The next question is from Yale Jen with Laidlaw & Company. Please go ahead.
Good morning, thanks for taking the questions. This may be a little bit forward-looking that, in terms of Eplontersen, if you get approved maybe in 2023. The question is that after you integrate the Akcea operations, what's the future sort of commercial infrastructure or strategy you have should that be the case then that this will be your next product to launch?
Thanks, Yale. I'll ask Onaiza to talk about our Eplontersen program, why we're so excited about it, not just for the polyneuropathy 2.3, but also why we're excited about this program as a potential best-in-class for cardiomyopathy as well. Onaiza, are you on?
I am. Yes, happy to talk about our program and our commercial launches. We are absolutely building the capabilities to prepare markets for Ionis commercial launches. You are right, this would be one of the first ones that we would bring to market. It is, as Brett said, a foundational treatment, best in class for both PN and cardiomyopathy. We expect to see proven benefit in neuropathy, quality of life, a very favorable safety profile, and optimal self-administration and at-home dosing. We're very excited about moving this program forward. There is a brand team that's been formed around it, and they're preparing the markets for launches as well. On cardiomyopathy as well as the second indication, it is important to remember that is where we have the largest trial in CM.
We have about 750 patients that we're recruiting, and we are conducting this trial to generate just a robust set of clinical data. We're excited about this program as the second indication for Eplontersen because it's going to be really the breadth of data and the diversity of data that it's going to provide for clinicians on how Eplontersen can be used in a very dynamic market, with or without standard of care. It's going to be really an advantageous place for Eplontersen overall. Really good program, great indications, and again, looking for foundational treatment as best in class for both PN and CM.
Okay, great. That's very helpful. Maybe just one more question here, which is that you will have the acromegaly data readout in second half of this year. Could you recap a little bit of this program and what sort of expectation you guys may have? Thanks.
Sure thing, Yale. As you said, we're planning to share the results of the phase II study for our growth hormone receptor LICA medicine in acromegaly patients who are poorly controlled despite the fact that they're taking somatostatin analog. This is on top of somatostatin analog in that study. The data that we plan to share in the second half of the year will include also open label extension data, which we think is important to characterize the long-term profile for growth hormone receptor LICA in this patient population.
We will be presenting data on target engagement, transthyretin binding, safety tolerability, impact on IGF-1, and also patient-reported outcomes and other measures of how patients are feeling with this disease in this readout. We haven't identified the venue or the way in which we'll present the data or get the data out in the second half of the year. We're still working on that, but we will get it out in the second half of the year.
We're still analyzing quite a bit of the open-label extension data. As I said, we think that that's quite important to include. As a reminder, this is one study of a program for this drug. We also have the phase II study for GHR LICA in patients frontline monotherapy in patients with acromegaly. That study is expected to read out next year. We're positioning this drug potentially as a treatment for patients who are poorly controlled with standard of care, as well as potentially frontline, depending on how the data reads out.
Okay, great. That's very helpful, and congrats on all the progresses.
Thank you.
The next question is from Jessica Fye with JP Morgan. Please go ahead.
Hey, guys. Two quick questions on tofersen. What read-across to the rest of your neuro pipeline do you think investors can and cannot make based on the upcoming phase III results? Second one related to that product, can you talk about the reason why the compassionate use is currently restricted to those patients with the most rapidly progressing disease? Thanks.
Sure thing, Jess. Thanks for the question. We're very much looking forward, as of course you know, to the phase III readout for tofersen in SOD1 ALS. As we said in our presentation, this has the potential to be the very first disease-modifying treatment for a genetic cause of ALS, really any cause of ALS, really, when you look at it. We're excited about it. The read-through is significant if positive. It will be another demonstration of what we believe is the leading platform for the treatment of neurodegenerative diseases of any, when you look at the size of our pipeline.
It'll be a further confirmation that not only can we engage targets that are at the root cause of these diseases in neuro, as we've done for over six, seven, eight programs to date, that we can hit these targets well, that the safety, the tolerability is attractive, and that we can provide clinical benefit in patients with neurodegenerative diseases. We think that this has significant read-through in two ways. One, to the rest of our ALS platform, right? It will demonstrate that this platform, our strategy to target ALS, works. It bodes very well for two other genetically caused forms of ALS, our C9orf program, which is due to read out phase II readout next year, and our FUS genetic ALS due to FUS mutations, which is in phase III development.
We believe it also has significant read-through to the broad ALS population that has no known genetic cause, our Ataxin-2 program. Also beyond that, for neuro in general, it demonstrates all the things I already said about target engagement and tolerability, and also that we can penetrate key regions within the CNS and provide meaningful, hopefully meaningful clinical benefit to patients.
As for compassionate use, that's really a question for Biogen. I really not want to get ahead of what statements they've made on this. As you know, there's been a lot of pressure on Biogen to make this drug available to patients with SOD1 ALS because of the devastating nature and the rapidly progressing nature of the disease. Simply put, they believe that this drug will be available to all patients with SOD1 ALS, that's the hope, of course, in the near future. They focused on those with rapidly progressing forms of the disease because those patients may not make it to the time in which this drug is available for all patients with SOD1 ALS. Quite simply, I think that's the rationale behind it.
Great. Thank you.
Yeah.
The next question is from Mani Foroohar with SVB Leerink. Please go ahead.
Hey, guys. Thanks for the question. A couple quick ones. I know it's been danced around on this call and others. Can you lay out for us whether or not we could expect potential exploratory cardiac measures from the NEURO-TTRansform study? One of your competitors has discussed at length exploratory cardiac measures from their polyneuropathy study. Failing that, from the cardiomyopathy side, can you give us a sense of what you are seeing in the marketplace as opposed to what you're seeing in a clinical trial execution setting around use of tafamidis alongside oligotherapy in patients with combined neuropathy and cardiomyopathy symptoms?
Sure, Mani. I'll take the first one, and I'll ask Onaiza to talk a little bit about how we see the market playing out right now with RNA-targeted therapies and tafamidis, really, probably more importantly, how we see it playing out in the future. Yes, indeed, we have cardiac measures in the polyneuropathy-eplontersen phase III study. These are secondary endpoints and maybe some exploratory endpoints as well.
All the classic endpoints will be looked at for those patients with mixed phenotypes with cardiac involvement. That'll include the ventricular load and what build up in the heart, markers such as NT-proBNP, and other markers in that study, as we did in the TEGSEDI study, phase III study. Be on the lookout for that next year when the data reads out, as well as, of course, the primary endpoints, which is mNIS+7. For the eight months, it's also TTR reductions, right, Richard?
Yeah.
Yeah. Then as we bring this study to its completion at 15 months, we'll also have quality of life as a primary endpoint at that point. I think Onaiza might be the best one. Comment on the market for stabilizers and RNA-targeted therapies.
Yeah, happy to. Hi, Mani, how are you? Thanks for the question. Really your question is like, it's a geographical answer. In the U.S., we're seeing some fair amount of use of tafamidis. Again, they're doing a really good job of diagnosing and getting patients treated. We've done some good work with KOLs and just good market research with clinicians who prescribe this, as well as payers. The sense we're getting from them is that this is a really sick population. These patients actually really need care, and that they could see a world where we can easily use a silencer and stabilizer together. I think, mechanistically, of course, it would've been nice to have the silencer on us first. That's not how the order of entry really worked out. The market is large.
It's diverse, it's dynamic, and what I really, again, go back to what I like, what we're doing, is we're actually looking at the future world and how it's evolving, and we will have a set of data for clinicians where they want to use this with or without a tafamidis in a wide and diverse patient population. From a payer perspective, also, we've seen really no hesitation to use these products alone or in combination as well. Again, going back to this is a very sick population, and we need to do what's right for the patient here.
Thanks, Onaiza. Mani, do you have-
Great. Thanks.
Okay.
Thanks. Yeah, I have one quick follow-up. There's been a lot of discussion around the role of six-minute walk as an approvable endpoint in cardiomyopathy. It's a little different than the experience that tafamidis, VYNDAMAX has had. In your sort of commercial as well as clinical trial experience, what's the state of feedback you're getting from clinicians regarding the receptiveness to use therapies approved on a six-minute walk, but without survival data in hand? How do you execute on that when you're launching against an oral asset that does have a survival benefit on the label?
Onaiza, you want to run with that?
Sure. Yeah, listen, I think, again, you have to look at where the market is, and the market has survival data in there. I think it's going to be really important to be able to deliver that, to effectively find a place for that new therapy that's coming on place in terms of what is the cardiovascular risk reduction. I think it's going to be and is claimed as a very important factor for making a decision for these patients. That being said, we have as our secondary endpoint in our studies, the functional improvements. Yeah, they're important for patients, and 6-minute walk is a good functional improvement.
Again, in a market where things are already established with CVRR, I think it's going to be about that as well as how quickly you actually see the effect on patients, because these patients do progress, and those are the two things that are coming up as really important for us.
Yeah.
In our criteria.
Just to add to that, Mani, as you know, for the mixed phenotypes, the hereditary phenotypes with cardiovascular cardiomyopathy and polyneuropathy, those six-minute walk tests are a little complicated because of the polyneuropathy component to the disease. If you're improving polyneuropathy in the feet, you may be able to improve six-minute walk distance that has nothing to do with improvements in cardiomyopathy. It's a little complicated. We believe the outcome data will drive the greatest, by far, value for these drugs when that's demonstrated.
Great. That takes the questions, guys.
The next question is from Myles Minter with William Blair. Please go ahead.
Hi, everyone. Just a quick question on the MAPT data at AAIC. I noticed that particularly on the total tau levels, they seem to keep decreasing even though these patients have been off four months of drug, or have been off drugs for four months. I'm just wondering how you're thinking or how Biogen may be thinking about dosing frequency in that particular indication as you move into a better powered phase II. In the publication, will that include CDR-SB, sum of the boxes followed up for this long-term extension part? Thanks.
Yes. As I said earlier, we think this is a great drug, and duration of action is one of the things that we've been working hard on. I think that continued tau reduction that's mentioned is evidence of that. We hope to expand on that with the publication as we share more data on the program and really demonstrate that this is an outstanding looking molecule. Of course, we'll design our studies to support the optimal dosing schedule. If you're doing intrathecal injection, fewer injections less frequently are a good thing.
The durability really is remarkable for the drug. It probably supports biannual dosing potentially. Not that is necessarily the dosing regimen for the phase II study, but certainly the data supports that. As Eric said, it's a reflection of the continued improvements we're making, not just in the drugs we identify in neuro, but across the board.
Just with the CDR-SB, sum of the boxes, is this something that will be included in the publication, or was that only measured as baseline to screen those patients in? Thanks.
I don't think we know yet whether or not the long-term extension will be in the publication. Typically, when we publish first in patient studies, it's just the randomized portion of the study. The long-term extensions will be presented at medical meetings to follow and those sorts of things, and maybe publications as well. Don't have a definitive answer for that question, Myles.
No worries. Thanks for answering .
Thank you.
The next question is from Esther Rajavelu with UBS. Please go ahead.
Hey, good morning. Thank you for taking my question. On FUS ALS, can you help us understand some of the trial design considerations for this phase III that you're starting to enroll compared to tofersen? I have a follow-up on another topic.
Richard, do you want to take that? Or should I?
Sure. This is FUS. Yes. It's similar in terms of the design and the regimen. It is a phase III registrational study, so it's moving directly from what has been an open label, single patient or a few patients being treated to a full registration with all the health authority input with the design, et cetera. I think in terms of where we are with FUS, we're very confident that the design that we've put together is one that will be supportive of this, again, a very good drug moving into phase III. We're excited that the program has started and patients are enrolling.
To add to that, Esther, the primary endpoint is the same as the tofersen, so there's a direct link there. The ALS functional rating scale. Obviously, we have the ability to measure target engagement in patients too, like we did with tofersen study. It's quite similar. It's a longer study than the six-month tofersen study. It's like 250, almost a year, I think, treatment, right?
Right. I think it's 272 days or something. The longer duration of treatment, is that specific to this patient phenotype, or what's the thought behind that?
ALS is a rapidly progressing neurodegenerative disease. There are certain forms of ALS that are more rapidly progressing than others. FUS is sort of your normal, if you will, if you want to use that word, progressing patient population for ALS. It takes a little longer, and therefore the study is longer.
Got it. Okay. Thank you. Then a quick follow-up on the transferrin receptor question that was asked earlier. You referred to cardiac indications, but can you maybe help us understand whether you're referring to cardiometabolic indications or more tied to the structural issues in the heart?
We're focused on diseases like heart failure. Targeting cardiac myocytes directly, not metabolic or those sorts of things. We're going after well-validated targets based on genetics as well as validated targets based on pre-clinical data that we've generated and others have generated, targeting directly cardiac myocytes. Different forms of heart failure is our primary focus there.
Understood. Thank you very much.
The next question is from David Lebowitz with Morgan Stanley. Please go ahead.
Thank you very much for taking my question. When you look forward to the phase I readout, could you just run us through what we could expect to see in that readout? What you think needs to be achieved as far as being able to exceed regulatory thresholds? That would be very helpful. Thank you.
Sure, David. Obviously, this is a randomized, placebo-controlled, six-month trial, tofersen placebo versus placebo. Primary endpoint, ALS Functional Rating Scale. That's where the focus is to demonstrate statistically significant clinical benefit to patients on drug versus placebo. There'll also be quite a bit of supportive long-term extension data from that study as well.
We do not believe that SOD1 reduction, the biomarker, will be sufficient for an approval by itself. With that said, there's enormous outcry for this drug today by the ALS community. This is a very active patient community that has cried out for, as we touched on earlier in the compassionate use study that Biogen opened up, cried out for this drug a long time ago to get access to it.
There are no treatments for this disease, and it's a severe neurodegenerative disease, as you know. That's what we're looking for. That's what we're feeling confident about based on the phase II data and the fact that we're targeting the known cause of this disease. There are no treatments for this disease, so I do believe that regulators will be open-minded on trying to deliver a drug like this to patients as rapidly as possible.
Thank you very much for taking the question.
Thank you, David. I think that that's our last question. With that, I'd like to thank everybody who joined us on our call today. We have a lot of momentum going into the second half of the year, and as the year unfolds, we're really looking forward to providing further updates as we continue to execute on all of our goals. Until then, thanks for joining us today, and have a great day.
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.