Good morning, and welcome to the Ionis Pharmaceuticals third quarter 2022 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the conference over to Ms. Julie Tepper, Investor Relations, to lead off the call. Please go ahead, ma'am.
Thank you, Chuck. Before we begin, I encourage everyone to go to the investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Richard Geary, Executive Vice President of Development, and Elizabeth Hougen, Chief Financial Officer. Joining us for the Q&A portion of the call are Eric Swayze, Executive Vice President of Research, Eugene Schneider, Chief Clinical Development Officer, and Onaiza Cadoret-Manier, 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 SEC filings for additional detail. With that, I'll turn the call over to Brett.
Thanks, Julie. Good morning, everybody, and thanks for joining us on today's call. This year has been catalyst-rich and strategically important for Ionis, enabling us to conclude 2022 in a position of significant strength and setting us up for substantial growth. We're looking forward to potentially adding 2 new commercial products from our rich phase III pipeline to our portfolio next year. These are, of course, eplontersen for ATTR polyneuropathy and tofersen for SOD1-ALS. In addition, we've made excellent progress advancing our late and mid-stage pipeline. With 8 positive key data readouts so far this year, our rich phase III pipeline is poised to expand, with 2 new phase 3 starts expected in the first half of next year.
Based on all our pipeline progress, we're well-positioned to continue delivering a steady cadence of phase III data readouts in 2023, 2024, 2025, and beyond. This year, we have also advanced our commitment to deliver transformative medicines to the market with our go-to-market commercial preparations for our near-term product opportunities, eplontersen, olezarsen, and donidalorsen. We have also made great progress expanding and diversifying our technology with the recent advancement of three new programs into IND-enabling development activities. These programs involve our first medicines incorporating LICA technology for enhanced delivery to muscle, and our mesylphosphoramidate or MSPA backbone chemistry designed to improve both efficacy and durability. These advancements further enhance and expand our drug discovery capabilities for both our new programs and our follow-on programs. We've also taken additional steps to support our future growth.
We recently began work on a new state-of-the-art manufacturing facility. This facility will ensure we have the capacity we need to continue to successfully deliver our medicines to patients and continue to expand into new chemistries. We also recently capitalized on the record demand for life science real estate assets by monetizing several of our facilities through a sale leaseback transaction. This transaction further strengthens our balance sheet to support our plans for accelerated growth. With that, I'll turn the call over to Richard to discuss our recent key data readouts, pipeline updates, and preview our upcoming catalysts. Beth will review our third quarter financial results, the financial impacts of our recent real estate transactions, as well as review our full year financial guidance. After Beth, I'll wrap up our prepared remarks before taking your questions. Now over to Richard.
Thank you, Brett. Well, our pipeline has certainly performed extremely well this year. We've reported eight positive data readouts so far this year. As a result, we are looking forward to potentially having two new medicines on the market and expanding our rich phase 3 pipeline next year. Over the next few minutes, I will review our recent achievements and then preview our upcoming catalysts. Our next potential medicine to reach the market is tofersen, our medicine for patients with SOD1-ALS. Tofersen is currently under priority review with the FDA, has the potential to become the first approved disease-modifying medicine for the treatment of a genetic form of ALS. Tofersen has a PDUFA date of April 25, 2023. In September, we presented positive eplontersen data from the phase 3 NEURO-TTRansform study in patients with ATTR polyneuropathy at the International Symposium on Amyloidosis.
In the eight-month interim analysis, eplontersen achieved highly statistically significant and clinically meaningful change compared to historical placebo for its co-primary and key secondary efficacy endpoints, including demonstrating robust TTR reduction from baseline, with improvements in neuropathy impairment and quality of life relative to baseline in a substantial portion of patients. With these very positive data, we and AstraZeneca look forward to filing for regulatory approval in patients with TTR polyneuropathy in the U.S. before the end of the year. Additionally, we are extremely pleased with the continued progress of CARDIO-TTRansform, the largest and longest study in patients with ATTR cardiomyopathy to date. Since we initiated CARDIO-TTRansform in late 2019, patients are being diagnosed much earlier in the course of their disease as a result of greater disease awareness and improved disease detection methods.
This evolution in the ATTRCM landscape is supported by new published and presented data from the scientific community. Based on these new findings, along with careful monitoring of patient demographics and blinded event rates in our study, we've increased the target enrollment goal to 1,400 patients. This increase will ensure our study fully reflects the entire population of patients, including patients with less severe disease. We believe this further increases our probability of delivering a highly positive study outcome that best positions eplontersen to successfully compete and lead in this growing dynamic and global market. Importantly, based on our current rate of enrollment and the added power from additional patients, we remain on track to report data in the first half of 2025. Our broad olezarsen development program in FCS and severe hypertriglyceridemia is also progressing nicely.
The phase 3 BALANCE FCS study is fully enrolled, is planned to read out mid-next year. Our broad clinical program supporting the larger severe high triglycerides or SHTG indication also continues to progress well. CORE, our first pivotal study in patients with SHTG remains on track for data in 2024. CORE2, our confirmatory pivotal study in the same population, is now underway with data also expected in 2024. We recently initiated ESSENCE, a supportive phase 3 study. ESSENCE is designed to build out the safety database for the much larger SHTG indication. With first-mover advantage, we remain very confident in the potential of olezarsen to be a substantial driver of future growth. Now, our donidalorsen OASIS phase 3 program in patients with hereditary angioedema remains on track for data also in 2024.
We will report new longer-term data from the phase 2 OLE study this Sunday, November 13th, at the American College of Allergy, Asthma, and Immunology annual scientific meeting. The goal of the OLE study is to reinforce donidalorsen's potential best-in-class profile by demonstrating long-term protection from HAE attacks, along with longer-term safety and tolerability in patients treated for one year. We look forward to sharing our OLE data with you on Sunday. Recently, we and our partners presented positive data from several of our mid-stage programs further advancing our rich pipeline. We recently presented positive and competitive phase 2 data from IONIS-FB-LRx in patients with IgA nephropathy at the American Society of Nephrology's Kidney Week.
This study was designed to demonstrate clinical proof of concept for the potential to treat IgA nephropathy by targeting complement factor B and the alternative complement pathway, and of course, to evaluate safety and tolerability. IONIS-FB-LRx met the primary endpoint, demonstrating substantial and clinically meaningful reductions in 24-hour urinary protein in patients with IgA nephropathy, with a mean reduction of 44%. Additionally, patients effectively maintained their eGFR throughout the study and together with this, achieved a favorable safety and tolerability profile. Based on these positive data, Roche already announced their plan to advance IONIS-FB-LRx into phase 3 development by mid-next year. Also at Kidney Week, Bayer reported positive phase 2b study for fesomersen, our Factor XI LICA medicine for the treatment of thrombosis.
The goals of the RE-THINC ESRD study were to demonstrate dose-dependent and substantial reductions in factor eleven levels and no increase in bleeding risk compared to placebo in patients with end-stage renal disease. Safety and tolerability were also key outcomes. We were pleased that fesomersen exceeded all of the goals of the study. Fesomersen achieved dose-dependent and sustained median reductions in steady state factor eleven levels that exceeded 85% at the top dose and with no imbalances in major bleeding or non-major bleeding compared to placebo. Additionally, incidences of dialysis circuit clotting and AV access thrombosis diminished significantly with decreasing factor eleven levels, both of which were exploratory efficacy endpoints. Fesomersen demonstrated favorable safety and tolerability in this study. Despite these highly positive results, Bayer made the decision to only advance their small molecule factor eleven medicine to phase 3 and therefore returned fesomersen to Ionis.
While we understand Bayer's decision not to move a second Factor XI drug forward, we and our clinical advisors believe that these positive data support advancing fesomersen into pivotal studies. Given the large potential addressable patient population and numerous potential indications to explore, we are focused on getting fesomersen into the hands of the right partner to deliver it to the market as soon as possible. Turning now to the exciting bepirovirsen data GSK reported at AASLD. Bepirovirsen is a potentially transformative treatment for people living with chronic hepatitis B. HBV is responsible for approximately 900,000 deaths annually. The goal of the Phase 2b B-CLEAR study was to assess efficacy, safety, and tolerability in HBV patients treated with bepirovirsen.
This was an important study because it demonstrated for the first time that bepirovirsen alone or in combination with antiviral nucleoside or nucleotide inhibitors can deliver a sustained and substantial reduction in both viral DNA and HBV surface antigen, which together are key measures of efficacy. The results show that 9% of patients on nucleoside/nucleotide analog treatment, 10% of patients on bepirovirsen alone achieved the primary outcome of viral DNA and HBV surface antigen below the limit, the lower limit of quantification at 24 weeks after bepirovirsen treatment. These data strongly support the potential for bepirovirsen to achieve functional cures in people suffering with chronic HBV infection. Based on these encouraging data, GSK is currently in discussions with regulators on the design of the phase 3 studies, with plans to initiate a robust phase 3 program in the first half of next year.
Well, it has been an eventful and catalyst-rich year, and we anticipate continuing the momentum with the remainder of the year and in the year ahead. We're looking forward to presenting our upcoming HAE data this coming Sunday, and we are on track to file the NDA for eplontersen by the end of the year. Next year, we're looking forward to more key catalysts, including the potential approval of tofersen in the first half of the year. Full 66-week data from the NEURO-TTRansform study of eplontersen. The potential FDA approval of eplontersen later in the year. Phase 3 data from olezarsen in FCS patients, along with the initiation of two new phase 3 programs, among other important advances. With that, I will turn the call over to Beth.
Thank you, Richard. This morning I'll provide a summary of our third quarter results, discuss our recent real estate transactions, and then touch on our full year guidance. We earned revenues of $160 million and $435 million for the third quarter and year to date, respectively, an approximately 20% increase over last year. Our revenue continues to be derived from numerous diverse sources with approximately half from our marketed products and the balance from numerous partner programs. Our operating expenses for the quarter and year- to- date reflect our continuing investments in advancing our rich pipeline and commercial readiness activities. Notably, we continue to maintain our healthy balance sheet with cash and investments staying steady at approximately $2 billion through the end of Q3.
Spinraza's global sales were $431 million for the third quarter and $1.3 billion year -to- date. As a result, we earned $62 million and $175 million in royalty revenue for the corresponding period. In the US, Spinraza sales continued to stabilize in the third quarter. Additionally, we continued to see positive trends in discontinuation rates. We expect to see the same dynamics play out in markets outside the US, which we see as a path for Spinraza to return to growth. Spinraza's potential to return to growth is further supported by Biogen's continued geographic expansion and their robust lifecycle management program. This includes the work Biogen is undertaking to further characterize the remaining unmet medical need of patients with SMA with their ASCEND, RESPOND and DEVOTE studies.
We earned R&D revenue of $87 million in the third quarter and $212 million year -to- date, both of which increased substantially compared to the same periods last year. Year- to- date, we earned $85 million from Biogen for advancing neurological disease programs under our strategic collaboration. We also earned $63 million from Roche for licensing and advancing IONIS-FB-LRx and $55 million in cost-sharing payments from AstraZeneca for their portion of eplontersen's development costs. Our non-GAAP operating expenses increased in the third quarter and year to date compared to last year and were in line with expectations. The increase was driven by higher R&D expenses from advancing the six phase 3 studies we are currently conducting, with eplontersen comprising our largest investment.
Our R&D expenses also included increased spending for CMC and medical affairs activities to support our near-term commercial opportunities. SG&A expenses increased in the third quarter compared to last year as we ramped up our go-to-market preparation. Year-to-date, SG&A expenses were below the same period last year, continuing to reflect the substantial savings we realized from the Akcea integration and Sobi transactions. As Brett mentioned, we recently took two important steps to support our future growth. We entered into a long-term lease to construct a state-of-the-art manufacturing facility, significantly increasing our capacity to bring our medicines to the market and to expand into new chemistry. We will oversee the design and construction of the facility, ensuring it will incorporate advanced sustainability and environmental protection features. For example, we expect that approximately 50% of the new facility's power requirements will come from renewable energy sources.
We anticipate completing this project in 2025. Based on our early design work, we expect it to cost us approximately $350 million. We also entered into a sale leaseback transaction, which took advantage of the record demand for high-quality life science real estate assets. This transaction bolstered our cash balance with approximately $240 million in net proceeds, plus funding to expand our R&D campus. It also enabled us to retain control over the operation of our facilities. We used a portion of the proceeds to pay off our existing mortgage on these properties. In doing so, we reduced our long-term debt.
By putting this cash to work, we believe we can generate substantially more value advancing our growth initiatives, including expanding and advancing our pipeline and technology, preparing for multiple product launches, and building our new manufacturing facility. Our Q3 results keep us on track to meet our 2022 revenue, operating expense, and net loss guidance. We continue to expect revenues of more than $575 million, with commercial and R&D revenues roughly split 50/50. As our phase 3 studies continue to progress, we expect our R&D expenses to increase between 25% and 30% this year compared to last year. 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.
In total, we expect our non-GAAP operating expenses to come in at the lower end of our guidance, which is between $825 million and $850 million. Since our recent sale leaseback transaction was not contemplated in our guidance, we are increasing our 2022 cash guidance from $1.7 billion to $2 billion. Looking to the future beyond 2022, we expect our strong financial foundation to continue to serve us well. As we continue to invest in advancing our strategic priorities, we are poised to deliver significant future growth. With that, I'll turn the call back over to Brett.
Thanks, Beth. As summarized this morning, we made great progress this year in advancing our key priorities to grow our commercial pipeline, to deliver an abundance of new transformational medicines to the market, and expand and diversify our technology. We're on track to file the eplontersen NDA by the end of this year, and with tofersen currently under priority review with the FDA, we're positioned to add these two new medicines to our commercial portfolio next year, assuming approval. Our late-stage pipeline continues to advance and expand, setting itself to extend our phase 3 data readouts next year and for many, many years to come. We've made important advances to expand and diversify our technology with more advancements still to come, and we've taken additional steps to support our growth. Importantly, we have the resources to continue executing on our priorities to drive substantial value for all stakeholders.
This has been a great year for Ionis so far, and I think next year and the years to come are going to be even better. We're looking forward to sharing more on our progress in the coming months. With that, I'll now open the call up for questions. Operator, if you could open up the queue, please.
Will do. 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're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we'll pause momentarily to assemble our roster. The first question will come from Gary Nachman with BMO Capital Markets. Please go ahead.
Hi. Good morning. First on eplontersen, just explain a little bit more the rationale for further expanding the cardiomyopathy study, what you were seeing in terms of having too many earlier-stage patients. Did you consider extending the duration of the study at all beyond what you did previously? And just how you're confident that the timeline won't change in terms of getting those data. That's one. And then just on the tofersen NDA, it was extended 3 months. Just explain why, you know, if the FDA asked for any additional information, and if you guys are still anticipating a panel, and how you and Biogen are preparing for that, what you think the, you know, might be discussed if there is a panel. Thank you.
Sure thing, Gary. Maybe I'll take a stab at the tofersen question, then I'll turn it over to Eugene to discuss the rationale, reasoning behind the eplontersen protocol, cardiomyopathy protocol amendment. For tofersen, yeah, there was an extension of the timeline for the NDA PDUFA date to April 25, 3-month delay, major amendment. Primarily because the FDA has communicated that they just need more time to review all the data. It's really not a request for any substantial or significant additional data that they needed to do the review. It was really a bandwidth issue principally. You know, they have a lot going on in the neuro division, especially this past fall, for similar indications.
We suspect, although not, you know, definitive, that that probably caused them to have to take more time to review the dataset. We're very much looking forward to the data readout, the decision, the outcome from the review by the FDA. Nothing new on the position by the FDA on a AdCom. We haven't heard anything new. We're still assuming that they're planning to have an AdCom at some point, and we're very much looking forward to that as well. Eugene, why don't you take us through the rationale, and also, you know, the importance of the change to the cardiomyopathy phase three trial for TTR?
Sure, Brett. Thanks for your question. As Richard already mentioned in his remarks, it is clear to us and to many of the advisors we've been talking to that the population with ATTR cardiomyopathy has changed substantially over the past several years. As you recall, the primary source for us to power the study, the original study that we started back in 2019 was the ATTRACT dataset, which the study that Pfizer conducted quite a few years back. The more data became available to us, internally as well as externally, and importantly, quite a few publications have now endorsed that the patient population has changed in a meaningful way. Specifically, they come to a definitive diagnosis earlier than they used to.
As a result of that's a factor of greater disease awareness, better diagnostic measures, and that results in the patient journey being relatively different to what it used to be. When ATTRACT was conducted, patients came to attention late in their clinical presentation and had multiple early events that were again, as I said, used for the original powering of the study. As we assimilated all of the data externally and internally coming from our study, it became clear that the study was not powered properly based on those outdated assumptions, and we needed to resize the study accordingly. Of course, the question about duration is an important one, and we've looked at that as well.
We've considered against it, extending the duration even further because that would substantially delay the timing of the readout. We felt that, again, the upsizing of the study alone was sufficient to ensure that it's properly powered without taking a significant penalty of time.
Thanks, Eugene. I'll just add, and of course, we also have patients in the open label extension of the phase 3 CARDIO-TTRansform study who have now completed the 140 weeks, so we wouldn't wanna lose those patients. We can accomplish the same objectives, the same goal by increasing the sample size, which we did. We think that this is a strategic, important move to the study to really help ensure for the most successful outcome possible for CARDIO-TTRansform.
Okay. That's very helpful. Just to confirm, you don't need to increase the number of sites and, I guess enrollment has been going quite well. Maybe just comment on that. Thank you.
Yeah. Right. You know, adding 400 patients and not changing the timing for the readout means that we're well ahead in enrollment. Enrollment's going very well. We're not needing to open up new sites for the study. Same existing sites, and we're just moving ahead rapidly to get to the 1400 number.
Okay, great. Thanks.
Sure.
The next question will come from Yanan Zhu with Wells Fargo. Please go ahead.
Hi, thanks for taking my questions and congrats on the progress in the quarter. Have a follow-up on CARDIO-TTRansform study and also a question on Lp(a). For CARDIO-TTRansform, how does the changing demographics change your powering assumption in terms of event rate in the control arm and effect size? And what proportion of on tafamidis patients did you assume in your powering assumption? For Lp(a), you know, how do you and your partner, Novartis, view the data for olpasiran presented at the AHA meeting, where they showed up to 100% Lp(a) reduction? How does that affect your outlook for pelacarsen? Thank you.
Thanks, Yanan. Two great questions. I'll ask Eugene to share what he can share about powering assumptions and so on, and then Richard to talk about pelacarsen. Sure. Thanks, Yanan, for your question. Related to our original assumptions, you may recall we did what we thought was responsible and conservative thing to do, which was assuming that all of our placebo patients will be on the background of tafamidis. We took essentially the tafamidis arm event rate in our original power calculations. As I just said, even that rate turns out to be overly quite a bit different from what we're seeing in what's been published recently to be the case in patients in general in today's care.
Even that rate was overly high relative to the population available today. We haven't really changed any of our other assumptions on the treatment effect. As you know, the true treatment effect is not known, and we're not prepared to change any of our assumptions, nor have we commented on what specifically we used other than to say that we used what our advisors said would be considered clinically meaningful for them. Thanks, Eugene. I'll just add, you know, we're focused on the CARDIO-TTRansform study, of course, Yanan, but, you know, this change in demographics for TTR cardiomyopathy, we think, applies to all contemporary studies evaluating investigational medicines.
We're in a very strategic position and made a very strategic move to ensure for a very successful outcome in the study. We think this is a very important move, and it gives us even greater confidence in a successful outcome. Pelacarsen, Richard.
Yeah, speaking directly to the question, how does it change our view on pelacarsen? Doesn't change it at all. Just to take you back to a reminder of phase 2 for pelacarsen, the dose that we took into phase 3 achieved taking 98%+ of the patients to goal. The goal is to get below that threshold of 50 milligrams. It's not to get to zero. Just, it's a little bit different than LDL. It's a different way of thinking. Lower is not better, but getting below that threshold is the goal. We're going into phase 3 with a product that gets nearly 100% of the patients to where they need to be out of risk. We're well ahead of the competition.
There's competition, and that just gives us all the urgency that we've had all along to get this thing to the market as quickly as possible.
Yeah. Thanks, Richard. Probably worth noting too that the epidemiology data is substantial, continues to grow, reinforcing the conclusion that that threshold is where you need to be, below that threshold is where you need to be to get out of harm's way. As Richard said, pelacarsen delivers on that, based on a very significant large phase 2 study, which we were studying the same patient population, the same phase 3 dose. Also, there's now emerging data, published data indicating that if you go too low on Lp(a), you can also, you know, cause some problems. There are publications now out there that says if you go very low on Lp(a), that you can actually have an increased risk for diabetes.
That's associated, not causal, not proven, but there's no need to go that low. All it does is bring further risk. I also wanna add this. This study is fully enrolled. This study is well on its way to reading out. This study gets reviewed by oversight committees, independent oversight committees regularly. That drives risk down, right? Competitors are going from a small phase two study to a large phase three outcome trial, okay? That brings risk. We like our risk profile today, fully enrolled, on our way to read out, well ahead of the competition, and getting virtually all the patients into the safe zone for Lp levels. I hope that answers your question, Yanan.
Yes. Thank you for all the helpful color, and congrats again on the progress this quarter.
Thank you, sir.
The next question will come from Myles Minter with William Blair. Please go ahead.
Hey, just a quick question on fesomersen. Just with your new partner considering you did show the data in ESRD with dialysis and it looks to be hitting everything that you set out to demonstrate, what sort of indications would you encourage a new sponsor to chase with that asset versus the oral inhibitor competitors that look to be going for a more acute setting?
Thanks, Miles. You know, as I think we've been very transparent with you over the last, you know, I think really last year, we were hoping Bayer was gonna take fesomersen forward based on positive phase 2b, really positive phase 2b data, which ended up being very positive. But we were also anticipating preparing for the eventual potential return because Bayer had three independent modalities being developed for targeting factor eleven: their own homegrown small molecule, in-licensed monoclonal antibody, and in-licensed fesomersen. As I said, as you know, the some of the small molecule data has been presented already at ESC. You know, a lot of aspects look good. I think it's a bit of a mixed bag. We're very pleased with the phase 2b data for fesomersen, the antibody data isn't out yet.
They made the decision to go forward with one drug forward. You know, Bayer was focused on end-stage renal disease as a potential population for fesomersen. We believe that that's too limited. We believe that a once a month, highly effective Factor XI inhibitor that achieves knockdown of Factor XI beyond 85% could be used for any prophylactic treatment to prevent thrombosis. You know, atrial fibrillation, secondary stroke prevention, end-stage renal dialysis, so on. We think that this has the potential to be used broadly, and that's what we're gonna be looking for in a partner.
A partner that can bring, as Richard said in his statements, to bring it to the market as quickly as possible, but also to really maximize the opportunity as a thromboprophylactic treatment for thrombosis.
Okay, cool. A quick one on CARDIO-TTRansform study. Just with the 400 patients that you're going to additionally enroll, are they gonna be equally balanced across the patients? Groups like wild type versus hereditary, tafamidis experience versus naive, or are they specific subpopulations as you've seen the demographics of the 1,000 patients currently that you might wanna bolster with the addition of these 400 patients coming into the trial? Thanks.
Yeah. Thanks for your question, Myles. This is Eugene. Clearly the opportunity here is to be fairly intentional with the remaining portion of the population that we're enrolling. Because we're in a position where all sites are open, we have an ability to be kind of more targeted in the types of patients that are being brought in, and that's what we're doing. As you said, of course, if you look at the epidemiology data, the risk is different for certain types of patients with regard to outcomes, and that's what we're trying to maximize here.
Of course, bringing in more hereditary patients, fewer patients who are on tafamidis therapy and obviously patients at later stages of their cardiomyopathy progression is going to be a priority, and that's what we're trying to do with the remainder of enrolled population.
Okay. Thanks for the questions.
Thanks, Myles.
The next question will come from Jessica Fye with JP Morgan. Please go ahead.
Hey there. Good afternoon. Thanks for taking my question. Can you give us an update on the Angelman program? Where does that stand, and when can we expect an update? Thank you.
Unfortunately, Jessica, we don't have a whole lot new to provide. We're enrolling a study. As you know, it's an open label extension study. You know, we're looking forward to completing the study as rapidly as possible. We're not really planning to share any data, right, Eugene. On you know, like, you know, on anecdotal observational data as we go forward. We wanna get the study completed. It's dose ranging, and it's intended to set us up for a phase 3 start, as quickly as possible.
Yeah, absolutely. It's also a partner program, so because of the open label nature and the fact that it's really in early stages of dose escalation, we're not really commenting on the timing other than to say it's going according to the plan.
It's going according to plan. It's enrolling well and, you know, we're just moving along.
Thank you.
All right. Thanks, Jess.
The next question will come from Luca Issi with RBC. Please go ahead.
Oh, great. Thanks for taking our questions. This is Lisa on for Luca. This question's for Brett, just a bigger picture. I know you've talked in the past about broadening your reach to technologies beyond antisense oligonucleotides. I was wondering if you can comment, what your latest thinking is there. Thanks.
Sure. Lisa, thanks for the question. We, as I mentioned in my prepared remarks, today, we're making great progress in advancing our technology in many different ways. We've now moved with a partner a new program using a new LICA targeting muscle. Can't talk more about the target or the indication at this point because it's a highly competitive area, but we're looking forward to providing an update, maybe next year. That has the potential to open up new diseases for Ionis as well as for partners targeting going after targets in the muscle. We've also now brought forward a new backbone chemistry called MsPA. We brought into development now on supporting toxicology studies for two CNS targets using that backbone.
That backbone is intended to increase efficacy, potency, as well as durability, so less frequent dosing. We expect that to translate to both CNS as well as systemic applications. Stay tuned for that. They're both for broad indications, one with a partner, one Ionis wholly owned. We expect to keep that one ourselves as well. As far as other approaches, as I've been saying now for quite some time, we will continue as we've been now for the last couple of years, evaluating siRNA strategies as well as ASO strategies. Our philosophy is let the best drug win based on preclinical data and bring it to the clinic.
We're expecting to move our first siRNA into development IND-enabling tox stage probably early next year, if not early this year. There are specific applications where we see advantages for siRNA, and there are specific advantages or areas where we see advantages for ASOs. You know, we're gonna be multi-modal here. As far as new platforms go, we're in sort of screening and evaluation phase right now about diversifying our platform capabilities. I really can't say much more about it than that, Lisa, except stay tuned. We hope to be able to make some progress in the future about, you know, some of our thoughts, ideas in that area.
Excellent. Thanks for taking our question.
Thank you, Lisa.
The next question will come from Gena Wang with Barclays. Please go ahead.
Thank you for taking my question. I just have one regarding the HAE update this Sunday. You already show pretty impressive early efficacy. With this early data, should we expect further improvement in attack reduction given the longer follow-up? And also, which data point will be more important regarding percentage of patient attack free versus percentage of a reduction in attacks?
I'll start at the beginning, but then I'd like Onaiza Cadoret-Manier to talk from a commercial standpoint, maybe what she views since we're planning to launch this drug ourselves, what is most important to patients and the prescribers for a prophylactic for HAE. Can't get ahead of the presentation on Sunday. That wouldn't be fair. We're expecting, you know, our plan is to show. I mean, it's hard to get better than the phase 2 data, right? I mean, these patients were essentially attack-free once we got to steady state after 5 weeks, after 1 dose. I mean, it's hard to get better. What we're really looking to do is to show whether that unprecedented efficacy is actually sustained for a year, right? As well as compliance, as well as the long-term tolerability.
Those go hand in hand from an approval standpoint, as you know, Gena, tolerability as well as sustained efficacy. That's really. I don't think we can go beyond. I mean, maybe. But it's really one disease and two disease of patients, or percentage points, I should say, because you can't get much better than the efficacy we showed in phase 2. What do you think, Onaiza. What's most important to patients?
Yeah, I would say to both physicians and to patients, Gena, you know, efficacy is first and foremost. We tested a hierarchy, an order of efficacy, just to kind of glean, like, what's most important. The zero attack rate is the number one efficacy measure, then followed by mean attack reduction, and then followed by how much you're actually withdrawing them off of the acute treatment. Those are. That's the order of hierarchy, but zero attack rate's basically the name of the game here. As Brett said, we in our phase twos, as you've already seen, showed a mean, kind of a max clinical efficacy of 97% zero attack rates, that we achieved, in weeks 5 to 17, so as quickly as after your first dose.
Also important to note that in this marketplace we also just completed some market research to say, "Okay, well, where are the patients at currently, with Takhzyro being the market leader, and the number one prophylactic agent that is used out there?" Again, with a pretty significant zero attack rate. We're still seeing patients have reported on average there are about 3 HAE attacks happening in a year. That's pretty substantial still. We do believe that we're gonna really fulfill this unmet need that still exists in the marketplace.
Thank you very much.
The next question will come from Joseph Stringer with Needham & Company. Please go ahead.
Hi, thanks for taking our questions. A quick one on the GSK partnered HBV program, the bepirovirsen. Just wondering if you could talk about the differentiation of your approach from, say, competitor approaches that are using dual or even triple combo therapy, some of which are RNAi-inhibitory knockdown based.
A great question, Joey. Thanks. I'm gonna ask Eric to comment on that.
Yeah, sure. Really, I think the key differentiator is that bepirovirsen as a single agent was able to do things that the other approaches really haven't been able to accomplish. That was evidenced by the B-CLEAR results, both showing around a 30% HBsAg below the limit of detection level at the end of treatment, and then maintaining that for about 10% of the patients at 24 weeks post-study. This highlights the potential of that drug to achieve the ever-elusive functional cure in HBV, where patients are being able to remove from therapy. I think, you know, GSK is doing a great job with this program and thinking about combination approaches.
They have the B-Together study ongoing right now, which is adding interferon on top of that. I think some of the competitive studies you're referring to are using HBV RNA lowering agents in combination with interferon and showed some HBsAg loss. That was at the end of study, not after removal of treatment. I think the field is moving forward. It's actually great to talk about HBV functional cures and having the buzz around it at the recent meeting that that's happening, and I think it's good for patients. Ultimately, we in GSK think that bepi will be a foundation for treatment of HBV, including combinations involving bepi that will hopefully increase the rate of patients that can remain therapy-free.
Yeah. I think that's something I just wanna emphasize what Eric just closed on, is that the 9-10% functional or undetectable levels 24 weeks after completing dosing, so off all drugs 24 weeks later, undetectable in about 10% of patients, whether monotherapy or on nucs, really is unprecedented and is the foundation to build from. That alone, we believe is an approvable mark, benchmark. That's a marketable endpoint or achievement. It's the beginning. Once we get into combination treatments and selecting subpopulations, we know that the undetectable levels were even greater in patients that had less HBV burden coming into the study in the 20-30% range, right? You know, all this is just the beginning.
It's still really impressive, but off we go. GSK is gonna be taking a comprehensive approach, phase 3 approach to looking at various combinations, immunotherapy, interferon combinations and so on, to maximize the value of bepirovirsen for HBV patients.
Great. Thanks for taking our question.
Thanks, Joseph.
The next question will come from Paul Matteis with Stifel. Please go ahead.
This is James on for Paul Matteis. Thanks for taking our question. Maybe just one on olezarsen. It looks like it could potentially be Ionis' first kind of independent drug launch. I guess one is that how you're thinking about it today to launch it yourself? If so, what would, you know, the investment there look like? Then maybe just separately, quickly, it'd be great to just get your thoughts on what you would wanna see efficacy and safety-wise to have confidence in a competitive drug profile there. Thanks so much.
Sure. Onaiza, you wanna take that?
Sure. Yes, that is a very correct assumption that this will be the first Ionis self-commercialization outside of Akcea, eplontersen being the first one. We are looking at 2 indications, as you know. The first one is in FCS, and then the second one in severe hypertriglyceridemia. Severe hypertriglyceridemia is a large patient population in the US with close to 3 million patients available for treatment over here with elevated SHTGs. This is the investment that's required is actually gonna be pretty focused, I would say. It would seem on the face of it, because of a large patient population, you're gonna go out and you know have to call on GPs and stuff.
We've done, you know, a fair amount of work to see where the referral patterns are for these patients, and they're coming into a couple of specialties. We're gonna be actually very targeted there. We're also gonna employ just, you know, really, good, more innovative tools such as omni-channel and, just a lot of AI to identify where the patients are from predictive analytics to be able to manage our investments, to get to this large patient population. We are working very actively in terms of preparing as these trials are all in phase 3s right now. The 2 core trials, which are the pivotal and confirmatory trials, and then the ESSENCE, which is safety trial that just got initiated as well.
As to what's the competitive profile, listen, the standard of care are fibrates and niacin and Vascepa, and their triglyceride reductions were in the 20%-30% range. We expect to do about 2.5-3x more of that. We have real good confidence that we'll get there based on our phase 2s, which as a reminder, the phase 2s were substantial, but were not in these really high elevated SHTGs. They were in the 200-500 milligram range. In that, we already showed a 62% placebo-corrected TG lowering. If you take a look at what we expect in the severe hypertriglyceridemia range, we expect that it's gonna be higher. As a reminder, we are also studying two doses, both the 50 milligram and the 80.
Our original phase 2s were at the 50. We have a very competitive profile. A reminder, we are well ahead of the competition, and we have a first mover advantage over here by a substantial margin. We'll get to really prepare the market, shape the market, and price the market.
Very helpful. Thank you.
Thank you.
The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.
Thanks for taking our question. This is Tommy on for Salveen. Our question is on eplontersen and polyneuropathy. Could you envision sharing detailed functional data over time, such as mNIS+7 trajectories at 1.5, 2 years, so that people can see the benefit that you're getting on these measures over time? Thank you.
Yeah. Thanks for your question. We are anticipating providing a pretty thorough and wholesome update on all of the co-primaries and key secondary endpoints once we look at our primary endpoint week 66 data next year, around mid-next year. As we said until that point, the key results have been disclosed, but we're obviously not able to share additional details. Once the week 66 data become available, the study results will be shared more broadly and more exhaustively.
Yes, Tommy, we expect to have that data by mid-year next year, and we'll also prepare a publication, presentation, so on. We're very much looking forward to sharing the full data set, the week 66 data at that time when we have it, when we have the data.
Thank you.
Mm-hmm.
The next question will come from Yaron Werber with Cowen. Please go ahead.
Hi, this is Brendan on for Yaron. Thanks for taking the questions. Just quick ones from us. First on cimdelirsen for acromegaly. I know you guys have so many things advancing, we can't really get to all of them here. But just wanted to see what the latest thinking is for timing and presentation of that data and maybe whether you're targeting a medical meeting for the release or not. And then just quickly wanted to see if there are any new updates on the Huntington's program with Roche, either on the timing or just the overall clinical plan with tominersen there. Thanks.
For our acromegaly program, we're still planning to review the data, the phase 2 data, the monotherapy data this year, right, Richard?
Correct.
I don't know if we're gonna have the opportunity to present the data because the year's rapidly coming to a close. Certainly a medical meeting is out of the question. We'll see what we can do. It's a relatively small phase 2 study. Probably not gonna be able to get that data out until next year. We're gonna try to get it out as quickly as we can. For Huntington's, Roche has done a pretty good job of sharing a lot of data on the post-hoc analysis recently. It's post-hoc, but it's compelling that patients with less disease burden were doing better and were doing better with less frequent dosing of tominersen. They've also laid out their trial design, right? Their phase 2 trial design in pretty detail.
It's a big study. There's, as I recall, I'm looking at you, Richard, there's 3 cohorts, about 120 patients per cohort, 2 doses, 1 placebo. Is that right?
Yeah. That's about right.
Yeah. It's a big-
Yeah.
It's a big study. They haven't given timing on exact first patient dose, but it's not far out there.
All right. Great. Thanks very much, guys.
The next question will come from Yale Jen with Laidlaw & Company. Please go ahead.
Great. Thanks for taking the questions. For GSK as well as Roche, given they are advancing the program forward to pivotal phase 3 study, do we anticipate any milestone payments to the company later this year or early next year?
You were asking about the GSK HBV program, Yale?
Yes. As well as the
Yes, sure.
HD for Roche.
Oh, it's the HD, and the property. Yeah. Beth?
On the milestones, I think with the license fee and milestones we've already earned in the second and third quarter this year, we will be looking forward to regulatory approval milestones for that drug going forward, and then potentially milestones as the geographic atrophy study continues to advance with that same drug, with the IONIS-FB-LRx.
Okay. That's very helpful. Maybe one more question here, which is for the AGT, for the treatment-resistant hypertension. Do we have a data readout? Could we get a little bit more color what to expect later this year? Thanks.
Yeah. Thank you, Yale. We have three studies in progress, right? We have the refractory hypertension with the Gen 2 LICA molecule. We also have the heart failure study with the Gen 2 LICA molecule, which is still, you know, in process. Both studies are in process. We have the Gen 2.5 in hypertension patients. We're probably gonna present the data. We're gonna pull all the data together and probably have a presentation in some form or another or announcement probably early next year. We want, we really wanna look at the full data set for both indications as well as both drugs because the next question that we're gonna get once we present this data, if we do it in pieces, is what are the next steps, right?
We don't know what the next steps will be until we look at all the data from two drugs and two indications. We'll certainly have completed at least one of those studies this year, but we'll probably wait till all the studies are complete before getting the data out there. Yeah.
Okay, great.
It's the responsible thing to do. Thanks, Yale.
Thank you.
Thanks, everybody. Yeah. We're gonna have to close it out. Thanks, Yale. Thanks, everybody, for your joining us, participating in today's call. We're really pleased with the quarterly results. We're very much looking forward to the rest of the year as well as moving into next year as well and continuing to provide you with updates on the progress we're making. Thanks again, and have a great day.
The conference is now concluded.
Bye-bye.
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