Good morning, and welcome to the Ionis Pharmaceuticals second quarter 2022 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Julie Tepper, investor relations, to lead off the call. Please begin.
Thank you, Betsy. Before we begin, I encourage everyone to go to the investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Beth Hougen, Chief Financial Officer, and Richard Geary, Executive Vice President of Development. 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, everyone, and thanks for joining us today. In the first half of this year, we moved significantly closer to delivering an abundance of transformational medicines to the market. The first half was highlighted by the positive results from the phase 3 NEURO-TTRansform study of eplontersen in patients with TTR polyneuropathy. Eplontersen met the co-primary and key secondary endpoints in NEURO-TTRansform, demonstrating highly statistically significant and clinically meaningful improvements in neuropathy impairment and in quality of life. Based on these positive results, we're well on our way towards filing an NDA later this year. At the same time, we and our partner AstraZeneca are advancing our global go-to-market preparations to launch eplontersen for the treatment of ATTR polyneuropathy.
We're also continuing to advance our ongoing CARDIO-TTRansform phase 3 study, which we expect will enable us to move into this much larger market for patients with ATTR cardiomyopathy. We and AstraZeneca are quite confident that eplontersen is well-positioned to successfully compete in this space. We're also pleased that tofersen is now under priority review with the FDA for the treatment of SOD1-ALS. If approved, tofersen could become the first disease-modifying therapy for a genetic cause of ALS. With a PDUFA date of January 25, 2023, tofersen has the potential to be our next product on the market, with eplontersen following shortly behind. Additionally, we continue to advance our late-stage pipeline, including completing enrollment in two of our phase 3 studies.
We have now fully enrolled the BALANCE study of olezarsen in patients with familial chylomicronemia syndrome or FCS, making this study our next potential phase 3 data readout planned for next year. Novartis also achieved full enrollment of more than 8,000 patients in the Lp(a) HORIZON cardiovascular outcome study of pelacarsen, further solidifying our first-mover advantage for this important medicine. Beyond the positive data we reported from our late-stage pipeline, we also reported positive data from six of our mid-stage programs so far this year. Based on positive phase 2 study results, our partners are planning to advance two new medicines into phase 3 studies next year. As a result, we expect to expand our rich phase 3 pipeline to at least eight medicines across 10 different indications.
In addition to advancing our pipeline, we're also making excellent progress in advancing our go-to-market activities for our near-term product opportunities eplontersen, olezarsen, and donidalorsen. With the potential to add two new medicines to our commercial portfolio next year, along with a steady cadence of phase 3 data readouts in the near and mid-term, we're looking forward to bringing numerous transformational medicines to the market. All of this positions us well to maximize value for patients and value for shareholders. With that, I'll turn the call over to Beth to review our second quarter financial results. Then Richard will discuss our recent key data readouts, pipeline updates, and will preview upcoming catalysts for the rest of the year. After Richard, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.
Thank you, Brett. In addition to achieving key pipeline milestones, we delivered strong financial results, earning revenues of $134 million and $276 million for the second quarter and first half of this year, respectively. Our revenues increased in the quarter and year-to-date over the same period last year, driven by revenue from numerous diverse sources, with just over half from our marketed products and the balance from our partnered programs. We continued to invest in advancing our rich late-stage pipeline and in our commercial readiness activities. Our operating expenses and net loss for the quarter and year-to-date reflect these important investments. Notably, we maintained our cash and investments essentially flat from Q1 to Q2 at $2 billion. SPINRAZA's global sales were $431 million for the second quarter and $904 million year-to-date.
As a result, we earned $60 million and $113 million in royalty revenue for the corresponding periods. In the U.S., SPINRAZA sales stabilized on a year-to-date basis compared to last year. Additionally, we remain encouraged that in the U.S., discontinuations decreased during the quarter, a positive trend we have seen consistently for several quarters. We anticipate SPINRAZA could return to growth as the dynamics seen in the U.S. play out across other geographies. Additionally, Biogen is executing on a robust lifecycle management program that we and Biogen believe further supports SPINRAZA's return to growth. The RESPOND and ASCEND studies are evaluating SPINRAZA's potential to benefit patients who were previously treated with competitive products. As open-label studies, RESPOND and ASCEND can provide Biogen with a continuous stream of data supporting SPINRAZA's market leader position.
The DEVOTE study, which is in the randomization phase, is evaluating the potential of higher-dose SPINRAZA to provide even greater efficacy. If the data are positive, they could support filing for approval. All three of these studies are progressing well. In addition, the future of our SMA franchise includes the follow-on medicine ION306. Based on preclinical data, ION306 may offer the potential to substantially extend dosing intervals. We earned R&D revenue of $56 million in the second quarter and $126 million year to date, both of which increased compared to the same periods last year. We generated R&D revenue from several different partners for advancing numerous programs, demonstrating a key element of our financial strength. We earned $57 million in the first half of this year from Biogen for advancing neurological disease programs under our strategic collaboration.
We also earned $37 million from AstraZeneca for their portion of eplontersen's development costs, and $22 million from Roche for advancing IONIS-FB-LRx in development. In line with our goal to invest in our pipeline and commercial capabilities, our non-GAAP operating expenses increased in the second quarter and year to date compared to last year. The increase was driven by higher R&D expenses from advancing the six phase 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 opportunities. SG&A expenses decreased year over year for both periods. This was largely due to the substantial savings from the Akcea integration and Sobi transaction last year. We are redeploying some of those savings as we invest in our go-to-market preparations for eplontersen, olezarsen, and donidalorsen.
Our results for the first half of this year keep us on track to meet our 2022 financial guidance. As we look forward to the rest of the year, we anticipate our Q3 revenues to be similar to Q2. In fact, we have already earned nearly $45 million from Roche and Biogen this quarter. As our phase 3 studies continue to progress, we expect our R&D expenses to increase between 25% and 30% this year compared to last year, consistent with our guidance. We project our SG&A expenses to be in line with last year, even while we increase our investments in preparing to bring our near-term opportunities to the market.
With $2 billion in cash and investments at the end of June, together with the revenue and cash we generate from numerous diverse sources, we continue to have a strong financial foundation. By investing in our strategic priorities, including advancing our goal to deliver a steady stream of new medicines to the market, we are poised to deliver significant future growth. With that, I'll turn the call over to Richard.
Well, thank you, Beth. Our mid and late-stage pipeline continues to perform extremely well with eight positive data readouts so far this year. These achievements position us to add to our commercial products and expand our rich phase 3 pipeline in the near term. Over the next few minutes, I will review the key highlights from these recent pipeline achievements and then preview the key catalysts we expect in the second half of this year. The most important event in the first half of this year was the positive data from the phase 3 NEURO-TTRansform study of eplontersen in patients with ATTR polyneuropathy. As we reported in the pre-specified interim analysis at 35 weeks of treatment, eplontersen met its co-primary endpoints of serum TTR concentration and mNIS+7, as well as the key secondary endpoint, Norfolk Quality of Life.
Eplontersen demonstrated highly statistically significant and clinically meaningful changes from baseline in each of these endpoints as compared to historical placebo. Importantly, a substantial number of eplontersen-treated patients showed improvement in neuropathy impairment and quality of life in the study. We're looking forward to presenting data from the interim analysis at the International Symposium on Amyloidosis, or ISA in September. With these data in hand, we and AstraZeneca are finalizing the NDA and planning to file for regulatory approval for TTR polyneuropathy in the U.S. later this year. Additionally, our CARDIO-TTRansform study, the largest and longest study to date for patients with ATTR cardiomyopathy, also continues to progress well. Our broad olezarsen development program remains the lead medicine targeting ApoC3 in clinical development to treat patients at risk for effects of triglyceride-driven disease.
We recently achieved full enrollment in the BALANCE FCS study, which is on track for data next year, making this our next planned phase 3 data readout. Our core SHTG or severe hypertriglyceridemia study for the much larger indication with more than 3 million patients in the US alone remains on track for data in 2024. Additionally, we expect to initiate a second confirmatory pivotal study of olezarsen called CORE 2 later this year, also projected to read out in 2024. Our donidalorsen OASIS phase 3 program in patients with hereditary angioedema also continues to progress well and remains on track for data in 2024. We recently initiated OASISplus study that includes a switch cohort for HAE patients previously treated with other prophylactic therapies.
Coming up later this year, we plan to report new longer-term data from the phase 2 open label extension study in HAE patients treated for one year to demonstrate long-term durable efficacy. With a differentiated efficacy, safety, dosing, and administration profile, we believe donidalorsen has the potential to be a best-in-class treatment in the attractive and growing HAE market. We are also very pleased that the NDA for tofersen is now under priority review with the FDA. This expedited review underscores the significant unmet need of patients with SOD1-ALS, and it also emphasizes the tremendous value tofersen could deliver to patients as potentially the first disease-modifying treatment approved for a genetic cause of ALS.
The filing includes new integrated data from the phase 3 VALOR study and ongoing OLE study, which shows tofersen significantly slowed decline across multiple measures of ALS disease progression, and importantly led to robust and sustained reductions in neurofilament, a marker for neuron degeneration. With a January 25th, 2023 PDUFA date, tofersen is on track to be our next product to enter the market. Additionally, we believe these new encouraging data also support the promise of our leading neurology pipeline with 11 medicines in development today to treat rare and broad neurological diseases. Our leading cardiovascular franchise, comprised of medicines in development to treat major cardiovascular risk factors, also continues to progress nicely. Importantly, the safety and tolerability seen across our LICA pipeline enables us to address these broad indications. An excellent example of this is pelacarsen.
Novartis recently completed enrollment in the Lp(a) HORIZON cardiovascular outcomes study, enrolling more than 8,000 patients. Pelacarsen has the potential to be the first medicine on the market to address cardiovascular risk driven by elevated Lp(a). Elevated Lp(a) cannot be adequately addressed with currently available treatments, nor with lifestyle changes such as diet and exercise. As a result, with over 8 million people estimated to be affected worldwide who also have cardiovascular disease, pelacarsen represents a multibillion-dollar opportunity. Pelacarsen is on track for data and a potential regulatory filing in 2025. We also recently reported several positive mid-stage data readouts, including from our Factor XI program, our HBV program, and for IONIS-FB-LRx in IgA nephropathy. As a result of these positive data readouts, our phase 3 pipeline is poised to expand to at least 8 medicines addressing 10 indications.
Today, we anticipate a steady cadence of phase 3 data readouts that have started this year, expands to 2023, 2024, and 2025. As we expand our phase 3 pipeline, we'll be extending the steady flow of phase 3 data readouts beyond 2025. We are looking forward to building on the substantial positive pipeline progress we have delivered so far this year with additional key data readouts and program updates. In addition to eplontersen, our second half highlights include phase 2b data from IONIS-AGT-LRx, our medicine for treatment-resistant hypertension, OLE data from donidalorsen intended to demonstrate long-term durability in HAE patients, and monotherapy data from cimdelirsen, our medicine to treat acromegaly. With that, I'll turn the call back over to Brett to close this portion of the call.
Thank you, Richard.
As you've heard this morning, it's been a great year so far for Ionis. We made great progress in advancing our key priorities to grow our commercial pipeline and deliver an abundance of new transformational medicines to the market. We're looking forward to potentially adding eplontersen and tofersen to our commercial portfolio as early as next year. We continue to make excellent progress in advancing our other near-term opportunities, olezarsen and donidalorsen. With multiple positive mid-stage data readouts, we're well-positioned to expand our phase III pipeline to at least eight medicines across 10 indications. In addition to all of our pipeline advances, we've been making excellent progress in expanding and diversifying our technology as well. Specifically, we are focused on advancing new chemistries, including expanding our LICA platform beyond liver. We look forward to providing updates on these exciting advances in the future.
The second half of this year, we expect to continue our positive momentum by delivering additional key milestones highlighted by the NDA filing for eplontersen. Importantly, we have the resources needed to continue executing on our priorities to drive substantial growth and value for all stakeholders. With that, I'll now open the call up for questions. Operator, can we start the question session?
We will now begin the question and answer session. To ask a question, you may press star, then one on your touch tone phone. If you are using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question today comes from Yanan Zhu with Wells Fargo. Please go ahead.
Great. Thanks for taking our questions, and congratulations on a very productive quarter. So, on eplontersen in TTR polyneuropathy, what do you hope to show at the upcoming presentation at the ISA meeting? As we try to compare the data with the existing data from approved TTR silencers, what should we focus on to get a sense of the competitiveness of eplontersen? Would it be the change in mNIS+7 from baseline, Norfolk QOL or, you know, proportion of patients with improvement? Any color would be helpful. Thank you.
Sure, Yanan. Thank you for the question. We couldn't be more pleased, as we try to, you know, drive the message in our prepared remarks, more pleased with the overall package for eplontersen, the efficacy, safety, tolerability, target engagement. There really is. We couldn't have hoped for more. As we also said in our prepared remarks earlier, we're well on our way to submitting the NDA for potential approval and preparing for launch next year for eplontersen for TTR polyneuropathy. We're very much looking forward to sharing results from our 35-week interim analysis data in polyneuropathy, ISA, and we're looking forward to sharing a lot of the results at ISA.
We're certainly gonna be looking forward to sharing the safety and tolerability profile, the rich and the really exciting target engagement for TTR lowering, as well as efficacy data and so on at the meeting. As you know, it was a co-primary endpoint in the at week 35, and we also had the key secondary endpoint. Primary endpoints were mNIS+7, as well as TTR lowering, and the key secondary endpoint was Norfolk quality of life. In addition to safety and tolerability, we're looking forward to sharing some of the efficacy results as well. As for comparison, you know, TTR amyloidosis is a big indication.
I think the comparison will be important to be looking at in the primaries and the secondary endpoints, as well as the exploratory endpoints for polyneuropathy. Beyond that, it's really the cardiomyopathy data that I think is gonna be incredibly important for eplontersen. You know, we're running the most robust, richest, largest and longest trial ever done for TTR cardiomyopathy and really believe that that is gonna be a key differentiator for this very large market in the future. Stay tuned for that, and stay tuned for the presentation at ISA.
Got it. If I have a very quick follow-up on cardiomyopathy, and that is, could you share your thoughts on the APOLLO-B top-line data and whether that changes your thinking around the powering of your cardiomyopathy study, including the recent upsizing of the study size? Thank you.
Thanks, Yanan. Good follow-up. We, you know, we've been in this field for many years now, nearly a decade, I think, and keep developing therapies for TTR amyloidosis. We couldn't be more pleased that that there's new encouraging data that shows that silencers could be very effective in the broad cardiomyopathy disease indication. We couldn't be more pleased and happy with the trial design for our CARDIO-TTRansform study. As I mentioned, it's very robust. We're gonna be able to generate data in several different important patient subpopulations, including eplontersen compared to naive, as well as on top of tafamidis and so on. We're expecting a very rich, robust data set in the cardiomyopathy study, and it's a cardiovascular outcome trial.
We think that outcome data is absolutely essential key to driving uptake into this very attractive market. There's no data that we've seen that is changing our assumptions that our trial design is the right design. It's a study that's enrolling very well now, and we're looking forward to bringing it to its conclusion as planned. We're also looking forward to additional data that has come out from APOLLO-B in the future, which could shed additional light on things. Right now we're not planning to change our trial design in any way based on any new data that has come out today.
Great. Thanks for all the color. The next question comes from Paul Matteis with Stifel. Please go ahead.
Hey, this is Katie on for Paul. Thanks so much for taking our question. I had a quick question on the tofersen recent NDA filing acceptance. I guess, would you consider filing any of your other neuro or ALS programs with NfL as a surrogate endpoint? I guess, in other words, do you see any read-through on this acceptance onto any of your other neuro programs? Thanks so much.
Sure. I'm gonna ask Richard to take a stab at that one, Katie.
Yeah, of course, the tofersen package is an important one, and there are many learnings from that program. One of those is that functional endpoints don't change as rapidly as some of the biomarkers. Of course, we get engagement with the target. We can see that in a very short period of time. Following that, we saw the neurofilament decrease very strong, very robust. Seeing it again with the placebo patients going on to tofersen kind of brings that whole thing home, that you're actually having an impact on neurodegeneration through this potential biomarker. Will we be looking at the potential of filing on biomarker alone? I think biomarker alone is probably not the play, but rather looking at the biomarker is a very good early surrogate for what can happen as we play it out.
For FUS, we have a robust design for our study. We have interim analysis built in that doesn't force us to be static in the way that we look at the endpoints. We'll be able to see when we're having good movement in functional as well as, of course, neurofilament is part of the design.
Okay, great. Thank you.
The next question comes from Jessica Fye with J.P. Morgan. Please go ahead.
Hey, guys. Good morning. Thanks for taking my question. Maybe sticking with TTR and following up on the APOLLO-B question, recognizing that all the details are not yet, can you just remind me whether you plan to take an interim in CARDIO-TTRansform and maybe talk about whether or how you see the APOLLO-B results affecting that decision, if it is sort of up to you to whether to take an interim? And then second, I think you mentioned planning additional studies for eplontersen. Can you talk in a little more detail about what those might include? Thank you.
Sure, Jess. Eugene, take that.
Yeah, sure. Good question. Well, I'll start in the order of your questions. Related to the early look option for CARDIO-TTRansform, we certainly have that option, and we plan to be very judicious in taking that option when the timing is right. But it is within our protocol to have an option for an early look into the primary endpoint, and we are using primary endpoint for that, which is CV mortality and morbidity. It's important to, again, distinguish that from the current readout in APOLLO-B, which really was more of an early look at the functional changes. Having said that, we are looking forward to seeing the full results from the APOLLO-B, of course, as is everyone else.
It is important to look at magnitude of these differences from placebo to understand their clinical significance, not just statistical significance.
On the additional eplontersen trials you alluded to?
Yeah. That continues to be an area of active work and discussion with our partners, and we're not really prepared to start, you know, disclosing all of the life cycle management activities. I kind of use that term broadly for this group of studies. There are important clinical questions that need to be
Answered. We believe that we will have a profile that is highly differentiated from competitors. Stay tuned.
Yeah. Yeah, Jess, just stay tuned. We're working, as Eugene said, on several sets of studies, lifecycle management, imaging studies, et cetera, with our partner. Those will be hitting clinicaltrials.gov in the future. We'll be able to talk more about it at that time.
Great. Thank you. The next question comes from Do Kim with Piper Sandler. Please go ahead.
Great. Thank you for taking my question. First, as you think about and look at the data for NEURO-TTRansform, are there aspects to that, or just the drug profile in general that physicians will find compelling, to switch from the recently launched Amvuttra with vutrisiran? Or do you think you'll be competing for just newly diagnosed patients?
I'd like to ask Onaiza to maybe address that question. Onaiza, can you take that?
Sure. Yeah. Hi, Do. You know, I think it's really important to know that, with polyneuropathy and the mixed phenotype patients, this is fairly a large market. With the first generation silencers, we've only put really a marginal dent in getting these patients diagnosed and treated. As a result, there is really still continues to be, you know, about a good, you know, 40,000 patients in this population that I think both drugs will have access to. We do expect to get a lot of new patients on. We have a very compelling product profile.
Richard went through it in his prepared remarks, that we're gonna have, you know, a product profile with great improvements of the mNIS+7, plus more for quality of life, which are actually really clinically meaningful, important considerations for physicians. That packaged in with our go-to-market strategy with AstraZeneca and trying to identify, diagnose, and treat these patients, as rapidly as possible in all types of settings, because they do present in a variety of different settings, not just in a neurologist office. We will be able to kinda access that broad population very quickly. Yeah, we're expecting to go in and find these patients readily and get them diagnosed and treated on eplontersen.
Great. Thank you.
Just to add to that. Thanks, Onaiza. Just to add to that, Do, of course, polyneuropathy is just a start. As you know, cardiomyopathies were the big population, the big opportunity, and the biggest unmet medical need today. There we think we have several key differentiators for eplontersen. One is the study design that we've already emphasized. We think the amount of data, the quality of the data, the details of all the data we're gonna generate from that study is gonna be very differentiating.
The fact that we have a global powerhouse in the cardiovascular space in AstraZeneca to maximize delivery of eplontersen to as many patients as possible globally is another key advantage for eplontersen, in addition to the really exciting neuropathy data that we've generated in NEURO-TTRansform.
It's a great point, Brett. Very strong clinical data package that's being generated here. I wanna remind everybody that we are powered with the longest acting and the largest study to be able to make sure that these data are available in our label, so we can, you know, provide that to all types of physicians in a very promotionally sensitive and what is turning out to be a competitive market.
Perfect. Thanks for taking my question.
The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you for taking my questions. Maybe I would just ask regarding your HBV program with your partner GSK, you know, any additional color you can provide regarding the second half of this year, the data update? Also quickly on the HAE program, phase 2 only data, if you can give a little bit more color on the type of data you'll be sharing.
Yeah. Eric, do you wanna take the HBV question for Gena?
Yeah, sure. Thanks, Brett. You know, Gina, as I'm sure you're aware, GSK presented some nice data at EASL on the 24-week into treatment time point for bepirovirsen and showed what I think is really remarkable data in 28% and 29% of patients either not on therapy or on co-therapy with nucleosides showing going below the limit of detection in the antigens. This has been—it's really been unprecedented monotherapy to see that level of decline in this patient population. We think the data is very encouraging and as does GSK, as they've announced their intention to go to a phase 3 program in the near future.
Really the keys for that will be seeing if that's sustained in the continued B-Clear data and also in the B-Sure study, which is an open-label extension with those patients. That'll be the key one of the key bits of information for that program moving forward.
Yeah. I think the buzz phrase is functional cures, right? Functional cures with the durability that GSK plans to present, second half additional data second half this year is to really nail down whether or not we're achieving functional cures in these patients. As far as HAE, yeah, we're looking forward to presenting the open-label extension data. These will be patients now treated for a year with donidalorsen. As you recall, Gina, the efficacy was remarkable in phase two. I mean, you know, unprecedented reductions in HAE attacks as well as greater than 90% of the patients were completely attack-free during that period. The objective for the presentation for the second half of the year is to show that those effects are durable.
That's what we're planning to present in the second half of this year is the durability of the remarkable efficacy that we showed in phase two. In addition, there'll be some data for monthly and bimonthly dosing because patients were eligible to do either in the open-label extension. You'll see some of that as well and how well the bimonthly holds up with the monthly and so on.
Thank you very much.
You're welcome.
The next question comes from Yale Jen with Laidlaw & Co. Please go ahead.
Good afternoon, and thanks for taking the questions. Besides the GSK, I understand that Roche also will move their program into phase 3 FB program. Could you elaborate a little bit more about that? I have another follow-up.
Yeah, Yale. You know, that's 2 of our you know, we have 4 phase 2B studies. 5, I'm sorry. 5 phase 2B studies reading out this year. We already have put out 3 positives. PCSK9, factor B that you just referred to in IgA nephropathy, and our fesomersen program, Factor XI, and more coming. The results in patients with IgA nephropathy were really compelling. Looks like some of the best efficacy that's been disclosed by targeting factor B with our LICA medicine, FBLRX. Based on the data, Roche is really excited about moving it into phase 3 development, as we announced next year.
In addition, that same drug is in a larger trial in patients with geographic atrophy, dry AMD. That study continues to enroll today and is progressing well.
Okay, great. That's very helpful. Maybe one more question on your preclinical data. You talked about you will have a muscle LICA program, I guess, earliest study readout to come this half. Any elaboration on that point? Thanks.
Sure. Eric?
Well, we're planning on getting a muscle LICA program into preclinical development. We don't have any more elaboration on that right now, but certainly are happy with the multiple technologies we've moved forward into targeting the muscle, including some of the things we've talked about, like the Bicycle collaboration with Bicycle Therapeutics, using fairly small bicyclic peptides to engage the transferrin receptor and target them to muscle. We have multiple programs progressing. That's one of them, and look forward to getting them started in development across multiple therapeutic areas in the not-too-distant future.
Okay, great. Thanks a lot, and congrats.
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Hi. Thanks for taking our question. This is Tommy on for Salveen. Ours is about the upcoming hypertension data. How are you thinking about potential efficacy bars there? And, then on the program in Angelman, can you help us kinda gauge the differentiation from other potentially disease-modifying therapies in this space? And, I guess provide us maybe with an update on when we could see data from this program. Thank you.
Sure. Richard, you wanna talk to the AGT program and what we're expecting from the phase 2b data?
Sure. For AGT Lyca, we have a phase 2b in resistant hypertension that will read out in the second half of this year. In addition to that, we have a safety study in heart failure that will read out either late this year or early next year.
The endpoints heart failure study?
In the heart failure study.
No, I'm sorry, in the hypertension study, the phase 2b study.
Of course, the endpoints in the hypertension study are systolic blood pressure decrease compared to placebo. This has powered two different dose groups and powered against the control to show a significant decrease.
Eric, could you address the differentiation in Angelman?
Yeah, sure. I'm gonna talk about Angelman a little bit. As I'm sure you're aware, and it's certainly all the programs I'm aware of that are disease-modifying are using the same general mechanism of trying to target this antisense transcript that regulates the causal gene and then upregulates the gene that's deficient in Angelman syndrome.
Our drug certainly does that. You know, for differentiation, we hope it's the best molecule in the space. We spend a lot of time trying to identify the best molecule. We think we're pretty good at finding optimal drugs for CNS delivery and engagement of their targets. We're advancing our program. Our program is a first-in-human study, so the primary endpoint is safety, of course, but we're always looking for target engagement, and we'll be monitoring other clinical endpoints as well to try and see how the drug behaves. I don't believe Tafi's been given timing on when that readout will come out. Our goal is to advance the program as fast as we can to try and get a drug out for patients.
That's what we're trying to do.
Thank you.
The next question comes from Luca Issi with RBC. Please go ahead.
Oh, great. Thanks so much for taking my question. Congrats on the quarter. Maybe on ATTR cardiomyopathy. You know, I know you have not seen the phase 3 from Alnylam, APOLLO. But is there a scenario where you elevate six-minute walk test from a secondary endpoint to a primary endpoint in your phase 3 so you can actually get to market faster? Again, I think they hit on six-minute walk on a trial that is three times smaller than yours. I would think you may have a good shot at hitting the stats there. Wondering if that is an option. Maybe circling back on AGT, it looks like you have a lead compound and a backup compound.
Wondering if you can remind us what's the difference between the two, and why does it make sense to continue to invest in both instead of just pivoting to the next gen? Thanks so much.
Yeah. Eugene, would you address the six-minute walk?
Yeah, sure.
-elevation and...
Sure. For CARDIO-TTRansform, we are looking at six-minute walk. However, it is our secondary endpoint, not primary, for the main reason being that the current standard of care already has mortality data and significant benefit on mortality and cardiovascular events, which we believe is really the most meaningful and expected outcome for this indication, certainly in terms of demonstrating a value to physicians as well as payers, importantly. While in theory, you could potentially get to the market or at least through regulatory gate faster, what we're really playing here is a long game, as Brett indicated.
We are assembling the most definitive data set for this indication that will be useful for physicians and patients in when this drug is on the market, not trying to kind of, you know, find a shortcut to approval. We feel that, you know, playing the long game here is critical for us to have a best-in-class therapy here.
Onaiza, you wanna expand on that, from a commercial perspective on the value a six-minute walk endpoint would bring versus the outcome data?
Yeah. I think, you know, we've obviously been preparing for our cardiomyopathy clinical data package and really working closely with the development team as Eugene described. In looking out there in the marketplace across a robust set of physicians, you know, the most important element that physicians are gonna want, and it depends on the type of patient that they're gonna have in their office, is that what is the cardiovascular risk reduction on top of standard of care tafamidis? Or if I don't have a patient on tafamidis, then I'd like to see the total cardiovascular risk reduction for a patient who's naive to therapy. We believe that generating both types of data is the most robust clinical data package that we will need to demonstrate our best-in-class profile.
In addition, I think payers will also require that, particularly as you're thinking about adding on therapies. This is a very sick population, and these patients are at risk for, you know, terminal death at the end of the day. We do not believe this is a place where physicians will be switching. As a result, we're gonna have to demonstrate the best value proposition and clinical utility on top of standard of care for payers for reimbursement as well. We believe we're well-positioned across, you know, the broadest set of data, the broadest set of demographics. We're really striving for label-enabling data to ensure that we're very competitive, and
Thanks, Onaiza. Luca, regarding AGT hypertension, as Richard pointed out, we have two studies in progress with our lead molecule, Gen 2.0 chemistry with LICA. Phase 2b refractory hypertension will read out by the end of this year, and then our heart failure study is progressing nicely. In addition, we initiated development of another molecule, a Gen 2.5 chemistry, LICA, targeting AGT. Really there we're focusing on really just comparing and profiling 2.5 versus 2. We expect greater potency. We also probably expect greater durability, and that's what we're gonna be looking for. That study is now in phase 2 in hypertension. We're gonna look at all the data.
We're gonna look at the hypertension data with the 2.0, we're gonna look at the heart failure data, and we're gonna look at the 2.5 data next year and develop our strategy or implement our strategy accordingly based on data-driven decisions. So, further as far as further investments go, we made our investments, and we're gonna look at which is the molecule we wanna invest further in, and we'll make that decision next year.
Super helpful. Thanks so much, guys.
The next question comes from Myles Minter with William Blair. Please go ahead.
Hey, thanks for taking the questions. The first one's just a clarification question for you, Brett. You said that the IgAN data for the Factor B inhibitor was the best you've seen thus far. Was that targeting just Factor B, or is that relevant to the complement space more broadly? The second question is on the GOLDEN study in geographic atrophy. I think clinicaltrials.gov has that ending in October 2022. I'm just wondering whether we expect top-line data disclosure in the second half because it's not in your press release. Thanks for that.
Yeah. Thanks, Myles. The data that we've seen in IgA nephropathy to date positions our Factor B-L(Rx) very competitively. We believe that based on the data we've generated to date, this has the potential to be the most efficacious approach for IgA nephropathy bar none, not just Factor B, not just complement, anything that has been publicly disclosed to date in this patient population. That's why Roche you know really quite aggressively pulled the trigger to move to phase 3 rapidly. Not just Factor B, but really everything that has been laid out in the public domain to date. Regarding the GOLDEN trial, no, we're not planning to have data readout from the dry AMD study this year.
We haven't really put a timeline on that for when the data will read out. It's a big study, more than 300 patients, I think, with dry AMD, and we're still enrolling the study. Stay tuned, but you know, we really haven't put out any details on when to expect data from that study.
Okay, beautiful. Just a very, very quick clarification again. That IGAN comment includes data from the endothelin receptor antagonist class, that's inclusive of everything?
That's inclusive of everything. Yep. Everything includes everything.
Okay. Sorry. I just had to go on the record. Appreciate the question. Thanks, guys.
Thanks.
The next question comes from Yaron Werber with Cowen. Please go ahead.
Yes. Hi. I have three questions on three different drugs, if you don't mind. Just the first one on eplontersen. Can you give us any insight as to when are you thinking and AstraZeneca is thinking about filing with EMA, for polyneuropathy? Secondly, can you just confirm that you've not done an interim analysis on CARDIO-TTRansform before you expanded to 1,000 patients? Just a question also on 306 or BIIB115. I don't know what you could say about it. It sounds like it's gonna be extended duration. Is it exactly the same sequence as SPINRAZA, or what's the differentiation there as well? What's timing to starting phase 1? Thank you.
Yaron, thanks. Actually, Richard, why don't you talk a little bit about our strategy for the EMA filing for eplontersen?
For eplontersen.
Yeah.
Eplontersen polyneuropathy, of course, we'll file in the U.S. this year and follow with the week 65 or week 66 data as endpoint data that will be included in the EMA filing. That means that the staging will be very close, but it's going to be. We're good on EMA follows the FDA, and it will ultimately include the final endpoint, week 65, 66.
We're preparing the European filing now, Yaron. It's just it'll be in segments. The final full filing will require the week 65 data to be complete. As far as the decision we made to expand the sample size and the duration for the CARDIO-TTRansform study, that was entirely based on a few factors. One was the demographics in the study that we wanted to make sure that we had the right mix of sicker patients in patients suffering with TTR cardiomyopathy, so the right balance. It wasn't really based at all on event rates or anything like that. It was really based on what the demographics were looking like for patients coming into this study. This disease is being diagnosed earlier and earlier.
Patients have milder and milder disease when they're getting diagnosed, and we're seeing that globally. We're not the only ones seeing that. That was really the basis for that. There was no look at any data, any interim data at all that factored into that. As far as the follow-on to SMA, very excited about this drug. This drug has the potential, you know, based on the wealth of preclinical data, it's positioned to be able to extend the dosing interval substantially, maybe once every 9 months, every 12 months or so, dosing. We have to prove that in the clinic, but the preclinical data is very strong. Biogen has not put out any details on the timing for the start of the new study.
You have to stay tuned for that. We don't wanna get ahead of our partners on that one.
Okay, great. Then if you don't mind, I'm just gonna throw one quickly for acromegaly, cimdelirsen. It sounds like that's fully enrolled now. Is it monotherapy. I know you can enroll both naïve or experienced. Do you have a sense what the split is between the two patients, and what are you expecting. What would you like to see to then move into phase three. Thank you.
The study that we'll read out the second half of this year, Yaron, is monotherapy. These aren't patients that are on treatment today, if that's your question. It's a pure monotherapy treatment in patients with acromegaly. What we're looking for is, you know, substantial movement reductions in IGF-I biomarker, approvable biomarker for the treatments for acromegaly. We're hoping also to get a substantial number of patients into the normal range of their IGF-I as well. We have to see if we can achieve that. Really, any IGF-I lowering that's achieved in these patients has been shown to have a meaningful impact on the quality of life for these patients. That's our objective.
Right. Brett, what was I asking, do you expect patients to be? This is a monotherapy study. Do you expect patients to have seen therapy before with other drugs, like some somatostatin analogs, or be experienced? Are these naive or experienced?
Yeah.
throughout the therapy? They're, I think all are postsurgical.
Yeah. It's really the eligibility criteria just define what patients are entering the study. You're right, some patients will have been treated before, and either not tolerated for a number of reasons or did not respond. We'll obviously look. It's important to characterize safety and efficacy in both of these types of patients, which is what we intend to do. It is a monotherapy trial.
Thank you.
The next question comes from Joseph Stringer with Needham & Co. Please go ahead.
Hi. Thanks for taking our question. Just on the muscle LICA preclinical program, I understand based on your initial preclinical data and some of the features of the targeting technology, are there a set of indications that you intend to focus on or would consider best fits, or are you indication agnostic at this point? Thanks for taking our question.
I can take a crack at that. I wouldn't call this indication agnostic, but there's lots of indications. We're looking at both the neuromuscular space and because we've seen good success in getting uptake into the cardiomyocyte with this class of targeting ligand. We're also looking at various cardiovascular indications. We think it's gonna be broadly useful in multiple indications and multiple programs, which is one of the reasons why we're so enthusiastic about our current targeting approach for muscle.
Yeah.
I mean, obviously, Joey, heart failure is a key area where we have a lot of. We have a great pipeline of drugs in the cardiovascular heart failure space, and we're looking for opportunities to expand on that with a muscle like it to the heart. Stay tuned for that. Hopefully, we'll be able to have more to share by the end of the year. Maybe we have time for one last question before wrapping up. We're getting a little long on time.
The next question comes from Gary Nachman with BMO Capital Markets. Please go ahead.
Great. Thanks for squeezing me in. On olezarsen, with enrollment completed in FCS, remind us about the duration of the study. Will you have data more likely in the first half or second half of next year? What should our expectations be with the data, what you're looking for? What sort of read-through, if any, might there be for the high trigs study once we see the FCS data? I have a couple of follow-ups.
Sure, Gary. Richard, you wanna-
Sure.
Talk to the FCS then?
Absolutely. Fully enrolled, I think we reported that in June. It is a one-year study, so your data readout's gonna be mid-year. I think what we're looking for, obviously, as primary endpoint is triglyceride lowering. What we've seen, I mean, what we know from WAYLIVRA, which is the same sequence, by the way, this is the LICA of WAYLIVRA, essentially. What we saw in the very high triglyceride patients, FCS patients, was actually even a greater response than we saw in some of the lower triglyceride baseline patients. We expect very robust triglyceride lowering with this ApoC3-targeted drug. With it being a LICA, safety is gonna be pristine, which is going to be a very important component of this package.
In secondaries, we're looking for the effects of triglycerides on these patients generally drives abdominal pain, issues with their pancreatitis.
We're looking for reduction in some of those, as well as a quality of life tool that we've developed for these patients. We've been in FCS for quite a number of years, and we're excited to see how this study rolls out. It's one of the largest FCS studies ever conducted.
Yeah. As far as read-through to sHTG, Gary, we expect a very strong read-through. Our phase 2 data was actually in milder patients with milder triglyceride elevations, and we saw there 60% or higher reductions in triglycerides, and that was at 50 milligrams per month. Our phase 3 study will have 50 and 80 milligrams per month. We're seeing great safety and tolerability in the various phase 3 studies involving olezarsen. But with the higher dose, we're expecting even greater TG reductions. Looks like a great drug, and we're leading the way. ApoC3 is a great target for managing patients suffering with TG-related diseases. You had a follow-up, Gary?
Yeah. First on that, you're starting the second high trig phase 3 study. Is that gonna be the same design and scope as the first one? I mean, anything you can do to accelerate enrollment for these studies if you have the resources to do that, is that a possibility?
It's very similar. CORE 2 is very similar to CORE. This is a broad indication, so requires two phase 3 studies, a confirmatory study, and that's basically what this is. This is a confirmatory study. As far as enrollment, we're always looking at ways to enhance enrollment. It's you know a lot of patients in the phase 3 study for olezarsen, phase 3 studies for olezarsen. So takes time to enroll a study involving more than 1,000 patients across the studies. We're always looking at opportunities to do it. It's less about more resources, it's more about just finding the right sites, finding the patients. Anything you wanna add to that, Eugene?
No.
Okay.
Okay.
Yep. Yeah. Then just one last one, eplontersen in PN. After you file in the U.S., are you expecting a priority review? Then just maybe a few details on you and AstraZeneca, just in terms of the plans for the launch. Any idea yet about sizing of the sales force? Any initial conversations with payers? If you said this, I missed it, I apologize, but maybe just run through some of the key activities as you're prepping for that. Thanks.
Priority review, Eugene.
Yeah, sure. For as far as the US filing is concerned for polyneuropathy, we're clearly in discussions with regulators now and things are progressing very well for the NDA filing this year. With regard to getting priority review, that's an FDA decision. That's multifaceted. There's nothing that depends on our approach. It really is something that we need to wait once the filing is accepted and FDA decides on that.
Yeah. It wouldn't be appropriate for us to speak for the FDA at this point, Gary. Maybe Onaiza could talk a little bit about how our plans for commercial launch of eplontersen are going, and our co-co with AstraZeneca as to maybe.
Yep.
roles and responsibilities and so on.
Yeah. You know, I have to say, Gary, it's one of the best collaborations I've been a part of, and I've been part of many in my career. They're a great partner, and our teams are just syncing up really well. We're taking the lead on medical affairs. We've been in this category in amyloidosis and know the investigators and KOLs for, you know, over a decade. It's really one of our core strengths that we bring to the go-to-market activities. We're in field. We're getting lots of great, you know, requests based on our top-line sharing of the phase 3 data.
We hope after ISA, we'll be able to kind of, you know, share more of the robust safety profile and other indicators as well with these physicians. We are also, you know, haven't sized up the total sales team yet, which is something we're working on pretty actively. As a reminder, as I'd said, I think earlier, that these patients present in a variety of different settings. You know, you have the neurologist, but as a reminder, AstraZeneca is already in with cardiologists with their cardiovascular agent and heart failure, the SGLT2. You know, just really trying to think through where all these patients present so we can make sure our promotional efforts are all in the right place.
We're also actively preparing payer conversations as well as sizing up our nurse case team on the Ionis side and whole host of other activities to make sure we're planning for a very robust and fulsome launch.
Okay, great.
Thanks, Onaiza.
Thanks, guys.
Thanks, Gary. I think that wraps up our Q&A section. I'd like to thank everybody who joined us today on our call. Really great first half of the year for Ionis. We're really looking forward to continuing to share the progress throughout the remainder of the year. Until then, thanks again for joining, and have a great day.
Goodbye.
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