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spk14: Good morning and welcome to the IONIS third quarter 2023 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Mr. Wade Walk, Senior Vice President of Investor Relations, to lead off the call. Please begin, sir.
spk21: Thank you, Chuck. Before we begin, I encourage everyone to go to the investor section of the IONIS website to view the press release and related financial tables we will be discussing today. including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Oneza Katare, Chief Global Product Strategy and Operations Officer, Richard Geary, Chief Development Officer, and Ben Haugen, Chief Financial Officer. Eric Swayze, Executive Vice President of Research, and Eugene Schneider, Chief Clinical Development Officer, will also join us for the Q&A portion of the call. 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 details. With that, I'll turn the call over to Brett.
spk23: Thanks, Wade. Good morning, everyone, and thanks for joining us on today's call. Since taking the helm at Ionis nearly four years ago, we have executed on a strategy to deliver next-level value, and we have done so with a clear vision and laser focus on our strategic objectives to bring our medicines directly to patients, build our wholly-owned pipeline, and to extend our leadership in oligonucleotide therapeutics. Our successes this year, which are a direct result of our efforts in these key areas, move us closer to achieving our ultimate goal to deliver a steady cadence of new transformational medicines to patients and to generate next-level value for all Iona stakeholders. We are on the cusp of delivering our near-term commercial medicines to patients, starting with the first potential approval of epilontersin this year. We and our co-commercialization partner, AstraZeneca, are prepared to launch Eplon-Tersen following U.S. approval. We're also executing on a global regulatory strategy with potential approvals in the EU and Canada next year. Additional filings are also planned, positioning us for a steady cadence of approvals around the world. We recently achieved another of our key objectives for Eplon-Tersen with the publication of a comprehensive review of the Phase III Neurotransform study results in JAMA. Publishing our results in a highly respected journal like JAMA reflects the importance of our Phase III neurotransform study for the treatment of ATTR polyneuropathy and showcases the strength and quality of our results. Based on its strong overall profile, including highly positive Phase III data, together with the freedom of a simple at-home monthly self-administration profile, we believe Eplon-Tersen is well-positioned to become the therapy of choice for ATTR patients who remain underserved by current therapies. Falling closely behind Eplon-Tersen are Olazarsen and Donny-Delorsen, our wholly-owned near-term commercial opportunities. We were very pleased with the positive top-line data we reported last month from our Olazarsen Phase III balance study in patients with FCS. Olazarsen showed significant triglyceride reductions, which was the study's primary efficacy endpoint, along with a favorable safety and tolerability profile. But most importantly for patients, Olazarsen demonstrated substantial reductions in acute pancreatitis events, making Olazarsen the first lipid-lowering therapy to achieve this result in a clinical setting. With these highly positive results, we are on track to file for marketing approval in the U.S. and EU early next year, positioning Olazarsen for its first potential approval as early as the end of next year, assuming priority review in the U.S. We also continue to be encouraged by the performance of donidolorsin, our medicine for the prophylactic treatment of HAE. We recently reported two-year open-label extension data, which demonstrated favorable safety and tolerability, along with durable and sustained protection against HAE attacks, consistent with the previously reported one-year OLE results and our Phase II results. We are getting closer and are looking forward to our Phase III readout with data expected in the first half of next year for donidolorsin. We also made significant progress recently in further strengthening our wholly-owned neurology pipeline by advancing Zilgenersen, our treatment for Alexander disease, into Phase III development. Advancing Zilgenersen further expanded our rich Phase III pipeline to a total of nine drugs in development for 11 separate indications. And importantly, we remain on track to accomplish our other key strategic goals across the business, including achieving our 2023 financial guidance. With that, I'll turn the call over to Ineza to discuss our expectations for the Epon-Thurston launch and to briefly review the status of our go-to-market activities for Olizarsen and Donny Dolorsen. After Ineza, Richard will discuss our recent pipeline progress. And after that, Beth will review our third quarter financial results. And then I'll wrap things up before taking your questions. And with that, over to Ineza.
spk09: Thank you, Brad. As Brett outlined, and as you will hear from Richard in more detail in a moment, Ionis' pipeline holds tremendous promise. And today, we are ready to begin delivering our medicines to patients. With an estimated 40,000 patients worldwide and fewer than 20% of patients on an approved treatment, hereditary ATTR polyneuropathy remains significantly underdiagnosed and a largely underserved disease. In large part, the low rate of diagnosis is driven by the systemic nature and the heterogeneous presentation of this disease. While peripheral neuropathy may be the most important symptom in many patients, others may present with cardiomyopathy and still others with symptoms like GI disease leading to muscle wastage. By leveraging Ionis' deep knowledge of ATTR and AstraZeneca's significant commercial reach, we are uniquely positioned to recognize ATTR in undiagnosed patients, and get them on treatment early in their disease progress. And in doing so, we are well-positioned to grow this largely untapped market. Our field team is built and deployed and already executing on our strategy to drive equine person growth through disease education and brand awareness. Additionally, we recently launched our unbranded disease education campaign called See the Patterns, aimed at accelerating diagnosis by helping HCPs spot potential ATTR, in patients with seemingly disparate symptoms. We also recently launched our healthcare professional website aimed at driving disease and brand awareness among ATTR treaters. Additionally, we are investing in rich data sources with the potential to identify ATTR PN patients and support the field team's effectiveness to improve the diagnosis and treatment rate. With its potential approval in about six weeks, we in AstraZeneca are ready to deliver Eplon-Tersen to patients with ATTR polyneuropathy. And as our launch gets underway, a key measure of our success will be in achieving our goal of Eplon-Tersen becoming the preferred choice for newly diagnosed patients with ATTR polyneuropathy.
spk07: We expect Olisarcin to be the first medicine we launch independently.
spk09: We are developing olitharcin in two indications, the rare FCS indication and the broader SHTG indication with potential first mover advantage in both settings. Additionally, the fast track designation we have for FCS gives us the potential for an expedited review. And together with the extremely positive results we reported from the phase three balance study in patients with FCS in hand, we are moving forward with our launch preparations with even greater pace. With the capabilities established for the Epon-Tersen launch, we are in strong position to build upon this foundation and enable stronger launch readiness for FCS. And as we prepare for the follow-on SHTG indication, we plan to further scale these capabilities to realize the full potential of the product pending phase three trial results and FDA approval. We expect our next independent launch to be with Donna DeLorsen for the prophylactic treatment of HAE. This is an attractive market for us because it involves a fairly concentrated set of prescribers, allowing us to deliver Donna DeLorsen to HAE patients with an efficiently sized field team. With the compelling Phase II and OLE data we have seen to date, together with a once-monthly self-administration profile, we believe Donna DeLorsen is positioned to be an important new prophylactic treatment for HAE patients once approved. I'm pleased to say that we are right where we should be in preparing for our first independent launches of Olazarsen and Donatelorsen. Our commercial infrastructure is in place, and we are ready to begin delivering our medicines to people in need as they come to the market. This is a very exciting time for Ionis. I'm proud to be part of it, and I look forward to keeping you up to date as our next important steps unfold. Now over to Richard.
spk03: Thank you, Anaza. We could not be more pleased with the performance of our pipeline. Eplon-Tersen has continued to perform exceptionally well, demonstrating durable and sustained efficacy and safety through 85 weeks of treatment in patients with ATTR polyneuropathy. Just this morning, we presented new data at the European ATTR amyloidosis meeting that further reinforces these results, demonstrating improvements in measures of neuropathy impairment and quality of life, that were seen in a substantial number of patients at 35 and 66 weeks and were sustained through the 85-week analysis. And benefit across secondary endpoints at 85 weeks showed improved neuropathy-specific and physical health-related patient quality of life, stabilized or improved ambulatory status, and stabilized nutritional status with Eplon-Tersen treatment. And last month at HFSA, We showed data demonstrating improvement in cardiac function and structure in a predefined cardiac subpopulation of polyneuropathy patients from the NeuroT-Transform study. The positive results from NeuroT-Transform also support our confidence in the potential for Eplon-Tersen to benefit patients in the larger ATTR cardiomyopathy indication. With Cardiot's Transform fully enrolled, we remain on track for data as early as the first half of 2025. As a reminder, with over 1,400 patients, CardioT-Transform is the largest study in this patient population to date, designed to generate the data physicians and payers want and need to understand the value Applin-Thurston offers for patients and to enable the best possible treatment decisions for patients. Following eplentersin, olisarcin is the next drug we expect to bring to the market and is the first we expect to commercialize independently. In the balanced study, the 80 milligram dose of olisarcin demonstrated statistically significant reductions in triglycerides, robust target engagement, and a favorable safety and tolerability profile consistent with the profile seen with our other like medicines. In addition, olisarcin demonstrated unprecedented, substantial, and clinically meaningful reductions in acute pancreatitis attacks. This is remarkable because it's the first time a lipid-lowering therapy has ever achieved this result in a clinical trial setting. Based on the positive data we reported from the Phase III balance study, we believe that olisarcin is poised to become the standard of care for patients with FCS. Our next step will be to file for marketing approval in the US and EU in the first half of next year, positioning olisarcin for its first potential approval in late 2024, assuming priority review in the US. In addition to our clinical development program for SCS, we also have an ongoing program for patients with severe hypertriglyceridemia, or SHTG. Phase III studies in SHTG patients are ongoing, and we expect those studies to read out in late 2024 or early 2025, depending on enrollment. Following closely behind olisarcin is our next wholly-owned medicine, donadolorsin, to treat patients with hereditary angioedema. Despite several treatments already on the market, HAE continues to represent a significant unmet need. For example, In a study recently conducted by the Hereditary Angioedema Association of over 500 patients with HAE, only 13% of these patients reported having good control of their disease, with more than 85% reporting two or more attacks per year. Data reported from the ongoing phase two open label extension study of Donna DeLorsen show sustained and durable reductions in HAE attacks and, favorable safety and tolerability over two years, and support Donna Doloresen's potential to address the unmet need. We look forward to presenting a comprehensive look at the two-year OLE data next week at the ACAAI conference. With enrollment completed into phase three, OASE's HAE study, we remain on track for data in the first half of next year. And from our robust late-stage pipeline, we look forward to updates from Epiravirsin and Ionis FBLRX. Next week at AASLD, CSK plans to present new data from the Phase II B-B-Together study of Epiravirsin in combination with Fegylated Imicinib. And this weekend at Kidney Week, we plan to present new interim results from our ongoing Phase II study of our Roche-partnered medicine, Ionis FBLRX, in patients with IgA nephropathy. We also made significant advances with our industry-leading neurology franchise this year. Today, we have two approved breakthrough medicines for neurological disease on the market, Spinraza and CalSati, and we have another 12 in clinical development and more than 10 new programs in preclinical development or lead optimizations. Among our partner neurology programs, we recently completed enrollment in the phase 1-2 study of ION582 in patients with Angelman syndrome, putting us on track for data around the middle of next year. And we were encouraged by the positive data our partner Biogen recently reported from the phase 1B and long-term extension studies of IONISMAP-TRX in patients with early Alzheimer's disease. Data presented at the clinical trials on Alzheimer's disease conference showed numerical improvements on multiple cognitive and functional scales and continued favorable safety and tolerability in this small early stage study. And data published in JAMA Neurology showed a rapid substantial and sustained reduction in tau and phosphorylated tau in CSF as well as reduced tau pathology on PET imaging with up to 100 weeks of Ionis and MAP-TRX treatment. And we're particularly excited with the progress we're making in building and advancing our wholly-owned neurology pipeline, which represents one of our highest priorities. As Brett mentioned, we advanced Silvanersen into Phase III development in patients with Alexander disease, a rare debilitating pediatric leukodystrophy with no approved treatment. We're on track to advance ION 717 into Phase 1-2 first in human study in patients with prion disease before the end of the year. And following ION 717, we expect to advance three more wholly-owned neurological disease medicines into the clinic next year. This has been an eventful year so far, and we're looking forward to several additional key events in the coming months, including the U.S. Zeppelin-Tersen approval, launch and additional regulatory filings and approvals outside the U.S., OSRS and regulatory filings in FCS, and Donna Dolores in Phase 3 data. We will keep you updated on our progress on these events and more throughout the coming year. And with that, over to Beth.
spk08: Thank you, Richard. Our year-to-date financial results keep us on track to achieve our 2023 financial guidance. while we continue to execute on our strategy to unlock next level value. Revenue continued to be substantial and sustained with revenues of $144 million and $463 million in the three and nine months ended September 30th, 2023, reflecting a 10% decrease and a 6% increase, respectively, compared to the same periods last year. and driven by the timing of certain partner payments. As anticipated, our operating expenses and operating loss for the third quarter and year to date increased over the same periods last year as we advanced our commercial readiness activities and our pipeline, especially our late stage program. We remain well capitalized with $2.2 billion in cash and investments at the end of September. enabling us to continue investing in our strategic goals. Our commercial revenue from Spinraza royalties was $67 million and $179 million in the third quarter and year to date, respectively. Reflecting Spinraza's resilience against emerging competition in the U.S. and abroad, Spinraza's global sales in the third quarter demonstrated a low single-digit increase compared to last quarter and compared to the same quarter last year. As a result, our revenue from Spinraza Royalties increased by 9% compared to last quarter and 8% compared to the same quarter last year. We earned R&D revenue of $60 million in the third quarter and $233 million year to date. The significant R&D revenue we continue to generate reflects the value that IONIS' technology is creating as numerous partnered programs advance. In line with our goal to invest for revenue growth, our non-GAAP operating expenses increased in the third quarter and year to date compared to last year. With most of our ongoing phase three studies fully enrolled, our study costs increased as expected which resulted in higher R&D expenses. And as we prepare to launch Aplon-Turcin, Olazarsen, and Danone-Delorsen, our SG&A expenses also increased modestly year-over-year. Our year-to-date results keep us on track to meet our 2023 financial guidance. We continue to project revenues of more than $575 million. Our fourth quarter R&D revenue to be driven by the potential $50 million milestone payment from AstraZeneca for the U.S. approval of Eplon-Tersen. R&D revenue from continued development of Eplon-Tersen. And additional revenue from Biogen and from our recently expanded collaborations with Novartis and Roche. We project our 2023 non-GAAP operating expenses to come in at the higher end of our guidance. which is between $970 million and $995 million. And looking ahead, we expect to generate a substantial and sustained base of R&D revenue from multiple sources in 2024 as our partner programs advance. And we expect Appalachian Tours will continue to be an important source of revenue in 2024. We have the potential to earn a milestone payment for an additional Eplen-Turston approval outside the U.S. We also expect to begin generating modest royalty revenue next year, with growth expected as the launch ramps up. We project our expenses to grow modestly next year, with our R&D expenses approaching steady state as our late-stage programs are fully enrolled. and our SG&A expenses to ramp up in line with the planned launches of Eplen Turson, Ola Zarsson, and Donita Larson. We have a strong financial foundation, substantial recurring R&D revenues, plus substantial and sustainable royalty revenue that can continue to grow. And we expect to add new product revenue from our advancing and expanding wholly owned pipeline. Together with our prolific technology, we believe we are on a path to successfully bring our medicines to patients and to unlock next level value. With that, I'll turn the call back over to Brett.
spk23: Thanks, Beth. We are very proud of the remarkable progress we've made this year. We believe that the successes we've achieved so far this year position us to drive substantial value for patients, our shareholders, and all Iona stakeholders. Strategically, we have arrived where we are today by being focused on a clear vision and by being focused on all our supporting strategic objectives necessary to achieve our vision. We have now established all of the functional capabilities we need to deliver a steady cadence of new and potentially transformational medicines to the market. We are advancing and growing our wholly owned pipeline and have established Ionis as a leader in cardiovascular and neurology drug development. We continue to extend our leadership position in oligonucleotide therapeutics by expanding and diversifying our technology, further optimizing our capabilities for existing therapeutic areas and opening up new areas for drug discovery. And we continue to strengthen our financial foundation, providing the means to support all our strategic objectives. And today, with one of the most robust late-stage pipelines in the industry, with nine medicines in development for 11 indications, We're turning that promise into new medicines for patients in need. And not just one or two, but a steady and growing cadence of new transformational medicines over the mid and long term. And in achieving this goal, we are positioned to drive great value for all Iona stakeholders. With that, I'll now open the call up for questions. Operator?
spk14: Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then 2. And at this time, we'll pause momentarily to assemble our roster. And the first question will come from Gary Nachman with Raymond James. Please go ahead.
spk17: Hi, thanks for taking the question. So on Eplon-Tersin for ATTRPN, any additional updates regarding your interactions with the FDA and how everything is progressing in front of the PDUFA? Have they requested any additional data and are label discussions progressing in the way you would like them to? And then just on the commercial plans, given the competitive dynamics in the space with Ambutra and on PATRO, how will payers be viewing Eplon-Tersin What's your work telling you there? Will all these drugs be covered on most formularies? And where is AstraZeneca on the hiring of the sales force? Just give us a sense of how big you think that'll be. Thanks.
spk23: Thank you, Gary. I'll take the first one and briefly give you an update on regulatory. And then I'll ask Onesa to cover the second part of your question on competitive dynamics. It's, you know, we don't comment on ongoing regulatory discussions for drugs under review for potential approval. But what I can say with high confidence is that we're very pleased with the progress we're making with the FDA and bringing up on TERS into an on-time potential approval on our PDUFA date on December 22nd. So there's been really, everything is moving on track. with that. And I also want to remind you, everybody, that we're now under review with our filings accepted in Canada and in Europe with potential approvals for those markets as well for next year for Eplon, Turson, and TTR polyneuropathy. Oneza?
spk09: Hi, Gary. Yeah, launch plans are really underway. I would say they're actually in place. We have hired all the necessary people for a very effective launch. The salespeople, as you know, is being led by AstraZeneca, are hired and deployed in market. They are in the field. They are working on disease and brand awareness. Really, given that this is a very growth market, identifying with different physician sets, the types of symptoms that ATTRPN patients present with is very much underway. You've seen some of the campaigns on, you know, see the patterns. So they're out there really since the last month in field. And we are just awaiting approval. PDUFA is December 22nd, and all things are in motion. Our nurse case managers on the Iona side are hired and have been trained. And since they're mostly post-approval, we would deploy them right after. And as you know, the field medical team has been in place for the last 18 months to two years. So All signals are ready to go. From a payer perspective, I think we have a very strong payer strategy. We've done a lot of research with the majority of the payers in the U.S. We don't expect anything different than other kind of PN agents that have been, you know, priced on the analogs of rare disease pricing. Again, we believe this is a really active rare disease. We do not expect tons of beyond the normal prior authorization for a rare disease to get through. We haven't seen much shift in the landscape here so far.
spk05: All right, great. Thank you.
spk14: The next question will come from Luca Ice with RBC Capital. Please go ahead.
spk15: Oh, great. Thanks so much for taking my questions. Maybe two quick ones. One on hepatitis B. What was your reaction to GSK in licensing the siRNA from Arrowhead and J&J? Given that they already had a silencing agent with you, why do you think they need a second one? And then maybe circling back to the prior question, some TTR-cold neuropathy in the PDUFA. Any color on manufacturing? Has the tech transfer to AstraZeneca been successfully completed? Has the FDA inspected the facility that will provide the commercial supply? Just trying to understand if there is anything that keeps you up at night ahead of the PDUFA. Thanks so much.
spk23: Thanks, Luca. So, you know, we have a very good relationship with GSK. We, you know, were aware of what was coming, what was announced this week. The way to think about it is that the acquisition of the RNAi molecule from Janssen really represents a double down, a triple down, if you will, on Depoversin. Depoversin is the only treatment that has produced a meaningful increase percentage of patients receiving, achieving a functional cure, patients with HPV, chronic HPV. And in the phase, in the phase to be clear, in the clear study, what we demonstrated with GSK was about a 10% functional cure rate. However, in patients with a lower HPV burden, like below 1,000 IUs per mill, I think per milliliter, that functional cure rate was well into the 20% plus range. which is really impressive. And so the strategy that GSK has stated for bringing in the RNAi molecule, which has not shown functional cures, but what it has shown is reductions in HBV antigen levels, two levels in which a substantial percentage of patients could get below that 1,000 IU level, is to do a sequential treatment to reach even more patients, to achieve even greater percentage of functional cures patients down to a level maybe below 1,000, more patients below 1,000 IUs per milliliter, and then coming in with bepiviricin. So this is an added dimension to a very comprehensive clinical program for bepiviricin to reach as many patients as possible and to achieve the highest percentage possible for functional cures for bepiviricin. And it's also consistent with everything GSK has been saying in which they will be exploring different combinations for bepaversin to maximize success on this market, which as you know is hundreds of millions of people suffering from chronic HPV. So we're very pleased. We're very pleased about this new outcome for CSK for bepaversin. And Beth, maybe you could talk a little bit about where we are with the launch preparations for commercial supply.
spk08: Sure, absolutely. We are all ready to go just as we are on the commercial side and the medical affairs side. All of the products needed for launch has been manufactured. It was manufactured through the registration process, regulatory process, has been reviewed, is ready to go. We just are waiting for a final label to do label and packaging and get product into channel shortly after approval. And all of the tech transfer necessary from Ionis to AstraZeneca with the commercial manufacturer, the contract manufacturer is done. And all of that has gone extremely well. So we are all systems ready to go.
spk05: Great. Thanks so much.
spk14: The next question will come from Yeo Jin with Late Law and Company. Please go ahead.
spk01: Good morning, and thanks for taking the questions. I've got two quick ones here. The first one is for the Spinarasa cells. I believe that will be ultimately announced by Biogen. But nevertheless, as you indicated that the growth, small growth quarter over quarter, should we believe that this is, again, consistent with the stabilization of the franchise in the larger SME? Then I have a quick follow-up.
spk08: So what I would say is we're very pleased with the low single-digit growth in against last quarter and against the previous quarter, same quarter last year. We believe that demonstrates FINRAAS' continued resiliency even in the face of emerging competition. Beyond that, I really need to respect Biogen's earnings call next week, and I really can't go any further.
spk01: Okay, great. That's helpful. And in terms of JAMA publication regarding the volunteers and sustained benefits, how should we think about that to incorporate into the marketing strategy, particularly for biogen? on newly treated or untreated patients. And thanks.
spk23: The publication specifically? I mean, that's going to be a really effective tool, right, Anazen?
spk09: Yeah, I think with the promotional and regulatory kind of, you know, guidance, looking at the JAMA publication and where our promotional messages are headed is going to be highly supportive. The JAMA publication is also very consistent with the label that we expect, so that will allow for use by both the medical teams as well as the sales teams as well, and that's what we expect.
spk23: Yeah. So, in other words, Yale, although our package that's under review at the FDA is based on the week 35 interim data that we reported last year, Having this publication for week 66 and week 85 is very, very helpful from a marketing standpoint, and we expect to utilize that publication very effectively. I think that was the basis of your question.
spk05: Okay, great. Thanks a lot, and congrats.
spk14: The next question will come from Paul Matthias with Stifel. Please go ahead.
spk16: Hi, this is James on for Paul. Thanks for taking our question. Just one on Ola Zarsson quickly. You know, I guess, you know, as we get ready for the FCS launch, I guess, how are you thinking about pricing just given that, you know, the higher Trigs opportunity may be coming behind it and assuming there'll be different price points there. And I guess just as you've kind of put some of this commercial infrastructure in place for the FCS launch, how much, I guess, leverage either from like Salesforce or spend perspective do you anticipate getting from this FCS infrastructure as you think about launching the higher TRIGS opportunity. Thanks so much.
spk09: Sure. So, you know, we've done some extensive work with payers to understand kind of this dual indication that we're going after in prevalent and rare disease. Does that actually really make a shift in your pricing strategy? Do we We know that once we, you know, once we have the more prevalent price, prevalent indication, the pricing will obviously be in line with good kind of cardiovascular premium price products. We see really no indication in terms of thinking about this differently as a result of the two indications. If they were, to single indications in different molecules. We've priced the rare disease along rare disease pricing corridors and the broader indication along the corridors of a good, you know, cardiovascular premium price benchmark as well. So you should, you know, think about it that way. I would say that the FCS account sales team We'll be calling on obviously a much smaller portion than the total universe of physicians you would call on for SHTG. It will be, you know, more focused on the lipidologists, but extend out a bit beyond that as well for where we believe the SCS patient population is. We're doing a lot of work from our integrated data analysis and qualifying where those physicians are that actually have SCS patients. And then as we get into the broader indication, those sales teams will obviously stay on board, and we will extend the size of the sales team for the broader SHTG market to incorporate some of the other physician specialties that we believe will be very important for the uptake of that product.
spk05: Makes sense. Thank you.
spk14: The next question will come from Allison Bratzel with Piper Sandler. Please go ahead.
spk00: Hi, thanks for taking the question. So first, I guess I just wanted to ask on the anti-tau update last week for BIB 80. I know Biogen is responsible for development of the asset, but I'd still be curious just to get your thoughts on how that approach could fit into the Alzheimer's treatment paradigm, you know, be it in combo or monotherapy or what have you. And then hoping you could also just describe how that data maybe influences your confidence in the wholly owned neurology assets. And then on a second front, just on the complement factor B program, you know, looking at that interim phase two data being presented at ASN in a couple days, is there any update just on your view of the IgA nephropathy market and potential opportunity in IGAN, just given the... context of an evolving competitive landscape there. Thank you.
spk23: Thank you, Allison. So the Phase 2 study evaluating tau in patients with Alzheimer's disease is underway and enrolling, and it's a very – it's really quite an extensive study. with more than 700 patients to be treated for well over a year, with the primary endpoint really being efficacy, improvement in cognition. And the purpose of that phase two study is to really make a decision to set up and support a path forward to go to phase three development for a pivotal study. And in this study, we are exploring different dose levels as well as different dose regimens, including twice a year dosing, and that's based The data that you're referring to, which is the Phase I-II study that is now published in JAMA Neurology and was presented at CTAD last week and is incredibly supportive of that Phase II study and the TAL program overall. We and our partner, Biogen, could not be more thrilled with the data that was generated from the long-term extension of the Phase I-II study in patients with Alzheimer's disease. You know, tau is considered by essentially all the experts in the field as being the most important target for Alzheimer's disease based on, you know, the neurofibrillary tangles that appear just before cognition impairment occurs. It's downstream of beta amyloid, which can be present long before cognition deficits occur. But it's a difficult-to-drug target because what matters most is intracellular tau, and that causes the neurofibrillary tangles and neurodegeneration. What we've shown for the first time is not only can we substantially lower all forms of tau in CSF, but we can actually reverse tau pathology in the long-term extension data in patients by PET imaging. But now we also have, from the long-term extension data, actually signs, trends, that patients are actually improving in cognition. So we couldn't be more thrilled about the data, and this has built on our confidence from the Celia Phase II study that's underway that I referred to earlier. As far as combination, monotherapy, that kind of thing, this is the start of a development program for a drug that's leading the way to target tau. The Phase II study is intended to assess the benefits of tau on cognition as a monotherapy. That does not preclude future studies looking at different combinations as this field evolves, whether it be with a beta amyloid treatment in combination with a tau drug and so on. That will require further development. But it can make sense. We can see how those two mechanisms can actually, you know, complement each other, maybe even synergize with each other. So all that is on the table. But right now, Biogen and Ionis are focused on the phase two study to bring that forward as quickly as possible. And as far as confidence in neuro, this is just another piece of data, evidence, validation of our leading neurology platform. I would start with Spinraza. and CALSATI to approve breakthrough treatments for neurodegenerative diseases using the same platform as TAO, using the same platform as our Angelman's program, using the same platform as all of our 12 drugs that are currently in clinical development for all kinds of different neurodegenerative neurodevelopmental disorders. And as Richard highlighted in his earlier remarks, we expect to start a prion program, a whole young program by the end of this year. and three more next year that are wholly on neurology programs for diseases that have a high unmet medical need for both rare and large indications. So, you know, it just adds to our confidence in our leading neurology platform. As far as IGAN FBLRX to be presented at Kidney Week coming up, This will be an additional data cut that was presented at Kidney Week last year in patients with IgA nephropathy, just showing more data, more patients, longer treatment, showing reductions in proteinuria in that study. As far as the competitive landscape, it's crowded. There's no question. And we're glad Roche is taking the lead on this because they have a tremendous global might, global strength. global presence to, you know, if the drug is successful, to bring it to as many patients as possible. But, you know, I really think that that's to be determined once we see the phase three data and to see how this positions itself. But really, we couldn't be more pleased to have, you know, when you're in a competitive market like this with a high-end med need, it's great to have the global strength of a partner like Roche.
spk14: The next question will come from Yonon Vu with Wells Fargo. Please go ahead.
spk11: Great. Thanks for taking the questions. Three questions, if I may. On EplonPerson, what launch metrics would you provide so that we can have an understanding of how the drug is performing in the market in the early launch quarters? On the TAO program, can you talk about how you see the feasibility of the infosequel route of the administration in this very large indication. Lastly, on the Endelman syndrome program, following the recent updated data from Ultragenyx, any insights you could share regarding how your program could be differentiated from that program as we look forward to data in mid-2024? Thank you. Thanks, Yan.
spk23: And maybe we'll start with launch metrics for that person?
spk09: Sure. So, Yanen, I think, you know, the way to think about this market, as I said, is it's a growth market, and we have a lot of patients to get diagnosed and get treated on epilontursin. And I think the phenomenon that you might be seeing now with switches is very temporary, and I think we will have a They will have worked through that. We're squarely focused on growth and growth mindset on newly diagnosed patients. As such, our launch success will be measured on getting F1 tersen as the preferred choice for newly diagnosed patients, new to silencers.
spk02: Got it. Thank you.
spk23: Next year, we'll be providing some metrics and we'll see how, you know, with that. So stay tuned for that again. Regarding the Tau program, so Alzheimer's disease, despite the really remarkable progress that's been made recently on delivering medicines to the market to patients for AD, this is still a very severe neurodegenerative disease with a very high unmet medical need. And like I touched on earlier, we think Tau is the best target. for treating this disease broadly. And with that comes the need for treatments and we don't, we believe the interest equal delivery will be well accepted if the drug is efficacious and as efficacious as we expect it to be. With that said, the TAO program is an example of the great progress we're making in further optimizing and advancing our neurological disease medicinal chemistry, and just experience. In the TAO program, we actually have a treatment arm that we expect will be efficacious with twice-a-year dosing. So we've moved from monthly to every three months for many programs, and now we're even moving some programs to twice-per-year dosing intrathecal. That is part of the TAO program that's in Phase II development today. In addition, as we highlighted at Innovation Day, a few weeks ago, we're making great progress on our research organization in overcoming the blood-brain barrier as an obstacle for delivery of our treatments, our drugs, for using subcutaneous or intravenous administration. And, you know, obviously programs like TAO are on our radar as are other programs. We also think that that could be in the future for a large population chronic disease indication like Alzheimer's disease. So no promises there yet, but we're very pleased with the progress we're making there. Regarding Angelman syndrome, I prefer not to comment on other people's programs, other companies' programs. What I will say is that we are fully enrolled in our Angelman's program. We actually over-enrolled the study a bit. We expect data mid-year next year. We expect data on, you know, efficacy as well as, of course, safety and biomarker data from that trial. And that trial is designed to set up a potential phase three decision based on all that. And then what I'll also say is that, and it's kind of related to the earlier question that I got, that I tried to address, which is we have a vast amount of experience with our platform in neurological diseases. Thousands and thousands and thousands of patients have been treated for very extended periods of time with our chemical platform, with our know-how, with everything. And we think that that bodes very well for the Angelman's patient community because they're going to benefit from the vast experience that we have at Ionis with delivering drugs for the treatment of severe neurological diseases like Angelman syndrome. So, stay tuned for all that. We're very much looking forward to the data next year.
spk11: Great. Very helpful. Thank you.
spk14: The next question will come from Debjit Chattopadhyay with Guggenheim. Please go ahead.
spk18: Hey, good morning, team. This is Robert on for Debjit. Thanks for taking our questions. Two from us this morning. First, could you share any pricing thoughts on upland terracin? Specifically, would you anticipate launch price in line with current PN treatments on the high end or CM treatments in the low end? And for the Alexander program, what paceman enrollment would you hope to see in the phase three? And subsequently, when would you potentially anticipate a phase three readout based on those timelines? Thank you.
spk23: Want to take the launch price PNCM?
spk09: Yeah. So, Robert, I think that, you know, we would expect that, again, the two indications are both rare disease indications, but they are priced differently if you looked at analogs in the marketplace. You know, based on all the work that we've done, we don't believe there is any reason to kind of shift from that in terms of our pricing strategy. So I would expect that as the price is set by AZ that we would expect polyneuropathy to be priced according to the analogs and benchmarks of other polyneuropathy products.
spk23: And regarding our newest phase three program, our Alexander disease program, You know, sometimes, not sometimes, but most of the time, enrolling rare disease indications can be challenging because they are rare. And finding patients to get into your study obviously can present challenges. But what's unique about our phase three program for Alexander disease is that we designed a seamless phase one through three. design such that it's all the same sites, it's all the same, the protocol's already been baked and everything like that. And after our phase two results, which was, you know, which when we reviewed it, we had two decisions to make, really. One was to dose escalate or to move into phase three development. And during that review process, when you go through all the data, you're collecting the data, you're cleaning the data and before we actually review the data, enrollment is put on pause, right, because we don't know what the next step will be for the program. And what happened in this situation is that patients were on the sideline waiting to get into either the dose escalation phase of the next step or the phase three part of the program. So with that said, we think actually enrollment will go well for the Alexander program because we have patients on the sideline waiting to qualify to enter our phase three program now that we've activated it. So, enrollment is ongoing and we expect data in 2025.
spk05: The next question will come from Jeroen Werber with CalWIN.
spk14: Please go ahead.
spk10: Hi, guys. This is Brendan on for your own. Thanks so much for taking the question. Just a couple quick ones from us. Just another one on MAPT, excuse me. Sorry if I missed this, but I'm just wondering if there's any plan for any interim look at the Phase 2 study or any possibility of any additional data updates there before the full Phase 2 reads out, assuming maybe 2026 for the full Phase 2. So just wondering if we can expect anything new there in the meantime. And then quickly on Donnie DeLorsen, obviously you have a few different studies ongoing there, but I think you're planning to incorporate into one filing, maybe including the switching study, et cetera. So can you just maybe give us a sense of timing for data beyond the top line readout in the first half of next year? Maybe how long thereafter do you think you'd need to collect and analyze data? And if you're thinking to maybe file in the second half of next year, that's fair to assume. So thanks very much.
spk23: Sure. There's no plan for an interim look in the Phase II study for the TAO program at this time. So that's a short answer, quick answer. It's very important to get this study right and get the richest data set as you possibly can. And as I mentioned earlier, what we're looking for here is actually evidence to support a Phase III decision that we're improving cognition, cognition impairment. So that's going to take time. That study's over a year long, as I mentioned earlier, more than 700 patients. So no interim look at this time. For Donna DeLorsen, I don't think we've said that we're expecting to include switch data in the filing for the NDA. Really, the phase three data, along with all the other data that we've generated from phase one and phase two, will be sufficient to support a filing assuming a positive outcome. With that said, We expect switch data from our switch study, which as a reminder, to our knowledge, we're the only sponsor that has actually conducted a true switch study in which patients that are on an existing treatment therapy, prophylactic treatment, are switched over to our investigational medicine, Donna DeLorsen, and investigational medicine, which in our case is Donna DeLorsen. And then we assess everything. including, you know, protection against HAE attacks, identifying, you know, demonstrating that there's no gaps between one treatment switching to another treatment, tolerability, sustained efficacy, and actually be able to generate the information that prescribers are going to want to have to understand how do I do this. okay, I want to switch to your drug. I want my patient to go on your drug, but how should I do this? And that's really the goals of the SWITCH study. We expect that data to be out next year, or at least a cut into that data next year that's going to really allow us to actually demonstrate the value of dominoes in this market, which is the SWITCH market. But we have no plans to include that at this time, to my knowledge, in the NDA filing. All right.
spk09: If we believe that the publication will be more than sufficient to be consistent with label to be used actively by our sales teams in promotion, and to the extent if it's all ready alongside of it, we could actually add it in, but it's really not a requirement, nor do we think it's really necessary for commercial uptakes. We like it in the publication.
spk07: That's what we're really looking for as our strategy going forward.
spk05: Great. Thanks very much.
spk14: The next question will come from Jessica Fye with JP Morgan. Please go ahead.
spk06: Hey, guys. Good afternoon. Thanks for taking my questions. Can you remind me of your expectations around whether, in addition to a clear impact on triglycerides, whether you believe you could show an impact on pancreatitis or oligosarcin in FHTG? And then second, and forgive me if you stated this, but for CardioTransform, I believe the follow-up is up to 140 weeks. I just wanted to clarify, is there a minimum planned follow-up for those who do not reach 140 weeks? I noticed some of the endpoints are assessed at week, I think, 121. Is that the minimum, assuming the study is not stopped early? Thanks.
spk02: Eugene, you want to take those?
spk20: Sure. Happy to. Maybe I'll start with the last one. So, as you said, Of course, there's excruciating level of detail in the statistical analysis plan, but just to summarize it, the exposure in the study is up to 140 weeks, which means that in some patients, if the study reads out early, the exposure will be less than that. We've defined the minimal exposure and the time points, specific time points for those early looks in our SAP, and I don't think that we've come out included specific timelines on those other than sort of the general statement about early opportunity for closing the study earlier based on some specific conditions being met. And then.
spk07: In the event you don't stop the study early, what the minimum would be?
spk20: Well, if we don't stop the study early, we go all patients will be treated for 140 weeks. That's the double blind period.
spk15: Okay.
spk23: And then likelihood of achieving AP and SHTG?
spk20: Yeah, so SHTG, again, it's, of course, a very different population from FCS in terms of risk for AP events. Having said that, again, the program that we designed, the two very large studies, certainly we believe we'll have an opportunity to show an effect. And what we are also going to be looking at is combination of those two studies. So looking at sort of integrated analysis of efficacy, combining those two large studies, which together amount to about almost 1,000 patients. So we're fairly confident, of course, today. We don't know what the data will show, what we, can say is that we were extremely pleased with the effect on AP events in our FCS population. So, we do believe that the thesis is very strong, but we need to wait until the data read out. Yep.
spk14: The next question will come from Kossis Belouris with BMO Capital Markets. Please go ahead.
spk12: Hi, everyone. Thanks for taking our question. One quick question from us on ATTR. This morning, Intelia presented data from the literature demonstrating that in addition to the percentage of TTR reduction, the absolute serum TTR levels after treatment are also very important as they can contribute to the ongoing fibril formation and they actually have an impact on survival. That said, I'm wondering whether you have any thoughts around that, given that most of the discussions in this space focus on the percentage of TTR reduction rather than the absolute levels of TTR post-treatment. Thank you.
spk02: Thanks, Costas.
spk23: Not a lot of, you know, thoughts on gene editing efforts in the TTR space. The progress that they're making, you know, is steady. Percent reductions in TTR are absolutely important for efficacy. I don't think there's a, I think we've known for a long time that there's not a threshold effect, if that's your question, that there's a specific threshold by which if you lower TTR that you'll achieve benefit on neuropathy or cardiomyopathy or whatever. but that it's actually individualized per patient and percent reductions is very important. And we're very pleased with the mid-80% mean reductions that we've achieved in the neurotransform study for epilonters in polyneuropathy patients, mid-85% range. And as you know, we've actually, a substantial number of patients actually improved in both MNIST plus 7 and MNIST. and quality of life. So I don't know what else to say about those other programs, except that they have a long way to go. You know, cardiomyopathy indications are going to require an outcome trial, in our view, to not just be provable, but to actually compete. And it's going to take a long time to get there. And it's a new platform that you never know what will come up. So, I don't know what else to say about it other than that, Costas, but we love our program and we're very much ahead.
spk05: Thank you very much.
spk14: The next question will come from Joseph Stringer with Needham and Company. Please go ahead.
spk13: Hi. Thanks for taking our question. Just a quick one on the phase two golden trial and geographic atrophy. When can we expect top line data and given some of the competitor data that's out there. Can you handicap expectations on what a successful phase two outcome looks like? And if the results are sufficiently positive, what would be the next steps in the program collaboration with Roche? Don't take that, Richard.
spk03: Yeah, I'll take a stab at it. I think, of course, we want a positive trial on geographic atrophy and comparable if not better results than have been presented by other competitors. So that's the goal. We have no insight into, you know, what that is today. But the data will be out next year, second half.
spk23: Yeah. So second half, as Richard said, second half next year. What I can add to that, Joey, is that, you know, We also had an interim look in this phase two study that allowed us to select the doses to complete this study, right? We started with a number of doses and then whittled those down to two doses to complete the golden phase two study and bring it to the finish line. We're seeing excellent tolerability. We're seeing profound reductions in factor B. And in downstream effects like split products, exactly where we expect to be. So we're getting great target engagement. We're not seeing any risk associated with that target engagement by blocking the alternative complement pathway. It's going great. And what we expect to see is, what we hope to see is, you know, slowing down of lesion formation and improvement in visual acuity. I mean, these are the outcomes that we're expecting to support a decision whether to go to phase three or not. As far as competitive landscape, this is a sub-Q once-per-month drug using, which could use an auto-injector once it got to the market, if it gets there. Simple at-home auto-injector like Gepon-Tersen, whereas the drugs that are under review or have recently been approved are intravitreal, and they have side effects, as you well know. I think this, although there's been progress made in GA, I think patients are desperately waiting for a drug that's not so invasive and simple and convenient like a sub-Q at-home administration.
spk05: Great. Thank you for taking our questions.
spk14: The next question will come from Miles Minter with William Blair. Please go ahead.
spk22: Hey, I just had a question on ION904. I think you've got an upcoming presentation at American Heart Association. Just wondering whether we should be thinking about similar AGT knockdowns to the previous Leica molecule and just more infrequent dosing, or is there potential to get more than that sort of 75% that we're seeing with that molecule? Thanks very much.
spk23: You got it, Myles. So our presentation on our AGT program at AHA will really focus on, you know, the dose-dependent reductions in AGT that, you know, we sought to achieve in the Phase II study. This is a molecule that is being dosed monthly. Our earlier generation molecule that you mentioned was weekly. And we expect to see greater reductions in our earlier generation molecule because it's a more advanced chemistry. So that's what we're expecting.
spk02: Cool. Thanks for the question.
spk14: The last question will come from David Lebowitz with Citi. Please go ahead.
spk19: Thank you very much for taking my question. With respect to olizaris and given the recent pivotal data, As you look forward to severe hypertriglyceridemia, I know that you achieved benefits with respect to pancreatitis. You received reductions. But given dynamics and differences in that population, how easy do you think it's going to be to show a pancreatitis benefit?
spk23: Yeah. That's a great question, David. And it's a question that our answer today is a lot different than it would have been earlier this year. The SCS data, you know, we, in our wildest dreams, we hoped to see the AP reductions that we saw in SCS. And those wildest dreams turned into reality. So it's, you know, And as we mentioned in our remarks earlier, you know, we couldn't have been more pleased, and this is the first time anyone has demonstrated that blowing a lipid like triglycerides can actually result in positive outcome in AP. My point is that our confidence has grown because the efficacy was so remarkable on reduction in AP events. And that lends confidence to the SHTG population, which although it's not a genetic, form of severely elevated triglycerides, at least no known genetic causes. It's not a monogenic disease like FCS. These patients still suffer from highly elevated triglycerides, much like FCS patients. Sure, some of those patients could be in the above 500 range to 1,000 range, but many, many of these patients are in the multiple thousands or at least above 1,000, which puts them at very high risk for AP. So I think we're going to get AP events in the phase 3 SHTG study. And based on the effect size or the effect that we saw with oligosarcin and FCS, our confidence has grown. But we have to see that. And despite the fact that the number of AP events per patient may be less in SHTG versus FCS, it's such a bigger study. It's a much bigger study, so we're going to have much more data that we're going to collect. And as Eugene said, we have the ability to combine two phase three studies, core and core two, to really look at overall the impact of all of this on AP events in SHTG, so.
spk05: Thanks so much for taking my question.
spk23: Thank you, David. And thanks, everybody, for joining us today and everyone who's participated in our call. We really are proud of all the progress we've made this year, and we believe that the future has never been brighter here at Ionis. And we plan to continue our momentum by delivering on additional key commercial updates, pipeline updates, technology updates, objectives as we go forward. And we very much look forward to it. But until then, thank you again, and everybody have a great day.
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