Good morning, and welcome to Ionis' third- quarter 2026 financial results conference call. As a reminder, today's event is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.
Thank you, Chris. 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, Kyle Jenne, Chief Global Product Strategy Officer, Holly Kordasiewicz, Chief Development Officer, and Beth Hougen, Chief Financial Officer. I would like to draw your attention to slide three, which contains our forward-looking language statement. During this call, we will be making forward-looking 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.
As a result, you are cautioned not to rely on these forward-looking statements. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I will turn the call over to Brett.
Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. Through the first three quarters of 2026, Ionis has continued to evolve and grow as a commercial-stage biotechnology company, achieving numerous important milestones. In addition to TRYNGOLZA for FCS and DAWNZERA for HAE, our Ionis-owned commercial portfolio now includes TRYNGOLZA for severe hypertriglyceridemia, or sHTG, our first launch in a large patient population, and ZANVASTRO, our first independent launch in neurology. Although two recent phase III readouts did not deliver the outcomes we hoped for, we have achieved a number of other important firsts for patients across our business that position us for further growth. This includes the approval of HIBSAGO for chronic hepatitis B virus in the U.S. and Japan, and positive phase III results for sefaxersen in IgA nephropathy and ulefnersen in FUS-ALS.
Our substantial progress keeps us on track to achieve our full- year 2026 total revenue, operating loss, and cash guidance. DAWNZERA's continued positive momentum supports our confidence in achieving its 2026 product sales guidance. For TRYNGOLZA, we are lowering our 2026 full-year revenue guidance to approximately $50 million to reflect the more gradual launch ramp than we had anticipated. As the first and only treatment approved to reduce triglycerides and the risk of acute pancreatitis in people living with sHTG, TRYNGOLZA requires HCPs to adopt a new approach to patient care, which takes time. In these early days, we are encouraged by the fundamentals underlying the launch, including strong physician enthusiasm. We are refining our launch tactics to translate this enthusiasm into action. We have identified key executional priorities and implemented specific initiatives across these priorities, which Kyle will discuss in detail.
Importantly, we remain confident in TRYNGOLZA's multi-billion- dollar peak sales potential. Beyond TRYNGOLZA, Kyle will provide further perspective on DAWNZERA and share initial insights on ZANVASTRO. Holly will then go over our recent pipeline progress. Beth will review our third quarter results and outlook for the rest of 2026. With that, I'll turn the call over to Kyle.
Thank you, Brett. I'd like to start by recognizing our highly engaged commercial team for their dedication to bringing important medicines to patients. Their deep expertise, strong commitment to each of our launches, and clear priorities to expand physician adoption and help patients access treatment gives us confidence in our ability to drive growth across our commercial portfolio. Following TRYNGOLZA's June approval for sHTG, HCPs continue to express strong enthusiasm for TRYNGOLZA's compelling clinical profile, including placebo-adjusted mean reductions in triglycerides of up to 72% and a favorable safety and tolerability profile. These triglyceride reductions resulted in a profound reduction in acute pancreatitis events by up to 91%. Physicians also appreciate the dosing flexibility and are prescribing both the 50 and 80 mg doses, allowing them to tailor treatment to individual patient needs.
For patients, TRYNGOLZA offers the convenience of a once-monthly auto-injector that can be self-administered in about 10 seconds. We are seeing HCPs prescribe TRYNGOLZA for high-risk sHTG patients who are the focus of our initial commercial efforts. These are patients with triglyceride levels of 880 mg per deciliter or higher, or 500 or higher with a history of acute pancreatitis or other comorbidities. We are also seeing prescribing beyond our initial focus, consistent with the broad sHTG label. Our post-launch market research reinforces HCPs' strong intent to prescribe TRYNGOLZA. As we establish a new treatment paradigm, we are focused on translating this strong intent to prescribe into action with three executional priorities designed to increase prescribing and help patients move efficiently from prescription to treatment. First, we are focused on broadening the prescriber base, specifically among high-priority physicians who care for high-risk sHTG patients.
We are accelerating our education efforts across these specialists and practice teams to increase their understanding of the burden of sHTG, the risk of acute pancreatitis, and TRYNGOLZA's demonstrated ability to reduce that risk. In parallel, we are supporting patient education through HCP conversations with their patients and patient support programs so that people living with sHTG better understand their disease, the importance of treatment, and the role TRYNGOLZA can play in reducing triglycerides and the risk of acute pancreatitis. Our field teams are meeting more frequently with high-priority HCPs who have not yet prescribed to instill a sense of urgency into patient identification and treatment. The goal is to help physicians incorporate TRYNGOLZA into routine care for appropriate patients. From sHTG approval to the end of September, approximately 1,500 prescribers across all anticipated specialties had prescribed TRYNGOLZA.
In the weeks since our field team put these initiatives into action, our initial prescriber base has started to broaden further. Second, we are focused on increasing the depth of prescribing among HCPs who are early adopters of TRYNGOLZA. Since the sHTG launch to the end of September, approximately 24% of prescribers had written more than one prescription. Prescribers want to see how a patient responds to treatment before prescribing more broadly, consistent with how HCPs often adopt new specialty medicines. We saw a similar pattern when we launched in FCS, where physicians became more confident prescribing TRYNGOLZA as they gained experience and observed its impact. While the sHTG population is much broader, our FCS experience gives us confidence that TRYNGOLZA's novel mechanism of action and groundbreaking patient outcomes can support broader prescribing over time.
Our field team is executing on this priority by following up with prescribers to discuss their initial treatment experience and support them in identifying additional patients who may benefit from TRYNGOLZA. Notably, we have seen recent increases in repeat prescribing, suggesting these efforts are starting to have an impact. Third, we are working to make the path from prescription to treatment more efficient. As expected at this early stage of the launch, a majority of TRYNGOLZA prescriptions required a medical exception. Some physicians are hesitant to prescribe newly approved therapies broadly before formal coverage is in place, a pattern seen in other specialty launches, especially in the cardiovascular space. To address this, our dedicated access team is educating physician offices on the reimbursement process and payer requirements. Additionally, we have a Quick Start program that enables patients to begin TRYNGOLZA treatment while coverage is being secured.
The program has been well received, with meaningful utilization to date, and we expect it to continue to expand. Ionis Every Step, our patient support program, also helps eligible patients navigate the insurance process and access treatment. We are working with payers to establish coverage policies and are making good progress. By the end of September, plans representing 33% of commercial lives had added the sHTG indication for TRYNGOLZA to their formularies. Importantly, all current policies provide coverage aligned with the broad TRYNGOLZA label for adults with triglyceride levels of 500 or higher, extending beyond the high-risk patients who represent our initial commercial focus. As payers review the reimbursement policies for TRYNGOLZA, we are on track for additional policies to take effect this year, with more expected throughout 2027.
As we address these early launch dynamics, we remain confident in TRYNGOLZA's potential to achieve more than $3 billion in peak annual sales. That confidence begins with the substantial unmet need. More than 3 million people in the U.S. have sHTG, including approximately 1 million high-risk sHTG patients. TRYNGOLZA's efficacy, dosing flexibility, and self-administered auto-injector provide a compelling profile for these patients. As we establish a new treatment paradigm and build the market, our priorities are clear: broaden and deepen prescribing, and improve payer access to simplify the path to treatment. While we recognize it will take some time for these initiatives to deliver accelerating prescription volume, we are confident our actions position TRYNGOLZA for future growth. Outside the U.S., Sobi continuing to advance the launch in FCS while preparing for the upcoming anticipated broader launch in sHTG following the recent positive CHMP opinion. Turning to DAWNZERA.
The launch continues to gain momentum, with product sales increasing substantially each quarter since launch. DAWNZERA has continued to capture a meaningful share of the U.S. HAE prophylaxis market, where adoption is largely driven by patients switching therapies. We are seeing a growing base of repeat prescribers alongside adoption by patients with different treatment histories. In addition to growth from patients switching from other prophylactic therapies, we have also seen patients initiate DAWNZERA treatment who were previously only using on-demand treatment or who were treatment-naive. Physician and patient feedback has been positive, highlighting DAWNZERA's strong efficacy and favorable safety, differentiated RNA-targeted mechanism, and compelling switch data. Its patient-friendly profile, including dosing every four or eight weeks with a self-administered auto-injector, is also resonating with physicians and patients. DAWNZERA has been a key driver of commercial revenue growth through the third quarter.
Its growing base of repeat prescribers and adoption across patients with different treatment histories give us confidence in continued growth ahead. Outside the U.S., DAWNZERA access has continued to expand through our partners. This progress includes the recent approval in Canada and advancement of the European launch with positive reimbursement decisions in multiple countries and additional market access activities underway. Turning to ZANVASTRO, the recent approval provides children and adults with Alexander disease, the first FDA-approved disease-modifying treatment for this progressive and often fatal neurological disorder. As planned, we were able to get ZANVASTRO into the channel shortly after approval, and I am pleased to share that the first patients have received commercial treatment. Our launch is centered on four priorities. First, we are working to transition patients receiving ZANVASTRO through the clinical study or expanded access program to commercial therapy while ensuring continuity of care.
This will take time as patients await their next quarterly dose, institutions navigate reimbursement, and some patients move to treatment centers closer to home. Second, we are engaging physicians who care for patients already diagnosed with Alexander disease to provide education on ZANVASTRO and support access for appropriate patients. Although exact prevalence is not well understood, the U.S. prevalence is estimated to be approximately 300 people, with about half identified through medical claims. Third, we are raising disease awareness to help identify additional undiagnosed patients. Our focus is on approximately 25 neurology centers, including 12 Leukodystrophy Centers of Excellence, with disease education extending to physicians outside this network. Fourth, we are working with payers and treatment centers to establish coverage and access. ZANVASTRO is administered quarterly by intrathecal injection and reimbursed as a medical benefit, so providing education on the buy-and-bill process is an important part of our launch execution.
Our Ionis Every Step program for ZANVASTRO is tailored to the Alexander disease community, providing education and assistance, navigating the reimbursement process for patients and families, and access and reimbursement support for healthcare providers and site staff. We expect uptake to increase as patients from our clinical studies and expanded access program transition to commercial treatment, additional patients are identified, and access is established. Outside the U.S., Recordati is planning for regulatory filings in the EU and Japan next year, with additional submissions to follow. Across our multiple ongoing launches, our priorities are clear. Our team is focused, energized, and committed to delivering on these priorities for patients. With that, I'll turn the call over to Holly.
Thanks, Kyle. This quarter, we made important progress across our wholly owned and partnered pipeline, advancing medicines with the potential to transform care for people with serious diseases. At the European Society of Cardiology Congress in August, we presented new data reinforcing our leadership in the management of severe hypertriglyceridemia. This included positive long-term data for TRYNGOLZA, the first and only approved treatment to reduce triglycerides and the risk of acute pancreatitis in adults with sHTG. In the CORE and CORE2 open-label extension study, TRYNGOLZA delivered substantial and sustained triglyceride reductions for up to two years of treatment. More than 90% of patients achieved levels below 500 mg per deciliter, and nearly 60% achieved normal levels. Patients also achieved persistent reductions in the risk of acute pancreatitis, and the safety and tolerability profile remained favorable.
These findings further strengthen TRYNGOLZA's clinical profile, reinforcing its durability and long-term safety profile, both of which are essential when treating a chronic disease like sHTG. Beyond sHTG, our leading neurology pipeline continues to make exceptional progress, highlighted by the recent approval of ZANVASTRO. ZANVASTRO is the first and only disease-modifying treatment for Alexander disease, an ultra-rare, progressive, and often fatal neurological disorder. We were pleased that the FDA approved ZANVASTRO with a broad label for children and adults. This approval builds on our long history of discovering and developing first-in-class treatments for rare neurological diseases. Today, our leading neurology pipeline includes seven wholly owned medicines targeting challenging diseases such as Dravet syndrome, prion disease, and Angelman syndrome. In light of the recent results from the ASPIRE study of apazunersen, I'll review obudanersen for Angelman syndrome and our design of the phase III REVEAL study.
Obudanersen is a product of Ionis chemistry and know-how in delivering breakthrough treatments for CNS diseases, experiences that led to SPINRAZA, QALSODY, and ZANVASTRO, groundbreaking approved medicines for devastating neurological diseases. We are evaluating an 80-mg dose in REVEAL, which was the maximal dose we evaluated in the phase I/II HALOS open-label extension study. Based on our data, we believe that the apazunersen dose in ASPIRE was not high enough to be efficacious. Equally important is our choice of endpoint. The primary endpoint in our REVEAL study is expressive communication, measured using the Bayley-4. We selected this endpoint because expressive communication brings stable and natural history data that show robust improvement with obudanersen treatment in HALOS. With up to two years of treatment data in HALOS, we continue to see durable improvements in expressive communication and other functional domains relative to natural history.
We plan to publish an update of our long-term extension study soon and look forward to phase III results in the second half of next year. While our partner pipeline had two phase III disappointments, it also delivered recent approvals and two positive phase III readouts since our last update. HIBSAGO, partnered with GSK, was recently approved in the U.S. and Japan as the first-in-class treatment offering unprecedented functional cure rates in chronic hepatitis B, a disease affecting millions of people worldwide. Sefaxersen, partnered with Roche, met the primary endpoint in the interim analysis of the phase III IMAgINATION study in adults with IgA nephropathy, with favorable safety and tolerability consistent with prior data. Roche plans to share the data with health authorities, with a potential U.S. approval next year.
We also announced positive phase III FUSION topline results for ulefnersen, partnered with Otsuka, in people with FUS-ALS, a rare and rapidly progressive form of ALS that affects a broad age range. These results bring us closer to what could be the first disease-modifying treatment for FUS-ALS. Looking ahead, our pipeline offers multiple opportunities to build on our progress. Next year, in addition to the phase III results for olezarsen, our growing mid-stage pipeline of wholly owned medicines are advancing to a proof-of-concept data readout that could enable us to further expand our late-stage pipeline. We also anticipate further regulatory progress that will expand the global reach of our marketed medicines. This includes the planned launch of TRYNGOLZA for sHTG in the EU, and the continued launch of HIBSAGO, and potential approvals and launches for sefaxersen and ulefnersen next year.
Our recent progress reinforces the strength of our R&D engine and our confidence in the next wave of opportunities to reach more patients. With that, I'll turn the call over to Beth.
Thank you, Holly. The substantial progress we've made this year is reflected in our third quarter financial results, with growing revenue across our diverse revenue streams and continued investment in our launches and pipeline to drive future growth. Recent advances in several late-stage partner programs provide additional opportunities ahead. Overall, our results and outlook keep us on track to achieve our full- year total revenue, operating loss, and cash guidance. Revenues in the third quarter and year- to- date were $243 million and $757 million respectively, representing year-over-year growth of 55% and 64% compared to the same periods last year, excluding the $280 million one-time payment we received for sapablursen last year. Commercial revenue increased to $136 million in the third quarter and $363 million, excuse me, year- to- date, up 18% and 23% respectively, pardon me, from the same periods last year.
Notably, commercial revenue outpaced R&D revenue in the third quarter. These increases were driven primarily by DAWNZERA, with product sales of $37 million in the third quarter and $79 million year- to-d ate. DAWNZERA product sales have increased each quarter since launch, including increasing approximately 40% in the third quarter. TRYNGOLZA generated product sales of $9 million in the third quarter, its first full quarter following the approval for sHTG, and $41 million year- to- date. As Brett mentioned, we are lowering our full- year TRYNGOLZA net product sales guidance to approximately $50 million. With the launch underway, our third quarter results also included initial product revenue for ZANVASTRO. Our partner portfolio continued to serve as a financial amplifier, generating revenue of $107 million in the third quarter and $394 million year- to- date, reflecting milestones from multiple partners as programs advanced.
Operating expenses increased as expected in the third quarter and year- to- date compared to the same periods last year, driven by investments in the commercialization of TRYNGOLZA, DAWNZERA, and ZANVASTRO. We also continued to invest in our advancing wholly owned pipeline, supporting the next wave of opportunities. We ended the third quarter with $1.9 billion in cash and investments. Our year-to-date results and fourth quarter outlook keep us on track to achieve our 2026 total revenue of $875 million-$900 million, underpinned by strong momentum from DAWNZERA and substantial contributions from our partnered programs. We continue to expect DAWNZERA net product sales of $110 million-$120 million. As we establish a new treatment paradigm in sHTG, our updated TRYNGOLZA net product sales guidance reflects a more gradual initial launch.
Our guidance also takes into account the expansion of our Quick Start program, which helps patients begin treatment while coverage is being secured. We expect this program will support both broader adoption and revenue growth over time as patients transition to paid therapy. Importantly, we remain confident in TRYNGOLZA's potential to deliver sustained long-term revenue growth and multi-billion dollar peak sales. Our partner programs also continue to deliver meaningful value through R&D revenue and royalty streams. For example, in the fourth quarter, we earned a $30 million milestone payment following HIBSAGO's recent U.S. approval, and we expect to begin earning royalties as the global launch gets underway. On the expense side, we continue to expect full- year operating expenses to increase in the low teens percentage range compared to last year, driven primarily by sales and marketing investments in our ongoing launches.
We project R&D expenses to remain consistent with last year as several late-stage studies conclude and resources are deployed across our advancing wholly owned pipeline. With strong revenue generation from multiple sources and prudent expense management, we continue to project a non-GAAP operating loss of $425 million-$475 million. This is similar to our 2025 operating loss after adjusting for the one-time sapablursen licensing. Finally, we continue to project a year-end cash balance of greater than $1.6 billion. Our financial outlook reflects the strength of our diversified revenue streams, with growing commercial revenues and contributions from our partnered programs. It also reflects investments in our advancing pipeline to drive continued growth. Importantly, we remain committed to achieving sustained positive cash flow and continuing to create value for patients and shareholders. With that, I'll turn the call back over to Brett.
Thank you, Beth. Our growing commercial portfolio and the continued progress across our rich, diverse pipeline demonstrate the strength of Ionis' science and its potential to address the significant unmet needs of patients. For TRYNGOLZA, we remain confident in its multi-billion dollar peak sales potential, and we're taking action to translate HCP enthusiasm into broader adoption. DAWNZERA continues to demonstrate a significant growth trajectory, and ZANVASTRO extends our leadership in neurology. With a growing portfolio of marketed medicines, a rich pipeline, and a team with the capabilities to deliver, we are executing on multiple value drivers for continued growth. We are confident in Ionis' outlook and are committed to turning these opportunities into sustained positive cash flow and creating lasting value for patients and our shareholders. With that, we'll open the call up for questions.
Thank you. We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. As a reminder, if your question has been addressed and you would like to withdraw it, please press star then two. Today's first question comes from Jay Olson with Oppenheimer. Please go ahead.
Oh, hey. Thanks for providing the update and taking the question. For TRYNGOLZA, could you help separate physician adoption from the operational steps between prescription and paid treatment, and maybe talk about where you see the greatest friction today in terms of identifying appropriate patients or securing coverage or converting prescriptions into starts? Which leading indicators should we keep an eye on? Thank you.
Thanks, Jay. Kyle, you want to touch on the key challenges that we're addressing for TRYNGOLZA launch and as well as the KPIs?
Yeah. Thanks, Jay. Let me first by just addressing the market overall. There is a significant unmet need here in this market, obviously greater than 3 million patients overall and greater than 1 million that are at high risk for sHTG, which is our initial launch focus. We've got a differentiated label. We've got very strong clinical data, including a 72% reduction in triglyceride levels, up to 91% reduction in pancreatitis events, and numbers needed to treat of approximately 20 in the overall patient population and four in the highest risk patient population. The focus here, obviously, in the first quarter is to build a market with the first-of-its-kind treatment in this large population. We had approximately 1,500 prescribers as of the end of September. 24% of those prescribers had written more than one prescription.
This is the only approved treatment right now to reduce triglycerides and the risk of acute pancreatitis in people living with sHTG. So, it's taking some time for HCPs to adopt this new approach, to see the response from patients once they put the patient onto TRYNGOLZA for the first time. We've got a couple of key priorities that I referenced in my remarks, but I'll reiterate. First and most importantly is to get more HCPs to prescribe for the first time so that they can gain this experience with a new modality and see the outcome in that patient that they're treating. Number two, those that have prescribed one time, we're trying to broaden the depth of prescribing, helping them to understand additional patients in their practice that might be able to benefit, so deepening that base and increasing repeat prescribing.
Then the access component, and Jay, you were just asking about that. We had 33% of commercial plans come on board in the first quarter of the sHTG launch. So they obviously have added sHTG to their policy and included the 50 mg dose along with the 80 mg dose, which is important for HCPs to have dosing flexibility, which they very much appreciate with the profile of the drug. So, our real focus here are on those three components, getting HCPs to gain initial experience, those that gain experience to treat more patients, and then finally, the ease of access and getting payer policies to come on board, which is exactly what we're executing against.
I continue to be very encouraged by the enthusiasm from HCPs as we do build this market with the compelling profile that TRYNGOLZA has and the early experiences that we have in the first quarter. We want to build on that and make sure that that continues through the end of this year. 2027 is going to be a very important year for us as we continue to establish this brand in a new market.
Jay, the metrics to continue to monitor are really the ones that we highlighted so far today. I mean, our prescriber base, repeat prescribers, payer coverage, and of course, quarterly revenue.
Great. Super helpful. Thank you.
Thank you.
The next question comes from Yanan Zhu with Wells Fargo. Please proceed.
Oh, great. Thanks for taking our questions. I was wondering, and thanks for the color on the TRYNGOLZA launch. I was wondering, looking at the 4Q, implied 4Q number, it seems to be flat from third quarter. It seems to imply no new patients added. Is that a function of estimate being very approximate, or is there any other dynamics? In general, can you comment on what has the trends been since the beginning of the fourth quarter? Thank you.
Yeah. Thanks, Yanan. This is Kyle. I will address that. There are a few factors, I think, that could impact Q4 revenues, and Beth mentioned this in her remarks. Number one is the Quick Start program. We believe that that program will be used and has been used effectively up to this point and will continue to be used in Q4. So it is the timing of those patients starting and the use of Quick Start.
Number two, we are still navigating the medical exception process, which can take time for many of these patients, right? We are very encouraged by our payer access and the way that payers are coming on board, and the fact that payers are adding TRYNGOLZA per the labeled indication of greater than 500. The payers are also, when they are putting policies in place, the criteria for use is consistent with the clinical trial design.
So being on background therapy, for example, of a fibrate or omega-3, compliance with diet, et cetera. So the policies are coming on board, but that will take time. The third component is just around seasonal dynamics. We have got the holidays and things that are happening right now, so there could be just some limited number of days with patients coming into the office. But I think that the first signs of progress, I think, that everyone should be looking to is what Brett just emphasized, is that we want to see more prescribers come on board, which we are seeing in the fourth quarter already. We want to see more repeat prescribing, which we are seeing already in the fourth quarter.
Then we want to see that payer access and coverage continue to improve, which I believe will happen not only in the fourth quarter, but also as we advance the launch in 2027.
Thanks, Kyle. Just to add to that, Yanan, I just want to make the point, the obvious point, is demand is increasing for TRYNGOLZA. We are also very pleased with the persistency that TRYNGOLZA is demonstrating. Patients are staying on TRYNGOLZA, and we are quite encouraged by that. It is really, that is all matched up against the dynamics that Kyle highlighted specifically, as well as the fact that we are still very early on in a launch in a market that we are creating. It is a brand-new market. We have a fantastic drug that is going to, we believe, is addressing the needs of a very large and patient population with high unmet need. But we are balancing demand persistency along with the dynamics that Kyle highlighted.
Got it. Thanks for the color.
Our next question comes from Jason Gerberry with Bank of America. Please go ahead.
Hi, guys. Thanks for taking my questions. Maybe two for Beth. Just curious how investors should be thinking about maybe cash runway, your burn level against the $2 billion cash on hand, and need for any additional licensing or financing instruments. Is that contingent on launch trajectory? I know there was some prior break-even commentary, so just curious how to think about it in that context. Then, how do you foresee the launch evolving in 2027 from a revenue recognized perspective? Just any commentary you guys are willing to provide on the current consensus, which is roughly, I think, $370 million. Thanks.
Let me start with that one, Jason. On the 2027 guidance, if you will, we will look forward to providing that guidance when we get to the February year-end earnings call, as we always do. So stay tuned for that. As far as cash runway goes, we ended this quarter with $1.9 billion. We anticipate ending the full- year with greater than $1.6 billion. Obviously, that's all really important for us to continue to invest and execute on the commercial launches, in particular TRYNGOLZA, as well as advancing the pipeline and our technology. We'll continue to be in a period of investment for the next short while as our commercial products ramp towards peak. We'll be obviously very aware of ensuring that we're well capitalized to be able to support that investment. That means we'll be looking, as we always do, at our needs for financing.
If we do, we'll be very careful and very cognizant of cost of capital and dilution as important factors and considerations. Just to and as far as positive cash flow, that's still something we're highly committed to. We want to achieve sustained and achieve positive cash flow and sustain positive cash flow. Obviously, the timing of that is dependent on the TRYNGOLZA launch ramp. Based on the recent phase III setbacks and the slower-than-anticipated TRYNGOLZA launch, we do expect the timing to shift from 2028 to 2029. However, our goal is to continue to balance investment and growth with operating discipline and to achieve that sustained positive cash flow.
Got it. Thank you.
The next question is from Gary Nachman with Canaccord Genuity. Please go ahead.
Thanks. Good morning. Just back on TRYNGOLZA. What portion of the physicians that you are targeting are high-priority docs, and how often do you need to communicate with them in terms of frequency to increase their prescribing? If you want to expand breadth and depth of prescribing, do you have the right sales team in place in order to be able to do that? Then just, if there is some net pricing pressure that we are seeing into Q4, maybe from Quick Start, just how should we think of that, and when could it normalize? Would it be next year or the year after, now that you have that program in place? Thank you.
Yeah. Thanks, Gary. A couple things. Field force size is absolutely adequate for the size of the opportunity for the high-risk sHTG patient population that we are starting with. We have a couple hundred representatives out there that can address about 20,000 of the highest sHTG treaters in the U.S. Now, the increasing frequency that we are focused on are on our tier one HCPs, which are a subset of that. We know that these HCPs see the highest volume of high-risk sHTG patients, so we are trying to do exactly what you described, which is deploy those representatives to those offices more frequently so that HCPs will get their first experience with the first patient and then broaden the prescribing from there. We also have a field access team that is supporting the reimbursement and access process with those offices, which is the other dynamic here.
We believe that when HCPs gain experience using this new modality and they see the clinical outcomes with these patients, combined with a smooth process in terms of getting those patients started on treatment, we believe that that will unlock more patients for them to be able to treat appropriately with TRYNGOLZA. In terms of frequency, it varies, right? Some of the early adopters, you are seeing five or six times. I think some of the others may take upwards of 10-plus times to be seen before they come on board. Part of that is education around the product, some of that is education around reimbursement, and some of that is around the appropriate patient to treat. We really are focused on the high-risk sHTG patient population that are at the highest risk of having an acute pancreatitis event.
In terms of the Quick Start Program, that will be an ongoing situation for us because those will be patients that are able to go on to free drug for a period of time while reimbursement comes into play for that patient or access is secured. So we will see that now and moving forward in terms of patients benefiting from that program and helping them get on drug quickly while they are navigating the reimbursement process.
Okay.
Thank you, Gary. Next question, please.
The next question comes from Joon Lee with UBS. Please go ahead.
Hi. Thanks for taking our questions. It is reassuring that the demand for TRYNGOLZA is increasing. But as you broaden the prescriber base, is there a particular specialty you are targeting, and is it different than the prescribers you were already targeting for FCS indication? For the prescribers who need, quote-unquote, "education," what exactly is the difficulty in understanding the value proposition of TRYNGOLZA? Finally, what were some unexpected hurdles that led you to cut your guidance? Thank you.
Yeah. In terms of the specialties, very consistent with FCS, but a broader number of HCPs that we are reaching at this point. We were reaching about 3,000 mix of cardiologists, endocrinologists, and lipid specialists for FCS. As we expanded the sales team last year, we are now reaching, as I mentioned, about 20,000 cardiologists, endocrinologists, and lipidologists. The largest percentage of those is cardiology, just because of the size of that specialty population. The education is just more about building a market here, right? There is HCP enthusiasm when they learn about TRYNGOLZA. They do see that TRYNGOLZA has a compelling profile. It has a broad indication of greater than 500. It also has acute pancreatitis as outcomes and reduction in AP in the indication statement. So, there is HCP enthusiasm and a belief in a compelling profile.
When you get down to the underlying numbers, reductions of triglycerides of up to 72% on top of standard of care that they're using today, up to a 91% reduction in acute pancreatitis, and getting approximately 60% of patients to goal is very encouraging for these HCPs. So, the education is more about, "Which patients do I treat? When am I going to see those patients? And then when am I going to prescribe TRYNGOLZA for the first time in order to gain this clinical experience?" And that just takes a little bit of time, is what we're learning here.
Yeah. And on the—
Thank you.
—on the guidance, it's really nothing more, Joon, than slower-than-expected launch ramp. We're very pleased with the enthusiasm by HCPs to prescribe. Demand is increasing, and we're very pleased with payer coverage to date. We're getting coverage on agreements that we have gotten in place so far to label, which means a very broad label, 500 mg per deciliter of triglycerides and above. So, the metrics are lining up positively. It's just a slower launch ramp than what we initially expected.
Thank you.
Our next question is from Mike Ulz with Morgan Stanley. Please go ahead.
Good morning. Thanks for taking the question. Maybe another one on TRYNGOLZA. It looks like out of the gates, you are getting some nice breadth there in terms of the prescribers and starting to see some depth. As we kind of move forward into next year, what is the key to sort of driving greater depth? Is it just more experience? Is there something else? Is it education? Maybe a little more color on your thoughts there. Thanks.
Yeah, I think there are a couple of things there, Mike. Experience is one, and what we are seeing is some of these HCPs are treating the most severe patient first, right? History of AP, for example. So I think that they potentially could start with the highest risk patient and then start moving beyond that to patients that are just greater than 880 or patients that are over 500 with comorbidities, for example. But we believe that really to help these HCPs unlock these patients, they need to see the clinical outcomes of using this new treatment that they have never had access to. Number two, the process in order to get coverage and access needs to be smooth and straightforward for their offices.
And those are the two really key things that we're working through these offices with here on the outset, then talk to them about more patients that could potentially benefit and how they could broaden their prescribing.
Great. Thank you.
The next question is from Jessica Fye with JP Morgan. Please proceed.
Hey, guys. Good morning. Thanks for taking my question. You've been talking about the TRYNGOLZA launch just progressing a little bit slower than you initially thought. Can you talk about how you think about the timeline to get to that $3 billion U.S. peak target? Then my follow-up sort of still related to TRYNGOLZA would just be, can you talk about specific Quick Start expansion change that you're making? Thank you.
I will touch on peak, Jess, and we have not up to this point provided any insight in towards to time to peak. What I will mention is the large patient population that is addressable here of greater than 3 million patients, 1 million of which are at high risk of acute pancreatitis, and there is an opportunity for TRYNGOLZA to address a significant unmet need here. I have been through the profile a couple of times in terms of what the strength of the profile of TRYNGOLZA represents. We do believe that we will continue to build this market. The HCP enthusiasm will continue to grow. We will get more experience with new prescribers, and those prescribers that have written will prescribe more, and access will open up over time. This is a function of building a new market that has never been in existence before.
The Quick Start expansion point, I do not want to get into a lot of the details there just because it is a competitive space, but obviously we have a number of different programs to make sure that patients can get on treatment and get on treatment quickly and able to stay on treatment long term. I think that is important for our patient services program, and it is important for the patients that can benefit from those types of programs.
On the timeline, I will just add, thanks, Kyle. Jess, it is real important to remember that we are three months into. These numbers represent three months into a launch, delivering a medicine that is providing benefit to patients that physicians have never had experience with before, right? That requires education, that requires physicians to bring patients in to get their triglycerides measured and then get them onto medicine. We are looking forward to 2027. We think 2027 will be a very important year for TRYNGOLZA.
Okay.
Our next question comes from Eric Joseph with Citi. Please go ahead.
Good morning. Thanks for taking the questions. Just a couple more on TRYNGOLZA. Would be curious to know on the payer access dynamic so far, if you could speak to the success rate of getting on formulary. Have there been any refusals by any plans to cover TRYNGOLZA or for sHTG? What is your expectation as to when the outstanding formulary reviews could complete? Thanks for taking the question.
Yeah. Thanks, Eric. We have not had significant pushback or challenges or issues related to our payer negotiations up to this point. As I mentioned, the end of Q3 through to the end of September, we had 33% of commercial plans within a three-month period already begin putting policies in place for sHTG and adding the 50 mg dose, so the 50 and 80 were available. We believe on a pricing standpoint, we priced at $40,000 WAC, and that took place on April 1st of this year. We priced exactly for this reason, which was to make sure that we had coverage to label, which is for all patients greater than 500, and we wanted to make sure that we reduced the blocks and limitations where payers did not put in place restrictions around history of AP or being a high-risk patient over 880, for example.
I think we have been very successful at working with payers and talking about the patient population that is addressable here and putting policies in place that reflect the broad label, and also obviously the prior authorization criteria being consistent with the clinical trial design, which is typically what we are seeing with these plans. We are very encouraged by payer access coming on board. We believe we will have more coverage and access open up the end of this year and going on throughout 2027. We are in a good place as it relates to access.
Great. Thanks for taking the question.
The next question comes from Akash Tewari with Jefferies. Please go ahead.
Hey. Thanks so much. This is what I'm trying to kind of parse out. I think on September in an investor transcript, you were saying, July and August were good months when you were thinking about scripts for TRYNGOLZA. Then obviously, the implied guidance cut today is a pretty stark contrast. Can you talk about when you were talking about July, August being good months, how were you defining that, and then what really kind of broke down? I think my concern is really if July and August were good months, that we're actually seeing a downward trajectory in terms of demand as we got into September and the back half of the year. Also, I know you went away from PANTHERx to multiple specialty pharmacies. How much of that maybe has played a role with uptake here?
Do you feel like patients need more high-touch service? Thank you.
Thanks, Akash. Early comments during the early part of the launch really reflected the data that we had available at the time. We were very pleased with the label we received, with the indication statement, including acute pancreatitis reduction. We also were seeing a great deal of enthusiasm by HCPs for the overall drug profile and their desire to prescribe at the time. But remember, we were a few weeks into the launch at that time, so it was really based on what we were hearing from the HCP community and their enthusiasm for TRYNGOLZA, which continues today. Now we just have to bring these patients through and get them onto covered drug. With regard to the pharmacies, specialty pharmacies, and so on, Kyle, would you take that?
Yeah, the multiple SPs, Akash, we have the right programs in place. We have the Ionis Every Step program, our patient support program, to make sure that patients are educated from the disease state standpoint, product standpoint, and that we also have programs in place to help financial situations if necessary in order for those patients to get on and stay on treatment. I think we've got the right programs there. As it relates to expanding the SPs, the SPs are doing very well. We've got four SPs that address some of the largest payers as well. We believe that we've got the right SPs to help us make sure that the prescription process gets navigated and we get drug to patient.
But we've also got our field access team out there working directly with offices on the reimbursement process and making sure that we're educating around which plans have policies in place and what the criteria for use are for those respective plans. So, that HCP office education is another key component to this beyond just the SP expansion as well.
The next question comes from David Lebowitz with BMO Capital Markets. Please go ahead.
Thank you very much for taking my question. When you try to bucket how the launch is going in various groups, there's a lot of talk about the high-risk patients above 880, about the patients above 500. What about the patients that specifically have had pancreatitis events? Have we seen any uptick, notable uptick in that group?
Yeah. Thanks, David. We are absolutely laser-focused on the high-risk sHTG patients here out of the gate to establish TRYNGOLZA and to begin building this market. The patients above 500 with history of AP are a cornerstone of that focus. Our sales team and our medical affairs team obviously educating HCPs around the need to treat those patients and the risk, now that these patients have had one AP event, of subsequent events going up exponentially in terms of risk potential. We are seeing those patients get prescriptions. Some of it is an office dynamic of when those appointments are scheduled and when those patients are coming in to see their HCP, so it's a timing situation.
But that is a really strong focus of our communications and our education and the launch in order to build this market and get patients treated with TRYNGOLZA for the right reasons.
Thanks for taking my question.
The next question comes from Ellie Merle with Barclays. Please go ahead.
Hey, guys. Thanks for taking the question. Maybe just to take a step back, could you kind of highlight, I guess, what exactly contributed to the slower-than-expected launch versus what you had initially anticipated? Is this driven by reimbursement factors, use of free drug, or is this slower-than-expected demand? If you could kind of break that out or characterize that a little bit, I think that would be helpful. Then, just again on the Quick Start program, you did mention that there's been meaningful utilization. If you could give us any color or characterize, I guess, what proportion of overall starts are on free drug, and I guess your expectations for the average duration that patients will be on free drug before converting to paid. Thanks so much.
Yeah. Kyle, want to reiterate what's driving the slower-than-expected launch?
Yeah. Thanks, Ellie. I'll just revert back. We're building a market here. That's the first thing, right? HCPs, the majority, some that have treated FCS have experience using TRYNGOLZA. But the majority of these HCPs that we're calling on are learning about a new modality, a new product, and trying to make sure that they understand which patients to treat and the potential value of treating those patients. So it's about market building and creating this market. It requires HCP education, which is exactly what we're doing with our field team with personal promotion. It also takes non-personal promotion, like our omni-channel capabilities and the way that we are educating through digital means, which is really important here as well to drive awareness and an understanding of sHTG and TRYNGOLZA. Then there's also the patient dynamic.
We're doing a lot of work to educate patients, not only through omni-channel, but also through our patient advocacy work and the engagements that we're having with different groups in order to make sure people understand what sHTG is, what risks are associated with sHTG, and the potential benefits of being treated with TRYNGOLZA would look like. So, that's really what's taking time, I think, in terms of the process to build the market. In terms of Quick Start, I don't want to get into really any more details surrounding that program. I mean, it's a program that I think is important for patients to be able to get on treatment quickly and for HCPs to be able to assess how patients are doing, and to make sure that patients can stay on treatment long term. So, it's an important program for patients and HCPs.
Thanks, Kyle. Thanks, Ellie. I think we have time for one more question, please.
The next question comes from Myles Minter with William Blair. Please proceed.
Hi, this is Jake on for Myles. Thanks for taking our question. Should [inaudible] be approved in sHTG, do you expect them to take similar headwinds in initial uptake, or is this just sort of the curse of being the lead blocker here? Then maybe a follow-up for Beth. You changed your break-even guidance from 2028 to 2029. Just wanted to confirm that the TRYNGOLZA uptake was the key driver there and that there were no other factors for updating that guidance. Thank you.
Thanks, Jake. I will start. Beth, feel free to jump in. As Beth said in her prepared remarks, our shift to 2029 cash flow break-even was related to the slower-than-expected launch ramp for TRYNGOLZA, but it was also impacted, as was stated, by the disappointment, phase III disappointment for eplontersen in ATTR- cardiomyopathy and pelacarsen for Lp(a)- CVD. That guidance to achieve cash flow break-even will be driven, in addition to pipeline successes, in large part by the TRYNGOLZA launch as we go forward. As far as competitor programs, we have no comments on what they should expect. We see no reason why they would be in any different position than we are with respect to the dynamics that we are facing for the TRYNGOLZA launch to date.
What we are thrilled about, of course, is the compelling product profile that we have for TRYNGOLZA, which has shown unprecedented reductions in triglycerides, reductions in acute pancreatitis, all with good safety, tolerability, and convenience. Stay tuned. We are looking forward to 2027 for the launch of TRYNGOLZA. It is a very important year, and like I said, we are very much looking forward to it. With that, I think we are going to end the call. Thanks, everybody, for joining us today. We look forward to sharing our progress as we further advance our launches and the next wave of medicines from our pipeline. Have a good day, everybody.
The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.