Latest news with #TRYNGOLZA
Business Wire
19-05-2025
- Business
- Business Wire
Ionis announces positive topline results from Essence study of olezarsen in people with moderately elevated triglycerides
CARLSBAD, Calif.--(BUSINESS WIRE)-- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced positive topline results from the Essence study of olezarsen in people with moderate hypertriglyceridemia (fasting triglycerides ≥150 mg/dL to <500 mg/dL) with or at risk for atherosclerotic cardiovascular disease (ASCVD). Nearly all the participants were on current standard of care lipid-lowering medicines. The trial met its primary endpoint with a statistically significant placebo-adjusted 61% and 58% reduction in triglyceride (TG) levels at 6 months with the 80 mg and 50 mg monthly doses, respectively (p <0.0001). Olezarsen also met all key secondary endpoints in the study. The vast majority of participants reached <150mg/dL, reflecting a reduction to normal TG levels. Olezarsen demonstrated a favorable safety and tolerability profile in the study. Ionis plans to submit an abstract for presentation at an upcoming scientific conference. Data from the pivotal Phase 3 CORE and CORE2 studies evaluating olezarsen for the treatment of severe hypertriglyceridemia (sHTG) are expected in Q3 2025. 'The positive results of this study are an important step in bringing forward a potential new treatment for people with severely elevated triglycerides. Following the FDA approval and encouraging launch of TRYNGOLZA (olezarsen) for people living with familial chylomicronemia syndrome (FCS), a rare, genetic form of severely elevated TGs, these data support olezarsen's potential to benefit the much broader population of people living with sHTG,' said Sam Tsimikas, M.D., senior vice president, global cardiovascular development at Ionis. 'We look forward to seeing the results of our pivotal Phase 3 studies, CORE and CORE2, in Q3 2025, which will be the basis for our potential sNDA filing in sHTG by year-end.' Olezarsen demonstrated a favorable safety and tolerability profile in the study. The most common treatment-emergent adverse event that occurred more frequently than placebo in the olezarsen groups was injection site reactions, with the majority being mild in severity. About the Essence Study The Phase 3 global, multicenter, randomized, double-blind, placebo-controlled study (Essence-TIMI 73b), conducted with Ionis' research partner, The TIMI Study Group, supports the exposure database for olezarsen (NCT05610280). Essence enrolled 1,478 participants aged 18 and older with moderate hypertriglyceridemia (HTG), defined as fasting triglyceride levels ≥150 mg/dL to <500 mg/dL, who were diagnosed with or at risk for atherosclerotic cardiovascular disease (ASCVD). A small percentage of participants (9%) had fasting triglycerides ≥500 mg/dL at baseline. Participants in the study received stable and optimized standard of care lipid-lowering therapies for at least four weeks prior to screening. Participants were randomized to receive 50 mg (n=276) or 80 mg (n=832) of olezarsen or placebo (n=369) every 4 weeks via subcutaneous injection for 12 months. The primary endpoint was the percent change from baseline in fasting TG levels at six months compared to placebo. Key secondary endpoints included percent changes in triglyceride levels at 12 months, proportion of patients who achieve fasting TG<150 mg/dL and percent changes in other lipid parameters, including apoC-III, remnant cholesterol, non-HDL-C and apoB, compared to placebo over the treatment period. About Hypertriglyceridemia Triglycerides (TG) are a type of fat the body uses as a source of energy. While optimal levels for adults are typically below 150 mg/dL, levels higher than 150 mg/dL are a sign of hypertriglyceridemia. Levels higher than 500 mg/dL are a sign of a common condition called severe hypertriglyceridemia (sHTG), which puts millions of people at risk of potentially life-threatening acute pancreatitis (AP) and atherosclerotic cardiovascular disease (ASCVD) despite current standard of care. People with sHTG whose triglyceride levels are more than 880 mg/dL, including those with familial chylomicronemia syndrome (FCS), face a greater risk of AP. About Olezarsen Olezarsen is an investigational RNA-targeted medicine being evaluated for the treatment of sHTG. Olezarsen is designed to lower the body's production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood. The investigational medicine is currently being evaluated in two Phase 3 clinical trials – CORE and CORE2 – for the treatment of sHTG. Olezarsen has not been approved for the treatment of sHTG by regulatory authorities. Olezarsen was recently approved in the U.S. as an adjunct to diet to reduce triglycerides in adults with FCS under the tradename TRYNGOLZA™ (olezarsen). For more information about TRYNGOLZA, visit U.S. INDICATION for TRYNGOLZA™ (olezarsen) TRYNGOLZA is an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONS The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading pipeline in neurology, cardiology and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit and follow us on X (Twitter), LinkedIn and Instagram. Ionis Forward-looking Statements This press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of our commercial medicines, olezarsen, additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2024, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals ® and TRYNGOLZA™ are trademarks of Ionis Pharmaceuticals, Inc.
Yahoo
19-05-2025
- Business
- Yahoo
Ionis announces positive topline results from Essence study of olezarsen in people with moderately elevated triglycerides
– Olezarsen met the primary endpoint with a statistically significant mean reduction in triglycerides versus placebo at 80 mg and 50 mg doses –– Olezarsen met all key secondary endpoints –– Olezarsen demonstrated a favorable safety and tolerability profile –– Nearly 1,500-person Phase 3 study supports the exposure database for olezarsen –– Data from pivotal Phase 3 CORE and CORE2 studies of olezarsen in severe hypertriglyceridemia (sHTG) expected in Q3 2025 – CARLSBAD, Calif., May 19, 2025--(BUSINESS WIRE)--Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced positive topline results from the Essence study of olezarsen in people with moderate hypertriglyceridemia (fasting triglycerides ≥150 mg/dL to <500 mg/dL) with or at risk for atherosclerotic cardiovascular disease (ASCVD). Nearly all the participants were on current standard of care lipid-lowering medicines. The trial met its primary endpoint with a statistically significant placebo-adjusted 61% and 58% reduction in triglyceride (TG) levels at 6 months with the 80 mg and 50 mg monthly doses, respectively (p <0.0001). Olezarsen also met all key secondary endpoints in the study. The vast majority of participants reached <150mg/dL, reflecting a reduction to normal TG levels. Olezarsen demonstrated a favorable safety and tolerability profile in the study. Ionis plans to submit an abstract for presentation at an upcoming scientific conference. Data from the pivotal Phase 3 CORE and CORE2 studies evaluating olezarsen for the treatment of severe hypertriglyceridemia (sHTG) are expected in Q3 2025. "The positive results of this study are an important step in bringing forward a potential new treatment for people with severely elevated triglycerides. Following the FDA approval and encouraging launch of TRYNGOLZA (olezarsen) for people living with familial chylomicronemia syndrome (FCS), a rare, genetic form of severely elevated TGs, these data support olezarsen's potential to benefit the much broader population of people living with sHTG," said Sam Tsimikas, M.D., senior vice president, global cardiovascular development at Ionis. "We look forward to seeing the results of our pivotal Phase 3 studies, CORE and CORE2, in Q3 2025, which will be the basis for our potential sNDA filing in sHTG by year-end." Olezarsen demonstrated a favorable safety and tolerability profile in the study. The most common treatment-emergent adverse event that occurred more frequently than placebo in the olezarsen groups was injection site reactions, with the majority being mild in severity. About the Essence StudyThe Phase 3 global, multicenter, randomized, double-blind, placebo-controlled study (Essence-TIMI 73b), conducted with Ionis' research partner, The TIMI Study Group, supports the exposure database for olezarsen (NCT05610280). Essence enrolled 1,478 participants aged 18 and older with moderate hypertriglyceridemia (HTG), defined as fasting triglyceride levels ≥150 mg/dL to <500 mg/dL, who were diagnosed with or at risk for atherosclerotic cardiovascular disease (ASCVD). A small percentage of participants (9%) had fasting triglycerides ≥500 mg/dL at baseline. Participants in the study received stable and optimized standard of care lipid-lowering therapies for at least four weeks prior to screening. Participants were randomized to receive 50 mg (n=276) or 80 mg (n=832) of olezarsen or placebo (n=369) every 4 weeks via subcutaneous injection for 12 months. The primary endpoint was the percent change from baseline in fasting TG levels at six months compared to placebo. Key secondary endpoints included percent changes in triglyceride levels at 12 months, proportion of patients who achieve fasting TG<150 mg/dL and percent changes in other lipid parameters, including apoC-III, remnant cholesterol, non-HDL-C and apoB, compared to placebo over the treatment period. About HypertriglyceridemiaTriglycerides (TG) are a type of fat the body uses as a source of energy. While optimal levels for adults are typically below 150 mg/dL, levels higher than 150 mg/dL are a sign of hypertriglyceridemia. Levels higher than 500 mg/dL are a sign of a common condition called severe hypertriglyceridemia (sHTG), which puts millions of people at risk of potentially life-threatening acute pancreatitis (AP) and atherosclerotic cardiovascular disease (ASCVD) despite current standard of care. People with sHTG whose triglyceride levels are more than 880 mg/dL, including those with familial chylomicronemia syndrome (FCS), face a greater risk of AP. About OlezarsenOlezarsen is an investigational RNA-targeted medicine being evaluated for the treatment of sHTG. Olezarsen is designed to lower the body's production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood. The investigational medicine is currently being evaluated in two Phase 3 clinical trials – CORE and CORE2 – for the treatment of sHTG. Olezarsen has not been approved for the treatment of sHTG by regulatory authorities. Olezarsen was recently approved in the U.S. as an adjunct to diet to reduce triglycerides in adults with FCS under the tradename TRYNGOLZA™ (olezarsen). For more information about TRYNGOLZA, visit U.S. INDICATION for TRYNGOLZA™ (olezarsen)TRYNGOLZA is an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONSTRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity ReactionsHypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONSThe most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. About Ionis Pharmaceuticals, three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading pipeline in neurology, cardiology and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit and follow us on X (Twitter), LinkedIn and Instagram. Ionis Forward-looking StatementsThis press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of our commercial medicines, olezarsen, additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2024, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals® and TRYNGOLZA™ are trademarks of Ionis Pharmaceuticals, Inc. View source version on Contacts Ionis Investor Contact: D. Wade Walke, 760-603-2331 Ionis Media Contact: Hayley Soffermedia@ 760-603-4679 Error in retrieving data Sign in to access your portfolio Error in retrieving data Error in retrieving data Error in retrieving data Error in retrieving data
Yahoo
20-02-2025
- Business
- Yahoo
Q4 2024 Ionis Pharmaceuticals Inc Earnings Call
Wade Walke; Senior Vice President, Investor Relations; Ionis Pharmaceuticals Inc Brett Monia; Chief Executive Officer, Director; Ionis Pharmaceuticals Inc Kyle Jenne; Executive Vice President - commercial; Ionis Pharmaceuticals Inc Richard Geary; Executive Vice President, Chief Development Officer; Ionis Pharmaceuticals Inc Elizabeth Hougen; Chief Financial Officer, Executive Vice President - Finance; Ionis Pharmaceuticals Inc Eugene Schneider; Executive Vice President, Chief Clinical Development Officer; Ionis Pharmaceuticals Inc Mike Ulz; Analyst; Morgan Stanley & Co LLC Jessica Fye; Analyst; JPMorgan Chase & Co Akash Tewari; Analyst; Jefferies Yanan Zhu; Analyst; Wells Fargo Securities Jay Olson; Analyst; Oppenheimer & Co. Inc Chi Meng Fong; Analyst; BofA Securities Gary Nachman; Analyst; Raymond James Yaron Werber; Analyst; TD Cowen Operator Good morning, and welcome to Ionis' fourth-quarter and full-year 2024 financial results conference call. As a reminder, this call is being this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead the call. Please begin. Wade Walke Thank you, MJ. 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 me on the call this morning are Brett Monia, our Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; Richard Geary, Chief Development Officer; and Beth Hougen, our Chief Financial Officer. And joining us for the Q&A portion of our call will be Eric Swayze, Executive Vice President of Research; and Eugene Schneider, Chief Clinical Development Officer.I would like to draw your attention to slide 3, 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. I encourage you to consult the risk factors contained in our SEC filings for additional with that, I'll turn the call over to Brett. Brett Monia Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. As we begin a new year, I'm thrilled to share that Ionis has begun a new chapter as a fully integrated commercial-stage biotechnology company with our first independent launch of TRYNGOLZA the FDA approval of TRYNGOLZA in late December, adults with familial chylomicronemia syndrome, or FCS, for the first time, have access to a treatment that substantially and sustainably reduces triglyceride levels and substantially reduces the risk of life-threatening acute pancreatitis. Our highly experienced team has been executing the launch flawlessly which enables TRYNGOLZA to be in the hands of patients within a couple of weeks following the December 19 TRYNGOLZA is just the beginning. We're on track to deliver three additional independent launches over the next three years. Donidalorsen, a potential treatment -- preferred treatment for hereditary angioedema later this year; a second indication for Olezaresen in severe hypertriglyceridemia, or SHTG, a large patient population with high unmet need; and Zilganersen for Alexander's disease, a rare leukodystrophy with no approved therapies. These programs collectively provide the opportunity to help tens of thousands of patients and represent multibillion-dollar revenue addition to our independent launches, we also expect four launches from late-stage partnered programs over the next three years. These important medicines are poised to treat a range of serious life-threatening diseases, including several that target broad patient populations. Pelacarsen for Lp(a) cardiovascular disease, addressing an independent cardiovascular disease risk factor with high unmet need with no approved for a TTR cardiomyopathy, a progressive fatal condition that continues to be underdiagnosed with a significant need for more effective treatments. Bepirovirsen for chronic hepatitis B virus, a serious disease that affects hundreds of millions of people globally. And Sefaxersen, previously referred to as IONIS-FB-LRx in development for IgA nephropathy, one of the most common causes of chronic kidney disease and kidney approved, these important investigational medicines would join our other marketed partnered medicines, including SPINRAZA for SMA and WAINUA for hereditary TTR polyneuropathy, which are generating considerable value for patients and revenue for partnered medicines enable our innovative science to reach even more patients, bolster our strong revenue base and provide substantial growth potential, while allowing us to focus our efforts on advancing the medicines we plan to commercialize. Ionis is on a path to bring important medicines to patients for years to come. And in turn, we are positioned to achieve substantial and sustained revenue growth and positive cash flow. Our recent accomplishments and ongoing investments position us well to drive accelerated value for all Ionis with that, I'll turn the call over to Kyle. Kyle Jenne Thank you, Brett. As we start this important new chapter as a fully integrated commercial stage biotech, I cannot be prouder of our team. Their seamless execution of initial launch activities ensured that our first independently launched medicine, TRYNGOLZA, got to FCS patients the approval of TRYNGOLZA, the first prescription was written within 24 hours. The team got drug in channel within one week and the first patient self-administered TRYNGOLZA within two weeks of approval. And today, we are encouraged by seeing both genetically confirmed and clinically diagnosed patients on it's early in the launch, we are encouraged by the positive response in several key areas: The breadth of physicians identifying FCS patients and prescribing TRYNGOLZA; the mix of prescribers, including endocrinologists and cardiologists with an interest in lipids and that we're already seeing numerous repeat prescribers, the rapid time from prescription to patients receiving TRYNGOLZA and coverage by payers for both commercial and Medicare experienced team is laser focused on continuing this momentum. As the first ever treatment in the US, we are capitalizing on our first-mover advantage that is enabling us to develop the market, identify and onboard patients early, and create positive treatment experience that encourages long-term adherence. Additionally, it has enabled us to establish a strong presence in the patient community, all of which we expect will drive long-term success for total addressable US FCS patient population is estimated to be up to approximately 3,000 people. And currently, the vast majority of the FCS population remains unidentified and undiagnosed. As a result, there are multiple critical steps that we are taking to get patients identified and on TRYNGOLZA. First, our team is focused on patient finding efforts, working to identify FCS patients who are not yet on these efforts, our team is working to increase FCS awareness through HCP education to drive increased diagnosis and our commercial field team is actively engaging with HCPs who treat patients with high triglycerides. Once patients are identified and diagnosed, the team works closely with prescribers and patients to obtain coverage and initiate treatment for have deployed a suite of services to accomplish this anchored by our innovative Ionis every step patient support program. As part of this program, dedicated patient education managers provide patient disease and nutrition education, auto-injector administration training, reimbursement support and more. For HCPs, Ionis every step streamlines the TRYNGOLZA prescribing process by offering insurance authorization and coverage assistance as well as coordinating delivery, reauthorizations, and date, we have had very high engagement with patients sharing their excitement as they now have a treatment in the services that they are experiencing from the program. Our market access and reimbursement teams have been actively engaged with a broad set of US payers, representing the vast majority of covered through these efforts, payers have recognized the significant burden FCS places on patients. With this recognition, we are pleased to report that in the early days of the launch, patients have received timely access to our omnichannel capabilities extend the reach of our commercial team and amplify our efforts with patients and physicians. Our launch trajectory will reflect the time it takes to execute on these efforts which we fully expect will gain momentum as the year unfolds. To realize the full blockbuster potential of Olezaresen, we plan to further scale our commercial organization and infrastructure to address the much larger SHTG patient population, where we have substantial first-mover is comprised of people with triglycerides over 500 milligrams per deciliter and is a symptomatic disease where people can suffer debilitating chronic symptoms that impact all aspects of their life, including severe abdominal pain and cognitive impairment. In the most severe manifestation, SHTG patients can suffer from life-threatening pancreatitis events that require intensive hospital a result, physicians recognize the importance of lowering severely elevated triglycerides with established guidelines already in place. Many people with SHTG are severely underserved by current treatment options and in many cases, are unable to reduce triglyceride levels to current recommended guidelines with available options. This is why we are excited about the potential Olezaresen could offer to people with SHTG. Today, the team is focused on pre-commercialization activities ahead of an anticipated launch next our co-commercialized medicine with AstraZeneca for hereditary ATTR polyneuropathy has now been on the market for about a year, and we couldn't be more pleased with the strong progress of the launch. WAINUA delivered accelerating sequential growth throughout last year, including strong demand in the fourth quarter, with product sales nearly doubling compared to the third quarter. Uptake continues to be strong with the majority of top centers of excellence prescribing WAINUA and broadening use into the community growth continued to come from patients new to treatment as well as switches and patients adding WAINUA to their existing therapy. We consistently receive positive feedback from physicians about their patients' experience with WAINUA, including patients' quality of life improvements, their ability to rapidly access WAINUA, and patients' ability to easily self-administer we are pleased with the reimbursement and affordability dynamics we saw in 2024. The vast majority of patients who initiated a WAINUA treatment regardless of insurance type paid zero dollars out of pocket. We and AstraZeneca are confident WAINUA will continue to provide a differentiated experience for patients. The growing global ATTR polyneuropathy launch sets the foundation for our efforts to address ATTR cardiomyopathy, a substantial opportunity with 300,000 to 500,000 people estimated gears to Donidalorsen with the potential approval just six months away, the team is preparing for our second independent launch. In fact, we recently hired the Head of Donidalorsen sales and plan to add the customer-facing team soon, ensuring that they will be ready to bring Donidalorsen to patients quickly after anticipated team is also leveraging and building upon the WAINUA and TRYNGOLZA launches. For example, we will expand our innovative Ionis every Step patient support program to include the needs of HAE patients. Our medical affairs team has been in the field meeting with physicians. This includes ensuring high visibility at key medical conferences, building awareness of Ionis' platform technology, and presenting the positive clinical data generated from our robust Phase 3 program ahead of our anticipated than 20,000 people are estimated to have HAE in the US and Europe. In the US, while the HAE market is well defined, prophylactic treatment continues to grow with a meaningful segment of patients switching treatment in search of a better option. Based on Donidalorsen's strong clinical data, including the positive data in patients switching from current prophylactic treatments to Donidalorsen and the simplicity of monthly or every two-month self-administration via an auto-injector, we believe Donidalorsen offers the attributes that many people with HAE are looking while we expect the Donidalorsen launch ramp to take time as we work to convert patients from existing treatment, we believe Donidalorsen has the potential to be a preferred prophylactic treatment for many HAE have built a highly experienced, efficient, and scalable commercial organization. With the TRYNGOLZA-FCS launch underway, we are focused on delivering its full potential, while preparing to successfully execute our three additional launches planned over the next three years with more to follow positioning Ionis for sustained growth and long-term that, I'll now turn it over to Richard. Richard Geary Thank you, Kyle. We had many important pipeline achievements in 2024 that position us well for success in 2025. These included numerous positive late-stage data readouts, which resulted in multiple regulatory submissions and our first independent launch. Additionally, as our pipeline advances, we are on track for multiple late-stage data readouts and regulatory actions this year and next, positioning Ionis to bring transformational medicines to people with serious diseases for years to with TRYNGOLZA, the first-ever approved treatment for adults with FCS in the US, the positive data from the Phase 3 BALANCE study formed the basis for TRYNGOLZA's approval. In the BALANCE study, TRYNGOLZA 80 milligrams, demonstrated substantial and sustained triglyceride reductions, clinically meaningful reductions in acute pancreatitis a substantial reduction in all-cause hospitalization and days spent in the hospital, and a favorable safety and tolerability profile in people with FCS. We believe these positive data underscore the tremendous benefit TRYNGOLZA can brain to adults with while we are starting with FCS, we expect to quickly expand to a second broader indication, SHTG. Many SHTG patients are unable to manage their triglycerides with currently available treatments and physicians are eager for a more effective a reminder, we have three separate studies. We expect to report top line results from ESSENCE, our supported safety EXPOSURE study first with data expected in mid this year. ESSENCE is being conducted primarily in patients with triglyceride levels between 150 and 500 mgs per deciliter who are not at high risk for acute pancreatitis. This is not the patient population we're targeting commercially. Rather the ESSENCE study was designed to satisfy the regulatory requirements for a safety database to support a highly prevalent look forward to data from our pivotal studies CORE and CORE2 to truly understand the Olezaresen profile in SHTG. These studies are evaluating Olezaresen in our target patient population who have triglycerides greater than 500 milligrams per deciliter. We are on track for data from CORE and CORE2 in the second half of this year. And once we have data in hand for both of these studies, we will report the assuming these data are positive, we plan to submit our sNDA before year-end. With significant first mover advantage in both FCS and SHTG and compelling results already demonstrated in FCS coupled with our expectation for similarly positive data in SHTG, we believe Olezaresen could be the standard of care for both closely behind TRYNGOLZA is Donidalorsen, a potential advance for patients with hereditary angioedema. We're pleased that Donidalorsen is now under regulatory review in both the US and EU. Our regulatory submissions were based on positive data generated from our Phase 2 and Phase 3 studies, including a separate SWITCH the Phase 3 program, long-term Donidalorsen treatment demonstrated substantial reductions in HAE attack rates of more than 90% with both monthly and by monthly dosing and a favorable safety and tolerability profile. These reductions translated to a high level of disease control and clinically meaningful improvements in quality-of-life the SWITCH study, patients who switched to Donidalorsen from prior prophylactic treatment showed a further reduction in HAE attack rates from baseline with nearly 85% of the patients surveyed preferring Donidalorsen. With a PDUFA date of August 21, we look forward to bringing this potential preferred prophylactic treatment to HAE patients later this year, assuming out our Ionis on late-stage pipeline is Zilganersen, our medicine to treat Alexander's disease, an ultrarare leukodystrophy that profoundly impacts patients and families and has no approved disease-modifying treatments. Last year, Zilganersen was granted fast track designation by the FDA, reflecting the serious unmet need that exists for this rare disease. We are looking forward to reporting Phase 3 data for this program late this year. The rest of our rich pipeline is also making excellent includes ION582, our wholly owned investigational medicine for Angelman syndrome, which we believe has transformational potential for the tens of thousands of patients living with this serious rare disorder last year, based on the positive early results from the HALO study of ION582 in children and adults with Angelman Syndrome, we reached alignment with FDA to conduct the most robust and comprehensive Phase 3 study in this patient population to study will focus on clinical end points that reflect the most pressing and meaningful outcomes for people living with Angelman syndrome, endpoints that showed positive results in our HALO study. We remain on track to start ION582 Phase 3 study in the first half of this we look to our key value-driving events, we have already made excellent progress. In addition to launching TRYNGOLZA, we are pleased that higher dose Nusinersen is one step closer to the market with the recent FDA and EMA acceptances of Biogen's regulatory submissions. With the well-characterized profile of SPINRAZA established over the past 10-plus years and the positive data from the higher dose SPINRAZA, we believe SPINRAZA is well positioned to continue to bring benefit to SMA patients around the summarize, key near-term value-driving events, we anticipate many late-stage data readouts, significant regulatory actions, and numerous product launches. By the end of 2026, we expect seven Phase 3 data readouts, including two Ionis owned medicines. This year, Olezaresen for the broad SHTG indication in Zilganersen for Alexander's five Ionis discovered medicines are on track for Phase 3 data, most of which are for very broad patient populations. If positive, these groundbreaking medicines could start to reach patients as soon as next year. And we expect to have five launches underway, including four independent launches. All of this sets us up to bring a steady cadence of new Ionis medicines to patients for years to that, I'll turn it over to Beth. Elizabeth Hougen Thank you, Richard. We've made excellent progress advancing our strategic growth priorities, including executing our first independent launch while simultaneously upholding our commitment to drive operating leverage. This important progress is reflected in our strong financial results for last year and our outlook for this year, both of which I am happy to share with you delivered a non-GAAP operating loss of $345 million, a significant improvement compared to our 2024 guidance. We also substantially exceeded our 2024 revenue guidance by more than $130 million, earning revenues of $705 million last year. During 2024, SPINRAZA remained the primary source of commercial revenue with $216 million of royalties for the were encouraged by SPINRAZA's performance and look forward to the anticipated launch of the higher dose options. WAINUA product revenue achieved accelerating sequential growth throughout last year, driven by strong underlying demand. Notably, WAINUA product revenue increased 84% in the fourth quarter compared to the third quarter. WAINUA product sales were $85 million for last year, which we earned for which we earned $20 million in planned, our non-GAAP operating expenses increased slightly for 2024 over 2023. The 12% increase year-over-year in sales and marketing expenses reflected our investments in the US launch of TRYNGOLZA and preparations for the upcoming launch of Donidalorsen. Our SG&A expenses also included our minority portion of WAINUA's sales and marketing costs, which are in the high teens to low 20% line with our plan, we kept R&D expenses stable year-over-year, while appropriately funding our rich pipeline. Our excellent progress last year, coupled with our disciplined financial management, positions us well for continued growth and value financial guidance for this year reflects our evolution to a fully integrated commercial-stage biotech company, focused on maximizing the value of our innovative medicines while remaining steadfast in our commitment to deliver strong operating leverage. We project to earn more than $600 million in revenue from numerous sources including a shift towards commercial revenue with the addition of TRYNGOLZA product revenues and initial Donidalorsen product revenues, assuming TRYNGOLZA, it's important to remember that FCS is a rare and under-recognized disease, and we anticipate an initial gradual buildup of launch momentum, especially in the first few quarters. As our efforts aimed at driving physician awareness and patient identification progress, we expect the number of new patients diagnosed with FCS to increase, which in turn will translate to an acceleration of our launch also looking forward to adding Donidalorsen product revenues beginning in late Q3, assuming approval in August. And since this is primarily a [switch] market, we expect the launch to reflect the time it takes to convert patients from their existing therapy to our partnered programs, we anticipate earning substantial royalties from medicines on the market today. These include SPINRAZA, which continues to be our largest commercial revenue source. We expect the resilience SPINRAZA has demonstrated to continue and our royalties to reflect that. And this also includes WAINUA, which we expect will continue its upward trajectory this year. With these expected launch dynamics, coupled with the resetting of the royalty rate for SPINRAZA at the beginning of each year, we anticipate that our commercial revenue will increase as the year R&D revenue remains a meaningful contributor to our total revenue guidance, although we expect it to be lower this year than it was last year. With a rich pipeline and many partnered programs advancing, we have the potential to earn numerous milestone payments. And based on the timing of anticipated milestones, we expect to earn much of our R&D revenue in the second half of the as we continue to conduct the cardio transform study, we will continue to earn revenue from AstraZeneca for its 55% share of the study cost. We project our 2025 operating expenses to increase in the high single-digit percentage range compared to last year. This modest increase reflects our commitment to bring our medicines directly to patients and advance our pipeline while also continuing to exercise sound fiscal stewardship.[Business] in 2024, our planned expense growth will come from increases in our sales and marketing expenses and as we invest to support the success of our multiple ongoing and planned launches. We expect our R&D expenses to remain steady in 2025 similar to last year, as several of our late-stage studies have recently concluded or are on track to wrap up this year, we are able to reallocate our resources toward our next wave of opportunities, just as we have done for the Phase 3 development of ION582 for Angelman sizable revenues and modest expense growth, we are projecting a non-GAAP operating loss of less than $495 million. We project to end the year with cash and investments of approximately $1.7 billion. Our projected year-over-year change in cash reflects our investments to bring our medicines directly to patients in addition to advancing our wholly-owned medicines in development while exercising prudent fiscal beyond 2025, with the numerous opportunities before us, we are on track to deliver substantial and sustained revenue growth. This revenue growth, combined with our commitment to drive operating leverage positions us well to also generate positive cash flow. To achieve our goal, we expect to continue making significant investments to advance our pipeline and bring our growing portfolio of medicines directly to estimate that the programs in our pipeline today have a combined multibillion-dollar peak revenue potential. This includes estimated annual peak sales of more than $3 billion from our Ionis-owned medicines including Olezaresen and based on our partner's peak sales estimates, we could earn more than $2 billion annually in royalties from our late-stage partnered medicines. So as you can see, with robust revenue growth potential, we have a clear path to achieve positive cash with that, I'll turn the call back to Brett. Brett Monia Thank you, Beth. Becoming a fully integrated commercial stage biotechnology company required the commitment and hard work for all Ionis employees, and we expect to continue our great progress as we enter this next exciting chapter for Ionis. Innovation has always been a key differentiator for Ionis. And through innovation, we've established a proven and prolific discovery and development engine that has provided us with a rich pipeline of medicines with transformational potential and this will pipeline is consistently delivering with three important FDA drug approvals in just under two years, (technical difficulty), WAINUA for ATTR polyneuropathy, and now TRYNGOLZA for FCS, and a fourth FDA approval anticipated later this year, Donidalorsen for also achieved several important approvals outside the US, and we expect a great deal more this year and incoming years. And with an advancing late-stage pipeline, we have delivered several positive Phase 3 data readouts with more expected this year and next that are being developed to treat both rare and broad patient today, we have a scalable, highly experienced, innovative commercial organization in place currently launching TRYNGOLZA for FCS and positioned for three additional launches over the next three years. This progress provides us with a clear path to achieve positive cash flow driven by our expectation for substantial top-line revenue growth. This sets us up to deliver accelerating value for all on with that, we'll now open the call over for questions. MJ? Operator (Operator Instructions) Mike Ulz, Morgan Stanley. Mike Ulz Maybe just one on Olezaresen and SHTG, just given the ESSENCE study is supposed to read out midyear ahead of the core studies. And I realize it's more of a safety study and you're enrolling a different population. But what kind of read-through could we make from ESSENCE to your core studies? Thanks. Brett Monia Thank you, Mike. The ESSENCE study, just as a reminder, is the patient population as Richard described before, that is not our target commercial patient population. It's mildly elevated triglycerides 150 to 500. Our target patient population is SHTG 500 milligrams per deciliter (technical difficulty) So it is a safety study, as you say, for read-through, safety will certainly be a key read-through to demonstrate and we think confirm further validate the safety that we've seen in the FCS patient population. So that's very important. As well, the APOC3 reductions that we expect in that study. We, of course, will be looking at triglyceride reductions in that study. That as a predictor of what we'll see in SHTG is somewhat less direct, but we still think it will be -- still an indicator of what to expect in SHTG to some extent, a lesser extent because it's a slightly different patient we're really focused on the safety in that study and the target engagement as a read-through to SHTG. Operator Jessica Fye, JPMorgan. Jessica Fye I was hoping if you could talk a little bit about what you're seeing in the TTR polyneuropathy market? For example, what portion of new starts do you think you're capturing there? Brett Monia Yeah. Thanks, Jess. As Beth communicated earlier, we're so excited about the continued progress here with the launch of WAINUA and ATTR polyneuropathy, the growth quarter-over-quarter of an increase of 84% and $42 million in Q4 and $85 million on the year. I think what that speaks to is the strong demand and the continued growth that's within that category right the new to brand share is about 40% for WAINUA. So we are continuing to capture in terms of new patient starts, a significant portion of those, and we expect that to continue to grow over time. We're seeing not only centers of excellence, but also community physicians begin prescribing. So the expansion, neuros and cardiologists are both prescribing and we're still seeing a mix of naive switches as well as combination treatment for 2025 is really setting up, I think, to be a very strong year for WAINUA to see the continued growth that we saw in 2024 quarter-over-quarter. Operator Akash Tewari, Jefferies. Akash Tewari Can you talk a little more about your design for SHTG, the Phase 3? I mean you've mentioned previously the enrollment rate in that trial is 10x that of FCS. What does that imply for the effect size you've powered for, particularly on acute pancreatitis and severe abdominal pain?And really, how does your event rate assumption maybe differ versus FCS, but also that ESSENCE study that you mentioned isn't necessarily representative of your other trials? And then any feedback from KOLs on what would be a clinically meaningful reduction would be very helpful as well. Thank you. Brett Monia Thank you, Akash. Let me take a stab that there were a few things there to unpack, very important questions, but then also Eugene can jump in. So our study -- our SHTG Phase 3 study CORE and CORE2 are powered -- of course, while powered for diglyceride reductions, which is our primary end point. As far as acute pancreatitis -- impact acute pancreatitis events in the SHTG core studies, this has really never been studied did not believe we were well powered for a positive AP outcome in FCS, and we were pleasantly surprised to see what a tremendous impact we had at reducing AP events in that patient population, even though it was a very small study. The higher the triglycerides in patients, the greater the risk of acute pancreatitis, that's obvious and well SHTG population has somewhat milder triglycerides on average compared to FCS. So you might expect a lower rate of acute pancreatitis in that study -- in that patient population. Nevertheless, we have more than 10 times the number of patients in our core studies, which, of course, allows us to accumulate potentially more although we're not necessarily powered and no one's ever studied this before so it would be difficult to power a study on the reduction of AP in SHTG, certainly, the balance FCS data lends us some confidence that we'll see a significant or a meaningful signal in acute pancreatitis and like to add anything to that, Eugene? Eugene Schneider No, not really. There was another question about clinical meaningfulness of reduction. Of course, that's -- as Brett said, it's not really clear. There is no particular threshold that is considered to be clinically meaningful in terms of AP reduction. So what we're hoping to see is really any significant reduction overall. But as Brad said, of course, the powering of the study is not something that we were able to model based on any existing data. Operator Yanan Zhu, Wells Fargo Securities. Yanan Zhu First, I wanted to have a quick follow-up to a prior question on the WAINUA polyneuropathy 84% quarter-over-quarter growth. How much of that growth is driven by switching because this year, they're both naive patients and switching patients, but wondering how much of a force is the switch from my main question: I think Biogen announced a couple of updates to some neurology collaboration programs. Could you provide a little more color and what's the plan for those programs? Thank you. Brett Monia Sure. Kyle, please take the question on quarter-over-quarter the growth, what's driving that. And I'll happy to comment on Biogen. Kyle Jenne Yeah. The growth, as we know in this market, less than 20% of the patients are currently being treated in the polyneuropathy space with the therapy today. So the opportunity here remains to grow this market. And that's really what we're seeing, and that's the focus that AstraZeneca and our teams have in terms of identifying newly diagnosed patients and getting those naive patients started on we are hearing consistently from physicians is that there is improvement in quality of life, the safety profile, and the tolerability of WAINUA is very strong and access to treatment is extremely strong. The majority of patients, as I highlighted, have a zero-dollar out-of-pocket expense. That's regardless if they are commercial or Medicare to be able to afford the medication on top of the profile and the ability to self-administer WAINUA at a place that they're choosing continues to resonate extremely well. So as the market expands, physicians are choosing way over some of these other in the instances where there are switches from other therapies, the main driver for that really is the ability of the self-administer. We're seeing very good access and very good coverage. And if patients were able to do this on their own and not have some of the challenges associated with site of care and they can do this at a place of their choosing, physician and patients are choosing with a very highly performing medication combined with the ability to self-administer, it's really making a differentiation possible quarter-over-quarter, and we're seeing that growth due to that. Brett Monia And then regarding the other part of your question, Yanan, we couldn't be more pleased to retain global rights for both of these programs. These programs that you're referring to or our alpha-synuclein program that is in development, Phase 2 development for multiple system atrophy and the [LRRK2] program, which is indicated for Parkinson's disease. We couldn't be more thrilled to retain full control of these a little color to add to these, the alpha-synuclein program required a decision by Biogen to opt in on this based on partial data. It's a study that's ongoing -- and in fact, they really only had access to the low-dose cohort at the time. This was based on the contract with Biogen for this particular program. And like I said, we're thrilled to have the full control of this very important forward, the LRRK2 program was a very small study, 12 weeks of treatment. Obviously, you're not going to have any clinical data, meaningful data in a 12-week study in PD patients. The study was designed for safety and target engagement, and we're very pleased with what we saw in safety. We were very pleased with the magnitude of LRRK2 reductions we saw in the study. This drug definitely deserves to be further developed, and we're looking forward to forging a path forward for both programs, LRRK2 and alpha-synuclein, we're expecting to have data in MSA later this year. Our partnership with Biogen remains very strong, and this was essentially a R&D prioritization decision by Biogen. Operator Jay Olson, Oppenheimer. Jay Olson Congrats on all the progress. TRYNGOLZA, I think you mentioned 3,000 patients in the US. Can you just talk about how many of those patients are currently diagnosed and available for treatment? And if it's not too early, how many of those patients are on treatment or any other important metrics you could share to help track the launch of TRYNGOLZA? Kyle Jenne Yeah. Thanks, Jay. I can't be more excited than to kind of talk about TRYNGOLZA. Obviously, a rare disease population, we're doing a lot of work right now to number one, identify; number two diagnosed and then finally, get prescriptions written and get these patients on drug. The launch is going very, very well. When you look at the label that we received, it's a very broad label. It's a clean label. It allows the physicians to prescribe TRYNGOLZA for clinically or genetically diagnosed have AP in the label, demonstrating substantial reductions in acute pancreatitis and we got first-mover advantage, which allows us to develop this market and to take the patients that you're asking about and move them on to TRYNGOLZA very quickly. The feedback that we're receiving already is that all of the stakeholders, be it patients, HCPs, the advocacy groups, payers, et cetera, have been very, very positive about TRYNGOLZA. They are really excited to have a treatment option when they've never had a treatment option terms of execution around this plan, we had product and channel before the end of the year. we launched in 2024 and everything that we've been trying to do to be able to deliver treatment to these patients is going very well. Now of the 3,000 patients, there are several hundred right now that are currently identified and they are continuing to come in, as I mentioned, and become diagnosed formally and get prescriptions written for us. So we've got some time in terms of the momentum in the launch ramp the metrics, we're not disclosing too many metrics. Obviously, this is a competitive market that we're in. But what we're really encouraged by right now is the number of physicians that we've seen identifying and prescribing. So we've got a good breadth of prescribers. We are seeing a mix of specialties prescribing as well. So we have endocrinologists and cardiologists. Those that have an interest in lipids and also pancreatology, are prescribing TRYNGOLZA, which was to be other thing that we're keeping an eye on is time to prescription and how long it takes to go from prescription to actually getting the drug filled into the patient. And that's going very, very quickly, faster than we had expected here early on. And what that's telling us is that the FCS diagnosis, if it's either clinical or genetic is confirming these patients and physicians are working through the medical exception process in order to justify the prescription and getting these patients on treatment the final thing I'll say is our Ionis Every Step program is executing very well, and that allows us to interact directly with patients and do disease education and product education and support them through the reimbursement process and patients are giving us very positive feedback about the ability to self-administer with an auto-injector on a monthly basis. And the profile of the drug is playing out very positively here in the first couple of weeks of thanks for asking. Operator Jason Gerberry, Bank of America. Chi Meng Fong This is Chi on for Jason. I guess I would like to follow up TRYNGOLZA launch in FCS. Thanks for all the commentary on early launch experience so far. I'm curious, based on early launch experience, what insurance company you think are requiring in terms of documentation for reimbursement consideration?With (technical difficulty) and one thing that we have heard is that genetic confirmation is the most straight-forward documentation to get insurance company on board, somewhat a bit of a gray area when it comes to clinical diagnosis, part of it is the lack of consensus that knows this criteria. Some of it is what insurance company, except as clinical diagnosis criteria. Can you talk about that?And when you talk about several hundred patients currently identify and become formally diagnosed, how many of those are getting genetically confirmed? and How many of those are getting clinically diagnosed. And if you can talk about that mix within that 3,000 patients US prevalence that you have estimated, that will be great as well. Kyle Jenne Yeah. Thanks, Chi. First, let me just touch on the insurance process. The first three to six months as is typical is going to go through a medical exception process. So there are really -- there are very few plans so far that have established formal criteria to say this is what's absolutely then the question becomes what is the history of the patient, what steps has the physician gone through to actually substantiate or validate that this truly is an FCS patient so that they can get the coverage by the plan and ultimately get the drug approved. The most straightforward is a genetic confirmation. I think that's the easiest we have seen both clinically and genetically diagnosed patients work through the medical exception process very efficiently with justification of outpatient triglyceride levels, the history of the patient, age of diagnosis, symptomatology, right abdominal pain, acute pancreatitis potentially in their history. So there are a lot of other things to unpack in terms of the patient presentation that ultimately will justify or qualify that patient for an approval from the health as I mentioned as well, we're seeing this through both the commercial and Medicare segments of the business. So what we're most optimistic about is that physicians are doing this the right way. They're identifying FCS patients, they're justifying it through one of those two means and supporting that patient through the process very quickly.I don't have a number that I can share with you in terms of how many have been clinically versus genetically confirmed at this point that have gone through our process. But obviously, both are being approved in terms of getting that approval. The lack of consensus we have not heard yet. Using the NAFCS scoring tool that [Dr. Hagley] published at the end of last year, seems to be a pretty straightforward tool for them to be able to use and substantiate and validate for these patients is what we're seeing based on the fact that it has been not to break out the mix, but other than that, I'm very encouraged early on at the coverage -- there's more to learn in terms of coverage, and then payers will be establishing criteria throughout the first six months or so, and we're working directly with the payers in order to make sure that there's a reasonable path forward for these patients to be able to have access to TRYNGOLZA. Brett Monia And just -- points that I'll just add to that, Chi. We're very pleased with the speed to genetic diagnosis that we're experiencing so far in one to two weeks with a genetic diagnosis (technical difficulty) go that route. And I also think it's reasonable to assume that any aspect of diagnosis that physicians are unfamiliar with today, they will become more familiar with it as time goes on. And we're driving a lot of that work, especially utilizing the North American FCS diagnosis criteria to build that familiarity or physicians. So expect that to improve as we go forward. Operator David Lebowitz, Citi. This is (technical difficulty) on for David Lebowitz. I also have one on the SHTG readout. It's regarding the 12-month time point in the trial is on the primary. So we know that these SHTG patients, they're going to be coming in lower -- with much lower TG levels than in FCS and likely different rates of FCS at baseline as well. And so I'm wondering if there's no clinical consensus on how much TG lowering is actually beneficial as you said, just wondering what the reasoning was behind the selection of that 12-month time line?And just overall, what is our understanding in this population so far as to what they need? Brett Monia So thank you for the question, and Richard follow up with anything that you want to touch on after my comments. So the primary endpoint is triglyceride lowering at six months. The full study readout is at 12 months. So the primary end point is at six months on TGs. We have a very rapid response on APOC3 reductions, substantial lowering of APOC3, substantial and rapid lowering of triglycerides based on our previous clinical data for TRYNGOLZA as well as our balanced FCS data. So we're out -- we strongly -- well powered on the primary end acute pancreatitis, as I mentioned earlier, although the rate of AP in SHTG patients is not well documented in the literature, it will be after our Phase 3 outcome. We believe that we have -- we're in a good position based on our FCS REIT data as a read-through to show clinically meaningful reductions in acute pancreatitis in this study. And that's based on what we saw in BALANCE. I think that's driving a lot of that. Don't you, Richard? Richard Geary Yeah -- I would also say that we see events being adjudicated by our independent adjudication committee, and the events are accruing over the course of the study, and it's looking very good. The other thing I would say about triglycerides and clinically meaningful. That has been determined by the regulatory agencies. Certainly, the FDA has said significant risk occurs above 500 and it increases as the triglyceride levels by decreasing triglyceride levels by whatever the amount is, you are decreasing the risk for these patients having an acute pancreatitis. So I think that's the primary goal of the study, obviously, is to reduce their triglyceride and risk for acute pancreatitis, and we'll be able to monitor that and see the results very soon. Kyle Jenne Yeah. And let me add to that from a commercial viewpoint. Currently, patients with severely elevated triglycerides are on fibrates and fish oils and other things, statins to try to reduce their triglycerides. And cardiologists and endocrinologists are not getting these patients low enough. They need a better, more effective triglyceride-lowering treatment in order to meet the established guidelines that are already in the guidelines are there already that say you need to be below 500 in order to get out of risk as Richard was talking about from a regulatory standpoint, but most importantly, from a commercial standpoint, we know that physicians are trying to get there, and they're treating hundreds of thousands of patients already, and they're just unfortunately not able to do so because they don't have a therapy that's sufficient in order to accomplish that. And that's what we hope to be able to bring to the market shortly with an approval in SHTG with Olezaresen. Brett Monia Yeah. I think it's also important to emphasize that this, SHTG is not an asymptomatic disease. It's a very serious symptomatic disease that in addition to acute pancreatitis, these patients suffer from serious cognitive [problems] serious cognitive impairment, serious body pains, nausea, and so forth and often land in a hospital even without an AP event, because they are in such fear of having an AP event because of the body pain. And we think that, that will go a long way in the commercial success of TRYNGOLZA and SHTG. Operator Gary Nachman, Raymond James. Gary Nachman Hi. Thanks, and my congrats as well on the progress. So as you prepare for new launches for Doni in HAE and Olezaresen in SHTG, just talk about how you're scaling the commercial organization following the FCS launch. What's in place versus what you need to add, specifically in terms of reps for those other programs? And then just for the Angelman program, just what's your expectations for enrollment timing given the competitive dynamics there? Thank you. Kyle Jenne Yeah, Gary, thanks for the question. I'll start. This is Kyle. Fortunately, with the co-commercialization on WAINUA, then we were able to build towards our FCS readiness internally. So we've got teams around commercial operations and our market access group, we have our capability with our Ionis every step patient support program. Those are the core fundamental foundational components to the commercial team that we've got in place and they're ready to go that allow us to scale accordingly whenever we add on new commercial therapies into the mix, such as Donidalorsen, later this year and SHTG to we're at right now, for example, with Donidalorsen is, we hired the Vice President of Sales, we will build out our Regional Director team and ultimately our customer-facing field teams from there. And that is in time and in sequence with what we are doing for the regulatory process for the anticipated approval on August I mean, I think right now, as we build -- it's been a sequential build over time, and it's been a purposeful build and it's been an intentional build as well to make sure that we're building the right capabilities at the right time and also investing the right amount within those respective functions. When we get to SHTG, it will grow exponentially as you would expect, based on the size of the market that we'll be entering into but we'll be able to add our customer-facing and field teams at the right I'm just excited about the talent and the tremendous accomplishments that we have already had with our teams that are in place and the good product that we have within the commercial group overall. Brett Monia And Gary, on the Angelman's enrollment. So we are still well on track to initiate our Phase 3 study in the first half of this year, things are going well. (technical difficulty) we've also established internal metrics to achieve with respect to enrollment this year by our team. That sets us up for completing enrollment in 2026 next year. We do not believe that this trial will be difficult to enroll. There's pent-up really encouraged by the enthusiasm by the community inquiring about our program when they will be able to enlist enrolling the study. And this is a relatively large patient population with tremendous unmet need. So that's our expectations for enrollment. Operator Yaron Werber, TD Cowen. Yaron Werber I have a quick question also as you think about -- if you think about how do you power the Angelman Phase 3 study, I know you haven't announced before full [product] design yet, but on expressive communications. And then maybe just for Beth, as you think about revenue, as you mentioned, it's more second half weighted. Are there particular milestones we need to keep in mind that are driving that? Thank you. Brett Monia Eugene, would you comment on the powering -- of course, Richard can jump in too. Eugene Schneider Yeah, sure. So as you know, our primary endpoint is expressive communication as assessed by [daily 4]. There is quite a bit of natural history data available, utilizing slightly older version of daily, but nonetheless is we are able to see and kind of make estimates on how the patients are expected to progress with regard to their ability to communicate, which is unfortunately kind of unknown primary deficiency in this population. They have little to no expressive that, combined with our Phase 2 very encouraging Phase 2 data really allowed us to make some assumptions on the treatment effect size that we're expecting to see in a placebo-controlled setting for Phase 3. As you know, we're also testing two dose levels. So again, it's a 2:1 randomization. But essentially, that and the knowledge of natural history trajectory in this patient population is what we used in our assumptions. Yaron Werber Are both doses powered against placebo? Thank you. Eugene Schneider Yes. So our -- our goal is to see an effectiveness of both doses. Brett Monia So the two doses are the same two doses that we studied in the Phase 2 HALO study, both of which showed really, really encouraging evidence of efficacy across all domains that we examined using all instruments, whether it be daily, for Vinland, VASCGI, et cetera, at Orca. And as a reminder, expressive communication uniformly demonstrated (technical difficulty) best outcome in our Phase 2 HALO study, which that, combined with the fact that this end point, this part of the Angelman's phenotype is the most burdensome among the coupled with that's where we integrated magnitude is why we settled on the expressive communication in our Phase 3 study. And that certainly was very important along with the natural history data that Eugene mentioned in the power and our powering assumptions for our study, which is what, nearly 300 patients to three cohorts in the Phase 3 study design, randomized 1:1 or 2:1 when you look at on treatment versus you had -- there's also a question for you in the room. Elizabeth Hougen Yeah. So on the -- on our revenue guidance for this year, I think just to reemphasize, really anticipate a shift to commercial revenue this year with SPINRAZA, WAINUA continuing to grow quarter-over-quarter, the addition of TRYNGOLZA revenues and in the back half of the year, the Donidalorsen in revenues assuming we think about R&D revenues, as you know, we have lots of different partnerships, some optemedicines in development under those partnerships. No one particular medicine has a very significant milestone. So there's no sort of large milestones that I could point to that are going to really be the cornerstone of our R&D revenue this year. A big piece of it will be the continued R&D funding we get from AstraZeneca as we conduct the cardio transform Phase 3 get 55% of those all-in costs reimbursed to us from AstraZeneca and that we book as revenue. And then there's a whole host of partnered programs, particularly with Biogen and others AstraZeneca that as they advance, we would anticipate seeing milestones over the course of the year with, as I said, much of that being back-end loaded. Wade Walke Thanks, Beth. Thank you, Yaron. We have time for one more question. Operator Myles Minter, William Blair. This is Jake on for Myles. A couple for you. The first is on SHTG. We're wondering if you get some color on your plans for potential ex-US launch and whether you would be comfortable going in alone or whether you're looking to find a partner in that as you did for then second, we wanted any updates you have on the next-generation (technical difficulty) targeting asset with Novartis and whether clinical development or clinical entry is contingent on a positive readout from the HORIZON study. Thank you. Brett Monia Thanks, Jake. So before we get into ex-US SHTG, let me start with FCS. For both FCS and then, subsequently, SHTG, we're planning to secure a US commercial partner like we did for Donidalorsen Morrison. Discussions are progressing very nicely. And it's consistent with our commercial strategy that we laid out five years ago that initially, we will focus on the US market and secure OUS commercial partners programs we bring to the market that will evolve, and that will change in due time. And we're working on that now, where we will emerge from the US market. But today, we will secure an OUS partner to commercialize TRYNGOLZA, for SCS and HT outside the US.I really do not have much to offer with respect to whether or not Novartis will wait for the (technical difficulty) readout before initiating clinical testing for our follow-on molecule that we provided to them and they licensed last year. It's a great (technical difficulty) but the follow-on really does look like a best-in-class molecule with respect compared to everything that's been publicly disclosed to date.I don't think it matters much on the timing because (technical difficulty) isn't that far away first half of next year. And the follow-on molecule for Lp(a) CBD that we provided is starting IND-supporting toxicology studies now. So I think it has to run its course through there and then prepare for clinical testing. So that's really a question more specifically that's best suited for Novartis. But thank you for the questions, and thanks to everybody who joined us today and participating in our call. We're really looking forward to an outstanding year ahead and sharing our progress along the way with you. But until then, thanks again, and everybody, have a great day. Operator Goodbye. The conference has now concluded. Thank you for your participation. You may now disconnect your lines. Sign in to access your portfolio
