Tryngolza (olezarsen) / Ionis, Theratechnologies - LARVOL DELTA

Novel Therapeutics for Familial Chylomicronemia Syndrome. (PubMed, Curr Atheroscler Rep) - "Volanesorsen, an ASO targeting APOC3, has shown effectiveness in managing FCS, multifactorial chylomicronemia, and familial partial lipodystrophy, but its use is limited by thrombocytopenia. Emerging therapies, Olezarsen (ASO anti-APOC3) and Plozasiran (siRNA anti-APOC3), both conjugated with GalNAc, show promise in reducing acute pancreatitis risk without platelet concerns. ANGPTL3 inhibition requires residual lipoprotein lipase (LPL) activity, with only siRNA-based therapies-zodasiran and solbinsiran-under investigation. Suppressing APOC3 expression and targeting ANGPTL3 via siRNA offer significant potential, but long-term studies are needed to confirm their efficacy and safety. Future research may explore gene-editing strategies using lipid nanoparticle-based CRISPR-Cas9 delivery for more durable treatment outcomes."

Journal • Review • Familial Chylomicronemia Syndrome • Hematological Disorders • Lipodystrophy • Metabolic Disorders • Pancreatitis • Rare Diseases • Thrombocytopenia • ANGPTL3 • APOC3 • LPL

Olezarsen for the Treatment of Familial Chylomicronemia Syndrome. (PubMed, Ann Pharmacother) - "Olezarsen represents a new treatment for FCS, offering a targeted approach to significantly reduce triglyceride levels. Its integration into clinical practice has the potential to transform the management of FCS; however, more studies are needed to firmly establish its role."

Journal • Review • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Genetic Disorders • Hypertriglyceridemia • Infectious Disease • Novel Coronavirus Disease • Pain • Severe Hypertriglyceridemia • Targeted Protein Degradation • APOC3

A Study of Olezarsen (ISIS 678354) in Participants With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease, or With Severe Hypertriglyceridemia (clinicaltrials.gov) - P3 | N=1478 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial primary completion date: Mar 2025 ➔ Aug 2024

Trial primary completion date • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Severe Hypertriglyceridemia • APOB

4016 - A Major Milestone in the Treatment of Familial Chylomicronemia Syndrome (FCS) (ACC 2025) - "A Major Milestone in the Treatment of Familial Chylomicronemia Syndrome (FCS)Join IONIS to learn about TRYNGOLZA{TM} – the first and only FDA-approved therapy for adults with familial chylomicronemia syndrome (FCS), as an adjunct to diet...Industry-Expert Theater presentations are not part of ACC.25, as planned by its Program Committee, and do not qualify for continuing medical education (CME), continuing nursing education (CNE) or continuing education (CE) credit. Sponsored by Ionis Pharmaceuticals"

Familial Chylomicronemia Syndrome

OLEZARSEN REDUCES ALL-CAUSE HEALTHCARE UTILIZATION IN PATIENTS WITH FAMILIAL CHYLOMICRONEMIA SYNDROME - Asia Sikora Kessler (ACC 2025) - "In Balance, olezarsen treatment was associated with a significant reduction in all-cause hospitalizations and total inpatient days compared to placebo. Data suggest olezarsen may reduce healthcare utilization in patients with FCS."

Clinical • HEOR • Dyslipidemia • Familial Chylomicronemia Syndrome • Genetic Disorders • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia

EFFICACY AND SAFETY OF ANTISENSE OLIGONUCLEOTIDE THERAPIES TARGETING APOCIII IN PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS - Muhammad Ahmad Qureshi (ACC 2025) - "This meta-analysis confirms that ASOs Volanesorsen and Olezarsen effectively lower triglycerides and improve lipid profiles in severe HTG. Despite adverse effects, especially with Volanesorsen, these therapies may reduce the risk of acute pancreatitis compared to placebo. Overall, ASOs targeting APOC3 are valuable for managing HTG."

Retrospective data • Dyslipidemia • Hematological Disorders • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia • Thrombocytopenia • APOA1 • APOB • LPL

OLEZARSEN REDUCES LIPOPROTEIN(A)-ASSOCIATED TRIGLYCERIDE CONTENT IN PATIENTS WITH MODERATE HYPERTRIGLYCERIDEMIA - Sotirios Tsimikas (ACC 2025) - "Compared to placebo, olezarsen significantly results in remodeling of Lp(a) particles by reducing their triglyceride and cholesterol content, without affecting Lp(a) concentration. These data suggest Lp(a) particles are triglyceride enriched in patients with hypertriglyceridemia. Ongoing clinical trials of triglyceride and Lp(a) lowering may define the clinical implications of this observation."

Clinical • Dyslipidemia • Hypertriglyceridemia • APOC3

EFFECT OF OLEZARSEN ON LIPOPROTEIN-ASSOCIATED APOC-III IN PATIENTS WITH FAMILIAL CHYLOMICRONEMIA SYNDROME - Sotirios Tsimikas (ACC 2025) - "Olezarsen 50 and 80 mg selectively reduces apoC-III content on total apoB, representing mainly chylomicrons in this FCS population, as well as in HDL particles. Measuring apoC-III on specific lipoproteins in addition to total apoC-III may allow refinement of pancreatitis and cardiovascular risk prediction in patients with disorders of triglyceride metabolism."

Clinical • Cardiovascular • Familial Chylomicronemia Syndrome • Pancreatitis • APOA1 • APOB

EFFECT OF OLEZARSEN IN PATIENTS WITH HYPERTRIGLYCERIDEMIA-A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS - Ameer Haider Cheema (ACC 2025) - "Olezarsen reduces triglyceride and ApoCIII levels and increases HDL levels but does not significantly reduce LDL levels."

Retrospective data • Atherosclerosis • Diabetes • Dyslipidemia • Hypertriglyceridemia • Pancreatitis

2024 FDA TIDES (Peptides and Oligonucleotides) Harvest. (PubMed, Pharmaceuticals (Basel)) - "Interestingly, among the strategies employed in recent approvals to enhance stability and/or delivery, the prodrug approach, exemplified by palopegteriparatide and pegulicianine, is emerging as a more targeted and precise therapeutic strategy. Additionally, the Enhanced Stabilization Chemistry (ESC)-GalNAc platform has been expanded for hepatic delivery of a new oligonucleotide drug, olezarsen. Furthermore, novel modifications to the ribose moiety in oligonucleotides, such as the 3'-amino substitution in imetelstat, enhance their stability. This review examines the TIDES approved in 2024 based on their chemical structure, medical targets, modes of action, administration routes, and common adverse effects. In addition, it highlights how the prodrug strategy has improved targeting efficiency and extended the half-lives of the active drugs."

Journal • Review • Developmental Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders

Ionis expands partnership with Sobi to include olezarsen commercialization outside the U.S. (Businesswire) - "Ionis Pharmaceuticals, Inc...announced that it has entered into a license agreement under which Sobi receives exclusive rights in countries outside the U.S., Canada and China to commercialize olezarsen as a potential treatment for familial chylomicronemia syndrome (FCS) and severely elevated triglycerides....Sobi will be responsible for future regulatory submissions and commercialization in ex-U.S. geographies except Canada and China. Olezarsen was licensed to Theratechnologies for commercialization in Canada."

Licensing / partnership • Familial Chylomicronemia Syndrome

Safety and efficacy of antisense oligonucleotides on triglyceride, apolipoprotein C-III, and other lipid parameters levels in hypertriglyceridemia; a network meta-analysis of randomized controlled trials. (PubMed, Lipids Health Dis) - "APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen."

Clinical • Journal • Retrospective data • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • APOC3

Olezarsen in Patients with Hypertriglyceridemia at High Cardiovascular Risk: Rationale and Design of the Essence-TIMI 73b Trial. (PubMed, Am Heart J) - P3 | "Targeting apoC-III to facilitate clearance of triglyceride-rich lipoproteins is a potential therapeutic strategy for lowering triglyceride levels, regressing atherosclerosis, and reducing cardiovascular risk. The phase 3 Essence-TIMI 73b trial, which has enrolled nearly 1,500 patients, including over 550 in a coronary CTA substudy, should provide key insights into the efficacy and safety of olezarsen in patients with largely moderate hypertriglyceridemia and elevated cardiovascular risk."

Clinical • Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • Severe Hypertriglyceridemia

Apolipoprotein C-III inhibitors for the treatment of hypertriglyceridemia: A meta-analysis of randomized controlled trials. (PubMed, Metabolism) - "APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia."

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia

Familial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA. (PubMed, Atherosclerosis) - "Reduced TG, lower rates of acute pancreatitis events, and similar proportions of adverse events in placebo and treated patients were recently demonstrated in placebo-controlled phase 3 trials of patients with FCS treated with olezarsen in Balance and with plozasiran in PALISADE. This review discusses causes and consequences of FCS and the rationale and progress made in developing APOC3 RNA-targeted therapeutics for the treatment of FCS."

Journal • Review • Dyslipidemia • Familial Chylomicronemia Syndrome • Hypertriglyceridemia • Pancreatitis • APOC3 • LPL

Olezarsen: First Approval. (PubMed, Drugs) - "Olezarsen received its first approval in the USA on 19 December 2024 under priority review as an adjunct to diet to reduce triglycerides in adults with FCS. This article summarizes the milestones in the development of olezarsen leading to this first approval for FCS."

Journal • Review • Dyslipidemia • Familial Chylomicronemia Syndrome • Hematological Disorders • Severe Hypertriglyceridemia • Thrombocytopenia

Design and Rationale of the CORE -TIMI 72a and CORE2 -TIMI 72b Trials of Olezarsen in Patients with Severe Hypertriglyceridemia. (PubMed, Am Heart J) - P3 | "Pooled analyses of CORE and CORE2 will also assess olezarsen's effect on acute pancreatitis events and change in hepatic steatosis. Together, CORE -TIMI 72a (NCT05079919) and CORE2 -TIMI 72b (NCT05552326) are designed to establish the efficacy and safety of olezarsen in patients with severe HTG."

Journal • Dyslipidemia • Familial Chylomicronemia Syndrome • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia • LPL

A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) in Participants With Familial Chylomicronemia Syndrome (FCS) (clinicaltrials.gov) - P3 | N=60 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Apr 2025 ➔ Feb 2028 | Trial primary completion date: Jan 2025 ➔ Feb 2028

Trial completion date • Trial primary completion date • Familial Chylomicronemia Syndrome

Targeting apolipoprotein C-III: a game changer for pancreatitis prevention in severe hypertriglyceridemia. (PubMed, Curr Opin Endocrinol Diabetes Obes) - "SHTG is a high-burden metabolic disorder that is associated with a significantly increased incidence and severity of acute pancreatitis. Traditional lifestyle interventions and conventional therapies, including fibrates and n-3 fatty acids, often provide only modest reductions in triglycerides and fail to prevent sHTG-associated acute pancreatitis. The emergence of novel and targeted RNA-therapies represents a potential breakthrough in the management of sHTG and acute pancreatitis prevention."

Journal • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • Severe Hypertriglyceridemia

Olezarsen (Tryngolza) for familial chylomicronemia syndrome. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Familial Chylomicronemia Syndrome

Current and Emerging Treatment Options for Hypertriglyceridemia: State-of-the-Art Review. (PubMed, Pharmaceuticals (Basel)) - "Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Hematological Disorders • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • Severe Hypertriglyceridemia • Thrombocytopenia • ANGPTL3 • FGF21

Ionis reports fourth quarter and full year 2024 financial results (Businesswire) - "'Over the next three years, we expect three more independent launches, including donidalorsen later this year for hereditary angioedema and olezarsen for severe hypertriglyceridemia in 2026, pending Phase 3 results in the second half of this year. Additionally, our partners are on track to launch four Ionis-discovered medicines over the same time period, including several that address broad patient populations'...WAINUA...Generated sales of $85 million resulting in royalty revenue of $20 million in the year ended December 31, 2024...SPINRAZA...generated global sales of $1.6 billion resulting in royalty revenue of $216 million in year ended December 31, 2024...Higher dose nusinersen under regulatory review in U.S. (PDUFA date of September 22, 2025) and EU. QALSODY (tofersen) for the treatment of SOD1-ALS generated global sales of $32 million resulting in royalty revenue of $4 million in the year ended December 31, 2024."

Launch • P3 data • PDUFA • Sales • Amyloidosis • Amyotrophic Lateral Sclerosis • Cardiovascular • Genetic Disorders • Hereditary Angioedema • Muscular Atrophy • Severe Hypertriglyceridemia

Novel RNA-Based Therapies in the Management of Dyslipidemias. (PubMed, Int J Mol Sci) - "This article discusses the latest data from completed and ongoing trials on RNA therapies for dyslipidemia, including inclisiran, pelacarsen, olpasiran, zerlasiran, lepodisiran, volanesorsen, olezarsen, plozasiran, zodasiran, and solbinsiran. Each therapy targets specific molecules while also significantly impacting other lipid parameters. The promising results of these trials indicate potential improvements in lipid therapy and cardiovascular risk reduction, with ongoing studies expected to further refine the role of the novel RNA-based agents in effective lipid management."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • ANGPTL3

Molecular Therapeutics in Development to Treat Hyperlipoproteinemia. (PubMed, Mol Diagn Ther) - "Inhibition of APOC3 messenger RNA expression by olezarsen and plozasiran significantly lowers plasma triglyceride levels and markedly reduces pancreatitis risk in patients with familial chylomicronemia syndrome. Finally, angiopoietin-like protein 3 inhibition by the monoclonal antibody evinacumab has transformed management of patients with homozygous familial hypercholesterolemia. Together, these novel agents expand the therapeutic cache, offering personalized lipid-lowering strategies for high-risk patients with hyperlipoproteinemia, improving clinical outcomes and addressing previously unmet medical needs."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Pancreatitis

Exploring emerging pharmacotherapies for type 2 diabetes patients with hypertriglyceridemia. (PubMed, Expert Opin Pharmacother) - "These were identified by a PubMed search and mainly focus on pemafibrate and the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3)...Inhibitors of apoC3 are effective in reducing triglycerides even in familial chylomicronaemia syndrome and olezarsen and plozasiran in this group are being studied in patients with combined hyperlipidemia. The ANGPTL3 inhibitor evinacumab has been approved for homozygous familial hypercholesterolemia and other ANGPTL3 inhibitors may prove be useful to reduce triglycerides in T2D."

Journal • Review • Cardiovascular • Diabetes • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Hypertriglyceridemia • Metabolic Disorders • Type 2 Diabetes Mellitus • ANGPTL3