Tryngolza (olezarsen) / Ionis, Theratechnologies - LARVOL DELTA

The ASO drug olezarsen targets familial chylomicronemia syndrome. (PubMed, Trends Pharmacol Sci) - No abstract available

Journal • Familial Chylomicronemia Syndrome

Clinical Pharmacology of Olezarsen, a Novel ApoC-III Targeted Antisense Inhibitor, for Reducing Triglycerides in Patients with Familial Chylomicronemia Syndrome (NLA 2025) - P1, P2, P3 | "Conclusions The overall clinical pharmacology properties of olezarsen are favorable and support the recommended dosing regimen of 80 mg olezarsen subcutaneous injection once monthly as safe and effective treatment in adults with FCS. No dose adjustment is required for intrinsic/extrinsic factors."

Clinical • Familial Chylomicronemia Syndrome

Comparison of diagnostic genetic testing and clinical scoring results for familial chylomicronemia syndrome (FCS) in the 66-patient Balance study (NLA 2025) - "Objective/Purpose To evaluate the sensitivity of the NAFCS scoring system in the 66 genetically identified FCS patients enrolled in Balance, a phase 3 study on the efficacy and safety of olezarsen...In Balance, the NAFCS score showed a sensitivity of 74% for the highly selective score of ≥ 60 and 95% for ≥ 45. These results suggest that the NAFCS scoring system might simplify diagnosis of FCS, supporting earlier access to treatment."

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

A Single-Dose, Randomized, Open-Label, Two-Period Crossover Bioequivalence Study in Healthy Adults Comparing Two Subcutaneous Formulations of Olezarsen: (Vial and Autoinjector) at Two Dose Levels (NLA 2025) - P1 | "Olezarsen was well-tolerated with no clinically meaningful differences in safety profiles between formulations. Conclusions This study demonstrated the therapeutic equivalence of the olezarsen autoinjector and vial presentations at both 50 mg and 80 mg doses, supporting the interchangeable use of these formulations at the same dose."

Clinical • Familial Chylomicronemia Syndrome

† Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk - A systematic review and meta-analysis (NLA 2025) - "Despite higher rates of serious adverse events, its overall safety profile remains acceptable. Further long-term studies are necessary to confirm these findings and optimize dosing."

Retrospective data • Review • Cardiovascular • Dyslipidemia • Gastrointestinal Disorder • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • APOA1 • APOB • APOC3

Prevalence, baseline characteristics, and reclassification of indeterminate genetic results in patients eligible for the Balance trial with olezarsen (NLA 2025) - P3 | "In patients with indeterminate genetic results, pending refinement of genetic testing, consideration should be given for using clinical risk scores to diagnose FCS. A global curated public database of FCS-related DNA variants in racially diverse populations may allow more accurate classification of pathogenic FCS variants."

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

Ionis announces positive topline results from Essence study of olezarsen in people with moderately elevated triglycerides (Ionis Pharmaceuticals Press Release) - P3 | N=1,478 | Essence-TIMI 73b (NCT05610280) | Sponsor: Ionis Pharmaceuticals, Inc. | "Ionis Pharmaceuticals...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."

P3 data: top line • Hypertriglyceridemia

Ionis Pharmaceuticals targets $750M revenue for 2025 with multiple launches underway (MSN News) - "The company is preparing for several upcoming launches, including donidalorsen for hereditary angioedema (HAE) in Q3 2025 and olezarsen for severe hypertriglyceridemia (sHTG) next year, positioning Ionis for substantial growth....The company plans to submit a supplemental New Drug Application (sNDA) for olezarsen by year-end, following Phase III data from CORE and CORE2 studies expected in Q3 2025."

FDA filing • Launch • P3 data • Hereditary Angioedema • Severe Hypertriglyceridemia

CORE-OLE: A Study of Olezarsen (ISIS 678354) Administered Subcutaneously to Participants With Severe Hypertriglyceridemia (SHTG) (clinicaltrials.gov) - P3 | N=800 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Sep 2026 ➔ Mar 2027 | Trial primary completion date: May 2026 ➔ Mar 2027

Trial completion date • Trial primary completion date • Dyslipidemia • Hypertriglyceridemia • Severe Hypertriglyceridemia

Ionis reports first quarter 2025 financial results (Businesswire) - "TRYNGOLZA (olezarsen), the first-ever treatment for adults living with familial chylomicronemia syndrome (FCS) as an adjunct to diet, generated net product sales of over $6 million in its first full quarter following approval in the U.S. on December 19, 2024; Commercialization rights in countries outside of the U.S., Canada and China licensed to Sobi; EU approval decision anticipated in H2:2025." "

EMA approval • Sales • Familial Chylomicronemia Syndrome

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