Breakthrough Clinical Results
Ionis Pharmaceuticals announced positive topline results from pivotal Phase 3 CORE and CORE2 studies of olezarsen in patients with severe hypertriglyceridemia (sHTG). Olezarsen demonstrated a highly statistically significant placebo-adjusted mean reduction in fasting triglycerides of up to 72% and an 85% reduction in acute pancreatitis events. The favorable safety and tolerability profile supports the planned submission of a supplemental new drug application (sNDA) to the FDA by the end of the year. These results build upon previous positive data from the Essence study in patients with moderate hypertriglyceridemia.
Key Highlights
- Up to 72% placebo-adjusted mean reduction in fasting triglycerides
- 85% reduction in acute pancreatitis events
- Favorable safety and tolerability profile
- sNDA submission planned by end of year
Incidence and Prevalence
Global Prevalence and Incidence of Severe Hypertriglyceridemia
Severe hypertriglyceridemia usually results from a combination of genetic and environmental factors. Recent epidemiological data from various countries provide insights into its global prevalence.
Regional Prevalence Data
In Russia, the most recent data (2016) shows that the prevalence of very high triglycerides (≥5.6 mmol/L) was 0.11% and severe hypertriglyceridemia (≥10.0 mmol/L) was 0.011% in a dataset of 357,072 individuals. In a Russian nested sample of 54,602 individuals, the prevalence of very high TG and severe hypertriglyceridemia was 0.25% and 0.016%, respectively. Almost one-third (29.2%) of Russians have hypertriglyceridemia, but severe disease (TG ≥10.0 mmol/L) is rare.
A 2010 Spanish study of 594,701 workers found that 7,081 (1.1%) had moderate hypertriglyceridemia (400-999 mg/dL), and 224 (0.03%) had severe hypertriglyceridemia (≥1000 mg/dL). In this population, 90% of workers with hypertriglyceridemia were male.
In a 2024 study from Saudi Arabia, among 300 patients with hypertriglyceridemia, the pre-treatment mean triglycerides (TG) was 3.2±2.3 mmol/L. In this study, one-third of patients with high triglycerides developed ischemic heart disease.
A 2024 study of CHD patients in Israel found that two-thirds had TG levels < 150 mg/dL. Among Israeli subjects with levels ≥ 150 mg/dL, 4-6% had severe hypertriglyceridemia (≥ 500 mg/dl).
In a 2017 Chinese study of 21,435 subjects, the prevalence of hyperlipidemia was 51.09% (52.04% in male and 50.21% in female). A more recent 2024 study of middle-aged and older adults in China found a prevalence rate of hyperlipidemia among 6,629 participants was 26.32%.
A 2017 Thai study of 101 subjects with triglyceride levels ≥ 10 mmol/L (886 mg/dL) found genetic factors played a significant role, with rare variants in LPL found in 13% of patients.
Demographic Variations
Gender differences are notable, with males having a greater risk of hypertriglyceridemia than females (risk ratio 1.25). In Russia, prevalence of hypertriglyceridemia increased with age, peaking at 40-49 years in males (42.8%) and 60-69 years in females (34.4%). A Japanese study spanning 30 years found a conspicuous gender imbalance in severe hypertriglyceridemia cases (79 males, 3 females).
In a 2022 Indian study of 8,135 young adults (18-45 years) with dyslipidemia, the youngest age group (18-25) had higher prevalence of hypertriglyceridemia (63.2%) compared to older groups.
Associated Conditions
In patients with hypertriglyceridemia, diabetes mellitus is a significant factor, with a 2025 Israeli study noting that two-thirds of patients with TG levels ≥ 150 mg/dL had HbA1c levels > 6.4%. Patients with severe hypertriglyceridemia had higher rates of uncontrolled diabetes mellitus.
Other risk factors associated with hypertriglyceridemia include age, obesity, type 1 and 2 diabetes, alcohol consumption, and vitamin D deficiency.
Economic Burden
Economic Burden of Treating Severe Hypertriglyceridemia in USA and Europe
The economic burden of treating severe hypertriglyceridemia is substantial across both the USA and Europe, with costs escalating significantly when complications like acute pancreatitis occur.
United States Cost Estimates
According to a 2013 study, patients with chylomicronemia incurred significantly higher annual per-patient medical costs by $808 compared to controls ($8029 vs $7220, p<0.01). Notably, approximately half of these additional costs were directly attributable to chylomicronemia-related services.
The financial impact becomes dramatically higher when complications develop. Patients with chylomicronemia and a history of acute pancreatitis faced substantially greater total medical costs of $33,587 compared to $4402 for matched controls (p<0.01). Each episode of acute pancreatitis (based on 104 episodes analyzed) generated average medical costs of $31,820, primarily from inpatient hospitalizations.
A 2015 study revealed that patients with more severe hypertriglyceridemia (TG ≥ 1500 mg/dL) experienced the highest healthcare utilization and costs, with mean all-cause medical and pharmacy costs of $8850 at baseline. At follow-up, these costs increased to $12,642 per patient, with $3730 being dyslipidemia-related. Particularly alarming was the finding that acute pancreatitis episodes were associated with a >300% increase in total all-cause costs for patients with TG ≥1500 mg/dL.
European Cost Estimates
In Europe, a 2021 Russian study evaluated the economic impact of using omega-3 acid ethyl esters 90 for primary prevention of cardiovascular catastrophes in patients with residual hypertriglyceridemia. The study found only a 0.32% increase in expenses compared to high-dose statin treatment alone, while achieving a 10% decrease in fatal ischemic cardiovascular complications.
Cost-Effectiveness of Interventions
A 2000 study demonstrated that medical nutrition therapy (MNT) led to an annual cost savings of $27,449.10 or $638.35 per patient. For every dollar spent on MNT, a cost saving of $3.03 in statin therapy was realized.
Most pharmacological treatment strategies for hyperlipidemia were found to be cost-effective across most examined low- and middle-income countries.
Global Perspective
In 2020, a study reported that in Mexico, CVD expense was equivalent to 4% of total health expenditure in 2015, with CVD ranking first in health expenditures in almost all mega-countries including the USA.
The economic burden of hypertriglyceridemia is expected to remain significant for decades, highlighting the need for more aggressive management and prevention of acute pancreatitis to generate cost savings. Healthcare utilization and costs consistently scale with the magnitude of TG elevation, with patients having more severe hypertriglyceridemia requiring greater medical and pharmacy services.
Drug used in other indications
Olezarsen Clinical Trials Beyond Severe Hypertriglyceridemia
Based on the available information, there is no evidence that Olezarsen is currently being trialed for indications beyond hypertriglyceridemia. The existing clinical data focuses exclusively on its use in lipid disorders characterized by elevated triglyceride levels.
Current Clinical Trial Focus
Olezarsen is an antisense oligonucleotide that targets messenger RNA for apolipoprotein C-III (APOC3), which has been genetically validated as a target for triglyceride lowering. The available clinical trial data shows:
- A phase 2b randomized controlled trial tested Olezarsen in adults with moderate hypertriglyceridemia (triglyceride levels 150-499 mg/dL) and elevated cardiovascular risk
- This trial (Bridge-TIMI 73a, ClinicalTrials.gov number: NCT05355402) was conducted at 24 sites in North America
- The study included 154 patients with a median age of 62 years and median triglyceride level of 241.5 mg/dL
Efficacy Results
In the documented trials, Olezarsen demonstrated significant efficacy:
- Doses of 50-mg and 80-mg reduced triglyceride levels by 49.3 and 53.1 percentage points respectively compared to placebo
- At the highest doses in the longest clinical trial follow-up, Olezarsen lowered triglycerides by 55.2% of baseline levels
- The medication also significantly reduced levels of APOC3, apolipoprotein B, and non-HDL cholesterol
- It increased HDL-C levels and lowered remnant cholesterol
Current Research Direction
Olezarsen is described as: - The "next in-line chylomicron lowering agent" that is currently being researched - One of the "newer RNA interference (RNAi) therapies" for managing conditions associated with hypertriglyceridemia - Having a better safety and efficacy profile than its predecessor, volanesorsen - "Promising for the treatment of sHTG" (severe hypertriglyceridemia)
Safety Profile
In terms of safety, Olezarsen was well-tolerated with: - No higher risk of serious adverse events or injection-site reactions - Some increased likelihood of mild platelet count decreases without clinical harm
There is no information available about intervention models for trials beyond hypertriglyceridemia, as the current research focus appears to be exclusively on dyslipidemic disorders characterized by elevated triglyceride levels.