Olezarsen shows promise in hypertriglyceridemia

27 June 2024

In the Bridge–TIMI 73a trial, treatment with olezarsen, an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), significantly reduced triglycerides (TG) in patients with moderate hypertriglyceridemia and high cardiovascular risk.

Bergmark BA, Marston NA, Prohaska TA, et al. Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk. N Engl J Med 2024; DOI: 10.1056/NEJMoa2402309

STUDY SUMMARY

Objective To investigate the efficacy and safety of olezarsen in patients with moderate hypertriglyceridemia and elevated cardiovascular risk, and in patients with severe hypertriglyceridemia.
Study design Phase 2b, randomized, placebo-controlled, double-blind trial. Adults with moderate hypertriglyceridemia and elevated cardiovascular risk, or with severe hypertriglyceridemia, were allocated in a 1:1 ratio to either a 50 mg or 80 mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The treatment period was 12 months, followed by a 13-week follow-up period.
Study population 154 patients (mean age 62 years, 42% women) with moderate (n=128, TG 150 to 499 mg/dL) or severe (hypertriglyceridemia (TG ≥500 mg/dL) were assigned to monthly treatment with olezarsen 50 mg (n=58), olezarsen 80 mg (n=57), or matching placebo (n=39). An independent data and safety monitoring board reviewed safety in the trial.
Main study variables Primary: percent change in the TG level from baseline to 6 months, reported as the difference between each olezarsen dose group and placebo.
Key secondary: changes in levels of APOC3, apolipoprotein (apo)B, non–high-density lipoprotein cholesterol (non-HDL-C), and low-density lipoprotein cholesterol (LDL-C).
Methods Patients who had received at least one dose of either olezarsen or placebo were analysed (modified intention-to-treat population). An analysis-of-covariance model (which included log-transformed baseline TG levels) was used to compare each dose of olezarsen separately with the pooled placebo group. Least-squares mean estimates of the between-group percent change from baseline were determined and the data were combined to provide an overall estimate with corresponding 95% confidence intervals (CI).

RESULTS

At baseline, almost all (97%) patients were receiving lipid-lowering therapy, and 31% were receiving two or more lipid-lowering therapies. The median TG level was 241.5 mg/dL (2.7 mmol/L). Baseline characteristics were generally well balanced across the trial groups.

The mean decrease in TG from baseline to 6 months was 57.1% (95% CI, 50.9 to 63.2) in the olezarsen 50 mg group and 60.9% (95% CI, 54.7 to 67.1) in the olezarsen 80 mg group versus 7.8% (95% CI, 0.2 to 15.3) in the placebo group. The absolute difference in the olezarsen groups versus placebo was -49.3% (95% CI -39.5 to -59.0) in the 50 mg group and -53.1% (95% CI, -43.4 to -62.9) in the 80 mg group (p<0.001 for both comparisons) (Table 1). Among 128 patients with moderate hypertriglyceridemia at baseline, TG <150 mg/dL at 6 months was reported for 42/49 patients (86%) in the olezarsen 50 mg group and 42/45 patients (93%) in the olezarsen 80 mg group, compared with 4/34 patients (12%) in the placebo group (p<0.001 for each comparison with placebo).

 

Table 1. Key lipid variables at baseline and 6 months

Variable

mg/dL

Olezarsen 50 mg

(n=58)

Olezarsen 80 mg

(n=57)

Placebo

(n=39)

Baseline TG, median (IQR)

230.0

(182.5–331.5)

241.5

(179.5–357.5)

249.3

(219.5–284.5)

 % reduction at month 6 vs. placebo

49.3%

p<0.001

53.1%

p<0.001

–

 

 

 

 

Baseline median (IQR) APOC3

15.3 (12.0–19.3)

13.4 (11.5–17.9)

15.8 (13.2–18.7)

% reduction at 6 months vs. placebo

64.2%

p<0.001

73.2%

p<0.001

 

 

 

 

 

Baseline median (IQR) VLDL-C

41.0 (34.0–62.5)

43.0 (31.0–56.7)

41.5 (36.0–61.0)

% reduction at 6 months vs. placebo

46.2%

p<0.001

49.7%

p<0.001

 

 

 

 

 

Baseline median (IQR) non-HDL-C

132.2

(103.5–156.5)

126.0

(110.0–150.5)

134.5

(110.0–161.5)

% reduction at 6 months vs. placebo

25.4%

23.1%

 

 

 

 

 

Baseline median (IQR) apoB

90.8 (75.5–105.0)

93.0 (78.0–107.0)

94.0 (78.0–114.5)

% reduction at 6 months vs. placebo

18.2%

p<0.001

18.5%

p<0.001

 

 

 

 

 

Baseline median (IQR) LDL-C

83.8 (59.5–106.0)

80.5 (62.0–102.0)

81.5 (62.0–104.5)

% reduction at 6 months vs. placebo

9.9%

NS

7.7%

NS

 

NS not statistically significant; VLDL-C Very low-density lipoprotein cholesterol

 

Each dose of olezarsen also significantly reduced levels of APOC3, apoB, and non-HDL‑C with no significant change in LDL-C levels (Table 1).

 

Clinically meaningful increases in liver aminotransferases were rare, with no significant differences among trial groups, and there were no major elevations in bilirubin. Severe thrombocytopenia occurred in no patients during treatment with olezarsen.
Author conclusion In patients with predominantly moderate hypertriglyceridemia and elevated cardiovascular risk, monthly administration of olezarsen at a dose of 50 mg or 80 mg significantly reduced TG levels as compared with placebo without major safety concerns. Olezarsen also led to meaningful reductions in levels of apoB and non-HDL-C, markers of atherogenic risk.

COMMENT

There is extensive evidence from observational and genetic studies, as well as insights from clinical trials, that an elevated level of TG-rich lipoproteins and their remnants, is a causal risk factor for atherosclerotic cardiovascular disease (1). To date, however, there is limited evidence (beyond REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) (1) that lowering TG levels is associated with reduction of cardiovascular risk against a background of best evidence-based preventive therapy (3,4). In view of the complexity of TG-rich lipoprotein metabolism, the search for novel TG-lowering therapeutics that act at different metabolic targets and are well tolerated continues.

Olezarsen (ISIS 678354) is an investigational N-acetylgalactosamine–conjugated antisense oligonucleotide that acts at APOC3 mRNA to lower TG levels. Based on favourable results in a phase I study in healthy subjects (5), and a small phase 2 dose-ranging trial (6) the Bridge–TIMI 73a trial investigated the efficacy and safety of olezarsen in patients with either moderate or severe hypertriglyceridemia. The majority of patients included in this trial had moderate hypertriglyceridemia (150 to 499 mg/dL [1.7 to 5.6 mmol/L]) and 22% had atherosclerotic cardiovascular disease. Median TG at baseline were 241.5 mg/dL (2.7 mmol/L) implying that the patient population was appropriate for testing the effect of a TG-lowering agent.

The results of this study show that treatment with olezarsen was effective in lowering TG levels by ~50% at 6 months (49.3% in the 50 mg group and 53.1% in the 80 mg group versus placebo) and the response was durable over the follow-up period. Olezarsen treatment was also associated with meaningful reduction in other markers of atherogenic risk, including non-HDL-C (by ~25%) and apoB (18%), and also reduced LDL-C levels (~8-10%) although this latter effect was not statistically significant. Importantly, there was no adverse safety signal associated with olezarsen treatment. Thus, the results of the Bridge–TIMI 73a trial support the conduct of larger studies of longer duration with olezarsen.

References 1. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular dis ease, and emerging therapeutic strategies: a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
2. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
3. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020;324: 2268-80.
4. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-34.
5. Alexander VJ, Xia S, Hurh E, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J 2019;40:2785-9.
6. Tardif JC, Karwatowska-Prokopczuk E, Amour ES, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J 2022;43:1401-12.
Key words triglycerides; triglyceride-rich lipoproteins; cardiovascular disease; apolipoprotein CIII; olezarsen