Contribution To Literature:

CORE-TIMI 72a and CORE2-TIMI 72b trials found that olezarsen significantly reduced triglyceride levels at 6 months, as well as decreased the incidence of acute pancreatitis.

Study Design:

Total number of enrollees: 1,061 patients

CORE-TIMI 72a: 617 patients
CORE2-TIMI 72b: 444 patients

Randomization 1:1:1 ratio

Monthly administration of olezarsen 50 mg, olezarsen 80 mg, or placebo.

Duration of follow-up: 12 months
Median patient age: 55 years
Demographics (i.e., gender and race, etc.):

 
CORE-TIMI 72a

CORE2-TIMI 72b

Characteristics
Placebo (n=208)
Olezarsen, 50 mg (n=205)
Olezarsen, 80 mg (n=204)
Placebo (n=148)
Olezarsen, 50 mg (n=149)
Olezarsen, 80 mg (n=147)

Female- no. (%)
42 (20.2)
52 (25.4)
53 (26)
27 (18.2)
39 (26.2)
37 (25.2)

White
195 (93.8)
191 (93.2)
189 (92.6)
124 (83.8)
125 (83.9)
114 (77.6)

Black
7 (3.4)
2 (1.0)
4 (2)
1 (0.7)
3 (2)
5 (3.4)

Asian
5 (2.4)
3 (1.5)
4 (2.0)
17 (11.5)
15 (10.1)
13 (8.8)

Hispanic or Latino
10/202 (5)
7/195 (3.6)
12/200 (6)
31/148 (20.9)
33/149 (22.1)
35/147 (23.8)

Principal Findings:

Primary outcome:

Percentage change in triglyceride levels at 6 months

Variable
CORE-TIMI 72a

CORE2-TIMI 72b

Triglycerides
Placebo
Olezarsen, 50 mg
Olezarsen, 80 mg
Placebo
Olezarsen, 50 mg
Olezarsen, 80 mg

At baseline – mg/dL
1,208 +/- 1,295.4
1,168.9 +/- 825.8
1,168 +/- 973.7
1018.6 +/- 1053.7
967.8 +/- 599.9
1088.4 +/- 964.5

At 6 months – mg/dL
1083.7 +/- 1,105.1
389.9 +/- 581.6
267.1 +/- 300.5
809.6 +/- 935.4
315.3 +/- 383.8
289.6 +/- 349

Placebo-adjusted least-squares mean (LSM)- %
 
-62.9 (-72.2 to -53.6) p<0.001
-72.2 (-81.4 to -63.1) p<0.001
 
-49.2 (-59.7 to -38.8) p<0.001
-54.5 (-65.1 to -44) p<0.001

Secondary outcomes:

Percentage change from baseline in:

Triglyceride level at 12 months
Apolipoprotein C-III
Remnant cholesterol
Non-high-density lipoprotein (non-HDL)

Acute pancreatitis events:

Mean rate ratio: 0.15 (95% CI, 0.05 to 0.40); p<0.001.
Number needed to treat (NNT):

Overall: 20
High-risk group (prior pancreatitis): 4

Safety:

No significant differences in:

Adverse events
Serious adverse events
Discontinuation due to adverse events across Olezarsen and placebo groups during the 12-month treatment period.

Variable
CORE-TIMI 72a

CORE2-TIMI 72b

Apolipoprotein C-III
Placebo
Olezarsen, 50 mg
Olezarsen, 80 mg
Placebo
Olezarsen, 50 mg
Olezarsen, 80 mg

At baseline – mg/dL
37.4 +/- 15.9
39.4 +/- 16
36.9 +/- 15
36.5 +/- 13.6
38 +/- 15.6
36.9 +/- 14.8

At 6 months – mg/dL
35.3 +/- 18.1
10.8 +/- 10.9
6.9 +/- 7.4
31.5 +/- 17
11.7 +/- 13.2
8.3 +/- 9.4

Placebo-adjusted least-squares mean (LSM)- %
 
-68.3 (-73.9 to -62.8) p<0.001
-77.4 (-83 to -71.9) p<0.001
 
-56.5 (-63.9 to -49.2) p<0.001
-63.5 (-70.9 to -56) p<0.001

Remnant Cholesterol
 
 
 
 
 
 

Placebo-adjusted least-squares mean (LSM)- %
 
-57.2 (-65.3 to -49.2); p<0.001
-70.1 (-77.9 to -62.2) p<0.001
 
-50.6 (-62.4 to -38.7) p<0.001
-52.2 (-64.2 to -40.1) p<0.001

Non- HDL Cholesterol
 
 
 
 
 
 

Placebo-adjusted least-squares mean (LSM)- %
 
-24.8 (-30.3 to -19.3) p<0.001
-32.6 (-38 to -27.3) p<0.001
 
-19.3 (-25.3 to -13.3) p<0.001
-22.3 (-28.4 to -16.1) p<0.001

Interpretation:

In patients with persistent severe hypertriglyceridemia despite optimal standard lipid-lowering therapies, olezarsen administered monthly at 50 mg or 80 mg demonstrated a dose-dependent reduction in triglycerides, with nearly half of patients achieving normalization at the highest dose. Additionally, significant reductions in apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were observed. The treatment was associated with a marked reduction in acute pancreatitis risk, particularly in high-risk individuals, with no significant safety concerns identified.






References

Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk. N Engl J Med. Published online Nov. 8, 2025. doi:https://doi.org/10.1056/nejmoa2512761

Presented by Nicholas A. Marston, MD, at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 8, 2025.


Clinical Topics:
Diabetes and Cardiometabolic Disease, Dyslipidemia


Keywords:
AHA25, AHA Annual Scientific Sessions, Dyslipidemias, Metabolic Syndrome