Lipid-efficacy RCT · N Engl J Med 2024
ARCHES-2 trial
Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.
The bottom line
In adults with mixed hyperlipidemia, zodasiran (an RNAi therapy against ANGPTL3) produced significant, dose-dependent reductions in triglycerides and improvements in non-HDL-C, ApoB, and LDL-C compared with placebo, with a signal of transient HbA1c elevation in diabetic patients at the highest dose.
Primary lipid endpoint metUS status: Investigational
At a glance
- Medicine
- Zodasiran (subcutaneous injections of 50, 100, or 200 mg on day 1 and week 12)
- Compared with
- Placebo
- People
- 204
- Who took part
- Adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter)
- Design
- Double-blind, placebo-controlled, dose-ranging phase 2b trial, randomized 3:1
- Follow-up
- Followed through week 36; primary endpoint at week 24
- Main question
- Percent change in triglyceride level from baseline to week 24
Main result
Significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons)
Effect on LDL cholesterol
for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively (50, 100, 200 mg vs placebo)
Other results
for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively
Safety
We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.
In the trial's own words
“At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons).”
Quoted from the abstract of N Engl J Med 2024, checked word for word against PubMed. PubMed 38809174 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Zodasiran and solbinsiran
Common questions
What did the ARCHES-2 trial find?
In adults with mixed hyperlipidemia, zodasiran (an RNAi therapy against ANGPTL3) produced significant, dose-dependent reductions in triglycerides and improvements in non-HDL-C, ApoB, and LDL-C compared with placebo, with a signal of transient HbA1c elevation in diabetic patients at the highest dose.
Who was in ARCHES-2?
204 people. Adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter).
What was ARCHES-2's main result?
Significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons)
How much did LDL cholesterol change in ARCHES-2?
for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively (50, 100, 200 mg vs placebo)
Related trials
- Balance (2024)In patients with familial chylomicronemia syndrome, olezarsen 80 mg significantly lowered triglycerides and markedly reduced acute pancreatitis episodes compared with placebo, with the 50-mg dose not reaching significance for the triglyceride endpoint.
- Bridge-TIMI 73a (2024)In patients with moderate-to-severe hypertriglyceridemia and elevated cardiovascular risk, monthly olezarsen substantially lowered triglycerides, APOC3, apolipoprotein B, and non-HDL cholesterol compared with placebo, without major safety concerns.
- SHASTA-2 (2024)Plozasiran markedly and durably lowered triglycerides (with most patients falling below the acute pancreatitis risk threshold) and APOC3 in severe hypertriglyceridemia, with a favorable safety profile, though it raised LDL-C without increasing ApoB and its effect on clinical complications remains unproven.
- CTX310 phase 1 (2025)A single dose of the CRISPR-Cas9 gene-editing therapy CTX310 was generally well tolerated and produced dose-dependent reductions in ANGPTL3 levels, supporting further clinical development for dyslipidemia.
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