News from TRANSLATE-TIMI 70 with vupanorsen, ANGPLT3 antisense oligonucleotide

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21 September 2022

In TRANSLATE-TIMI 70 (ClinicalTrials.gov Identifier: NCT04516291) treatment with vupanorsen, an antisense oligonucleotide that inhibits hepatic angiopoietin-like 3 (ANGPTL3) protein synthesis, reduced non-high-density lipoprotein cholesterol (non-HDL-C) in statin-treated patients. Triglycerides were also reduced in a dose-dependent manner.

Bergmark BA, Marston NA, Bramson CR, et al. Effect of vupanorsen on non-high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol: TRANSLATE-TIMI 70. Circulation 2022;145:1377-1386.

STUDY SUMMARY

Objective:

TRANSLATE (Targeting ANGPTL3 with an Antisense Oligonucleotide in Adults with Dyslipidemia)–TIMI (Thrombolysis in Myocardial Infarction) 70 trial investigated the effect of escalating doses of vupanorsen on non–HDL-C levels in statin-treated adults with hyperlipidaemia.

Study design:

This was a placebo-controlled, double-blind, randomized, phase 2b trial. Patients were randomly assigned 2:1:1:2:1:2:2:2 by a permuted block schedule to placebo or 1 of 7 doses of subcutaneous vupanorsen (80 mg, 120 mg, or 160 mg every 4 weeks, or 60 mg, 80 mg, 120 mg, or 160 mg every 2 weeks). The duration of treatment was 24 weeks, with an additional 12 weeks of safety monitoring after the last dose of study drug.

Study population:

Statin-treated adults ≥40 years old and with non–HDL-C ≥100 mg/dL and triglycerides 150 to 500 mg/dL.

Study Outcomes:

The primary end point was placebo-adjusted percentage change from baseline in non–HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.

Methods:

The primary efficacy analysis was based on the number of patients who received at least one dose of the allocated study drug, had a baseline non–HDL-C level, and at least one post-baseline non–HDL-C level. The effect of vupanorsen (pooled doses) on the primary end point was evaluated using an ANCOVA model adjusting for baseline value, treatment group, subgroup status, and an interaction term for treatment by subgroup.

Main results:

The study randomized 286 patients (median age 64 years, 44% female), 44 to placebo and 242 to vupanorsen. Patient characteristics were similar across the treatment groups. Overall, 50% of patients had type 2 diabetes, 51% were on a high-intensity statin regimen, with only 5% taking ezetimibe.

Treatment with vupanorsen inhibited ANGPLT3 by up to 95% (Table 1). The placebo-corrected reduction in non-HDL-C ranged from 22% (80 mg 4-weekly) to 26.5% (160 mg 2-weekly); all reductions were significant (p<0.001) compared with placebo. Vupanorsen also reduced TG significantly (p<0.001) in a dose-related manner, ranging from 41% with 120 mg 4-weekly to 57% with 160 mg 2-weekly. The effects on LDL-C and ApoB were more modest and without a clear dose-response relationship (Table 1).

Table 1. Effect of vupanorsen on key lipid variables. Data are shown as least squares mean (95% CI) for placebo-corrected % change at 24 weeks.

Variable

4-weekly regimen

2-weekly regimen

80 mg (n=23)

120 mg

(n=23)

160 mg

(n=45)

60 mg (n=24)

80 mg (n=45)

120 mg (n=46)

160 mg (n=36)

Non-HDL-C

-22.4

(–32.1 to –12.7

–24.1

(–34.1 to –14.2)

–26.6

(–34.5 to –18.8)

–22.0

(–31.7 to –12.4)

–27.7

(–35.7 to –19.6)

–24.7

(–32.5 to –16.9)

–26.5

(–35.4 to –17.6)

–44.0

(–57.1 to –30.8)

–41.3

(–54.8 to 27.8)

–45.9

(–56.5 to –35.2)

–43.8

(–56.9 to –30.7)

–50.5

(–61.4 to –39.6)

–50.7

(–61.2 to –40.1)

–56.8

(–68.9 to –44.7)

LDL-C

–10.0

(–22.9 to 2.9)

–11.4

(–24.7 to 1.8)

–14.5

(–25.1 to –3.9)

–7.9

(–21.0 to 5.2)

–16.0

(–26.7 to –5.3)

–7.9

(–18.3 to 2.5)

–9.0

(–20.8 to 2.9)

ApoB

–15.1

(–23.7 to –6.5)

–11.5

(–20.3 to –2.7)

–12.6

(–19.5 to –5.6)

–10.6

(–19.2 to –2.1)

–12.5

(–19.7 to –5.3)

–6.0

(–13.0 to 1.0)

–8.5

(–16.4 to –0.6)

ANGPLT3

–69.9

(–81.6 to –58.1)

–77.1

(–89.4 to –64.9)

–80.4

(–89.9 to –70.9)

–79.6

(–91.5 to –67.7)

–86.3

(–96.2 to –76.3)

–92.2

(–101.9 to –82.6)

–95.2

(–106.2 to –84.2)

Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%).

Conclusion:

Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non–HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction.

COMMENT

With increasing evidence supporting elevated TG-rich lipoproteins and their remnants as a contributor to cardiovascular risk (1), attention has focused on targets of TG metabolism in the search for novel therapeutics. Genetic studies identified ANGPTL3 as one such target, with genetic inhibition associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease (2,3). Vupanorsen, an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver selectively inhibits ANGPTL3 protein synthesis. A previous study in patients with elevated TG, type 2 diabetes, and hepatic steatosis showed favourable effects on the atherogenic lipid/lipoprotein profile suggesting a potential role in targeting residual cardiovascular risk (4). TRANSLATE-TIMI 70 built on these findings by assessing the efficacy and safety of higher vupanorsen doses in patients with elevated non-HDL-C and elevated TG on statin treatment. Non-HDL-C is also correlated with apoB, which encompasses all atherogenic apoB-containing lipoproteins, including LDL-C, TG-rich lipoproteins and remnants, and lipoprotein(a) (5).

Overall, TRANSLATE TIMI 70 showed that treatment with vupanorsen resulted in dose-related changes in non-HDL-C, ranging from 22.0% to 27.7% (the primary endpoint), as well as reduction in TG and other lipid parameters. These effects need to be balanced against more prevalent hepatic enzyme elevations and injection site reactions at higher total monthly doses, as well as a dose-related increase in hepatic fat. Additionally, the more modest effect of vupanorsen on apoB levels suggests that this treatment mainly decreases the TG content (as well as cholesterol content) of very-low-density lipoprotein particles rather than reducing the number of such particles, which may have ramifications for potential effects on reducing residual cardiovascular risk.

Despite the limitations of study population size and lack of ethnic heterogeneity (predominantly white), the study adds to evidence suggesting therapeutic potential for inhibition of ANGPTL3 to reduce residual risk.

References

1. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
2. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017;377:211–21.
3. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054–63.
4. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020;41:3936-45.
5. Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J Am Coll Cardiol 2021;77:1439-50.

Key words

ANGPTL3; vupanorsen; non-HDL-C; apolipoprotein B; residual cardiovascular risk