First in-human trial of novel siRNA for lowering lipoprotein(a)

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Macrovascular Residual Risk Studies

12 March 2024

Lepodisiran, a novel short-interfering RNA (siRNA), reduced lipoprotein(a) [Lp(a)] concentration by 97% at highest single dose with response sustained in the long-term.

Nissen SE, Linnebjerg H, Shen X, et al. Lepodisiran, an extended-duration short interfering RNA targeting lipoprotein(a): a randomized dose-ascending clinical trial. JAMA 2023;330:2075-83.

STUDY SUMMARY

Objective:

To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran, a short interfering RNA (siRNA) directed at hepatic synthesis of apolipoprotein(a), on Lp(a) concentrations after single doses of this drug.

Study design:

Randomised, single ascending-dose phase I trial.

Study population:

48 adults (mean age 46.8 years, 35% women) without cardiovascular disease and with Lp(a) serum concentrations of ≥75 nmol/L or (≥30 mg/dL).

Main variables:

Primary: safety and tolerability of lepodisiran
Secondary: plasma levels of lepodisiran for 168 days after dose administration; changes in fasting Lp(a) serum concentrations up to 336 days (48 weeks) after dosing

Methods:

Subjects were randomised to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously, and were followed for up to 48 weeks.

Results:

Plasma concentrations of lepodisiran attained peak levels within 10.5 hours after dosing and were undetectable by 48 hours.

Baseline Lp(a) levels and the maximal median change in Lp(a) at 168 days after administration of lepodisiran are summarised by dose group in Table 1. The treatment groups were comparable for baseline Lp(a) concentration. The median maximal decrease in Lp(a) plasma concentration ranged from 41% for the 4 mg dose to 97% for the 608 mg dose (versus 5% for placebo). After 48 weeks, the median change in Lp(a) concentration was -94% (interquartile range -94% to -85%) in the 608 mg lepodisiran group.

Table 1. Baseline Lp(a) concentration and maximal median change at Day 168

Lp(a)

Placebo

Lepodisiran (mg)

304

608

Baseline (IQR), nmol/L

111

(78,134)

(50, 152)

(86, 107

120

(110, 188)

167

(124, 189)

(72, 132)

130

(87, 151)

% Maximal median change (IQR)

-5

( -16, 11)

-41

(-47, -20)

-59

(-66,

-53)

-76

(-76,

-75)

-90

(-94,

-85)

-96

(-98,

-95)

-97

(-98,

-96)

IQR interquartile range

Authors’ conclusion:

In this phase 1 study of 48 participants with elevated Lp(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum Lp(a) concentrations. The findings support further study of lepodisiran

COMMENT

Extensive evidence from epidemiologic and genetic studies supports a causal association between Lp(a) concentration and atherosclerotic cardiovascular disease and aortic stenosis (1). Elevated Lp(a) is also a residual cardiovascular risk factor in the setting of optimally managed low-density lipoprotein cholesterol (2,3). To date, however, there are no approved therapies for managing elevated Lp(a) concentration, with current approaches focusing on consideration of managing global cardiovascular risk with available therapies (1). Inhibiting apolipoprotein(a) production in the hepatocyte with nucleic acid-based therapeutics has emerged as an effective approach to reducing plasma Lp(a) levels (4).

Lepodisiran is a short interfering RNA (siRNA) that targets LPA mRNA and is conjugated to N-Acetylgalactosamine (GalNAc), a sugar with high-affinity to asialoglycoprotein receptors expressed almost exclusively in hepatocytes. Once internalized in hepatocytes, lepodisiran blocks synthesis of apo(a) that is a necessary component of Lp(a) particles. The current phase I study showed that single doses of lepodisiran were effective in reducing Lp(a) concentrations by up to 97% and the response was durable for up to 48 weeks. These promising findings support further clinical development of this novel treatment.

References

1. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
2 Takahashi D, Wada H, Ogita M, et al. Impact of lipoprotein(a) as a residual risk factor in long-term cardiovascular outcomes in patients with acute coronary syndrome treated with statins. Am J Cardiol 2022:168:11-16.
3. Hoogeveen RC, Ballantyne CM. Residual cardiovascular risk at low LDL: remnants, lipoprotein(a), and inflammation. Clin Chem 2021;67:143–53.
4. Tsimikas S, Moriarty PM, Stroes ES. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol 2021;77:1576-89.
Key words: lipoprotein(a); lepodisiran; RNA therapeutics targeting apo(a)

Key words

lipoprotein(a); lepodisiran; RNA therapeutics targeting apo(a)