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Leqvio Non-Responder Profile: Who Doesn't Get Full LDL Reduction from Inclisiran?

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At a glance

  • ORION-10 LDL-C reduction vs placebo, day 510 / 52.3% (95% CI 48.8% to 55.7%) [2]
  • ORION-11 LDL-C reduction vs placebo, day 510 / 49.9% (95% CI 46.6% to 53.1%) [2]
  • ORION-9 (HeFH) difference vs placebo, day 510 / 47.9 percentage points lower with inclisiran [3]
  • Setting linked to smaller reductions / Moderate hepatic impairment [1]
  • Renal impairment / Higher exposure, similar LDL-C lowering [1]

The 50% figure is an average

Inclisiran is a small interfering RNA that directs breakdown of PCSK9 messenger RNA in liver cells, which increases LDL receptor recycling and lowers circulating LDL-C [1].

ORION-10 randomized 1,561 adults with atherosclerotic cardiovascular disease and ORION-11 randomized 1,617 with ASCVD or a risk equivalent, all on a maximally tolerated statin [2]. At day 510 the placebo-corrected LDL-C reduction was 52.3% (95% CI 48.8% to 55.7%) in ORION-10 and 49.9% (95% CI 46.6% to 53.1%) in ORION-11 [2]. In ORION-9, 482 adults with heterozygous familial hypercholesterolemia, LDL-C fell 39.7% on inclisiran and rose 8.2% on placebo, a between-group difference of 47.9 percentage points [3].

What the label records

Leqvio is 284 mg given subcutaneously by a healthcare professional, initially, again at 3 months, then every 6 months. It is indicated for adults with hypercholesterolemia and for patients 12 and older with heterozygous or homozygous familial hypercholesterolemia [1].

Where the label records a smaller reduction

In the label's hepatic impairment study, mild to moderate impairment raised peak concentration 1.1- to 2.1-fold and total exposure 1.3- to 2.0-fold; in moderate impairment, baseline PCSK9 was lower and LDL-C reductions were smaller than with normal liver function [1]. Inclisiran has not been studied in severe hepatic impairment [1]. Mild to severe renal impairment raised exposure 1.6- to 2.3-fold, yet LDL-C reductions were similar across renal function groups [1]. The label recommends no dose adjustment for any degree of renal impairment or for mild to moderate hepatic impairment [1].

Missed doses and when to measure

If a planned dose is missed by less than 3 months, the label says to give it and continue the original schedule; if it is missed by more than 3 months, the label calls for restarting with an initial dose, a dose at 3 months, then every 6 months [1]. LDL-C lowering can be measured as early as 30 days after the first dose, regardless of dose timing [1]. The headline trial results were measured at day 510 [2].

Frequently asked questions

What LDL-C drop should someone expect from Leqvio?
In the two large adult trials the placebo-corrected reduction at day 510 was 52.3% (ORION-10, 1,561 patients) and 49.9% (ORION-11, 1,617 patients) [2]. In adults with heterozygous familial hypercholesterolemia the difference from placebo was 47.9 percentage points [3].
Does liver or kidney disease change how inclisiran works?
In the label's hepatic impairment study, moderate impairment came with lower baseline PCSK9 and smaller LDL-C reductions than normal liver function, and severe hepatic impairment was not studied [1]. Renal impairment raised exposure but LDL-C reductions were similar across groups [1].
What happens if a Leqvio dose is missed?
A dose missed by less than 3 months is given and the original schedule continues; a dose missed by more than 3 months means restarting with an initial dose, a dose at 3 months, then every 6 months [1].
How is response to inclisiran assessed?
By measuring LDL-C. The label says the LDL-lowering effect can be measured as early as 30 days after the first dose and at any time afterward, without regard to dose timing [1].

References

  1. U.S. National Library of Medicine, DailyMed. LEQVIO (inclisiran) prescribing information. LEQVIO (inclisiran) label
  2. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507-1519. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
  3. Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
Evidence overview for Leqvio Non-Responder Profile: Who Doesn't Get Full LDL Reduction from Inclisiran?