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EAS2018 Late Breaking Clinical Trial: ORION-1

Tuesday 8 May 2018   (0 Comments)
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ORION-1: Sustained lowering on atherogenic lipoproteins

Inclisiran is a small interfering RNA therapeutic which is an alternative to PCSK9 monoclonal antibody therapy.1 Unlike evolocumab and alirocumab, inclisiran acts intracellularly in the liver to inhibit synthesis of PCSK9 protein in hepatocytes, thereby reducing low-density lipoprotein (LDL)-receptor turnover and lowering plasma LDL cholesterol levels.

ORION-1 was a dose-ranging trial in 501 patients (69% with a history of ASCVD and 79% on statin therapy) which assessed six possible starting regimens (single doses of 200, 300, or 500 mg, and two-dose regimens of 100, 200, or 300 mg. administered 90 days apart). Measurement of LDL cholesterol was continued for up to 12 months so as to assess the dosing interval for the maintenance phase. The study showed that this therapeutic approach reduced LDL cholesterol (on average by 50%), generally similar to the response seen with PCSK9 monoclonal antibody therapy.2-4

Professor Kausik Ray (Imperial College, London, UK) presented data from a pre-specified analysis of the effects of inclisiran on other atherogenic lipoproteins, notably apolipoprotein (apo) B, non-high-density lipoprotein (HDL) cholesterol, as well as lipoprotein(a); results are summarised in Table 1. These were generally comparable with findings for PCSK9 monoclonal antibody therapy.  There were also reductions in triglycerides and very low-density lipoprotein cholesterol, as well as increases in apoA-1 and HDL cholesterol.  These effects of inclisiran on lipoprotein measures was sustained in the longer-term. Inclisiran appears to be well tolerated, with no signal for unintended adverse effects on liver function in the pool of patients studied to date.

Table 1. Reduction in other atherogenic lipoproteins at Day 180

Lipid measure

1 x 300 mg inclisiran

2 x 300 mg inclisiran

Non-HDL cholesterol

35%

46%

ApoB

31%

41%

Lipoprotein(a)

14%

26%

 

In general, the magnitude of benefit of inclisiran on atherogenic lipoproteins was similar to that observed with PCSK9 monoclonal antibody therapy. However, this therapy offers the advantage of 6-monthly dosing, as opposed to 2 weekly or monthly dosing with PCSK9 monoclonal antibody therapy. This is likely to have favourable impact on patient adherence, an issue implicated in low attainment of lipid targets in the latest news from EUROASPIRE V (see below)

Professor Ray discusses inclisiran and the ORION-1 trial in an accompanying video >>

References

1. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41-51.

2. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-40.

3. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.

4. ACC News Story. http://www.acc.org/latest-in-cardiology/articles/2018/03/05/15/53/sat-9am-odyssey-outcomes-cv-outcomes-with-alirocumab-after-acs-acc-2018

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