Safety and efficacy of inclisiran for hypercholesterolemia

Three placebo-controlled phase 3 trials have evaluated the efficacy and safety of inclisiran. Inclisiran lowered low-density lipoprotein (LDL) cholesterol similarly across all ages with an acceptable safety profile [1]. The efficacy and safety profile of inclisiran was generally similar in both sexes [2].

Prof. R. Scott Wright (Mayo Clinic, USA) presented the results of 2 pooled analyses evaluating the efficacy and safety of inclisiran according to age and sex, respectively. Both analyses included data from three phase 3 placebo-controlled trials:

1. 
   
   1. ORION-9 in patients with heterozygous familial hypercholesterolaemia (HeFH);
   2. ORION-10 in patients with atherosclerotic cardiovascular disease (ASCVD); and
   3. ORION-11 in patients with ASCVD or ASCVD risk equivalents.

In the first analysis, a total of 3,660 patients were categorised according to age: <65 years (not old; n=1,737), 65 to <75 years (old; n=1,431), or ≥75 years (very old; n=492) [1]. After 18 months (540 days) of follow-up, the placebo-corrected change in LDL cholesterol with inclisiran was around 50% in not old, old, and very old patient groups: −51.3%, −49.9%, and −51.0%, respectively (P<0.0001 from baseline for all). The co-primary endpoint of time-adjusted change in LDL cholesterol from baseline to day 90 up to day 540 yielded very similar results: −49.6%, −51.5%, and −50.8% (P<0.0001 for all). Rates of adverse events (AE) and serious AE increased with age and were similar to placebo in all groups, with the exception of injection-site reactions, which were higher with inclisiran across all ages.

The second analysis found a similar efficacy of inclisiran for both primary endpoints in men (67.5%; n=2,470) and women (32.5%; n=1,190). Women had higher LDL cholesterol at baseline: 122.9 versus 105.8 mg/dL. Placebo-corrected mean absolute reduction in LDL cholesterol at day 510 was also higher in women (62.6 vs 54.0 mg/dL), as was time-adjusted reduction from days 90 to 540 (59.0 vs 51.5 mg/dL) (both P<0.05). Safety of inclisiran was generally similar in both sexes, again except for injection-site AEs, which were more frequent compared with placebo, more frequent in women (women 9.4% vs 0.2%, men 2.8% vs 0.9%), and generally mild.

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   1. Wright RS, et al. Efficacy and Safety of Inclisiran According to Age: A Pooled Analysis of Phase III Studies (ORION 9, 10 and 11). P2250, AHA Scientific Sessions 2020, 13–17 Nov.
   2. Wright RS, et al. Efficacy and Safety of Inclisiran According to Sex: A Pooled Analysis of the ORION 9, 10 and 11 Trials. P2253, AHA Scientific Sessions 2020, 13–17 Nov.

 



Posted on 17 February 202113 June 2024