Results from a prespecified analysis of pooled data from three phase III studies evaluating the safety and efficacy of Inclisiran, a first-in-class investigational treatment for hyperlipidemia in adults, were presented at the American College of Cardiology’s Annual Scientific Session Together with World Congress of Cardiology ( ACC.20/WCC Virtual ).
The pooled analysis of the ORION-9, -10 and -11 phase III trials has shown a durable and potent reduction in LDL-C ( LDL-cholesterol ) of 51% when Inclisiran was used in addition to other lipid-lowering therapies over 17 months of treatment.
The prespecified analysis of pooled data is consistent with the efficacy and safety findings of the individual phase III trial results published in The New England Journal of Medicine ( NEJM ).
Additionally, a prespecified exploratory analysis using the safety reporting from all three trials indicated fewer MACE ( major adverse cardiac events ) with Inclisiran compared to placebo ( 7.1%, 9.4% respectively ).
The overall safety and tolerability profile was generally similar between the Inclisiran and placebo groups.
The pooled analysis has included data from Inclisiran’s ORION-9, -10 and -11 trials, which are multicenter, double-blind, randomized, placebo-controlled, 18-month studies evaluating Inclisiran in patients with heterozygous familial hypercholesterolemia [ ORION-9 ], atherosclerotic cardiovascular disease (ASCVD ) [ ORION-10 ] and ASCVD or ASCVD risk equivalents [ ORION-11 ].
The primary endpoints for these studies were percentage change in LDL-C from baseline to 17 months and time-adjusted percentage change in LDL-C from baseline between 3 months and up to 18 months.
The primary endpoints were achieved in all three studies.
In the prespecified analysis of pooled data, Inclisiran resulted in placebo-adjusted LDL-C reduction at 17 months of 51% and a time-adjusted placebo-adjusted percentage reduction in LDL-C between 3 and 18 months of 51%.
In a prespecified exploratory safety analysis, MACE were significantly lower with Inclisiran versus placebo ( 7.1%, 9.4% respectively ); measures included non-fatal myocardial infarction ( 5.2%, 7.8% ), stroke ( 0.9%, 1.0% ), cardiovascular death ( 0.9%, 0.8% ) and resuscitated cardiac arrest ( 0.2%, 0.1% ).
The overall safety and tolerability profile was generally similar between Inclisiran and placebo groups.
No differences in adverse outcomes were observed between groups.
In the phase III studies, Inclisiran was reported to be well-tolerated with a safety profile similar to placebo.
The most common adverse reactions reported ( greater than or equal to 3% of patients treated with Inclisiran and occurring more frequently than placebo ) were, diabetes mellitus, hypertension, nasopharyngitis, arthralgia, back pain, dyspnea, bronchitis and upper respiratory tract infection.
Adverse events at the injection site were more frequent with Inclisiran than placebo and were generally mild and none were severe or persistent.
Inclisiran is the first and only LDL-C lowering siRNA treatment. It is intended to be administered by a healthcare professional by subcutaneous injection with an initial dose, again at 3 months and then every 6 months thereafter.
Inclisiran is a double-stranded siRNA, conjugated on the sense strand with triantennary N-acetylgalactosamine ( GalNAc ) to facilitate uptake by hepatocytes. In hepatocytes, Inclisiran increases LDL-C receptor recycling and expression on the hepatocyte cell surface, thereby increasing LDL-C uptake by hepatocytes and lowering LDL-C levels in the circulation. ( Xagena )
Source: Novartis, 2020