Three pivotal phase 3 clinical trials for inclisiran (Novartis) were recently published in 2 online articles in The New England Journal of Medicine for a potential first-in-class small interfering RNA (siRNA) investigational agent for hyperlipidemia in adults.

All 3 trials reached their primary endpoints, specifically percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to 17 months and time-adjusted percentage change in LDL-C from baseline from 3 to 18 months.

The findings suggest that after 2 starter doses, twice-yearly subcutaneous (SC) dosing with inclisiran resulted in durable and potent LDL-C reductions versus placebo.

Hyperlipidemia is defined as the high level of lipids (fats, cholesterol, and triglycerides), such as LDL-C, found in the blood that are either acquired or a result of genetic disorders. The amount of time a person has elevated LDL-C levels is understood to be causal to atherosclerotic cardiovascular disease (ASCVD), which can lead to a cardiovascular event, such as heart attack or stroke.

LDL-C is the most readily modifiable risk factor for ASCVD6-11; those who are on lipid-lowering therapies often do not reach optimal LDL-C levels and are at an increased risk for morbidity and mortality associated with the condition.

ORION-10 and ORION-11 evaluated the use of inclisiran in addition to maximally tolerated lipid-lowering therapies in patients with ASCVD (ORION-10) or ASCVD and ASCVD risk equivalents (ORION-11) through 18 months.

At 17 months, inclisiran resulted in placebo-adjusted LDL-C reduction of 52% and 50% respectively in ORION-10 and -11. Time-adjusted reduction from 3 through 18 months of 54% and 49% also occurred respectively. Treatment-emergent adverse events were generally similar between the inclisiran and placebo groups.

In a separate study, ORION-9, inclisiran was used in treatment for heterozygous familial hypercholesterolemia, a rare hereditary disease that causes high levels of LDL-C and leads to early onset of ASCVD. Inclisiran reduced LDL-C by 50% at 17 months with a time-adjusted reduction of 45% from 3 through 18 months compared with placebo. In addition, there was a strong reduction of LDL-C with all familial hypercholesterolemia genotypes. Treatment-emergent adverse events were similar between inclisiran and placebo.

In all 3 of the phase 3 trials, patients received inclisiran or placebo in addition to maximally tolerated lipid-lowering therapy. A twice-yearly dosing regimen preceded by 2 starter doses was administered subcutaneously by a health care provider.

Inclisiran is an investigational cholesterol-lowering therapy and is on track to be the first and only LDL-C lowering siRNA medicine. It is intended to be administered by a health care professional with 2 starter doses and then every 6 months thereafter. It is a twice-yearly dose by SC injection and may integrate seamlessly into a patient’s health care routine.

In all of the phase 3 studies, inclisiran was reported to be well-tolerated with a safety profile similar to placebo. The most common adverse events (AEs) reported were diabetes mellitus, hypertension, nasopharyngitis, athralgia, back pain, dyspnea, bronchitis, and upper respiratory tract infection. At the injection site, AEs were more frequent with inclisiran than placebo and were generally mild; none were severe or persistent.

Novartis announces NEJM publication of three pivotal trials showing durable and potent efficacy of inclisiran, an investigational first-in-class siRNA cholesterol-lowering therapy [news release]. Basel, Switzerland; Novartis: March 18, 2020. Accessed March 18, 2020.