Novartis announces NEJM publication of three pivotal trials showing durable and potent efficacy of inclisiran

The findings were published in two online articles ahead of print in The New England Journal of Medicine. The primary endpoints were achieved in all three trials. Namely, percentage change in LDL-C from baseline to 17 months and time-adjusted percentage change in LDL-C from baseline from 3 through 18 months. This demonstrates that after two starter doses, twice-yearly subcutaneous dosing with inclisiran resulted in durable and potent LDL-C reductions versus placebo. Inclisiran was well-tolerated with a safety profile similar to placebo.

Hyperlipidemia refers to the high level of lipids (fats, cholesterol, triglycerides), such as LDL-C, found in the blood that are either acquired or a result of genetic disorders. The length of time a person has elevated LDL-C levels, is understood to be causal to ASCVD, which can lead to a cardiovascular event such as a heart attack or stroke. LDL-C is the most readily modifiable risk factor for ASCVD6-11. People who are on lipid-lowering therapies often do not reach optimal LDL-C levels, leaving them at increased risk for significant morbidity and mortality associated with this condition. Approximately 40 million patients in the US have been diagnosed with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) and are at risk of a cardiovascular event.

ORION 10 and 11

One article reported the results from the ORION-10 and -11 studies, which 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.

In ORION-10 and -11, at 17 months inclisiran resulted in placebo-adjusted LDL-C reduction of 52% and 50% respectively and time-adjusted reduction from 3 through 18 months of 54% and 49% respectively.

Treatment-emergent adverse events were generally similar between the inclisiran and placebo groups.

“Inclisiran and its twice-yearly dosing schedule in three large trials consistently delivered potent and sustained cholesterol-lowering and was generally well tolerated,” said Kausik Ray, M.D., ORION-11 principal investigator, Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Deputy Director of Imperial Clinical Trials Unit, Imperial College, London. “These data provide support for this groundbreaking approach to reducing LDL-C in patients who are not achieving LDL-C treatment goals with the current standard of care.”

“Elevated LDL-C is an important modifiable risk factor for cardiovascular events for millions of people, particularly those with ASCVD,” said ORION-10 principal investigator R. Scott Wright, M.D., Professor of Medicine, Consultant in Cardiology, Mayo Clinic in Rochester, Minnesota. “The data from ORION-10 shows that inclisiran results in significant and sustained reductions in LDL-C over a six-month period with a safety profile similar to placebo.”

ORION 9

A separate article on ORION-9 highlighted results of treatment with inclisiran in HeFH, a rare hereditary disease that causes high levels of LDL-C and leads to early onset of ASCVD.  In this study, inclisiran reduced LDL-C by 50% at 17 months with a time-adjusted reduction of 45% from 3 through 18 months, compared to placebo. There was a robust reduction of LDL-C with all FH genotypes.

Treatment-emergent adverse events were similar between inclisiran and placebo2.

“Familial hypercholesterolemia remains a difficult condition to treat but the potential addition of inclisiran gives hope to many FH patients to help meet and maintain guideline-recommended LDL-C levels with two injections of inclisiran per year,” said Frederick Raal, M.D., University of the Witwatersrand, Department of Medicine, University of the Witwatersrand  Kallend, South Africa.

In all three Phase III trials patients received inclisiran or placebo in addition to maximally tolerated lipid-lowering therapy. The twice-yearly dosing regimen, which followed two starter doses, was administered subcutaneoulsy by a healthcare provider.

“There are over 50 million secondary prevention patients worldwide with atherosclerotic cardiovascular disease or familial hypercholesterolemia on current standard of care who don’t achieve their desired LDL-C goal and remain at increased risk of cardiovascular events,” said Marcia Kayath, M.D., Global Head of Medical Affairs and Chief Medical Officer, Global Pharmaceutical Division, Novartis. “With inclisiran’s unique twice-yearly dosing, we’re reimagining what potent and durable control of LDL-C looks like for patients and physicians with the potential to improve adherence and keep patients’ cholesterol levels low over the long term.”

Inclisiran is currently under review by the U.S. Food and Drug Administration and European Medicines Agency for use in adults with ASCVD or HeFH who have elevated LDL-C while being on a maximum tolerated dose of a lipid-lowering therapy. If approved, inclisiran will be the first and only cholesterol-lowering treatment in the siRNA class.