Date: 03-Sep-2020

Novartis Phase III ORION-10 And -11 Trials Show High Consistency In Lowering LDL-C In Individual Response With Investigational Inclisiran

Novartis announced results from a post-hoc analysis of pooled data from the phase III ORION-10 and -11 trials evaluating the individual responses of patients on low-density lipoprotein cholesterol (LDL-C) reduction with inclisiran, a first-in-class investigational treatment for hyperlipidemia in adults. This new analysis of inclisiran showed a highly consistent effect, with a safety and tolerability profile similar to placebo, on a twice-yearly dosing schedule after an initial dose and one 3 months later, across individual patients with atherosclerotic cardiovascular disease (ASCVD) or risk equivalents over 17 months of treatment.

Presented at the ESC Congress 2020, the annual meeting of the European Society of Cardiology, the analysis evaluated the efficacy and tolerability of inclisiran on top of a maximally tolerated dose of statins, in two studies of more than 2,300 patients (of which 1,164 were on inclisiran) from the phase III trials. Results demonstrated a low inter-individual variability, with 99% of inclisiran-treated patients showing a placebo-adjusted =30% reduction of their LDL-C levels with a mean reduction of 54.1% from baseline (observed values).

“This analysis confirms that as a small interfering RNA (siRNA), inclisiran provides a remarkably consistent treatment profile. Nearly all patients from these trials achieved clinically meaningful reductions of their LDL-C levels over the 17 month period, and inclisiran had a safety and tolerability profile similar to placebo,” said ORION-11 principal investigator Kausik Ray, MD, Professor of Public Health, Consultant Cardiologist, Imperial College London. “These efficacy and safety results showcase the promise of inclisiran as a therapy for those ASCVD patients who cannot reach their LDL-C goals.”

An LDL-C reduction of at least 50% was reached by 88.4% of patients at any time point in the study (observed values). After 17 months, 66.4% of the inclisiran group had a reduction in LDL-C of at least 50% as compared to 2.5% from the placebo group (observed values). Overall, inclisiran was well-tolerated with a safety profile similar to placebo. All patients were on twice-yearly dosing, following an initial dose and one 3 months later.

“There remains an urgent need for innovative LDL-C-lowering therapies for patients not reaching their LDL-C target goals with current standard of care. This analysis reinforced our view of inclisiran’s therapeutic value and its potential as the first cholesterol-lowering siRNA,” said David Soergel, M.D, global head of Cardiovascular, Renal and Metabolic Drug Development, Novartis. “With a unique twice-yearly dosing, if approved, inclisiran may fit seamlessly into patients’ regular healthcare visits and help us reimagine treatment for ASCVD.”

Inclisiran is currently under review by the US Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) for the treatment of primary hyperlipidemia (including Heterozygous Familial Hypercholesterolemia) in adults who have elevated LDL-C while being on a maximally tolerated dose of statin therapy.

ORION-10 was a pivotal phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of inclisiran sodium 300 mg administered subcutaneously by a healthcare professional in an initial dose, again at 3 months, and then every 6 months thereafter in 1,561 participants with atherosclerotic cardiovascular disease (ASCVD) and elevated low-density lipoprotein cholesterol (LDL-C), despite a maximum tolerated dose of LDL-C-lowering therapies (e.g. a statin or ezetimibe). For the primary endpoints of ORION-10, inclisiran delivered mean placebo-adjusted percentage change in LDL-C reductions of 52% (P<.0001) at 17 months and demonstrated time-adjusted percentage change in LDL-C reductions of 54% (P<.0001) from 3 through 18 months (observed values). The study was conducted at 145 sites in the United States1.

ORION-11 was a pivotal phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of inclisiran sodium 300 mg administered subcutaneously by a healthcare professional in an initial dose, again at 3 months, and then every 6 months thereafter in 1,617 patients with ASCVD or ASCVD-risk equivalents and elevated LDL-C despite a maximum tolerated dose of statin therapy (with or without ezetimibe). For the primary endpoints of ORION-11, inclisiran delivered placebo-adjusted change in LDL-C reductions of 50% (P<.0001) at 17 months and demonstrated time-adjusted LDL-C reductions of 49% (P<.0001) from 3 through 18 months (observed values). The international study was conducted at 70 sites in seven countries.

Atherosclerosis corresponds to the accumulation of lipids over time – mainly LDL-C – in the inner lining of the arteries. Unexpected rupture of the atherosclerotic plaque can cause an atherosclerotic cardiovascular event such as a heart attack or stroke. Atherosclerotic Cardiovascular Disease (ASCVD) accounts for over 85% of all cardiovascular disease deaths. ASCVD is the primary cause of death in the EU and its burden in the US is greater than that from any other chronic diseases.

Inclisiran, an investigational cholesterol-lowering treatment, was added to the pipeline from the Novartis acquisition of The Medicines Company. Inclisiran will potentially be the first and only LDL-C-lowering small-interfering RNA (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. Its twice-yearly dosing by subcutaneous injection may integrate seamlessly into a patient’s healthcare routine. As a siRNA, inclisiran is thought to harness the body’s natural process of clearing LDL-C from the bloodstream.

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. Data from each of the phase III studies was recently published online, ahead of print, in The New England Journal of Medicine. A cardiovascular outcomes trial, ORION-4, is ongoing.