Inclisiran is twice-yearly potent injectable LDL cholesterol lowering drug reveals Phase 3 clinical trial

The results of phase 3 clinical trial revealed a durable and potent low-density lipoprotein-cholesterol (LDL -C) lowering drug with twice-yearly dosing. The results of the trial were presented during a late-breaking science session at the European Society of Cardiology’s ESC Congress 2019 in Paris.

Inclisiran is a chemically synthesized small interfering RNA (siRNA) that targets proprotein convertase subtilisin-kexin type 9 (PCSK9) messenger RNA. The subcutaneous (SC) injectable is being investigated for its ability to lower low-density lipoprotein cholesterol (LDL-C) through twice-a-year dosing.

Inclisiran achieved 54% LDL-C lowering with time-adjusted reductions of 50% sustained over 18 months of treatment. ORION-11 study demonstrates inclisiran’s excellent safety profile, including no treatment-related liver or renal abnormalities.

The Medicines Company presented the findings of ORION-11, its first pivotal Phase 3 clinical study of inclisiran, an investigational twice-yearly therapy to reduce low-density lipoprotein cholesterol (LDL-C) and the first and only cholesterol-lowering therapy in the siRNA (small-interfering RNA or “sir-nah”) class. In ORION-11, twice-yearly dosing with inclisiran sodium 300 mg met all primary and secondary efficacy endpoints, was well-tolerated and demonstrated an excellent safety profile.

“The cumulative effects of long-term uncontrolled low-density lipoprotein cholesterol continue to place millions of people at increased cardiovascular risk,” said Kausik Ray, M.D., principal investigator of ORION-11, professor of public health and Consultant Cardiologist at Imperial College London. “The results of the ORION-11 trial support the unprecedented potential of inclisiran to deliver assurance to clinicians and patients that LDL-C can be lowered in a sustained fashion over the long-term with an infrequent dosing regimen and an excellent safety profile. This is a groundbreaking new approach for preventing atherosclerotic cardiovascular disease with exciting implications at a population health level.”

For the primary endpoints of ORION-11, inclisiran delivered placebo-adjusted low-density lipoprotein cholesterol reductions of 54% (p<0.0001) at day 510 and demonstrated time-averaged placebo-adjusted LDL-C reductions of 50% (p<0.0001) from days 90 through 540.

The overall adverse event profiles of the placebo- and inclisiran-treated groups in ORION-11 were similar. A similar proportion of patients in the placebo- and inclisiran treated groups experienced at least one serious treatment-emergent adverse event (22.5% vs. 22.3%). The incidence of deaths (1.9% vs. 1.7%) and malignancies (2.5% vs 2.0%) was similar between the placebo and inclisiran groups, respectively. A difference between placebo and inclisiran was observed in the incidence of fatal and non-fatal myocardial infarctions (2.7% vs. 1.2%) and fatal and non-fatal strokes (1.0% vs. 0.2%).

Clinically relevant elevations in liver function tests (ALT 0.5% vs. 0.5%, AST 0.5% vs. 0.2%) and serum creatinine increases (1.4% vs. 0.6%) were similar between the placebo and inclisiran groups, respectively. The incidence of clinically relevant injection site reactions between the placebo and inclisiran groups was infrequent (0.5% vs. 4.7%), with events predominantly mild and transient.

“The exceptional data from ORION-11 show that inclisiran delivers durable and potent low-density lipoprotein cholesterol reductions through twice-yearly dosing that we believe can address adherence challenges in a way that no other currently used low-density lipoprotein cholesterol lowering medicine can,” said Mark Timney, Chief Executive Officer of The Medicines Company. “We are excited at the prospect of bringing forward a remarkable, transformative advance in the treatment of cardiovascular disease.”

ORION-11 data will be submitted to a peer-reviewed medical journal. The sequential release of topline Phase 3 data readouts for the ORION-9 and ORION-10 studies is expected to continue later in the third quarter in advance of anticipated regulatory submissions in the U.S. in the fourth quarter of 2019 and in Europe in the first quarter of 2020.

Patients who have completed their respective Phase 3 studies are now enrolling into ORION-8, an open-label, long-term extension study where patients completing ORION-9, ORION-10 and ORION-11 will receive inclisiran for three years to evaluate the efficacy, safety and tolerability of long-term dosing of inclisiran.

ORION-11 Study Design

The efficacy and safety of inclisiran in patients with atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia is being studied in the ORION clinical trial program.

ORION-11 is a pivotal Phase 3, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety, and tolerability of inclisiran sodium 300 mg administered subcutaneously in 1,617 patients with ASCVD or ASCVD-risk equivalents and elevated low-density lipoprotein cholesterol despite maximum tolerated a dose of statin therapy (with or without ezetimibe). The international study was conducted at 70 sites in seven countries (ex-US).

Each study participant received inclisiran sodium 300 mg administered as a subcutaneous injection initially, again at three months and then every six months thereafter. The primary endpoints are the percentage change in LDL-C from baseline to day 510 (17 months) and time-adjusted percentage change in LDL-C from baseline after day 90 (three months) and up to day 540 (18 months). Key secondary endpoints include the mean absolute change at Day 510 (17 months), the average absolute reduction from Day 90 (three months) up to Day 540 (18 months), and changes in other lipids and lipoproteins.

The population enrolled in ORION-11 was representative of a high-risk cohort of ASCVD and risk-equivalent patients, with balanced randomization between placebo and inclisiran. Mean age was 65, and 87% of patients had diagnosed ASCVD, with the remainder (13%) diagnosed with ASCVD risk equivalents. Average baseline LDL-C at study day 1 was 106 mg/dL across the study population. Nearly all patients (96%) were taking underlying statins, with the majority on high-intensity statins (90%).