The Medicines Company (NASDAQ: MDCO) today announced detailed results from ORION-10, the second of three pivotal 18-month low-density lipoprotein cholesterol (LDL-C) lowering Phase 3 clinical studies of inclisiran, an investigational twice-yearly therapy to reduce LDL-C and the first and only cholesterol-lowering treatment in the siRNA (small-interfering RNA) class. In ORION-10, twice-yearly dosing with inclisiran sodium 300 mg met all primary and secondary efficacy endpoints, was well-tolerated and again demonstrated an excellent safety profile. Full study results were presented during a late-breaking science session at the American Heart Association (AHA) Scientific Sessions in Philadelphia.
"Cumulative exposure to high LDL-C levels presents a significant risk of future heart attacks and strokes for millions of people, particularly those with ASCVD," said study principal investigator R. Scott Wright, M.D., Professor of Medicine, Consultant in Cardiology, Mayo Clinic in Rochester, Minnesota. "The data from ORION-10 show that inclisiran lowers LDL-C significantly and sustains reductions over a six-month period with a safety profile similar to placebo."
For the primary endpoints of ORION-10, inclisiran delivered placebo-adjusted LDL-C reductions of 58% (p<0.0001) at day 510 and demonstrated time-averaged placebo-adjusted LDL-C reductions of 56% (p<0.0001) from days 90 through 540.
The overall adverse event profiles of the placebo- and inclisiran-treated groups in ORION-10 were similar. A similar proportion of patients in the placebo and inclisiran groups experienced at least one serious treatment emergent adverse event (26.3% vs. 22.4%). The incidences of deaths (1.4% vs. 1.5%) and malignancies (3.3% vs. 3.3%) were also comparable between the placebo and inclisiran groups, respectively.
Clinically significant elevations in liver function tests (ALT 0.3% vs. 0.3%, AST 0.6% vs. 0.5%) and serum creatinine increases (3.9% vs. 3.9%) were similar between the placebo and inclisiran groups, respectively. Clinically relevant adverse events at the injection site, predominantly mild and always transient, were reported in 0.9% of placebo-treated patients vs. 2.6% of inclisiran-treated patients.
"The results from ORION-10 are outstanding and provide yet another confirmation of the highly differentiated clinical profile of inclisiran," said Mark Timney, Chief Executive Officer of The Medicines Company. "We believe that inclisiran is ideally suited to address the effects of cumulative exposure to LDL-C and has the potential to change the course of how healthcare professionals manage ASCVD risk for the millions of patients who struggle to reach their LDL-C goals."
ORION-10 data will be submitted to a peer-reviewed medical journal. The company expects to file regulatory submissions in the U.S. in the fourth quarter of 2019 and in Europe in the first quarter of 2020.
Data from ORION-9, a Phase 3 clinical study of inclisiran in patients with heterozygous familial hypercholesterolemia (HeFH), will be presented at AHA on Monday, November 18, 9:24am EST, during Late Breaking Science VI: New Frontiers in Lipid Therapy. The company previously announced (click here) topline results of ORION-9.
ORION-10 Study Design
The ORION program is studying the efficacy and safety of inclisiran in patients with ASCVD and FH, with ORION-9, ORION-10 and ORION-11 comprising the pivotal Phase 3 LDL-C lowering studies.
ORION-10 is a pivotal Phase 3, placebo-controlled, double-blind, randomized study to evaluate the efficacy and safety of inclisiran sodium 300 mg administered subcutaneously in 1,561 participants with ASCVD and elevated LDL-C, despite maximum tolerated dose of LDL-C-lowering therapies (e.g., a statin or ezetimibe). The primary endpoints are 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 study was conducted at 145 sites in the United States. 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 majority of study participants were taking inclisiran or placebo in addition to existing lipid-lowering therapy with a maximally tolerated statin (with or without ezetimibe).
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 and safety of long-term dosing of inclisiran.