Positive interim results from ORION-3 study of inclisiran twice yearly dosing for LDL patients

The Medicines Company announced interim results from the ongoing ORION-3 open-label extension study (Group 1, n=290) which showed that twice-a-year dosing with inclisiran sodium 300 mg resulted in consistent lowering of low density lipoprotein cholesterol (LDL-C) by more than 50 percent with overall follow-up of up to three years. Inclisiran was well tolerated, and no material safety issues were observed in the study. These results were presented during a late-breaking clinical trial session at the National Lipid Association (NLA) Scientific Sessions in Miami.

Inclisiran, the first cholesterol-lowering therapy in the siRNA class, is in Phase III clinical development to evaluate its ability to lower LDL-C through twice-a-year dosing. Pivotal Phase III readouts for inclisiran are expected in the third quarter. ORION-3 (n=382) is an open-label extension study of the Phase II ORION-1 trial to assess the efficacy, safety and tolerability of long-term dosing of inclisiran.

In this interim analysis of ORION-3, inclisiran demonstrated a 51 percent (64.0 mg/dL, p<0.001) reduction in LDL-C levels through day 210, which was the study’s primary endpoint. The time-averaged absolute LDL-C reduction with inclisiran was 59.4 mg/dL (p<0.001). These effects were independent of dose level and number of doses of inclisiran previously given in the ORION-1 study. With overall follow-up of approximately three years from the first dose in ORION-1, no change in the overall safety profile was observed in this interim analysis of ORION-3 compared to the one-year follow-up in ORION-1. Inclisiran was well tolerated and no material safety issues were observed, including no elevations of liver enzymes or changes in renal function considered related to study medication. Clinically relevant injection site reactions were infrequent, mild or moderate, and transient, in line with observations in ORION-1.

Background on ORION-1 and ORION-3 : Subjects who completed ORION-1 and met all inclusion and exclusion criteria enrolled into ORION-3 in two groups. In Group 1, subjects (n=290) previously treated with any inclisiran dose in ORION-1 received twice-a-year injections of inclisiran sodium 300 mg. The ORION-3 primary endpoint was mean percent change in LDL-C from the ORION-1 baseline value, measured at day 210 in Group 1. The interim analysis of ORION-3 presented on May 18, 2019, reported safety and efficacy of inclisiran for Group 1 only (NLA Scientific Sessions, “Long-term twice-a-year dosing of inclisiran, a novel siRNA therapy, results in persistent LDL-C lowering in Phase II extension study (ORION-3),” speaker: John J. P. Kastelein, M.D., Ph.D.). In Group 2, subjects (n=92) previously treated with placebo in ORION-1 received one year of treatment with evolocumab (140 mg injections every two weeks) followed by three years of treatment with inclisiran sodium 300 mg given on day 360 and 450 and every six months thereafter. For Group 2, safety and efficacy of switching from evolocumab to inclisiran will be assessed in an exploratory manner. Follow up for Group 2 is ongoing, and completion is projected to occur in 2022 followed by anticipated presentation of data in a scientific forum.