New data and analyses from the ORION development program for inclisiran have been presented at the National Lipid Association (NLA) 2018 Scientific Sessions held in Las Vegas, NV. Multiple studies in the ORION development program demonstrate that the proposed dosing regimen is likely to be the same for a wide range of dyslipidemia patient populations, including those hard-to-treat patients with homozygous familial hypercholesterolemia (HoFH) and other sub-groups.
Inclisiran is an investigational GalNAc-conjugated RNA interference therapeutic, which inhibits the synthesis of PCSK9 protein in liver cells, thereby reducing liver cell LDL-receptor turnover, and lowering plasma LDL-C.
Dr. David Kallend, MBBS, Chief Medical Officer of The Medicines Company, presented data that demonstrated that the inclisiran dosing regimen (300 mg injection administered on day 1, day 90 and then every six months thereafter) achieved substantial PCSK9 and LDL-C lowering in patients with HoFH and primary dyslipidemia, as well as in various sub-groups, such as patients with renal impairment and diabetes. The data showed that inclisiran lowered LDL-C by more than 50% across a wide range of dyslipidemia patient populations and sub-groups, and by up to 44% in HoFH patients.
John J.P. Kastelein, M.D., Ph.D., Professor of Medicine and Chairman of the Department of Vascular Medicine at the Academic Medical Center of the University of Amsterdam, and Chairman of the ORION-1 and ORION-9, ORION-10 and ORION-11 Steering Committees, says in a press release, "New therapies are needed to treat HoFH patients, who are refractory or intolerant to current approaches for the management of their LDL-C levels. The simplicity and convenience of a one-size-fits-all dosing regimen, without the necessity of dose adjustment, is a highly-attractive therapeutic option for health care professionals, and could make a significant difference in busy clinical practice.”
Dr. Kallend added, “The data presented confirm the consistent efficacy of inclisiran’s dosing regimen across all patient populations and sub-groups, with no safety concerns observed in any patient population.”
ORION-1 was a placebo-controlled, double-blind, randomized phase II trial of single or multiple subcutaneous injections of inclisiran in a total of 501 patients with atherosclerotic cardiovascular disease (ASCVD), or ASCVD-risk equivalents (e.g., diabetes and FH), and elevated LDL-C despite maximum tolerated doses of LDL-C lowering therapies. The trial compared the effect of different doses of inclisiran and evaluated the potential for an infrequent dosing regimen. The primary endpoint of the trial was the percentage change in LDL-C from baseline at day 180. ORION-2 is an ongoing single-arm, open-label pilot study of inclisiran in patients with genetically-confirmed HoFH. The primary endpoint is the percentage change in LDL-C from baseline to day-90 and day-180. ORION-5 is also ongoing and focusses on HoFH patients, while ORION-9 is including patients with heterozygous FH.
ORION-7 was a phase I, open-label, parallel-group trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a single 300 mg dose of inclisiran in patients with mild, moderate and severe renal impairment, compared to patients with normal renal function. The primary endpoint of the trial was to evaluate the impact of renal impairment on the pharmacokinetics of inclisiran and establish dosing recommendations for these patients.
Of all trials that are being conducted with inclisiran, 5 patient-years of safety data are collected.