By a News Reporter-Staff News Editor at Heart Disease Weekly The Medicines Company (NASDAQ: MDCO) and Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) announced the initiation of the Phase III clinical program for inclisiran, with the commencement of patient dosing on November 1, 2017 in the ORION-11 trial, a Phase III study of inclisiran versus placebo in patients with atherosclerotic cardiovascular disease (ASCVD), or ASCVD-risk equivalents (e.g., type 2 diabetes and familial hypercholesterolemia), and elevated LDL-cholesterol (LDL-C) despite maximum tolerated doses of LDL-C lowering therapies (see also Clinical Research - Clinical Trials and Studies).
The ORION-11 trial is a double-blind study in which 1,500 eligible patients will be randomized 1:1 to receive either inclisiran or placebo. The primary objective of the study is to evaluate the effect of inclisiran treatment on percent change in LDL-C levels from baseline at Day-510 and time-adjusted percent change in LDL-C levels from baseline between Day-90 and Day-540.
Building on the highly-successful ORION-1 Phase II trial, which defined the optimal dosing of inclisiran for the Phase III clinical program, in ORION-11, the starting dose of inclisiran is 300 mg given subcutaneously on Day-1 and Day-90, followed by maintenance doses of 300 mg of inclisiran given subcutaneously on Day-270 and Day-450. The treatment and observation duration of ORION-11 is 18 months. Approximately 100 clinical sites in seven European countries and South Africa are participating in the study, which is being performed in partnership with Pharmaceutical Product Development, LLC (PPD), a leading global contract research organization.
Principal Investigator for ORION-11, Professor Kausik Ray, Professor of Public Health, Imperial College London, United Kingdom, and Honorary Consultant Cardiologist, Imperial College NHS Trust, said, "We are very excited to have commenced the inclisiran Phase III clinical program with the ORION-11 trial. The ease of dosing - small volume, subcutaneous injections twice a year, most likely given by healthcare professionals - promises to improve patient adherence to lipid therapy, which has been a significant problem with all other approaches. Data from the ORION-1 Phase II trial gives us considerable confidence in inclisiran's potential effectiveness, dosage regimen and safety profile, underscoring the remarkable potential for inclisiran to become a best-in-class therapeutic for millions of patients."
The ORION-11 trial is one of four Phase III pivotal trials for inclisiran, which also include the ORION-10 trial in approximately 1,500 ASCVD patients treated in North America; the ORION-9 trial in approximately 400 patients with heterozygous familial hypercholesterolemia (FH) treated in North America, Europe, Israel and South Africa; and the ORION-5 trial in approximately 60 patients with homozygous FH treated in Europe, the Middle East and North America. The Company continues to expect that all of these trials will commence before the end of 2017 and, subject to the progress and results of the Phase III clinical program for inclisiran, that data from the four trials that comprise the program will support the submission of a New Drug Application (NDA) in the United States and a Marketing Authorization Application (MAA) in the European Union at or around the end of 2019.
David Kallend, MBBS, Senior Vice President and Global Medical Director of The Medicines Company, stated, "We expect a rolling start for all four pivotal trials, and we believe the entire LDL-C lowering program will be completed in the second half of 2019 in anticipation of regulatory submissions in United States and the European Union. The trials cover the entire spectrum of today's subjects who need LDL-C lowering beyond established treatments for atherosclerotic cardiovascular disease, including secondary prevention for those with prior heart attacks, strokes and peripheral artery disease, and primary prevention for those with familial hypercholesterolemia or other risk factors, such as type 2 diabetes and 20% or greater risk of a major cardiovascular event."
Kevin Fitzgerald, Ph.D., Senior Vice President of Research at Alnylam, said, "We are delighted by the progress that investigators and our partner, The Medicines Company, have made with inclisiran, and we look forward to watching its progress in this comprehensive Phase III program in thousands of patients. In addition, these studies will provide substantial safety data that we expect will support the overall safety profile of our RNAi therapeutics platform."
Anshul Thakral, Senior Vice President and Global Head of Biotech at PPD, said, "We are pleased to partner with The Medicines Company to conduct the ORION Phase III trials using our innovative approach to chronic disease studies, which includes a closed-loop site network and patient enrollment solution. We believe that these trials can rapidly accumulate pivotal data to support NDA and MAA submissions for inclisiran and we're excited to contribute to the development of this potentially important new therapy." About ORION-11 ORION-11 is a Phase III, placebo-controlled, double-blind, randomized study in 1,500 patients with ASCVD (coronary heart disease, cerebrovascular disease and peripheral arterial disease), or ASCVD-risk equivalents (e.g., type 2 diabetes, FH and 20% or greater risk of a cardiovascular event as assessed by Framingham risk score or equivalent), and elevated LDL-C despite maximum tolerated doses of LDL-C lowering therapies, designed to evaluate the efficacy, safety, and tolerability of subcutaneous inclisiran injection(s).
Patients may be included if they are =18 years of age with serum LDL-C =1.8 mmol/L (=70 mg/dL) for ASCVD patients or =2.6 mmol/L (=100 mg/dL) for ASCVD-risk equivalent patients, and fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
Patients on statins should be receiving a maximally-tolerated dose, which means the maximum dose of statin that can be taken on a regular basis without intolerable adverse events. Patients not receiving statins must have documented evidence of intolerance to all doses of at least two different statins. Lipid-lowering therapies (such as a statin and/or ezetimibe) should be stable for =30 days before screening with no planned medication or dose change during study participation. Patients on monoclonal antibodies directed towards PCSK9 within 90 days of screening are excluded. Other exclusion criteria comprise standard clauses commonly used in pivotal licensing trials for lipid-lowering therapies.
Lipids and lipoproteins will be measured at various visits, including LDL-C, total cholesterol, triglycerides, HDL-cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein cholesterol and apolipoprotein, as well as PCSK9 and high-sensitivity C-reactive protein.
Safety assessments, including adverse events, serious adverse events, electrocardiograms, concomitant medications and safety laboratory parameters, will also be collected during the study. An independent Data Monitoring Committee will review safety data on a regular basis. About inclisiran Inclisiran (formerly known as PCSK9si or ALN-PCSsc) is an investigational GalNAc-conjugated RNAi therapeutic targeting PCSK9 - a genetically-validated protein regulator of LDL receptor metabolism - being developed for the treatment of hypercholesterolemia. In contrast to anti-PCSK9 monoclonal antibodies that bind to PCSK9 in blood, inclisiran is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver.
The Medicines Company and Alnylam Pharmaceuticals, Inc. are collaborating in the advancement of inclisiran pursuant to the terms of their 2013 agreement. Under the terms of that agreement, Alnylam completed certain pre-clinical studies and the Phase I clinical study, with The Medicines Company leading and funding the development of inclisiran from Phase II forward, as well as potential commercialization. About ASCVD and risk equivalent disease Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death worldwide, resulting in over 17 million deaths annually. Eighty percent of all CVD deaths are due to coronary heart disease (CHD) or strokes. Elevated LDL-C is a major risk factor for the development of CVD and has recently been described as causative. Lowering LDL-C has been shown to reduce the risk of cardiovascular death or heart attack, and within the range of effects achieved so far, the clinical risk reduction is linearly-proportional to absolute LDL-C reduction.
Approximately 100 million people worldwide are treated with lipid lowering therapies, predominantly statins, to reduce LDL-C and the associated risk of death, nonfatal myocardial infarction (MI) and nonfatal stroke or associated events. However, residual risk for cardiovascular events remains and statins are associated with well-known limitations. First, not all subjects reach LDL-C levels associated with optimal protection against clinical events. Second, not all subjects tolerate statins or are able to take statins at sufficiently-intensive doses. Third, observational studies have demonstrated that >50% of patients do not adhere to statin therapy for more than six months.
There is an unmet need for additional treatment options beyond currently-available treatments for lowering of the LDL-C level to reduce cardiovascular risk.
Keywords for this news article include: Alnylam Pharmaceuticals, Pharmaceutical Companies, Placebos, Cardiology, Lipoproteins, Therapeutics, Dyslipidemias, Lipid Research, Hyperlipidemias, Type 2 Diabetes, Drugs and Therapies, Risk and Prevention, The Medicines Company, Adverse Drug Reactions, Cardiovascular Research, Diagnostics and Screening.
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