The Medicines Company and Alnylam Pharmaceuticals Announce Initiation of Phase III Clinical Trials of Inclisiran
– Patient dosing commenced –
– Comprehensive Phase III clinical program to assess LDL-C lowering and safety in a wide range of patients –
– Efficient, focused and rapid program designed to support US and EU regulatory filings –
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
Principal Investigator for ORION-11, Professor
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
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
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.
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.
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.
Despite statins alone or in combination with other lipid lowering medications, current therapies for the management of elevated LDL-C remain insufficient in some subjects. This is particularly true in patients with pre-existing CHD and/or diabetes or a history of FH, who are at the highest risk and require the most intensive management.
About PCSK9 and PCSK9 inhibition
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the serine protease family, plays a key role in controlling the levels of low-density lipoprotein receptors (LDLR) on the surface of hepatocytes. PCSK9 is expressed and secreted into the bloodstream predominantly by the liver, binds LDLR both intracellularly and extracellularly and promotes the lysosomal degradation of these receptors in hepatocytes, thereby increasing the circulating LDL-C levels. Loss of function mutations in PCSK9 have been found to lead to increased LDLR in the liver, reduced serum LDL-C, and a lower risk for CHD, with no apparent negative health consequences.
Recently-developed and approved PCSK9-blocking monoclonal antibodies reduce circulating PCSK9 levels and lower LDL-C levels. Preliminary reports indicate that treatment with such antibodies can lead to the reduction of cardiovascular events compared with placebo. Results from the first completed large cardiovascular outcomes trial (FOURIER) were reported in
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, and which yielded inclisiran (licensed to The
Alnylam (NASDAQ: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, and hepatic infectious diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform and deep pipeline of investigational medicines, including four product candidates that are in late-stage development. Looking forward, Alnylam will continue to execute on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam employs over 600 people in the U.S. and
The Medicines Company Forward Looking Statements
Statements contained in this press release that are not purely historical may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates," "expects," “potential,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include the timing and success of a commercial launch of inclisiran in
Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam's views with respect to the potential for inclisiran to be a safe and effective treatment for hypercholesterolemia, the timing of clinical studies and potential regulatory filings for approval of inclisiran and the expected safety database to be generated through the Phase III studies of inclisiran, its expectations regarding the development and potential commercialization of inclisiran by its partner The
Inclisiran has not been approved by the
The Medicines Company
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