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Early Clinical Trial Shows RNA Therapy Lowers Cholesterol

Human heart and arteries (Yale School of Medicine/Wikimedia Commons)

(Yale School of Medicine/Wikimedia Commons)

A clinical trial by the biopharmaceutical company Alnylam Pharmaceuticals in Cambridge, Massachusetts shows that one dose of a drug made from interfering ribonucleic acid (RNA) cuts LDL, or bad, cholesterol levels more than a placebo. Results of the study, conducted with colleagues from University of Texas-Southwestern in Dallas and medical centers in the U.K., appear online today in the journal The Lancet (paid subscription required).

The trial, an early stage study with 32 adult volunteers, tested the safety and tolerability of Alnylam’s therapy ALN-PCS designed to treat patients with hypercholesterolemia, or high levels of low-density lipoproteins (LDL) cholesterol. People with hypercholesterolemia, a condition affecting some 34 million Americans, face a higher risk of developing plaque build-up in arteries, leading to coronary artery disease. It is the most common inherited form of high cholesterol.

ALN-PCS is one of a class of small interfering RNA therapies made by Alnylam that target messenger RNA, the genetic molecules that create proteins associated with specific disorders. The drug is expected to aid hypercholesterolemia patients who do not respond to conventional cholesterol-lowering drugs, such as statins.

ALN-PCS is designed to block production in the liver of proprotein convertase subtilisin/kexin type 9 or PCSK9, a protein that regulates LDL cholesterol by destroying the receptors that clear LDL cholesterol from the blood. Earlier studies indicate mutuations in the gene producing PCSK9 can cause cholesterol levels to fluctuate, depending on the amount of the protein produced.

Participants in the clinical trial had elevated LDL cholesterol levels, but were otherwise healthy. Some 24 of the volunteers were randomly assigned to receive different intravenous doses of ALN-PCS, while 8 received a saline-solution placebo. None of the test subjects were taking statins or other cholesterol-lowering medications.

The results show participants receiving ALN-PCS experience immediate reductions in PCSK9, with those receiving higher doses having longer-lasting effects. PCSK9 levels among participants receiving the highest doses of ALN-PCS drop on average by 70 percent, with LDL cholesterol falling by 40 percent, compared to the placebo.

Alnylam says ALN-PCS was well tolerated, although 8 to 9 in 10 participants in both the test and placebo groups experienced mild to moderate adverse reactions. None of the participants had to discontinue taking ALN-PCS (or the placebo), nor were there differences between test and placebo groups in indicators of liver functions or inflammation.

In February 2013, Alnylam licensed ALN-PCS to The Medicines Company in Parsippany, New Jersey for product development and commercialization. Under the deal Alnylam will continue preclinical studies and early-stage clinical trials of the intravenous and injected forms of ALN-PCS, while The Medicines Company will be responsible for later-stage trials and product marketing. Alnylam received an upfront payment of $25 million and will be eligible for milestone payments of up to $180 million.

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