Statin substitutes go beyond drawing board

New cholesterol-lowering drugs help people who can?t take the usual ones

By Nathan Seppa

Web edition: November 5, 2012

LOS ANGELES ? People who can?t take cholesterol-lowering drugs called statins may someday have an alternative drug option that works about as well. Three new studies show that antibodies developed to target specific proteins in cells can knock down LDL, the so-called bad cholesterol, at a rate comparable to the highly successful statins, which go by brand names including Lipitor and Crestor.

The experimental drugs take a unique biological approach to clearing LDL from the blood, suggesting that they might replace statins in people who cannot abide those drugs? side effects, particularly muscle pain. The new drugs may even work in conjunction with statins in people who inherit extremely high cholesterol.

Called biological products or ?biologics? because they contain natural components, the new drugs may fill a niche currently vexing doctors. ?We have been bumping up against statin intolerance in patients,? often in people who have had a heart attack, said Peter Wilson, an endocrinologist at Emory University and the Veterans? Affairs Medical Center in Atlanta. Wilson, who wasn?t part of these studies, estimates that 5 to 15 percent of people who need statins can?t take them. ?We now have biologics to treat this hyper-cholesterolemia, and they?re effective.?

The new drugs, including AMG-145 and RN-316, are still in the testing stage. But researchers offered tantalizing early results November 5 at a meeting of the American Heart Association. Cardiologist Evan Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati reported that people with very high LDL who got AMG-145 injections every four weeks experienced a 41 to 51 percent drop in LDL scores by 12 weeks, depending on the dose. That study was also released online in the Journal of the American Medical Association.

Another AMG-145 study showed LDL reductions of 43 to 55 percent in people with inherited high cholesterol. Those findings also appeared in Circulation. The drug is made by Amgen.

RN-316, made by Pfizer, knocked down LDL by up to 75 percent in a 12-week trial, reported Barry Gumbiner, an endocrinologist at Pfizer in San Diego. ?This is a new drug that shows a lot of promise, but there?s still a long way to go,? he said.

The drugs are antibodies that free up a protein on cells called the LDL receptor that lowers LDL by pulling it out of circulation. The antibodies do this by targeting a troublesome protein called PCSK9 that binds to LDL receptors, bogging them down.

?Cholesterol is essential for the normal functioning of cells,? said Frederick Raal, an endocrinologist at the University of the Witwatersrand in Johannesburg who presented the Circulation study. Even as LDL receptors remove LDL from the blood, the PCSK9 protein acts as a brake on that process, he said. Targeting PCSK9 allows the receptors to snag more LDL.

Besides helping people who cannot take statins, Raal said, the drugs may be added to therapy in those who can tolerate statins but who fail to benefit fully from those drugs even at high doses. That includes people with hereditary high cholesterol. Only a few hundred people in the United States have an extreme form of this condition inherited from both parents, Wilson said.? But about 500,000 have inherited the condition from one parent and fight high cholesterol all their lives, he said. Statins alone often don?t get their LDL levels into the safe range.

This line of research has come full circle. PCSK9 was originally found because people who lack it have few heart problems, Gumbiner said. ?Their LDL levels are much lower, and they live long, healthy lives,? he said. ?That was the genesis for looking at this as a drug target.?

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Citations

B. Gumbiner. Effects of 12 Weeks of Treatment with RN316 (PF-04950615), a Humanized IgG2?a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects on High and Maximal Dose Statins. Oral presentation session LBCT.04. November 5, 2012, American Heart Association Scientific Sessions, Los Angeles.

F. Raal et al. Reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD): Results from a phase 2, randomized, double-blind, placebo controlled trial. Oral presentation session LBCT-04. November 5, 2012, American Heart Association Scientific Sessions, Los Angeles.

F. Raal et al. Low-density lipoprotein cholesterol lowering effects of AMG-145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia. Circulation. Published online Nov. 5, 2012. doi: 10.1161/CIRCULATIONAHA.112.144055.

E.A. Stein et al. Goal achievement after utilizing ananti-PCSK9 antibody in statin-intolerant subjects (GAUSS): Results from a randomized, double-blind, placebo-controlled study. Oral presentation session LBCT-04. November 5, 2012, American Heart Association Scientific Sessions, Los Angeles.

D. Sullivan et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients. Journal of the American Medical Association. Published online November 5, 2012. doi: 10.1001/jama.2012.25790.

E.A. Stein et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. Vol. 380, July 2012, p. 29. doi:10.1016/S0140-6736(12)60771-5.

Source: http://www.sciencenews.org/view/generic/id/346251/title/Statin_substitutes_go_beyond_drawing_board

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