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Alnylam Gives Sneak Peek of Hypercholesterolemia Program at OTS Meeting; Additional Work Underway

Alnylam Pharmaceuticals last week gave a quick glimpse into one of its early-stage drug-development programs, showing preclinical data that suggest siRNAs targeting PCSK9 could cut cholesterol levels in mice by as much as 30 percent.
However, Alnylam researcher Akin Akinc, who presented the data at the second annual meeting of the Oligonucleotide Therapeutics Society held at Rockefeller University in New York, stressed that the results were preliminary and came from early-stage screening experiments.
PCSK9, or proprotein convertase subtilisn/kexin type 9, is a protease that degrades the LDL receptor. Alnylam formed a partnership with the University of Texas Southwestern Medical Center in July to develop RNAi-based therapeutics targeting the PCSK9 gene.
“If we’re able to silence PCSK9, we would expect an increase in the levels of LDL receptor on the surface of the liver, as well as on peripheral cells, thereby removing more of the LDL particles from the circulation” and reducing both LDL cholesterol and total cholesterol, Akinc said.
Akinc said that one of the biggest reasons Alnylam thinks “this is a very promising target for the treatment of hypercholesterolemia” is the existence of both mouse and human data indicating that PCSK9 suppression can safely impact cholesterol levels.
He pointed to a paper published in the Proceedings of the National Academy of Sciences in 2005 in which researchers from UTSMC describe the creation of PCSK9 knockout mice.
“These mice are normal, they’re fertile, they have normal amounts of plasma triglycerides, [and they have] normal apoB levels,” Akinc said. “However, they do have 48 percent lower plasma cholesterol than their wild-type littermates. Also, they have an increased LDL receptor protein level — about three-fold.”
Additionally, “there is no difference at the mRNA transcript level, [which] points to the fact that PCSK9 is acting at the protein level, not the mRNA level,” he noted. “But what is even more compelling is that we have human validation for this target.”
Earlier this year in the New England Journal of Medicine, researchers from UTSMC published the results of a study examining the effect of nonsense mutations in PCSK9 on the incidence of coronary heart disease in a large population over a 15-year period.

“If we’re able to silence PCSK9, we would expect an increase in the levels of LDL receptor on the surface of the liver, as well as on peripheral cells, thereby removing more of the LDL particles from the circulation,” and reducing both LDL cholesterol and total cholesterol.

According to the NEJM paper, of the 3,363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9, which were associated with a 28-percent reduction in mean LDL cholesterol and an 88-percent reduction in the risk of coronary heart disease.
”Of the 9,524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15-percent reduction in LDL cholesterol and a 47-percent reduction in the risk of CHD,” the paper’s authors wrote.
In light of these findings, Alnylam conducted experiments to see if it could knock down PCSK9 in mice, Akinc said. As expected, some of the 16 siRNAs the company created didn’t work at all, while some had a moderate effect on gene expression. Two of the 16, however, showed roughly 60-percent silencing activity, with a “nice correlation” between knockdown and cholesterol levels.
“Those two particular siRNAs that gave about a 60-percent [silencing] gave about 30-percent reduction in total cholesterol,” Akinc said. He added that the siRNAs were formulated with a lipid in-licensed from the Massachusetts Institute of Technology.

In response to questions from attendees of the Oligonucleotide Therapeutics Society meeting, Akinc said that Alnylam has thus far only conducted siRNA screening experiments in the PCSK9 program, and that additional studies are ongoing.

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