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Isis Debuts Data on PCSK9-Targeted Antisense Oligo; Formal Development Unlikely Soon

Isis Pharmaceuticals recently posted on its website data showing that an antisense inhibitor of proprotein convertase subtilisn/kexin type 9, or PCSK9, significantly cut both low-density lipoprotein and total cholesterol levels in mice fed a high-fat diet.
The findings, which were published in late January in the online version of the Journal of Lipid Research, also demonstrated that the antisense agent had no effect on LDL receptor-deficient mice, validating earlier work establishing a role for PCSK9 in promoting LDL degradation.
“Opposing PCSK9’s activity to preserve liver LDLR levels may be an attractive therapeutic means by which to reduce harmful serum cholesterol levels,” Isis said. “Systemically delivered antisense drugs distribute preferentially to the liver, making PCSK9 an especially appropriate target for antisense drugs. Isis has an active PCSK9 drug discovery program ongoing and has human PCSK9 antisense drug candidates in preclinical development.”
And while Isis collaborator Alnylam Pharmaceuticals has for some time been developing siRNAs against PCSK9 — a program it recently added to its formal development pipeline (see RNAi News, 12/7/2006) — statements made by Isis Chairman and CEO Stanley Crooke suggest that the antisense firm has no immediate plans to follow suit.
“PCSK9 is an interesting target … [and] it demonstrates one of the strengths of antisense technology in that we could rapidly evaluate the target and present the data,” he said during a conference call last week to discuss Isis’ financial results for the fourth quarter and full-year 2006.
However, “we have not made a decision to move PCSK9 into development yet,” Crooke added. “We think there is more work to be done before we do that.”
In the near-term, Isis expects to focus most of its attention on its phase II high cholesterol therapy Isis 301012, an antisense agent that targets apolipoprotein B-100, he said. The company is slated to present new data on the drug at the upcoming American College of Cardiology annual meeting later this month.
The Target
PCSK9 is a protease that degrades the cell-surface receptor for low-density lipoprotein. In 2005, Alnylam collaborators at the University of Texas Southwestern Medical Center published data in the Proceedings of the National Academy of Sciences showing that knockout mice lacking the PCSK9 gene had decreased plasma cholesterol and hypersensitivity to statins. that knockout mice lacking the PCSK9 gene had decreased plasma cholesterol and hypersensitivity to statins.
Further evidence supporting PCSK9’s promise as a target for high cholesterol came late last year with the publication of a study examining the effect of nonsense mutations in PCSK9 on the incidence of coronary heart disease in 3,363 black subjects and 9,524 white subjects over a 15-year period.
According to that work, conducted by the same UTSMC researchers and published in the New England Journal of Medicine, 2.6 percent of the black subjects 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.
By comparison, 3.2 percent of the white subjects 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.
They added that the data “indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.”
Building off of these findings, Alnylam conducted preclinical experiments in which two siRNAs were able to silence about 60 percent of PCSK9 in normal mice, which translated into about a 30-percent reduction in total cholesterol levels (see RNAi News, 10/26/2006).

“PCSK9 is an interesting target … [and] it demonstrates one of the strengths of antisense technology in that we could rapidly evaluate the target and present the data. [However], we have not made a decision to move PCSK9 into development yet.”

In follow-up in vivo studies conducted in collaboration with UTSMC, an Alnylam-designed siRNA active against human PCSK9 was able to lower levels of the PCSK9 transcript over 80 percent 72 hours after intravenous administration (see RNAi News, 12/7/2006). Additionally, treatment with the siRNA cut PCSK9 plasma protein levels 500- to 1,000-fold at two days after injection.
The Data
In its Journal of Lipid Research paper, Isis researchers administered an antisense oligo targeting mouse PCSK9 intraperitoneally twice weekly to mice receiving a high-fat diet. After six weeks of treatment, the researchers evaluated levels of PCSK9 and LDL receptor.
According to the paper, treatment with the antisense oligo selectively reduced hepatic PCSK9 mRNA levels by 92 percent after six weeks. “As previously observed in PCSK9-deficient mice, suppression of PCSK9 did not affect levels of hepatic LDLR or [apolipoprotein]-B mRNA,” the authors wrote.
Total cholesterol levels were reduced 53 percent after treatment with the antisense drug, while LDL levels dropped 38 percent.
“Moreover, inhibition of PCSK9 expression resulted in a two-fold increase in hepatic LDLR protein levels,” a phenotype that “closely resembles” one previously reported in PCSK9-deficient mice, the paper’s authors added.
“Based upon these compelling initial results, studies are in progress to further evaluate the potential of PCSK9 as a targeted intervention for cholesterol lowering in animals which have more similar serum lipid profiles to humans, such as hamsters and non-human primates,” they wrote.
“Very recently a second-generation antisense inhibitor, [Isis 301012] … has resulted in significant dose-dependent effects on apoB-100 and all apoB-100 containing atherogenic lipids, both as a single agent and in combination with statins with an acceptable safety profile,” they added.
“Thus, a PCSK9 drug of this class should be effective and well tolerated in the clinic and may indeed provide therapeutic benefit in patients at risk for cardiovascular disease,” the authors concluded.

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