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For Isis, Interest in Phase II Cholesterol Tx Led to Deal for Earlier-Stage Candidate

Isis Pharmaceuticals’ newly forged collaboration with Bristol-Myers Squibb to develop an antisense-based inhibitor of proprotein convertase subtilisin/kexin type 9 for cardiovascular disease was largely fueled by the big pharma’s interest in a possible licensing deal for one of Isis’ more developed drug candidates, according to Isis officials.
Speaking during a conference call last week to discuss the company’s first-quarter financial results, Isis Chairman and CEO Stanley Crooke noted that although his company had published promising data in January showing that antisense agents targeting PCSK9 could cut cholesterol levels in mice, it was strong phase II data on its flagship cholesterol-lowering therapy Isis 301012 that first caught the attention of Bristol-Myers Squibb and other potential partners.
In March, Isis presented data at the American College of Cardiology’s annual meeting showing that in phase II studies Isis 301012 was able to significantly cut levels of apolipoprotein-B and related atherogenic lipids in both polygenic hypercholesterolemia and homozygous familial hypercholesterolemia patients with no serious adverse effects.
As a result of the data, Isis received numerous inquiries from pharmaceutical firms interested in partnering on the drug, Crooke said. With additional phase II studies underway and being planned, however, Isis won’t be ready to begin negotiations until sometime later this year, he added.
Yet, “as people were starting to do their homework and realizing the potential for antisense … [they began looking at] the opportunities for other targets that [could be partnered] more rapidly because there was less data” on them, Kate Corcoran, Isis’ vice president of corporate development, told RNAi News this week.
One of those targets was PCSK9, a protease that degrades the cell-surface receptor for low-density lipoprotein and which is also being developed as a target for an siRNA-based drug by Alnylam Pharmaceuticals (see RNAi News, 12/7/2006).
Before Isis began its PCSK9 program last summer, there was a significant amount of evidence suggesting the PCSK9 gene could be an effective target for treating high cholesterol.
In 2005, researchers 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.
Then, late last year, the same UTSMC team published 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, 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.
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,” the UTSMC researchers wrote.
Isis followed these publications with a paper of its own in the Journal of Lipid Research showing that that an antisense oligo targeting mouse PCSK9, administered intraperitoneally twice weekly to mice receiving a high-fat diet, reduced hepatic PCSK9 mRNA levels by 92 percent after six weeks (see RNAi News, 3/15/2007).
Total cholesterol levels were reduced 53 percent after treatment with the antisense drug, while LDL levels dropped 38 percent, according to the Journal of Lipid Research study.
Addressing these findings two months ago during a conference call discussing Isis’ fourth-quarter 2006 financials, Crooke suggested that while the PCSK9 mouse data was promising, the company would not likely rush it into a formal development program.

“As people were starting to do their homework and realizing the potential for antisense … [they began looking at] the opportunities for other targets that [could be partnered] more rapidly because there was less data” on them.

“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 the March call. However, “we think there is more work to be done before” Isis makes the investment to advance it into the pipeline.
But with the financial backing of Bristol-Myers Squibb, Isis can afford to be more aggressive with the program, Corcoran said.
Before the Bristol-Myers Squibb deal, PCSK9 was viewed by Isis as an “attractive target,” but one that remained far from clinical development with the company’s attention and resources primarily going to Isis 301012.
“Partnering gets it going … rapidly, but not on our dime,” she said.
Under the companies’ partnership, “the very first order of business is to finalize the initial human development candidate, as well as follow on with additional compounds with more advanced chemistries,” Corcoran said. “That is something we expect to happen quickly [in order to] get it into formal preclinical testing as soon as possible.”
She declined to provide a specific timeline on when that testing could begin, but noted that “based on [the] precedent of what we can do with antisense,” the selection of a lead drug candidate sometime this year “is not an unreasonable expectation.”
Francis Cuss, senior vice president of discovery and exploratory clinical research at Bristol-Myers Squibb, said in a statement that "PCSK9 is an attractive, genetically validated target in the field of cardiovascular disease, and Isis' antisense technology offers us a strong therapeutic platform for potentially bringing new cardiovascular medicines rapidly to market."
A spokesman for Bristol-Myers Squibb said the company had no additional comments on the deal with Isis.
The Financials
For the first quarter, Isis reported a sharp drop in revenues to $2.5 million from $5 million in the same period a year earlier, in part reflecting lower revenues from the company’s collaborators.
Research and development spending climbed to $20 million in the quarter from $18.4 million in the first quarter last year, while selling, general, and administrative expenses edged up $800,000 to $3.4 million.
Isis’ first-quarter net loss from operations climbed to $20.9 million from $16 million in the year-ago quarter. The company’s loss per share fell to $0.16 from $0.24, in part due to the issuance of roughly 8 million shares under an equity financing that raised $75 million.
As of March 31, Isis had cash, cash equivalents, and short-term investments totaling $285.6 million.

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