Making sense of antisense

CARLSBAD, Calif.—In what is perhaps a harbinger of things to come in a potential new class of drugs targeting RNA's role in certain diseases, Isis Pharmaceuticals recently announced a cardiovascular disease collaboration with Bristol-Myers Squibb to discover, develop and commercialize novel antisense drugs targeting proprotein convertase subtilisin kexin 9 (PCSK9).

As part of the collaboration, Isis has licensed to BMS exclusive access to its PCSK9 program. PCSK9 is known to help regulate the amount of cholesterol in the bloodstream and Isis has recently produced data in this area that shows the mechanism by which it contributes to high levels of low-density lipoprotein (LDL) cholesterol.

As part of the deal, Bristol-Myers Squibb will pay Isis a $15 million license fee and will additionally provide $9 million of funding over a three-year period for continued PCSK9 research. If Isis can hit all of its milestones for the first drug in this collaboration it stands to earn an additional $168 million, with additional payments due for follow-on compounds.

According to Kate Corcoran, vice president of corporate development at Isis, interest in its PCSK9 program was fueled by its ongoing research and in particular interest from potential licensees of its most advance candidate, ISIS 301012, which also targets cardiovascular disease and is currently in Phase II clinical trials.

"As companies were starting to get interested in [ISIS 301012] they were starting to realize that the platform and the technology offer tremendous promise for the treatment of chronic diseases including cardiovascular disease," says Corcoran. "Therefore, they started to look at other targets that they might be able to get in on and replenish their pipeline."

As a result, there was more than one company interested in collaborating with Isis to advance the research it was conducting in PCSK9, a target that has recently been validated via the study of genetic mutations in humans.

"It is our understanding that there are lots of companies that have had small-molecule PCSK9 targeting discovery efforts in place," Corcoran notes. "The issue is that PCSK9 is an enzyme, it's a protease that breaks down other proteins, but other than that enzyme activity, the particular substrate of the enzyme is not known, which, obviously, makes it very hard to design small molecules.

"On the other hand, all we need to know is the gene sequence, because antisense is based on targeting the RNA, which makes the protein. And if you use the gene sequence to target the RNA you don't ever have to worry about inhibiting a mature protein."

For BMS, the opportunity to get in on what is very early research is an effort to maintain a grasp on the cholesterol treatment market, to go along with its current cholesterol drug, the statin Prevachol.

"The interest here is that, going back in time, we have been interested in the work done by Dr. Helen Hobbs and colleagues that showed mutations which decreased levels of PCSK9 resulted in a decrease of LDL levels," says Eric Miller, a BMS spokesman. "Statins work differently from antisense and so this is potentially the next evolution of cholesterol treatment."

While Corcoran says Isis is quite pleased with the level of funding it received for research that to date has very little data, the deal provides a couple of other benefits. Most importantly, it allows Isis to accelerate the research it is doing on PCSK9. "But it also allows us to continue to focus on ISIS 301012 and the licensing process there," she notes.

While neither company released specifics of how the BMS funded research will be split between the two companies, Corcoran points out that it is logical to assume that Isis will do the medicinal chemistry, lead optimization and some of the animal-related preclinical work that is specific to antisense while BMS will do other lipid-based model systems.