Bristol-Myers Squibb Company and Isis Pharmaceuticals Inc. has announced a collaboration to discover, develop and commercialise novel antisense drugs targeting proprotein convertase subtilisin kexin 9 (PCSK9) for the prevention and treatment of cardiovascular disease. PCSK9 helps regulate the amount of cholesterol in the bloodstream.

As part of the collaboration, Isis licensed to Bristol-Myers Squibb exclusive access to its PCSK9 research programme. This programme has recently produced new data shedding light on the mechanism by which PCSK9 contributes to high levels of low density lipoprotein (LDL) cholesterol. With its second- generation antisense PCSK9 compounds, Isis has shown in mice that reducing PCSK9 leads to increased levels of LDL receptor and consequently to lower LDL- cholesterol in the bloodstream. Decreasing LDL-cholesterol is thought to play a key role in reducing the risk of coronary artery disease.

While Bristol-Myers Squibb will fund all activities under the collaboration, both companies will be responsible for preclinical development. Bristol-Myers Squibb will be responsible for clinical development, regulatory, and commercialisation activities. In addition, Bristol-Myers Squibb will work with Isis to leverage Isis' extensive oligonucleotide medicinal chemistry expertise for identification of follow-on PCSK9 antisense drugs with advanced antisense chemistries that may offer even greater potency and oral bioavailability.

Bristol-Myers Squibb will pay Isis a $15 million upfront licensing fee, and will provide Isis with at least $9 million in research funding over a period of three years. Isis will also receive up to $168 million for the achievement of pre-specified development and regulatory milestones for the first drug in the collaboration, as well as additional milestones associated with development of follow-on compounds. Bristol-Myers Squibb will also pay Isis royalties on sales of products resulting from the collaboration.

"There is a clear need for new treatment options for many patients at high risk for cardiovascular disease due to high LDL-cholesterol levels," said Francis Cuss, MD, senior vice president, discovery and exploratory clinical research, Bristol-Myers Squibb. "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."

"This collaboration is an important step in the continued validation of Isis' cardiovascular programme," said Lynne Parshall, JD, executive vice president and chief financial officer, Isis Pharmaceuticals. "We look forward to combining our expertise in antisense technology with the strong scientific and clinical expertise of Bristol-Myers Squibb, with its cardiovascular and metabolic disease focus, to advance the PCSK9 compounds through development to patients as quickly as possible."

PCSK9 is a member of a large family of proteases that degrade specific cellular components, but the particular cellular substrate of PCSK9 is not known. PCSK9 helps regulate the amount of cholesterol in the bloodstream, and human cases of alterations in PCSK9 that have prompted interest in this target. People with too much PCSK9 have severely high LDL-cholesterol, and people with mutations that reduce the levels of PCSK9 have low LDL-cholesterol and reduced risk of coronary artery disease, with normal liver function.