BMS invests in cholesterol-busting compound

Despite the programme still being at the preclinical stage, BMS has pledged up to $192m (€142m) for the research, although only $15m of that will be paid upfront as a licensing fee. BMS also said the three year collaboration will cost at least $9m in research costs. There are many marketed drugs aimed at reducing levels of low density lipoprotein (LDL) or 'bad' cholesterol, which is thought to play a key role in reducing the risk of coronary artery disease. Whereas a great deal of research is focussed on the LDL receptor and its ligand apolipoprotein B, this Isis programme has researched a third target - proprotein convertase subtilisin kexin 9 (PCSK9). "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 Dr Francis Cuss, head of discovery and exploratory clinical research at BMS. "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 protein target is a member of a large family of proteases that degrade specific cellular components. In a Journal of Lipid Research​ article, Isis revealed that preclinical research showed that that an antisense strand reduced PCSK9 levels in mice by 92 per cent, approximately doubled levels of LDL receptor, and consequently led to lower levels of LDL cholesterol in the bloodstream. A study this year showed levels of total cholesterol and LDL were reduced by 53 per cent and 38 per cent respectively. Although the particular cellular substrate of PCSK9 is not known, people with high levels of PCSK9 have severely high LDL-cholesterol, according to Isis. Also, people with mutations that reduce the levels of PCSK9 have low LDL-cholesterol and a reduced risk of coronary artery disease, with normal liver function Isis specialise in developing antisense drugs, DNA-like strands of nucleotides that block protein production. DNA is made up of an antisense and a sense strand. During transcription, the antisense strand is used as a template to make messenger RNA (mRNA). This can leave the cell nucleus and travel to the ribosome where it is used to produce proteins during translation. However, antisense drugs are designed to bind to specific areas of mRNA, degrading it and preventing the corresponding protein from ever being produced. However, according to Isis, there are at least 12 different ways that mRNA is destroyed and these mechanisms are not fully understood. There have been several disappointments with this type of therapy, in the form of failed late stage trials and approval applications being rejected. However, this collaboration concerns second generation antisense drugs, which scientists hope will show better results. BMS will fund the collaboration although both companies will conduct the actual research. BMS also said it will use "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"​. Of the 18 products shown in Isis' pipeline, all but 6 have already been partnered, often to significantly larger companies such as Merck & Co, Eli Lilly and Novartis.