Despite showing a high reduction in LDL-cholesterol (LDL-c) levels, the much hyped proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) are struggling to get market share. Both Sanofi/Regeneron's Praluent (alirocumab) and Amgen's Repatha (evolocumab) have achieved poor market penetration due to their high price and reimbursement issues. The positive results from FOURIER, the cardiovascular outcomes trial for Repatha presented at ACC.17, could convince payers to pay for these high priced therapies. However, Alnylam Pharmaceuticals in alliance with The Medicine Company have developed inclisiran, a novel drug targeting PCSK9 that could steal considerable market share from the currently available agents.

Unlike Repatha and Praluent, which are monoclonal antibodies, inclisiran interferes with the RNA that creates PCSK9 and thus reduces circulating levels. The data from the ORION-1 trial presented at ACC.17 is really exciting. Inclisiran achieved an LDL-c reduction of up to 81% at 6 months but the really interesting thing about inclisiran is its dosing interval. Compared to dosing every two or four weeks for the available PCSK9is, the dosing of inclisiran could be twice a year, which may allow for a much lower per annum cost. Moreover, treatment compliance could be improved by administration of the drug in clinic or by reducing the treatment burden of patients.

The FOURIER trial adds to the evidence from statins and ezetimibe trials that reduction in LDL-c levels reduces the risk of cardiovascular events. The Medicines Company could use the experience from FOURIER and Pfizer’s SPIRE-1 and -2 trials to design a robust phase III program. However, a longer dosing interval could also be associated with certain drawbacks. Once administered the drug will be active for at least six months, so it needs to be thoroughly tested not only for adverse drug events, but also for possible drug interactions.

Overall, if inclisiran matches Repatha and Praluent for safety and improvement in cardiovascular outcomes, we believe that the greater convenience and compliance benefits offered by this drug, at a lower cost, could see it claim considerable market share from the available PCSK9is.

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