• The Medicines Company on Saturday released data from a long-term safety study of its experimental cholesterol-lowering drug inclisiran in heart disease patients, showing the therapy maintained its benefit three years post treatment while leading to fewer side effects than its would-be rivals Repatha and Praluent. 
• Inclisiran is in three pivotal Phase 3 studies that are expected to read out later this year, results of which will determine whether it can achieve Food and Drug Administration approval. The data will also be crucial in influencing how much insurers would be willing to pay for a drug that requires two injections a year to reduce cholesterol levels.
• The Medicines Company’s future hinges on the outcome of inclisiran, as it sold off its marketed products in order to fund the inclisiran development program, with the last, Angiomax, being sold to Novartis’ Sandoz unit in 2018.

If the forthcoming Phase 3 data match what was seen in inclisiran’s earlier phases of development, the drug could be a useful new addition for management of low-density lipoprotein (LDL), or “bad cholesterol,” in heart disease patients.

With just twice-yearly injections in patients already taking statins, inclisiran is able to lower LDL levels by about 50%, on a par with Repatha (evolucumab) and Praluent (alirocumab), which require injections as frequently as once every two weeks.

All these agents act on the same target, proprotein convertase subtilisin kexin type 9 (PCSK9), which impedes LDL metabolism in the liver. Amgen’s Repatha and Sanofi and Regeneron’s Praluent do so by binding directly to the enzyme, while inclisiran does so by regulating PCSK9 production through RNA.

The data released Saturday at the National Lipid Association meeting came from a long-term safety extension of inclisran’s Phase 2 Orion-1 study. The key finding was that no medication-related elevations of liver enzymes were detected in a small trial population of 490 — one patient experienced this, but it was the result of another medication, trial investigators said. Liver enzyme abnormalities were detected in 2.5% of Praluent patients. 

Trial investigators also made an estimate of how many cardiovascular deaths and complications could be averted through use of inclisiran based on the LDL reductions. They predicted in the Phase 3 Orion-9, -10 and -11 trials, the risk of cardiovascular events would be reduced by 44%, 30% and 31%, respectively, relative to placebo. 

Similar predictions were made for Praluent and Repatha. The drugs fell well short, however, meaning trial investigators have set a very high bar for inclisiran. Because of their comparatively modest outcomes, Repatha and Praluent suffered through a series of price cuts and now cost about $6,000 a year at list, down from near $15,000 at launch.

Based on inclisiran’s LDL-lowering profile, the Medicines Company will have its work cut out for it in justifying a price much above $6,000 a year, less frequent dosing schedule notwithstanding. A finding that inclisiran can prevent heart attacks and strokes by 30% or more probably would give it more pricing flexibility, but those data will not be seen for two or three more years yet.