The Medicines Company has posted more late-phase data (PDF) linking its siRNA inclisiran to steep declines in LDL cholesterol. Inclisiran achieved a placebo-adjusted drop in LDL cholesterol of 58%, although it failed to drive the positive changes in cardiovascular outcomes seen in an earlier study.
Medicines Company dialed up hopes for inclisiran earlier this year when it presented data showing giving the drug every six months safely triggers comparable LDL-C reductions to monthly delivery of Amgen’s Repatha and Sanofi and Regeneron’s Praluent. The anti-PCSK9 antibodies have failed to live up to commercial expectations, but inclisiran has more convenient dosing than those drugs.
Now, Medicines Company has presented data from another of its phase 3 trials. The results validate the LDL-C improvements seen in the early study by linking inclisiran to another 50%-plus reduction in the lipoprotein. The safety profile, a potential concern for the siRNA drug, again came in clean.
The only potential negative in the data for inclisiran comes from an exploratory endpoint that looked at adverse cardiovascular events. Numerically, more patients in the inclisiran group had a heart attack or stroke or died of cardiovascular causes. The differences between the arms are small but may raise doubts about the improved cardiovascular outcomes seen in the earlier phase 3 trial.
In the earlier study, ORION-11, the rate of cardiovascular death, heart attack and stroke was 47% lower in the inclisiran arm than the placebo group. Neither phase 3 trial was powered to detect differences in major adverse cardiovascular events (MACE), but the trend seen in ORION-11 raised hopes for an ongoing outcomes trial.
The MACE data from the second phase 3, ORION-10, could have the opposite effect on hopes, but analysts at Jefferies pooled results from the two studies to suggest the overall data generated to date remain positive.
“We caution that the trial was not powered for CV endpoint and also that the events were not adjudicated,” the analysts wrote in a note to investors. “The imbalance [with] higher MACE events in the inclisiran arm in ORION-10 is an unfortunate surprise, but the MACE reduction persists across the combined ORION-10 and -11 studies.”
It will be some time before the situation is cleared up definitively. Medicines Company’s cardiovascular outcomes trial, ORION-4, is due to deliver data in 2023.