A novel drug that dramatically lowers LDL cholesterol and needs to be administered only a few times a year has reached a new milestone. Positive results from a phase II study with the drug, now known as inclisiran, were reported at the American College of Cardiology meeting in Washington, DC and published simultaneously in the New England Journal of Medicine.
501 patients were randomized to 1 or 2 shots (at days 1 and 90) of placebo or inclisiran in a multicenter, dose-ranging trial. The drug, under development by The Medicines Company, uses RNA interference technology to inhibit the synthesis of PCSK9 in the liver and yields reductions in cholesterol similar to that achieved with PCSK9 inhibitors, but it requires only a few injections a year. Preliminary results from the trial were presented last November at the American Heart Association.
LDL cholesterol at 180 days— the primary endpoint of the trial— was reduced by 27.9-41.9% after one dose and by 35.5-52.6% after two doses of inclisiran. In the group that received two doses of 300 mg, nearly half of the patients (48%) had LDL levels below 50 mg/dl at 180 days. LDL levels were still significantly lower at 240 days.
11% of patients in the inclisiran group and 8% in the placebo group had serious adverse events; 5% of patients in the inclisiran group had injection-site reactions.
The Medicines Company announced that it was “actively preparing to advance” the drug into a “comprehensive, global Phase III development” program in the United States and Europe.
“Inclisiran’s universal and practically constant effect is unprecedented in my experience of over 30 years of dyslipidemia clinical trials,” said trial investigator John Kastelein (University of Amsterdam), in a company press release. “The unique dosing regimen virtually eliminates variability in LDL-C levels over time and inclisiran may, therefore, solve one of the most vexing challenges of cardiovascular medicine – namely, how to make sure everyone responds to treatment.”
The findings, the trial investigators wrote, “suggest that inhibiting the translation of PCSK9 mRNA in the liver represents an alternative to targeting circulating PCSK9 and would almost certainly involve a lower injection burden.”
Despite the success of the trial Medicines Company stock closed down 8% on Friday. This almost certainly was a reflection of the negative response to FOURIER, which was presented earlier in the day. The FOURIER trial demonstrated for the first time that a PCSK9 inhibitor could reduce cardiovascular events in a large population, but the effect was not as powerful as many had anticipated. The cholesterol marketplace may have reached the point of diminishing returns.
“There was no significant difference in cardiovascular death or all-cause mortality.” OK. That’s what Table 2 shows. The drug appears to be slightly deadlier than the placebo but the difference isn’t statistically significant.
“The authors calculated that 74 patients would need to be treated for 2 years to prevent a CV death, MI, or stroke.”
That looks to be a dishonest calculation since the drug does not prevent CV deaths, as we have just seen. Once one suspects the authors of being dishonest one begins to wonder what else in the paper might be dishonest. Why do researchers insist on behaving so badly?