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ACC: Novel Drug Delivers Long-Term Cholesterol Reduction

— RNA interference drug inhibits synthesis of PCSK9

MedpageToday

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WASHINGTON -- 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 here and .

In it, 501 patients were randomized to one or two 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. were presented last November at the American Heart Association meeting.

LDL cholesterol at 180 days -- the primary endpoint of the trial -- was reduced by 27.9% to 41.9% across the dose groups after one dose and by 35.5% to 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.

Serious adverse events occurred in 11% of patients in the inclisiran group and 8% in the placebo group; 5% of patients in the inclisiran group had injection-site reactions.

The Medicines Company 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 , 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.