–The PCSK9 synthesis inhibitor from The Medicines Company is getting close to phase 3 trials.
More early information continues to accumulate about a novel cholesterol drug under development by The Medicines Company. The drug, which was initially created by Alnylam Pharmaceuticals, uses RNA interference technology to inhibit the synthesis of PCSK9 in the liver. The main theoretical advantage of inclisiran, as it is now being called, is that it would yield reductions in LDL cholesterol similar to that achieved with PCSK9 inhibitors but with only 2, 3, or 4 injections a year.
In a late-breaking clinical trial session at the American Heart Association meeting in New Orleans, Kausik Ray presented preliminary results from the ongoing ORION-1 phase II trial of inclisiran. The interim analyses were prespecified and predefined. Although the final results were not presented Ray said the trial had already achieved its main goal, which was to select a dose regimen for the phase III study. Ray said that the phase III study will use a 300 mg dose two or three times a year.
ORION 1 randomized 501 patients to six doses of inlisiran. 81% of the patients were taking statins and 37% were taking ezetimibe. The principal endpoint is the reduction in LDL at six months. At the AHA Ray presented the results of the entire study population at 90 days and 6 month followup in about 200 patients. With the 300 mg dose inclisiran treatment resulted in a 50% reduction in LDL with one dose, 55-60% at two doses, with a 4-6 month duration of effect. The drug was well tolerated with a good safety profile, he reported.
Ray concluded that “inclisiran provides sustained and robust reductions in LDL-C on top of standard of care.” Because of its profile “inclisiran has the potential to ensure adherence and thus favorably impact CV outcomes,” he concluded.
The designated discussant for Orion-1, Borge Nordestgaard, said that so far “the balance of effects versus side effects seem to be tipped toward effects.” However, he warned that there were numberous questions that still need to be answered in larger and longer studies. In particular, Nordestart said he wants to know whether the effect on LDL is sustainable and if this will be shown to translate into a cardiovascular and a mortality benefit.
The day before Ray’s presentation the New England Journal of Medicine published the results of a phase 1 trial with inclisiran in which the drug was tested in a small number of patients at different doses. The authors observed that “the magnitude of the lowering of the LDL cholesterol level that we found with inclisiran was generally similar to that observed previously with anti-PCSK9 antibodies or intensive statin therapy.” No serious adverse events were reported. They said that “inclisiran has the potential to provide effective management of hypercholesterolemia with administration every 3 or 6 months, as compared with the recommended regimens of administration once or twice monthly for the currently approved antibodies.”