The Medicines Company on Monday presented detailed results from the Phase III ORION-11 study at the European Society of Cardiology (ESC) conference, showing that inclisiran nearly halved LDL-cholesterol in patients with high LDL levels despite treatment with statins. Last week, the company reported that the siRNA therapeutic targeting PCSK9, which is administered through twice-yearly dosing, had met the trial's primary endpoint.
Principal investigator Kausik Ray said the ORION-11 data "support the unprecedented potential of inclisiran to…[lower LDL-cholesterol] in a sustained fashion over the long-term with an infrequent dosing regimen and an excellent safety profile." Ray added that "this is a groundbreaking new approach for preventing atherosclerotic cardiovascular disease (ASCVD) with exciting implications at a population health level."
The randomised, placebo-controlled study involved 1617 patients with ASCVD or ASCVD-risk equivalents and elevated LDL-cholesterol despite maximum tolerated doses of statin therapy, with or without ezetimibe. Participants received inclisiran administered as a subcutaneous injection initially, again at three months and then every six months thereafter. The average baseline LDL-cholesterol level at the start of the trial was 106 mg/dL across the study population, with 96% of patients taking underlying statins, and 90% of these being on high-intensity statin therapy.
The study's primary objectives are changes in LDL-cholesterol from baseline to 17 months and the time-adjusted percentage change in LDL-cholesterol from baseline after three months and up to 18 months. Secondary goals include the mean absolute change at 17 months, the average absolute reduction from three months up to 18 months, and changes in levels of other lipids and lipoproteins.
Results demonstrated that among inclisiran-treated patients, LDL cholesterol levels dropped 49% to 58 mg/dl, which was a 54% improvement versus placebo over the course of the study. Further, average LDL-cholesterol levels in the inclisiran group were also a time-averaged 50% lower than placebo from three months to 18 months after the first injection.
The Medicines Company said overall adverse event profiles between the two groups were "similar." In the inclisiran and placebo arms, 22.3% and 22.5% of patients, respectively, experienced at least one serious treatment emergent adverse event. Further, the incidence of deaths and malignancies was also similar between the two groups, as were elevations in certain liver function tests and serum creatinine increases. The company noted that there was a difference between inclisiran and placebo in terms of the incidence of fatal and non-fatal myocardial infarctions, which occurred at rates of 1.2% and 2.7%, respectively, as well as fatal and non-fatal strokes, where the respective rates were 0.2% and 1.0%.
CEO Mark Timney said the "exceptional" ORION-11 data demonstrate that inclisiran, which is being co-developed with Alnylam Pharmaceuticals, "can address adherence challenges in a way that no other currently used LDL-cholesterol lowering medicine can." The release of topline Phase III data readouts for the ORION-9 and ORION-10 studies is expected to continue later in the third quarter in advance of anticipated regulatory submissions in the US in the fourth quarter of 2019 and in Europe in the first quarter of next year. Meanwhile, final results from the company's 15,000-patient outcomes study, ORION-4, are expected in 2024.
Timney said talks with payers have already begun, and The Medicines Company is considering "value-based agreements" that could tie inclisiran's price to its performance. Insurers have balked at the prices of Sanofi and Regeneron Pharmaceuticals' Praluent (alirocumab) and Amgen's Repatha (evolocumab), the two PCSK9 inhibitors currently approved in the US, with the drugmakers slashing the prices on both products by nearly 60% in the past year. "We've learned a lot" from watching the PCSK9 story play out, "and we've got a fundamentally different approach," Timney remarked.
According to the CEO, the "cost of goods" for inclisiran differs from Repatha and Praluent. Timney claims inclisiran will be a high-volume, lower-cost drug to produce, which could allow his company to "reduce the price relatively quickly" as more patients gain access. Further, he noted that patients at risk of a heart attack or stroke may already be seeing a doctor every six months, which could make insurers more willing to ante up for a treatment that is timed for those regular visits.
For related analysis, see ViewPoints: The Medicines Company gets an eventful quarter off to a strong start. See also, ViewPoints: Inclisiran passes final pre-test test.
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