MAASTRICHT, Netherlands--(BUSINESS WIRE)--
- Inclisiran administration led to consistent LDL-C reductions, with no dose adjustment required regardless of renal function, in a combined analysis of ORION-1 and ORION-7 studies
- Late-breaking abstract presentation of ORION-2 study showed that inclisiran significantly lowered LDL-C without need to increase dose in homozygous familial hypercholesterolemia
- Pivotal Phase 3 data readouts for inclisiran expected in 3Q-2019 followed by regulatory filings expected in the U.S. in 4Q-2019 and Europe in 1Q-2020
The Medicines Company (MDCO) today announced presentation of analyses of two clinical studies of inclisiran at the 87th European Atherosclerosis Society (EAS) Congress in Maastricht, Netherlands. A combined analysis (N=279) from the Phase 2 ORION-1 and Phase 1 ORION-7 trials, presented during an e-poster session, demonstrated that patients across a range of renal function levels achieved consistent reductions in low-density lipoprotein cholesterol (LDL-C) with no dose adjustment necessary for patients with renal impairment. Results from the Phase 2 ORION-2 pilot study, presented as a late-breaking abstract, showed that inclisiran provided durable reductions in LDL-C levels up to day 180 in patients with homozygous familial hypercholesterolemia (HoFH), a genetic disorder characterized by very high levels of LDL-C and early onset of cardiovascular disease, without the need to increase the dose of inclisiran.
“The information discussed at EAS supports inclisiran’s potential to address the high burden of cardiovascular disease caused by cumulative exposure to elevated LDL-C,” said Peter Wijngaard, Ph.D., Chief Development Officer of The Medicines Company. “We are pleased with these findings that demonstrate inclisiran’s potent, durable and consistent lowering of LDL-C, as well as favorable tolerability and safety, in patients with renal insufficiency or HoFH.”
Inclisiran, the first cholesterol-lowering therapy in the siRNA class, is The Medicines Company’s investigational therapy in Phase 3 clinical development to evaluate its ability to lower LDL-C through twice-a-year dosing. The company expects pivotal Phase 3 data readouts for inclisiran in the third quarter of 2019 followed by anticipated regulatory filings in the U.S. in the fourth quarter of 2019 and in Europe in the first quarter of 2020.
“There remains significant unmet need in the treatment of ASCVD, as approximately four out of five statin-treated patients are not at LDL-C goals, with poor adherence to therapy a major underlying cause,” said Mark Timney, Chief Executive Officer of The Medicines Company. “We are excited at the prospect of bringing forward a revolutionary approach to treat cardiovascular disease using a twice-a-year therapy with unique potential to address the need for additional LDL-C lowering and long-standing medication adherence challenges faced by millions of people.”
ORION-1 and ORION-7
The aim of the combined analysis of data from ORION-1 and ORION-7 was to determine whether dose adjustment of inclisiran was necessary for patients with impaired renal function. Therefore, the objectives were to evaluate the pharmacokinetics and pharmacodynamics in patients across a range of renal function levels and to assess the relationship between estimated glomerular filtration rate (eGFR, a measure of renal function) and adverse events.
The analysis demonstrated that patients who received inclisiran sodium 300 mg achieved consistent reductions in LDL-C and proprotein convertase subtilisin-kexin type 9 (PCSK9) regardless of renal status at study entry. Among all patients in the analysis, treatment-emergent adverse event rates were not influenced by renal impairment and were not different from placebo. There was no relationship between inclisiran administration and eGFR levels, including no exacerbation of renal impairment. No dose adjustment of inclisiran was required for patients with renal impairment (mild, moderate or severe).
ORION-1 (N=501) is a Phase 2, placebo-controlled, double-blind, randomized trial to evaluate the efficacy, safety, and tolerability of inclisiran in participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies. The trial compares the effect of different doses of inclisiran and evaluates the potential for an infrequent dosing regimen. The primary endpoint of the trial is the percentage change in LDL-C from baseline to day 180. A sub-group analysis was performed to evaluate long-term pharmacodynamics and safety of a single-dose (N=60) or two doses (N=59) of inclisiran sodium 300 mg in subjects with normal renal function or with mild or moderate renal impairment.
ORION-7 (N=31) is a Phase 1, single-dose, open-label trial to evaluate the effects of a single dose of inclisiran sodium 300 mg in participants with mild, moderate and severe renal impairment compared to participants with normal renal function. The primary endpoint is to determine the pharmacokinetic and pharmacodynamic parameters, as well as safety, of inclisiran in subjects with normal and impaired renal function at 48 hours post-dose. Secondary endpoints include changes from baseline in lipids and lipoproteins, as well as PCSK9, to day 60.
Data from the combined analysis of ORION-1 and ORION-7 were presented on May 27 during an e-poster session at the 87th EAS Congress (abstract #EAS19-0576, Efficacy, Safety and Pharmacokinetics of Inclisiran by Renal Function, Kallend et al).
ORION-2 results presented at EAS showed that HoFH patients (N=4) who received inclisiran sodium 300 mg met the primary efficacy endpoint of durable LDL-C lowering up to day 180 and all patients achieved reductions in PCSK9 and apolipoprotein B. The effects were similar to those of anti-PCSK9 monoclonal antibody medicines in this patient population, but without the need to increase the treatment dose. Secondary endpoints of reductions in PCSK9 and apolipoprotein B from baseline to day 90 and day 180 were also achieved. Inclisiran was reported to be well-tolerated, with no drug-related adverse events. A larger Phase 3 study of inclisiran in HoFH (ORION-5) is ongoing.
ORION-2 (N=4) is a Phase 2 pilot study to assess the safety, tolerability and efficacy a single dose of inclisiran sodium 300 mg in participants with genetically confirmed HoFH. The primary endpoint is percentage change in LDL-C from baseline to day 90 and day 180.
Data from ORION-2 were presented on May 27 during a late-breaking abstract session at the 87th EAS Congress (abstract #EAS19-1122, Inclisiran Durability Lowers LDL-C and PCSK9 Expression in Subjects with Homozygous Familial Hypercholesterolaemia: The ORION-2 Pilot Study, Raal et al).
Inclisiran, the first cholesterol-lowering therapy in the siRNA class, is The Medicines Company’s investigational therapy in Phase 3 clinical development to evaluate its ability to lower low-density lipoprotein cholesterol (also known as LDL-C or bad cholesterol) through twice-a-year dosing. As a siRNA, inclisiran directly targets messenger RNA and harnesses one of the body’s powerful natural mechanisms, RNA interference, to prevent production of the PCSK9 protein at its source in the liver and facilitate removal of LDL-C from the bloodstream. In Phase 2 studies, inclisiran provided clinically significant LDL-C reductions greater than 50 percent in addition to the effects of statins and/or ezetimibe, and LDL-C reductions were sustained throughout the six-month dosing interval. Inclisiran is not yet approved for use by the FDA or any other regulatory authority. The Medicines Company obtained global rights to develop, manufacture and commercialize inclisiran under a license and collaboration agreement with Alnylam Pharmaceuticals.
In the U.S. alone, approximately 15.1 million people are currently treated with lipid-lowering therapies to manage cardiovascular risk. Approximately 80 percent of high-risk ASCVD patients are not achieving LDL-C treatment goals with current therapies, and up to two-thirds of patients do not adhere to available first-line cholesterol-lowering treatments after one year. This implies a population of at least 12.7 million Americans who could potentially benefit from the investigational candidate inclisiran, the first cholesterol-lowering siRNA with the potential to deliver potent, durable and consistent lowering of LDL-C levels via twice-a-year dosing that can help address two critical unmet needs – additional LDL-C lowering and poor adherence to therapy.
About The Medicines Company
The Medicines Company is a biopharmaceutical company with a singular, relentless focus on addressing the greatest global healthcare challenge and burden today – cardiovascular disease. Our purpose is to halt the deadly progression of atherosclerosis and the cardiovascular risk created by high levels of LDL-C, or bad cholesterol. The Company is headquartered in Parsippany, New Jersey. For more information, please visit www.themedicinescompany.com and follow us on Twitter @MDCONews and LinkedIn.
Statements contained in this news release about The Medicines Company that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words “believes," “anticipates,” “plans,” “expects,” “should,” and “potential,” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include the ability of the Company to effectively develop inclisiran; whether inclisiran will advance in the clinical trials process on a timely basis or at all, or succeed in achieving its specified endpoints; whether the Company will make regulatory submissions for inclisiran on a timely basis; whether its regulatory submissions will receive approvals from regulatory agencies on a timely basis or at all; and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission (SEC), including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the SEC on April 26, 2019, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.