The Medicines Company, a biopharmaceutical company, announced the immediate discontinuation of the clinical development programme for MDCO-216, its investigational cholesterol efflux promoter. Data from the recently-completed MILANO-PILOT trial did not show drug effects on intracoronary atherosclerotic plaque sufficient to warrant further development. The safety profile of MDCO-216 was excellent.

Information now available to the company from the MILANO-PILOT trial of MDCO-216, when evaluated in light of the evolving treatment landscape for atherosclerotic cardiovascular disease, including the emergence of highly-positive data from the ORION-1 trial of the company’s PSCK9 synthesis inhibitor, drove the Company’s decision to discontinue further investment in the clinical development of MDCO-216. The company’s decisive move will free up substantial additional capital, which will be reallocated and focused onto the development of its PCSK9 synthesis inhibitor, which demonstrated significant and durable LDL-C reduction in the ORION-1 trial — reaffirming a triannual, and potentially biannual, dosing regimen with high standards of safety and tolerability and a highly-competitive profile. Results from the ORION-1 trial, including Day 90 follow-up for all 501 patients, as well as top-line data from a preliminary analysis of Day 180 follow-up for up to 200 patients, will be presented in the Late-Breaking Clinical Trial Session at the AHA Scientific Sessions 2016, on November 15, 2016, in New Orleans.

“We deliberately focused our initial development investment in MDCO-216 on clinical proof of concept. Unfortunately, the efficacy data from MILANO-PILOT do not support a prudent decision to make the significant, near-term investment required to move MDCO-216 forward,” stated Clive Meanwell, M.D., Ph. D., Chief Executive Officer of The Medicines Company. “In spite of promising earlier research findings, and impressive progress with manufacturing development and safety, in the light of these efficacy data and in view of the potentially enormous opportunity and highly-favorable risk-reward profile presented by our PSCK9 synthesis inhibitor, we have been decisive in immediately terminating the MDCO-216 development program. This decision will allow us to reallocate substantial additional capital to the further development of our PCSK9 synthesis inhibitor. We are extremely grateful for the leadership of our lead investigators, Dr. Stephen J. Nicholls, MBBS, Ph.D., FRACP South Australian Health and Medical Research Institute, Adelaide, Australia, and Dr. Steven E. Nissen, M.D., Chairman of Cardiovascular Medicine, Cleveland Clinic, who continue to blaze a trail in the field with sophisticated and groundbreaking coronary ultrasound imaging studies. We have ensured that Drs. Nicholls and Nissen have full access to all data from MILANO-PILOT for analysis, presentation and publication. We also thank the patients and collaborators who participated in the MILANO-PILOT trial.”

The company is supporting the close-out of the MILANO-PILOT trial and results will be presented by Dr. Nicholls, its principal investigator, in the Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2016, on November 15, 2016, in New Orleans.

The company is working to ensure that all MILANO-PILOT trial investigators, regulatory authorities and collaboration partners are informed of the decision to discontinue further development of MDCO-216.

The company does not expect to incur any charge associated with the discontinuation of the MDCO-216 development programme.

MILANO-PILOT was a proof-of-concept, double-blind, placebo-controlled, randomized study utilizing IVUS (Intravascular Ultrasound) to measure the effect of MDCO-216 on atherosclerotic plaque burden and to evaluate MDCO-216's impact on cholesterol efflux. The study involves 120 patients with ACS and will likewise assess the safety of weekly 20mg/kg MDCO-216 infusions over a five-week period.

MDCO-216, an investigational product not approved for commercial use in any market, is a complex of dimeric recombinant apolipoprotein A-1 Milano (ApoA-1 Milano) and a phospholipid (POPC) which was under development to improve cardiovascular outcomes by reducing plaque burden in patients with atherosclerotic disease. MDCO-216 mimics pre-beta HDL and induces cholesterol efflux, which is the first step in the reverse cholesterol transport, a process of removal of deposited cholesterol from vessel walls and therefore has a potential to reduce plaque burden in patients with coronary artery disease. ApoA-1 Milano is a protein discovered in residents of a Northern Italian village who remarkably have little atherosclerotic build-up despite exceptionally low levels of cardioprotective HDL in combination with elevated levels of harmful triglycerides.

ORION-1 is a placebo-controlled, double-blind, randomized Phase II trial of single or multiple subcutaneous injections of PCSK9si in a total of 501 patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (e.g., diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated doses of LDL-C lowering therapies. The trial compares the effect of different doses of PCSK9si and evaluates the potential for an infrequent dosing regimen. The primary endpoint of the study is the per centage change in LDL-C from baseline at Day 180.

PCSK9si (also known as ALN-PCSsc) is an investigational GalNAc-conjugated RNAi therapeutic targeting PCSK9 – a genetically validated protein regulator of LDL receptor metabolism – being developed for the treatment of hypercholesterolemia. In contrast to anti-PCSK9 monoclonal antibodies (MAbs) that bind to PCSK9 in blood, PCSK9si is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver.

In a previous, single-ascending dose study, PCSK9si was associated with maximal PCSK9 knockdown of 88.7 per cent with mean maximum knockdown of up to 82.3 ± 2.0 per cent and maximal LDL-C reduction of 78.1 per cent with mean maximum lowering of up to 59.3 ± 5.0 per cent. At Day 180, a single dose of PCSK9si was associated with an up to 53 per cent reduction in LDL-C, with a least squares mean per cent lowering of 47.0 per cent in the 300 mg dose cohort.

In a previous multiple ascending dose study, PCSK9si was associated with maximal PCSK9 knockdown of 94.4 per cent with mean maximum knockdown of up to 88.5 ± 1.6 per cent and maximal LDL-C reduction of 83.0 per cent with mean maximum lowering of up to 64.4 ± 5.4 per cent.

PCSK9si was generally well tolerated following single and multiple subcutaneous dose administration, with no serious adverse events or discontinuations due to adverse events.

The Medicines Company and Alnylam Pharmaceuticals are collaborating in the advancement of PCSK9si per the companies' agreement formed in early 2013. Under the terms of the agreement, Alnylam completed certain pre-clinical studies and the Phase 1 clinical study, with The Medicines Company leading and funding the development of PCSK9si from Phase 2 forward, as well as potential commercialization.