Development of MDCO-216, an investigational cholesterol efflux promoter, discontinued due to poor efficacy
Immediate discontinuation of the clinical development program for MDCO-216, an investigational cholesterol efflux promoter, was announced.
Data from the 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.
The Medicine Company is focusing onto the development of its PCSK9 synthesis inhibitor, which has 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.
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 has involved 120 patients with acute coronary syndrome ( ACS ).
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 percentage 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.
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% with mean maximum knockdown of up to 82.3 ± 2.0% and maximal LDL-C reduction of 78.1% with mean maximum lowering of up to 59.3 ± 5.0%.
At day 180, a single dose of PCSK9si was associated with an up to 53% reduction in LDL-C, with a least squares mean percent lowering of 47.0% in the 300 mg dose cohort.
In a previous multiple ascending dose study, PCSK9si was associated with maximal PCSK9 knockdown of 94.4% with mean maximum knockdown of up to 88.5 ± 1.6% and maximal LDL-C reduction of 83.0% with mean maximum lowering of up to 64.4 ± 5.4%.
PCSK9si was generally well tolerated following single and multiple subcutaneous dose administration, with no serious adverse events or discontinuations due to adverse events.
Source: The Medicines Company, 2016