MILANO-PILOT Falters, Effectively Ending the ApoA-1 Milano Saga

It was once hyped as liquid Drano for the coronary arteries, but based on disappointing data from the MILANO-PILOT study, the apolipoprotein A-1 (apoA-1) Milano saga appears to have to a come to an end.

In the study, which included patients with acute coronary syndrome who received weekly injections of a recombinant apoA-1 Milano/phospholipid complex over a 5-week period, there does not appear to have been a meaningful effect on coronary atherosclerosis as assessed by IVUS when compared with patients who received placebo injections.

Based on the results, which have not yet been disclosed, the Medicines Company announced they will discontinue development of MDCO-216, as the drug is known. Instead, the company is turning their attention to the development of their PCSK9 synthesis inhibitor (PCSK9si), an investigational RNA-interference therapy that lowers LDL cholesterol levels.

ApoA-1 Milano is a variant of the apoA-1 protein found in HDL and was first discovered in residents of a Northern Italian village. Carriers of the naturally occurring variant had low levels of coronary atherosclerosis, much less than would be expected considering they also had very low HDL cholesterol levels and high triglycerides. In 2003, Steven Nissen, MD (Cleveland Clinic, OH), presented and published data showing that treatment with apoA-1 Milano yielded significant regression of IVUS-assessed coronary atherosclerosis.

Since 2003, however, results have not panned out. The Medicines Company acquired the rights to apoA-1 Milano from Pfizer in 2009 and developed MDCO-216, which is designed to enhance reverse cholesterol transport. The apoA-1 Milano compound was initially developed by Esperion Therapeutics, a company purchased by Pfizer for $1.3 billion in 2004.

In a statement, the Medicines Company said they will now focus on ALN-PCSsc, an investigational drug targeting PCSK9, a regulator of LDL receptor metabolism. ALN-PCSsc differs from the currently approved PCSK9 inhibitors alirocumab (Praluent, Sanofi-Aventis/Regeneron Pharmaceuticals) and evolocumab (Repatha, Amgen) in that it is given every 3 or 6 months (rather than once every 2 weeks as with alirocumab and once every 2 to 4 weeks as with evolocumab).

In October, the Medicines Company announced topline 90-day results of an interim analysis of ORION-1, a randomized, placebo-controlled phase II study testing the safety and efficacy of ALN-PCSsc in 501 patients. The analysis showed “significant and durable” reductions in LDL cholesterol, with no adverse safety signals. At the American Heart Association Scientific Sessions 2016, set to begin this Saturday in New Orleans, LA, the 180-day follow-up of approximately 200 patients will be presented during a late-breaking clinical trials session on November 15 starting at 10:45 AM.

In the same session, the full results of MILANO-PILOT will be presented, as will the complete results from the GLAGOV trial. Amgen previously announced the topline results of GLAGOV, a study evaluating atherosclerosis in 968 patients with coronary artery disease treated with once-monthly evolocumab or placebo, in September, as reported by TCTMD.