Novel Cholesterol Therapy Flops And Company Ends Development

–13 years after ApoA-1 Milano sparked excitement the novel HDL therapy appears to be dead.

After 13 years and despite the efforts of 3 separate companies, the novel cholesterol therapy known as ApoA-1 Milano appears to be dead.

On Monday afternoon the Medicines Company announced that it had discontinued development of the drug and would instead focus its efforts on another cardiovascular drug, a PCSK9 synthesis inhibitor (PCSK9si).

ApoA-1 Milano became the subject of intense interest in 2003 when a study in JAMA by Nissen et al found that the naturally occurring variant of the ApoA-1 HDL apolipoprotein caused a significant regression of atherosclerosis as measured by IVUS. The company that was developing ApoA-1 Milano, Esperion Therapeutics, was subsequently acquired by Pfizer. But Pfizer placed a big bet on its CETP inhibitor, torcetrapib, and appeared to neglect ApoA-1 Milano. After the spectacular failure of torcetrapib Pfizer sharply curtailed its cardiovascular research. In 2009 the Medicines Company acquired the worldwide rights to ApoA-1 Milano from Pfizer. The Medicines Company then developed a compound, MDCO-216, which was designed to induce cholesterol efflux and thereby enhance reverse cholesterol transport.

In its announcement the Medicines Company said that top-line efficacy data from the MILANO-PILOT trial “provide insufficient basis for further investment by the Company.” The full results of the 126 patient trial will be presented by Stephen Nicholls at a Late-Breaking Clinical Trial Session at the American Heart Association meeting in New Orleans next week. The intravascular ultrasound (IVUS) study “did not show drug effects on intracoronary atherosclerotic plaque sufficient to warrant further development,” the company reported. But the compound’s safety profile, according to the company “was excellent.”

“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,” said Clive Meanwell, CEO of The Medicines Company.

The shift in focus toward the company’s PCSK9si compound follows the Medicines Company’s announcement in October of positive findings from its Orion-1 study. Preliminary results from this phase 2 trial of the drug will be presented at the same late-breaking session on November 15 at the American Heart Association meeting. The company said the results demonstrate “significant and durable LDL-C reduction” and support a triannual and perhaps even a biannual dosing regimen.

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