DUBLIN – Amgen Inc. is doubling down on its presence in the dyslipidemia market by acquiring Dezima Pharma BV for $300 million up front plus up to $1.25 billion more in development and commercial milestones, as well as sales royalties.

The acquisition adds to its portfolio Dezima's potent, once-per-day cholesterol ester transfer protein (CETP) inhibitor TA-8995, which hit the primary endpoint in a phase IIb trial last year, results of which appeared in the June 3, 2015, issue of The Lancet. (See BioWorld Today, June 5, 2015.)

It's less than three weeks since Thousand Oaks, Calif.-based Amgen gained FDA approval for Repatha (evolocumab), its antibody-based PCSK9 inhibitor, which has demonstrated dramatic effects on reducing low-density lipoprotein cholesterol (LDL-C) – typically by 60 percent on top of the effects mediated by other therapies. CETP inhibitors, an emerging – or re-emerging – class of oral cholesterol-lowering drugs are not as powerful but will cost much less and will reach a larger patient population, notably those who are resistant or refractory to statins.

"I think it's a very strategic and wise decision from Amgen, to have both a Ferrari and a Volkswagen, because you can cover the entire highway, so to speak," John Kastelein, founder and chief scientific officer of Naarden, the Netherlands-based Dezima, told BioWorld Today.

The high cost of PCSK9 inhibitors will likely limit their initial use to high-risk patients, including those with homozygous or heterozygous familial hypercholesterolemia or with clinical atherosclerotic cardiovascular disease. Even before its approval – and that of rival drug Praluent (alirocumab), developed by Sanofi SA and Regeneron Pharmaceuticals Inc. – payers were queuing up to criticize the cost. "They are safe and they are very powerful," Kastelein said. "I think the price – I'm talking from this side of the Atlantic – will be prohibitive for a lot of countries."

CETP inhibitors block the transfer of cholesteryl esters – the species responsible for transporting cholesterol in the circulation – from high-density lipoprotein (HDL) to LDL and other lipoprotein particles. TA-8995, combined with a statin, resulted in LDL-C reductions of up to 68 percent in the phase IIb trial. Even without accompanying statin therapy, it cut LDL-C by 45 percent. It also resulted in a maximum increase in HDL-C of 179 percent. Kastelein, a highly influential cardiovascular scientist, who also leads the Department of Vascular Medicine at the Academic Medical Center of the University of Amsterdam, got sight of the drug during discussions with Mitsubishi Tanabe Pharma Corp., of Osaka, Japan. "They were not very enthusiastic about further development – and I was really enthusiastic about further development," he said.

The CETP inhibitor class had been tainted by previous failures at Pfizer Inc. and at Roche AG, but Kastelein said he has been "completely hooked" by the mechanism since 1997. "I've always strongly believed in this mechanism and the concept, while most people have left it," he said. "I was still convinced we had the wrong drugs to test the hypothesis."

TA-8995 looked like a better bet than other efforts. "The oral availability is very high, which means the drug ends up not in the toilet but in the circulation, which is where you want it to be," he said. What's more, it is also very potent. Dezima was planning to take a 5-mg dose into phase III trials, whereas two rival molecules, evacetrapib and anacetrapib, in development at Eli Lilly and Co. and at Merck & Co. Inc., respectively, were dosed at 130 mg and 100 mg. Anacetrapib, which is highly lipophilic, has the added complication of being retained in the body for up to two years, whereas TA-8995 is washed out several weeks after patients stop taking the drug.

In the phase IIb trial, TA-8995 had a placebo-like safety profile. "There was really nothing there, which is rare these days," Kastelein said.

Evacetrapib and anacetrapib are both undergoing cardiovascular outcomes trials, to see if their LDL-C-lowering effects translate into clinically meaningful reductions in cardiovascular events and improvements in survival. Dezima has been planning to move TA-8995 into a similar study, either alone or with a strategic partner. Raising the necessary cash through an IPO was "definitely doable," Dezima CEO Rob de Ree told BioWorld Today. "We made a choice for the latter."

For its lead investor, Forbion Capital Partners, the deal represents a savvy piece of business, although it has not disclosed the actual numbers. "In a qualitative way, this is our biggest exit in absolute terms in our company's history," managing partner Sander Slootweg told BioWorld Today.

That statement holds with or without the milestones, given the large stake Naarden-based Forbion holds in Dezima. Mitsubishi Tanabe will share in the upside, although, again, the parties involved are not disclosing any numbers.

Amgen faced "serious competition" for the deal, Slootweg said. But given its large development organization and its recent experience with Repatha, the deal "is a match made in heaven."

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