Regeneron cholesterol drug faces sudden challenge

Mon Mar 26, 2012 11:30am EDT

* Regeneron drug cuts LDL up to 75 pct at 2-week dosing

* Researcher says potency waned with 4-week dosing

* Success of Amgen drug at 4-week dosing poses challenge

By Ransdell Pierson

CHICAGO, March 26 (Reuters) - A new type of drug being developed by Regeneron Pharmaceuticals Inc slashed levels of cholesterol almost in half when given every four weeks, but fell short of reductions reported a day earlier with once-monthly injections of Amgen Inc's rival product.

Both monoclonal antibodies work by blocking a protein called PCSK9, and are shaping up to be the next big thing in preventing heart attack and stroke. Wall Street expects the new class of drugs, including those in earlier stages of development at Merck & Co and Bristol-Myers Squibb Co, to generate annual future sales of up to $20 billion.

Regeneron is developing its entry, called REGN 727, in partnership with French drugmaker Sanofi. The product, which has completed mid-stage trials and is heading toward far larger Phase III studies, has been considered to be the clear front runner.

Amgen's drug, AMG 145, is just entering mid-stage studies and is considered about a year behind REGN 727 in development. Although it is far less-known than the Regeneron antibody, stellar results from a Phase I trial of the Amgen product raised its profile considerably when reported on Sunday at the annual sessions of the American College of Cardiology in Chicago.

In the 51-patient study, patients receiving monthly injections of AMG 145 and taking low to moderate doses of statins had up to a 66 percent reduction in "bad" LDL cholesterol by the eighth week of the study.

"We gave two doses, four weeks apart, and at the eighth week there was minimal tapering off" of the drug's potency, Clapton Dias, Amgen's medical services director, told Reuters.

By contrast, data presented Monday at the Chicago heart meeting showed that the effect of REGN 727 in a mid-stage trial, when given at high doses every four weeks, tapered off unacceptably.

"The cholesterol lowering was consistent at two weeks, but at four weeks you could see effectiveness of the drug begin to wane," its lead researcher, James McKenney, said in an interview.

"LDL began to come back up," said McKenney, who is chief executive officer of Richmond, Virginia-based testing company National Clinical Research. He speculated that future late-stage trials of REGN 727 will therefore likely be built around two-week dosing.

Given every two weeks, the Regeneron drug cut LDL levels up to 72 percent, McKenney said. That is roughly in line with maximum reductions of 75 percent seen with AMG 145. No serious side effects have been reported for either medicine.

CONVENTIONAL WISDOM

The conventional wisdom in the pharmaceutical industry is that drugs given infrequently -- once a day instead of twice daily, or monthly as opposed to biweekly -- have a decided commercial advantage because of their greater convenience to patients. It applies especially to injectable drugs.

Steven Nissen, head cardiologist at the Cleveland Clinic, on Sunday said those assumptions are breaking down as more injectable biotech medicines come to market.

He said he did not believe less-frequent dosing would render a big advantage to either of the two companies.

A four-week dosing schedule may be "modestly more attractive" to patients and doctors than injections every two weeks, Nissen said in an interview at the heart conference.

"But the frequency is not a make-or-break consideration," he added, because patients would be able to inject themselves with the same types of tiny needles that are already widely used and accepted for other conditions, including diabetes.

Although it did not pan out for monthly dosing, McKenney said REGN 727 had "remarkable" and persistent potency when patients received injections every two weeks along with one of three available daily doses of Pfizer Inc's statin Lipitor.

Those receiving 50 milligram doses of Lipitor achieved an additional 40 percent reduction in LDL cholesterol, beyond that seen with patients taking Lipitor alone. He said 64 percent and 72 percent reductions in LDL were seen among patients who received, respectively, 100 milligram or 150 milligram daily doses of Lipitor.

"Forty percent, 64 percent, 72 percent reductions. I'm saying, 'Wow!' -- I've never seen anything like this," McKenney said, recalling his excitement when data from the Regeneron-sponsored trial became unblinded. "In three decades of doing clinical research in the cardiovascular field, this is the most impressive drug I've ever seen, so I have great hope this could be a breakthrough."

McKenney said REGN 727 and Lipitor, when taken together virtually guarantee that patients will achieve their cholesterol-lowering goals.

"You've taken it to the limit. You can't lower LDL cholesterol any more than bringing these drugs together."

But a growing number of drugmakers, including Amgen, can be expected in coming years to challenge McKenney's thesis.