Roche Holding AG (ROG) is planning a final-stage trial of a drug that taps into a gene mutation to lower cholesterol and heart attack risk beyond what statins such as Pfizer Inc. (PFE)'s $9.6 billion-selling Lipitor can do.
The experimental treatment, developed by the drugmaker's Genentech unit, has been tested in enough people to show it reduces bad cholesterol as expected, said Hal Barron, chief medical officer at Basel, Switzerland-based Roche. Roche hasn't published data on the drug or mentioned it in news releases.
The effort puts Roche into the middle of one of the most promising and competitive areas of drug development. High cholesterol is a leading contributor to cardiovascular disease, the No. 1 cause of death in the world. Cholesterol-lowering treatments were a $38.7 billion market in 2011, according to IMS Health. Sanofi and partner Regeneron Pharmaceuticals Inc. (REGN), Amgen Inc. (AMGN) and Pfizer are among the companies working on similar medicines targeting the PCSK9 gene.
"These drugs allow us to go where no one has gone before," Steven Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic in Ohio, said by phone a few hours after a meeting with Amgen about the design of another study. "There's a tremendous amount of interest among a broad range of makers of pharmaceuticals to get involved." Nissen isn't involved in Roche's research.
Mutated Gene
Roche is enrolling patients in a mid-stage trial of the drug. Next year, the company plans to begin the third and usually final phase of clinical testing needed before seeking regulatory approval to sell the new medicine, according to an article in an internal Roche newsletter.
Roche hasn't talked about the project publicly because anti-PCSK9 research is very competitive, said Robin Snyder, a Genentech spokeswoman, in an e-mail. Executives plan to discuss it at a presentation to analysts and investors in London in September.
Roche doesn't have a cardiovascular drug among its 10 biggest-selling products. The company in May abandoned an effort to develop dalcetrapib, a treatment to increase so-called good cholesterol, after an independent group of experts said patient trials didn't show clinically meaningful efficacy.
The PCSK9 gene makes a protein that disrupts the ability of liver cells to strip bad cholesterol out of the blood. About 3 percent of people have a mutated version of this gene, resulting in less accumulation of bad cholesterol. The experimental medicines may extend that benefit to people who don't have the mutation. Most of the drugs are given as a once- or twice- monthly injection.
Sanofi, Regeneron
Anti-PCSK9 drugs could help some 1.5 million Americans who aren't able to take statins, or as many as 11 million people including those whose cholesterol doesn't go low enough on a statin, Regeneron Chief Financial Officer Murray Goldberg said in June.
Sanofi (SAN) and Regeneron said in March that their drug cut levels of LDL, the bad cholesterol, by as much as 72 percent on top of Lipitor in a 183-person trial. Tarrytown, New York-based Regeneron and its Paris-based partner are beginning final-phase trials.
Those results shouldn't have surprised anyone who understands the science behind the project, Barron said in an interview last week at Genentech's South San Francisco headquarters.
"If this didn't work, we should all go home," he said. "It behaved exactly as expected."
Ceiling Effect
What's unclear is exactly what companies will need to do to get an anti-PCSK9 drug approved in an environment where so many patients are already taking statins, he said. Companies may need to show whether their drugs help prevent heart attacks, not just that they lower cholesterol more than statins, he said.
"It's not incredibly intuitive that it's just going to be a linear relationship: the lower the lower the lower, the better the better the better," Barron said. "There may be a ceiling effect."
While only the Food and Drug Administration can say for sure what kinds of testing will be required, the agency will probably approve the drugs based on their cholesterol-lowering properties and a "very good demonstration of safety," as long as companies promise to follow up with studies that look at disease and death rates, Nissen said. The cardiologist is a former chairman of the agency's CardioRenal Advisory Panel.
The Roche corporate executive committee gave the go-ahead in February for the drug to move toward phase three, which is usually the last of the stages of patient trials, according to the newsletter. Nothing has been decided about the design of that study, said Snyder.
'Geared Up'
"Phase three is being geared up," said Richard Scheller, Genentech's chief scientific officer, in a separate interview last week at the unit's headquarters. He said he expects Roche will need to show the outcome of treatment with the drug and whether it's effective at helping people.
"The early part of the trial goes very quickly, because you can just measure cholesterol and see that it goes down," he said. "But then again you have to show it's effective, which it will be, because it lowers cholesterol, and you have to show that it's safe, again a major deal for drugs in areas outside oncology."
Anti-PCSK9 is less risky than dalcetrapib, the drug that failed to boost good cholesterol, or HDL, Scheller said.
'Proven Target'
"It's considerably less risky because it's approaching a proven -- a proven in tens of millions of people proven -- target, versus HDL, which was in a number of ways a more innovative target, but much greater risk," Scheller said.
Amgen is testing its anti-PCSK9 drug in five second-stage trials, the Thousand Oaks, California-based company said this week. New York-based Pfizer said this week its compound is in late phase two development.
Also researching in the area are Merck & Co. (MRK), based in Whitehouse Station, New Jersey; New York-based Bristol-Myers Squibb Co. (BMY); and Alnylam Pharmaceuticals Inc. (ALNY), based in Cambridge, Massachusetts.
If anti-PCSK9 drugs prove to be safe and effective, "it will be hard for me to imagine them not having blockbuster potential," Alnylam Chief Executive Officer John Maraganore said in a telephone interview, meaning drugs with more than $1 billion a year in sales.
The future for anti-PCSK9 drugs may be in showing how they fit together and which has the most desirable characteristics, Barron said.
"There may never be -- or at least not in the near future -- a class of drugs with the impact of statins," Nissen said. "But this is a big one. This is a very promising class of drugs."
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