Insight: Next big drug against cholesterol takes shape

NEW YORK (Reuters) - A handful of drugmakers are racing to develop a new class of medicines they believe could be the biggest weapon against heart disease since statins were introduced in the 1980s.

The contest is taking place largely out of public view, but researchers and industry analysts say excitement is building over the injectable medicines. They work by blocking PCSK9, a protein whose natural function is to preserve levels of "bad" LDL cholesterol in the bloodstream.

Researchers in Paris, Montreal and Dallas, through experiments with thousands of patients that began in 1999, discovered the gene behind PCSK9 and deciphered its function.

Biotechnology company Regeneron and its big pharmaceutical partner Sanofi are now ahead of the pack in developing a drug that goes after PCSK9. A single injection of their medicine, called REGN727, slashed LDL levels by more than 60 percent for a month in an early trial. Results from mid-stage studies are expected later this year.

"The PCSK9 mechanism is perhaps one of the best examples we have in all of medicine of how the study of genetics can identify new targets for developing new therapies," said Dr. Daniel Rader, a noted heart researcher at the University of Pennsylvania.

Although no serious side effects have been seen with REGN727, larger trials are needed to rule out problems such as liver toxicity or raised blood pressure that have wrecked other promising heart drugs, including Pfizer Inc's experimental torcetrapib.

Rader, who is a consultant to several of the companies developing PCSK9 inhibitors, said most drugmakers are working on once-a-month injections that would likely be self-administered by patients using very small needles. Some drugs might eventually be administered every two to three months, he said.

Amgen Inc, Merck & Co, Alnylam Pharmaceuticals Inc and a partnership between Bristol-Myers Squibb Co and Isis Pharmaceuticals In c are in hot pursuit, with rival drugs of their own.

The anti-PCSK9 medicines are expected to be used alongside statins, such as Pfizer's Lipitor and AstraZeneca Plc's Crestor, for patients who do not achieve cholesterol-lowering goals with statins alone.

They would also be used on their own for a much smaller group who cannot tolerate statins -- oral drugs with global annual sales of $ 20 billion that inhibit the liver's production of LDL cholesterol.

In the United States, more than 10 million patients could ultimately be candidates for the new family of medicines. Industry analysts say the products could command $ 1,000 a month or more because of their potential importance to high-risk patients. Statins cost about $ 130 a month for branded pills like Lipitor, which is due to lose U.S. patent protection later this year, or far less for other products already av ailable as generics.

For a graphic on top-selling cholesterol fighters, see: r.reuters.com/wuq43s

BETS ON A MAGIC BULLET

The clearest advantage so far has been seen in Regeneron's new drug. Data from initial studies suggests REGN727 may be able to reduce LDL by another 50 percent when used in combination with statins, which themselves can cut LDL in half.

"Regeneron's anti-PCSK9 antibody really looks like a magic bullet against LDL cholesterol" said Ziad Bakri, a biotechnology analyst with T. Rowe Price. His firm is one of Regeneron's largest shareholders, with a 9.5 percent stake as of the end of June.

Assuming longer-term studies demonstrate the drug is safe and prevents heart attacks and stroke, Bakri estimates it could capture annual sales "in the billions of dollars" if approved.

"Taking advantage of this pathway is a creative leap forward," said Dr. Kristin Newby, a Duke University heart researcher who has no involvement in PCSK9 research.

But she cautioned that other classes of novel medicines have stumbled because of unexpected safety problems.

She cited torcetrapib, a drug to raise "good" HDL cholesterol that Pfizer had expected to reap annual sales of more than $ 10 billion. Meant to drive down the incidence of heart attacks, the drug instead was linked to deaths and was scrapped in 2006 after costly late-stage trials.

Data from a similar HDL-raising drug being developed by Roche Holding AG will be released on Sunday at the annual meeting of the European Society of Cardiology in Paris. But cutting LDL cholesterol remains the most proven way of reducing heart attacks and stroke, and is the industry's prime focus.

Should PCSK9 inhibitors stumble, it would be a keen disappointment for some of the world's biggest drugmakers.

Amgen, the largest global biotech company, is wrapping up early-stage trials of its PCSK9 inhibitor and will soon advance it into Phase II studies.

"There's a real opportunity to change the paradigm of treating cardiovascular disease with this therapy," said Scott Wasserman, Amgen's global project leader for cardiovascular medicines.

Andrew Plump, head of cardiovascular discovery for Merck, cautions that long-term trials must confirm the value of PCSK9 blockers. But he predicts that when used with statins, they could reduce heart attack and stroke risk 25 to 30 percent beyond the 25 to 30 percent reduced risk seen with statins alone.

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"PCSK9 is one of the most interesting proteins in the human body," Plump said. "We didn't know anything about it a decade ago, and the speed at which drug programs have progressed is astounding."

Merck has not disclosed details of its PCSK9 program, but Plump said the company is interested in developing injectable and pill formulations.

Former Merck chief executive Roy Vagelos, who introduced the world's first statin Mevacor in 1987, is helping oversee development of Regeneron's product as chairman of its board.

Two Nobel Prize winners whose research directly led to discovery of statins, Michael Brown and Joseph Goldstein, are members of Regeneron's board, as is Christine Poon, former head of Johnson & Johnson's pharmaceuticals group.

"This is a big, enormous opportunity," Regeneron Chief E xecutive Leonard Schleifer said in an interview. "It could become one of the biggest drugs in biotechnology."

Regeneron also hopes to benefit from the expertise of partner Sanofi, whose Plavix blood clot preventer has annual sales of more than $ 9 billion. The companies aim to split any profits evenly from their PCSK9 medicine.

GENE MUTATIONS PROTECT THE HEART

In a series of experiments conducted separately by four research teams, scientists showed that PCSK9 wipes out LDL receptors, proteins that bind to LDL cholesterol in the liver and remove the artery-clogging substance from the bloodstream.

The mechanism is one of many ways the body regulates LDL to make sure there is enough of it to perform vital body functions, although not more than is necessary. But when PCSK9 goes overboard in destroying LDL receptors, LDL rises to harmful levels.

While early studies focused on patients with genetic mutations that triggered sky-high production of LDL, Helen Hobbs and colleague Jonathan Cohen theorized in 2005 that other mutations in PCSK9 might exist and have the opposite effect: of inactivating the gene and thereby leading to lower LDL levels.

They examined the structure of the gene in African-Americans who had low LDL. Their research showed that 2 percent of them had an inherited mutated form of the gene, and that their LDL levels were about a third lower than individuals without the mutation. The two researchers from the University of Texas Southwestern Medical Center went on to show that the subjects were protected from heart disease.

The findings strongly suggested the possible benefits of blocking PCSK9 or its activity.

"We knew what we had right away : the potential for a new way to lower LDL levels in humans," Hobbs said.

Two young women found to have no PCSK9 at all had LDL levels of just 14 to 16 -- one-eighth normal levels. Yet they were deemed to be in good health, suggesting to Hobbs and others that blocking PCSK9 may not pose great safety risks.

"The reaction to Dr. Hobbs' findings was electric among those who understood the field," said Dr. Daniel Steinberg, professor emeritus at the University of California-San Diego. "The science was solid and suggested that blocking PCSK9 could be as important as statins in terms of controlling coronary artery disease."

Steinberg, who has written extensively on PCSK9, said that patients with the protective mutation were shown to have an almost 90 percent reduced risk of coronary artery disease, compared with the general population.

"That's probably because their LDL has been low from birth," he said. Steinberg said anti-PCSK9 drugs could save tens of thousands of lives a year, as statins now do.

Statins actually raise levels of PCSK9, thereby undermining their own effectiveness in reducing LDL. "So if you give a statin, plus a PCSK9 inhibitor, you could get a bigger bang for your buck," Steinberg said.

Patients taking PCSK9 inhibitors might also be able to take lower doses of statins, and thereby avoid their side effects, such as muscle weakness and liver toxicity.

Some studies suggest PCSK9 may help regenerate liver tissue, so drugs that block it theoretically could pose a risk to alcoholics or others with existing liver damage.

Studies will test the liver risk, and also show whether the new medicines affect HDL cholesterol or cause side effects in oth er organs where PCSK9 is concentrated.

While safety must be established, Alnylam research executive Akshay Vaishnaw is betting on PCSK9 drugs.

"There's no question that this is going to be the greatest intervention, following statins, for treatment of high cholesterol. It's absolutely going to be the next big thing."