* Data from two pivotal trials due soon
* Regulatory filings planned for first-half 2011
By Deena Beasley
LOS ANGELES, Aug 1 (Reuters) - Isis Pharmaceuticals Inc ISIS.O will soon release key data from pivotal trials of its experimental cholesterol drug that will be closely parsed for evidence of any safety risks, particularly liver toxicity.
The drug, mipomersen, is designed to lower “bad” LDL cholesterol in patients with severely high cholesterol.
Isis is expected to report any day now results from two trials: one in patients with high cholesterol who are at high risk of heart disease and another in patients with a condition known as severe hypercholesterolemia.
Trial results released in February showed six months of treatment with the Isis drug lowered LDL cholesterol by 28 percent in patients with heterozygous familial hypercholesterolemia (HeFH) — caused by a defective gene inherited from one parent.
But some patients developed elevated liver enzymes, a possible sign of liver damage, raising concerns regulators might require more studies before considering using the drug in patients beyond those so sick they would otherwise be dependent on an expensive blood filtering system.
The February trial results sent Isis shares down as much as 20 percent. The full data set is expected to be presented at a medical meeting later this summer.
“The one thing that could really hurt this drug is liver toxicity,” said Cowen & Co analyst Eric Schmidt.
He also noted the dropout rate for mipomersen trial patients has been fairly high because of injection-site reactions.
Isis, which has partnered with Genzyme Corp GENZ.O> to develop mipomersen, argues that changes in liver enzymes are common with any drug that lowers cholesterol, including commonly-used statins such as Lipitor.
“Even today no one can tell you why statins cause liver enzymes to go up,” Isis Chief Executive Officer Stanley Crooke told Reuters in a recent interview. “It’s a general phenomena associated with adjustment of lipids.”
Crooke said he was “quite comfortable” with mipomersen’s safety profile.
Cholesterol-lowering drugs such as statins work by helping to clear LDL from the bloodstream by improving the action of LDL receptors. Mipomersen is designed to reduce actual production of the fatty material that can build up in artery walls.
The Isis drug, which is given weekly by injection, is based on a technology known as antisense, which aims to interfere at the genetic level to prevent rogue proteins from being formed.
Isis is a pioneer in the field and has a wide-ranging pipeline of experimental antisense drugs. Analysts, on average, have forecast mipomersen sales of $354 million in 2014, according to Thomson Pharma.
“All drugs that come up to the FDA (U.S. Food and Drug Administration) are looked at very carefully for liver issues these days,” said Isis consultant Dr. Willis Maddrey, a liver expert and professor at the University of Texas Southwestern Medical Center.
He acknowledged elevated liver enzymes have been observed in roughly 10 percent of trial patients treated with mipomersen, adding “the important point is I haven’t seen a single case of liver disease or liver injury.”
Genzyme, which is expected to get a takeover bid any day now from France’s Sanofi-Aventis SA (SASY.PA), is responsible for regulatory applications for mipomersen.
Isis said any Genzyme buyer would take on the partnership, but, if that company did not want mipomersen, Isis would retain any money received and could relicense the drug.
The plan is to file in the first half of next year for approval of mipomersen for use by patients with homozygous familial hypercholesterolemia (hoFH).
Patients with familial hypercholesterolemia are unable to properly metabolize LDL due to dysfunctional LDL receptors.
There are two forms of the disease: hoFH, in which a defective gene is inherited from both parents, and heFH, in which a defective gene is inherited from only one parent so some LDL receptor function is preserved.
HoFH is estimated to affect about one in a million people worldwide. HeFH is a more common form of the disorder, affecting about one in 500 people.
Isis said the regulatory filings may also include patients with severe hypercholesterolemia.
The aim is to first address the highest-risk patients, followed by potential expansion into patients who have persistently high LDL levels despite being treated with other lipid-lowering drugs. These groups would include heterozygous FH, severe hypercholesterolemia, and high-risk patients who remain far from their LDL goals. (Reporting by Deena Beasley; editing by Andre Grenon)