* Data from two pivotal trials due soon
* Regulatory filings planned for first-half 2011
By Deena Beasley
LOS ANGELES, Aug 1 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
PARTNERED WITH GENZYME
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
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
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
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)