Reuters Health Information: INSIGHT-After hep C cure, companies target next big liver disease market
INSIGHT-After hep C cure, companies target next big liver disease market
Last Updated: 2014-11-10
By Bill Berkrot
NEW YORK (Reuters) - Now that new medicines promise to cure
millions of hepatitis C patients in coming years, drugmakers
including Gilead Sciences Inc are turning their attention to
other liver diseases, with a potential market that could rival
the success of statins, which generated more than $30 billion a
year in sales at their peak.
Several companies are working on treatments for hepatitis B,
which can be controlled but not yet cured, and for fatty liver
conditions caused by rising obesity, which without treatment
could affect half of all Americans by 2030, according to the
American Liver Foundation (ALF). Some of the drugs will address
advanced fibrosis and cirrhosis, which are the scarring that
virtually all liver diseases cause without effective treatments.
Each of these drugs, once approved, could reach annual sales of
as much as $10 billion, industry analysts said.
Most of the treatments are now in early Phase I or Phase II
clinical trials, with more informative interim data on several
expected over the course of the next year.
Gilead, which was first to market with its hepatitis C cure
Sovaldi late last year and has been racking up about $3 billion
in sales each quarter, is a solid bet to be among the leaders in
the next wave of liver therapies, experts said.
"The Gilead program is encouraging," said Dr. Naga
Chalasani, director of gastroenterology and hepatology at
Indiana University Hospital in Indianapolis, who is
participating in clinical trials of promising drugs from Gilead
Drugmakers are working to address the fatty liver disease
known as NASH, or nonalcoholic steatohepatitis. Without
treatment, NASH can progress to liver-destroying cirrhosis and
ALF estimates that non-alcoholic fatty liver disease,
including NASH, affects up to 30% of people in the United
States. It can be caused by bad diets and alcohol abuse, and has
also been tied to diabetes.
"We have no treatment for that condition other than tell a
patient they need to lose weight," said Dr. Mauricio
Lisker-Melman, director of the hepatology program at Washington
University School of Medicine in St Louis.
Intercept Pharmaceuticals has attracted the most attention.
Just released final data from a mid-stage clinical trial showed
its obeticholic acid halted NASH progression and improved liver
scarring in primarily moderately ill patients. "For now, no one
else has demonstrated an antifibrotic effect in this population,
and I believe we are ahead of the pack in that sense," said
Intercept Chief Executive Mark Pruzanski.
Intercept plans to begin a Phase III trial with at least
1,000 more seriously ill patients next year.
Dr. Scott Friedman, dean for therapeutic discovery at Mt.
Sinai Hospital in New York, who has worked with virtually all
the companies in the field, said most were first testing drugs
in patients whose liver damage is not advanced.
"Gilead has sort of leapfrogged that," Friedman said,
tackling more serious damage, as its simtuzumab targets fibrotic
scarring directly, rather than inflammation or other drivers of
disease. Reversing cirrhosis and improving liver function is
"the highest bar I can think of in this business, and it would
be spectacular," he said.
Gilead faces competition from several smaller companies with
promising drugs in development, including Intercept, France's
Genfit, Israel's Galmed, Galectin Therapeutics, Conatus
Pharmaceuticals and Raptor Pharmaceuticals, specialists said.
Gilead's antibody simtuzumab blocks an enzyme called LOXL2
that is directly involved in laying down bands of collagen that
form the scar tissue behind cirrhosis. The collagen bands, which
result from a wide variety of assaults on the liver, including
alcohol and drug abuse, cross link haphazardly to destroy the
liver's architecture and function.
Gilead expects to have a strong indication of whether its
drug is working when one-year data from a two-year Phase II
study becomes available next year.
"We have a very active research program," said Mani
Subramanian, head of liver disease clinical research at Gilead.
"We're targeting everything: metabolic issues, inflammation and
fibrosis directly." He acknowledged challenges faced by
drugmakers trying to address more advanced liver disease: "It's
been a graveyard for drugs that try to reverse fibrosis,"
NOT FOR FAINT OF HEART
Chalasani at Indiana University Hospital estimated there may
be 20 different drugs being tried by various drug companies that
seem to be good targets.
But betting on them is not for the faint of heart.
Intercept's shares shot from about $72 to over $400 in a matter
of days in January after it was announced the trial of its drug
would meet the intended goal. On the flip side, Galectin lost
nearly two thirds of its value in July, when its NASH drug using
a different approach had a setback in a Phase I trial.
Conatus is first testing its drug, emricasan, in patients
facing acute liver failure, which has a 50% mortality rate in 28
days. Chief Executive Steven Mento said the goal was to "rescue
these patients and prevent catastrophic organ failure." The
company plans to work its way back, testing on less severely ill
patients. The drug targets inflammation and excessive cell death
seen as drivers of the disease.
Dr. David Bernstein, chief of hepatology at North Shore
University Hospital in Manhasset, N.Y., called the Conatus drug
exciting and the initial trial a sensible approach.
"There's limited downside because there's nothing else that
can be done anyway," said Bernstein, who expects to be involved
in future emricasan trials. "If you can reverse cirrhosis, you
really will change the impact of liver disease worldwide."
Drugs that succeed in reversing cirrhosis "can be as big a
class as the class of statins," said Conatus's Mento, referring
to cholesterol drugs, such as Pfizer's Lipitor, which alone at
its peak had annual sales of about $13 billion.
Raptor, by contrast, is developing a drug for NASH in
children, a growing problem that has left liver specialists
fearing an obese generation that could require liver transplants
in the prime of life.
Raptor is testing a drug already approved for use in
children for an extremely rare kidney disease. "In terms of
safety, it's well established," said Raptor President and CEO
designate Julie Anne Smith. It is now engaged in a year-long
mid-stage trial of 169 children whose NASH was confirmed by
liver biopsy with data expected in the first half of next year.
Companies are waiting for the U.S. Food and Drug
Administration to outline what it will take to approve a NASH
drug. "The FDA is struggling with what constitutes a meaningful
improvement with a patient," Gilead's Subramanian said.
Goals such as reducing fat buildup or modestly improving
fibrosis would likely be simpler and quicker to achieve, for
example, than avoiding need for liver transplants.
The FDA is working "to identify clinically meaningful
endpoints for NASH and related liver diseases to help guide drug
development," it said in a statement.
The uncertainty from the FDA also creates risks for
investors and has led some analysts to focus on other liver
therapies. RBC Capital Markets analyst Michael Yee favors
companies taking on hepatitis B, such as Arrowhead Research Corp
, Canada's Tekmira Pharmaceuticals, Gilead and Isis
Pharmaceuticals in partnership with GlaxoSmithKline. And one
private company not to be ignored, OnCore Biopharma, founded by
former Pharmasset executives, including the inventor of Gilead's
While finding a cure for hepatitis B will not be easy,
trials would mirror those for hepatitis C, with a simple blood
test yielding clear results in months rather than years.