By Bill Berkrot
NEW YORK, Nov 9 (Reuters) - Now that new medicines promiseto cure millions of hepatitis C patients in coming years,drugmakers including Gilead Sciences Inc are turning theirattention to other liver diseases, with a potential market thatcould 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 liverconditions caused by rising obesity, which without treatmentcould affect half of all Americans by 2030, according to theAmerican Liver Foundation (ALF). Some of the drugs will addressadvanced fibrosis and cirrhosis, which are the scarring thatvirtually all liver diseases cause without effective treatments.Each of these drugs, once approved, could reach annual sales ofas much as $10 billion, industry analysts said.
Most of the treatments are now in early Phase I or Phase IIclinical trials, with more informative interim data on severalexpected over the course of the next year.
Gilead, which was first to market with itshepatitis C cure Sovaldi late last year and has been racking upabout $3 billion in sales each quarter, is a solid bet to beamong the leaders in the next wave of liver therapies, expertssaid.
"The Gilead program is encouraging," said Dr. NagaChalasani, director of gastroenterology and hepatology atIndiana University Hospital in Indianapolis, who isparticipating in clinical trials of promising drugs from Gileadand others.
Drugmakers are working to address the fatty liver diseaseknown as NASH, or nonalcoholic steatohepatitis. Withouttreatment, NASH can progress to liver-destroying cirrhosis andpotentially cancer.
ALF estimates that non-alcoholic fatty liver disease,including NASH, affects up to 30 percent of people in the UnitedStates. It can be caused by bad diets and alcohol abuse, and hasalso been tied to diabetes.
"We have no treatment for that condition other than tell apatient they need to lose weight," said Dr. MauricioLisker-Melman, director of the hepatology program at WashingtonUniversity School of Medicine in St Louis.
Intercept Pharmaceuticals has attracted the mostattention. Just released final data from a mid-stage clinicaltrial showed its obeticholic acid halted NASH progression andimproved liver scarring in primarily moderately ill patients."For now, no one else has demonstrated an antifibrotic effect inthis population, and I believe we are ahead of the pack in thatsense," said Intercept Chief Executive Mark Pruzanski.
Intercept plans to begin a Phase III trial with at least1,000 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 allthe companies in the field, said most were first testing drugsin patients whose liver damage is not advanced.
"Gilead has sort of leapfrogged that," Friedman said,tackling more serious damage, as its simtuzumab targets fibroticscarring directly, rather than inflammation or other drivers ofdisease. Reversing cirrhosis and improving liver function is"the highest bar I can think of in this business, and it wouldbe spectacular," he said.
Gilead faces competition from several smaller companies withpromising drugs in development, including Intercept, France'sGenfit, Israel's Galmed, GalectinTherapeutics, Conatus Pharmaceuticals andRaptor Pharmaceuticals, specialists said.
Gilead's antibody simtuzumab blocks an enzyme called LOXL2that is directly involved in laying down bands of collagen thatform the scar tissue behind cirrhosis. The collagen bands, whichresult from a wide variety of assaults on the liver, includingalcohol and drug abuse, cross link haphazardly to destroy theliver's architecture and function.
Gilead expects to have a strong indication of whether itsdrug is working when one-year data from a two-year Phase IIstudy becomes available next year.
"We have a very active research program," said ManiSubramanian, head of liver disease clinical research at Gilead."We're targeting everything: metabolic issues, inflammation andfibrosis directly." He acknowledged challenges faced bydrugmakers trying to address more advanced liver disease: "It'sbeen a graveyard for drugs that try to reverse fibrosis,"Subramanian said.
NOT FOR FAINT OF HEART
Chalasani at Indiana University Hospital estimated there maybe 20 different drugs being tried by various drug companies thatseem 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 matterof days in January after it was announced the trial of its drugwould meet the intended goal. On the flip side, Galectin lostnearly two thirds of its value in July, when its NASH drug usinga different approach had a setback in a Phase I trial.
Conatus is first testing its drug, emricasan, in patientsfacing acute liver failure, which has a 50 percent mortalityrate in 28 days. Chief Executive Steven Mento said the goal wasto "rescue these patients and prevent catastrophic organfailure." The company plans to work its way back, testing onless severely ill patients. The drug targets inflammation andexcessive cell death seen as drivers of the disease.
Dr. David Bernstein, chief of hepatology at North ShoreUniversity Hospital in Manhasset, N.Y., called the Conatus drugexciting and the initial trial a sensible approach.
"There's limited downside because there's nothing else thatcan be done anyway," said Bernstein, who expects to be involvedin future emricasan trials. "If you can reverse cirrhosis, youreally will change the impact of liver disease worldwide."
Drugs that succeed in reversing cirrhosis "can be as big aclass as the class of statins," said Conatus's Mento, referringto cholesterol drugs, such as Pfizer's Lipitor, which alone atits peak had annual sales of about $13 billion.
Raptor, by contrast, is developing a drug for NASH inchildren, a growing problem that has left liver specialistsfearing an obese generation that could require liver transplantsin the prime of life.
Raptor is testing a drug already approved for use inchildren for an extremely rare kidney disease. "In terms ofsafety, it's well established," said Raptor President and CEOdesignate Julie Anne Smith. It is now engaged in a year-longmid-stage trial of 169 children whose NASH was confirmed byliver biopsy with data expected in the first half of next year.
Companies are waiting for the U.S. Food and DrugAdministration to outline what it will take to approve a NASHdrug. "The FDA is struggling with what constitutes a meaningfulimprovement with a patient," Gilead's Subramanian said.
Goals such as reducing fat buildup or modestly improvingfibrosis would likely be simpler and quicker to achieve, forexample, than avoiding need for liver transplants.
The FDA is working "to identify clinically meaningfulendpoints for NASH and related liver diseases to help guide drugdevelopment," it said in a statement.
The uncertainty from the FDA also creates risks forinvestors and has led some analysts to focus on other livertherapies. RBC Capital Markets analyst Michael Yee favorscompanies taking on hepatitis B, such as Arrowhead Research Corp, Canada's Tekmira Pharmaceuticals, Gilead andIsis Pharmaceuticals in partnership withGlaxoSmithKline. And one private company not to beignored, OnCore Biopharma, founded by former Pharmassetexecutives, including the inventor of Gilead's Sovaldi.
While finding a cure for hepatitis B will not be easy,trials would mirror those for hepatitis C, with a simple bloodtest yielding clear results in months rather than years. (Reporting by Bill Berkrot. Editing by Michele Gershberg andJohn Pickering)
Glaxosmithkline (GSK)