As drugmakers develop new medicines to battle a liver disease epidemic, they have created an urgent need for better diagnostics to select patients for treatment and assess their drugs' effectiveness.
About 30 percent of people in the U.S. now suffer from fatty liver diseases, such as NASH (nonalcoholic steatohepatitis), fueled by obesity, diabetes and over-indulgent lifestyles, according to the American Liver Foundation. Without treatment, sufferers can develop advanced damage, including the scarring known as fibrosis; cirrhosis, which destroys liver function; and even cancer.
For now, testing patients in trials of experimental medicines involves a liver biopsy, a painful, expensive and potentially risky test. Its accuracy is also limited as it draws just a tiny piece of the liver, which may not be affected uniformly by disease.
"It's a pretty nasty test involving a needle five inches long you plunge blindly into a patient's side," said Dr. Scott Friedman, dean of therapeutic discovery at Mt. Sinai Hospital in New York and one of the world's top liver disease experts. "We don't like to do them. You can't do more than one at the beginning, one at the end (of a trial). So there's this frantic effort now to develop (diagnostics) that will give us the information necessary to know if a drug is working."
More than a dozen drugmakers are working on new treatments for fatty liver disease. Frontrunners include Gilead Sciences Inc, a leader in the hepatitis C field, Intercept Pharmaceuticals and France's Genfit. If approved, each of their drugs could reap sales of $10 billion annually, Reuters reported last year.
They will find eager partners in several small companies, such as KineMed and Perspectum Diagnostics, often spawned from academic or hospital research, which are working on alternatives to liver biopsy.
Some of the new techniques use MRI scans that view the entire liver. Others involve blood tests to measure liver scarring or function. One diagnostic evaluates liver damage via exhaled breath. They could replace biopsy or be used to provide interim results during lengthy studies.
U.S. health regulators "recognize that biopsy is an inadequate way to power trials," Friedman said. "We can't get interim data about efficacy."
The U.S. Food and Drug Administration declined to discuss tests in development. The agency "supports innovation, especially where new tests and diagnostic procedures might eliminate or decrease the need for an invasive procedure such as a liver biopsy," a spokesman said.
New diagnostics will also help U.S. health insurers determine which patients are most in need of treatment to keep a closer watch on cost. Gilead's hepatitis C cure Sovaldi racked up $10.3 billion in its first year on the market, prompting a campaign by U.S. payers to reduce the cost of new medications.
"Who is at risk for progressing to serious liver disease? That's a giant question," said Marc Hellerstein, president and chief scientific officer of KineMed and a professor of nutritional science and toxicology at the University of California, Berkeley. "We cannot possibly treat 60 million people for a new disease with expensive new medicines.”
KineMed's test has a patient drink a small amount of water with the non-radioactive hydrogen molecule, deuterium, which accumulates in new collagen, the main component of fibrotic scarring. Using a highly sensitive mass spectrometer, KineMed can distinguish in a small blood sample how much collagen is being made. The information could tell companies whether a drug is working in a month versus years.
"If you've reduced the scar formation rate by 50 percent, then you know that in a year or two that's going to add up," Hellerstein said.
KineMed, which is eyeing going public perhaps late this year or early 2016, is in talks with several drugmakers on using its test in clinical trials, Hellerstein said.
Collagen Medical, which was spun out of research at Boston's Massachusetts General Hospital, has developed a contrast agent that binds to collagen and uses MRI to provide a 3D image of the whole liver.
"If you have liver fibrosis then that part of the liver becomes very bright in the MRI scan," said company co-founder Peter Caravan, director of the Institute for Innovation and Imaging at Mass General. The company expects to begin testing on humans for both liver and cardiac fibrosis with help from grants from the National Institutes of Health.
Perspectum Diagnostics, started by Oxford University researchers, has another MRI-based test that won U.K. approval last year.
Chief Executive Rajarshi Banerjee said he was stunned by the prevalence of liver disease he found during a medical rotation in the Channel Islands off the coast of Normandy, France, which have a reputation as a tax haven for the rich
"You had very wealthy women presenting in their 50s with end-stage liver disease," he said. "You don't expect that in the U.K. equivalent of the Hamptons."
His company's Liver MultiScan takes about 15 minutes and offers easy-to-read full liver images that measure inflammation, fibrosis and iron build-up, producing a score that can determine need for medical intervention. It could also help select patients for clinical trials depending on whether a drug is targeting inflammation or fibrosis.
He shared with Reuters an image of the liver of a 12-year-old boy with a 41-inch waist whose advanced NASH was obvious even to an untrained eye, with large areas of the liver showing dense fat deposits.
"The chances of this boy reaching pensionable age are minuscule unless we do something about it," Banerjee said. "It's a sad indictment of the way we live."
Raptor Pharmaceuticals is testing a drug in children whose NASH was confirmed through biopsy. Having non-invasive tests or biomarkers that can prove a drug works would be "a giant leap forward for the field," Raptor CEO Julie Anne Smith said.
Aurora, Colorado-based HepQuant has discussed using its blood test with Gilead and others, said company founder Greg Everson, who's also director of hepatology at the medical school at the University of Colorado, Denver. Patients either drink or are injected with a liquid that contains a non-radioactive molecule. A series of blood tests over 90 minutes measures how it is cleared by the body, providing information on liver function and physiology.
"We found that the test had tremendous sensitivity over the full range of liver disease, not just at late stage," Everson said. "We're hoping we can work with the FDA to set a pathway that's not too onerous and get this available quickly."
The idea of a breath test for liver function has been around for decades, but Israeli-based Exalenz Bioscience Ltd may be the first to bring one to market.
A patient drinks a small amount of water containing a non therapeutic drug that interacts with the liver. Breath exhaled through the nose is measured for an isotope, C13, which is released in carbon dioxide. The less C13, the higher the likelihood of poor liver function, said Exalenz CEO Lawrence Cohen.
"We've got extremely good results that correlate with biopsies," he said.