Drugmakers set their sights on the next potential blockbuster disease: NASH

With at least 20 global Phase-II clinical trials, blockbuster sales estimates, and millions of prospective patients, the market for NASH, or non-alcoholic steatohepatitis, is viewed in many ways as one of the largest potential categories for new drugs in recent years.

The NASH market, currently with no approved treatments, is already drawing comparisons from analysts to other diseases with lucrative new drugs like hepatitis C.

Last week, Allergan in less than 12 hours announced the acquisition of two companies developing NASH therapies — Tobira Therapeutics and Akarna Therapeutics. Allergan isn’t the first large drugmaker to join this race. Gilead Sciences, Merck, AstraZeneca, and Novo Nordisk are all currently developing NASH drugs.

NASH is the manifestation of obesity in the liver, said Dr. Leon Henderson-MacLennan, co-founder and medical consultant for the inThought Research Group. The disease is tied to metabolic syndrome, which includes conditions like high blood pressure and excess body fat. While cardiovascular disease, also common in obese patients, targets hearts and arteries and diabetes affects the pancreas, NASH threatens the liver.

“You’re seeing the effects of this scourge of obesity in this country,” Henderson-MacLennan explained. “We’re consuming too many calories, eating the wrong food stuffs, and essentially intoxicating ourselves.”

The cause of NASH is not well understood by physicians but risk factors for the disease include obesity, high cholesterol, and type 2 diabetes.

inThought estimates that there are between 10 and 15 million million patients in the U.S. with this disease, and that between one-fifth and one-fourth of those people are at risk for cirrhosis, or chronic liver damage. NASH is expected to be the leading cause of liver transplants within the next five years and is currently the second leading cause of liver transplants, according to a study in Gastroenterology. The precursor to NASH, nonalcoholic fatty liver disease, affects one in four people in the United States, according to the American Liver Foundation.

Alethia Young, an analyst with Deutsche Bank, believes that the patient population is slightly smaller, estimating that about 6.5 million adults in the U.S. and the five largest European countries have advanced NASH, according to an analyst note from July 2014. She estimates that the peak market for NASH medicines will be between $35 billion and $40 billion by 2025. Allergan said that the current NASH market is worth near $8 billion.

One reason for the lofty estimates is because the disease is tied to obesity. The prevalence of nonalcoholic fatty liver disease in the morbidly obese population has been estimated to be as high 92%, according to the Journal of Lipid Research.

LEADING TREATMENT CANDIDATES

Another similarity between the NASH and HCV markets is that, again, biotechnology firms are leading the charge in developing new treatments. “The pace has been set by smaller, nimbler companies,” Henderson said.

New York-based Intercept Pharmaceuticals is considered by two experts interviewed for this story to have the candidate furthest along in development: obeticholic acid.

Obeticholic acid (OCA), currently in a Phase-III trial, is a modified version of a compound in the liver called a bile acid. Bile acids are used by the body to help with digestion as well as liver function.

Intercept plans to conduct an interim analysis a year and a half after the trial’s start date, which was September 2015. The company has said it expects that analysis to form its application to the FDA. The drug received a Breakthrough Therapy designation in January 2015.

OCA may also benefit from already being tested in real-world settings. The drug was cleared by the FDA’s accelerated approval program in May to treat primary biliary cholangitis, a rare liver disease, as Ocaliva.

Intercept’s primary competition is another biotech, the French manufacturer Genfit, which is developing elafibranor. Elafibranor is thought to play a role in liver acid transport and anti-inflammatory activities inside the body.

The company announced in March that it had enrolled its first patient in a Phase-III trial for elafibranor and said it expects to fully enroll the trial by the beginning of next year. The company believes elafibranor should be on track for a potential launch by the second half of 2019.

Right now, Henderson said he’s “more impressed” with Intercept’s program and there will likely be a “greater degree of comfort” among physicians prescribing OCA since it has already received approval in another indication.

“There’s a clear path forward for this agent,” he said. “It’s looking at a nice sample size in the trial and with good enrollment at the time.”

Of the 10 million to 15 million U.S. patients that his firm estimates have NASH, he said that 80% to 90% of that patient population would be eligible for OCA barring any significant adverse events.

Dr. Amit Dhawan, medical director for Kantar Health, also sees Intercept as the current leader in development. But he points out that Gilead Sciences, which brought to market Harvoni and Sovaldi, the game-changing hepatitis-C treatments, has been very involved in this field. Gilead has a strong background in liver sciences with its HCV franchise and already has relationships with hepatologists.

“They have multiple shots on goal,” Dhawan said, referring to the multiple products Gilead can offer liver specialists and adding that “they have products that are somewhat far along.”

Gilead is currently developing simtuzumab, a monoclonal antibody designed to treat the effects of NASH, cirrhosis, and advanced liver fibrosis, rather than treating the disease itself. The drugmaker is currently investigating five different drugs for the disease.

If any of the drugs in development are approved to treat NASH, Henderson said that drugmakers should target hepatologists, endocrinologists, and primary-care physicians. Disease awareness campaigns would also be prudent for this new class of drugs in order to alert prescribers about potential new treatment options.

“All three [types of physicians] need to be addressed quickly: the hepatologists due to the specter of cirrhosis; the endocrinologist because you’re going to have to administer these agents with oral hypoglycemics and insulin; and primary care physician because they will oversee a patient’s entire treatment plan,” Henderson said.

MARKET UNCERTAINTIES

The size of the prospective population, the breadth of agents in clinical development, and analysts’ lofty market estimates paint a rosy picture of the market potential for NASH therapies, but there are a number of risk factors that could send these drugs’ billion-dollar sales estimates off the rails.

For one, the emergence of payers in prescribing decisions puts a lot of uncertainty in the market, lest one forgets the last time a compelling drug for a liver disease with an $84,000 price tag became available — in this case, it was Gilead Sciences’ Sovaldi — and these drugs are not proven cures, like Sovaldi is.

Craig Mattson, senior director of clinical programs for pharmacy benefit manager Prime Therapeutics, said the company is “very concerned” about the potential cost implications of treating this disease. So much so that Prime is currently discouraging off-label use of Intercept’s OCA by requiring prior authorization before a patient can start taking the drug as a NASH treatment. He also said the company is currently waiting for more data from Intercept’s Phase-III program, and other programs as well, to determine how it will eventually cover these drugs for its clients if approved by the FDA.

Payers may also be reluctant to cover potentially expensive medications, in part because lifestyle changes are often the first-line treatment for this disease. Doctors often recommend patients first work to reduce their overall cholesterol levels, exercise more frequently, and better control their diabetes — if that’s a factor.

Another hurdle for drugmakers will be diagnosis. NASH is known as the “silent killer,” because patients don’t experience symptoms during the early stages of the disease and the only way to confirm a diagnosis for NASH is through a liver biopsy, which is an invasive procedure. Those factors may not only limit the number of patients who could receive treatment but could also hinder current enrollment for large Phase-III clinical trials.

Both Henderson and Dhawan said they expect drug developers to work toward developing new techniques to identify the disease in patients. “The type of [biomarker] does not have to be proprietary necessarily, it could be an imaging diagnostic — whether that’s ultrasound or MRI imaging,” Henderson said.