Tuesday morning, FDA scientists published a thick document describing their view of the drug obeticholic acid as a treatment for a rare form of liver disease called primary biliary cirrhosis. With that document in mind, a panel of outside advisors will spend Thursday grilling the drug’s maker, New York-based Intercept Pharmaceuticals (NASDAQ: ICPT), and recommend to the FDA whether to approve it for PBC patients or not.
The vote will be important for Intercept, which has no products on the market yet. But the panel’s recommendation will also serve as tea leaves for a potentially much larger group of patients down the road with a more prevalent liver condition called nonalcoholic steatohepatitis. The condition, known as NASH, has sparked a burst of biopharma activity in recent years. This week has provided some of the biggest headlines to date: the FDA meeting for obeticholic acid could have big implications for future use in NASH; and on Monday, Gilead Sciences (NASDAQ: GILD), which has been assembling a pipeline of potential NASH treatments, announced a major deal for another NASH drug well behind Intercept’s in development.
NASH has become a leading cause of liver cirrhosis, or scarring, and liver failure, just like alcoholics suffer—but driven by the epidemic of obesity, diabetes, and high cholesterol, even in children. It’s normal to have a few fat cells in the liver. But as the amount grows beyond five or 10 percent, so does a person’s risk of disease. NASH is a disease of the modern world. In 1980, as this Mayo Clinic paper noted, it had only recently been named.
There are huge financial and societal costs to NASH. In 2011, researchers reported in the medical journal Hepatology that the condition was the third most common reason for liver transplants in the U.S. and was on course to be the most common. Estimated 2011 costs per transplant were $577,100, according to the United Network for Organ Sharing.
To be clear, the data under the microscope this week come only from tests of obeticholic acid in people with PBC—a rare disease in which the immune system attacks the liver—not NASH. But Philip Rosenthal, a specialist in pediatric liver disease and surgery at the University of California, San Francisco, says the data and the discussion will flesh out a better picture of OCA’s potential in NASH.
“I want to know the efficacy and safety of the drug,” writes Rosenthal in an email, noting that in the so-called FLINT trial—Intercept’s Phase 2 trial testing OCA in people with NASH—“there were some concerns surrounding itching and lipid levels.” In other words, people taking OCA had more itching than the placebo group—serious enough to drive one patient off the drug completely—and they also saw their so-called “bad cholesterol” levels rise, although Intercept reported that the levels dropped back down once they started taking anti-cholesterol statins.
In the FDA’s briefing documents released Tuesday, the same problems were noted in the PBC trial, with particular attention focused on the itching. The briefing documents point the outside advisors to the questions that need to be raised during the meeting. There do not seem to be red flags raised by the FDA scientists, unlike some other recent cases. (When FDA advisors considered the Duchenne muscular dystrophy drug drisapersen last November, one panelist said that after reading the materials, “it was clear that this wasn’t going to get approved at this point. This just needs more work.”)
Investors boosted Intercept shares 13.3 percent to close at $151.31 Tuesday.
For PBC patients, Intercept is proposing a daily pill of 5 mg, to be bumped to 10 mg after three months if the patient shows tolerance to the drug. In its Phase 3 test, about 210 patients were split into thirds: One third took placebo, one third started at 5 mg with a bump to 10 mg, and one third started at 10 mg.
About 60 percent of the patients taking OCA in the Phase 3 PBC trial had to be treated for itching, compared to 50 percent on placebo. Seven patients—10 percent of those taking the higher dose—had to drop out of the study.
The cholesterol problem didn’t stand out in the Phase 3 trial, with patients taking OCA only showing a “transient increase” that seemed to resolve after 12 months on the drug, according to the briefing documents. It’s also worth noting that the FDA scientists’ report pooled all patients ever to receive at least one dose of OCA—more than 1,500—and noted a number of liver abnormalities. “It is our opinion that a causal relation with OCA cannot be ruled out,” the document states, in part because OCA in certain settings caused liver problems at doses higher than what Intercept is proposing for patients.
Any time a drug is tied to liver problems, it’s worth watching.
Those safety questions are certain to arise during Thursday’s daylong discussion with the 11-member advisory committee, which includes gastroenterologists from the Department of Veterans Affairs, Emory University, and the University of California, Los Angeles.
Also on the table is whether OCA really makes people with PBC better. The data were positive, but those data showed that OCA reduced an enzyme in the blood, alkaline phosphatase, that is linked to PBC. The panel will consider whether it’s enough to use the alkaline phosphatase reduction as a predictor for a health benefit, which FDA described as fewer deaths or liver transplants.
The issue of surrogate endpoints, as such predictors are called, can loom large over a drug. The FDA approved two next-generation cholesterol drugs last year, known as PCSK9 inhibitors, based on their ability to reduce bad cholesterol.
But the drugs have not yet been shown to actually improve health outcomes, and insurers are proving extremely stingy in paying for their use. Instead, they are waiting for the drug makers, Regeneron Pharmaceuticals (NASDAQ: REGN), Sanofi (NYSE: SNY), and Amgen (NASDAQ: AMGN), to reveal results of those longer-term, expensive outcome trials in the next year or two.
Further clouding the outlook for OCA—especially if one is looking past the immediate discussion regarding PBC and toward the horizon of NASH—is that very few PBC patients received OCA on its own. Most were also taking the standard of care, ursodeoxycholic acid, which is only effective in early stages of the disease.
UCSF’s Rosenthal says drug trials for NASH, especially Intercept’s FLINT trial, have shown “pretty good” evidence that with treatment, damage from NASH in adults and children could be reversible. But there are no drugs approved to date. A host of companies are racing to develop them. Gilead just paid $400 million for a drug that’s only been through Phase 1, with $800 million more to come if Gilead can move it to market. Gilead has another NASH drug in its pipeline, simtuzumab, although it recently failed to show any benefit in patients with the lung scarring known as idiopathic pulmonary fibrosis.
The French firm Genfit, with a presence in Cambridge, MA, has a NASH drug that just began a 2,000-patient Phase 3 trial. The company hopes to show enough for a faster approval by reading data from roughly half the patients after 72 weeks of treatment.
And after shelving its lead drug in HIV in 2013, Tobira Therapeutics (NASDAQ: TBRA) of South San Francisco, CA, shook up management and pushed the same drug ahead instead in NASH, with a Phase 2b trial underway.
Intercept’s OCA has made the biggest splash. The FDA granted it a breakthrough designation for NASH in early 2015, which could help speed up the review process. A year before, the Phase 2 FLINT trial ended early because OCA was performing so well, sending its stock to all-time highs over $450 a share. But that glow faded after more data emerged that underscored the itching and cholesterol concerns, followed by gloomier results in a separate trial in Japan.
A worldwide Phase 3 trial is ongoing, with final data due in 2021, but Intercept, like Genfit, wants to stop roughly half way to see if the data warrant an early approval. Because those patients would only take the drug for 72 weeks before evaluation, the benefit would be based on surrogate endpoints—it’s not enough time to show actual health benefits.
That’s why NASH followers want to see how the FDA’s advisors, and ultimately the agency itself in a final decision, react to the data Intercept is presenting for PBC patients. Intercept itself highlighted the uncertainty in recent regulatory filings: “We will face these risks for OCA for the treatment of NASH because of our plan to seek accelerated approval based on the [Phase 3] trial which incorporates interim co-primary surrogate endpoints.”
The panel’s recommendation Thursday isn’t binding, but the FDA doesn’t often stray too far from the advice it gets at these hearings. The agency’s final approval decision is due May 29.
Photo “White Oak — FDA” courtesy of thisisbossi via a Creative Commons license.