The first-ever marketed medicine for the fatty liver disease known as nonalcoholic steatohepatitis, or NASH, could be on the horizon. The data, from a closely watched drug known as obeticholic acid, aren’t perfect. But they are nonetheless expected by the drug’s developer, Intercept Pharmaceuticals, to be good enough to support approval.
Intercept (NASDAQ: [[ticker:ICPT]]) this morning provided an interim look at a 2,370-patient NASH study known as REGENERATE. The New York company said OCA, a once-a-day pill, succeeded in one of two main goals of the study: The drug, over 18 months of treatment, helped reduce liver scarring in NASH patients better than a placebo.
OCA didn’t hit on its other main goal. It didn’t lead to a statistically significant difference in NASH “resolution”—that is, an agreed-upon abatement of various symptoms of the debilitating disease, which is a leading cause of liver cirrhosis and liver failure. But OCA still did enough to succeed: When Intercept amended the trial’s design in early 2017, succeeding on just one of its two main goals was deemed enough by the FDA to file for approval. Intercept thus plans to file its application—which would be the first ever for the disease—in the U.S. and Europe in the second half of 2019.
Intercept will present detailed data from the study at the European Association for the Study of the Liver’s International Liver Congress in April. Intercept CEO Mark Pruzanski said on a conference call to discuss the preliminary data that the company believes the data are enough to support regulatory approval, even if the study hit only the liver scarring reduction goal, or endpoint.
“We’ve long been saying that of the two, that is by far and away the more important, more clinically, and frankly, commercially, relevant endpoint,” he said.
Intercept shares surged 23 percent, to $136 apiece, in pre-market trading on Tuesday.
NASH is a liver disease driven recently by the obesity epidemic and sugary diets. It occurs when the livers of a portion of patients with fatty liver disease becomes inflamed, stiff, and scarred, and it leads to thousands of liver transplants a year in the U.S. alone. There are no approved drugs for NASH: OCA is the first in a long, growing line of experimental treatments to near the finish line, followed by a drug from the French firm Genfit (NASDAQ: [[ticker:GNFT]]) and many more. Pharmaceutical companies and biotechs including Gilead Sciences (NASDAQ: [[ticker:GILD]]), Bristol-Myers Squibb (NYSE: [[ticker:BMY]]), Allergan (NASDAQ: [[ticker:AGN]]), Madrigal Pharmaceuticals (NASDAQ: [[ticker:MDGL]]), Viking Therapeutics (NASDAQ: [[ticker:VKTX]]), and more are all in the race with different types of drugs.
Intercept has been well ahead of the pack ever since announcing Phase 2 results in early 2014 that effectively put the company, and NASH, on the map. Today’s results solidify that position.
The results come from 931 NASH patients with either stage 2 or stage 3 liver disease—Stage 1 is normal and Stage 4 is cirrhosis—on either a placebo (311 patients) or a low (10 mg, 312 patients) or high (25 mg, 308 patients) dose of OCA for 18 months.
For the study goal that it hit, Intercept said 17.6 percent of patients on a low dose of OCA and 23.1 percent of those on a high dose of OCA saw a reduction in scarring—that is, by at least one stage—with no worsening of their disease compared to 11.9 percent of placebo patients.
On the measure OCA missed, 11.2 percent and 11.7 percent of low and high dose patients, respectively, had NASH resolution and no increase in liver scarring, compared to 8 percent of placebo patients. The results weren’t statistically significant.
The most common side effect seen with OCA, as in other studies of the drug, was itching. Intercept said most of these cases were mild to moderate, though severe cases were seen in 5 percent of patients in the high-dose group—and in some instances led patients to drop out of the study.
The other significant concern going into the REGENERATE study was OCA’s impact on patients’ cholesterol levels. Patients with liver disease often die of heart disease, so clinicians have expressed concern with the idea of chronically giving NASH patients a drug—OCA—that could raise their cholesterol. Intercept said OCA was associated with a peak increase of 22.6 mg per deciliter of blood of LDL-C, or “bad” cholesterol after four weeks, but those numbers reversed and decreased to a 4.0 mg/dL increase from the start of the study after 18 months. There were “few and varied” serious cardiovascular events in the study, and they were balanced across each arm of the trial: 2 percent of placebo patients, 1 percent of low dose OCA patients, and 2 percent of high-dose OCA patients.
Additionally, more patients (3 percent) on a high-dose OCA had either gallstones or cholecystisis—an inflammation of the gall bladder—compared placebo (less than 1 percent) or low-dose OCA (1 percent) patients.
Taken together, “the overall magnitude of benefit and the associated safety/tolerability profile [of OCA] raises questions about the drug’s commercial prospects,” wrote Leerink analyst Joseph Schwartz, in a note to investors. Schwartz considered the drug’s effectiveness “less-than-stellar,” leaving it unclear how much OCA will help NASH patients over the long haul. Schwartz was also concerned “about the impact of [itching] and drug discontinuation rates on commercial uptake.”
OCA is already FDA approved to treat a different liver disorder, primary biliary cholangitis (PBC), in which a patient’s immune system attacks the organ. Intercept markets the drug under the brand name Ocaliva. Executives said it’s too early to discuss how OCA in NASH would be priced compared to Ocaliva. But Pruzanski said that itching is a known side effect that has been addressed for PBC patients.
“We feel in the vast majority of patients, it is very manageable out in the real world setting,” he said during the conference call. “That has certainly been our experience in marketing Ocaliva for PBC. We’re confident we’ll be able to do so again on the NASH side.”
Another analyst, Jay Olson of Oppenheimer, asked during the call whether the itching experienced by patients in the NASH study indicates those most likely to respond to the drug. Pruzanski said it’s an “intriguing question,” and the company’s experience in PBC shows that the itching is dose dependent, but whether that correlates with improvement in the liver needs more study. How the company adjusts the dosage in NASH is something Intercept will need to discuss with regulators, he said.
Intercept still hopes to build a better case for OCA. The REGENERATE study will continue tracking patients, and Intercept will see whether it can lower rates of death, hospitalization, cancer, and more.
Here’s more on Intercept and NASH.
