[Corrected 4/25/17, 12:30 p.m. See below.] About 7,000 liver transplants occur in the U.S. each year. A condition that few people can pronounce, and no one has a treatment for, has become a main reason for those transplants.
That’s why several rich, powerful drug companies are in the final expensive stage of testing new drugs to treat the liver disease nonalcoholic steatohepatitis, or NASH: there is urgent medical and financial incentive to stem the transplant tide. NASH can also lead to liver cancer.
As the name implies, it’s not drinking that leads to the serious liver damage that characterizes NASH, but typically bad diet and sedentary lifestyle—yet more fallout from the obesity epidemic, with an estimated three to 12 percent of Americans already showing signs of NASH.
Even though it is lagging behind others closer to regulatory approval, privately held NGM Bio thinks it can compete. Researchers are presenting data today that show a handful of NASH patients had the fat in their livers revert to normal levels after 12 weeks of daily injections of a drug from NGM, based in South San Francisco, CA. Their liver fat content was “normalized” back under the threshold of five percent, according to Stephen Harrison, medical director of Pinnacle Clinical Research in San Antonio, TX, and the lead investigator in NGM’s Phase 2 study. Harrison is presenting the data today at the annual International Liver Congress in The Netherlands.
Thanks to a major deal with Merck (NYSE: MRK), NGM’s research is mainly paid for, which is why they can jump into the high-stakes NASH fray. But Merck does not have rights to NGM’s NASH candidate, called NGM-282, which is an engineered version of the hormone FGF19.
The new results are full of caveats, not least of which is the small sample size. In the double-blind study, fifty-three people received NGM-282 and received either a lower or higher dose. (Twenty seven more received placebo.) Of those receiving NGM-282, 79 percent saw at least a five percent reduction in liver fat—the main goal of the study—and 34 percent, or 18 people, returned to a normal level after 12 weeks.
In the two dose groups combined, 47 of 53 patients had a reduction of liver fat of at least 30 percent.
“The data are encouraging, showing the reversal in such a short time,” said Anjana Pillai, medical director of the University of Chicago’s Liver Tumor Clinic. [A previous version of this story misspelled Pillai’s name.]
(Rivals Gilead Sciences and Bristol-Myers Squibb also presented Phase 2 NASH liver-fat reduction data at EASL yesterday. Bristol’s study was roughly the same size as NGM’s, with 24 of 44 patients across two dose levels hitting the 30 percent reduction mark; Gilead presented data from only 10 patients.)
Pillai and other liver specialists not involved in the study were cautious about the NGM data. A fatty liver does not necessarily lead to NASH, and so a reduction of liver fat doesn’t necessarily equal treatment of NASH.
For a NASH treatment to be successful, two other factors would also need to be reversed: scarring (also called fibrosis) and inflammation. “Ideally it would be best for all three markers to regress,” said Pillai.
Easier said than done. It’s unclear why roughly 10 to 20 percent of people who show the early signs of fatty liver develop the severe fibrosis of NASH, while many others don’t.
The NGM study noted that the level of several proteins associated with liver damage, and fibrosis in particular, also went down after 12 weeks. But Harrison was careful not to draw conclusions. Two proteins, abbreviated as TIMP1 and PIIINP, are not yet “well accepted” as stand-ins, or surrogates, for NASH fibrosis. Their decrease “begin(s) to tell a story that there may be an effect on fibrosis,” he said via email. “However, we would not expect a significant change in fibrosis at only 12 weeks.”
“We need to see the long term effects, for sure,” said Pillai. “Is there really reversibility, and how much? If you have Stage 2 scarring and can go back to Stage 1”—with Stage 1 being normal and Stage 4 indicating cirrhosis—“that would be very encouraging.”
It will take a much longer study to see potential fibrosis reversal. And NGM is also years behind NASH drugs from Tobira Therapeutics, a division of Allergan (NYSE: AGN), Intercept Pharmaceuticals (NASDAQ: ICPT, Genfit, and Gilead Sciences (NASDAQ: GILD). All are in Phase 3 studies that aim to show over years, not weeks, that they can reverse fibrosis. Intercept’s drug is the first to be approved—for a different degenerative liver condition called primary biliary cirrhosis.
Another caveat was a notable spike in bad cholesterol levels among the patients taking NGM-282. It wasn’t too surprising; the Intercept NASH drug obeticholic acid (OCA) also caused a cholesterol jump in an earlier Phase 2 trial called FLINT. In FLINT, the levels went back down after treatment with statins, the standard medicine for high cholesterol.
NGM has also reported at EASL that a similar up-and-down effect occurred in a preclinical trial with NGM-282, using monkeys as test subjects, also taking statins. A human study is underway; NGM has data on 15 people so far and says the effect is similar to that in monkeys.
But doctors are keeping an eye on the cholesterol data; regulators are likely to take note, too, and weigh the added risk against the benefit of treating a rapidly growing unmet medical need. “Most patients with fatty liver disease will die of heart disease, not liver failure,” said Jaideep Behari, founder of the University of Pittsburgh Medical Center’s Fatty Liver Clinic. “So a medicine that increases cardiovascular risk is obviously concerning, especially if you have to take it long-term.”
At some point, NGM president Jeff Jonker said NGM will explore a version of NGM-282 that would require less frequent injections. For now, though, the daily injections the drug requires gives pause to University of California, San Francisco director of pediatric hepatology Philip Rosenthal. Many NASH patients are diabetic, as well, so they might have two daily injections to deal with. “I’m sure patients will love that,” said Rosenthal with a note of sarcasm.
Jonker said that strong results would “overcome any hesitancy” about a daily injection, and that people already taking daily shots for diabetes would be “familiar” with the regimen. (NGM declined to discuss pricing, saying it was too early.)
NGM’s next step: Start what they’re calling a “Phase 2b” trial to test doses of NGM-282 lower than 3 mg. The study will be designed to test not just if NGM-282 can trigger the short-term indirect signs of fibrosis reversal that cropped up in the Phase 2 study, but also if it can lead to longer-term changes, taken from a liver biopsy.
Jonker declined to say how long the Phase 2b patients will stay on the drug, or whether it will be designed to lead directly to a request for FDA approval. The design of the trial, Jonker said, “will permit the assessment of the full impact of the compound after an appropriate duration of treatment.”