The National Institutes of Health estimates as many as 12% of U.S. adults have an illness called non-alcoholic steatohepatitis, or NASH. That's about 30 million people.
NASH is a kind of fatty liver disease characterized by inflammation and scarred tissue, which in turn can lead to liver cirrhosis and, in the some severe cases, cancer. In spite of its large patient population and potential life-threatening effects, no Food and Drug Administration approved treatments are on the market.
But that could change in the not-too-distant future. Several candidates are in late-stage testing, and dozens more occupy earlier spots in the global pipeline.
The viability of these treatments isn't guaranteed, though. NASH frequently goes undiagnosed, in part because to do so requires a liver biopsy — a procedure that physicians are loathe to do without a clear need. Better diagnostics are on the way, but they aren't the sole limiting factors.
Investors and analysts have been skeptical of the approval chances for some of the most advanced NASH candidates. And on a larger scale, they're still trying to figure out the market segment that will suit each candidate.
Few near-term prospects
BioMedtracker, a product from business intelligence firm Informa, counts 48 NASH drugs in clinical trials: 14 at Phase 1, 30 at Phase 2 and four at Phase 3. Making up the latter group are:
- Gilead Sciences' selonsertib, an inhibitor of apoptosis signal-regulating kinase 1
- Allergan's cenicriviroc, a dual antagonist of C-C chemokine receptor types 2 and 5
- GenFit ’s elafibrinor, a dual agonist of the peroxisome proliferator−activated receptors alpha and delta
- Intercept Pharmaceuticals' Ocaliv (obeticholic acid), an agonist of farnesoid X receptor
Selonsertib obstructs the activation of two enzymes, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that can cause inflammation, hepatocyte injury and fibrosis, the liver scarring that can be a result of NASH.
Cenicriviroc helps in mediating the immune cascade for inflammation and fibrosis.
Elafibrinor aids proteins that maintain liver homeostasis and helps to stop the main cells responsible for liver fibrosis.
And Ocaliva promotes a protein that regulates triglyceride levels in the liver, among other things.
These drugs command much of the attention surrounding NASH treatment. But, as was the case with hepatitis C, combination therapies are also stealing some of the spotlight. Gilead, for instance, has been investigating selonsertib paired with two other of its NASH assets, GS-0976 and GS-9674.
NASH pipeline crowds at mid-stage, but has few advanced candidates
- butanoic acid
- BI 1467335
- remogliflozin etabonate
- Ocaliva (obeticholic acid)
Each of the four late-stage assets have trial readouts coming next year, but the drugs have garnered different levels of optimism from shareholders and physicians.
Recent surveys from Cowen & Co. found investors held a more favorable view of the chances of Phase 3 success for Intercept's Ocaliva than did a panel of physicians. The opposite was true for Allergan's cenicriviroc. Both groups reported modest optimism for Gilead's selonsertib and skepticism for GenFit's elafibrinor.
The mixed views reflected a variety of factors, including concern over Ocaliva's recent black box warning for its other indication, and what Cowen called "murky" data from the Phase 2 GOLDEN trial of elafibrinor. Phase 2 data also raised eyebrows for cenicriviroc, whereas the outlook for selonsertib was generally positive — provided Gilead only enrolls a specific group of patients in the later-stage investigations.
To that end, weighing on all the treatments were the patients they target. The severity of fibrosis falls on a ranking system with F0 denoting no fibrosis and F4 marking cirrhosis. Gilead is looking to show through its tests that selonsertib is effective in F3 and F4 patients, while other drugmakers are shooting for more moderate populations.
"I'm not sure the critical need in the earlier stage NASH patient is quite as much as the later stage, where you're looking at a liver transplant as more imminent. The earlier stages can resolve on their own with a dietary change and lifestyle change, so the commercial potential there might not be as great," Jack Allen, senior analyst at Informa subsidiary Datamonitor Healthcare, told BioPharma Dive.
Outside of Phase 3, Madrigal Pharmaceuticals investors are keeping a close eye on MGL-3196, which targets Thyroid Hormone Receptor-beta, a protein that contributes to the regulation of cholesterol and triglyceride levels in the liver.
It's currently in mid-stage testing, with 36-week liver biopsy data coming soon. Analysts and physicians have highlighted the drug's promising mechanism of action and efficacy (Phase 2 trial results showed patients treated with MGL-3196 had an average 36.3% reduction in liver fat compared to placebo after 12 weeks). Investors predict its chances of success in Phase 3 are around 50%, according to Cowen.
In an April 8 note, EvercoreISI analysts wrote they have "a high degree of optimism for strong biopsy results," for MGL-3196, though they recognized many unknowns remain. "We think the best approach is to take some of the pressure off expectations for the data, realizing the sound mechanism and early path trends is a great start. If we get much more than that, we’re more than happy to take it!"
Notably, Cowen's surveys found the NASH community most bullish on MGL-3196 and the triple combination of Gilead's drugs.
But where is the pipeline headed?
The NASH population breakdown isn't precisely known. Cowen gathered through its surveys that an estimated 30% of patients with the disease are at the F3 stage, while 20% are at F2.
But the data is mixed. A January study in The New England Journal of Medicine said a smaller amount, approximately 25%, of NASH patients have F2 or worse fibrosis.
"These differential risks will therefore likely play into the treatment strategy for NASH in the future, and should be kept in mind when considering the commercial potential of drug candidates in development," Cowen wrote in its report. "Anti-fibrotics would likely be used for the more advanced patients, while lipid-lowering/anti-inflammatory agents would be prescribed for the less advanced NASH population."
Again, better diagnostic testing will provide a clearer window into segmentation. But some expect there will be plenty of money to go around; often-cited analyst predictions have the global NASH drug market hitting a crest between $20 billion to $35 billion. The market for NASH biomarkers is also slated to reach the multi-billion-dollar mark by 2025, according to a July 2017 report from Grand View Research.
Still, some say these valuations may be a little overzealous.
"A lot of the companies have been saying recently that they think the market is a little bit overvalued right now, and people are paying pretty extreme premiums," Allen said. "So I'm not sure that anyone's going to jump into a space that hasn't really even been fully drawn out yet and take that risk in the immediate future."
For the companies already on the frontlines of drug development, there's much to prove. In addition to demonstrating the safety and efficacy of NASH treatments, they'll have to contend with pricing decisions and securing payer support should their candidates gain approval.
"You would like to think that insurers and others would say clearly this is a good investment because ... otherwise we're going to be looking at having to treat people who have cirrhosis or perhaps advanced cirrhosis, liver cancer and transplantation," American Liver Foundation President and CEO Tom Nealon told BioPharma Dive.
Nealon added that while there may be concerns NASH goes the way of new hepatitis C treatments — which essentially cured patients but carried high list prices — the bigger worry in the liver disease arena is payer pushback.
Yet the unmet medical need continues to put pressure on healthcare providers.
Nealon says that in talks with doctors, "they all agree that it is rapidly becoming the number one national health crisis and they certainly are eager for something because they regularly are encountering younger and younger people who have serious [NASH] issues."