Although the number of people with nonalcoholic fatty liver disease, which progresses to nonalcoholic steatohepatitis (NASH), is growing, the health system is still trying to get a handle on which patients to target and how to identify them before the first treatments come to market, explained panelists during a session at AMCP Nexus 2019.
Although the number of people with nonalcoholic fatty liver disease (NAFLD) is growing, the health system is still trying to get a handle on which patients to target before the first treatments come to market, explained panelists during a session at AMCP Nexus 2019.
Wing-Kin Syn, MD, PhD, attending physician, Medical University of South Carolina, started the session with a discussion of clinical progression and how to identify patients for treatment. NAFLD is a result of accumulation of fat in the liver, and it is commonly associated with risk factors like obesity, type 2 diabetes, hypertension, and hyperlipidemia. Some of the less known risk factors are obstructive sleep apnea, polycystic ovary syndrome, gout, and hypothyroidism, explained Syn.
NAFLD states as simple fat, which impacts and 20% to 30% of those individuals who progress to nonalcoholic steatohepatitis (NASH). Another 20% to 30% of individuals progress to more advanced NASH fibrosis, and the final stage is NASH cirrhosis. It used to be thought that progression from early stage NAFLD to cirrhosis took decades, but recent studies have shown that some people progress rapidly within 2 years. However, research has also shown that there is reversibility.
“The question, then, is who are the individuals who regress?” Syn asked. “Well, that remains a challenge to identify.” It is also unclear how to identify those people who have slow progression versus rapid progression.
Not all fatty liver disease is the same, Syn added. Patients with a lot of scar damage are at the most risk of liver death. Patients can be stratified by stages of fibrosis (0-4) and those in stages 2-4 have additional complications and are most likely to succumb to liver death. Patients who have NASH fibrosis also have lower patient-reported outcomes with worse physical health, more fatigue, and less vitality.
It’s important to pay attention to NAFLD because of the cost of the disease and the real public health impact it is having. About 2% to 3% of the US population has NASH cirrhosis, which compares with 8% for type 2 diabetes, 2% for hepatitis C virus (HCV) infection, 0.5% for HCV cirrhosis, and 0.3% for colorectal cancer.
“The elephant in the room really is this condition,” Syn said. He added that the annual direct medical costs are estimated to be more than $100 billion.
An important area will be figuring out which patients to target. Right now, liver biopsy is the gold standard, but it is expensive and painful with bleeding. Other tests being used include liver function tests, which are neither predictive nor indicative of NASH or fibrosis; ultrasound, which is the cheapest and quickest to do; and cross-sectional imaging, which isn’t routinely done and only can distinguish very extreme cirrhosis.
There are some noninvasive tests available that are not widely used, such as vibration-controlled transient elastography, which measures liver fat, and magnetic resonance elastography. However, a lot of the modalities are still under research.
“It is clinically important to identify those with significant or advanced fibrosis,” but at this time it’s difficult to identify those patients at risk, Syn said.
So far, NASH has been staying under the radar since there is nothing approved yet to treat it, said Karen Watkins, PharmD, BCOP, emerging therapeutics strategy pharmacist, MedImpact. There had been comparisons of NASH to hepatitis C, but that isn’t the most accurate comparison, she said, since there is not only a high prevalence of NASH, but it is also chronic in nature.
NASH, she said, is not going away. This is not going to be a hot topic for just a few years. “It’s more likely to be the next diabetes, not the next hep C, which I would say is probably even a little bit more alarming,” Watkins said.
Even though there are no FDA-approved drugs, Vitamin E and pioglitazone are both recommended to be used off-label to treat NASH as of now. Vitamin E can only be used in noncirrhotic patients, and there are concerns about increased death in patients taking high doses, as well as higher rates of prostate cancer and hemorrhagic stroke. Pioglitazone is an antidiabetic, and it could be associated with weight gain, which is an issue in patients with NASH since the majority of them are already obese—weight gain would not be an acceptable side effect for this population.
“Clearly, there is significant unmet need in terms of drug therapy in NASH, and this is why it is a major area of drug development and there is a lot of interest in this space currently,” Watkins said.
On day 1 of AMCP Nexus 2019, Aimee Tharaldson, PharmD, senior clinical consultant for emerging therapeutics at Express Scripts, detailed the NASH pipeline in her session. During her session, Tharaldson noted that most of the drugs in development have different mechanisms, which Watkins also highlighted. The fact that there are many different mechanisms being explored means any treatments are unlikely to be magic bullets—we’re likely going to see combination therapies instead.
There are currently 18 drugs in phase 1 development, 38 in phase 2, 4 in phase 3, and only 1 is under FDA review: obeticholic acid (OCA). For NASH trial design, there are 2 surrogate end points that support accelerated approval:
Only 2 drugs (OCA and cenicriviroc) have achieved significant improvement in fibrosis. There are others that have rates of fibrosis improvement but did not achieve statistical significance. And only 3 drugs (elafibranor, resmetirom, and aramchol) achieve statistically significant rates of NASH resolution.
“I think it’s interesting to highlight that there was no drug that achieved a statistical benefit for both of these end points,” Watkins said. “I think that goes back to…the fact that we’ll likely need multiple drugs to really have benefit on all these end points at once.”
Until one or more of these drugs hit the market, there will be a host of unanswered questions, such as the size of the population, details of the label, what guidance there will be on who can get treatment, and price points.
OCA is expected to be used in a more limited population, at least initially, and so there is likely going to be a higher specialty drug price point, Watkins said. There are predictions that the cost may be $10,000 to $20,000 when OCA first launches. However, as more drugs hit the market and combination therapies start coming out, prices will likely come down as the landscape changes.
“…This will be a rapidly evolving landscape, so what we see in the next year or so will look very different in the next 5 to 10 years,” Watkins said.