There is a June 22 PDUFA date for obeticholic acid, which if approved would become the first FDA-approved treatment for NASH.
For patients with non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), June 22 could be a historic moment as the long wait for a US Food and Drug Administration (FDA) approved treatment might come to an end.
If all goes according to plan, Intercept’s obeticholic acid (OCA) will become the first ever approved treatment for NASH on June 22, a sigh of relief for the growing number of patients with the disease.
But it also begs the question, why has it taken so long for a treatment to emerge for a disease that currently impact between 80 and 100 million individuals in the US?
The answer to that is multi-pronged.
“The disease is complex. The FDA’s standards are challenging. It is difficult to recruit patients,” are all answers by doctors and stakeholders when asked this question.
In an interview with HCPLive®, Arun Jesudian, MD, a transplant hepatologist NewYork-Presbyterian Hospital/Weill Cornell Medical College, said the lack of approved treatments up until this point is not due to a lack of trying.
“I think the easy answer is that NAFLD and Nash is a complicated disease to treat medically,” Jesudian said. “Clearly, we know fat leads to inflammation and fibrosis and scarring in the liver. But how to address that in terms of medications is a complicated undertaking.”
This is largely because the FDA looks for specific outcomes in clinical trials, in this case they want liver biopsies to show the actual fat and inflammation resolve and and/or the amount of scarring fibrosis improves or doesn’t get worse. These have largely been difficult outcomes to meet.
It remains difficult, if not impossible, to make meaningful reductions in the prevalence of a disease in absence of an FDA approved therapy. While diet and exercise can go a long way toward accomplishing this goal, lifestyle interventions are difficult to implement when the patient likely wouldn’t see immediate results.
But there is some hope that the FDA will relax the stance on biopsies being the predominant tool to assess liver disease.
“I think there is some momentum building towards noninvasive assessments of both fat and inflammation and even fibrosis in the liver,” Jesudian said. “There's a lot of hope that it'll be easier to enroll patients and trials, if we can replace biopsy with non-invasive assessments.”
He said technology has improved in recent years giving up that non-invasive maneuvers can prevail. For example, MRI’s have emerged as a potential assessment tool with the ability to determine the different liver manifestations of NAFLD and NASH.
For the time being, the hope lies in OCA, with the June prescription drug user fee act (PDUFA) date. The drug has shown safety and efficacy in the phase 3 REGENERATE study of patients with pre-cirrhotic liver fibrosis due to NASH. The results show OCA 25 mg consistently demonstrated double the response rate of placebo in reduction in liver fibrosis stage without worsening of any of the three histologic components of NASH—fat, inflammation, and fibrosis.
In addition, there are a number of classes of medications currently being explored as viable treatments for NAFLD and NASH, largely because the actual pathway that leads from fat in the liver to inflammation to fibrosis is extremely complicated.
One issue that has plagued clinical trials in the past is assessing the disease through liver biopsies can lead to do sample errors because certain areas of the liver can have more fibrosis or more inflammation. A. Sidney Barritt IV, MD, MSCR, Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Director, UNC Liver Center, said trials for NASH often have screen fail rates that can approach 70-80%.
Furthermore, NASH trials show a very high placebo rate, sometimes reaching a placebo rate approaching 33%, creating a higher bar for a drug to show efficacy.
Another challenge that is hampering clinical trials is that many patients with NASH have significant metabolic comorbidities. For example, many trials are enrolling patients with diabetes, which could lead to challenges in achieving success.
“And some trials allow hemoglobin A1c’s that go up to 8%, 8.5%, even 9%,” Barritt said. “And if you have a liver centric drug that's looking to say reverse fibrosis, yet a patient has very poorly controlled diabetes and thus sort of the ongoing impetus for fat inflammation and ultimately scar tissue. It becomes very difficult for these trials to show success.”
In absence of an approved treatment, the main advice from clinicians to patients centers on weight loss and other lifestyle interventions.
“When we talk about patients with NAFLD and Nash, that they have metabolic syndrome comorbidities and that can include weight, insulin resistance for overt diabetes, dyslipidemia, and hypertension,” Barritt said. “And so all of this starts with risk factor control and maintaining a healthy weight or losing weight is a big part of the other 3 metabolic syndrome risk factors.”
The current estimate is NAFLD presents in approximately 75% of individuals who are overweight and 90% of individuals with severe obesity.
Barritt said weight loss is proven to really help patients with fatty liver disease. For example, a 5% weight loss can reduce fat in the liver, a 7% weight loss can reduce inflammation, and a 10% drop in weight can help reduce fibrosis in the liver.
Moreover, how the patient loses weight is also important.
“We want patients to lose weight through constructive processes,” Barritt said. “We don't want somebody developing maladaptive relationships with food in order to satisfy a number on a scale. And so it's about reducing high fructose corn syrup producing trans fats and sort of cleaning up what they're eating.”
In addition, the dietary changes must be paired with exercise. In fact, research has shown that both aerobic and anaerobic exercise can help patients with fatty liver by burning excess calories and increasing skeletal muscle to increase the resting metabolic rate and improve insulin resistance.
Barritt is part of the ongoing TARGET-NASH program, an observational study of participants with NAFLD and/or NASH in usual clinical practice. TARGET-NASH is part of a series of Target RWE studies focused on several diseases, including inflammatory bowel disease and asthma.
Should a treatment gain FDA approval in the coming years, the value of a program like TARGET-NASH comes in the role of post-marketing surveillance of real-world safety and efficacy of the treatments.
“Once these drugs are clinically available, or commercially available, rather, a lot of people are going to be taking them and are these drugs as effective in these heterogeneous real world populations as they were in the clinical trials,” Barritt said. “So a clinical trial can show us efficacy. What we're looking for through the TARGET-NASH cohort is to show clinical effectiveness in real world populations. Hopefully, those two things will be the same.”
There also is a perception problem when it comes to liver disease. Lorraine Stiehl, chief executive officer of the American Liver Foundation, said many in the general population assume liver disease is universally caused by alcohol abuse.
“I think part of it is people were writing off fatty liver as they have behavioral issue,” Stiehl said. “There was a thought it was behavioral and exercise diet could handle it. Well, exercise diet can handle type 2 diabetes, and cardiovascular and yet, look at all the drug classes that have emerged.”
The perception of liver disease has also trickled down to drug development.
“I think our world had focused on type 2 diabetes, obesity, cardiovascular issues, that is where all of the drug activity, drug development has occurred,” Stiehl said. “And they don't talk the day downstream of those comorbidities, which is fatty liver and NASH.”
While there is only so much that can be done until there is an approved treatment, organizations like the American Liver Foundation do have a role in improving care for patients with either NASH or NAFLD. For example, they operate a screening program called “Think Liver Think Life” to help increase early screenings for the diseases.
And there remains a big need for advocacy groups and programs to emerge in the hepatology space.
“I think that the liver has been ignored for decades,” Stiehl said. “And that is, in all honesty, probably the association with alcohol and liver, people think you have a liver problem, they immediately think you have a problem with alcohol. And there are hundreds of diseases in the liver space. And I just saw how few resources were going into liver and yet the problem is just even that much greater. And I think a part of it is that we haven't had the national awareness and attention.”
And ultimately an FDA approval can go a long way toward incentivizing drug development companies in testing new and innovative products for liver disease and treat the growing problem that is fatty liver diseases in the US.
“Once you pave the way, with one FDA approval of drug, so many more companies are going to step up and engage,” Stiehl said. “Forget the past, the future is now and let's get something approved. And then they'll be it'll open the floodgates.”