On the podcast this week, we are looking at recent advances in treating certain liver diseases. Jennifer Schranz is senior vice president and global head of rare diseases in the R&D division at Ipsen, and she discusses a breakthrough treatment for primary biliary cholangitis and cholestatic liver disease.
What is primary biliary cholangitis?
Primary biliary cholangitis is a genetic, chronic, progressive, autoimmune liver disease that affects more women than men. It involves inflammation and storage of toxins and bile acids in the liver that leads to cholestasis. This is where the flow of bile from the liver to the duodenum is impaired.
Schranz said this can lead to inflammation of the liver, which then causes many other symptoms, including fibrosis, or scarring. If untreated, this can lead to cirrhosis of the liver due to the toxins. And that can lead to complications, and ultimately, the need for a liver transplant, or death.
“It’s a chronic progressive liver disease that many women and men who have this condition may not be diagnosed with until they’ve had it for quite a bit of time because there is a period of time where it’s asymptomatic.
Schranz said around two or three people per 100,000 may have the disease.
“And there is some recent epidemiology that the prevalence seems to be increasing. So there most likely is a genetic predisposition. It’s got an autoimmune component, but there seems to be an event that leads to triggering it and then you get the buildup of the bile acids and the toxicity in the liver,” Schranz said.
What symptoms accompany primary biliary cholangitis, and what are the current treatments addressing this liver disease?
Schranz said symptoms such as fatigue, muscle aches and pains and joint pain are common, and it isn’t necessarily a disease. She said a simple blood test can diagnose primary biliary cholangitis, and early diagnosis is important.
The treatment available for around 30 years is called UDCA (ursodeoxycholic acid), Schranz said. It is a naturally-occurring bile acid. However, Schranz said, 40% of patients don’t respond to therapy, and some of the symptoms aren’t addressed.
She added there is a second-line treatment available, Ocaliva (obeticholic acid) in the U.S. and in Europe. The response rate to that drug is only 50%, Schranz noted. The other issue with the current second-line treatment, she explained, is that it may also worsen pruritis.
“What’s been exciting is that we have a potential new class of drugs that can hopefully help prevent the progression of the liver disease as well as improve some of the symptoms,” Schranz said.
What are the challenges in primary biliary cholangitis treatment?
Schranz said there are several challenges when it comes to developing new drugs to treat primary biliary cholangitis.
“Finding patients and getting them diagnosed appropriately, so diagnostic delay is a problem,” Schranz admitted.
“And often there’s misdiagnoses as well. The innovation requires creativity in doing clinical development because often you’re paving the path and trying to establish what the clinical endpoints could be for getting regulatory approvals, as well as often a challenge is really understanding the natural history of the disease so that you can appropriately make sure that what you’re studying in your clinical studies is appropriate for approval by the regulatory authorities, but also answering questions for the patient.”
Shrank added there are challenges with innovation as well. She noted the importance of collaborating with patient organizations to hear the voice of the patient; what they need and what the unmet need is for the disease.
“It’s really important to collaborate with regulatory authorities as well as payers for reimbursement because without that collaboration of all those groups the drug when approved will not get to the patient. So that’s really the importance of making sure there’s access,” Schranz said,
What is elafibranor?
Elafibranor is an investigational medicine, a PPAR alpha-delta, or a peroxisome proliferator-activated receptor alpha-delta, better known as a PPAR alpha-delta.
“It’s a new class of medicines and it’s a target for primary biliary cholangitis because it has an important role to play in bile acid metabolism inflammation as well as hopefully modifying, moderating the immune response,” Schranz explained.
“There hasn’t been a new class for primary biliary cholangitis for over 10 years. And so, we’re excited that this is really kind of the next generation for developing treatments for patients.”
Elafibranor is an oral medication, a pill taken once a day. As there is no cure for primary biliary cholangitis, the drug must be taken for life.
The ELATIVE trial
Ipsen presented full phase 3 primary biliary cholangitis treatment results from the ELATIVE trial at the AASLD’s (American Association for the Study of Liver Diseases) Liver Meeting recently in Boston, U.S.
“There was a lot of buzz regarding the fact that there’s a new class of drugs for this rare liver disease,” Schranz said.
“This is really the next generation for developing treatments for patients (with PBC).”
The ELATIVE study, which lasted for 52 weeks, has a long-term extension for up to five years.
“The study met its primary end point. One was the alkaline phosphatase level less than 1.67 times the upper limit of normal and greater than 15% reduction from baseline as well as having a total bilirubin, which is another blood test, under the upper limit of normal.
“So, with that biochemical composite endpoint, we were able to show that 51% of patients met it which is highly statistically significant, compared to 4% with placebo, which means if you’re on the medication, you’re 13 times more likely to get a biochemical treatment response. And currently, the thoughts are that this biochemical treatment response will be a predictor of long-term improvement on the inflammation and preventing the fibrosis and scarring. That has yet to be proven over the long-term studies, but this is the current clinical thought.”
Is a cure for primary biliary cholangitis in sight?
While there is currently no cure, Schranz said: “I think once these new class of agents become available and we can follow long-term to see whether we can prolong the health of patients, prolong liver health, avoid the long-term complications, as long as the drugs are taken chronically, that will be really an important scientific innovation.
“In my role at Ipsen, we’re always looking for the next generation of therapies both in cholestatic liver disease and other liver diseases. So, we’re always striving to find the best in class or first in class medicines to help treat these diseases.”
Next steps for elafibranor
Schranz said the next step for the drug is simultaneous global regulatory submissions.
“And then it’s our job to ensure that we then work with the regulators to get the drug approved and then ensure that once that happens, we can work with payers and access such that patients have the drug such that patients have the drug available to them as quickly as possible.”
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