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Liver disease is becoming more prevalent in the UK, and it is the only major chronic disease where death rates are rising.1
Over the past few decades, new medications, technologies, and other innovations have been developed to try and tackle this growing need, but innovations in rare liver disease are still lacking.
For example, there have been no new effective treatments for primary biliary cholangitis (PBC) – a rare, auto-immune cholestatic liver disease – for more than a decade.
Now, exciting new trial data is providing a glimmer of hope for patients affected by this debilitating disease.
To gain a better understanding of PBC and the treatment and management options, PHT spoke to Jennifer Schranz, Senior Vice President and Global Head of Rare Diseases at Ipsen.
What is primary biliary cholangitis (PBC)?
Primary biliary cholangitis is a “rare, chronic, progressive liver disease,” explains Dr Schranz.
It is an autoimmune disease which progressively destroys the bile ducts, causing bile and other toxins to build up in the liver (known as cholestasis).
PBC affects two to three people per 100,000; primarily women aged 40 and older, with nine women diagnosed for every man.2,3
If left untreated, PBC can lead to cirrhosis and liver failure, and it is a leading cause of liver transplantation.4
Symptoms of PBC
Patients with PBC are likely to present with symptoms such as pruritis (itch), fatigue, and brain fog. In advanced stages, patients may present with jaundice and oedema.
“However, around 60% of the time, it’s asymptomatic,” Dr Schranz explains, with symptoms only appearing when the disease becomes advanced.
Itch and fatigue have the most significant negative impact on quality of life, and Dr Schranz says pruritus can be “so severe that it keeps patients up all night.”
Despite the severity of these symptoms, Dr Schranz says a lot of the time “women are not listened to.”
“They go to their doctor and say ‘I’m tired, I work a lot and I’ve got kids’, and it gets [brushed off]. The doctor may think the patient has an allergy which is causing the pruritus, and the fatigue is simply down to their lifestyle.”
The fatigue can be particularly debilitating in patients with advanced PBC, and patients may struggle to carry out day to day tasks, like going to work, cooking and cleaning.
In fact, 60% of patients report a loss of work productivity, whether that be in the home or outside of the home.5
“So it has a pretty devastating impact on the economy considering the role women play,” Dr Schranz says.
The impact this disease has on patients has been recognised by UK-PBC and the British Society of Gastroenterology (BSG), who recommend that all patients with PBC should be offered the chance to seek support from patient support groups.6
Mo Christie, Head of Patient Services, PBC Foundation, UK said: “Living with PBC can be very challenging for many people. The fear of the disease progressing hangs over you, and you have to manage as best you can with the daily symptom burden, symptoms that can sometimes be so debilitating it takes every ounce of strength to get through another day.”
“As someone who is living with PBC, I appreciate the need for clinicians, other patients, and families to understand the condition and the impact that coming to terms with living with an incurable condition can have on a person’s life. The impact can be enormous, so it is vitally important to all aspects of our lives that we can access knowledge, care and effective medicines, when we see our clinicians.”
Diagnosing PBC
Patients who present with any of the above symptoms should be screened for PBC, as this may indicate abnormal liver function.
Around 95% of patients with PBC have circulating anti-mitochondrial antibodies (AMA), which can be screened for with a blood test.7
Physicians should also conduct an Alkaline Phosphatase (ALP) test, as patients with PBC typically have high levels of this enzyme in the blood.
Although liver biopsy is not mandatory for diagnosis, it can help to diagnose patients with AMA-negative PBC and to help stage the disease and differentiate PBC from other cholestatic liver disorders.
Delayed diagnosis common among PBC patients
Research shows that most patients with PBC are diagnosed between the ages of 35 and 55.7 Dr Schranz says this is partly due to a lack of awareness among healthcare professionals, which can cause symptoms such as pruritus and fatigue to be overlooked.
Dr Schranz highlights the importance of listening to patients and taking symptoms such as fatigue and itching seriously.
“When the itching and fatigue is out of proportion and it’s not getting better with topical steroids and antihistamines, that’s when it’s time to think about PBC,” she said.
“Doctors should be performing routine bloodwork and conducting the alkaline phosphatase test if they suspect PBC.
“It’s important to diagnose it early before the cholestasis sets in, as this causes necrosis … which can lead to fibrosis and then cirrhosis,” she added.
Treatment and management of PBC
Ursodeoxycholic acid (UDCA) is the main first-line treatment for PBC. It’s a natural bile acid which can help to prevent or delay liver damage in most people if treatment is begun in the early stages of the condition.
However, this treatment is not effective in around 40% of patients, and it does not improve symptoms such as pruritus and fatigue.8
Guidance states that those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure should be considered for second-line therapy.6
Currently, the only second-line treatment for PBC licensed by NICE is obeticholic acid (OCA). OCA has been associated with improvements in biochemical surrogates of disease activity reasonably likely to predict improved outcomes.6
The addition of OCA is therefore recommended for patients with an inadequate response to UDCA or patients who are intolerant of UDCA.
Emerging treatments
With only two licensed treatment options for this life-limiting disease, Ipsen has been working hard to develop another treatment option for patients with PBC, and now, a Phase III clinical trial has shown promising results.
“We’re super excited about elafibranor because it’s the first innovation in over a decade to help treat PBC,” said Dr Schranz.
Elafibranor is an oral, dual PPAR α,δ agonist, which modifies the metabolism of bile acids and prevents ongoing fibrosis.9
In the trial, elafibranor significantly improved the biomarkers of disease progression, with roughly half (51%) of patients on elafibranor 80mg achieving a biochemical response compared to 4% in the placebo group.9
This was defined as a reduction in alkaline phosphatase and bilirubin at 52 weeks, both of which indicate reduced cholestatic injury and improved liver function. However, improvements were seen as early as week four.
Not only can elafibranor effectively control the disease progression, but it can also improve debilitating symptoms such as pruritus, as Dr Christopher Bowlus, the lead investigator explains.
“We haven’t seen significant advances in new treatments for PBC for nearly a decade and current treatments have significant limitations, as many patients are either unresponsive or can’t tolerate them.
“Elafibranor has the potential to control the progression of the disease, which is our first priority as physicians. It also has the potential to improve the symptom of persistent and severe itch, which is a significant quality of life issue.
“I believe elafibranor will provide physicians and patients new options for the management of PBC,” he said.
Ipsen also hope the treatment will help to prevent liver transplants, which are often required in advanced cases and when the pruritus can’t be controlled.
“It’s really important to have a new class of drugs that can help with the pruritus as well as the inflammation and metabolism of the bile acids and bilirubin,” Dr Schranz added.
Elafribanor now has now been granted breakthrough therapy designation by the FDA, and Ipsen say they are currently “in discussion with the EU and US regulatory authorities,” and the process is “progressing as planned.”
Addressing the ‘ignored epidemic’
Elafribanor is just one of many exciting new innovations in liver disease, according to Ipsen . However, with liver disease in the top three for inequitable healthcare alongside heart and respiratory disease, there is still a long road ahead to address this ignored epidemic.10
While new and experimental drugs are providing hope for new treatments in rare and common liver diseases, experts argue innovation is still needed in three key areas:
- diagnostics within the community
- integrating diagnostics across primary and secondary care
- utilising digital healthcare to enhance patient care.10
Public awareness campaigns are now needed alongside the creation of new treatments to help improve the early detection of liver disease and improve patient outcomes.
References
- British Liver Trust. Liver disease in numbers – key facts and statistics. (N.D) Available at: https://britishlivertrust.org.uk/information-and-support/statistics/
- Marschall HU, Henriksson I, Lindberg S, Söderdahl F, Thuresson M, Wahlin S, Ludvigsson JF. Incidence, prevalence, and outcome of primary biliary cholangitis in a nationwide Swedish population-based cohort. Sci Rep. 2019 Aug 8;9(1):11525.
- British Liver Trust. Primary Biliary Cholangitis (PBC). (N.D) Available at: https://britishlivertrust.org.uk/information-and-support/liver-conditions/primary-biliary-cholangitis/
- Yoshida EM, Mason A, Peltekian KM, Shah H, Thiele S, Borrelli R, Fischer A. Epidemiology and liver transplantation burden of primary biliary cholangitis: a retrospective cohort study. CMAJ Open. 2018 Dec 21;6(4):E664-E670
- Levy, C., Williams, B., Sowell, F., Serafini, P., Giao Antunes, N.T., Zein, C., Dietrich, J., Addy, C., Vargas, D., and Schattenberg, M. Understanding the Experience of Patients with Primary Biliary Cholangitis and Pruritus. Poster number: PCR34. Presented at ISPOR 2023.
- Hirschfield GM, Dyson JK, Alexander GJM, et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018;67:1568-1594.
- PBC Foundation. About PBC. (N.D.) Available at: https://www.pbcfoundation.org.uk/what-is-pbc/about-pbc/
- Barba Bernal R, Ferrigno B, Medina Morales E, Castro CM, Goyes D, Trivedi H, Patwardhan VR, Bonder A. Management of Primary Biliary Cholangitis: Current Treatment and Future Perspectives. Turk J Gastroenterol. 2023 Feb;34(2):89-100
- Results from Ipsen’s ELATIVE® pivotal Phase III trial of elafibranor in PBC presented as late breaking data at AASLD congress and published in New England Journal of Medicine. 2023. Available at: https://www.ipsen.com/us/press-releases/results-from-ipsens-elative-pivotal-phase-iii-trial-of-elafibranor-in-pbc-presented-as-late-breaking-data-at-aasld-congress-and-published-in-new-england-journal-of-medicine/
- Bennett L, Purssell H, Street O, Piper Hanley K, Morling JR, Hanley NA, Athwal V, Guha IN. Health Technology Adoption in Liver Disease: Innovative Use of Data Science Solutions for Early Disease Detection. Front Digit Health. 2022 Jan 28;4:737729.
