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Primary Biliary Cholangitis Treatment Remains Limited, but Promising
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According to the FDA, primary biliary cholangitis meets the criteria for a rare disease, afflicting fewer than 200,000 Americans. The single population-based U.S. study, conducted in 2000, showed there are about 47,000 people with PBC.
Yet, this rare disease saw the introduction of a new treatment in the past year and that smaller population is an engaged, active population of patients, as evidenced by recent changes in treatment and nomenclature.
Early detection of PBC is paramount, “before progression to cirrhosis and further complications,” Cynthia Levy, MD, an associate professor of medicine at the University of Miami in Florida, told Healio Gastroenterology. The disease is most prevalent in middle-aged women, with the mean age at presentation being 52 years. “But it can affect adults of any age,” Levy said. Women are also several times more likely to develop PBC than men.
However, there is no definitive cause of the disease. “We believe genetic predisposition is key, along with influence of environmental factors. Nonetheless, there are a lot of gaps in our knowledge,” Levy said. “Clinicians need to feel more comfortable recognizing PBC, so that cases can be properly treated.”
The typical patient is easy to diagnose: a middle-aged woman with prolonged elevation of serum alkaline phosphatase without any other cause for this abnormality, plus a positive antimitochondrial antibody in a high titer. “But some cases are more subtle,” Levy said.
A French study in the January edition of Hepatology found a substantial percentage of PBC cases go unrecognized, “even among patients whose antimitochondrial antibodies are detected as positive and who have elevated alkaline phosphatase,” Levy said. “The individuals ordering the tests do not always put two and two together to make the proper diagnosis.”
Cholangitis vs. Cirrhosis
PBC recently underwent a change in nomenclature, from primary biliary cirrhosis to the current primary biliary cholangitis.
Keith D. Lindor, MD, dean of the College of Health Solutions at Arizona State University in Phoenix, was one of the leading proponents of changing the name. “This is really a patient-driven change, mostly from Europe, but also from America,” he said. “Cirrhosis is largely inaccurate for patients with PBC. Most patients do not have cirrhosis, and many people wrongly believe that cirrhosis is tied to alcoholism.”
The name change of the disease from primary biliary cirrhosis to primary biliary cholangitis “was to reflect the fact that most patients with PBC do not have cirrhosis, although some may progress to cirrhosis or have cirrhosis at their initial presentation,” Kris V. Kowdley, MD, FACP, FASSLD, director of the Liver Care Network and Organ Care Research at Swedish Medical Center in Seattle, told Healio Gastroenterology.
In addition to avoiding confusion among patients and providers, the name change removes “any stigma or anxiety for patients in having the word cirrhosis incorrectly associated with the diagnosis,” Kowdley added.
Some patients were denied insurance and access to mortgages because of the previous name and the misinterpretation of the name, according to Lindor. “I have not seen the old term used over the past year,” he said.
The term primary biliary cholangitis “has the advantage of preserving the abbreviation PBC, which many patients recognize, and describes the histopathology of the disease more accurately,” Kowdley said. The name change will hopefully educate physicians about the correct classification of patients and increase awareness of the fact that PBC is a treatable condition, according to Kowdley. For patients, the name change will expectantly “increase hope and optimism,” he said.
Levy supports a name change for PBC. “Most of my patients are very grateful for the change because it removes the stigma associated with the word cirrhosis, so overall I think it is a positive change,” she said. However, it is “unfortunate that the nomenclature still fails to define the pathophysiology of the disease,” Levy said. “But that is because we do not have a full understanding of what causes the disease. I suspect we will change the name once again once we have a better knowledge.”
Diagnosis, Risk Stratification
Gideon M. Hirschfield, MD, PhD, a professor of autoimmune liver disease at the University of Birmingham in the United Kingdom, believes that most general gastroenterologists and hepatologists can recognize and diagnose PBC.
“Diagnosing PBC is relatively straight forward, based on blood tests and a specific antibody,” Hirschfield told Healio Gastroenterology. “It does not require a liver biopsy.”
Lindor agreed: “One of the things we have done is really simplify the diagnosis. ... It has moved away from requiring liver biopsies to being a diagnosis that can be made with blood tests.” However, as a medical specialty, “we need to do a better job finding people with PBC and getting them started on safe and well-tolerated therapy. We can see that the benefits of doing that are much greater than if we wait until a patient has more advanced disease.”
Clinicians need to better understand the varied risk of patients, according to Hirschfield; in other words, which patients fare well on current treatment and which do poorly. Risk can be characterized at presentation; for instance, “it is not particularly well known that those younger at onset are less likely to respond to first-line treatments,” he said.
Furthermore, men progress worse with PBC than women, “perhaps because men present late,” Hirschfield said. Patients who present with cirrhosis do worse as well. “We also know that after 6 to 12 months of treatment with ursodeoxycholic acid (UDCA), liver biochemistry clearly identifies the patient at greatest risk of progression to transplant over the next 10 to 20 years, compared to patients at very low risk for progression,” he said.
First-line Treatment
Lindor said that treatments for PBC in most cases “are quite helpful.” For example, data shows that earlier initiation of UDCA “will lead to a much better long-term outcome than waiting for people to develop more advanced disease and then starting treatment,” Lindor told Healio Gastroenterology.
The older drug fenofibrate has also been used to treat patients with PBC. “This lipid-lowering agent has been surprisingly promising in some studies,” Lindor said.
Hirschfield said that most clinicians are good at starting UDCA as lifelong therapy, but most are unaware that the dose of the oral medicine should be weight-based at 13 mg/kg to 15 mg/kg per day. “Patients can split the dose or take it all before they go to bed,” he said.
There are very few disadvantages of UDCA as first-line therapy. “It is generally a relatively inexpensive treatment that is very well tolerated in the vast majority of patients,” Hirschfield said. “About two-thirds of patients achieve an appropriate, adequate response.” Side effects, though, include bloating, thinning of hair and weight gain. Nonetheless, response to treatment “should proactively be sought,” Hirschfield said. “Patients who do not respond to treatment should be considered for further treatments.”
Following treatment with UDCA, patients can be stratified into high- and low-risk, based on blood tests. Patients at high risk are eligible for licensed therapy and clinical trials of new drugs “that may change the natural history for patients,” Hirschfield said.
However, clinicians fall short in effectively managing the symptom complex associated with PBC, according to Hirschfield. “This complex is broad and nonspecific, but significantly lowers the quality of life of patients,” he said.
Lindor also observed that the medical community has not made sufficient progress in symptomatic management of PBC. Neither of the two main symptoms — fatigue and itching — are alleviated by UDCA. “Either we need treatments that affect not only longevity, but also treat the symptoms, or we need to be happy that we have treatments that increase longevity, and then focus on other therapies that can address symptoms,” Lindor said.
Next Step Treatments
For those who do not respond to UDCA, Ocaliva (obeticholic acid, or OCA, Intercept Pharmaceuticals), which was approved in both the U.S. and Europe in 2016, offers a secondary treatment.
The recommended European treatment protocol for OCA is to start at 5 mg daily, then review at 6 months, at which time it can be dose titrated up to 10 mg daily, depending on symptoms. This compares to the U.S., where dose titration is allowed at 3 months.
“Because OCA is a new drug, we are still learning about its long-term safety,” Hirschfield said. “The presumption is that this will be lifetime therapy.” Moreover, the side effect profile of pruritus is amenable to intervention with drugs such as cholestyramine or rifampicin.
“Because 30% to 40% of patients with PBC do not achieve the optimal biochemical response to UDCA or are intolerant of this therapy, OCA has become a valuable second-line treatment option for patients who are at risk of disease progression,” Kowdley said.
Kowdley, who was part of three phase 2 trials and the one phase 3 trial of OCA for PBC, said that nearly half the patients in the POISE phase 3 trial attained a biochemical response with OCA, “given as either a 10-mg dose or a starting dose of 5 mg with titration up to 10 mg in appropriate patients. This was significantly greater than placebo.”
The biochemical endpoint of OCA achieved a reduction of serum alkaline phosphatase (ALP) to less than 1.67 times the upper limit of normal, “with at least a 15% reduction and maintenance of normal serum bilirubin level,” Kowdley said. “Previous studies have shown that patients who achieve and maintain this endpoint after UDCA therapy had significantly improved long-term outcomes, including survival.”
The main side effect of OCA therapy is pruritus, “which can usually be managed with standard therapies and dose reduction,” Kowdley said. Starting at a dose of 5 mg and titrating up to 10 mg in patients who have not attained the biochemical endpoint “appears to mitigate the degree of pruritus, as less than 1% of patients treated in this manner need to discontinue therapy due to pruritus.”
OCA may also cause fluctuations in serum lipid values, such as an increase in LDL and a decrease in HDL. “These changes in PBC patients are of unclear significance,” Kowdley said.
The approval of OCA for PBC is based on improvement in surrogate markers of disease. “Long-term studies are ongoing to determine whether OCA improves long-term clinical outcomes,” Kowdley said. Meanwhile, both observational studies and clinical trials are critical in determining best treatment options for PBC, “given the slow progression and long natural history of the disease.” Studies are also important, considering that PBC is a rare disease, for which “clinicians may encounter only a handful of patients in their practice,” Kowdley said.
Pipeline Treatments
With only two U.S. approved drugs for treating the PBC — the old standby UDCA and newly approved OCA — clinicians anxiously await study results of several pending oral medications.
Lindor said it is fortunate that his colleagues have been able to convince companies that PBC is a reasonable model for testing new drugs, thus several new options are under development. Lindor also believes that clinical studies to determine treatment protocols “are absolutely vital.”
Hirschfield said there are several companies developing new therapies for PBC “which target the peroxisome proliferator-activated receptor (PPAR) pathway.”
Elfibranor (GenFit) is an investigative drug in phase 3 clinical trials for nonalcoholic steatohepatitis and in early phase trials for PBC. “This is a PPAR alpha and delta agonist,” Hirschfield said. Elfibranor will be positioned as next-generation therapy in patients who do not have an adequate biochemical response to existing licensed therapies.
Levy is an investigator of a clinical trial of elfibranor for PBC that is underway. “The drug is currently under evaluation for a number of other liver diseases, including fatty liver disease,” she said. “In studies for other liver diseases, investigators have found improvement in some liver tests, including the alkaline phosphatase,” Levy said. Further, activation of these particular receptors leads to a choleretic and an anti-inflammatory effect.
A similar mechanism of action is found in the investigational drug MBX-8025 (CymaBay Therapeutics Inc.), “a selective PPAR-delta agonist which has shown promising results,” Levy said.
Additionally, there is a farnesoid X receptor agonist (Novartis) in development. “Given the positive results seen with OCA, we are hopeful that this drug will also show some encouraging results,” Levy said.
Levy believes clinical studies are extremely important in determining treatment protocols for PBC. “Studies will better define the safety profile and efficacy of the medications, as well as tolerance and compliance,” she said. But treatment protocols are a combination of clinical trials and real-life application, “where we can really evaluate effectiveness of a medication.” – by Bob Kronemyer
- References:
- Carey E, et al. Lancet. 2015:doi:org/10.1016/S0140-6736(15)00154-3.
- Dahlqvist G, et al. Hepatology. 2017;doi:10.1002/hep.28859.
- Dyson JK, et al. Nat Rev Gastroenterol Hepatol. 2015;doi:10.1038/nrgastro.2015.12.
- Hrad V, et al. Gastroenterol Res Pract. 2016;doi:org/10.1155/2016/3432640.
- Lee SP, et al. F1000Res. 2016;doi:10.12688/f1000research.8745.1.
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- For more information:
- Gideon M. Hirschfield, MD, PhD, can be reached at g.hirschfield@bham.ac.uk.
- Kris V. Kowdley, MD, FACP, FASSLD, can be reached at kris.kowdley@swedish.org.
- Cynthia Levy, MD, can be reached at clevy@med.miami.edu.
- Keith D. Lindor, MD, can be reached at keith.lindor@asu.edu.
Disclosures: Hirschfield reports he has consulted for GlaxoSmithKline, Intercept Pharmaceuticals and Novartis as well as being a study investigator for GlaxoSmithKline, Intercept, FF Pharma, CymaBay Therapeutics and Novartis. Kowdley reports grant and research support from Gilead Sciences, Intercept and Novartis as well as being a member of the speakers bureau for Gilead and Intercept, plus serves on the advisory board of Gilead, Intercept and Novartis. Levy reports being on the advisory board of Intercept and Novartis and a consultant to Target PharmaSolutions. Lindor reports no relevant financial disclosures.