The leading edge: New therapies redefine PBC treatment landscape
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Key takeaways:
- A wave of new approvals for PBC is redefining the treatment landscape.
- Triple combination therapy may be a future consideration.
Recent advancements have been made in the treatment of primary biliary cholangitis, particularly for patients who do not respond adequately to first-line treatment.
In a Healio exclusive interview, Kris V. Kowdley, MD, FACG, director of Liver Institute Northwest, discussed first- and second-line therapies for primary biliary cholangitis (PBC), the impact of lifestyle factors and comorbidities on treatment response, and key findings from the COBALT study.
Treatment options
For patients who do not demonstrate adequate response to first-line treatment, there are other options available.
“We are in a wonderful time right now,” Kowdley said. “Enormous progress has been made recently in the treatment of PBC," he said.
Since granting accelerated approval to Ocaliva (obeticholic acid, Intercept Pharmaceuticals), an FXR-agonist, in 2016, the FDA this year approved two peroxisome proliferator-activated receptor therapies, Iqirvo (elafibranor, Ipsen/Genfit) and Livdelzi (seladelpar, Gilead), for use with ursodeoxycholic acid (UCDA).
“By binding to these receptors, PPAR agonists cause transcriptional activation of a variety of genes resulting in net reduction of bile acids, along with anti-inflammatory and antifibrotic effects,” Kowdley said.
“An attractive feature of this class of drugs is that they tend to have a favorable effect on lipids,” he added, noting also that they do not increase pruritus and may even improve it.
The efficacy of all three therapies and their complementary mechanisms of action may ultimately lead to the use of triple combination treatments with the goal of achieving “complete biochemical normalization of liver tests, namely normal serum aminotransferases and bilirubin, as well as alkaline phosphatase,” Kowdley said.
“If you look at the leading edge of where we are in our field, many experts agree that the best long-term outcomes will be among patients who can achieve the goal of normalizing all liver tests.”
In addition, the combination of a fibrate drug, such as bezafibrate, with UDCA may reduce the risk for adverse events.
Obeticholic acid, elafibranor and seladelpar were granted accelerated approval based on the surrogate endpoint of improvements in serum alkaline phosphatase to below a threshold level associated with higher future risk of adverse liver-related outcome. Confirmatory trials demonstrating clinical benefit may be needed for full approval.
Kowdley contextualized these results in relationship to results gleaned from the COBLAT trial, which was conducted to confirm clinical benefit with obeticholic acid.
The study, published in The American Journal of Gastroenterology, examined the effects of obeticholic acid on clinical outcomes related to liver disease. The study was halted due to futility, and failed to demonstrate improved clinical outcomes with obeticholic acid treatment compared to placebo; however, “the trial was limited by confounding due to treatment crossover and functional unblinding,” Kowdley said. An additional analysis comparing patients treated with obeticholic acid compared to real-world external controls did demonstrate that OCA treatment reduced liver-related adverse outcomes.
“When you compare the patients who were in that trial and received obeticholic acid compared to appropriately selected external controls, there was a significant reduction in the need for liver transplantation or liver-related adverse outcomes,” he said.
“We are gathering a substantial amount of real-world evidence now that shows that adding second-line therapy does improve clinical outcomes,” Kowdley added. “However, we still need therapies to treat the vexing symptoms of pruritus and fatigue which may substantially impair quality of life in PBC”.
Novel ileal bile acid transporter inhibitors currently in development may help treat pruritus in patients with PBC, he explained, emphasizing that we still need therapies to treat in fatigue as well.
Factors affecting treatment response
In terms of the effects of lifestyle factors and comorbidities on treatment response, Kowdley noted that the impact is not fully known. “It’s not clear to me that comorbidities affect treatment response,” he said, emphasizing that patient quality of life is a significant driver of overall outcomes. “Symptoms are a key factor affecting patient outcomes.”
Patients with PBC often experience symptoms such as fatigue and pruritus, which can affect quality of life.
“We still do not have any clear evidence of any therapeutic agent improving fatigue,” he noted, underscoring this unmet need.
In addition, “there’s a wealth of data using functional MRI imaging in the brain and other methods showing that, in fact, neurocognitive function may be impaired in patients,” he noted.
Other factors such as excess weight or comorbidities such as diabetes and concurrent liver disease may adversely affect the disease, he said.
“Certainly, patients who have fatty liver disease, who consume excess alcohol or who take hepatotoxic drugs or herbal supplements would be at higher risk because they may have another underlying liver disease,” Kowdley said.
“It is very important to make sure we are counseling patients about how to optimize liver health, with particular focus on the supplements patients may be taking, some of which could be hepatotoxic, and counseling them about the importance of appropriate diet, nutrition and exercise,” he said.
In addition, osteopenia and osteoporosis are of notable concern among patients with PBC. “It’s very important to focus on bone health,” Kowdley said.
He also touched on the importance of focusing on thyroid disease, as hypothyroidism can affect up to one in three patients with PBC.
Insights from the COBALT study
Kowdley shared additional findings from the COBALT study.
“The key takeaway from the COBALT study is that the study did not meet its primary goal of showing that treatment with obeticholic acid would improve clinical outcomes, such as development of decompensated liver disease, need for liver transplant or overall survival.”
A high dropout rate among placebo patients could have been a contributing factor to the failure to meet the primary endpoint, he said, noting that patients may choose to withdraw from a study based on outside lab monitoring.
“We call this informative discontinuation leading to a bias in the results, and we think that is a very important takeaway from the study,” he said. “In this regard, the COBALT trial provides useful lessons for other confirmatory trials when a medication may already be on the market based on a surrogate endpoint.”
Although the study did not achieve its primary outcome, Kowdley emphasized the importance of external control comparisons.
“Based on the real-world cohort, there appeared to be substantially better outcomes in the obeticholic acid-treated patients, with a risk reduction that was very similar to several other databases,” he said. “In addition to adverse liver-related endpoints, clinical outcomes should also include how patients feel and function.”
Reference:
- Kowdley KV, et al. Am J Gastroenterol. 2024;doi:10.14309/ajg.0000000000003029.
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