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The phase 3 seladelpar investigator discusses the current landscape of care available for patients with PBC.
A new phase 3 study from CymaBay Therapeutics is seeking outcomes associated with seladelpar on levels of alkaline phosphatase (ALP) in patients with primary biliary cholangitis (PBC).
The recently announced IDEAL trial intends to enroll 75 patients with a history of incomplete PBC to be treated with the targeted receptor agonist currently in investigation for a handful of hepatic and metabolic conditions.
In the first segment of a Q&A with HCPLive regarding seladelpar and the IDEAL trial, investigator Cynthia Levy, MD, professor of medicine at the University of Miami, discussed the unique impacts of PBC, the current treatment landscape for the liver disease, and the role of ALP management in such patients.
HCPLive: What are the most prevalent burdens of PBC? How do patients generally present?
Levy: Primary biliary cholangitis (PBC) is a chronic disease. Many patients are asymptomatic at presentation. In fact, half of the patients with PBC have no idea that they have any medical problem when they’re first diagnosed and tend to find out about elevated liver enzymes during routine labs done for unrelated reasons. When symptoms are present, pruritus and fatigue are the most significant. Eventually, most patients will end up developing symptoms.
The 2 most common symptoms of PBC, pruritus and fatigue, are associated with poor quality of life, leading to depression, social isolation, self-mutilation in the case of itching and scratching to the point of bleeding, and sleep disturbances among other problems. As the itching is worse at night, it interferes with sleep and is associated with worsening in fatigue. These symptoms are truly disabling.
HCPLive: What is the current treatment landscape for PBC? Where do gaps remain in therapeutic/symptomatic improvement?
Levy: There is currently one first-line therapy approved for PBC: ursodeoxycholic acid (UDCA). This drug has been used for decades and has well-established safety and efficacy in PBC. It does slow down the disease progress and decreases mortality and the need for liver transplantation. But we have a few problems with it. The first issue is access. According to the most recent population-based studies (using data from electronic medical records), about one-third of patients with PBC are not being prescribed UDCA. The second issue is that among patients who receive UDCA treatment, about 40% do not have a sufficient response and remain at risk for disease progression. Intolerance to UDCA is reported by very few patients (3-5%).
We have only one second-line therapy currently approved in the US. and in many European countries, which is obeticholic acid (OCA). It’s not as well tolerated as UDCA because it can cause or worsen itching, and lead to drug discontinuation. Additionally, in terms of efficacy, only about half of the patients treated with OCA will have biochemical response, which means dropping their alkaline phosphatase (ALP) levels to below 1.67 times the upper limit of normal (ULN) and maintaining normal bilirubin levels. There are also some safety concerns with OCA for patients with more advanced liver disease – for example, it’s currently contraindicated for patients with advanced cirrhosis because it can lead to further decompensation.
Finally, there is the off-label use of fibrates (bezafibrate and fenofibrate)—a different class of drugs. Several studies have shown that fibrates can lead to very significant improvement in ALP. However, controlled data from clinical trials to assess the safety of fibrates are not as strong as the data we have for UCDA or even OCA. There are very few randomized controlled trials with fibrates. Nevertheless, the limited trial data available is showing promising results, including high rates of ALP normalization, good safety data, improvement in itch, and improvement in liver stiffness. However, this treatment is still off-label in the US, and bezafibrate, the drug for which most clinical data are available, is not commercialized in the US.
Therefore, there is still an unmet need for patients who don’t respond well to UDCA and want a drug that is safe, does not worsen and potentially improves their symptoms, and can be safely used for patients with cirrhosis.
HCPLive: What is the role of alkaline phosphate management in patients with PBC?
Levy: We consider alkaline phosphatase to be a very important biomarker. PBC is a chronic and slowly progressive disease. We often cannot see meaningful reduction in progression to cirrhosis, decompensation, need for transplant or death during the study timeframe. Instead, we use surrogate markers. ALP is the marker that has been shown again and again to correlate with these outcomes in PBC. However, we know it is not as simple as dropping ALP below a certain cut-off point, which is what’s currently used in clinical practice. There is more of a linear correlation between ALP and outcomes in PBC. In fact, when we evaluated patients who screen-failed for previous seladelpar studies due to having ALP < 1.67x ULN, we learned that a significant proportion of those patients had important risk factors for disease progression, such as elevated bilirubin levels or high ELF (enhanced liver fibrosis score).
Along these lines, there are more recent studies suggesting that normalization of ALP levels may be associated with a survival gain for patients with PBC. The evolving view is that younger patients and those with more significant fibrosis are more likely to benefit from this normalization of ALP. However, we still don’t know for sure which demographics really benefit from that normalization nor whether this can be accomplished safely for most patients.