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Kremer discusses new ad hoc findings from the phase 3 ENHANCE trial showing seladelpar's unique effect on pruritus in patients with PBC.
New post-hoc data from the phase 3 ENHANCE trial showed a dose-dependent decrease in interleukin 31 (IL-31) cytokine among patients with primary biliary cholangitis (PBC) treated with seladelpar.
The findings, presented at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting in Vancouver, BC, additionally conveyed a correlation between reduced serum IL-31 and improved pruritus among patients with PBC receiving seladelpar—suggesting a role of the interleukin cytokine in the effect of itch due to PBC, as well as its role as a potential biomarker related to the clinical benefit of seladelpar.
In an interview with HCPLive during ACG 2023, study author Andreas Kremer, MD, PhD, MHBA, head of hepatology at the department of gastroenterology and hepatology at the University Hospital Zurich in Switzerland, discussed the latest ENHANCE data and the evolving understanding of seladelpar’s benefit in patients with PBC.
HCPLive: Can you tell us about the mechanism of action of seladelpar? What exactly makes it a viable agent for patients with PBC, and what's our known history of it up to this point?
Kremer: Seladelpar is a delta-specific peroxisome proliferator-activated receptor agonist that exerts many beneficial effects which are important to treat the underlying disease. In particular, these are anti-cholestatic properties. We have a reduction in bile acid synthesis, for example, so we reduce the extent of cholestasis. There are further anti-inflammatory benefits mediated by PPAR agonism. And this is important because PBC is also an inflammatory disorder, where we see a lot of inflammation ongoing, and reduction of inflammation improves the disease severity in our patients.
And furthermore, we have insights that also the fibrosis may be improved by treatment of PPAR agonism. And finally, in contrast to the farnesoid X receptor agonism, we see an improvement of lipid metabolism and we see reduced LDL levels, which could in particular be beneficial for those patients with metabolic syndrome. And aside these effects on the underlying cholestatic liver disease, primary biliary cholangitis, we have also observed that PPAR agonism results in improvement in pruritis, and pruritis is one of the most important patient-reported outcomes and agonizing aspects of these patients.
In that regard, I think it's a very elegant approach not only to treat the underlying disease, but also to improve symptom burden in these patients.
HCPLive: With this phase 3 data that we're looking at, can you talk about the patient population that we're observing? What exactly is the manifestation and severity of disease? What are the patient demographics and characteristics?
Kremer: So, in this ENHANCE phase 3 study, patients with an inadequate response to the baseline therapy, UDCA (ursodeoxycholic acid) were included. This means that parameters of cholestasis, such as alkaline phosphatase had to be more than 1.67 times higher than the upper limit of normal. But the extent of cholestasis, we're not allowed to be too advanced, indicating that total bilirubin levels are maximally twice upper limit of normal.
So, there were roughly 20% of patients with cirrhosis included, but not the very advanced disease stages, but clearly patients at a significant risk for disease progression and requiring second-line therapies. And in that regard, it was interesting also to observe that there is a significant number of patients with symptom burden. And if we talk about pruritis in particular, those patients with moderate-to-severe pruritis are indicated by a numeric rating scale of >4 points, and roughly one-third of the patient population suffered from this intense pruritis.
HCPLive: What are some of the key takeaways from the findings?
Kremer: It is of note to report that this phase 3 study was early terminated, due to some histological findings in the NASH trial, which was running in parallel. And this limits a little bit the interpretation of the data, because we in particular could only investigate 3 months of therapy. But still, these 3 months clearly indicated a strong treatment response in regard to alkaline phosphatase, for example, as a surrogate marker of disease progression and PBC. And a new phase 3 study was set up, and those data will be presented at the AASLD meeting in Boston in 2 weeks. So, we will get further insights into these data of a full 12-months phase 3 study using this PPAR agonism. So, the full phase 3 study is very promising in that regard.
HCPLive: It seems like we have a number of agents in progression and in consideration to help better treat cholestatic disease. Based off of what we've observed thus far with seladelpar can you talk about what it may bring to our available armamentarium?
Kremer: I think PPAR agonism exerts these beneficial effects because it targets important signaling pathways, which drive disease progression. And in that regard, I think the different PPARs which are currently developed are very promising for our PBC patients requiring second-line therapies. Roughly, we can estimate that every third patient requires additional treatments next to UDCA, and we have seen that obeticholic acid improves those cholestatic parameters and surrogate markers, but can worsen itch severity, at least in some patients. And that limits its use in the real-life setting.
And hopefully, we will get further insights and promising results in particular for our patients in both the underlying disease and the symptom burden. We need a better understanding to which extent symptom burden is improved. Is it also other aspects of symptom burden—sleep disturbances, for example, or fatigue? I think in particular for our patients, it's a bright future. There's a glimmer at the horizon to more efficiently treat our patients adequately.