Starting disease marker levels may shape Iqirvo response in PBC
Less elevated ALP was tied to higher blood-based response rates
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Adults with primary biliary cholangitis (PBC) who have less elevated blood levels of the liver enzyme alkaline phosphatase (ALP), a marker of liver damage, at the start of treatment with Iqirvo (elafibranor) are more likely to achieve a response on blood-based liver function tests.
Still, while less elevated starting ALP levels are linked to higher rates of blood-based treatment response, Iqirvo was associated with reductions in model-estimated 15-year risk of needing a liver transplant or dying due to liver-related causes, regardless of initial ALP level.
That’s according to exploratory analyses of data from the Phase 3 ELATIVE clinical trial (NCT04526665), whose results helped support Iqirvo’s accelerated approval for PBC.
Higher starting ALP may make response goals harder to reach
“This research highlights that [Iqirvo] is effective, but people with high starting ALP levels might not achieve biochemical response according to the definition used in the study, even if they are benefiting from treatment; hence, it is important to consider overall changes in substances and other factors to understand if treatment is working,” the researchers wrote.
The findings were reported in the study “Baseline Alkaline Phosphatase Impacts Response Rates in Primary Biliary Cholangitis: Exploring Response to Elafibranor in ELATIVE,” published in Liver International.
PBC is a rare, chronic liver disease and form of cholangitis marked by damage to the small bile ducts in the liver. These ducts normally help carry bile, a digestive fluid, from the liver to the small intestine. Damage to the ducts can slow or stall bile flow, a condition called cholestasis, causing bile to build up to toxic levels in the liver and damage the organ.
Left untreated, PBC increases the chance of cirrhosis, or irreversible liver scarring, and liver failure, for which a liver transplant may be the only therapeutic option.
High blood levels of liver damage markers, including ALP and bilirubin, are signs of cholestasis and are associated with a poor prognosis in people with PBC.
“While biochemical response criteria in PBC clinical trials often rely on … a reduction in ALP and [bilirubin] to predefined levels, this approach may overlook meaningful biochemical improvements, particularly in patients with higher baseline [pre-treatment] ALP levels,” the researchers wrote. “Prognostic tools, such as GLOBE risk scores, incorporate continuous biochemical data and other variables to predict transplant-free survival, and offer a more nuanced view of treatment benefit.”
GLOBE scores estimate transplant-free survival in PBC
The GLOBE scoring system uses patient age and markers of disease severity in the blood to estimate transplant-free survival in people with PBC. In this analysis, researchers used GLOBE scores to estimate the risk of needing a liver transplant or dying due to liver-related causes over five, 10, and 15 years.
Iqirvo is approved to treat adults with PBC who have an inadequate response to or cannot tolerate first-line treatment with ursodeoxycholic acid, or UDCA, sold in the U.S. under the brand names Urso and Actigall. It is used with UDCA in patients with an inadequate response, or alone in those who cannot tolerate UDCA. Iqirvo is designed to activate PPAR alpha and PPAR delta, two proteins that regulate underlying PBC mechanisms, such as inflammation, scarring, and bile processing.
The therapy’s approval was mainly based on results from the ELATIVE study, which indicated that Iqirvo was generally well tolerated and superior to a placebo at promoting a biochemical response after one year (51% vs. 4% of patients).
Biochemical response was defined as blood ALP levels below 1.67 times the upper limit of normal (ULN), with a 15% or greater ALP reduction from baseline, and blood bilirubin levels at or below ULN.
The treatment showed some signs of easing itching, a common and burdensome PBC symptom, and improving itch-related quality of life, based on secondary measures.
Here, researchers conducted exploratory analyses of ELATIVE data to assess whether baseline ALP levels could influence rates of biochemical response and GLOBE scores.
The 108 participants treated with Iqirvo and the 53 assigned to placebo were divided into five groups by baseline ALP levels, ranging from up to two times the ULN to over four times the ULN.
Participants with higher baseline ALP levels tended to have more advanced liver disease, based on liver stiffness, bridging fibrosis, or cirrhosis, and higher baseline levels of other liver enzymes in the blood, suggesting more liver damage.
Less elevated ALP tied to higher response rates
In the Iqirvo group, the rate of biochemical response was higher among patients with less elevated baseline ALP (up to 2.5 times the ULN; 80% to 86.7%) than among those with more elevated starting ALP (over three times the ULN; 18.8% to 22.2%). In the placebo group, only patients with ALP levels up to two times the ULN achieved a biochemical response (13.3%).
Also, 90.4% of participants on Iqirvo with available data experienced a reduction in ALP levels after one year, with a mean drop of 38.9% compared with a 1.7% increase in the placebo group. ALP normalization occurred only in the Iqirvo group and was more common among patients with less elevated baseline ALP.
Iqirvo-treated patients had reductions in GLOBE-estimated risk of liver transplant and/or liver-related death within 15 years, regardless of biochemical response. Among patients receiving a placebo, a GLOBE-estimated risk reduction was observed only in those with a biochemical response.
The findings indicate that “response rates can vary depending on baseline ALP values,” and “that integrating additional considerations beyond … biochemical response rates can provide a more detailed understanding of a treatment’s biochemical efficacy,” the team concluded.
