Treatment with both elafibranor (Iqirvo, Ibsen) and seladelpar (Livdelzi, Gilead) led to alkaline phosphatase (ALP) normalization in the vast majority of patients with primary biliary cholangitis (PBC) who had elevated ALP levels after an incomplete response or intolerance to first-line therapy, two phase III trials showed.
Results from the ELSPIRE study showed that 85.3% of patients who received elafibranor achieved the primary endpoint of ALP normalization compared with 23.3% receiving placebo (P<0.0001) at week 52, reported Kris V. Kowdley, MD, of Liver Institute Northwest in Seattle.
The IDEAL trial demonstrated that 75.4% of patients treated with seladelpar achieved ALP normalization versus 16.1% of those receiving placebo (P<0.0001) at week 52, reported Cynthia Levy, MD, of the University of Miami Miller School of Medicine.
Results from both trials were presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting in Denver, and the ELSPIRE study was also published in Hepatology.
Elafibranor is an oral dual peroxisome proliferator-activated receptor (PPAR) agonist that was granted accelerated approval for the treatment of PBC in adults based on results from the ELATIVE trial.
Meanwhile, the oral PPAR-delta agonist seladelpar was granted accelerated approval for the treatment of PBC in adults based on data from the RESPONSE trial.
ELSPIRE
"The key issue in our understanding of PBC, and where we are in PBC, is that it has become more and more clear that if you look at the best outcomes in patients that have PBC, it is in those that have achieved normal alkaline phosphatase," Kowdley told MedPage Today. "So, for a long time, we knew that alkaline phosphatase was a predictor of long-term outcomes."
The POISE trial defined biochemical response as the achievement of ALP under 1.67 times the upper limit of normal (ULN), with a reduction of at least 15% from baseline, and a normal total bilirubin level.
"Ever since then, all studies have used alkaline phosphatase of 1.67 above the upper limit of normal as the cutoff for predicting worse outcomes," Kowdley noted. "But, what about patients who have an elevated alkaline phosphatase above the upper limit of normal, but less than 1.67 times the upper limit of normal? That intermediate group ... also has an increased risk of adverse liver-related outcomes over the long term."
Thus, the ELSPIRE researchers sought to evaluate elafibranor in patients with PBC and an ALP over 1.00 but under 1.67 times the ULN after an incomplete response or intolerance to first-line therapy with ursodeoxycholic acid (UDCA).
"And as a proof of concept, [the study shows] you can achieve normalization in a very high proportion of patients if you start them earlier in the stage of the disease," Kowdley said.
ELSPIRE included 92 patients (median age 61 years, 92.4% women) who had a mean baseline ALP of 149.4 to 151.5 U/L. All patients had ALP over the ULN but under 1.67 times the ULN at randomization, and 96.7% had ongoing UDCA treatment for a median duration of around 5 years.
ALP normalization was considered to be less than or equal to the ULN (defined as ≤120 U/L at week 52) without the use of rescue therapy for PBC, and without experiencing a liver-related event or death due to any cause.
Patients were randomized 2:1 to elafibranor or placebo, and stratified into two categories by ALP (>1 to ≤1.33 times the ULN and >1.33 to <1.67 times the ULN).
Greater proportions of patients in both categories achieved the primary endpoint of ALP normalization with elafibranor versus placebo: 80.4% versus 26.1% in patients with ALP >1 to ≤1.33 times the ULN (P<0.0001), and 87.5% versus 14.3% in patients with ALP >1.33 to <1.67 times the ULN (P=0.0017).
Treatment-emergent adverse events (TEAEs) were observed in 79% of patients treated with elafibranor versus 70% treated with placebo.
Increased weight was reported in 22.6% of patients receiving elafibranor and 6.7% receiving placebo, with five TEAEs of increased weight considered to be related to elafibranor treatment.
IDEAL
Levy and colleagues (including Kowdley) found that higher response rates were observed at all timepoints with seladelpar, with the effect observed as early as a month into treatment, with 52.3% of seladelpar patients achieving ALP normalization at that time point versus 6.5% in the placebo group.
"These results help inform treatment decisions for an understudied population and demonstrate biochemical normalization as a feasible goal," Levy and colleagues concluded.
In IDEAL, 96 patients were randomized 2:1 to receive seladelpar or placebo for 12 months. Mean age was 61 years, 93.8% were women, and mean baseline ALP was 153 U/L.
Patients were considered responders if they achieved a 15% or more decrease in ALP levels from baseline, and if blood levels of the enzyme were ≤1.0 times the ULN.
Serious adverse events were reported in 3.1% of patients in the seladelpar group and 12.9% in the placebo group, with none deemed related to the drug.
Disclosures
The ELSPIRE study was sponsored by Ipsen.
Kowdley reported relationships with Altimmune, Akero Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Corcept, 89Bio, Gilead, GSK, Hanmi, HighTide, Inventiva, Kowa, Madrigal, Mirum, Zydus, Inipharm, Ipsen, Novo Nordisk, UpToDate, CymaBay, Enanta, Genfit, Intercept, AbbVie, and AstraZeneca.
The IDEAL trial was sponsored by Gilead.
Levy reported relationships with Gilead, Ipsen, GSK, Intercept, Calliditas, Zydus, LISCure, TARGET RWE, Pliant, NGM Biopharmaceuticals, Mitsubishi Tanabe, DISC, Takeda, Kowa, and Mirum.
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