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Phase 3 data presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases demonstrated the safety and efficacy of seladelpar in patients with primary biliary cholangitis through 12 months of treatment.
Data from the phase 3 RESPONSE trial presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) showed treatment with seladelpar 10 mg resulted in statistically significant and durable improvements in markers of cholestasis and liver injury and improved pruritus in patients with primary biliary cholangitis (PBC) and incomplete response or intolerance to ursodeoxycholic acid.
Currently, there are 2 therapies approved by the US Food and Drug Administration for PBC: ursodeoxycholic acid and obeticholic acid. However, not all patients achieve and adequate response to either treatment and symptoms may not improve, leaving many with no way to treat their condition.
“We're left in a situation where we have patients with insufficient response to the current therapies and have symptoms such as itch,” explained Gideon Hirschfield, PhD, MB BChir, Lily and Terry Horner Chair in Autoimmune Liver Disease Research at the University of Toronto, in an interview with HCPLive. “That's why we're so excited to be looking at new treatments for this group of patients who currently have an unmet need, because if you leave these patients untreated, not only is their quality of life impaired, but in addition, their liver disease will progress, and we want to prevent liver disease progression and prevent the need for liver transplantation.”
Billed as a first-in-class oral, selective peroxisome proliferator-activated receptor delta agonist, or delpar, seladelpar has been shown to regulate critical metabolic and liver disease pathways through regulation of genes involved in bile acid synthesis, inflammation, fibrosis and lipid metabolism, storage, and transport.
“The way I like to think about it is patient priorities and what patients need from new treatments for PBC. Patients want potency,” Hirschfield said. “There's quite a lot of data already on seladelpar from a number of clinical trials in PBC, which have shown significant potential to benefit patients, and that's why everyone's been very excited to see the late breaker, which is a report of a very pivotal phase 3 clinical trial of seladelpar in patients with PBC, insufficient response to [ursodeoxycholic acid], and therefore an unmet need for new treatments.”
The trial enrolled 193 patients with a mean age of 56.7 years, a mean alkaline phosphatase (ALP) of 314.4 U/L, total bilirubin of 0.76 mg/dL, and 37.3% of whom reported moderate-to-severe itch. Patients were randomly assigned to receive either daily oral seladelpar 10 mg or placebo. The primary endpoint was a composite response of ALP <1.67xULN, ALP decrease ≥15% and TB ≤ULN at month 12. Key secondary endpoints included ALP normalization at month 12 and change in pruritus numerical rating scale at month 6.
Upon analysis, 61.7% of patients achieved the primary composite response endpoint with seladelpar compared to 20% with placebo (P < .0001). The secondary endpoint of ALP normalization occurred in 25% of those receiving seladelpar and 0% receiving placebo (P < .0001). The average decrease in ALP for seladelpar was -133.9 U/L and -16.9 U/L for placebo (P < .0001).
Seladelpar lowered alanine aminotransferase by 23.5% and gamma-glutamyl transferase by 39.1%, compared to 6.5% and 11.4% for placebo, respectively. The key secondary pruritus endpoint was met at month 6 with seladelpar-treated patients with baseline NRS >4 reporting decreases of 3.2 compared to 1.7 for placebo (P < .005), with improvement of pruritus NRS on seladelpar sustained through month 12 (P < .005).
“This drug is clearly demonstrating excellent signs of efficacy, but that needs to be rigorously assessed by the FDA. I think what clinicians are interested in seeing is further data on the durability of response, further data from other clinical trials on trying to identify more patients who might benefit from seladelpar,” Hirschfield explained. “And then, of course, what we also want to see is the use of this drug to not only improve liver tests, not only to improve symptoms, but ultimately to improve survival. And there are ongoing efforts to do clinical trials which will address all of these points.”
“Patients and clinicians can be excited with data such as this from seladelpar, which shows a very high biochemical efficacy, including a high rate of normalization, and statistically significant improvement in pruritis. It was tolerable and safe, and the vast majority of patients asked to stay on the drug in the long term safety extension, so I think that's why it's a late breaker and that's why there's a lot of excitement,” Hirschfield concluded.
Hirschfield G, et al. EFFICACY AND SAFETY OF SELADELPAR IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS IN THE RESPONSE TRIAL: A PHASE 3 INTERNATIONAL, RANDOMIZED, PLACEBO-CONTROLLED STUDY. Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023.