Seladelpar treatment reduces interleukin-31 and pruritus in patients with primary biliary cholangitis

BACKGROUND AND AIMS: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective PPAR-delta agonist, PBC patients experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's anti-pruritic effects, IL-31 and bile acid levels in PBC patients. APPROACH AND RESULTS: IL-31 levels were quantified in serum samples from the ENHANCE study of PBC patients receiving daily oral doses of placebo (n=55), seladelpar 5 mg (n=53) or 10 mg (n=53) for 3 months and for healthy volunteers (n=55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS (r=0.54, p<0.0001), and total (r=0.54, p<0.0001) and conjugated bile acids (up to 0.64, p<0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p=0.0003) and 10 mg (-52%, p<0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS≥2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS<2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids (r=0.63, p<0.0001) in the seladelpar 10 mg group. CONCLUSIONS: Seladelpar decreased serum IL-31 and bile acids in PBC patients. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement suggesting a mechanism to explain seladelpar's anti-pruritic effects

Captive-Carry Flight Demonstration of an Inert Test Rocket Using a Business Jet as an Air Launch Platform

This presentation is to discuss the Armstron airworthiness process and the work required to clear to GO1 Inert Test Article for captive carry flights

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Background and Aims: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) &lt; 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) (p &lt; 0.0001). ALP normalization occurred in 5.4% (p=0.08) and 27.3% (p &lt; 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: −3.14 (p=0.02); placebo: −1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p=0.0008); 10 mg: 16.7% (p=0.03); placebo: 4%]. There were no serious treatment-related adverse events. Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Background and Aims: ENHANCEwas a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n= 89), 10 mg (n= 89), placebo (n= 87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) &lt; 1.67xupper limit of normal (ULN), &gt;= 15% ALP decrease from baseline, and total bilirubin &lt;= ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score &gt;= 4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10mg: 78.2%) versus placebo (12.5%) (p &lt; 0.0001). ALP normalization occurred in 5.4% (p= 0.08) and 27.3% (p &lt; 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 (p= 0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p= 0.0008); 10 mg: 16.7% (p= 0.03); placebo: 4%]. There were no serious treatment-related adverse events.Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated