Conclusion: Galectin-3 expression and inflammasome activation are induced in PBC patients and in dnTGFβRII mice. DCA induces inflammasome activation in KC resulting in the release of proinflammatory mediators, in a galectin 3-dependent manner. Galectin-3 hence could be a potential therapeutic target in PBC. Disclosures: Natalie Torok – Consulting: Genentech/Roche The following people have nothing to disclose: Jijing Tian, Tzu-I Chao, Yu Sasaki, Fu-Tong Liu, M. Eric Gershwin, Joy Jiang Obeticholic acid (OCA, 6-ethyl chenodeoxycholic acid) is a highly potent, selective FXR agonist. In Ph2 PBC studies, 10-50mg OCA (±UDCA) produced significant biochemical
improvement in cholestasis and inflammatory markers. The Global PBC Study Group (GPBCSG) confirms patients with alkaline phosphatase (ALP) > 1.67x ULN or bilirubin >ULN have a greatly increased risk of liver transplant or death [HR (95% CI): 2.83 (2.4-3.4); p =1×10−34]. This was an international, double-blind, selleck chemicals placebo-controlled (PBO) trial. PBC patients ±UDCA (if taking UDCA, on a stable dose) with ALP≥1.67x ULN or bilirubin <2x ULN were
randomized to PBO, OCA 5 or 10mg for 12mo. Patients randomized to 5mg were titrated to 10mg after 6mo, if necessary; pre-study UDCA continued. The primary endpoint was attaining the GPBCSG ALP/Bilirubin goal and ALP reduction ≥15%. Markers of inflammation (CRP) and apoptosis (CK18) were also evaluated RXDX-106 research buy at 6 and 12mo. All groups were well-matched. Mean age: 55.8yrs, female: 91%, Caucasian: 94%. The median
UDCA dose was 15.4 mg/kg; 7% were UDCA-intolerant. Overall, 91% of patients completed the study. The primary endpoint was achieved: OCA was superior to PBO, a highly statistically significantly greater proportion of OCA treated patients achieved the ALP/Bili response goal (see table). After 6mo, ALP significantly improved (p<0.0001) with OCA dose: PBO, −6.8% (±3.5), 5mg, −27.4% (±3.4), 10mg, −36.5% (±3.5). Pruritus, generally mild to moderate, was the most common and dose related adverse event (AE). The incidence of AEs other than pruritus was no worse with OCA (PBO, 90%, 5/10mg OCA, 89%, 10mg OCA, 86%). An 82-yr old patient with pre-existing congestive heart failure taking OCA died due to worsening of the condition. Overall, serious adverse events (SAEs) occurred in 22 (10%) selleck compound of patients and, although there were more SAEs in the OCA groups, none were considered drug-related and there were no apparent patterns. Modest mean reductions in HDL (16%,5/10mg OCA, 26%,10mg OCA) were observed with OCA. OCA produced highly statistically, clinically meaningful improvements in biochemical criteria that are strongly correlated with clinical benefit. Pruritus was the principal AE, but had a lower incidence in the titration group compared to 10 mg. Starting patients on 5mg OCA and titration to 10mg based on the clinical response appears to be an appropriate dosing strategy.
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