Safety and pharmacokinetic results from a Phase 2 safety lead-in in participants with hepatic impairment support continued development of GSK4532990 in alcohol-related liver disease

초록

Background and aims: Alcohol-related liver disease (ALD) is a leading cause of morbidity, mortality and liver transplantation. Silencing of hydroxysteroid 17-beta-dehydrogenase-13 (HSD17B13) is a promising option, as loss-of-function (LOF) is associated with reduced ALD progression. GSK4532990, an N-acetylgalactosamine conjugated siRNA, selectively targets HSD17B13 in hepatocytes to mimic the LOF mutation. We report safety and pharmacokinetics (PK) from a Phase 2 study safety lead-in of GSK4532990 in participants (pts) with ALD (NCT06613698). Method: Eligible pts (18–70 yrs) had a history of alcohol consumption consistent with ALD/met-ALD, with either Child-Turcotte-Pugh (CTP) A or CTP-B hepatic impairment. Pts received a subcutaneous dose of GSK4532990 and were evaluated over 8 weeks for safety (vital signs, ECG, laboratory tests, adverse events [AEs]). Intensive PK were collected on Day 1 and analysed non-compartmentally. Results: In total,16 pts (n = 8 per CTP cohort) completed the study (no withdrawals). Eleven pts experienced treatment-emergent AEs (TEAEs); 4 had TEAEs related to study treatment. The most common treatment-related AEs were injection site reactions. Eight serious TEAEs were reported in 5 pts; none were related to study treatment. Two CTP-A pts experienced protocol-defined liver events, adjudicated as not causally related to GSK4532990. There were no safety findings regarding laboratory parameters, ECG and vital sign changes from baseline (BL). BL median (min, max) AST (U/L) was 120 (45, 194) for CTP-A, 56 (42, 120) for CTP-B pts; median change from BL (U/L) at Week (W)8 was –44 (–102, 201) for CTP-A, –7(–67, 9) for CTP-B. Median ALT values at W8 were also reduced, despite similar median PeTH at W8 vs. BL. Median Tmax was 6.0 hrs post-dose for CTP-A and CTP-B pts. Geometric mean apparent t1/2 (coefficient of variation %) was 6.4 (10.4; CTP-A) and 7.2 (19.8; CTP-B) hrs. Geometric mean Cmax and AUC0–24h were at least 19- and 24-fold lower for both cohorts, compared with corresponding exposures maximum tolerated dose in monkey toxicology studies. Conclusion: No safety concerns were identified in pts with CTP-A and CTP-B hepatic impairment after a single dose of GSK4532990. Liver biochemistry improved in both cohorts despite ongoing alcohol consumption. PK were comparable between CTP-A and CTP-B pts and demonstrated wide safety multiples relative to nonclinical toxicology. These results supported initiation of the main study and continued development of GSK4532990 in ALD.