The clinical effects of inclisiran, a first-in-class LDL-C lowering siRNA therapy, on the LDL-C levels in Chinese patients with hypercholesterolemia.

BACKGROUND: Inclisiran is a novel siRNA therapy that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9) by targeting the PCSK9 mRNA, consequently, decreases low-density lipoprotein cholesterol (LDL-C). OBJECTIVE: To assess the safety, PK and LDL-C lowering effects of inclisiran in the Chinese patients with elevated LDL-C despite treatment with maximally tolerated LDL-C lowering therapies. METHODS: Forty Chinese patients with hypercholesterolemia (LDL-C ≥100 mg/dL) who were on maximally tolerated statin were randomized to receive a single dose of either inclisiran sodium 100 or 300mg s.c. injection (each for 15 patients) or placebo (10 patients). Safety, pharmacokinetics and pharmacodynamics (i.e., PCSK9 and LDL-C levels) were evaluated for up to 90 days after the s.c. injection of study drug. RESULTS: Following single subcutaneous injections inclisiran sodium at 100 mg or 300 mg, inclisiran has a relative short elimination half-life (T1/2, 6.5 hours). Both plasma PCSK9 and serum LDL-C decreased rapidly and consistently, with the maximal reduction between Day 30 and Day 60; then the decreases of PCSK9 and LDL-C were generally maintained up to 56.4% and 49.6% of 100 mg, 74.9% and 58.3% of 300 mg, respectively, at day 90. All adverse events were mild or moderate in severity, and no discontinuations due to adverse events. There were no serious adverse events being reported. CONCLUSIONS: Inclisiran was generally safe and well tolerated. Single dose of both Inclisiran 100 and 300 mg significantly reduced PCSK9 and LDL-C levels in Chinese patients up to Day 90. The greatest reductions were observed with the 300 mg regimen of Inclisiran. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04774003.

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21-43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7-32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150.