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Kidney Week

Abstract: PO1198

Development of AL01211, a Novel Glucosylceramide Synthase Inhibitor, to Treat Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Babcock, Michael C., AceLink Therapeutics, Newark, California, United States
  • Zheng, Jianhong, AceLink Therapeutics, Newark, California, United States
  • Li, Li, AceLink Therapeutics, Newark, California, United States
  • Mei, Changlin, Shanghai Changzheng Hospital, Shanghai, Shanghai, China
  • Garovoy, Marvin R., AceLink Therapeutics, Newark, California, United States
  • Shen, Yuqiao, AceLink Therapeutics, Newark, California, United States

ADPKD is a common genetic disease affecting ~1:1000 individuals and is characterized by progressive renal cysts growth, kidney enlargement and renal dysfunction. Glycosphingolipids (GSL) are elevated in the kidneys of ADPKD animal models and ADPKD patients where they promote renal epithelial cell growth and kidney inflammation. Glucosylceramide synthase inhibitors (GCSi) reduce GSL production, slow cyst growth, and preserve kidney function in multiple animal models. Clinical development of other GCSi have shown that this enzyme can be safely targeted therapeutically. We are developing AL01211, a potent and selective GCSi with excellent drug-like properties, for the treatment of ADPKD.


The IC50 of AL01211 against GCS was determined in cells and cell-free activity assays. PK, PD, tissue distribution and clearance studies were conducted in mice, rats and dogs. AL01211’s pharmacological profile was characterized in vitro including off-target selectivity panels, plasma protein binding, transporter assays, cyp inhibition and induction, and other assays. Disease model efficacy studies were conducted in several murine models including pkd1 cKO and jck models.


AL01211 binds the active site of GCS and has an IC50 toward GCS of ~7 nM with limited off-target activity. PK studies support once daily, oral administration. AL01211 has low renal clearance in rats. AL01211 readily distributes to peripheral tissues (such as kidney) but does not cross blood-brain-barrier. Thus, it efficiently reduces GSL production in mouse, rat and dog kidney (reduced by >85% of control levels) with minimal effects in brain GSL. Importantly, AL01211 reduces cyst growth and kidney weight and preserves kidney functions in murine models.


Relative to other GCSi in development, AL01211 is more potent with single digit nanomolar potency, has greater reduction of GSL (>85%), is not subject to kidney clearance, and does not enter the brain. Phase I clinical trials, consisting of Phase IA (single ascending dose study in healthy volunteers), Phase 1B (14-day multiple ascending dose study in healthy volunteers, and Phase IC (28-day biomarker study in ADPKD patients), are underway.


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