Phase 1 Healthy Volunteer Study of AL01211, an Oral, Non-brain Penetrant Glucosylceramide Synthase Inhibitor, to Treat Fabry Disease and Type 1 Gaucher Disease.
Clin Pharmacol Drug Dev
; 13(6): 696-709, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38363061
ABSTRACT
Glycosphingolipid (GSL) storage diseases are caused by deficiencies in the enzymes that metabolize different GSLs in the lysosome. Glucosylceramide synthase (GCS) inhibitors reduce GSL production and have potential to treat multiple GSL storage diseases. AL01211 is a potent, oral GCS inhibitor being developed for the treatment of Type 1 Gaucher disease and Fabry disease. AL01211 has minimal central nervous system penetration, allowing for treatment of peripheral organs without risking CNS-associated adverse effects. AL01211 was evaluated in a Phase 1 healthy volunteer study with single ascending dose (SAD) and multiple ascending dose (MAD) arms, to determine safety, pharmacokinetics including food effect, and pharmacodynamic effects on associated GSLs. In the SAD arm, AL01211 showed a Tmax of approximately 3.5 hours, mean clearance (CL/F) of 130.1 L/h, and t1/2 of 39.3 hours. Consuming a high-fat meal prior to dose administration reduced exposures 3.5-5.5-fold, indicating a food effect. In the MAD arm, AL01211 had an approximately 2-fold accumulation, reaching steady-state levels by 10 days. Increasing exposure inversely correlated with a decrease in GSL with plasma glucosylceramide and globotriacylceramide reduction from baseline levels, reaching 78% and 52% by day 14, respectively. AL01211 was generally well-tolerated with no AL01211 associated serious adverse events, thus supporting its further clinical development.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fabry Disease
/
Enzyme Inhibitors
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Healthy Volunteers
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Gaucher Disease
/
Glucosyltransferases
Limits:
Adolescent
/
Adult
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Clin Pharmacol Drug Dev
/
Clinical pharmacology in drug development
/
Clinical pharmacology in drug development (Online)
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos