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Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral AL01211 in Healthy Chinese Volunteers

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Abstract

Background and Objective

Aberrant accumulation of glycosphingolipids (GSLs) in the lysosome leads to GSL storage diseases. Glucosylceramide synthase inhibitors (GCSi) have the potential to treat several GSL storage diseases by reducing the synthesis of the disease-causing GSLs. AL01211 is a potent oral GCSi under investigation for Type 1 Gaucher disease and Fabry disease. Here, we evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of AL01211 in healthy Chinese volunteers.

Methods

AL01211 was tested in a Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms.

Results

Results of AL01211 demonstrated dose-dependent pharmacokinetics, rapid absorption (median time to maximum plasma concentration [tmax] 2.5–4 hours), relatively slow clearance rate (mean apparent total clearance from plasma [CL/F] 88.3–200 L/h) and the mean terminal half-life above 30 hours. Repeated once-daily oral administration of AL01211 for 14 days had an approximately 2-fold accumulation, reaching steady-state levels between 7 and 10 days, and led to a 73% reduction in plasma glucosylceramide (GL1) on Day 14. AL01211 was safe and well tolerated, with no identified serious adverse events.

Conclusion

AL01211 showed a favorable pharmacokinetic, pharmacodynamics, safety, and tolerability profile in healthy Chinese volunteers. These data support the further clinical development of AL01211 as a therapy for GSL storage diseases.

Clinical Trial Registry

Clinical Trial Registry no. CTR20221202 (http://www.chinadrugtrials.org.cn) registered on 6 June 2022 and ChiCTR2200061431 (http://www.chictr.org.cn) registered on 24 June 2022.

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Acknowledgments

The study was managed by the clinical CRO Hangzhou Tigermed Consulting Co., Ltd and conducted at the Second Hospital of Anhui Medical University Phase 1 Unit in Hefei, China. The bioanalytical work (pharmacokinetic and GL1 measurements) was performed at Wu** Tan, Marvin Garovoy & Jianhong Zheng

Authors
  1. Lei Dong
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  2. Jianxing **ang
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  3. Michael Babcock
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  4. Yuanzhi Cheng
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  5. Yan Wang
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  6. Yuqiao Shen
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  7. Li Li
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  8. Li** Tan
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  9. Marvin Garovoy
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  10. Wei Hu
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  11. Jianhong Zheng
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Corresponding authors

Correspondence to Wei Hu or Jianhong Zheng.

Ethics declarations

Funding

This study was funded by AceLink Therapeutics, Inc.

Conflict of interest

J.X., M.B., Y.S., L.L., and J.Z. are full-time employees of AceLink Therapeutics. L.T. and M.G. were AceLink Therapeutics employees at the time of this study. L.D., Y.C., Y.W., and W.H. have no relevant financial or non-financial competing interests to report.

Ethical approval

This study was approved by the Ethics Committee of the Second Hospital of Anhui Medical University (approval number: YW2022-050(F1); approval date: 25 April 2022) and was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP).

Consent to participate

All volunteers gave their written informed consent prior to any study-related procedure.

Consent for publication

Not applicable.

Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

M.B., J.Z., Y.S., M.G., and W.H. were responsible for study concept and study design. L.D., Y.C., Y.W., L.L., L.T., W.H., and J.Z. were responsible for study conduct and data acquisition. L.D., J.X., M.B., W.H., and J.Z. were responsible for analysis and interpretation. J.X. was responsible for original draft preparation. M.B., L.D., Y.S., M.G., J.Z., and W.H. were responsible for draft review and editing. All authors have read and agreed to the final version of this manuscript.

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Dong, L., **ang, J., Babcock, M. et al. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral AL01211 in Healthy Chinese Volunteers. Clin Drug Investig 44, 387–398 (2024). https://doi.org/10.1007/s40261-024-01362-2

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  • DOI: https://doi.org/10.1007/s40261-024-01362-2

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