Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs

Abstract

At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug Administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We have optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection and gene-expression analyses. In rats and dogs, the prodrugs are retained long term in liver tissue, and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.

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Fig. 1: Rational design of TEL-x-MM and semi-batch synthesis of TEL-x-BASP.
Fig. 2: PK and BD data for TEL-x-BASPs in healthy mice.
Fig. 3: Scalable synthesis of TEL-2-BASP.
Fig. 4: Safety and pharmacokinetic analysis of TEL-2-BASP in rodents.
Fig. 5: Design and efficacy of TEL-2-BASP and TEL in a chemically induced CCl4 mouse model.
Fig. 6: Assessing fibrosis reversal with PSR histological images.

Change history

  • 03 September 2018

    In the version of this Article originally published, the author Peter Blume-Jensen was not denoted as a corresponding author; this has now been amended and the author’s email address has been added. The ‘Correspondence and requests for materials’ statement was similarly affected and has now been updated with the author’s initials ‘P.B-J.’

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Acknowledgements

Funding was provided by XTuit Pharmaceuticals. J.A.J. acknowledges the National Institutes of Health (1R01CA220468-01) for support of this work. M.R.G. acknowledges the National Institutes of Health for a postdoctoral fellowship (1F32EB023101). H.V.-T.N. thanks the National Science Foundation for a Graduate Research Fellowship. The authors thank R. Bronson for assistance with histopathology analysis.

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M.R.G., J.L. and J.A.J. designed synthetic experiments. M.R.G., J.L., F.V., H.V.-T.N. and D.C.E. synthesized materials. J.L., J.K.S.-S., P.W.K. and D.E.C. developed the scaled process and produced materials for the safety and toxicology studies. J.N.A. and P.B.-J. planned in vivo experiments. P.B-J. and M.V.S. planned biomarker analyses. M.V.S., S.J.H., B.V., A.M.N., J.C.A. and J.B. performed biomarker analyses. All authors helped to analyse data. M.R.G., J.N.A., P.B.-J. and J.A.J wrote the manuscript. All authors read and edited the manuscript.

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Correspondence to Peter Blume-Jensen or Jeremiah A. Johnson.

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Competing interests

J.L., J.N.A., M.V.S., S.J.H., B.V., K.D.E., A.M.N., J.C.A., J.B., S.P., S.W.B., E.J.H., J.K.S.-S., P.W.K., D.E.C. and P.B.-J. are former employees and shareholders of XTuit Pharmaceuticals. P.B.-J. is President and Founder of Acrivon Therapeutics. J.A.J. is a Co-Founder of Acrivon Therapeutics.

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Golder, M.R., Liu, J., Andersen, J.N. et al. Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs. Nat Biomed Eng 2, 822–830 (2018). https://doi.org/10.1038/s41551-018-0279-x

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