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

Abstract

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.

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Fig. 1: Patient disposition.
Fig. 2: Changes in levels of serum alanine aminotransferase from baseline up to week 12.
Fig. 3: Change in relative liver fat content after 12 weeks of treatment with licogliflozin.
Fig. 4: Change in anthropometric parameters from baseline up to week 12.

Data availability

The authors declare that all data supporting the findings of this analysis are available within the article and its appendix. Requests for access to aggregate data and supporting clinical documents will be reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. Availability of trial data is according to the criteria and process described at www.clinicalstudydatarequest.com.

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Acknowledgments

We thank the patients for their participation in the study. The senior scientific writers, S. Kaur, Z. Birajdar and A. Meka of Novartis, provided medical writing and editorial support, which was funded by Novartis Institutes for BioMedical Research, Cambridge, MA, USA, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). The study and these analyses were funded by Novartis Institutes for BioMedical Research, Cambridge, MA, USA, which was the sponsor of the study.

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Contributions

All authors were involved in the preparation and critical review of the manuscript and approved the final version for submission. S.A.H., F.P.M., W.B.S., D. Alpenidze, D. Aizenberg, N.K., C.Y.C., E.Z., E.R., P.C., P.N.C., H.K., S.K., Z.B.A. and E.S., were involved in the acquisition of clinical data, and served as investigators in the clinical study from which data are reported in the manuscript. S.A.H. contributed to study design and review of protocol. A.E.M., Y.Z., M.M., S.M. S.K., S.T., A.P., M.K.B., Y.L.H. and C.U. were involved in the conception, design, statistical analysis and/or clinical conduct of the trial. All authors were involved in the interpretation of data in the manuscript. All authors agreed to be accountable for all aspects of the work and attest to the accuracy and integrity of the work.

Corresponding author

Correspondence to Stephen A. Harrison.

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Competing interests

S.A.H. reports advisory board fees, consultation and research grants from Akero, Altimmune, Axcella, CirU/Ls, Cymabay, Galectin, Genfit, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM and Northsea; consultation and research grants from CIVI, ENYO, Gilead, Novartis and Viking; also consultation for Canfite, Echosens, Foresite, Fortress, Kowa, Medpace, Prometic and Ridgeline. W.B.S. is an employee of Alliance for Multispecialty Research. S.K. reports advisory board fees and consultation work for Boehringer Ingelheim, Novo Nordisk and Merck, also grants and research support from Johnson & Johnson. E.R. reports funding from Novartis for the present study. E.S., F.P.M., D. Alpenidze, D. Aizenberg, N.K., C.Y.C., E.Z., P.C., P.N.C., H.K. and Z.B.A. have nothing to disclose. A.M., Y.Z., M.M., S.M., S.K., M.K.B. and Y.L.H. are employees of Novartis. A.P. and C.U. were employees of Novartis until August 2021 and February 2021, respectively. S.T. was an employee of Novartis until 2021.

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Nature Medicine thanks Kenneth Cusi, Raj Vuppalanchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editors: Jennifer Sargent and Javier Carmona, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Overview of the study design.

Patients were screened during a 28-day window, followed by a baseline run-in period of 14-days prior to the day of first treatment. Patients were then randomized in a 1:2:2 ratio to receive a placebo or licogliflozin at 30 mg or 150 mg daily. The study drug was stopped after 12-weeks of treatment and patients were subsequently followed up for 28-days.

Extended Data Fig. 2 Change in absolute liver fat content after 12 weeks of treatment with licogliflozin.

a, Absolute decrease in liver fat content (mean change from baseline); b, proportion of patients (%) with an ≥5% absolute reduction in liver fat content. Baseline is defined as the last available measurement prior to the first dose. P values based on two-sided ANCOVA test. Error bars represent s.e. n, number of patients in each treatment group.

Extended Data Fig. 3 Liver fat in subgroup of patients with baseline percentage liver fat content ≥10%.

a, Absolute reduction in liver fat content (mean change from baseline); b, relative reduction in liver fat content (% change from baseline). Baseline is defined as the last available measurement prior to the first dose. P values based on two-sided ANCOVA test. n, number of patients in each treatment group.

Extended Data Fig. 4 Change in serum AST and GGT levels after 12 weeks of treatment with licogliflozin.

a, AST; b, GGT. Data presented as geometric mean ratio to baseline. Baseline is defined as the mean of measurements taken at the screening and baseline visits. A repeated-measures ANCOVA was performed for the log-transformed ratio to baseline. P values based on two-sided ANCOVA test: *P < 0.05, **P < 0.01, and ***P < 0.001. Error bars represent s.e. n for placebo, licogliflozin 30 mg, and licogliflozin 150 mg for AST: 21, 42, 38 (day 7); 21, 43, 36 (day 14); 21, 41, 33 (day 28); 20, 40, 33 (day 56); 20, 40, 34 (day 84); 19, 39, 34 (EOS); GGT: 21, 42, 38 (day 7); 21, 43, 36 (day 14); 21, 42, 34 (day 28); 20, 42, 34 (day 56); 20, 40, 34 (day 84); 19, 39, 34 (EOS). Dotted gray line represents end-of-treatment time point.

Extended Data Fig. 5 Changes in ELF panel and its components after 12 weeks of treatment.

a, ELF; b, HA; c, PIIINP; d, TIMP1; e, ELF (patient ≥ 8.5); f, HA (patient ≥ 8.5); g, PIIINP (patient ≥ 8.5); h, TIMP1 (patient ≥ 8.5). All data presented as geometric mean ratio to baseline. Baseline is defined as the last available measurement prior to the first dose. P values based on two-sided ANCOVA test. N for placebo, licogliflozin 30 mg, and 150 mg are 18, 34, and 29 (ELF, HA, PIIINP, TIMP1); 14, 40, and 26 (ELF ≥ 8.5, HA ≥ 8.5, PIIINP ≥ 8.5, TIMP1 ≥ 8.5). n, number of patients in each treatment group. Error bars represent s.e.

Extended Data Fig. 6 Change in metabolic parameters from baseline up to week 12.

a, HbA1c; b, HOMA-IR. *Ten patients who received exogenous insulin were excluded from HOMA-IR calculation (placebo (n = 3), licogliflozin 30 mg (n = 5), and licogliflozin 150 mg (n = 2)). Data presented as geometric mean ratio to baseline. P values based on two-sided ANCOVA test. Baseline is defined as the last available measurement prior to the first dose. n, number of patients in each treatment group. N for placebo, licogliflozin 30 mg, and licogliflozin 150 mg for HbA1c are 20, 40, and 34; N for HOMA-IR are placebo (n = 16), licogliflozin 30 mg (n = 32), and licogliflozin 150 mg (n = 31). Error bars represent s.e.

Extended Data Fig. 7 Mean HbA1c by treatment at baseline and week 12.

Data presented as mean (%). Error bars represent SD. n for placebo, licogliflozin 30 mg, and licogliflozin 150 mg for baseline: 21, 43, 41; week 12: 20, 40, 34.

Extended Data Fig. 8 Changes in biomarkers of liver fibrosis after 12 weeks of treatment with licogliflozin.

Data presented in subfigures (a–c) as geometric mean ratio to baseline, and in subfigure d, as mean change from baseline. a, PRO-C3; b, APRI; c, FIB4; d, NAFLD fibrosis score. Baseline is defined as the last available measurement prior to the first dose. P values based on two-sided ANCOVA test. N for placebo, licogliflozin 30 mg, and 150 mg are 21, 43, and 37 (APRI, FIB4, NAFLD fibrosis score) 20, 42, and 34 (Pro-C3). Error bars represent s.e.

Extended Data Fig. 9 Study outcomes with licogliflozin treatment in patients with or without diarrhea.

a, Bodyweight; b, ALT; c, placebo-adjusted decrease in LFC. P values based on two-sided ANCOVA test: *P < 0.05, **P < 0.01, and ***P < 0.001. Dotted gray line represents end of treatment time point. Data in subfigure a presented as mean % change from baseline, b, as geometric mean ratio to baseline, and c, as mean (%) reduction. Error bars represent s.e. n for placebo, licogliflozin 30 mg, and licogliflozin 150 mg for bodyweight in subgroup with diarrhea: 12, 21, 8 (day 7); 12, 22, 8 (day 14); 11, 21, 5 (day 28); 11, 21, 7 (day 42); 11, 21, 7 (day 56); 10, 19, 7 (day 84); 10, 19, 7 (EOS); bodyweight in subgroup without diarrhea: 9, 21, 30 (day 7); 9, 21, 28 (day 14); 9, 21, 25 (day 28); 9, 21, 27 (day 42); 9, 21, 26 (day 56); 9, 21, 27 (day 84); 9, 21, 27 (EOS). ALT in subgroup with diarrhea: 12, 21, 8 (day 7); 12, 22, 8 (day 14); 12, 21, 7 (day 28); 11, 21, 7 (day 56); 11, 19, 6 (day 84); 10, 18, 7 (EOS); ALT in subgroup without diarrhea: 9, 21, 30 (day 7); 9, 21, 28 (day 14); 9, 21, 27 (day 28); 9, 21, 27 (day 56); 9, 21, 26 (day 84); 9, 21, 27 (EOS). LFC in subgroup with diarrhea: 11, 18, 7 (day 84) and in subgroup without diarrhea: 8, 21, 26 (day 84). LFC, liver fat content.

Extended Data Fig. 10 Summary of findings of licogliflozin in NASH.

1He, Y.L. et al. Diabetes Obes. Metab. 21, 1311–1321 (2019). 2Current study data. ALT, alanine aminotransferase; GLP-1, glucagon-like peptide 1; NASH, nonalcoholic steatohepatitis; SGLT, sodium–glucose cotransporters; wt, weight.

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Harrison, S.A., Manghi, F.P., Smith, W.B. et al. Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. Nat Med (2022). https://doi.org/10.1038/s41591-022-01861-9

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