Licogliflozin <i>versus</i> Placebo in Women with Polycystic Ovary Syndrome (PCOS): A Randomised, Double-Blind, Phase 2 Trial

Abstract

Licogliflozin versus placebo in women with polycystic ovary syndrome (PCOS): a randomised, double-blind, phase 2 trial. Background: PCOS is the most common endocrinopathy in women of childbearing age. Currently, there is no approved therapy available. The dual sodium-glucose transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. Its effect on androgens is unknown. Methods: In a multi-center, randomised, placebo-controlled, double-blind trial, patients with PCOS type A or B and insulin resistance were randomised to either licogliflozin 50 mg or placebo TID in a 1:1 ratio for two weeks. Change from baseline free testosterone (FT) serum concentrations served as primary outcome. Serum levels of various androgens and parameters of insulin resistance were secondary outcomes and exploratory objectives. Findings: Between October 4, 2017, and June 4, 2018, 29 patients were allocated to licogliflozin or placebo (n: 15 vs. 14). After exclusion per protocol of 5 and 4 patients in the licogliflozin and placebo groups, 10 patients were eligible for analysis in each group. The treatment effect of licogliflozin on FT (primary outcome) did not reach statistical significance (TRLIK066 :TRPCB(FT): 0·88; 90%CI: 0·70-1·11; p=0·353). Licogliflozin improved hyperandrogenaemia with reductions of androstendione (A4) by 19% (TRLIK066:TRPCB(A4): 0·81; 90%CI: 0·68-0·99; p=0·089) and dehydroepiandrosteronsulfate (DHEAS) by 24% (TRLIK066:TRPCB(DHEAS): 0·76; 90%CI: 0·65-0·89; p=0·008). Moreover, hyperinsulinaemia was reduced by 70% in the licogliflozin treatment group (highest insulin concentration (MAXI); TRLIK066:TRPCB(MAXI): 0·26; 90%CI: 0·20-0·34; p<0·001 and area under the curve insulin (AUCI); TRLIK066:TRPCB(AUCI): 0·32; 90%CI: 0·25-0·41; p<0·001). The most common adverse events were diarrhea and nausea without occurrence of serious adverse events. Interpretation: Dual inhibition of SGLT1/2 for two weeks reduced hyperinsulinaemia and as a trend hyperandrogenism in women with PCOS in a phase 2 trial. Licogliflozin may represent a promising novel treatment option for PCOS. Trial Registration: This trial is registered at ClinicalTrials.gov (NCT0315259) and EudraCT (2017-001373-16). Funding Statement: The study is funded by Novartis. Declaration of Interests: PM and MH are employees of Novartis. MZ, NH were employees of Novartis when the study was conducted. SI, DZ, and FW declare no competing interests. AD received honoraria for consultancy from Ablacare, Abbvie, Bayer, and Medtronics and received grant funding from the National Institutes of Health. DF received honoria and/or expenses for invited speeches from Eisai, Ipsen, and Sanofi Genzyme, is member of the advisory board of Eisai, Ipsen, and Sanofi Genzyme, and participated in funded research of Astra Zeneca, Bayer Pharma, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Eli Lilly, Horizon Pharma, Hoffmann-La Roche Ltd, HRA Pharma, Immunovant Sciences GmbH, Incyte Biosciences International Sarl, Ipsen, Janssen-Cilag GmbH, Lexicon Pharmaceuticals, Madrigal Pharmaceuticals, Novartis and Otsuka Pharmaceutical. JS received honoraria for talks and/or consultancy and/or research funding from Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb (BMS), GI- Dynamics, Glaxo Smith Kline (GSK), Intarcia, Ipsen, Janssen, LifeScan, Lilly, Merck Sharp Dohme (MSD), MedScape, Mundipharma, Novartis, NovoNordisk, Omniamed, Pfizer, Roche, Sanofi Aventis, Servier, Takeda and Ypsomed. KD participated in funded research of Astra Zeneca, Bayer Pharma, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Eli Lilly, Exelixis, Horizon Pharma, Hoffmann-La Roche Ltd, HRA Pharma, Immunovant Sciences GmbH, Incyte Biosciences International Sarl, Ipsen, Janssen-Cilag GmbH, Lexicon Pharmaceuticals, Madrigal Pharmaceuticals, Novartis and Otsuka Pharmaceutical. ST received honoria and/or expenses for invited speeches and/or consultancy from Abbott, Boehringer Ingelheim, BSN Medical, Chugai, Eli Lilly, Janssen-Cilag, KWHC, Merck, Nationale Gesundheitsakademie, Nova Biomedical, NovoNordisk, and Sanofi-Aventis, and participated in funded research of Astra Zeneca, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Eli Lilly, Exelixis, Horizon Pharma, Lexicon Pharmaceuticals, Madrigal Pharmaceuticals, Novartis, NovoNordisk, and Incyte Biosciences International Sarl. Ethics Approval Statement: Ethics approval Germany (University of Duisburg-Essen, University of Freiburg and Charite Research Organisation GmbH): 17-7599-AF; USA: University of Pennsylvania: 827907.