Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus.

Background and Objective: IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).
Methods: In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose.
Results: Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC _0-t : ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (C _max ): 1.12 [1.06; 1.18]. Semaglutide AUC _0-t was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide C _max was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone.
Conclusion: The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema.
Clinical Trial: ClinicalTrials.gov identifier: NCT03789578.
Competing Interests: Declarations Funding This study was funded by Novo Nordisk. Conflicts of interest L.W., L.A., S.T.B., T.K., N.R.K., E.N., L.N., T.M.P.R., D.B.S. and A.V. are employees and shareholders of Novo Nordisk. H.V.C. has no conflicts of interest to disclose. L.P.-M. is an employee and shareholder of Profil. Profil received research funds from Adocia, AstraZeneca, Betagenon, Biocon, Bioton, Crinetics, Eli Lilly, Genova, Nanexa, NeoDyne, Novo Nordisk, Sanofi, Spiden and Zealand Pharma. L.P.-M. received speaker honoraria from Eli Lilly, Gan and Lee Pharmaceuticals and Novo Nordisk. Availability of data and material Individual participant data will be shared in data sets in a de-identified/anonymised format. Datasets from Novo Nordisk sponsored clinical research completed after 2001 for product indications approved in both the EU and USA will be shared. Study protocol and redacted clinical study report will be available according to Novo Nordisk data sharing commitments. The data will be available permanently after research completion and approval of product and product use in both EU and USA. There is no end date. Data will be shared with bona fide researchers submitting a research proposal requesting access to data for use as approved by the independent review board according to the independent review board charter (see novonordisk-trials.com). The data will be made available on a specialised SAS data platform. Individual data from animal studies and in vitro studies will be shared upon reasonable request. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The clinical study was approved by an independent ethics committee (Ärztekammer Nordrhein, Düsseldorf, Germany; approval ID 2018242; approval date 12 November 2018). Animal studies were performed according to the Danish Act on Experiments on Animals, the Appendix A of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS 123), and European Union Directive 2010/63. The animal studies were performed under licenses granted by the Danish national Animal Experiments Inspectorate (no. 2010/561-1786 and no. 2015-15-0201-00540). Consent to participate Informed consent was obtained from all individual participants included in the clinical study. Consent for publication Not applicable. Code availability Not applicable. Author contributions L.W., N.R.K., L.N. and T.M.P.R. contributed to clinical study data analysis, critical manuscript revision and final manuscript approval; L.A., S.T.B., T.K., E.N., D.B.S. and A.V. contributed to animal and in vitro study design, data analysis, critical manuscript revision and final manuscript approval; H.V.C. and L.P.-M. contributed to clinical study data collection, critical manuscript revision and final manuscript approval.
(© 2024. The Author(s).)