Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes

Eriksson, OlofUppsala universitet,Science for Life Laboratory, SciLifeLab,Translationell avbildning med PET,Antaros Med AB, Uppsala Sci Pk,Dag Hammarskjolds Vag 14B, S-75183 Uppsala, Sweden (author)

Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [Ga-68]Ga-DO3A-Tuna-2 and [Ga-68]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 +/- 14.4% (SD) in N=5 patients and a GLP1R occupancy of 49.9 +/- 13.3%. Fasting Plasma Glucose levels (-3.30 +/- 1.14 mmol/L) and body weight (-3.87 +/- 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.

Haack, TorstenSanofi, R&D Res Platform, Integrated Drug Discovery, Frankfurt, Germany. (author)
Hijazi, YoussefSanofi, Translat Med, Frankfurt, Germany. (author)
Teichert, LenoreSanofi, R&D Clin Sci, Frankfurt, Germany. (author)
Tavernier, VeroniqueSanofi, R&D Clin Sci, Montpellier, France. (author)
Laitinen, IinaSanofi, Global Imaging, Frankfurt, Germany. (author)
Berglund, Jan ErikClin Trial Consultants AB, Uppsala, Sweden. (author)
Antoni, GunnarUppsala universitet,Preparativ läkemedelskemi(Swepub:uu)gunnarat (author)
Velikyan, Irina,1966-Uppsala universitet,Translationell avbildning med PET(Swepub:uu)irinveli (author)
Johansson, LarsAntaros Med AB, Uppsala Sci Pk,Dag Hammarskjolds Vag 14B, S-75183 Uppsala, Sweden. (author)
Pierrou, StefanAntaros Med AB, Uppsala Sci Pk,Dag Hammarskjolds Vag 14B, S-75183 Uppsala, Sweden. (author)
Wagner, MichaelSanofi, R&D Res Platform, Integrated Drug Discovery, Frankfurt, Germany. (author)
Tillner, JoachimSanofi Aventis Deutschland GmbH, Ind Pk Hochst,Bldg H831, D-65926 Frankfurt, Germany. (author)
Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)

By the author/editor: Eriksson, Olof; Haack, Torsten; Hijazi, Youssef; Teichert, Lenore; Tavernier, Veron ...; Laitinen, Iina; show more...; Berglund, Jan Er ...; Antoni, Gunnar; Velikyan, Irina, ...; Johansson, Lars; Pierrou, Stefan; Wagner, Michael; Tillner, Joachim; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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