Multiparameter Peptide Optimization toward Stable Triple Agonists for the Treatment of Diabetes and Obesity

Abstract

Historically, peptide optimization has mainly focused on pharmacological activity. Physicochemical properties have often been evaluated late in discovery, potentially providing molecules with suboptimal stability properties. Often, such issues cannot be overcome by formulation approaches but need additional optimization cycles for a redesign of the peptide. Here, early rational multiparameter optimization of exendin‐4 based agonists is described toward i) a balanced triple activity profile at the glucagon‐like peptide 1, glucagon, and gastric inhibitory polypeptide receptors for the treatment of diabetes and obesity and in parallel ii) robust physicochemical properties for 1‐daily subcutaneous application in a multiple‐dose pen device. In depth evaluation of an optimized candidate shows an excellent profile with respect to its physicochemical properties and pharmacokinetic/pharmacodynamic (PD) behavior in minipigs and monkeys.

Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography

“…The majority of the received dose in myocardium in the accepted dosimetry model is crossfire from passing blood in the circulation rather than actual uptake in the heart wall itself. Per previously described procedures (27), the blood pool data were used as proxy for red marrow since bone marrow is very difficult to delineate in PET images without having to accept severe partial volume effects. In fact, because of the higher radiosensitivity of red marrow (50 mSv annual maximal dose vs. 150 mSv for most other tissues), this tissue is the dose-limiting critical organ.…”

“…All chemicals and buffers were sourced from VWR Life Sciences Sweden, unless otherwise noted. Peptides (S02-GIP-T4, triple agonist 12 [TA12], GIP , GLP NH 2 ) were synthesized at Sanofi according to welldescribed procedures (27).…”

“…[ 68 Ga]S02-GIP-T4 PET/CT scanning of the pancreas was performed at baseline and after subcutaneous administration of 50 mg/kg of study drug TA12 (4,935.6 g/mol, 10.1 nmol/kg), a TA with high activity at the GIPR (see Table 1). The discovery and characteristics of TA12 have been described in detail previously (27). The follow-up PET/CT scan was performed at T max (2 h) for the study drug.…”

Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist

“…Four AAs were mutated in the exendin tail (positions 32, 34, 35, and 39) to improve the physicochemical profile in the presence of antimicrobial preservatives, particularly to avoid aggregation issues at acidic pH in the presence of phenolic preservatives (Evers et al, 2019). Further AA changes at positions 3, 13, 20, and 29 were introduced to achieve high and balanced activation at each receptor and to ameliorate chemical stability in buffer formulations (Evers et al, 2020). While the combination of all 4 changes is needed to achieve the desired overall profile, Leu in position 13 was especially important to ensure chemical stability in solution and the other 3 AAs to achieve high GIPR activation.…”

“…The resulting triagonist was evaluated in a series of preclinical rodent models of obesity and diabetes, showing impressive effects on body weight reduction and improved glucose control (Finan et al, 2015). Based on these highly promising preclinical data, several GLP-1-based unimolecular dual and triagonists have been subsequently evaluated (Clemmensen et al, 2019;Day et al, 2009;Di Prospero et al, 2021;Evers et al, 2020;Finan et al, 2013Finan et al, , 2015. To date, clinical data have only been published for dual incretin agonists (Ambery et al, 2018a;Di Prospero et al, 2021;Finan et al, 2013;Frias et al, 2017;Frı ´as et al, 2021;Nahra et al, 2021;Portron et al, 2017;Rosenstock et al, 2021;Schmitt et al, 2017;Tillner et al, 2019).…”