Fig. 5: IRPAs have improved therapeutic index in glucose lowering. | Nature Communications

Fig. 5: IRPAs have improved therapeutic index in glucose lowering.

From: Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists

Fig. 5

IRPA-3 lowers glucose effectively in acute testing with reduced hypoglycemic risk in mice (a; mean ± SD, n = 8). Plasma IRPA-3 measured at 2-h post dose was shown in (b; mean ± SD, n = 3 or 4). Acute glucose lowering by i.v. RHI (c) and IRPA-7 (d) in diabetic minipigs with dose escalation of 30% upwards. Improved therapeutic index of IRPA-7 is indicated by smooth titration of glucose lowering. Data is presented as mean ± SEM, n = 6 animals per dose group. IRPAs demonstrated protracted s.c. profile consistent with QD dosing in diabetic minipig (e, f). IRPA-1 and IRPA-7 dosed as single s.c. bolus yielded overall comparable PD profile relative to Tresiba® in diabetic minipigs. Plasma exposures for IRPA-1 and IRPA-7 were not different from those of Tresiba®. Data is presented as mean ± SEM, n = 20 animals for IRPA-1, n = 6 animals for IRPA-7 and n = 19 animals for Tresiba®. IRPA-7 was formulated in Glycerin, 16 mg/mL; Metacresol, 1.6 mg/mL; Phenol, 0.65 mg/mL; Anhydrous Sodium Phosphate, Dibasic, 7 mM; 0.671 equivalent Zn2+; pH 7.4. IRPA-1, IRPA-7 or Tresiba® dose used was 0.9, 0.9 or 0.35 nmol/kg, respectively. Source data are provided as a Source Data file.

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