Key publication slides Heinemann L, et al. Pharmacokinetic and pharmacodynamic properties of a novel inhaled insulin. Journal of Diabetes Science and Technology. 2017;11:148-56. Key publication slides No FXCX

Rationale for Developing Ultra-Fast-Acting Insulins Fast-acting insulin analogues (e.g. insulin lispro) have improved PK/PD properties compared with regular human insulin1 However, s.c. administration slows insulin absorption, resulting in delayed onset of action and prolonged duration of action compared with endogenous insulin activity in healthy individuals2,3 Delayed onset of action/prolonged duration of action can lead to: Suboptimal control of early postprandial hyperglycaemia Risk of late-postprandial hypoglycaemia Ultra-fast-acting insulin analogues with a more rapid onset of action and shorter duration of action are needed 1. Heinemann L, et al. Diabet Med. 1996;13:625-9. 2. Chen JW, et al. Diabetes Obes Metab. 2003;5:223-33. 3. Home PD. Diabetes Obes Metab. 2015;17:1011-20. PD, pharmacodynamic; PK, pharmacokinetic; s.c., subcutaneous.

Technosphere® Inhaled Insulin (TII): An Inhaled Insulin Delivery System Property Description Formulation Inhalation powder containing recombinant human insulin adsorbed onto FDKP microparticles Microparticle size 2.0–2.5 μm (optimized for delivery to the deep lung) Insulin absorption Upon delivery to the deep lung, mircroparticles dissolve in the alveoli, allowing for rapid absorption of insulin into circulation Excipient (FDKP) Biologically inactive and excreted unchanged in urine Inhaler MedTone® inhaler Required 2 inhalations per cartridge Gen2® inhaler Smaller, more efficient (less powder per dose) Requires 1 inhalation per cartridge Cartridges Contain 10, 20, or 30 U (labelled as 4, 8, or 12 U, respectively)a a Labels refer to equivalent dose for a patient transitioning from subcutaneously administered insulin). FDKP, fumaryl diketopiperazine; U, units. Heinemann L, et al. J Diabetes Sci Technol. 2017;11:148-56.

Faster onset of appearance and faster clearance vs insulin lispro PK Profile of TII 8 U TII 8 U Insulin lispro (s.c.) 10 20 30 40 50 60 70 80 Insulin (µU/mL) -20 20 60 120 140 180 200 220 240 280 340 360 40 100 160 260 320 300 80 Time (minutes) Faster onset of appearance and faster clearance vs insulin lispro Reproduced from Heinemann L, et al. J Diabetes Sci Technol. 2017;11:148-56 © 2016 Diabetes Technology Society.

Baseline-corrected GIR (mg/kg/min) PD Profile of TII 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 TII Insulin lispro (s.c.) Baseline-corrected GIR (mg/kg/min) 100 200 300 400 500 600 Time (minutes) Rapid onset of action and shorter duration of action vs insulin lispro Reproduced from Heinemann L, et al. J Diabetes Sci Technol. 2017;11:148-56 © 2016 Diabetes Technology Society. GIR, glucose infusion rate.

Clinical Use of TII Clinical data indicate that TII may reduce postprandial hyperglycaemia (including late-postprandial hypoglycaemia) compared with fast-acting insulin analogues1-3 Addition of TII to a closed-loop artificial pancreas system also improves postprandial glycaemic control without increasing the risk of hypoglycaemia4 Switching patients from s.c. insulin to TII Cartridges containing 10, 20, or 30 U (labelled as 4, 8, or 12 U) are used to replace s.c. doses of 4, 8, or 12 U, respectively Potency of inhaled insulin is less than s.c. equivalent, so dose titration is expected1 Adjustment of basal insulin dose may be necessary1 Due to its short duration of action, a second dose may be required 1.5–2 hours after first inhalation to manage extended postprandial hyperglycaemia2 1. Bode BW, et al. Diabetes Care. 2015;38:2266-73. 2. Rosenstock J, et al. Lancet. 2010;375:2244-53. 3. Kapsner P, et al. Diabeteologia. 2009;52 Suppl1:S386 [abstract 982]. 4. Zisser H, et al. J Diabetes Sci Technol. 2015;9:564-72.

Summary TII has a more rapid absorption and clearance than s.c. fast-acting insulin analogues These properties result in a faster onset of action and shorter duration of action May provide better glycaemic control in the early postprandial phase May reduce the risk of late-postprandial hypoglycaemia Transitioning patients from s.c. insulin to TII Dose titration of TII is expected An increase in the basal insulin dose may be necessary Due to its short duration of action, a second dose may be required 2 hours after the first to manage extended postprandial hyperglycaemia Heinemann L, et al. J Diabetes Sci Technol. 2017;11:148-56.