OBJECTIVE:To compare the glycemic response and pharmacokinetics (PK) of ultra-rapid lispro (URLi) versus lispro during manual basal rate reductions (BRRs) before exercise with conventional continuous subcutaneous insulin infusion (CSII) in active adults with type 1 diabetes. RESEARCH DESIGN AND METHODS:This study was a double-blind, four-period, crossover, randomized controlled trial. Exercise (60 min walking at 45-55% VO2max) was performed 4 h after a standardized meal, with either a 50% (-60 min) or 100% (-15 min) BRR before exercise using URLi or lispro. The primary end point was the change in glucose during exercise, and insulin lispro PK was the secondary end point. RESULTS:Twenty-five participants (mean ± SD age 36.7 ± 10.3 years; mean ± SD HbA1c 50.4 ± 8.5 mmol/mol [6.76 ± 0.8%]; 48% female) completed the study. URLi significantly attenuated the reduction in glucose level compared with lispro during both the 50% BRR (-26.8 ± 37 vs. -39.0 ± 39 mg/dL; P < 0.05) and the 100% BRR (-46.9 ± 32 vs. -60.5 ± 39 mg/dL; P < 0.01). Circulating insulin lispro concentrations rose in the first 15 min of exercise, but maximum concentration was lower with URLi versus lispro within each BRR strategy. Numerically less hypoglycemia was observed during exercise with URLi (6%) compared with lispro (16%). Following a postexercise meal, faster insulin absorption of URLi resulted in an earlier postprandial glucose lowering compared with lispro. CONCLUSIONS:Using URLi in conventional CSII pump therapy provides more effective BRRs prior to exercise compared with lispro, with fewer hypoglycemic events in active adults with type 1 diabetes.

AIMS:To evaluate the bioequivalence of orally administered orforglipron tablets and capsules in participants with obesity or overweight who were otherwise healthy. MATERIALS AND METHODS:This phase 1, multicenter, open-label, multiple-dose, dose-escalation study was conducted in 429 healthy adults. Study participants received each orforglipron capsule and tablet dose strength once daily for 7 days in the fasted state at capsule doses of 1, 3, 6, 12, 24, or 36 mg and corresponding tablet doses of 0.8, 2.5, 5.5, 9, 14.5, and 17.2 mg. The primary endpoint was steady-state area under the concentration-time curve from 0 to 24 h (AUC0-24,ss) and steady-state maximum observed drug concentration (C max,ss). A prespecified mixed scaling approach was applied to evaluate bioequivalence. Safety and tolerability of the tablets and capsules were also assessed. RESULTS:Bioequivalence was demonstrated between capsules and dose-adjusted tablets across all six doses. The 90% confidence interval of the ratios of the geometric least-squares means of AUC0-24,ss and C max,ss between each capsule dose and corresponding tablet dose met the predefined criteria for bioequivalence. The safety profiles were similar between tablets and capsules, with no apparent differences or trends in the incidence of treatment-emergent adverse events by presentation or with increasing dose. CONCLUSIONS:Once-daily orforglipron capsules and dose-adjusted tablets demonstrated pharmacokinetic bioequivalence at all tested doses and showed similar safety and tolerability profiles, with mostly mild treatment-emergent adverse events consistent with previous orforglipron clinical trials. ClinicalTrials .gov Identifier: NCT06440980.

Orforglipron is an orally administered, small-molecule glucagon-like peptide-1 receptor agonist in clinical development for the treatment of type 2 diabetes and obesity. Orforglipron is a substrate of CYP3A4, organic anion transporting polypeptides (OATPs) 1B/1B3, and P-glycoprotein (P-gp); however, precipitants commonly used to define these mechanisms have not been fully characterized. The enzyme- and transporter-mediated DDI profile of orforglipron and that of CYP3A4/OATP1B/P-gp precipitants were characterized in six phase 1 clinical studies in healthy participants. Orforglipron pharmacokinetics were assessed with clarithromycin, carbamazepine, cyclosporine, and quinidine. Precipitant effects on CYP3A and OATP1B activity were measured using midazolam and coproporphyrin-I (CP-I). Orforglipron effects on CYP3A, P-gp, BCRP, and OATP1B were evaluated using midazolam, digoxin, rosuvastatin, simvastatin, atorvastatin, and CP-I. Mechanistic interrogation of the simvastatin interaction was also conducted. Clarithromycin, carbamazepine, and quinidine had minimal effect on CP-I pharmacokinetics, while the cyclosporine effect was substantial. Cyclosporine and quinidine weakly increased midazolam exposure. Orforglipron exposure increased in the presence of clarithromycin and cyclosporine and decreased with carbamazepine, demonstrating orforglipron exposure is affected by precipitants of CYP3A4 and OATP1B. Quinidine did not meaningfully change orforglipron exposure. Orforglipron had no clinically meaningful effect on the exposure of midazolam, digoxin, or atorvastatin. A weak increase in rosuvastatin exposure was consistent with BCRP inhibition, as CP-I data confirmed orforglipron does not affect OATP1B. Increase in simvastatin acid exposure was attributed to the unique disposition of simvastatin rather than enzyme or transporter inhibition. These findings address mechanistic precipitant knowledge gaps and provide a framework for managing potential orforglipron DDIs in clinical practice.

In advanced cancer patients the CYP3A4-mediated clearance of drugs is dependent on the severity of inflammation. In a study in patients with advanced cancer (n = 44) with solid tumors, prior to cancer treatment, high inter-patient variability was observed in the plasma pharmacokinetic (PK) parameters of the CYP3A4 substrate midazolam. The neutrophil-to-lymphocyte ratio (NLR) was used to categorize the degree of inflammation of each patient and in turn to correlate increases in NLR to decreases in CYP3A4 expression. Patients with NLR ≥ 5 were categorized as having high inflammation, and patients with NLR < 5 as having low-to-moderate inflammation. A physiologically-based PK (PBPK) model of midazolam PK and a top-down approach was used to determine the reductions in CYP3A4 abundance in the liver and gut wall needed to match the PK parameters of midazolam in the NLR ≥ 5 and NLR < 5 groups of patients. The midazolam mean CL/F was 33 L/h in the NLR < 5 group, and midazolam CL/F was 20 L/h in the NLR ≥ 5 group. To match the PK of midazolam in the NLR < 5 group, the CYP3A4 expression was reduced 40

Orforglipron is a non-peptide, oral glucagon-like peptide 1 receptor agonist under development for glycemic control in adults with type 2 diabetes and weight management in people with obesity. Two phase 1, open-label studies evaluated the disposition and absolute bioavailability of orforglipron in healthy adults. Study A participants (N = 10) received a 1-mg orforglipron oral capsule while fasting and an intravenous dose of ∼21 µg of [14C]-orforglipron. Study B participants (N = 6) received an oral solution of 3 mg of orforglipron with ∼200 µCi of [14C]-orforglipron while fasting. In study A, total plasma radioactivity and [14C]-orforglipron were measured by accelerator mass spectrometry (AMS) and high-performance liquid chromatography (HPLC)/AMS, while orforglipron was measured by HPLC/MS. The mean absolute oral bioavailability of orforglipron was 79.1% ± 16.8%. In study B, urine and feces were analyzed for total radioactivity. Metabolic radioprofiling was performed on selected plasma and fecal samples by HPLC/high-resolution MS. The primary route of elimination for [14C]-orforglipron-related radioactivity was via the feces (87% ± 2.8%) with minimal urinary excretion (0.2% ± 0.02%). Total recovery of administered radioactivity was 88% over 384 hours after the dose. Metabolite profiling from study B showed that orforglipron underwent extensive oxidative metabolism, followed by microbial metabolism of the oxadiazolone ring. Orforglipron was the most abundant plasma component (93.3%) with minor oxidative metabolites M7 (3.3%) and M23 (1.6%).

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10-2,000 mg) or multiple ascending dose (MAD; dose range 100-1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21-65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5-3.5 hours, terminal half-life of 11.4-19.1 hours, and exhibited dose-dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL-17A levels within 12 hours of dosing. Four participants from the 400-mg (n = 1) and 1,000-mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post-last LY3509754 dose), consistent with drug-induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte-rich, moderate-to-severe lobular inflammation. We theorize that the DILI relates to an off-target effect rather than IL-17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [ 125 I]GLP-1(7-36)NH 2 or [ 3 H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( K i ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor K i value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R ( Glp1r S33W ) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1r S33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.

This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6‐11 years), adolescents (12‐17 years) and adults (18‐64 years) with type 1 diabetes mellitus (T1D).

Typically, therapeutic proteins (TPs) have a low risk for eliciting meaningful drug interactions (DIs). However, there are select instances where TP drug interactions (TP-DIs) of clinical concern can occur. This white paper discusses the various types of TP-DIs involving mechanisms such as changes in disease state, target-mediated drug disposition, neonatal Fc receptor (FcRn), or antidrug antibodies formation. The nature of TP drug interaction being investigated should determine whether the examination is conducted as a standalone TP-DI study in healthy participants, in patients, or assessed via population pharmacokinetic analysis. DIs involving antibody-drug conjugates are discussed briefly, but the primary focus here will be DIs involving cytokine modulation. Cytokine modulation can occur directly by certain TPs, or indirectly due to moderate to severe inflammation, infection, or injury. Disease states that have been shown to result in indirect disease-DIs that are clinically meaningful have been listed (i.e., typically a twofold change in the systemic exposure of a coadministered sensitive cytochrome P450 substrate drug). Type of disease and severity of inflammation should be the primary drivers for risk assessment for disease-DIs. While more clinical inflammatory marker data needs to be collected, the use of two or more clinical inflammatory markers (such as C-reactive protein, albumin, or interleukin 6) may help broadly categorize whether the predicted magnitude of inflammatory disease-DI risk is negligible, weak, or moderate to strong. Based on current knowledge, clinical DI studies are not necessary for all TPs, and should no longer be conducted in certain disease patient populations such as psoriasis, which do not have sufficient systemic inflammation to cause a meaningful indirect disease-DI.

AIMS:To compare the time to hyperglycaemia recovery after ultra rapid lispro (URLi; Lyumjev®) versus Humalog in a randomized, double-blind crossover study. MATERIALS AND METHODS:Thirty-two adults with type 1 diabetes on continuous subcutaneous insulin infusion participated in two periods: each period included hyperglycaemia induced by a missed mealtime bolus (day 1) and by suspension of basal insulin delivery (day 2). When hyperglycaemia [plasma glucose (PG) >240 mg/dl] occurred, a correction bolus of URLi or Humalog was given and time to hyperglycaemia recovery (PG = 140 mg/dl), pharmacokinetics and glucodynamics were compared. RESULTS:Following a missed mealtime bolus, URLi significantly reduced maximum PG (-13 mg/dl; p = .02), and produced numerically more rapid decline in PG (23 mg/dl/h; p = .07), and faster recovery from hyperglycaemia (-23 min; p = .1) versus Humalog, although differences were not significant. Following basal suspension, URLi significantly reduced maximum PG (-6 mg/dl; p = .02), and produced faster PG decline (24 mg/dl/h; p < .001) and faster recovery from hyperglycaemia (-16 min; p < .01) vs. Humalog. Following a correction bolus of URLi, accelerated insulin lispro absorption was observed versus Humalog: early 50% tmax was reduced by 6 or 12 min, and AUC0-15min was increased 2.5- or 4.3-fold after correction boluses by subcutaneous infusion (day 1) or injection (day 2), respectively (all p < .001). CONCLUSIONS:During episodes of hyperglycaemia commonly experienced in people with type 1 diabetes, URLi provided a faster recovery versus Humalog from a missed mealtime bolus or during basal insulin suspension. URLi shows significant acceleration of insulin absorption versus Humalog when boluses are administered by subcutaneous infusion or injection.

URLi is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. This 2-site, randomized, 2-period crossover, double-blind study evaluated the pharmacokinetics and glucodynamics during a liquid test meal, after a single 0.2 U/kg SC dose of URLi or Humalog in 13 children, 14 adolescents, 15 adults with T1D. Onset of insulin appearance was faster with URLi vs. Humalog in children (1.1 vs. 6.5 min; p=0.0002), adolescents (1.9 vs. 6.4 min; p=0.001), and adults (0.9 vs. 4.8 min; p=0.004). Early exposure (AUC0-15min) was greater with URLi vs. Humalog: 7-fold (p<0.0001) in children, 4 fold (p=0.0003) in adolescents, 5-fold (p<0.0001) in adults; late exposure (AUC3-7h) was reduced by 58% (p<0.0001) in children, 40% (p=0.013) in adolescents, 37% (p=0.021) in adults. Total exposure was similar in URLi and Humalog. At 1h, URLi reduced PPG by 42 mg/dL (p=0.008) in children, 19 mg/dL (p=0.195) in adolescents, 34 mg/dL (p=0.018) in adults, vs. Humalog. At 2h, URLi reduced the PPG by 32 mg/dL (p=0.11) in children, 39 mg/dL (p=0.051) in adolescents and was not statistically different in adults, vs. Humalog. URLi was well tolerated in all age groups. In summary, URLi accelerated insulin lispro absorption, reduced late exposure and early PPG following a test meal vs. Humalog in children, adolescents, and adults with T1D. Disclosure R. Aronson: None. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Leohr: None. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. R.K. Pollom: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Ultra rapid lispro (URLi) is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. The aims of this study were to demonstrate the bioequivalence (BE) of a concentrated formulation (U200) of URLi to the U100 formulation of URLi after subcutaneous (SC) administration and to evaluate the glucodynamics (GD) of these formulations. This phase 1, randomized, two‐sequence, four‐period, double-blind, replicate crossover study was conducted in 68 healthy subjects. At each dosing visit, subjects received a 15-U SC dose of either U100 URLi or U200 URLi followed by a 10-h euglycemic clamp procedure. Serum insulin lispro and blood glucose concentrations were measured, and the glucose infusion rate was continuously adjusted during the clamp to maintain the target blood glucose. Bioequivalence of U200 URLi relative to U100 URLi was demonstrated. The 90% confidence intervals (CIs) of the ratios of geometric least squares (LS) means for the maximum insulin concentration and total exposure were within the BE limits of 0.80–1.25. Additionally, the 90% CIs for the ratios of geometric LS means for maximum glucose infusion rate and total glucose infused were within the BE limits. The early 50% tmax occurred at approximately the same time for the U100 and U200 URLi formulations, and the insulin exposure within the first 15 min was similar for both formulations. The tolerability of the two URLi formulations was comparable. This study demonstrated that the U100 and U200 URLi formulations are bioequivalent. The accelerated insulin absorption observed for the U100 formulation was maintained with the U200 URLi formulation. Further, the GD were similar for both formulations, supporting the ability of individuals to transfer from U100 to U200 URLi in a 1:1 unit conversion. NCT03616977.

Background and aims Ultra Rapid Lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion.

Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM). This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated. This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. NCT03305822.

Purpose: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog (R)) at 3 dose levels in healthy subjects. Methods: This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured. Findings: Across all 3 doses, insulin lispro appeared in the serum 2-5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%-52% lower, and duration of exposure was 67-86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7-9 min faster and insulin action was similar to 3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%-45%, and duration of action was reduced by 47-67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro. Implications: URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited doseproportional increases in exposure in healthy subjects. (c) 2020 The Authors. Published by Elsevier Inc.

Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM). This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18–45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39–41% lower, and exposure duration was reduced by 72–74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11–12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44–54% lower, and duration of action was reduced by 34–44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.

URLi is a novel insulin lispro formulation developed to more closely match physiological insulin secretion. URLi U200 is a concentrated formulation. This randomized, double-blind, 4-period, replicated crossover, euglycemic clamp study (NCT03616977) assessed pharmacokinetics (PK) and glucodynamics (GD) after 15 U subcutaneous doses of U100 and U200 URLi in 68 healthy subjects (mean ± SD age 39.6 ± 9.6 y). Similar mean PK and GD profiles were observed after dosing U100 and U200 URLi. The formulations were bioequivalent (BE): the 90% CI of ratios of geometric least-square means for the maximum insulin concentration (Cmax) and total exposure (AUC0-∞) were within BE limits of 0.80-1.25. Additionally, the 90% CI for the ratios of geometric means for maximum (Gtot) and total glucose infused (Rmax) were within the BE limits. The time to early half Cmax (early 50% tmax) occurred at approximately the same time for both formulations. Additionally, insulin exposure within the first 15 and 30 minutes was similar for U100 and U200 URLi. The tolerability of the U200 and U100 URLi formulations were comparable. This study demonstrated that U100 and U200 URLi formulations were BE and the faster insulin absorption was maintained in the U200 formulation. The GD were similar and support the ability of patients to transfer from U100 to U200 URLi in a 1:1 unit conversion. Disclosure H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. M.A. Dellva: Employee; Self; Eli Lilly and Company. S. Lim: Employee; Self; Eli Lilly and Company. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. J. Leohr: None. Funding Eli Lilly and Company

Aims To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp (R) (Novo Nordisk, Bagsvaerd, Denmark), Humalog (R) (Eli Lilly and Company) and NovoRapid (R) (Novo Nordisk), in patients with type 1 diabetes (T1D). Materials and Methods This was a randomized, double-blind, four-period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal. Results URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half-maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (allP <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post-meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post-meal with URLi were comparable to those in healthy subjects. Conclusions URLi demonstrated the fastest insulin absorption and the greatest numeric PPG-lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.

URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion. This randomized, double-blind, 2 period, crossover, 10 h euglycemic clamp study assessed PK and glucodynamics after one 15U SC dose of URLi and lispro in 41 patients with T1D (mean ± SD age, 32.0 ± 6.8 y; duration of T1D, 17.7 ± 9.3 y; HbA1c, 7.2 ± 0.6%; BMI, 24.8 ± 2.4 kg/m2). After dosing URLi, onset of insulin lispro appearance in the serum was faster (1.3 vs. 6.8 min; p<0.0001) and early insulin lispro exposure was greater (7.2 fold in the first 15 min and 2.7-fold in the first 30 min; both p<0.0001) vs. lispro. The duration of exposure, when serum lispro levels fell below the limit of quantification, was 74 min shorter with URLi (p<0.0001). Onset of insulin action was also faster (20 vs. 31 min; p=0.0007) and early action was increased 2.8 fold (p<0.001) in the first 30 min for URLi vs. lispro. Late insulin action (glucose infused from 4 h to end of the clamp) was reduced by 54% (p<0.0001) and duration of action was 43.6 min shorter with URLi (Figure). Total insulin lispro exposure and glucose infused during the clamp did not differ and tolerability was similar between URLi vs. lispro. In patients with T1D, URLi accelerated insulin absorption with a reduced late exposure and overall shorter duration vs. lispro, resulting in faster onset of insulin action and reduced late insulin action. Disclosure H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. S. Reddy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. U. Hoevelmann: None. L. Plum-Moerschel: None. T. Herbrand: None. J. Leohr: Employee; Spouse/Partner; Accenture. Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Accenture. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company