Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist ...activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study.
In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20–70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7·0–10·5%, body-mass index of 23–50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802.
Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference –2·8 mmol/L 90% CI –4·63 to –0·94 for 3 mg; –3·1 mmol/L –4·91 to –1·22 for 3/6 mg; and –2·9 mmol/L –4·70 to –1·01 for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (–1·4% 90% CI –2·17 to –0·56 for 3 mg; –1·6% –2·37 to –0·75 for 3/6 mg; and –1·2% –2·05 to –0·45 for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to –8·96 kg 90% CI –11·16 to –6·75 in the 3/6/9/12 mg group).
In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development.
Eli Lilly and Company.
Aims
To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients with type 2 ...diabetes mellitus (T2D).
Materials and Methods
This was a two‐part, randomized, double‐blind Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 minutes postdose by 2.2‐fold and reduced the time to the early half‐maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal‐to‐dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%‐105% for all three dose timings (−15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing.
Conclusions
URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T2D.
Aim
To compare the pharmacokinetics (PK), glucodynamics (GD), and tolerability following single and multiple daily subcutaneous (SC) doses of ultra rapid lispro (URLi) and Humalog® in patients with ...type 1 diabetes mellitus (T1D).
Materials and Methods
This was a two‐part, randomized, double‐blind, Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 min before, immediately before, and 15 min after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2‐week period when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 min postdose by 2.2‐fold and reduced the time to early half‐maximal drug concentration by 37% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal compared with Humalog. Comparing the same meal‐to‐dose timing between the insulins, postprandial glucose excursion over 5 hours was reduced by 40%‐44% for all three dose timings (−15, 0, and +15 min) with URLi, achieving statistical significance for the 0‐ and +15‐min timings. The PK and GD profiles were sustained after daily SC dosing for 2 weeks in patients with T1D. The number of documented hypoglycaemic events was similar between URLi and Humalog during the postprandial period of the MMTTs and the outpatient period.
Conclusions
URLi showed accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T1D.
Abstract Background: Prasugrel is an oral antiplatelet agent approved for the reduction of atherothrombotic cardiovascular events in patients presenting with acute coronary syndrome and undergoing ...percutaneous coronary intervention. Although the approved loading dose is 60 mg, earlier studies of prasugrel suggested that active-metabolite exposure and pharmacodynamic response may be higher in Asian subjects than in white subjects. Objectives: This study compared the pharmacodynamic response to a single 30-mg dose of prasugrel in healthy Chinese and white subjects and the response to a single 30-mg dose of prasugrel and a single 300-mg dose of clopidogrel in healthy Chinese subjects. The pharmacokinetics and tolerability of both drugs were also assessed. Methods: This was an open-label, single-dose study conducted in Singapore. Chinese subjects were randomly allocated to receive prasugrel 30 mg or clopidogrel 300 mg; after a 14-day washout period, they received the alternative drug. White subjects received only prasugrel 30 mg. Blood samples for pharmaco-dynamic assessments were collected before dosing and at 0.5, 1, 2, 4, and 24 hours after dosing. Three methods were used to measure inhibition of platelet aggregation (IPA)—traditional light transmission aggregometry (LTA), the Verify Now P2Y12 (VN-P2Y12) assay, and a vasodilator-stimulated phosphoprotein (VASP) phosphorylation flow cytometry assay—and their results were compared. Blood samples for pharmacokinetic assessments were collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours after dosing. Concentrations of the active metabolite of prasugrel were measured using a validated LC-MS/MS method. Results: The study enrolled 18 Chinese subjects and 14 white subjects. Chinese subjects had a mean (SD) age of 31 (10) years and a mean body weight of 65.2 (8.9) kg; 83% were male. The corresponding values for white subjects were 30 (10) years, 77.2 (12.4) kg, and 86%. Thirty of the 32 enrolled subjects completed the study. Two Chinese men were withdrawn from the study, one due to a low platelet-rich plasma count after receipt of prasugrel 30 mg and the other due to mild, intermittent rectal bleeding after bowel movements that began ∼2 days after receipt of clopidogrel 300 mg. The mean IPA with prasugrel was significantly higher in Chinese than in white subjects at 0.5, 1, and 2 hours after dosing ( P < 0.05), but not at 4 or 24 hours. In Chinese subjects, mean maximal IPA (87%) occurred 1 hour after prasugrel dosing; in white subjects, mean maximal IPA (78%) occurred 2 hours after prasugrel dosing. In Chinese subjects, the mean IPA was significantly higher at all time points after administration of prasugrel 30 mg than after administration of clopidogrel 300 mg ( P <0.001). After administration of Clopidogrel 300 mg in Chinese subjects, mean maximal IPA (58%) occurred at 4 hours. The VN-P2Y12 and VASP phospho-rylation assays yielded results comparable to those obtained by LTA. Mean exposure to prasugrel's active metabolite was higher in Chinese than in white subjects (geometric least squares mean ratio for AUC0−t = 1.47 (90% CI, 1.24–1.73). Both drugs were well tolerated. Conclusions: In this study, platelet inhibition was significantly higher in Chinese than in white subjects up to 2 hours after a single 30-mg dose of prasugrel. Platelet inhibition was significantly higher in Chinese subjects at all time points after a 30-mg dose of prasugrel than after a 300-mg dose of clopidogrel. Both treatments were generally well tolerated.
Multi-receptor incretin agonists are being developed for several metabolic disorders. LY is an investigational triple agonist with potent activity on glucose-dependent insulinotropic polypeptide ...(GIP) , glucagon-like polypeptide-1 (GLP-1) , and glucagon receptors. LY was safely studied in a prior first-in-human study and pharmacokinetics properties supported once weekly dosing. The primary objective of this randomized, double-blind, placebo-controlled, Phase 1 proof-of-concept study was to assess the safety and tolerability of multiple ascending doses of LY in patients with type 2 diabetes (T2D) . Seventy-two patients were randomized (9:3:1) to 5 rising dose cohorts of subcutaneous LY, placebo, and dulaglutide 1.5mg, respectively. Within cohort, dose-escalation was implemented at highest 2 cohorts. Vital signs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. Efficacy was assessed by monitoring change in glycated hemoglobin (HbA1c) and body weight at week 12. The most common treatment-emergent AEs were gastrointestinal (nausea and diarrhea) , which were mostly mild in severity. By week 12, mean systolic and diastolic blood pressure decreased from baseline in LY compared to placebo group, while pulse and heart rate increased from baseline within most LY cohorts and dulaglutide, but not with placebo. By week 12, mean HbA1c decreased from baseline in all groups, with higher doses of LY showing statistically significant placebo-adjusted decreases of up to 1.56%. Except at the initial cohort, dose-dependent decreases in mean placebo-adjusted body weight of up to 8.96 kg were observed with LY. LY3437943 exhibits safety and tolerability profile similar to other incretins. Promising glycemic and body weight loss efficacy within this study highlights the potential for LY to provide additional benefit versus existing therapies in treatment of T2D and obesity.
Disclosure
S. Urva: Employee; Eli Lilly and Company. M. Loh: Employee; Eli Lilly and Company. T. Coskun: Employee; Eli Lilly and Company. Y. Du: None. C. Loghin: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly. Stock/Shareholder; Lilly. Z. Milicevic: Employee; Eli Lilly and Company.
Funding
Eli Lilly and Company
Abstract
Aims
To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients ...with type 2 diabetes mellitus (T2D).
Materials and Methods
This was a two‐part, randomized, double‐blind Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 minutes postdose by 2.2‐fold and reduced the time to the early half‐maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal‐to‐dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%‐105% for all three dose timings (−15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing.
Conclusions
URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T2D.
URLi (LY900014), a novel ultra-rapid mealtime insulin in Phase 3 development, is shown to reduce postprandial glucose after subcutaneous injection. This 2-part, randomized, double-blind, Phase 1b ...study evaluated the differences in PK and PD between URLi and insulin lispro (Humalog®; HL) in 30 patients with T1D. Part A used a 6´period crossover design to evaluate safety and compare PK and postprandial glucose response to solid mixed meal tolerance tests (MMTT) with URLi or HL at different injection to mealtime intervals (-15, 0, and +15 min). Part B evaluated the safety, PK, and PD during 2 weeks of multiple daily dosing (immediately before a meal) in a parallel design. In Part A, URLi reduced glucose excursions (assessed as change in area under the concentration curve vs. time ∆AUC) during the first 2 hours (∆AUC0-2h) and entire 5 hours (∆AUC0´5h) of the MMMT regardless of dose timing (Fig). URLi reduced ∆AUC0-2h by 103% (p=0.008), 39% (p=0.031), and 16% (p=0.096), and ∆AUC0-5h by 40% (p=NS), 44% (p=0.097), and 42% (p=0.026) vs. HL at -15, 0, and +15 min (significance level =0.1. The PK and PD profiles for URLi and HL were sustained after 2 weeks of outpatient dosing (Part B). Similar number of hypoglycemic events occurred between treatments during MMTTs. During 2 weeks of outpatient dosing, the number of events was lower for URLi vs. HL. Local tolerability was similar between treatments.
Disclosure
L. Plum-Moerschel: None. J. Leohr: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Accenture. Stock/Shareholder; Spouse/Partner; Accenture. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. S. Reddy: None. M.A. Dellva: Employee; Self; Eli Lilly and Company. S. Lim: None. M. Loh: Employee; Self; Eli Lilly and Company. M.P. Knadler: Other Relationship; Self; Eli Lilly and Company. T. Hardy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C.M. Kazda: Employee; Self; Eli Lilly and Company.
URLi (LY900014), a novel ultra-rapid mealtime insulin in Phase 3 development, is shown to reduce postprandial glucose after subcutaneous injection. This 2-part, randomized, double-blind, Phase 1b ...study evaluated differences in PK and PD between URLi and insulin lispro (Humalog®; HL) in 30 patients with T2D. Part A used a 6-period crossover design to assess safety and compare PK and postprandial glucose response to solid mixed meal tolerance tests (MMTT) with URLi or HL at different injection to mealtime intervals (-15, 0 and +15 min). Part B evaluated safety, PK and PD during 2 weeks of multiple daily dosing (immediately before a meal) in a parallel design.In Part A, URLi reduced glucose excursions (assessed as change in area under the concentration curve vs. time ∆AUC) during the first 2 hours (∆AUC0-2h) and entire 5 hours (∆AUC0´5h) of the MMTT regardless of dose timing (Fig). URLi reduced ∆AUC0-2h by 37% (p=0.014), 47% (p<0.0001), and 4% (p=NS) and ∆AUC0-5h by 49% (p=0.049), 105% (p<0.0001), and 29% (p=0.076) vs. HL at ´15, 0 and +15 min (significance level =0.1). The PK and PD profiles for URLi and HL were sustained after 2 weeks of outpatient dosing (Part B). More hypoglycemic events occurred with URLi during MMTTs but these were mild and mostly asymptomatic. Only a few events occurred in either group during 2 weeks of outpatient dosing. Local tolerability was similar between treatments.
Disclosure
C. Kapitza: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Johnson & Johnson Services, Inc., MedImmune, MSD K.K., Mylan, Nordic Bioscience, Novo Nordisk Inc., Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi-Aventis, Senseonics, Zealand Pharma A/S. J. Leohr: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Accenture. Stock/Shareholder; Spouse/Partner; Accenture. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. S. Reddy: None. M.A. Dellva: Employee; Self; Eli Lilly and Company. M. Matzopoulos: None. M.P. Knadler: Other Relationship; Self; Eli Lilly and Company. M. Loh: Employee; Self; Eli Lilly and Company. T. Hardy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C.M. Kazda: Employee; Self; Eli Lilly and Company.
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