Profil Institute for Metabolic Research

This trial evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of oral insulin Tregopil (Part 1; results discussed in this paper) and the post-prandial glucose control with different meal types in comparison with insulin aspart (Part 2) in patients with type 1 diabetes mellitus (T1DM). This Phase 1, open-label, multiple ascending dose (30/45/60 mg/60 + 30 mg rescue insulin Tregopil) trial enrolled 37 patients with T1DM (3 female [8.1%], 34 male [91.9%]; median age: 39.5 years). Following screening, patients entered a run-in phase to optimize their basal-bolus (insulin glargine and insulin aspart) insulin therapy, and insulin Tregopil was administered orally 10 min before the three major meals of the day in all cohorts during this period. Safety assessments included adverse events and hypo-/hyperglycaemic episodes, vital signs, electrocardiograms, laboratory safety parameters and physical examination. PK and PD were the secondary objectives. The overall safety profile of insulin Tregopil indicated no safety concerns except a PD effect (hypoglycaemia). The incidence of hypoglycaemia did not increase with increasing doses of insulin Tregopil, and none of the episodes were severe. In general, the variability of the PK/PD parameters was high. Insulin Tregopil demonstrated a rapid onset of action, with peak blood concentrations reached within 15-20 min post-dosing. Subsequently, insulin Tregopil exerted a PD effect for up to 105 min. Fixed-dose insulin Tregopil reduced the requirement for insulin aspart supplementation, although it was not a viable stand-alone option for the daily management of T1DM. Insulin Tregopil could be explored with a flexible dosing approach and be titrated based on individual needs. The trial is registered at Clinicaltrials.gov (CT.gov identifier: NCT04141423). The ethical approval number for the protocol is 2019146.

Methodology This randomized, double-blind, parallel study compared the effects of TZP 15mg (N=45), semaglutide (SEMA) 1mg (N=44) and placebo (N=28) on energy intake (assessed by an ad libitum lunch), appetite (visual analog scale [VAS] ratings of hunger, satiety, prospective food consumption [PFC], and fullness) and body composition (air-displacement plethysmography) at baseline and Week 28.

To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar Insulin N (Biocon's Insulin-N; Biocon Biologics Ltd., Bangalore, India) and US-licensed Humulin® N (Humulin-N; Eli Lilly and Company, Indianapolis, IN, USA) in healthy subjects. This was a phase-1, single-centre, double-blind, randomized, three-period, six-sequence, partially replicated, crossover, 24-h euglycaemic clamp study. Overall, 90 healthy subjects were randomized, of whom 85 completed the study. The subjects received either two single doses of Biocon's Insulin-N and a single dose of Humulin-N or two single doses of Humulin-N and a single dose of Biocon's Insulin-N subcutaneously at a dose of 0.4IU/kg. The primary PK endpoints were the area under the insulin concentration-time curve from 0 to 24 h (AUCins.0-24h ) and the maximum insulin concentration (Cins.max ). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 h (AUCGIR.0-24h ) and the maximum GIR (GIRmax ). Biocon's Insulin-N was found to be equivalent to Humulin-N for the primary PK (geometric 90% confidence interval for the least squares mean ratio: AUCins.0-24h , 100.98%-115.66% and Cins.max , 95.91%-110.16%) and PD endpoints (intra-subject variability ≥0.294; 95% upper confidence interval [(μT-μR)2 - θσ2 WR] <0; point estimates of geometric least squares mean ratio: AUCGIR.0-24h , 104.61% and GIRmax , 100.81%). The safety profile of Biocon's Insulin-N was similarto that of Humulin-N, and no serious adverse events were reported. PK and PD equivalence was shown between Biocon's Insulin-N and Humulin-N in healthy subjects, and both treatments were well tolerated and considered safe.

AimTo establish equivalence in the pharmacokinetic (PK) and pharmacodynamic (PD) endpoints between proposed biosimilar Insulin‐R (Biocon's Insulin‐R) and Humulin® R using the euglycaemic clamp technique in healthy subjects.Materials and MethodsIn this phase‐1 automated euglycaemic glucose clamp study, 42 healthy subjects were randomized (1:1) to receive a single dose of 0.3 IU/kg of Biocon's Insulin‐R and Humulin‐R. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 12 hours. Primary PK endpoints were area under the insulin concentration‐time curve from 0 to 12 hours (AUCins.0‐12h) and maximum insulin concentration (Cins.max). Primary PD endpoints were area under the GIR time curve from 0 to 12 hours (AUCGIR.0‐12h) and maximum GIR (GIRmax).ResultsEquivalence was demonstrated between Biocon's Insulin‐R and Humulin‐R for the primary PK and PD endpoints. The 90% confidence intervals were within 80.00% to 125.00% limits. The PK and PD profiles were comparable. There were no significant differences in the safety profiles of the two treatments, and no serious adverse events were reported.ConclusionPK and PD equivalence was demonstrated between Biocon's Insulin‐R and Humulin‐R in healthy subjects. Treatment with Biocon’s Insulin‐R and Humulin‐R was well tolerated.

AimTo 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 MethodsThis 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.ResultsURLi 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.ConclusionsURLi 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 An optimally designed once-weekly basal insulin with reduced day-to-day pharmacokinetic (PK)/pharmacodynamic (PD) fluctuations compared to daily basal insulins should have a low peak-to-trough ratio at steady state. An insulin with this flat profile could improve glycemic efficacy while reducing hypoglycemia. Basal insulin Fc (BIF; LY3209590) is an insulin IgG Fc-fusion protein developed for once weekly dosing. The results of the first in-human studies of BIF assessing the safety, tolerability, PK, and PD following single and once-weekly doses of BIF are presented below. The single ascending dose (SAD) study assessed 6 dose levels of BIF, administered to healthy subjects or patients with type 2 diabetes mellitus (T2DM). In the multiple ascending dose (MAD) study, patients with T2DM previously treated with basal insulin received a one-time loading dose at Week 1 followed by a once-weekly maintenance dose for 5 additional weeks. Four fixed-dose maintenance dose levels were evaluated. The loading dose was implemented to rapidly achieve steady-state BIF concentration at each dose level. Patients with T2DM in the control group received insulin glargine at the same dose as their previous daily insulin dose. Key objectives were safety and tolerability, PK endpoints with a focus on half-life and peak-to-trough ratio at steady state, and finally PD measures. The SAD study included 57 patients with T2DM and 16 healthy subjects. The mean age of patients with T2DM was 58.4 years and the mean BMI was 29.5±3.2 kg/m2. The mean age of healthy subjects was 35.8±9.3 years and the mean BMI was 26.1±3.1 kg/m2. In the SAD study, BIF demonstrated linear PK with dose-proportional concentration profiles in healthy subjects and patients with T2DM. The maximum BIF concentration was reached on Day 4. BIF had a mean half-life of approximately 17 days in patients with T2DM. Following a single dose of BIF, a decrease in FBG was observed on Day 1 and was sustained until at least 5 days post-dose. In the MAD study in 33 subjects with T2DM aged between 40 and 69 years, BIF demonstrated a nearly peak-less PK profile over a one-week dosing interval with a peak-to-trough ratio of ~1.1 at steady state. This flat profile is in contrast to insulin glargine. Following once-daily dosing, insulin glargine has a daily peak-to-trough ratio of ~2. Over the 6-week duration, the 7-point glucose profiles remained constant over time and were similar to insulin glargine profiles. BIF was well tolerated and had a safety profile similar to insulin glargine-treated subjects. In particular, hypoglycemia rates were also similar to insulin glargine and there was no occurrence of hypoglycemic events with cognitive dysfunction. These data support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.