New Insulins,Biosimilars,and Insulin Therapy

Background

Head-to-head comparison between the second-generation, ultra-long-acting insulin analogs degludec (U200) and glargine U300 regarding the risk of hypoglycemia in adults with type 2 diabetes.

Methods

Open-label, multicenter, treat-to-target trial in adults with type 2 diabetes previously treated with basal insulin±oral glucose-lowering drugs except insulin secretagogues, with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m², and with at least one predefined criterion for hypoglycemia risk. Participants were randomized to receive degludec U200 (n=733) or glargine U300 (n=734) once daily, and titrated to a fasting blood glucose target of 4.0–5.0 mmol/L. Endpoints were assessed during the last 36-week maintenance period of the trial and during the total treatment duration of up to 88 weeks. Primary endpoint was the rate of overall symptomatic hypoglycemic events (either severe hypoglycemia requiring third-party assistance or confirmed by blood glucose <3.1 mmol/L) in the maintenance period. Secondary hypoglycemia endpoints were number of nocturnal symptomatic events and number of severe hypoglycemic events during the same period.

Results

The rates of overall symptomatic hypoglycemic events during the maintenance period were not significantly different between degludec U200 and glargine U300 users, the rate ratio (RR) being 0.88 (95% CI: 0.73–1.06). Consequently, further confirmatory testing for superiority was stopped. Still, secondary endpoints were analyzed according to prespecified statistical models but were instead considered exploratory, showing lower rates of nocturnal symptomatic hypoglycemia (RR 0.63 [95% CI: 0.48–0.84]) and severe hypoglycemia (RR 0.20 [95% CI: 0.07–0.57]) in favor of degludec U200.

Conclusions

During the maintenance period, the rates of overall symptomatic hypoglycemia were comparable with insulin degludec U200 and glargine U300. Corresponding rates of nocturnal symptomatic hypoglycemia and severe hypoglycemia were nominally significantly lower with degludec U200 than with glargine U300.

Background

This prespecified subanalysis of the BRIGHT trial, which was the first published clinical head-to-head comparison between insulin glargine U300 and insulin degludec, has focused on glycemic control and hypoglycemic events during the initial 12-week insulin titration period.

Methods

The BRIGHT trial was a multicenter, open-label, two-arm, parallel-group, 24-week, noninferiority study where insulin-naive adults with type 2 diabetes with inadequate glucose control were randomized to initiate once-daily basal insulin therapy with glargine U300 (n=466) or degludec U100 (n=463). In this report, predefined efficacy and safety outcomes were analyzed during the initial 12-week dose titration period. Moreover, clinical characteristics and outcomes were assessed in descriptive terms, stratified by confirmed (≤3.9 mmol/l) hypoglycemic events during the titration period.

Results

At the end of the 12-week titration period, HbA1c was similar for glargine U300 (7.32%) and degludec U100 (7.23%) users, with comparable least squares (LS) mean reductions from baseline (−1.37% and −1.39%, respectively), the LS mean difference being 0.02 (95% CI: −0.08 to 0.12). Participants who had experienced hypoglycemic events during the titration period had numerically more pronounced HbA1c reductions at week 12 than those who did not (−1.46% vs. −1.28%) and had higher incidence of anytime (73.3% vs 35.7%) and nighttime (00:00–06.00 hours; 30.0% vs 11.9%) hypoglycemia during the remaining 13–24 weeks of the study period.

Conclusions

The use of glargine U300 or degludec U200 resulted in comparable improvements in glycemic control during the initial 12-week dose titration period of trial, when less anytime hypoglycemic events for glargine U300 than for degludec U100 were reported in the original BRIGHT trial publication. Having experienced hypoglycemic events shortly after starting basal insulin therapy with glargine U300 or degludec U100 may be associated with future risk of hypoglycemia.

Background

In this prespecified subgroup analysis from the BRIGHT trial, it was investigated whether clinical outcomes using glargine U300 and degludec U100 were influenced by kidney function.

Methods

The insulin-naive participants with type 2 diabetes who had been randomized to initiate basal insulin therapy with glargine U300 or degludec U100 were stratified according to baseline estimated glomerular filtration rate (eGFR) for the assessments.

Results

Heterogeneity of treatment effect across kidney function subgroups was demonstrated (P=0.02), showing a significantly greater mean reduction of HbA1c from baseline to end of trial (week 24) with glargine U300 vs degludec U100 in the eGFR <60 mL/min/1.73m² subgroup, the least squares mean difference being 0.43% (95% CI: 0.74%−0.12%). No difference in incidence and rates of hypoglycemia were observed between the basal insulin analogs in this subgroup. In the other kidney function subgroups, HbA1c reductions were comparable between glargine U300 and degludec U100, but heterogeneity was noted for annualized rates of daily (24 h) and nocturnal (00:00–05.59 hours) confirmed hypoglycemia (≤3.9 mmol/L) over the 24-week study period, with less hypoglycemia in glargine U300 vs degludec U100 users in the ≥90 mL/min/1.73 m² eGFR subgroup.

Conclusions

Kidney function appears to influence the glucose-lowering effects of glargine U300 vs degludec U100 in previously insulin-naive adults with type 2 diabetes. Greater HbA1c reductions without increase in risk of hypoglycemia using glargine U300 were observed in subjects with eGFR <60 mL/min/1.73 m².

Background

To compare efficacy and safety of insulin glargine 300 units/mL (Gla-300) and 100 units/mL (Gla-100) in children and adolescents (6–17 years old) with type 1 diabetes.

Methods

EDITION JUNIOR was a noninferiority, international, open-label, two-arm, parallel-group, phase 3b trial. Participants were randomized 1:1 to Gla-300 or Gla-100, titrated to achieve fasting self-monitored plasma glucose levels of 90–130 mg/dL (5.0–7.2 mmol/L), with continuation of prior prandial insulin. The primary endpoint was change in HbA1c from baseline to week 26. Other assessments included change in fasting plasma glucose (FPG), hypoglycemia, hyperglycemia with ketosis, and adverse events.

Results

In 463 randomized participants (Gla-300, n=233; Gla-100, n=230), comparable least squares (LS) mean (SE) reductions in HbA1c were observed from baseline to week 26 (−0.40% [0.06%] for both groups), with LS mean between-group difference of 0.004% (95% CI −0.17 to 0.18), confirming noninferiority at the prespecified 0.3% (3.3 mmol/mol) margin. Mean FPG change from baseline to week 26 was also similar between groups. During the 6-month treatment period, incidence and event rates of severe or documented (≤70 mg/dL [≤3.9 mmol/L]) hypoglycemia were similar between groups. Incidence of severe hypoglycemia was 6.0% with Gla-300 and 8.8% with Gla-100 (relative risk 0.68 [95% CI 0.35-1.30]). Incidence of any hyperglycemia with ketosis was 6.4% with Gla-300 and 11.8% with Gla-100.

Conclusions

Gla-300 provided similar glycemic control and safety profiles to Gla-100 in children and adolescents with type 1 diabetes, indicating that Gla-300 is a suitable therapeutic option in this population.

Background

In this nationwide, observational study, the efficacy and safety of insulin glargine U300 and insulin degludec were investigated using data from the Swedish National Diabetes Registry together with other national health registries.

Methods

The analyses included adults (≥18 years) with type 1 diabetes using basal insulin supplementation with glargine U100, and who either continued this therapy (n=11340) or had switched to glargine U300 (n=2398) or degludec (n=1719). Differences in clinical characteristics at baseline (index date), and changes thereafter in glucose control (HbA1c), weight, hospitalization due to hypoglycemia, and cardiovascular disease or death, were assessed.

Results

At baseline there were no apparent differences in clinical characteristics between the groups, although subjects remaining on glargine U100 were slightly older, and fewer in this group had previously been using insulin pumps and continuous glucose monitoring devices. Mean HbA1c levels were comparable between groups, and 4% of all subjects had evidence of cardiovascular disease. Mean follow-up time was 1.1 years for subjects who switched to glargine U300 or degludec and 1.6 years for those continuing with glargine U100. During this period, HbA1c was slightly reduced in all groups in a similar way, and body mass index remained unchanged. Rates of severe hyper- and hypoglycemia were small and comparable between groups. Percentages of overall cardiovascular mortality were 0.7%, 0.8%, and 1.95% with glargine U300, degludec, and glargine U100, respectively. All other severe adverse events were also numerically more evident in those using glargine U100, and with no apparent differences between glargine U300 and degludec.

Conclusions

The long-term efficacy and safety of using basal glargine U300 versus degludec seem to be comparable in adults with type 1 diabetes. The findings also suggest that these basal insulin analogs may provide additional advantages in comparison with glargine U100.

Background

This study describes an in silico head-to-head comparison of glargine U300 and degludec U100 using the University of Virginia (UVA)/Padua type 1 diabetes (T1D) simulator, which describes the intra- and interday variability of glucose-insulin dynamics and can be used as a valid bench-test for assessing glucose control for different basal insulin therapies.

Methods

A pharmacokinetic (PK) model, describing subcutaneous absorption of insulin degludec U100, was developed from T1D clinical data and, together with an already existing PK model for insulin glargine U300, fed into the simulator. One hundred in silico T1D subjects received once-daily (morning or evening dose) basal insulin with glargine U300 or degludec U100 for 12 weeks (8-week titration and 4-week stable maintenance dosing) in a basal/bolus regimen. Two different titration rules were used for up-titration to individual doses for all virtual subjects. Simulated continuous glucose monitoring data during the last 2-week period were used to assess various glycemic outcome metrics.

Results

The simulations showed no statistically significant differences between glargine U300 and degludec U100 in the main endpoints, including the mean percentage of time in the target range within 70–140 mg/dL (primary outcome).

Conclusions

The simulations suggest similar glucose control using either glargine U300 or degludec U100 in T1D and have been used to guide the design of a clinical trial intended to compare the two ultra-long-acting basal insulin analogs.

Background

Administering insulin to manage diabetes is often accompanied by hypoglycemia, which is typically alleviated by glucose-responsive smart insulin. Glucose-responsive smart insulin has the ability to self-regulate in response to the fluctuation of blood glucose level (BGL).

Methods

We prepared a new insulin analog by altering insulin with forskolin (designated as insulin-F), which is a glucose-transporter (Glut) inhibitor. In vitro, insulin-F is capable of binding to Glut on erythrocyte ghosts, which can be inhibited by glucose and cytochalasin B.

Results

With subcutaneous injection in type 1 diabetic mice, insulin-F keeps BGLs below 200 mg mL-1 for up to 10 h and can achieve 20 h with two sequential injections. Moreover, insulin-F also binds to endogenous Gluts.

Conclusions

During a glucose challenge, the increased level of glucose competitively replaces and liberates insulin-F that binds to Glut, quickly returning BGLs to the normal range.

Background

This paper proposes that a closed-loop system imitating pancreatic cell function by connecting to microneedles (MNs) that automatically “release” insulin in response to the blood glucose (BG) levels would decidedly improve the quality of life and health for patients with diabetes.

Methods

An easy, fast, and simple technique of coating a porous polymer layer on stainless steel (SS) MNs that release insulin in a glucose-responsive fashion was fabricated by sealing insulin, sodium bicarbonate (a pH-sensitive element [NaHCOз]), and glucose oxidase (glucose-specific enzymes [GOx]) into a porous polymer coating. Glucose can passively diffuse into the pores of the polymer coating and become oxidized to gluconic acid by GOx, thereby decreasing local pH. The reaction of protons with NaHCOз forms carbon dioxide (CO2), which produces pressure inside the pores, consequently rupturing the thin polymer film and emitting the encapsulated insulin.

Results

Field emission scanning electron microscopy (FE-SEM) images showed that when exposing the MNs to glucose-free phosphate buffer saline (PBS) with pH 7.4, the pores of the porous MNs were closed; meanwhile, in the MNs exposed to a hyperglycemic glucose level, the pores were opened and the thin film burst. These MNs exhibited both in vitro (in porcine skin and PBS) and in vivo (in diabetic rats) glucose-mediated insulin release under hyperglycemic conditions with rapid responsiveness.

Conclusion

This paper determined that the release of insulin from porous MNs effectively correlated with glucose concentration.

Background

The aim of this study was to determine the efficacy and safety of faster aspart compared with insulin aspart (IAsp), with insulin degludec both with and without metformin, in adults with type 2 diabetes that is not well controlled with a basal-bolus regimen.

Research design and methods

Participants were randomized to either faster aspart (n=546) or IAsp (n=545) in this multicenter, double-blind, treat-to-target trial. All available information, regardless of treatment discontinuation or use of ancillary treatment, was employed for evaluation.

Results

Noninferiority was confirmed for faster aspart versus IAsp (estimated treatment difference [ETD] −0.04% [95% CI −0.11; 0.03]; −0.39 mmol/mol [−1.15; 0.37]; P<0.001) for the change from baseline in HbA1c 16 weeks after randomization (primary endpoint). Faster aspart was superior to IAsp for change from baseline in 1 h postprandial glucose (PPG) increments using a meal test (ETD −0.40 mmol/L [−0.66; −0.14]; −7.23 mg/dL [−11.92; −2.55]; P=0.001 for superiority). In self-measured 1 h PPG increments, change from baseline for the mean over all meals favored faster aspart (ETD −0.25 mmol/L [–0.42; −0.09]); −4.58 mg/dL [−7.59; −1.57]; P=0.003). The overall rate of treatment-emergent severe or blood glucose (BG)-confirmed hypoglycemia was statistically significantly lower for faster aspart versus IAsp (estimated treatment ratio 0.81 [95% CI 0.68; 0.97]).

Conclusions

In combination with insulin degludec in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen, faster aspart provided effective overall glycemic control, superior PPG control, and a lower rate of severe or BG-confirmed hypoglycemia versus Iasp.

Background

Faster aspart is a novel formulation of IAsp that guarantees ultra-fast absorption and effect.

Aim

The aim of this study is to compare the pharmacokinetics between faster aspart and IAsp, based on free or total IAsp measurement, and explore the connection between anti-IAsp antibodies and faster aspart and IAsp pharmacological properties in children and adolescents with T1D.

Methods

Twelve children, 16 adolescents, and 15 adults (6–11, 12–17, and 18–64 years) received 0.2 U/kg double-blind, single-dose subcutaneous faster aspart or IAsp followed by a standardized liquid meal test in this randomized, two-period crossover trial.

Results

The pharmacokinetic profile was left-shifted among all age groups, including greater early exposure for faster aspart vs IAsp irrespective of free or total IAsp assay. Onset of appearance occurred 2.4 to 5.0 minutes (free) or 1.8 to 3.0 minutes (total) earlier for faster aspart vs IAsp (P<0.05). Treatment ratios (faster aspart/IAsp) for 0 to 30 minutes IAsp exposure were 1.60 to 2.11 and 1.62 to 1.96, respectively (children, free: P=0.062; otherwise P<0.05). The ratio of free/total IAsp for overall exposure (AUCIAsp,0-t ) was negatively associated with anti-IAsp antibody level across age. No obvious correlation was shown between anti-IAsp antibodies and meal test 1- or 2-hour postprandial glucose increment independent of age and insulin treatment (R2≤0.070; P≥0.17) when pooling with a previous similar trial.

Conclusions

Faster aspart provides ultra-fast pharmacokinetics regardless of free or total IAsp assay in children and adolescents with T1D. Elevated anti-IAsp antibodies are correlated with higher total IAsp concentration but do not impact faster aspart and IAsp glucose-lowering effect.

Aims

The goal of this paper is to compare the pharmacokinetic (PK) and glucodynamic (GD) qualities of ultra-rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp (Novo Nordisk, Bagsvaerd, Denmark), Humalog (Eli Lilly and Company), and NovoRapid (Novo Nordisk) in patients with T1D.

Materials and methods

Sixty-eight patients with T1D were involved in this randomized, double-blind, four-period crossover study. Just prior to consuming a liquid test meal, patients received the same individualized subcutaneous dose of each study drug. Twelve healthy subjects received the same test meal for purposes of comparison.

Results

Compared to the other insulins tested, URLi had significantly faster absorption. 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 (all P<0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. In postprandial glucose (PPG), URLi achieved the greatest numerical reduction at 2 hours postmeal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Moreover, glucose excursions over the first 3 hours postmeal with URLi were comparable to those in healthy subjects.

Conclusions

Compared to the other insulins tested, URLi showed the fastest insulin absorption and the greatest numeric PPG-lowering effect. URLi more closely matched the early physiological glucose control seen in healthy subjects.

Aims

The aim of this study is to assess the efficacy and safety of URLi versus lispro in adults with type 1 diabetes in a 26-week, treat-to-target, phase 3 trial.

Materials and methods

Patients were randomized to double-blind mealtime URLi (n=451) or lispro (n=442), or open-label postmeal URLi (n=329), after an 8-week lead-in to optimize basal insulin glargine or degludec. The primary endpoint was change from baseline glycated hemoglobin (HbA1c) to 26 weeks (noninferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions after a meal test.

Results

Mealtime and postmeal URLi showed noninferiority to lispro for HbA1c: ETD for mealtime URLi −0.08% (95% confidence interval [CI] − 0.16, 0.00) and for postmeal URLi + 0.13% (95% CI 0.04, 0.22), with a much higher endpoint HbA1c for postmeal URLi versus lispro (P=0.003). Mealtime URLi was superior to lispro in decreasing 1- and 2-hour PPG excursions during the meal test: ETD −1.55 mmol/L (95% CI −1.96, 1.14) at 1 hour and −1.73 mmol/L (95% CI −2.28, −1.18) at 2 hours (both P<0.001). The rate and incidence of severe, documented, and postprandial hypoglycemia (<3.0 mmol/L) was similar between treatments, but mealtime URLi showed a 37% lower rate in the period >4 h after meals (P=0.013). Injection site reactions were indicated by 2.9% of patients on mealtime URLi, 2.4% on postmeal URLi, and 0.2% on lispro. Overall, the incidence of treatment-emergent adverse events was similar among treatments.

Conclusions

This study demonstrated that URLi supplied good glycemic control, with noninferiority to lispro confirmed for both mealtime and postmeal URLi, whereas superior PPG control was seen with mealtime dosing.

Background

URLi is a new insulin lispro formulation that has accelerated absorption and improved postprandial glucose control compared with insulin lispro (Humalog). The compatibility and safety of URLi versus lispro were evaluated in patients with type 1 diabetes using continuous subcutaneous insulin infusion (insulin pump).

Methods

In this phase 3, double-blind, crossover study, 49 patients were randomized to two 6-week treatment periods after a 2-week lead-in period on lispro. The primary endpoint was the rate of infusion set failures due to a pump occlusion alarm, or unexplained hyperglycemia with blood glucose >13.9 mmol/L (250 mg/dL) that did not decrease within 1 h after a correction bolus.

Results

There was no significant difference in the rate of infusion set failures between URLi and lispro (0.03 vs 0.05 events/30 days, P=0.375). A higher rate of premature infusion set changes was observed with URLi (1.13 vs 0.78 events/30 days; P=0.028), translating to one additional infusion set change approximately every 3 months. A trend toward improved glycemic control was observed with URLi treatment: time in range 3.9–10.0 mmol/L (71–180 mg/dL) was 65.7% ± 1.3% versus 63.0% ± 1.3%. Treatment-emergent adverse events (TEAEs) were reported by 46.9% of patients on URLi treatment and 18.8% on lispro. This difference was driven by an increase in infusion site reactions—more than 90% were mild. Incidence of all other TEAEs and severe hypoglycemia was similar between treatments.

Conclusions

URLi was compatible with insulin pump use with a safety profile similar to lispro.

Background

This study used CGM to evaluate glucose control in adults with type 1 diabetes during treatment with URLi or lispro used in combination with insulin glargine or degludec in a substudy of the PRONTO-T1D study.

Methods

Ambulatory glucose profiles were evaluated in 269 patients from PRONTO-T1D assigned to double-blind URLi (n=97) or lispro (n=99) given 0–2 min before the start of the meal (mealtime), or open-label URLi (n=73) given 20 min after the meal (postmeal URLi). Blinded CGM was used for up to 14 days before baseline and the 26-week primary endpoint. The primary objective was to compare mealtime URLi and lispro with respect to incremental area under the serum glucose concentration versus time curve from 0 to 2 h (iAUC0-2h) after breakfast.

Results

Mealtime URLi was superior in reducing the iAUC0-2h when compared to lispro for breakfast (least squares mean [LSM] difference −28.1 mg·h/L, P=0.048) and for all meals combined. iAUC0-3h and iAUC0-4h were also reduced. Postmeal URLi resulted in similar PPG control to mealtime lispro, but less optimal PPG control compared to mealtime URLi. Mealtime URLi increased daytime time in range (71–180 mg/dL [3.9–10.0 mmo/L]) (LSM difference=+43.6 min, P=0.020) and decreased nighttime time in hypoglycemia (LSM difference ≤70 mg/dL [3.9 mmol/L]=−11.5 min, P=0.009) compared to mealtime lispro.

Conclusions

Results of this CGM substudy support the improved PPG control seen with mealtime URLi in the PRONTO-T1D study and show that mealtime URLi resulted in improved daytime time in target range.

Background

To evaluate the efficacy and safety of URLi versus lispro in patients with type 2 diabetes on a basal-bolus insulin regimen.

Background

This paper describes a phase-3, treat-to-target, double-blind, 26-week study that took place after an 8-week lead-in to optimize basal insulin glargine or degludec in combination with prandial lispro treatment, in which patients were randomized to blinded URLi (n=336) or lispro (n=337) injected 0–2 min prior to meals.

Methods

Patients could continue metformin and/or a sodium-glucose cotransporter 2 inhibitor. The primary endpoint was change in HbA1c from baseline to 26 weeks (noninferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions taking place during a standardized meal test.

Results

HbA1c improved for both URLi and lispro, and noninferiority was confirmed: ETD 0.06% (95% CI –0.05; 0.16). Mean change in HbA1c was −0.38% for URLi and −0.43% for lispro, with an end-of-treatment HbA1c of 6.92% and 6.86%, respectively. URLi was better than lispro in controlling 1- and 2-h PPG excursions: 1-h ETD, −0.66 mmol/L (95% CI −1.01, −0.30); 2-h ETD, −0.96 mmol/L (−1.41, −0.52). Much lower PPG excursions were apparent from 0.5 to 4.0 h postmeal with URLi treatment. There were no significant treatment differences in rates of severe or documented hypoglycemia (<3.0 mmol/L). Incidence of treatment-emergent adverse events was similar between treatments.

Conclusions

In a basal-bolus regimen for patients with type 2 diabetes, URLi compared with lispro was confirmed to be noninferior for HbA1c and superior to lispro for PPG control.

Background

We aim to determine the safety and efficacy of day-and-night fully closed-loop insulin therapy using faster (Faster-CL) compared with standard (Standard-CL) insulin aspart in young adults with type 1 diabetes.

Methods

Twenty patients with type 1 diabetes participated in a double-blind, randomized, crossover trial. The participants, on insulin pump therapy (11 females, aged 21.3±2.3 years, HbA1c 7.5±0.5% [58.5±5.5 mmol/mol]), underwent two 27-h inpatient episodes with unexpected afternoon moderate-vigorous exercise and unannounced/uncovered meals. In random order, we compared Faster-CL and Standard-CL. The fuzzy-logic control algorithm DreaMed GlucoSitter was used during both interventions. Intention-to-treat principle was used to evaluate glucose sensor data, with the difference (between Faster-CL and Standard-CL) in proportion to time in range 70–180 mg/dL (TIR) over 27 h as the primary endpoint.

Results

The proportion of TIR was close to the same for both arms: 53.3% (83% overnight) in Faster-CL and 57.9% (88% overnight) in Standard-CL (P=0.170). Moreover, the proportion of time in hypoglycemia <70 mg/dL was 0.0% for both groups. Baseline-adjusted interstitial prandial glucose increments 1 h after meals were greater in Faster-CL compared with Standard-CL (P=0.017). The gaps between measured plasma insulin and estimated insulin-on-board levels at the beginning, at the end, and 2 h after the exercise were smaller in the Standard-CL group (P=0.029, P=0.003, and P=0.004, respectively). No major adverse events occurred.

Conclusions

Fully closed-loop insulin delivery using either faster or standard insulin aspart was safe and efficient in reaching near-normal glucose concentrations outside postprandial periods. The closed-loop algorithm was better adjusted to the standard insulin aspart.

Background

When optimizing the performance of closed-loop automated insulin delivery systems, a major obstacle is the delay in insulin absorption and action that occurs due to the subcutaneous (SC) route of insulin delivery, which leads to exaggerated postmeal hyperglycemic excursions. We explored the effect of Afrezza inhaled insulin with ultra-fast in and out action profile on improving postprandial blood glucose control during hybrid closed-loop (HCL) treatment in young adults with T1D.

Research design and methods

We conducted an inpatient, three-way, randomized crossover standardized meal study to determine the efficacy and safety of Afrezza at a low (AL) and a high (AH) dose as compared with a standard SC rapid-acting insulin (aspart) premeal bolus during diabetes assistant (DiA) HCL treatment. Two sequential meals on three study days were given to participants, and premeal insulin bolus was determined based on home insulin-to-carbohydrate ratio for each meal (rounded up to the closest available Afrezza cartridge dose for AH and down for AL). The primary efficacy outcome was the PPG level that was determined by pooling data for up to 4 h after the start of each meal. Hyperglycemic, hypoglycemic, and euglycemic venous glucose metrics were secondary outcomes.

Results

The mean±SD PPG for the rapid-acting insulin control arm and AH was similar (185±50 mg/dL vs 195±46 mg/dL, respectively; P=0.45), whereas it was higher for meals using AL (208±54 mg/dL, P=0.04). The AH achieved significantly lower early PPG level than the control arm (30 min; P<0.001), and improvement in PPG waned at later time points (120 and 180 min; P=0.02), coinciding with the end of Afrezza glucodynamic action.

Conclusions

Afrezza (AH) premeal bolus decreased the early glycemic excursion and improved PPG during HCL compared with aspart premeal bolus. After the end of Afrezza glucodynamic action at 120 min, the improvement in PPG was not sustained.

Aim

The aim of this study is to assess the effect of final HbA1c levels on the incidences of hypoglycemia in patients with T1D who are treated with inhaled Technosphere Insulin or subcutaneous insulin aspart, as indicated in alignment with the International Hypoglycemia Study Group recommendations.

Methods

Adults (n=375) who had type 1 diabetes for ≥12 months and an HbA1c level of 58–86 mmol/mol (7.5%–10.0%) were randomized to receive basal insulin plus either inhaled Technosphere Insulin or subcutaneous insulin aspart in this phase 3, multicenter AFFINITY-1 study. This was a post-hoc regression analysis that reported on a subset (n=279) of the randomized AFFINITY-1 cohort concerning baseline and end-of-treatment HbA1c values. Incidence and event rates for levels 1, 2, and 3 hypoglycemia, respectively, defined as blood glucose levels of ≤3.9 mmol/l, <3.0 mmol/l, or requiring external assistance for recovery were the primary outcome measures.

Results

Participants treated with Technosphere Insulin had statistically significantly fewer levels 1 and 2 hypoglycemic events and a lower incidence of level 3 hypoglycemia than participants treated with insulin aspart. The lower rate of hypoglycemia with Technosphere Insulin was seen in all end-of-treatment HbA1c levels. Technosphere Insulin was correlated with higher rates of hypoglycemia 30–60 min after meals, but significantly lower rates 2–6 h after meals.

Conclusions

Participants who were administered Technosphere Insulin had clinically non-inferior glycemic control and lower hypoglycemia rates across a range of HbA1c levels compared with participants receiving insulin aspart.

Background

Hepatic-directed vesicle insulin (HDV) uses a hepatocyte-targeting moiety passively attaching free insulin, improving subcutaneous insulin's hepatic biodistribution. HDV-insulin lispro (HDV-L) versus insulin lispro (LIS) in patients with T1D were assessed in this study.

Methods

This study was a 26-week, phase 2b, multicenter, randomized, double-blind, noninferiority trial called Insulin Liver Effect (ISLE-1).

Results

In total, 176 randomized participants (HDV-L n=118, LIS n=58) were involved in this study. The difference in change from baseline A1C was 0.09% (95% CI −0.18% to 0.35%), confirming noninferiority (prespecified margin ≤0.4%). There were no statistically significant differences between treatments for hypoglycemia or insulin dosing overall, but baseline A1C modified the treatment group effect (interaction P<0.001) on clinically apparent hypoglycemia designated as severe by treatment-blinded investigators. Therefore, at higher baseline A1C, we observed less hypoglycemia and lower insulin dosing with similar A1C outcomes during HDV-L versus LIS, whereas we observed greater risk of hypoglycemia despite similar A1C outcomes and insulin doses with lower baseline A1C. Among participants who were poorly controlled (A1C ≥8.5%), incidence rates of severe hypoglycemia in the HDV-L and LIS arms were 69 and 97 events/100 person-years, respectively (P=0.03), whereas with A1C <8.5%, respective rates were 191 and 21 events/100 person-years (P=0.001). Similar A1C-dependent trends in hypoglycemia were noted with continuous glucose monitoring. Among participants who were poorly controlled, bolus insulin doses at endpoint were ∼ 25% lower with HDV-L (P=0.02), despite similar A1C outcomes. In better-controlled participants, insulin doses and A1Cs were stable in both subgroups over time. No safety signals were indicated.

Conclusions

Hepatic biodistribution of HDV-L seems to potentiate insulin effect in T1D, with divergent clinical outcomes in hypoglycemia dependent on baseline A1C.

Background

Although insulin has been used to treat diabetes for almost 100 years, the rapid-acting insulin formulations of today do not have fast enough pharmacokinetics to maintain tight glycemic control at mealtimes. The insulin hexamer is the primary association state of insulin in rapid-acting formulations. The rate-limiting step that leads to slow onset and extended duration of action involves dissociation of this hexamer.

Methods

A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using current formulation strategies and rapidly aggregates into amyloid fibrils. In this study, we apply high-throughput-controlled radical polymerization techniques to produce a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to lessen insulin aggregation.

Results

The best-performing AC/DC excipient candidate enabled the creation of an ultra-fast-absorbing insulin lispro (UFAL) formulation that remains stable under stressed aging conditions for 25±1 h, compared to 5±2 h for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL showed peak action at 9±4 min; meanwhile, commercial Humalog exhibited peak action at 25±10 min.

Conclusion

The ultra-fast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

FDA—Biosimilars

The last year was an important one with respect to BioIns in the United States, mainly because insulin and certain other biologic drugs transition to a different regulatory pathway. Until March 23, 2020, insulins were approved in the United States by a 505(b)(2) abbreviated pathway by the FDA; now they will be regulated through the 351(k) pathway, which was designed specifically for biosimilars (https:// www.fda.gov/news-events/press-announcements/fda-works-ensure-smooth-regulatory-transition-insulin-and-other-biological-products; https://www.fda.gov/news-events/press-announcements/insulin-gains-new-pathway-increased-competition). Any drug approved through this pathway will have a biologics license (BLA) instead of a New Drug Application (NDA). This means, also, until now insulins that were approved outside the United States as BioIns were not approved as such in the United States. This regulatory transition opens a regulatory pathway for products in the United States that are proposed as biosimilar to, or interchangeable with, the transitioned products. Approved BioIns will be able to come to the U.S. market now, and there is potential to reduce healthcare costs, especially in view of the high insulin prices in the United States. It remains to be seen how much the insulin prices will go down in the coming years; with other biosimilars, a price reduction by one-third was often observed.

Historically, it was more difficult to develop generic versions of (biosimilar) drugs under the Federal Food, Drug and Cosmetic (FD&C) Act due to scientific challenges and limitations on the scope of data that can be relied upon in a generic drug application. When the biosimilars pathway in the Biologics Price Competition and Innovation Act (BPCIA) of 2010 was created, a 10-year timeline for stakeholders to prepare for the regulatory transition of biological products that were historically regulated under the FD&C Act was implemented. This plan was established to improve the efficiency of the biosimilar and interchangeable product development and approval process and to maximize scientific and regulatory clarity for the biosimilar product development community. Over the last decade, the FDA has established a framework for the biosimilar and interchangeable regulatory pathway.

The end of the 10-year transition period means that approved applications for biologics, including insulin products, that were originally approved under the FD&C Act will be treated as though they were licensed under the PHS Act. Clearly the products themselves will not change as a result of bringing them under regulation as biologics as a matter of law. However, labeling for these products will change, and patients and their healthcare providers must be made aware of this fact. According to the FDA, the labeling changes will be minimal in nature; questions remain as to whether the same insulin product could be allowed on the market with two labels at the same time as products make their way through the supply chain. Removing products with older labels from sale would result in considerable wastage of insulin, and this could create concerns among patients with respect to their supplies of this crucial drug.

While it is important to acknowledge the recent changes in the U.S. regulatory situation, it is worth mentioning that outside the United States other rules are applied; however, also in the European Medicines Agency (EMA) guideline the option of a waiver for phase 3 studies exists. More recently, EMA makes use of this option—that is, with good preclinical and PK/PD-data neither FDA nor EMA will require phase 3 studies in the future.

Market Impact

This milestone for BioIns insulin can be expected to enable a competitive market; however, when the first BioIns are now approved in the United States, how drastically will this change the U.S. insulin market? The market success of Abasaglar, an insulin glargine that was developed by Eli Lilly and Boehringer Ingelheim (Basaglar in the United States), will be motivation for insulin manufacturers, whether it be the established large insulin manufacturer or the many new players that are able to manufacture insulin, to get their insulins approved like BioIns. However, this does not necessarily mean that development of BioIns is a low-hanging fruit, as the decision by Merck to pull out of their approved BioIns insulin glargine has shown. A recent post-marketing safety study in Japanese patients with type 1 diabetes or type 2 diabetes provided reassuring data on real-life effectiveness and safety of BioIns insulin glargine developed by Eli Lilly and Boehringer Ingelheim (19).

The three large manufacturers represent over 90% of the global insulin market and produce nearly 100% of the U.S. insulin supply. Until June 2020 even the two BioIns approved in the United States have been manufactured by two of these primary manufacturers and not by competitors. In June 2020 the third, Semglee, codeveloped by Mylan and Biocon Biologics, was approved by the FDA under the 505(b)(2) NDA pathway and, in accordance with the new legislation, is now considered a biologic under section 351(a).Other new companies are expected to bring their BioIns to the U.S. market now, like they have done in a number of other markets; however, it is not clear which share of the crowded insulin market they will get. Without selling a sufficient amount of insulin in a given time period (i.e., gaining a significant market share), some of the new players might not be able to stay on this market, as this might not be reasonable from an economic standpoint. We'll have to see if the insulin prices will go down when more than enough products compete for the same market (20). When the first BioIns will come to the market, there is a need for unbiased education material to inform patients and HCPs adequately, especially about products that have an interchangeability claim. BioIns will need to handle a complex world of payer contracts that handle reimbursement. Also, naming conventions can disturb patients (21). Such barriers might hamper the switch from brand products to BioIns.

Interchangeability Designation

Substitution means the practice of changing one insulin for another that is expected to achieve the same blood glucose–lowering effect in any patient with diabetes on the initiative or without the agreement of the physician. This requires that the insulin can be regarded as interchangeable, which is a regulatory designation that allows such a substitution and also a property of a given insulin (that should be shown in a switching study) (20). The FDA has now described in detail what their expectations are for such a label (https:// www.fda.gov/media/124907/download), with a clear focus on PK and PD parameters from euglycemic glucose clamp studies; however, until now none of the BioIns have received such a label (20, 22). An interchangeable designation can only be pursued for a product already designated a biosimilar by the FDA.

The U.S. basal insulin market is centrally driven by pharmacy benefit managers (PBMs); these could force switches and reduce the need for an interchangeable designation (23). Presumably, Mylan/Biocon would need to come in at a significant discount to other insulin glargines to make the switch worthwhile for PBMs. It is not easy to predict what the impact of, for example, an interchangeable insulin glargine on the insulin market will be when it comes to insulin prices and market share.

Immunogenicity

BioIns might differ in their immunogenic properties from the originator insulin. It should be kept in mind that even small differences in the structure of the insulin molecules manufactured (“micro-heterogeneity”) can have an impact on its immunogenicity. In November 2019, the FDA issued a guidance document for the industry called “Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products.” Interestingly enough, the FDA has changed their policies for testing for immunogenicity with BioIns; they do not require immunogenicity studies anymore. Previously, comparative clinical immunogenicity studies with 500 subjects were required. The European Medical Agency (EMA) still requires these studies during the approval process; a clinical study with a limited number of subjects (300) over a limited period of time (6 or 12 months) has to be performed. The question remains whether or not such a study includes all relevant patient groups for a sufficient period of time. A recent study performed in Russia with a BioIns of insulin glargine showed no differences in the immune response (or glycemic control) (24). Also, an in vitro evaluation of the immunogenic properties of a BioIns of insulin lispro showed no differences to both U.S.- and EU-approved Humalog based on a side-by-side biological similarity assessment (25).

A concern is that—at least in some patients—formation of (neutralizing) insulin antibodies is stimulated. Differences in immunological responses might be induced by certain differences between the BioIns and the originator insulin. If this is the case, the potential to increase the dose of insulin exists, and thereby the savings are lost. In addition, it might also be that the insulin bound and released by the antibodies induces changes in the PK and PD properties of the applied insulin, resulting in worsening of metabolic control. The background for these concerns is based on old data, which suggests that patients with type 1 diabetes require a higher dose of insulin in the presence of an increase in neutralizing antibodies. This information about insulin antibodies became available during the 1960s and 1970s when impure insulin formulations were still available. A resurgence of interest was seen when an increase in circulating insulin antibodies in response to treatment with pulmonary insulin was detected (26). It is worth mentioning that the observed increase in insulin antibodies was mainly driven by non-neutralizing antibodies, but the observed increase was not accompanied by any change in insulin requirements, insulin kinetics, or any other clinical parameter. Thus, this response of the immune system (i.e., exposure of immune competent cells in the lung to insulin) had no prominent adverse metabolic impact. Consequently, one interesting question from this observation is whether an increase in non-neutralizing antibodies would be induced by switching insulin formulations (with conventional subcutaneous administration), as well as whether this will have a clinically relevant impact. And what if the titers of neutralizing antibodies increase on switching from one insulin to another, and how can this be tracked? Also, what happens if for some reason only a subgroup of patients reacts in such a manner?

Consistency of Insulin Batches

In the same line of thinking, it would be interesting to know how good the quality of different batches of (originator) insulins and BioIns is over time (27). Insulin is manufactured in batches, and these might differ considerably from each other as a reflection of the complexity of the manufacturing process (28). To address concerns about variability between batches, the FDA advises insulin manufacturers to include data from at least 10 reference product lots acquired over several years to fully assess reference product drift. Sponsors should assess 6–10 batches of the proposed biosimilar, including both investigational and commercial-scale lots, validation batches, and batches manufactured on a different scale. The immunogenic potency of a given insulin can be influenced by the quality of the insulin. The control mechanisms to check and guarantee this quality are more or less in the hands of the manufacturer (with limited control by the authorities).

If a plethora of, for example, insulin glargines, insulin lispro, insulin aspart, and human insulins will be on the market in the future and patients switch from one to the other freely, mainly driven by the price, a given patient can develop insulin antibodies and it will not be easy to determine which insulin has induced these.

Pharmacovigilance

A critical topic in this respect is the pharmacovigilance systems that are in place. It is clear that, for example, with the regulatory requirements BioIns have to fulfil in the EU, only relatively small numbers of patients with diabetes are studied. Other patient groups that did not participate in these studies, or perhaps a small number of patients, could show, for example, immunological reactions. In order to be able to detect these, adverse events should be reported to the authorities. However, the question is whether or not these adverse events are reported in daily practice. Reporting of adverse events is a time-consuming and challenging process. Therefore, there is a high risk of underreporting of adverse events. This is not an issue for BioIns alone; this holds true for all drugs (also for the originator insulins). With other biosimilars (i.e., proteins that are used to treat other diseases), severe adverse events were detected more or less by chance. In this context it is worth mentioning that the risk of stimulating the immune system is not theoretical as with, for example. erythropoetin (EPO). In patients treated with different brands (i.e., biosimilars) of EPO, an increase in the dose was needed as reported in a number of studies. There were anecdotal reports about adverse events/differences in insulin doses with insulin copies in countries with relatively low regulatory requirements, for example, in Mexico (29). In a case report from this country the authors report on a hypersensitivity reaction of a 51-year-old woman with type 2 diabetes to a BioIns, an insulin glargine copy (30). In this case, the active pharmaceutical ingredient was from China; however, the insulin is formulated and marketed by a local company. The hypersensitivity reaction could be confirmed by laboratory measurements (abnormal basophil degranulation tests). The question is, is this reaction due to patient-specific conditions and/or, for example, quality issues of the insulin glargine used? Another interesting question is that if such a “side effect” shows up, who is then ultimately responsible for this? The reduction in the need for immunogenicity studies seen by EMA and FDA reflects that insulin antibodies appear to have limited clinical relevance. As outlined, this is different with erythropoetin; however, this is a much more complex molecule compared to insulin.

Clamp Studies

While the recent FDA guidance document put less focus on immunogenicity studies, it strengthens the importance of providing clear evidence for PK and PD bioequivalence in phase 1 studies. These studies usually use the euglycemic hyperinsulinemic glucose clamp technique. Performance of such (automated) glucose clamp studies requires certain equipment and experience. The guidance document (also the older guidance documents by the EMA) explains in detail important aspects of the design and conduct of glucose clamp studies for BioIns, as well as the acceptance criteria that has to be fulfilled to achieve bioequivalence designation. High glucose clamp quality is needed to achieve bioequivalence and thereby fulfill the requirements for the approval of BioIns in Europe and in the United States, but also in important Asian markets such as China and Japan.

Clinical Studies

In the last year a number of clinical studies dealing with BioIns were published, however, as well as a number of economical evaluations. These evaluated the impact of using BioIns on spending of the healthcare system/impact on the real-world budget (31). It will be of interest to see how the BioIns market will develop in the coming years.

In April 2020, the FDA guided drug makers on bioequivalence study disruptions amid COVID-19—that is, many clinical studies were halted or delayed due to the pandemic. It remains to be seen to what extent the development and approval of BioIns are hampered by the crisis.

Sanofi—Insulin Aspart SAR341402

It is of interest to note that an established insulin manufacturer like Sanofi has now the second BioIns of a rapid-acting insulin analog (i.e., insulin aspart; SAR341402) in clinical development. This is one of the few diabetes therapies that are still in development by Sanofi, following the company's exit from investing in most diabetes therapies. On April 30, 2020, this received a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) in Europe. However, the biosimilar insulin lispro by Sanofi (Admelog) has failed to gain meaningful traction in the United States until now, despite having a significantly lower price.

Background

The objective of this study was to demonstrate the pharmacokinetic and pharmacodynamic similarity among SAR341402 insulin aspart biosimilar/follow-on product, U.S.-sourced insulin aspart (NovoLog), and European Union–sourced insulin aspart (NovoRapid).

Methods

This was a single-center, randomized, double-blind, three-treatment, three-period, single-dose, crossover euglycemic study (NCT03202875) in 30 adult male subjects with T1D. Subjects received 0.3 U/kg of each treatment under fasted conditions and underwent a 12-h euglycemic clamp technique to assess pharmacokinetic and pharmacodynamic activity for up to 12 h. Primary endpoints were the area under the plasma insulin concentration–time curve from time zero to the last quantifiable concentration (INS-AUClast) and extrapolated to infinity (INS-AUCinf), maximum plasma insulin concentration (INS-Cmax), and the area under the body weight–standardized glucose infusion rate (GIR)–time curve from 0 to 12 hours (GIR-AUC0–12h) among the three treatments. GIRmax was the main secondary endpoint.

Results

Of the 30 subjects randomized, 29 completed all three treatment periods. Pharmacokinetic and pharmacodynamic profiles were similar in all groups. The extent of exposure (INS-Cmax, INS-AUClast, and INSAUCinf) and glucodynamic activity (GIR-AUC0–12h, GIRmax) was similar among the three treatments. The corresponding 90% confidence intervals for pairwise treatment ratios were completely contained within the limits of 80%–125%. SAR341402 was well tolerated.

Conclusions

The present study demonstrated similar pharmacokinetic exposure profiles and glucodynamic potency among SAR341402, NovoLog, and NovoRapid in subjects with T1D, supporting further clinical evaluation of SAR341402 as a biosimilar/follow-on product.

Background

This study compared the efficacy, safety, and immunogenicity of insulin aspart biosimilar/follow-on biologic product SAR341402 (SAR-Asp) with originator insulin aspart-Novo Log/NovoRapid (NN-Asp) in people with T1D or T2D treated with multiple daily injections in combination with insulin glargine (Lantus; Gla-100).

Methods

This 6-month, randomized, open-label, phase 3 study (NCT03211858) enrolled 597 people with T1D (n=497) or T2D (n=100). Participants were randomized 1:1 to mealtime SAR-Asp (n=301) or NN-Asp (n=296) in combination with Gla-100. The primary objective was to demonstrate noninferiority (by 0.3% margin in the intent-to-treat population) of SAR-Asp versus NN-Asp in HbA1c change from baseline to week 26. Immunogenicity was also assessed in terms of anti-insulin aspart antibody (AIA) status (positive/negative) and titers during the study.

Results

HbA1c was similarly improved in both treatment groups (SAR-Asp −0.38%; NN-Asp −0.30%); the least squares mean difference at week 26 for SAR-Asp minus NN-Asp was −0.08% (95% confidence interval: −0.192 to 0.039), thus meeting the criteria for noninferiority between SAR-Asp and NN-Asp and inverse noninferiority of NN-Asp versus SAR-Asp. Changes in fasting plasma glucose and seven-point, self-monitored plasma glucose profile, including postprandial glucose excursions, and insulin dosages were similar in both groups at week 26. Safety and tolerability, including AIA responses (incidence, prevalence), hypoglycemia, and adverse events (including hypersensitivity events and injection site reactions), were similar between groups.

Conclusions

SAR-Asp demonstrated effective glycemic control with a similar safety and immunogenicity profile to NN-Asp in people with diabetes treated for 26 weeks.

Background

SAR341402 (SAR-Asp) is a biosimilar/follow-on of the originator insulin aspart-NovoLog/NovoRapid (NN-Asp). This study investigated whether the efficacy, safety, and immunogenicity findings for SAR-Asp versus NN-Asp, observed over 6 months in people with type 1 (n=497) or type 2 diabetes (n=100) treated with multiple daily injections in combination with insulin glargine (Lantus), are maintained after 12 months.

Methods

GEMELLI 1 was a multicenter, randomized, open-label, phase 3 study. Participants completing the initial 6-month treatment period continued on SAR-Asp or NN-Asp, as randomized, for a 6-month safety extension.

Results

Of the 597 participants randomized, 264 out of 301 (87.7%) and 263 out of 296 (88.9%) assigned to SAR-Asp and NN-Asp, respectively, completed 12 months of treatment. Improved glycemic control was sustained at 12 months in both treatment groups, with similar least-squares mean reductions in HbA1c from baseline (SAR-Asp: −0.25%; NN-Asp: −0.26%). Fasting plasma glucose and seven-point, self-monitored plasma glucose profile changes, including postprandial glucose excursions, and changes in mealtime and basal insulin dosages were similar between groups. Safety and tolerability, including anti-insulin aspart antibodies (AIAs; incidence, prevalence, titers, cross-reactivity to human insulin), neutralizing antibodies (incidence, prevalence), hypoglycemia, and treatment-emergent adverse events (including hypersensitivity events and injection site reactions), were similar between groups. No relationship was observed between maximum individual AIA titers and change in HbA1c or insulin dose, hypoglycemia, or hypersensitivity reactions or between efficacy/safety measures and subgroups by presence or absence of treatment-emergent AIA.

Conclusions

SAR-Asp and NN-Asp demonstrated similar efficacy and safety (including immunogenicity) in people with diabetes over 12 months of treatment.

Background

The aim was to assess the safety and tolerability of the insulin aspart biosimilar/follow-on product SAR341402 (100 U/mL solution; SAR-Asp) and originator insulin aspart (100 U/mL; NN-Asp; NovoLog) self-administered through an insulin pump.

Methods

This randomized, open-label, 24-week crossover study enrolled 45 adults with type 1 diabetes (T1D). Participants were randomized 1:1 to the treatment sequence SAR-Asp/NN-Asp or NN-Asp/SARAsp. The basal and prandial insulin doses were individually titrated. The primary outcome was the number of participants with at least one infusion set occlusion (infusion set change due to failure-to-correct hyperglycemia [plasma glucose 250 mg/dL] by insulin pump bolus) during the 4-week treatment. The main secondary outcome was the number of participants with at least one episode of unexplained hyperglycemia (regardless of correction by an insulin pump bolus without apparent material defect; medical, dietary, insulin dosing reason; or pump problem).

Results

The number of participants reporting one infusion set occlusion were similar between treatments: 14/43 on SAR-Asp (33 events) and 12/43 on NN-Asp (24 events). The estimated difference in infusion set occlusion risk for SAR-Asp versus NN-Asp was 4.1% (95% confidence interval: −9.3% to 17.4%). The number of participants with one episode of unexplained hyperglycemia was similar between treatments (31/43 on SAR-Asp [154 events]; 32/43 on NN-Asp [175 events]). Hypoglycemia, treatment-emergent adverse events, hypersensitivity, and injection site reactions were similar between treatments.

Conclusions

SAR-Asp and NN-Asp were well tolerated and had similar infusion set occlusions over a 4-week period in insulin pump users with T1D.

Background

The aim of this study is to report phase 1 bioequivalence results comparing MYL-1501D, U.S. reference insulin glargine (US IG), and European reference insulin glargine (EU IG).

Methods

This study was a double-blind, randomized, three-way crossover study involving 114 participants with TDM. We compared the pharmacokinetic PK and pharmacodynamic PD characteristics of MYL-1501D, US IG, and EU IG. The participants received 0.4 U/kg of each study treatment under automated euglycemic clamp conditions. Over the span of 30 hours, insulin metabolite M1 concentrations, IG, and GIRs were assessed. Primary PK endpoints were area under the serum IG concentration–time curve from 0 to 30 hours (AUCins.0–30h) and maximum serum IG concentration (Cins.max). Primary PD endpoints were area under the GIR–time curve from 0 to 30 hours (AUCGIR0–30h) and maximum GIR (GIRmax).

Results

For the primary PK and PD endpoints, bioequivalence among MYL-1501D, US IG, and EU IG was demonstrated. Least squares mean ratios were close to 1, and 90% confidence intervals were within 0.80 to 1.25. The PD GIR–time profiles were almost superimposable. No major adverse events were reported, and there were no noticeable differences in the safety profiles of the three treatments.

Conclusions

In patients with T1DM, equivalence with regard to PK and PD qualities was shown among MYL-1501D, US IG, and EU IG. Each treatment was well tolerated and safe.

Background

The EMA recently approved MYL-1501D. It is being developed as a biosimilar (European Union) or a follow-on biologic (United States) to insulin glargine. The aim of this study was to assess the efficacy, insulin dose, safety, and immunogenicity of patients with T1DM who switched between MYL-1501D and reference insulin glargine (Lantus; Sanofi-Aventis US LLC, Bridgewater, NJ).

Methods

Participants from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n=63; insulin glargine for 36 weeks) or to the treatment-switching sequence (n=64; MYL-1501D [weeks 0–12], insulin glargine [weeks 12–24], MYL-1501D [weeks 24–36]). The primary efficacy endpoint used to show equivalence between the two treatment sequences was a change in HbA1c from baseline to week 36. Secondary endpoints were change in fasting plasma glucose (FPG), self-monitored blood glucose (SMBG), and insulin dose; immunogenicity; and adverse events, including hypoglycemia.

Results

From baseline to week 36, mean changes in HbA1c (least squares [LS] mean [standard error]) for the treatment-switching and reference sequences were −0.05 (0.032) and −0.06 (0.034), respectively (LS mean difference [95% CI], 0.01 [−0.085, 0.101]). Treatment sequences were similar in terms of secondary endpoints, including FPG, SMBG, and insulin dose, and the safety and immunogenicity profiles of the two sequences were similar.

Conclusions

MYL-1501D and reference insulin glargine showed equivalent efficacy and similar safety and immunogenicity when switching study participants from one to the other. This study indicated that patients taking reference insulin glargine can safely switch to MYL-1501D.