SEMGLEE Solution for injection Ref.[27592] Active ingredients: Insulin glargine

The pharmacodynamic profile for SEMGLEE was determined after subcutaneous administration of a single 0.5 U/kg dose in a euglycemic clamp study conducted in 116 type 1 diabetes patients. The median time to maximum effect of SEMGLEE (measured by the peak rate of glucose infusion) was approximately 11.3 hours. The pharmacodynamic profile of SEMGLEE following subcutaneous injection demonstrated sustained glucose lowering activity over 24 hours with no pronounced peak. The arithmetic mean area under the glucose infusion rate curve (AUC GIR 0-24h) and maximum glucose infusion rate were 1423 mg/kg and 1.8 mg/kg/min, respectively.

The time course of action of insulins, including SEMGLEE, may vary between individuals and within the same individual.

Absorption

After subcutaneous injection of a single 0.5 U/kg dose of SEMGLEE in a euglycemic clamp study conducted in 116 type 1 diabetes patients, the M1 active metabolite plasma concentration profile indicated a prolonged absorption and a relatively constant concentration/time profile over 24 hours.

The median time to maximum M1 plasma concentration was 12 hours after injection. The mean plasma observed area under the concentration-time curve for M1 from time zero to 24 hours and peak plasma concentration were 10.5 ng*hr/mL and 0.64 ng/mL, respectively.

Elimination

Metabolism

A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21 ^A-Gly-insulin) and M2 (21^A-Gly-des30^B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.

Specific Populations

Age, Race, and Gender

Effect of age, race, and gender on the pharmacokinetics of SEMGLEE has not been evaluated.

Obesity

Effect of Body Mass Index (BMI) on the pharmacokinetics of SEMGLEE has not been evaluated.

In mice and rats, standard two-year carcinogenicity studies with another insulin glargine product were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) on a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle.

Another insulin glargine product was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).

In a combined fertility and prenatal and postnatal study of another insulin glargine product in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

14.1 Overview of Clinical Studies

Following are the results of studies conducted with SEMGLEE and with another insulin glargine product in adult and pediatric patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus.

14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes

A 24 weeks multicenter, open-label, randomized, active-controlled study to evaluate the glucose lowering effect of once-daily SEMGLEE compared to that of once-daily administration of another insulin glargine product, 100 units/mL, in combination with mealtime insulin lispro was conducted in patients with type 1 diabetes. Mean age was 42 years, the majority of patients were Caucasian, 94.6%, mean BMI was 26.5 kg/m², mean duration of diabetes prior to entry into the study was 19 years, the mean exposure of 280 patients to SEMGLEE during the study was 50 weeks. At week 24, treatment with SEMGLEE was found to be non-inferior to that achieved with comparator insulin glargine product with regard to the mean change in HbA1c over 24 weeks of treatment.

Table 9. Adult Type 1 Diabetes Mellitus, SEMGLEE plus Mealtime Insulin versus Another Insulin Glargine Product plus Mealtime Insulin:

^* Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Missing Week 24 data were multiply-imputed with a mean for each subject equal to their respective baseline value.

In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B n=534) were randomized to 28 weeks of basal-bolus treatment with another insulin glargine product, 100 units/mL, or NPH insulin. Regular human insulin was administered before each meal. This other insulin glargine product was administered at bedtime. NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily.

In Study A, the average age was 39.2 years. The majority of patients were White (99%) and 55.7% were male. The mean BMI was approximately 24.9 kg/m². The mean duration of diabetes was 15.5 years.

In Study B, the average age was 38.5 years. The majority of patients were White (95.3%) and 50.6% were male. The mean BMI was approximately 25.8 kg/m². The mean duration of diabetes was 17.4 years.

In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with another insulin glargine product, 100 units/mL, or NPH insulin. Insulin lispro was used before each meal. This other insulin glargine product was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39.2 years. The majority of patients were White (96.9%) and 50.6% were male. The mean BMI was approximately 25.6 kg/m². The mean duration of diabetes was 18.5 years.

In these 3 studies, another insulin glargine product, 100 units/mL and NPH insulin had similar effects on HbA1c (Table 10).

Table 10. Type 1 Diabetes Mellitus–Adult:

Type 1 Diabetes – Pediatric (see Table 11)

In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Other insulin glargine product was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 11.7 years. The majority of patients were White (96.8%) and 51.9% were male. The mean BMI was approximately 18.9 kg/m². The mean duration of diabetes was 4.8 years. Similar effects on HbA1c (Table 11) were observed in both treatment groups.

Table 11. Type 1 Diabetes Mellitus–Pediatric:

14.3 Clinical Studies in Adults with Type 2 Diabetes

A 24 weeks multicenter, open-label, randomized, active-controlled study to evaluate the glucose lowering effect of once-daily SEMGLEE compared to that of once-daily administration of another insulin glargine product, 100 units/mL, both administered in combination with oral antidiabetic drugs, was conducted in patients with type 2 diabetes. Mean age was 55 years, more than half, 52.7%, of the patients were Caucasian, 26.6% were Hispanic, and 9.8% were Black, mean BMI was 31.5 kg/m², the mean duration of diabetes prior to entry into the study was 12 years, the mean exposure of 276 patients to SEMGLEE during the study was 22 weeks. At week 24, treatment with SEMGLEE was found to be non-inferior to that achieved with comparator insulin glargine product with regard to the reduction in HbA1c over 24 weeks of treatment.

Table 12. Adult Type 2 Diabetes Mellitus SEMGLEE plus Oral Antidiabetic Medication versus Comparator Insulin Glargine Product plus Oral Antidiabetic Medication:

^* Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Missing Week 24 data were multiply-imputed with a mean for each subject equal to their respective baseline value.

In a randomized, controlled clinical study (Study E) (n=570), another insulin glargine product, 100 units/mL was evaluated for 52 weeks in combination with oral anti-diabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 59.5 years. The majority of patients were White (92.8%) and 53.7% were male. The mean BMI was approximately 29.1 kg/m². The mean duration of diabetes was 10.3 years. This other insulin glargine product administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 13).

In a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral anti-diabetic medications (n=518), a basal-bolus regimen of another insulin glargine product, 100 units/mL once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59.3 years. The majority of patients were White (80.7%) and 60% were male. The mean BMI was approximately 30.5 kg/m². The mean duration of diabetes was 13.7 years. This other insulin glargine product had similar effectiveness as either once-or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 13).

In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with another insulin glargine product, 100 units/mL once-daily or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dose of this other insulin glargine product or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started this other insulin glargine product at a dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust this other insulin glargine product and NPH insulin doses to a target fasting plasma glucose ≤ 100 mg/dL. After this other insulin glargine product or NPH insulin dose was adjusted, other anti-diabetic agents, including premeal insulin were to be adjusted or added. The average age was 55.1 years. The majority of patients were White (85.3%) and 53.9% were male. The mean BMI was approximately 34.3 kg/m². The mean duration of diabetes was 10.8 years. This other insulin glargine product group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in this other insulin glargine product group (Table 13).

Table 13. Type 2 Diabetes Mellitus–Adult:

Another Insulin Glargine Product, 100 units/mL, Timing of Daily Dosing (see Table 14)

The safety and efficacy of other insulin glargine product administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in patients with type 1 diabetes (study H, n=378). Patients were also treated with insulin lispro at mealtime. The average age was 40.9 years. All patients were White (100%) and 53.7% were male. The mean BMI was approximately 25.3 kg/m². The mean duration of diabetes was 17.3 years. This other insulin glargine product administered at different times of the day resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 14). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to injection of this other insulin glargine product regardless of time of administration.

In this study, 5% of patients in this other insulin glargine product-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. The safety and efficacy of this other insulin glargine product administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n=697) in patients with type 2 diabetes not adequately controlled on oral anti-diabetic therapy. All patients in this study also received glimepiride 3 mg daily. The average age was 60.8 years. The majority of patients were White (96.6%) and 53.7% were male. The mean BMI was approximately 28.7 kg/m². The mean duration of diabetes was 10.1 years. This other insulin glargine product given before breakfast was at least as effective in lowering HbA1c as this other insulin glargine product given at bedtime or NPH insulin given at bedtime (see Table 14).

Table 14. Another Insulin Glargine Product, 100 units/mL, Timing of Daily Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus:

^* Intent-to-treat ***Not applicable

Five-Year Trial Evaluating the Progression of Retinopathy

Retinopathy was evaluated in the clinical studies with another insulin glargine product, 100 units/mL, by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for this other insulin glargine product and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.

Another insulin glargine product, 100 units/mL, was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with pre-specified post-baseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 15 for both the per-protocol and Intent-to-Treat populations and indicate similarity of this other insulin glargine product to NPH in the progression of diabetic retinopathy as assessed by this outcome.

Table 15: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint:

^* Difference = Another Insulin Glargine Product, 100 units/mL – NPH
^† Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function

The Origin Study

The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of another insulin glargine product, 100 units/mL, to standard care on major adverse cardiovascular outcomes in 12,537 participants ≥50 years of age with abnormal glucose levels [i.e., impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] or early type 2 diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline.

The objective of the trial was to demonstrate that use of this other insulin glargine product use could significantly lower the risk of major cardiovascular outcomes compared to standard care. Two coprimary composite cardiovascular endpoints were used in ORIGIN. The first coprimary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke. The second coprimary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.

Participants were randomized to either this other insulin glargine product (n=6264) titrated to a goal fasting plasma glucose of ≤95 mg/dL or to standard care (n=6273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of participants were 75 years of age or older. The majority of participants were male (65%). Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black. The median baseline BMI was 29 kg/m². Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6.5% (1.0). Fifty-nine percent of participants had had a prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors.

Vital status was available for 99.9% and 99.8% of participants randomized to this other insulin glargine product and standard care respectively at end of trial. The median duration of follow-up was 6.2 years [range: 8 days to 7.9 years]. The mean HbA1c (SD) at the end of the trial was 6.5% (1.1) and 6.8% (1.2) in this other insulin glargine product and standard care group respectively. The median dose of this other insulin glargine product at end of trial was 0.45 U/kg. Eighty-one percent of patients randomized to this other insulin glargine product were using this other insulin glargine product at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in this other insulin glargine group than in the standard care group.

Overall, the incidence of major adverse cardiovascular outcomes was similar between groups (see Table 16). All-cause mortality was also similar between groups.

Table 16. Cardiovascular Outcomes in ORIGIN -Time to First Event Analyses:

In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancer (Table 17) was similar between treatment groups.

Table 17. Cancer Outcomes in ORIGIN -Time to First Event Analyses: