Fiasp (Page 5 of 9)

12.3 Pharmacokinetics

Absorption

Pharmacokinetic results from a euglycemic clamp study in adult patients with type 1 diabetes (N=51) showed that insulin aspart appeared in the circulation ~2.5 minutes after administration of FIASP (Figure 3). Time to maximum insulin concentrations was achieved ~63 minutes after administration of FIASP.

Figure 3
(click image for full-size original)

Figure 3. Mean Insulin Aspart Serum Concentration Profile in Adult Subjects with Type 1 Diabetes (N=51) following a single 0.2 unit/kg dose (subcutaneous) of FIASP

Total insulin exposure and maximum insulin concentration increase proportionally with increasing subcutaneous dose of FIASP within the therapeutic dose range.

Distribution

Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.

Elimination

The apparent terminal half-life after subcutaneous administration of FIASP is about 1.1 hours.

Specific Populations

Age, gender, BMI, and race did not meaningfully affect the pharmacokinetics and pharmacodynamics of FIASP.

Patients with Renal and Hepatic Impairment

Based on studies conducted with insulin aspart, renal and hepatic impairment is not known to impact the pharmacokinetics of insulin aspart.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with insulin aspart at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, insulin aspart increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for insulin aspart was not significantly different than for regular human insulin. The relevance of these findings to humans is not known.

Insulin aspart was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

14 CLINICAL STUDIES

14.1 Overview of Clinical Studies

The efficacy of FIASP was evaluated in 3 randomized, active-controlled trials of 18 to 26 weeks duration in adults and one randomized, active-controlled, treat-to-target trial of 26 weeks duration in pediatric patients.

In total 1224 adult subjects (N=763 with type 1 diabetes; N=461 with type 2 diabetes) and 519 pediatric subjects with type 1 diabetes were randomized to FIASP. In adult and pediatric patients with type 1 diabetes, mealtime FIASP and postmeal FIASP led to non-inferior glycemic control compared to mealtime NovoLog, both in combination with basal insulin . In adult patients with type 2 diabetes, mealtime FIASP provided non-inferior glycemic control compared to mealtime NovoLog, both in combination with metformin. In addition, mealtime FIASP in a basal-bolus regimen with metformin also provided statistically significant improvement in the overall glycemic control compared to basal insulin therapy alone with metformin in adult patients with type 2 diabetes.

In adults with type 1 diabetes (N=472), FIASP led to non-inferior glycemic control compared to NovoLog when both were administered by continuous subcutaneous insulin infusion (CSII) pump.

14.2 Type 1 Diabetes — Adults

Study A (NCT01831765): FIASP added to insulin detemir in adult patients with Type 1 DM inadequately controlled at baseline.

The efficacy of FIASP was evaluated in a 26-week, randomized, active controlled, treat-to-target, multicenter trial in 1143 adult patients with type 1 diabetes inadequately controlled at baseline. Patients were randomized to either blinded mealtime FIASP (N=381), blinded mealtime NovoLog (N=380), or open-label postmeal FIASP (N=382), all in combination with once or twice daily insulin detemir. At randomization, patients were switched to FIASP on a unit to unit basis. Mealtime FIASP or NovoLog was injected 0-2 minutes before the meal, and postmeal FIASP was injected 20 minutes after the start of the meal.

The mean age of the randomized subjects was 44.4 years and mean duration of diabetes was 19.9 years. 59% were male, 93% were White, 2% were Black or African American, and 7% were Hispanic. The mean BMI was 26.7 kg/m2.

After 26 weeks of treatment, treatment difference in HbA1c reduction from baseline between mealtime FIASP compared to mealtime NovoLog, and the treatment difference between postmeal FIASP compared to mealtime NovoLog met the pre-specified non-inferiority margin (0.4%). See Table 7. Insulin doses were similar among study arms at baseline and at the end of the trial.

Table 7. Results from Study A: 26-Week Trial of Mealtime FIASP and Postmeal FIASP compared to Mealtime NovoLog Used in Combination with Insulin Detemir in Adults with Type 1 Diabetes

Mealtime FIASP

+ insulin detemir

Postmeal FIASP

+ insulin detemir

Mealtime NovoLog

+ insulin detemir

Number of subjects randomized (N)

381

382

380

HbA1c (%)

Baseline (mean)

7.6

7.6

7.6

Adjusted mean change from baseline

-0.32

-0.13

-0.17

Estimated treatment difference vs. mealtime NovoLog [95% CI]*

-0.15 [-0.23;-0.07]

0.04 [-0.04;0.12]

Baseline is based on the mean of the observed last available values prior to randomization.

* Tested for non-inferiority

Estimated treatment difference was calculated using mixed model for repeated measurements (MMRM).

7.6% of subjects on the Mealtime FIASP arm, 7.6% of subjects on the Postmeal FIASP arm, and 5.3% of subjects on the Mealtime NovoLog arm were missing the final HbA1c assessment.

14.3 Type 1 Diabetes — Pediatric Patients

Study E (NCT02670915): FIASP added to insulin degludec in pediatric patients with Type 1 DM.

The efficacy of FIASP was evaluated in a 26-week, randomised, multinational, active controlled, treat-to-target, 3-armed parallel-group trial in 777 pediatric patients with type 1 diabetes. Patients were randomized to either blinded mealtime FIASP (N=260), blinded mealtime NovoLog (N=258), or open-label postmeal FIASP (N=259), all in combination with once daily insulin degludec. Mealtime FIASP or NovoLog was injected 0-2 minutes before the meal, and postmeal FIASP was injected 20 minutes after the start of the meal.

The mean age of the subjects at baseline was 11.7 years (range 2 to 17 years) and the mean duration of diabetes was 4.4 years. 54% were male, 81% were Caucasian, 16% were Asian and 2% were Black or African American. The mean BMI was 19.7 kg/m2.

After 26 weeks of treatment, the treatment difference for change in HbA1c from baseline between mealtime FIASP compared to mealtime NovoLog, and the treatment difference between postmeal FIASP compared to mealtime NovoLog met the pre-specified non-inferiority margin (0.4%). See Table 8. Insulin doses were similar among study arms at baseline and at the end of the trial.

Table 8. Results from Study E: 26-Week Trial of Mealtime FIASP and Postmeal FIASP compared to Mealtime NovoLog Used in Combination with Insulin Degludec in Pediatrics with Type 1 Diabetes

MealtimeFIASP

+ insulin degludec

PostmealFIASP

+ insulin degludec

MealtimeNovoLog

+ insulin degludec

Number of subjects randomized (N)

260

259

258

HbA1c (%)

Baseline (mean)

7.57

7.58

7.53

Adjusted mean change from baseline

0.06

0.35

0.22

Estimated treatment difference vs. mealtime NovoLog [95% CI]*

-0.17 [-0.30; -0.03]

0.13 [-0.01; 0.26]

Baseline is based on the mean of the observed last available values prior to randomization.

*Tested for non-inferiority

Estimated treatment difference was calculated using ANCOVA. Week 26, change in HbA1c was missing for 1.5%, 1.9%, and 1.6% of subjects in mealtime FIASP, post-meal FIASP, and NovoLog respectively. Missing values were imputed with a missing at random assumption.

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