Xultophy 100/3.6 (Page 8 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

XULTOPHY 100/3.6

No studies have been conducted with the XULTOPHY 100/3.6 combination to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based upon studies with insulin degludec and liraglutide individually.

Insulin degludec

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin degludec.

In a 52-week study including human insulin (NPH insulin) as comparator, Sprague-Dawley rats were dosed subcutaneously with insulin degludec at 3.3, 6.7, and 10 U/kg/day, resulting in 5 times the human exposure (AUC) when compared to a human subcutaneous dose of 0.75 U/kg/day. Human insulin was dosed at 6.7 U/kg/day. No treatment-related increases in incidences of hyperplasia, benign or malignant tumors were recorded in female mammary glands from rats dosed with insulin degludec and no treatment related changes in the female mammary gland cell proliferation were found using BrdU incorporation. Further, no treatment related changes in the occurrence of hyperplastic or neoplastic lesions were seen in any animals dosed with insulin degludec when compared to vehicle or human insulin.

Genotoxicity testing of insulin degludec was not performed.

In a combined fertility and embryo-fetal study in male and female rats, treatment with insulin degludec up to 21 U/kg/day (approximately 5 times the human subcutaneous dose of 0.75 U/kg/day, based on U/body surface area) prior to mating and in female rats during gestation had no effect on mating performance and fertility.

Liraglutide

A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1.8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL).

A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats.

Studies in mice demonstrated that liraglutide-induced C-cell proliferation was dependent on the GLP-1 receptor and that liraglutide did not cause activation of the REarranged during Transfection (RET) proto-oncogene in thyroid C-cells.

Human relevance of thyroid C-cell tumors in mice and rats is unknown and has not been determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)].

Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats.

In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1.0 mg/kg/day, a high dose yielding an estimated systemic exposure 11- times the human exposure at the MRHD, based on plasma AUC. In female rats, an increase in early embryonic deaths occurred at 1.0 mg/kg/day. Reduced body weight gain and food consumption were observed in females at the 1.0 mg/kg/day dose.

14 CLINICAL STUDIES

14.1 Overview of Clinical Studies

A total of 3908 patients with type 2 diabetes participated in 6 randomized, parallel and active or placebo-controlled phase 3 trials of 26 weeks duration.

Three studies were conducted in patients inadequately controlled on one or more OADs (e.g. metformin, pioglitazone, sulfonylurea, or sodium-glucose cotransporter-2 inhibitors (SGLT2i) (Tables 5-7). Three studies were conducted in patients converting from liraglutide or basal insulin: one study was conducted in patients converting from liraglutide (with doses up to 1.8 mg), (Table 8), one study was conducted in patients converting from any basal insulin (Table 9), and one study was conducted in patients converting from insulin glargine U-100 (Table 10).

In all trials, XULTOPHY 100/3.6 was titrated twice weekly by increments or decrements of 2 units (2 units insulin degludec/0.072 mg liraglutide), towards a pre-specified fasting blood glucose target. The same titration algorithm was applied for basal insulin comparators.

14.2 Patients with Type 2 Diabetes Uncontrolled on OAD Treatment

NCT01336023: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin degludec and liraglutide, all administered once-daily, was studied in a 26-week randomized, open-label, three-arm parallel trial in 1660 patients with type 2 diabetes mellitus inadequately controlled on 1-2 OADs (metformin or metformin with or without pioglitazone).

The mean age of the trial population was 55 years and mean duration of diabetes was 6.8 years. 50.8% were male. 61.9% were White, 7.4% were Black or African American and 15.1% were Hispanic. 5.4% of patients had eGFR < 60mL/min/1.73m2; no patients had eGFR < 30mL/min/1.73m2. The mean BMI was 31.2 kg/m2.

The starting dose of XULTOPHY 100/3.6 was 10 units (10 units insulin degludec/0.36 mg liraglutide). The starting dose of insulin degludec was 10 units. XULTOPHY 100/3.6 and insulin degludec were titrated twice weekly towards a target fasting blood glucose goal of 72-90 mg/dL. Patients in the liraglutide arm followed a fixed dose escalation scheme with a starting dose of 0.6 mg and a dose increase of 0.6 mg weekly until a daily dose of 1.8 mg was reached. Patients continued on pre-trial treatment with metformin or metformin and pioglitazone throughout the trial.

At the end of 26 weeks, treatment with XULTOPHY 100/3.6, insulin degludec, and liraglutide resulted in a reduction in HbA1c from baseline of 1.81%, 1.35% and 1.21%, respectively, (see Table 5). The end of trial dose of XULTOPHY 100/3.6 was 38 units (38 units insulin degludec/1.37 mg liraglutide).

Table 5: Results of a 26-Week Trial with XULTOPHY 100/3.6 in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Alone or in Combination with Pioglitazone

XULTOPHY 100/3.6
+ metformin ± pioglitazone
Insulin degludec
+ metformin
± pioglitazone
Liraglutide
+ metformin
± pioglitazone

Total (N)

833
413
414

HbA1c (%)

Baseline

8.3
8.3
8.3

End of Trial (LS Mean)#

6.5
6.9
7.1

Change from baseline (LS Mean)#

-1.81
-1.35
-1.21

Estimated treatment difference [95% CI]#

-0.46%
[-0.59; -0.34]A
-0.60%
[-0.72; -0.47]A

Percentage of patients achieving HbA1c <7%##

74.1%
60.5%
56.0%

Fasting Plasma Glucose (FPG) (mg/dL)

Baseline

166
169
163

End of Trial (LS Mean)#

104
107
133

Change from baseline (LS Mean)#

-61.8
-59.2
-32.4

A p<0.01. Primary endpoint was tested for non-inferiority of XULTOPHY 100/3.6 to insulin degludec based on pre-specified non-inferiority margin of 0.3% and for superiority of XULTOPHY 100/3.6 to liraglutide.

# Estimated using an ANCOVA with treatment, baseline HbA1c stratum, sub-study, concomitant diabetes treatment and country as factors and baseline response as covariate. Multiple imputation modelled “return to baseline” of the treatment effect for subjects having missing week 26 data.

## Patients with missing HbA1c value at week 26 data were considered non-responders.

There were 11.8% of subjects in the XULTOPHY 100/3.6 arm, 12.3% in the insulin degludec arm and 15.5% in the liraglutide arm for whom HbA1c data was missing at week 26.

NCT01618162: The efficacy and safety of XULTOPHY 100/3.6 compared to placebo were studied in a 26-week randomized, double-blind, treat-to-target trial in 435 patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea alone or in combination with metformin.

The mean age of the trial population was 59.8 years, and mean duration of diabetes was 9.1 years. 52.2% were male. 75.4% were White, 6.7% were Black or African American and 9.2% were Hispanic. 10.6% of patients had eGFR < 60mL/min/1.73m2; no patients had eGFR < 30mL/min/1.73m2. The mean BMI was 31.5 kg/m2.

XULTOPHY 100/3.6 was started at 10 units (10 units insulin degludec/0.36 mg liraglutide) and titrated twice weekly towards a target fasting blood glucose goal of 72-108 mg/dL. Patients continued on pre-trial treatment with sulfonylurea, with or without metformin throughout the trial.

Treatment with XULTOPHY 100/3.6 for 26 weeks resulted in a statistically significant reduction in mean HbA1c compared to placebo (see Table 6). The end of trial dose of XULTOPHY 100/3.6 was 28 units (28 units insulin degludec/1.01 mg liraglutide).

Table 6: Results of a 26-Week Trial with XULTOPHY 100/3.6 in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Sulfonylurea Alone or in Combination with Metformin

XULTOPHY 100/3.6

+ sulfonylurea ###

± metformin

Placebo

+ sulfonylurea ###

± metformin

Total (N)

289

146

HbA1c (%)

Baseline

7.9

7.9

End of Trial (LS Mean)#

6.5

7.3

Change from baseline (LS Mean)#

-1.42

-0.62

Estimated treatment difference [95% CI]#

-0.81% [-0.98; -0.63]A

Percentage of patients achieving HbA1c <7%##

70.9%

26.7%

FPG (mg/dL)

Baseline

164

165

End of Trial (LS Mean)#

118

152

Change from baseline (LS Mean)#

-46.2

-12.1

A p<0.01. Primary endpoint was tested for superiority of XULTOPHY 100/3.6 to placebo.

# Estimated using an ANCOVA with treatment, region and pre-trial medication as fixed factors and baseline response as covariate. Multiple imputation modelled “jump-to-control” of the treatment effect for subjects having missing week 26 data.

## Patients with missing HbA1c value at week 26 data were considered non-responders.

There were 12.8% of subjects in the XULTOPHY 100/3.6 arm and 24.7% in the placebo arm for whom HbA1c data was missing at week 26.

### Dose of sulfonylurea was ≥ half of the maximum approved dose.

NCT02773368: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin glargine U-100, both administered once-daily, were studied in a 26-week randomized, open-label, two-arm parallel trial in 420 patients with type 2 diabetes mellitus inadequately controlled on a SGLT2i alone or in combination with other OADs (with or without metformin, pioglitazone, and/or dipeptidyl peptidase-4 [DPP4] inhibitor). At randomization, the DPP4 inhibitor was discontinued.

The mean age of the trial population was 56.7 years and mean duration of diabetes was 9.55 years. 58.8% were male. 82.4% were White, 1.2% were Black or African American and 16.2% were Hispanic. 2.6% of patients had eGFR < 60mL/min/1.73m2 ; none of the patients had eGFR < 30mL/min/1.73m2. The mean BMI was 31.2 kg/m2.

The starting dose of XULTOPHY 100/3.6 was 10 units (10 units insulin degludec/0.36 mg liraglutide). The starting dose of insulin glargine U-100 was 10 units. XULTOPHY 100/3.6 and insulin glargine U-100 were titrated twice weekly to target a fasting blood glucose goal of 72-90 mg/dL. Patients could not increase the dose of XULTOPHY 100/3.6 and insulin glargine U-100 by more than 4 units per week, and there was no maximum allowed dose of insulin glargine. The patients continued on pre-trial treatment with SGLT2i, with or without other OADs throughout the entire trial. The targeted fasting blood glucose goal was achieved by 49.0% of patients randomized to XULTOPHY 100/3.6 and 41.9% of patients randomized to insulin glargine at 26 weeks.

At the end of 26 weeks, XULTOPHY 100/3.6 resulted in a reduction in HbA1c from baseline of 1.97% and insulin glargine U-100 resulted in a reduction of 1.59% (see Table 7). At the end of trial, the average dose of XULTOPHY 100/3.6 was 36 units (36 units insulin degludec/1.01 mg liraglutide) and the dose of insulin glargine was 54 units; it is unclear that these observed differences in insulin doses are clinically important. The difference in HbA1c effect observed at 26 weeks may not necessarily reflect the effect in the care setting where insulin glargine may be more rapidly titrated.

Table 7: Results of a 26-Week Trial in Patients with Type 2 Diabetes Mellitus Inadequately

Controlled on SGLT2i Alone or in Combination with Metformin, Pioglitazone and/or DPP4 Inhibitor

XULTOPHY 100/3.6

+ SGLT2i

± metformin± pioglitazone

Insulin Glargine U-100

+ SGLT2i

± metformin± pioglitazone

Total (N)

210

210

HbA1c (%)

Baseline

8.2

8.4

End of Trial (LS Mean)#

6.3

6.7

Change from baseline (LS Mean)#

-1.97

-1.59

Estimated treatment difference [95% CI]#

-0.38% [-0.54; -0.23]A

Percentage of patients achieving HbA1c <7%##

79.5 %

68.6%

FPG (mg/dL)

Baseline

171

172

End of Trial (LS Mean)###

108

112

Change from baseline (LS Mean)###

-63.8

-59.9

A Primary endpoint was tested for non-inferiority of XULTOPHY 100/3.6 to insulin glargine U-100 on a non-inferiority margin of 0.3%.

# Estimated using an ANCOVA with treatment, pre-trial OAD group and region as factors and corresponding baseline value as covariate. For HbA1c (%), missing week 26 measurements from subjects who discontinued early were multiply-imputed using information from subjects who also discontinued early but still had a week 26 measurement (retrieved dropouts).

## Patients with missing HbA1c value at week 26 data were considered non-responders.

There were 6.2% of subjects in the XULTOPHY 100/3.6 arm and 2.4% in the insulin glargine U-100 arm for whom HbA1c data was missing at week 26.

### Missing week 26 FPG measurements from subjects who discontinued early were imputed using multiple imputation with a mean for each subject equal to their respective baseline value.

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