Ozempic, 1.34mg/ml 1.5 ml cartridges in syringe pens

Semaglutide is a GFP-1 receptor agonist (GFP-1P) produced by recombinant DNA biotechnology using Saccharomyces cerevisiae strain with subsequent purification.

Semaglutide is an analog of GFP-1 with 94% homology to human GFP-1. Semaglutide acts as an agonist of GFP-1P, which selectively binds and activates GFP-1P. GFP-1P serves as a target for native GFP-1.

PPPP-1 is a physiological hormone that has several effects on the regulation of glucose concentration and appetite as well as on the cardiovascular system (CVS). The effects on glucose concentration and appetite are specifically mediated by GFP-1P, located in the pancreas and brain. Pharmacological concentrations of semaglutide reduce blood glucose concentrations and body weight through a combination of effects described below.

GPP-1R is also present in specific areas of the heart, blood vessels, immune system and kidneys, where its activation can have cardiovascular (CV) and microcirculatory effects.
Unlike native GFP-1, the extended half-life of semaglutide (about 1 week) allows for subcutaneous (p/k) administration once a week. Binding to albumin is the main mechanism of the long-term action of semaglutide, which results in reduced renal excretion and protects it from metabolic breakdown. In addition, semaglutide is stable with respect to cleavage by the enzyme dipeptidyl peptidase-4.

Semaglutide reduces blood glucose concentration by glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion. Thus, when blood glucose concentration increases, there is stimulation of insulin secretion and suppression of glucagon secretion. The mechanism of glycemic reduction also includes a slight delay in gastric emptying in the early postprandial phase. During hypoglycemia, semaglutide decreases insulin secretion and does not decrease glucagon secretion.

Semaglutide reduces total body weight and adipose tissue mass, reducing energy intake. This mechanism affects overall appetite reduction, including increased satiety signals and decreased hunger signals, as well as improved control of food intake and reduced food cravings. Insulin resistance is also reduced, possibly by reducing body weight. In addition, semaglutide reduces preference for eating foods high in fat.

In animal studies, it has been shown that semaglutide is absorbed by specific areas of the brain and increases key satiety signals and weakens key hunger signals. By acting on isolated areas of brain tissue, semaglutide activates satiety-related neurons and suppresses hunger-related neurons.

In clinical trials (CT), semaglutide had positive effects on plasma lipids, lowered systolic blood pressure (BP) and reduced inflammation.
In animal studies, semaglutide suppressed the development of atherosclerosis by preventing further development of aortic plaques and reducing inflammation in plaques.

Pharmacodynamics
All pharmacodynamic studies were performed after 12 weeks of therapy (including a period of dose escalation) at an equilibrium concentration of semaglutide 1 mg once weekly.

The fasting and postprandial glycemia levels

Semaglutide reduces fasting glucose concentration and postprandial glucose concentration. Compared with placebo, therapy with semaglutide 1 mg in patients with type 2 diabetes mellitus (DM2) resulted in a decrease in glucose concentration in terms of absolute change from baseline (mmol/L) and relative reduction compared with placebo (%) with respect to: fasting glucose concentration (1.6 mmol/L; 22%); glucose concentration 2 hours after a meal (4.1 mmol/L; 37%); mean daily glucose concentration (1.7 mmol/L; 22%) and postprandial peaks in glucose concentration at 3 meals (0.6-1.1 mmol/L). Semaglutide reduced fasting glucose concentration after the first dose.

Pancreatic beta cell function and insulin secretion

Semaglutide improves pancreatic beta cell function. After intravenous glucose jet injection in patients with DM2, semaglutide, compared with placebo, improved the first and second phases of insulin response with a threefold and twofold increase, respectively, and increased the maximum secretory activity of pancreatic beta cells after the arginine stimulation test. In addition, compared with placebo, semaglutide therapy increased fasting insulin concentrations.

Glucagon secretion

Semaglutide reduces fasting glucagon concentration and postprandial glucagon concentration. In patients with DM2, semaglutide results in relatively lower glucagon concentrations compared to placebo: fasting glucagon concentration (8-21%), postprandial) glucagon response (14-15%) and mean daily glucagon concentration (12%).

Glucose-dependent insulin secretion and glucose-dependent glucagon secretion

Semaglutide reduced high blood glucose concentrations by stimulating insulin secretion and reducing glucagon secretion in a glucose-dependent manner. The rate of insulin secretion after administration of semaglutide to patients with T2DM was comparable to that of healthy volunteers.
During induced hypoglycemia, semaglutide, compared with placebo, did not alter the counterregulatory response of increased glucagon concentration, nor did it exacerbate the decrease in C-peptide concentration in DM2 patients.

Gastric emptying

Semaglutide caused a slight delay in early postprandial) gastric emptying, thereby reducing the rate at which postprandial glucose entered the bloodstream.

Body weight and body composition

A greater decrease in body weight was observed with semaglutide compared with the comparison drugs studied (placebo, sitagliptin, delayed-release exenatide (ER), dulaglutide, and insulin glargine). Weight loss with semaglutide was predominantly due to loss of fat tissue, exceeding the loss of muscle mass by a factor of 3.

Appetite, caloric intake, and food choice

Compared with placebo, semaglutide reduced caloric intake by 18-35% during three consecutive meals ad libitum. This was due to semaglutide-induced appetite suppression both on an empty stomach and after meals, improved control of food intake, and reduced food cravings, especially those high in fat.

Lipids on fasting and postprandial lipids

In comparison with placebo, semaglutide reduced fasting triglyceride and very low-density lipoprotein cholesterol (VLDL) concentrations by 12% and 21%, respectively. Postprandial increases in triglyceride and LDL cholesterol concentrations in response to high-fat meals decreased by more than 40%.

Heart electrophysiology (EPS)

The action of semaglutide on the repolarization process in the heart has been tested in the EPS study. The use of semaglutide at doses higher than therapeutic (at equilibrium concentrations up to 1.5 mg) did not result in prolongation of the corrected QT interval.

Clinical efficacy and safety

Both improved glycemic control and reduced CV morbidity and mortality are integral to the treatment of DM2.

The efficacy and safety of Ozempic^® at doses of 0.5 mg and 1 mg were evaluated in six randomized controlled Phase 3a trials. Of these, five CIs evaluated the effectiveness of glycemic control as the primary objective, while one CI evaluated as the primary objective CC outcome. In addition, two phase 3 trials of Ozempic^® were conducted with Japanese patients.

The therapy with Ozempic^® demonstrated sustained, statistically superior and clinically significant improvement in HbA_1c and weight reduction for up to 2 years compared to placebo and treatment with active controls (sitagliptin, insulin glargine, exenatide ZV and dulaglutide).

Age, sex, race, ethnicity, baseline body mass index (BMI) and body weight (kg) values, duration of diabetes mellitus (DM), and renal failure did not affect the effectiveness of Ozempic^®.

Monotherapy

Monotherapy with Ozempic^® at doses of 0.5 mg and 1 mg once weekly for 30 weeks compared with placebo resulted in a statistically more significant reduction in HbA_1c (-1.5%, -1.6% versus 0%, respectively), fasting plasma glucose (FPG) (-2.5 mmol/L, -2.3 mmol/L versus -0.6 mmol/L, respectively), and body weight (-3.7 kg, -4.5 kg versus -1.0 kg, respectively).

The drug Ozempic^® compared to sitagliptin, both in combination with 1-2 oral hypoglycemic drugs (PHGP) (metformin and/or thiazolidinedione group drugs)

Therapy with Ozempic^® 0.5 mg and 1 mg once weekly for 56 weeks compared to sitagliptin resulted in a sustained and statistically more significant decrease in HbA_1s (-1.3%, -1.6% vs -0.5%, respectively), HbA (-2.1 mmol/L, -2.6 mmol/L vs -1.1 mmol/L, respectively) and body weight (-4.3 kg, -6.1 kg vs -1.9 kg, respectively).

The therapy with Ozempic^® 0.5 mg and 1 mg compared with sitagliptin significantly reduced systolic BP from baseline of 132.6 mm Hg (-5.1 mm Hg, -5.6 mm Hg vs. -2.3 mm Hg, respectively). There were no changes in diastolic BP.

The drug Ozempic^® versus dulaglutide, both in combination with metformin
Therapy with Ozempic^® 0.5 mg versus dulaglutide 0.75 mg, both once weekly for 40 weeks, resulted in sustained and statistically superior reductions in HbA_1c (-1.5% versus -1.1%), GPA (-2.2 mmol/L versus -1.9 mmol/L) and body weight (-4.6 kg versus -2.3 kg), respectively.

The therapy with Ozempic^® 1 mg versus dulaglutide 1.5 mg both once weekly for 40 weeks resulted in a sustained and statistically superior reduction in HbA_1c (-l.8% vs -1.4%), HbA (-2.8 mmol/L vs -2.2 mmol/L), and body weight (-6.5 kg vs -3.0 kg), respectively.

The drug Ozempic^® compared with exenatide ST, both in combination with metformin or metformin together with a sulfonylurea derivative

Therapy with Ozempic^® 1 mg once per week for 56 weeks compared to exenatide TV 2.0 mg resulted in sustained and statistically more significant reductions in HbA_1c (-U5% vs -0.9%), GPA (-2.8 mmol/L vs -2.0 mmol/L) and body weight (-5.6 kg vs -1.9 kg), respectively.
Ozempic^® compared with insulin glargine, both in combination with 1-2 GGP (metformin monotherapy or metformin with a sulfonylurea derivative)

Therapy with Ozempic^® at doses of 0.5 mg and 1 mg once weekly compared with insulin glargine for 30 weeks resulted in statistically more significant reductions in HbA_1c (-1.2%, -1.6% vs -0.8%, respectively) and body weight (-3.5 kg, -5.2 kg vs +1.2 kg, respectively).

The decrease in GPA was statistically more significant for Ozempic^® 1 mg compared to insulin glargine (-2.7 mmol/L vs -2.1 mmol/L). No statistically more significant decrease in GPA was observed for Ozempic^® 0.5 mg (-2.0 mmol/L vs -2.1 mmol/L).

The proportion of patients who had severe or confirmed (<3.1 mmol/L) episodes of hypoglycemia was lower with Ozempic

sup>® 0.5 mg (4.4%) and Ozempic^® 1 mg (5.6%) compared with insulin glargine (10.6%).

More patients achieved an HbA_1c <7% without severe or confirmed episodes of hypoglycemia and without weight gain with Ozempic^® 0.5 mg (47%) and Ozempic^® 1 mg (64%) compared to insulin glargine (16%).

Ozempic^® versus placebo, both in combination with basal insulin
Therapy with Ozempic^® at doses of 0.5 mg and 1 mg compared with placebo for 30 weeks resulted in statistically more significant reductions in HbA_1c (-1.4%, -1.8% vs -0.1%, respectively), HbA (-1.6 mmol/L, -2.4 mmol/L vs -0.5 mmol/L, respectively) and body weight (-3.7 kg, -6.4 kg vs -1.4 kg, respectively).

The incidence of severe or confirmed hypoglycemic episodes did not differ significantly between Ozempic^® and placebo. The proportion of patients with an HbA_1c score ≤8% at screening who reported severe or confirmed (<3.1 mmol/L) episodes of hypoglycemia was higher with Ozempic^® compared to placebo and was comparable in patients with an HbA_1c >8% at screening.

Combination with sulfonylurea derivative monotherapy

A subgroup of 123 patients on sulfonylurea derivative monotherapy was evaluated at QI week 30. At week 30, HbA_1c decreased by 1.6% and 1.5% with Ozempic^® at doses of 0.5 mg and 1 mg, respectively, and increased by 0.1% with placebo.

The combination with pre-mixed insulin ± 1-2 GGP

A subgroup of 867 patients on pre-mixed insulin therapy (with or without 2 GGP) was evaluated at week 30 of the CI. At week 30, HbA_1c decreased by 1.3% and 1.8% with Ozempic^® at doses of 0.5 mg and 1 mg, respectively, and decreased by 0.4% with placebo.

Ratio of patients achieving target HbA reduction_1c

Up to 79% of patients achieved treatment targets for HbA_1c reduction <7%, and the proportion of these patients was significantly higher with Ozempic^® compared to patients treated with sitagliptin, exenatide ZV, insulin glargine, dulaglutide and placebo.
The proportion of patients who achieved an HbA_1c score of less than 7% without severe or confirmed episodes of hypoglycemia and without weight gain was significantly greater with Ozempic^® at doses of 0.5 mg and 1 mg (up to 66% and 74%, respectively) compared with patients receiving sitagliptin (27%), exenatide ST (29%), insulin glargine (16%), dulaglutide 0.75 mg (44%) and dulaglutide 1.5 mg (58%).

Body weight

Monotherapy with Ozempic^® 1 mg or therapy in combination with 1-2 drugs resulted in a statistically greater decrease in body weight (up to 6.5 kg loss) compared to therapy with placebo, sitagliptin, exenatide ST, insulin glargine or dulaglutide. The weight reduction was sustained for up to 2 years.

After one year of therapy, more patients who received Ozempic^® achieved weight loss ≥5% and ≥10% 0.5 mg (46% and 13%) and 1 mg (up to 62% and 24%), compared with patients on therapy with the active comparison drugs sitagliptin and exenatide ZV (up to 18% and up to 4%).

In the 40-week CI, a greater number of patients treated with Ozempic^® 0.5 mg achieved weight loss ≥5% and ≥10% (44% and 14%) compared with patients treated with dulaglutide 0.75 mg (23% and 3%). More patients who received Ozempic^® 1 mg achieved weight loss ≥5% and ≥10% (up to 63% and 27%) compared with patients who received dulaglutide 1.5 mg (30% and 8%).

In the CCI, a greater number of patients who received Ozempic

achieved weight loss of ≥5% and ≥10%.sup>® 0.5 mg (36% and 13%) and 1 mg (47% and 20%), compared with patients receiving placebo 0.5 mg (18% and 6%) and 1 mg (19% and 7%).

GPN and postprandial increases in glucose concentration

In all three daily meals, Ozempic^® 0.5 mg and 1 mg showed a significant decrease in GPA concentration to 2.8 mmol/L and a decrease in the postprandial increase in glucose concentration to 1.2 mmol/L (the difference between the pre- and post-meal values obtained after three meals).

Pancreatic beta cell function and insulin resistance

In therapy with Ozempic^® 0.5 mg and 1 mg there was an improvement in pancreatic beta-cell function and a decrease in insulin resistance, as evidenced by assessment of homeostatic models of pancreatic beta-cell function (NOMA-IR) and insulin resistance (HOMA-IR).

Lipids

An improvement in fasting blood lipid profile was observed during the Ozempic^® CI, predominantly in the 1 mg dose group.

Assessment of effects on CVD

3,297 patients with DM2 and high CV risk were randomized in a double-blind, 104-week study to receive the drug Ozempic^® 0.5 mg or 1 mg once weekly or placebo 0.5 mg or 1 mg in addition to standard SS therapy for the next two years.

Ozempic^® therapy resulted in a 26% reduction in the risk of a primary combined outcome including death due to CC disease, nonfatal myocardial infarction (MI) and nonfatal stroke. This was primarily due to a significant decrease in the rate of nonfatal stroke (39%) and a slight decrease in the rate of nonfatal MI (26%), but no change in the rate of death due to CC pathology.

The risk of myocardial or peripheral artery revascularization decreased significantly, while the risk of unstable angina requiring hospitalization and the risk of hospitalization due to heart failure decreased slightly.

Microcirculatory outcomes included 158 new or worsened cases of nephropathy. The relative risk for time to nephropathy (new cases of persistent macroalbuminuria, persistent doubling of serum creatinine concentration, need for ongoing renal replacement therapy, and death due to kidney disease) was 0.64.

In addition to standard CC therapy, therapy with Ozempic^® at doses of 0.5 mg and 1 mg compared with 0.5 mg and 1 mg placebo for 104 weeks resulted in a significant and sustained decrease from baseline in HbA_1c (-1.1% and -1.4% versus -0.4% and -0.4%, respectively).

Hypertension

A significant decrease in mean systolic BP was observed with Ozempic^® 0.5 mg (3.5-5.1 mm Hg).BP) and Ozempic^® 1 mg (5.4-7.3 mm Hg) in combination with PGHP or basal insulin. There was no significant difference in diastolic BP between Ozempic^® and the comparison drugs.

Pharmacokinetics

The drug is suitable for administration once weekly because the half-life of semaglutide is approximately 1 week.

Absorption

The time to reach maximum plasma concentration (C_max) was 1 to 3 days after administration of the drug dose.

The equilibrium concentration of the drug (AUC_τ/24) was reached after 4-5 weeks of single weekly administration of the drug. After the p/c administration of semaglutide at doses of 0.5 mg and 1 mg, its average equilibrium concentrations in DM2 patients were approximately 16 nmol/L and 30 nmol/L, respectively.

Exposure for semaglutide doses of 0.5 mg and 1 mg increases in proportion to the dose administered.
When semaglutide is administered p/c to the anterior abdominal wall, thigh or shoulder a similar exposure is achieved.

The absolute bioavailability of semaglutide after p/u administration was 89%.

Distribution

The average tissue distribution volume of semaglutide after p/c administration in patients with T2DM was approximately 12.5 L. Semaglutide was significantly bound to plasma albumin (>99%).

Metabolism

Semaglutide is metabolized by proteolytic cleavage of the peptide protein backbone and subsequent beta-oxidation of the side chain fatty acid.

Elimation

The gastrointestinal tract (GIT) and the kidneys are the major routes of excretion of semaglutide and its metabolites, with 2/3 of the administered dose of semaglutide excreted by the kidneys and 1/3 through the intestines.
Approximately 3% of the administered dose is excreted by the kidneys as unchanged semaglutide.

In patients with DM2 the clearance of semaglutide was about 0.05 l/h. With an elimination half-life of approximately 1 week, semaglutide will be present in the general bloodstream for approximately 5 weeks after the last dose of the drug.

Special patient groups

There is no need to adjust the dose of semaglutide based on age, gender, race, ethnicity, body weight, or the presence of renal or hepatic impairment.

Age

Based on data from a phase 3a CI that included patients aged 20 to 86 years, it is shown that age had no effect on the pharmacokinetics of semaglutide.

Position

Position had no effect on the pharmacokinetics of semaglutide.

Race

Racial group (white, black, or African American, Asian) had no effect on the pharmacokinetics of semaglutide.

Ethnicity

Ethnicity (Hispanic) had no effect on the pharmacokinetics of semaglutide.

Body weight

Body weight affected semaglutide exposure. Higher body weight resulted in lower exposure. Doses of semaglutide equal to 0.5 mg and 1 mg provided sufficient exposure to the drug over a body weight range of 40 to 198 kg.

Renal insufficiency

Renal insufficiency had no clinically significant effect on the pharmacokinetics of semaglutide. This was shown in patients with varying degrees of renal impairment (mild, moderate, severe, or dialysis patients) compared to patients with normal renal function in a study of a single dose of semaglutide equal to 0.5 mg. This has also been shown from phase 3a CI data for patients with DM2 and renal impairment, although experience with use in patients with end-stage renal disease has been limited.

Help failure

Help failure did not affect the exposure of semaglutide. The pharmacokinetic properties of semaglutide were evaluated in a study of a single dose of semaglutide equal to 0.5 mg in patients with varying degrees of hepatic impairment (mild, moderate, severe) by

Children and adolescents

There have been no studies of semaglutide in children and adolescents under 18 years of age.

Indications

Ozempic^® is indicated for use in adult patients with type 2 diabetes with diet and exercise to improve glycemic control as:

Active ingredient

Semaglutide

Composition

1 ml of the drug contains: