Summary Basis of Decision for Awiqli

Clinical Pharmacology

The primary activity of insulin icodec (the medicinal ingredient in Awiqli) is to regulate glucose metabolism. Insulin and its analogues lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis. Insulin icodec binds reversibly to albumin, resulting in a depot in the circulation from which insulin icodec is slowly released. When insulin icodec binds to the human insulin receptor it results in the same pharmacological effects as human insulin.

The pharmacokinetic and pharmacodynamic properties of insulin icodec following single and multiple dosing were well characterized in single- and multiple dose Phase I studies carried out in healthy subjects and in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM).

Exposures in both patient populations were approximately dose-proportional across the dosage range of 1.1 U/kg to 5.64 U/kg. The mean accumulation ratio was approximately 2 with steady state reached after 2 to 4 weekly doses. Both time to maximum plasma concentration (13 to 18 hours for T2DM and 16 to 18 hours for T1DM) and half-life (approximately one week [168 hours]) of insulin icodec were consistent between T1DM and T2DM patients. Relative bio-efficacy assessments suggest that insulin icodec provides an equivalent glucose lowering effect compared with daily insulin degludec or insulin glargine following equivalent dosing across a 7 day dosing interval (i.e., 7 times the daily insulin dose).

In T2DM patients, the glucose-lowering pharmacodynamic effect of insulin icodec at steady state was well covered by the weekly dosing interval and a consistent effect was observed across the entire dosing interval. The T1DM patients had a pharmacodynamic effect that increased during the first two to three days after dosing before decreasing over time, correlating temporally with an increased risk of hypoglycemia at day 2 to 4 post-dose in these patients. In addition, these patients exhibited more glucose fluctuations at the end of the dosing interval compared with T2DM patients.

Consistent pharmacokinetic and pharmacodynamic profiles for insulin icodec were observed following single dose administration into either the upper arm, abdomen or thigh. No clinically meaningful impact of either hepatic (mild, moderate or severe) or renal (mild, moderate, severe or end-stage renal disease) impairment was observed.

The most parsimonious structural population pharmacokinetic model for insulin icodec was a one-compartment model with first order absorption and elimination based on sparsely sampled pharmacokinetic data from a single Phase II study and four Phase III studies including one study in T1DM patients. The model was appropriately parameterized with no evidence of consistent bias, and fitted the observed data adequately. The main covariate on insulin icodec exposure was bodyweight, with decreasing exposure observed with increasing bodyweight. No dose adjustment is recommended due to bodyweight given the individualized posology with dose adjustments as necessary to achieve adequate glycemic control.

Immunogenicity was also assessed in these studies. Between 70% and 82% of subjects were positive for anti-drug antibodies against insulin icodec at any time across four Phase III studies and one Phase II study. Cross-reactivity of anti-drug antibodies against insulin icodec with human insulin was between 66% and 77%. However, no consistent effect of anti-drug antibodies on the pharmacokinetic, pharmacodynamic, efficacy or safety profiles of insulin icodec was observed.

For further details, please refer to the Awiqli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Awiqli (insulin icodec injection) was shown to be effective at controlling blood glucose in five studies conducted in adults with T2DM and one study conducted in adults with T1DM. Across these six Phase III studies, 2,170 subjects were exposed to Awiqli, of whom 1,880 had T2DM and 290 had T1DM.

For all studies, pre-study non-insulin anti-diabetic medications were continued as background therapy in both treatment arms throughout the entire study except for sulfonylureas and glinides, which were either discontinued at randomization (ONWARDS 1, 2, and 4) or were reduced at randomization by approximately 50% at the discretion of the investigator (ONWARDS 3 and 5).

Description of Clinical Studies

Studies conducted in adults with type 2 diabetes mellitus

The efficacy of Awiqli administered once-weekly in adult participants with T2DM used in combination with a mealtime insulin or in combination with common oral anti-diabetic agents and or glucagon-like peptide-1 receptor agonists were evaluated in three randomized, open-label, treat-to-target, active-controlled studies and one randomized, double-blind, treat-to-target, active-controlled study (ONWARDS 1, ONWARDS 3, ONWARDS 2, and ONWARDS 4). In addition, a randomized, open-label, active controlled study with real world elements in T2DM insulin naïve participants was conducted to investigate the safety and efficacy of Awiqli use with a digital titration application compared to daily basal insulins (ONWARDS 5).

ONWARDS 1 (NN1436-4477) - Awiqli administered weekly in combination with non-insulin anti-diabetic treatment in insulin naïve type 2 diabetes patients

The efficacy of Awiqli was evaluated in a 52-week randomized, open-label, active-controlled, parallel-group, multicentre, multinational, treat-to-target study that enrolled 984 insulin naïve adult subjects with T2DM who were inadequately controlled on one or more oral anti-diabetic agents or glucagon-like peptide-1 receptor (GLP-1) agonists.

The primary objective of the ONWARDS 1 study was to demonstrate the effect of a once-weekly dose of Awiqli on glycemic control when administered in combination with non-insulin anti-diabetic drugs, in insulin naïve patients with T2DM. This included comparing the difference in change from baseline in hemoglobin A1c (HbA1c) between Awiqli and insulin glargine after 52 weeks of treatment to a non-inferiority limit of 0.3%.

Study subjects were randomized to receive once-weekly doses of Awiqli or once-daily doses of insulin glargine (U-100) according to the approved labeling. A total of 66.1% of patients were Caucasian, 27.8% were Asian, 2.7% were Black or African American, and 10.8% Hispanic. The mean age of the study population was 59 years, 57% of subjects were male and 43% female, and the mean duration of diabetes was 11.5 years.

At baseline, study subjects had a mean HbA1c of 69 mmol/mol (8.5%), a mean fasting plasma glucose of 10.3 mmol/L, and a mean body mass index (BMI) of 30.1 kg/m². In 10.4% of subjects, the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m².

ONWARDS 3 (NN1436-4479) - Awiqli administered weekly in combination with non-insulin anti-diabetic treatment in insulin naïve type 2 diabetes patients

The efficacy of Awiqli was evaluated in a 26-week randomized, double blinded, active-controlled, parallel-group, multicentre, multinational, treat-to-target study that enrolled 588 insulin naïve adult patients with T2DM who were inadequately controlled on one or more oral anti-diabetic agents or GLP-1 receptor agonists.

The primary objective of the ONWARDS 3 study was to demonstrate the effect of once weekly doses of Awiqli on glycemic control when administered in combination with non-insulin anti-diabetic drugs, in insulin naïve patients with T2DM. This included comparing the difference in change from baseline in HbA1c between Awiqli and insulin degludec after 26 weeks of treatment to a non-inferiority limit of 0.3%.

Study patients were randomized to treatment with Awiqli once weekly or insulin degludec U-100 once daily according to the approved labeling. A total of 60.2% of subjects were Caucasian, 28.1% were Asian, 2.6% were Black or African American, and 27.9% were Hispanic. The mean age of the study population was 58 years, 63% of subjects were male and 37% female, and the mean duration of diabetes was 11.3 years.

At baseline, study patients had a mean HbA1c of 70 mmol/mol (8.5%), mean fasting plasma glucose of 10.1 mmol/L, and a mean BMI of 29.6 kg/m². In 7.5% of subjects, the eGFR was less than 60 mL/min/1.73m².

ONWARDS 2 (NN1436-4478) - Awiqli administered once weekly with or without non-insulin anti-diabetic drugs in adult type 2 diabetes patients previously treated with basal insulin

The efficacy of Awiqli was evaluated in a 26-week randomized, open label, active-controlled, parallel-group, multicentre, multinational, treat-to-target study in 526 insulin naïve adult patients with T2DM treated with once or twice daily basal insulin with or without oral anti-diabetic agents and/or with or without GLP-1 receptor agonists.

The primary objective of the ONWARDS 2 study was to demonstrate the effect of once- weekly treatment with Awiqli on glycemic control when administered with or without non-insulin anti-diabetic drugs, in patients with T2DM treated with basal insulin. This included comparing the difference in change from baseline in HbA1C between Awiqli and insulin degludec after 26 weeks of treatment to a non-inferiority limit of 0.3%.

Patients were randomized to treatment with Awiqli once weekly or insulin degludec U-100 once daily according to the approved labeling. A total of 56.7% of patients were Caucasian, 37.3% were Asian, 6.1% were Hispanic, and 4.4% were Black or African American. The mean age of the study population was 62 years, 57% of subjects were male and 43% female, and the mean duration of diabetes was 16.7 years.

At baseline, study subjects had a mean HbA1c of 65 mmol/mol (8.1%), a mean fasting plasma glucose of 8.4 mmol/L, and a mean BMI of 29.3 kg/m². In 15.2% of participants, the eGFR was less than 60 mL/min/1.73m².

ONWARDS 4 (NN1436-4480) - Awiqli administered once weekly in combination with a rapid-acting insulin analogue at mealtimes in adult type 2 diabetes patients

The efficacy of Awiqli was evaluated in a 26-week randomized, open-label, active-controlled, parallel-group, multicentre, multinational, treat-to-target study in 582 adult patients with T2DM inadequately controlled on once-daily basal insulin in combination with mealtime rapid-acting insulin with or without oral anti-diabetic agents or GLP-1 receptor agonists.

The primary objective of the ONWARDS 4 study was to demonstrate the effect of once weekly treatment with Awiqli on glycemic control when administered in combination with insulin-aspart, with or without non-insulin anti-diabetic drugs, in patients with T2DM on a basal-bolus regimen. This included comparing the difference in change from baseline in HbA1C between Awiqli and insulin glargine after 26 weeks of treatment to a non-inferiority limit of 0.3%.

Patients were randomized to treatment with Awiqli once weekly or insulin glargine (U-100) once daily according to the approved labeling both in combination with insulin before each meal. A total of 63.6% of subjects were Caucasian, 32.3% were Asian, 18% were Hispanic, and 3.6% were Black or African American. The mean age of the study population was 60 years, 52% of subjects were male and 48% were female, and the mean duration of diabetes was 17.1 years.

At baseline, patients had a mean HbA1c of 67 mmol/mol (8.3%), a mean fasting plasma glucose of 9.4 mmol/L, and a mean BMI of 30.3 kg/m². In 15.6% of participants, the eGFR was less than 60 mL/min/1.73m².

ONWARDS 5 (NN1436-4481) - Awiqli administered weekly in combination with non-insulin anti-diabetic treatment in insulin naïve type 2 diabetes patients

The efficacy of Awiqli was evaluated in a 52-week randomized, open label, active-controlled, parallel-group, multicentre, multinational study in 1,085 insulin naïve adult patients with T2DM who were inadequately controlled on one or more oral antidiabetic agents or GLP-1 receptor agonists.

The primary objective of the ONWARDS 5 study was to demonstrate the effectiveness of once weekly treatment with Awiqli used with digital titration software on glycemic control when administered in combination with non-insulin anti-diabetic drugs in insulin naïve patients with T2DM. This included comparing the difference in change from baseline inHbA1c between Awiqli used with digital titration software and once daily basal insulin analogues after 52 weeks of treatment to a non-inferiority limit of 0.3%.

Patients were randomized to treatment with Awiqli once weekly or once-daily basal insulin analogues, such as insulin degludec (U-100), insulin glargine (U-100), or insulin glargine (U‑300) according to local clinical practice. Participants in the Awiqli arm were instructed to use the Novo Nordisk-provided titration software to provide weekly dose guidance in agreement with the investigator and according to local clinical practice and label.

A total of 89.5% of patients were Caucasian, 8.8% were Hispanic, and 4.8% were Black or African American. The mean age of the study population was 59 years, 57% of subjects were male and 43% were female, and the mean duration of diabetes was 11.9 years.

At baseline, subjects had a mean BMI of approximately 32.8 kg/m². In 11.2% of patients, the eGFR was less than 60 mL/min/1.73m².

Efficacy results in adults with type 2 diabetes mellitus

The five studies conducted in T2DM subjects included three studies conducted in insulin-naïve patients, one study conducted in patients switching from another basal insulin, and one study conducted in patients switching basal insulins and also using bolus (mealtime) insulin. In all five studies, the primary efficacy endpoint was non-inferiority of Awiqli to daily-administration basal insulin comparators, defined as a difference in treatment effect of less than 0.3% points in HbA1c after 26 or 52 weeks of treatment. All five studies met this endpoint.

The estimated treatment differences between Awiqli and daily basal insulins ranged from -0.38 to +0.02 %-points after 26 or 52 weeks, the results met the criterion for non-inferiority in every case. In each of the five studies, there were more Awiqli (26.48% to 52.56%) than comparator (25.24% to 42.58%) patients who achieved HbA1c less than 7% without experiencing any severe (level 3) or clinically significant (level 2) hypoglycemic events.

Studies conducted in adults with type 1 diabetes mellitus

The efficacy of Awiqli administered once-weekly in combination with a mealtime insulin to adult patients with T1DM was evaluated in one randomized, open-label, treat-to-target, active-controlled study (ONWARDS 6).

ONWARDS 6 (NN1436-4625) - Awiqli administered in combination with a rapid-acting insulin analogue at mealtimes in adult type 1 diabetes patients

The efficacy of Awiqli was evaluated in a 26-week randomized, open-label, active-controlled, parallel-group, multicentre, multinational, treat-to-target study in 582 patients with T1DM. The primary objective of the study was to confirm the effect of treatment with once weekly Awiqli in combination with insulin aspart on glycemic control in patients with T1DM. This included comparing the difference in the change from baseline in HbA1c resulting from treatment with once-weekly Awiqli as compared to once-daily insulin degludec both in combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.

Subjects were randomized to treatment with Awiqli once weekly or insulin degludec U-100 once daily according to the approved labeling. Insulin aspart was administered before each meal in both treatment arms. Throughout the study period, a continuous glucose monitoring system, Dexcom G6, was used by all patients in both treatment arms. A total of 77% of subjects were Caucasian, 21.1% were Asian, 1.9% were Black or African American, and 3.4% were Hispanic. The mean age of the study population was 44 years, 58% of subjects were male and 42% were female, and the mean duration of diabetes was 19.5 years.

At baseline, subjects had a mean HbA1c of 60 mmol/mol (7.6%), a mean fasting plasma glucose of 9.7 mmol/L, and a mean BMI of 26.5 kg/m².

Efficacy results in adults with type I diabetes mellitus

In patients with T1DM, Awiqli and insulin degludec performed similarly in terms of HbA1c. At Week 26, the estimated treatment difference in change from baseline HbA1c was +0.05 %-points (95% confidence interval: -0.13, +0.23; p=0.0065), which met the criteria for non-inferiority (≤0.3 %-points). Awiqli had a marginally less favourable profile compared to insulin degludec for fasting plasma glucose and the proportion of patients achieving pre-specified HbA1c thresholds, but rates were generally within the expected ranges for T1DM. In addition, 9.55% of Awiqli versus 16.74% of insulin degludec patients achieved HbA1c less than 7% without experiencing severe (level 3) or clinically significant (level 2) hypoglycemia.

Overall Conclusion on Efficacy

Awiqli (insulin icodec injection) was authorized based on six Phase III, randomized, active-controlled studies in patients with T1DM and T2DM. Overall, there were 290 T1DM and 1,880 T2DM patients exposed to Awiqli across these studies.

The primary efficacy endpoint in all six studies was the non-inferiority of Awiqli to the daily-administration of basal insulin comparators, defined as a difference in treatment effect of less than 0.3 % in HbA1c after 26 or 52 weeks of treatment. All six studies met this endpoint.

Patients with T2DM treated with Awiqli showed similar or better profiles for other glycemic endpoints such as achievement of HbA1c less than 7% without experiencing severe or clinically significant hypoglycemia and fasting plasma glucose.

Patients with T1DM treated with Awiqli showed similar or less favourable profiles for glycemic endpoints such as fasting plasma glucose and achievement of HbA1c thresholds. T1DM patients treated with Awiqli experienced a higher incidence of severe or clinically significant hypoglycemic events as the comparator. The majority of these events were mild or moderate in nature. Overall the benefit-risk assessment in T1DM is marginally positive and Awiqli would be best suited to patients with good hypoglycemia self-awareness.

Indication

The New Drug Submission for Awiqli was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Awiqli (insulin icodec injection) is indicated for the once-weekly treatment of adults with diabetes mellitus to improve glycemic control.

For more information, refer to the Awiqli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation of Awiqli was based primarily on the six Phase III clinical studies previously described in the clinical efficacy section. A total of 2,170 patients were exposed to Awiqli, 1,880 of whom had T2DM and 290 of whom had T1DM. The study was 26 to 52 weeks for patients with T2DM, and 26 weeks for patients with T1DM.

Across the six studies, there were no consistent patterns in terms of the incidence of treatment-emergent adverse events, serious adverse events, severe adverse events, or drug-related adverse events. There also were no consistent patterns in terms of the incidence of deaths, treatment discontinuations or interruption due to adverse events, or dose reductions due to adverse events. The overall incidences of safety endpoints were not markedly different between the 26-week and 52-week studies, nor were there notable differences between T1DM versus T2DM patients (except for hypoglycemia-related endpoints; addressed further below).

Moreover, there were no consistent or clinically meaningful differences between the Awiqli and comparator arms for adverse events of special interest other than hypoglycemia, including but not limited to retinal disorders, hyperglycemia, hypersensitivity, microvascular complications, and cardiovascular disorders.

In all five T2DM studies and one T1DM study, subjects on daily basal insulins showed a relatively constant rate of hypoglycemic events over the course of a week, whereas subjects on Awiqli had a clear peak of events from Days 2 to 4.

Rates of severe or clinically significant hypoglycemic episodes ranged from 18.6 to 31.0 events per 100 person-years exposure (PYE) in insulin-naïve T2DM treated with Awiqli compared to rates of 14.5 to 16.1 per 100 PYE to those treated with the comparator basal insulin. Severe hypoglycemia was defined as hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery. Clinically significant hypoglycemia was defined as a plasma glucose value less than 54 mg/dL (3.0 mmol/L).

In basal insulin-experienced T2DM subjects, rates of hypoglycemic events were 72.8 per 100 PYE for Awiqli and 27.5 per 100 PYE for daily basal insulin subjects. In basal-bolus insulin-experienced T2DM subjects, rates were 564.1 events per 100 PYE for Awiqli and 562.4 events per 100 PYE for the comparator. In all studies, rates of hypoglycemia were highest on days 2 to 4 of the weekly dosing interval for Awiqli. This effect has been included in a Serious Warnings and Precautions box in the Awiqli Product Monograph.

Rates of severe or clinically significant hypoglycemic episodes in the maintenance phase of the study in patients with T1DM were 1,841.18 events per 100 PYE for Awiqli versus 860.54 events per 100 PYE for insulin degludec. In the T1DM study, there was an equal number of patients in each arm that experienced severe hypoglycemia (9 [3.1%] per arm) but there was a higher rate of events in the Awiqli treatment group that was at least partially attributable to a single outlier subject that experienced 33 events. Rates of severe events were within the expected range, based on labelling of other basal insulins.

In summary, in T2DM subjects, Awiqli presents a trade-off of marginally to moderately better glycemic control than daily basal insulin against a higher incidence of hypoglycemic adverse events. In T1DM subjects, the efficacy profile (aside from HbA1c) and safety profile were often better with the daily basal insulin comparator. Therefore, the benefit-risk assessment in T1DM subjects is marginally positive and Awiqli would be best suited for T1DM subjects with good hypoglycemia self-awareness.

A Serious Warnings and Precautions box has been included in the Awiqli Product Monograph describing the possible risk of hypoglycemia. Glucose monitoring should be performed for all patients with diabetes mellitus who are treated with insulin.

For more information, refer to the Awiqli Product Monograph, approved by Health Canada and available through the Drug Product Database.

In vitro and in vivo pharmacodynamic studies demonstrated the mechanism of action of insulin icodec (the medicinal ingredient in Awiqli) via the binding of the human insulin receptor.

In a 26-week study with a 12-week recovery period, rats were dosed subcutaneously with insulin icodec at 3.3, 6.7, 10, and 13 (male only) U/kg/day, resulting in 0.7 to 2.5-times the exposure from insulin icodec dosed at 230 U/week (the average clinical dose), based on the area under the concentration-time curve (AUC). The observed changes included decreased blood glucose levels, histopathological changes in the pancreatic islets (atrophy), brown fat (increased vacuolar and cellular size), liver (reduced glycogen), as well as axonal degeneration (sciatic and tibial nerves) with skeletal muscle degeneration. The no-observed-adverse-effect level (NOAEL) could not be determined due to the axonal degeneration observed in animals given the lowest dose.

In a 52-week study, rats were administered insulin icodec at doses of 3.3, 5 (females only), 6.7, and 10 (males only) U/kg/day by subcutaneous injection, resulting in 0.8 to 2‑times exposure at 230 U/week based on AUC. A control group of rats was administered human insulin (neutral protamine Hagedorn [NPH]) at a dose of 6.7 U/kg/day. The observed changes were consistent with the findings in the 26-week study. Notably, one low-dose male had limited or no use of its hindlimbs, without microscopic findings in nerves or muscle. One male and one female of the 6.7 U/kg/day dosing groups could not use their hindlimbs and were euthanized. Necropsy showed axonal degeneration. Tubular degeneration/atrophy in the testis was seen at 10 U/kg/day and myocardial fibrosis was seen at ≥3.3 U/kg/day. Similar testicular and myocardial changes were seen in rats dosed with human insulin. No treatment-related changes in the incidence of hyperplastic or neoplastic lesions were seen in animals dosed with insulin icodec when compared to animals dosed with vehicle or NPH insulin. An NOAEL for insulin icodec could not be determined due to the axonal degeneration observed in animals given the lowest dose.

In a 26-week study with a 12-week recovery period, dogs were administered insulin icodec at doses of 1, 1.5, and 2 U/kg twice per week by subcutaneous (SC) injection. Decreased blood glucose levels caused clinical signs of hypoglycemia. The NOAEL was 2 U/kg twice weekly (0.6 times the exposure at 230 U/week). The no-observed-effect-level (NOEL) was below 1 U/kg twice weekly.

In a combined fertility and embryo-fetal development study, rats were administered insulin icodec by SC injection at doses of 6.7, 10, and 17 U/kg/day for males or 1.7, 5, and 10 U/kg/day for females. Rats were dosed prior to mating, and during gestation for pregnant females. Insulin icodec did not affect mating performance, fertility, or embryo-fetal development. The NOAEL was 17 U/kg/day for male fertility (4.3-times the exposure at the 230 U/week based on AUC). The NOAEL was 10 U/kg/day for female fertility and embryo-fetal development (1.5-times the exposure at the 230 U/week based on AUC).

In an embryo-fetal development study, pregnant rabbits were administered insulin icodec during gestation at doses of 1, 2, and 3 U/kg/day by SC injection. Abortion was observed in females given the highest dose. The finding was attributed to maternal metabolic stress. The NOAEL for maternal toxicity was 1 U/kg/day and the NOAEL for embryo-fetal development was 2 U/kg/day (0.5 and 1.2-times the exposure at 230 U/week based on AUC, respectively).

In a pre- and post-natal development study, rats were administered insulin icodec from gestation Day 6 to lactation Day 20 at doses of 3.3, 5.8, and 8.3 U/kg/day. At the highest dose, some F0 females experienced body weight loss. Clinical signs of hypoglycemia and increased mortality were reported in F1 pups. The mortality in the F1 generation could be due to a maternal effect of insulin icodec (e.g., reduced breast milk production) and subsequent malnourishment in pre-weaned pups. However, insulin icodec was detected in the plasma of some pups on lactation Day 11. The potential for direct metabolic effects of insulin icodec on neonatal hypoglycemia cannot be excluded. The developmental NOAEL was 5.8 U/kg/day (0.9-times the exposure at 230 U/week based on AUC).

For more information, refer to the Awiqli Product Monograph, approved by Health Canada and available through the Drug Product Database.

The Awiqli drug substance (insulin icodec) is an acylated analogue of human insulin with a prolonged half life of approximately one week due to its ability to reversibly bind to albumin. When insulin icodec binds to the human insulin receptor, it results in the same pharmacological effects as human insulin.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that insulin icodec consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The Awiqli drug substance (insulin icodec) is produced by recombinant deoxyribonucleic acid (DNA) technology in saccharomyces cerevisiae expression system.

The manufacturing process of the drug substance consists of a series of stages which include cell expansion, fermentation, recovery, concentration, and purification (including enzymatic and chemical modification steps). The materials used in the manufacture of the drug substance are considered suitable and meet standards appropriate for their intended use.

The manufacturing process for the drug product Awiqli consists of several steps of solution preparation, dissolution of the drug substance and mixing, followed by pH and volume adjustment during formulation. The formulated bulk solution then undergoes sterile filtration at the point-of-fill, and aseptic filling into 1.5 or 3.0 mL cartridges. The filled cartridges are closed with rubber plungers, sealed with aluminum caps, and inspected prior to assembly with the pen-injector components. The drug product cartridge and assembled pen-injector are then labelled, packaged, and stored at 2 ^oC to 8 ^oC.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of insulin icodec with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

The results of process validation studies showed that predefined acceptance criteria for parameters related to quality, efficacy, and safety are consistently met.

Awiqli is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through this program, final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 30 months when stored at 2 ^oC to 8 °C, including an open in-use period of 12 weeks when stored at room temperature (below 30 °C) or in a refrigerator (2 ^oC to 8 °C) is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance and drug product manufacturing facilities was not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The Awiqli drug substance (insulin icodec) is produced by recombinant DNA technology in a Saccharomyces cerevisiae expression system, which is not a natural host for mammalian viruses.

There are no materials of human or animal origin used during the manufacturing of insulin icodec.