Summary Basis of Decision for Adlyxine

Clinical Pharmacology

Lixisenatide, the medicinal ingredient in Adlyxine, is a selective glucagon-like peptide-1 (GLP-1) receptor agonist. Lixisenatide increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying. These reduce the rate at which meal-derived glucose appears in the circulation. Overall, these effects contribute to reductions in fasting plasma glucose concentrations and post-prandial plasma glucose concentrations.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

In the presence of anti-drug antibodies (ADAs), the mean exposure to lixisenatide was increased approximately 5-fold, the mean apparent clearance was decreased, and there was a corresponding increase in the mean apparent half-life, compared to its pharmacokinetic parameters in the absence of ADAs in type 2 diabetes mellitus patients.

Lixisenatide was predominantly eliminated renally through glomerular filtration, followed by tubular reabsorption and subsequent proteolytic degradation, resulting in smaller peptides and amino acids.

Subcutaneous administration of lixisenatide in the abdomen, thigh or arm in obese subjects showed comparable pharmacokinetic profiles.

Age, sex, and race had no clinically meaningful effect on the pharmacokinetics of lixisenatide, based on a population pharmacokinetic analysis.

No dosing adjustment of lixisenatide is recommended in patients with renal impairment. Hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide, since lixisenatide is a peptide and it is predominantly eliminated renally.

Adlyxine delays gastric emptying, which may reduce the rate of absorption and increase the time to maximal concentrations of orally administered medications. No dosage adjustments are required, however, acetaminophen, atorvastatin, oral contraceptives and other medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, are recommended to be administered one hour before Adlyxine injection. In addition, closer monitoring of international normalized ratio (INR) is recommended when warfarin is co-administered with Adlyxine.

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

Clinical Efficacy

The clinical efficacy of Adlyxine in adult patients with type 2 diabetes mellitus was established primarily on the basis of data derived from 11 Phase III studies. Health Canada considered six placebo-controlled studies as pivotal in supporting the indications sought, including studies of Adlyxine as monotherapy, or as an add-on therapy to metformin, sulfonylurea (with or without metformin), pioglitazone (with or without metformin), or basal insulin (with or without metformin). Also assessed was the ELIXA study, a cardiovascular outcomes study required to establish the cardiovascular safety of Adlyxine in accordance with the Notice Regarding Interim Approach for Evaluating Cardiovascular Risk for New Antidiabetic Therapies to Treat Type 2 Diabetes Mellitus. The assessment of five supportive Phase III studies was aided by reference to the foreign reviews conducted by the United States Food and Drug Administration.

In the pivotal Phase III controlled studies, the main treatment period was 24 or 26 weeks, except for the monotherapy study where the treatment with Adlyxine lasted 12 weeks.

In six of the 11 Phase III controlled studies, at the end of the main treatment period, the use of Adlyxine was continued as a long-term, double-blind, placebo-controlled treatment (in five studies) or as an open-label active-controlled treatment (in one study).

Across the pivotal Phase III studies, the mean age of the study population ranged from approximately 54 years to 57 years. Proportions of patients aged 65 years or older were between 12.7% and 23.9%. A dedicated elderly study (GetGoal-O) only recruited patients 70 years of age or older. The proportion of males ranged from 43% to 52%. The proportion of Caucasian patients was between 52% and 90%, Asian patients between 4.5% and 45%, and Black patients between 0.8% and 4.8%. The patients' mean baseline body mass index ranged from 30 kg/m² to 34 kg/m² . In the monotherapy study, and the add-on to metformin or to pioglitazone studies, the mean baseline HbA1c ranged from 8.0% to 8.1%. In the add-on to sulfonylurea or to basal insulin studies, mean baseline HbA1c was between 8.2% and 8.4%. In the monotherapy study, which recruited treatment-naïve patients, the mean duration of diabetes mellitus was 2.5 years. The mean duration of diabetes mellitus in the other studies ranged from 6 to 12.4 years.

The primary efficacy endpoint of the Phase III efficacy trials was the change from baseline in HbA1c. A consistent and clinically meaningful mean reduction from baseline HbA1c at endpoint was observed across the six pivotal Phase III trials, as well as across the five Phase III supportive trials. In the pivotal studies, mean reductions from baseline HbA1c varied from -0.73% to -0.92%. The reductions were statistically significantly greater than in the placebo groups, with placebo-adjusted changes ranging from -0.36% to -0.74%. Decreases in HbA1c were generally paralleled by increases in the proportions of patients achieving a target HbA1c of <7.0%, which ranged from 28% to 52%.

In active comparator studies, the active comparator exenatide yielded a greater reduction in HbA1c than Adlyxine, although the observed difference fell below the prespecified non-inferiority margin of 0.4%. Similarly, the active comparator insulin glulisine (administered three times daily) resulted in a greater reduction in HbA1c than Adlyxine, when added to an insulin glargine background, but the difference met the prespecified non-inferiority margin. The change in HbA1c was comparable between Adlyxine and insulin glulisine administered once daily.

Adlyxine has an immunogenic potential. Approximately 70% of Adlyxine-treated patients developed ADAs by Week 24. There was a diminished glycemic response among the ADA-positive patients for whom antibody levels were quantifiable (roughly 20% of all treated patients). The observed decrease in glycemic response was greater with increasing ADA titers.

The secondary endpoints for glycemic control (post-prandial plasma glucose, and, to a lesser extent, fasting plasma glucose) generally demonstrated consistent results with the results reported for the primary efficacy endpoint.

The effect of Adlyxine on reduction in body weight was a secondary endpoint in all but one of the Phase III studies. In some studies, patients treated with Adlyxine experienced modest placebo-adjusted mean reductions in body weight (up to -1.28 kg) from baseline at Week 24 or 26.

Indication

The New Drug Submission for Adlyxine was filed by the sponsor with the following proposed indication:

• Adlyxine (lixisenatide) is indicated for once-daily administration as an adjunct to diet and exercise for treatment of adults with type 2 diabetes mellitus to achieve glycemic control in patients who are not controlled on existing therapy:
   
  • In combination with the following oral antidiabetics: metformin, a sulfonylurea, a thiazolidinedione, or a combination of these agents;
  • In combination with a basal insulin alone, or in combination with metformin, and/or in combination with a sulfonylurea.

To ensure safe and effective use of the product, Health Canada approved the following indication:

Adlyxine (lixisenatide injection) is indicated for use as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus in combination with:

• • metformin,
  • a sulfonylurea (alone or with metformin),
  • pioglitazone (alone or with metformin),
  • a basal insulin (alone or with metformin),

when the therapy listed above does not provide adequate glycemic control.

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

Clinical Safety

A total of 8,050 patients were exposed to Adlyxine across all Phase II/III clinical studies, including 6,631 patients in placebo-controlled studies. Of the patients in Phase II/III studies (excluding the study conducted in elderly patients), 6,000 patients (4,958 placebo-controlled) were exposed to Adlyxine for ≥24 weeks, 4,474 patients for ≥52 weeks, and 1,661 patients for ≥104 weeks.

In the Phase III placebo-controlled safety/efficacy studies, the most frequently reported adverse events which occurred more often in Adlyxine-treated patients than in placebo-treated patients were nausea (25.3%), vomiting (9.8%), hypoglycemia (13.7%), headache (8.5%), diarrhea (7.7%), and dizziness (6.7%). Hypoglycemia was reported chiefly in Adlyxine-treated patients already receiving a background regimen of a sulfonylurea with or without metformin (Adlyxine 14.5%, placebo 10.6%) or basal insulin with or without metformin (Adlyxine 28.3%, placebo 23%). The incidence of hypoglycemia was below 3% when Adlyxine was administered in combination with other regimens. The most common adverse events leading to discontinuation were nausea (2.8%) and vomiting (1.2%). Injection site reactions were common (Adlyxine 3.8%, placebo 1.6%).

Both injection site reactions and allergic reactions were more common in patients who developed ADAs than those without ADAs. In the clinical development program, a number of Adlyxine-treated patients developed independently adjudicated anaphylaxis reactions which could not be attributed to an alternative etiology.

The GLP-1 receptor agonists have been associated with post-marketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Similarly, cases of pancreatitis were reported in patients treated with Adlyxine during the clinical trials. A small numerical increase in cases of pancreatitis was observed in the Adlyxine-treated groups compared to placebo, however, the difference was not statistically significant (20/6,455 Adlyxine-treated patients versus 13/4,842 placebo-treated patients; exposure-adjusted relative risk versus placebo 1.25, 95% confidence interval [CI]: 0.62-2.61).

No clinical signal of an increased risk of thyroid neoplasms was seen in the Adlyxine clinical trials database. However, possibly clinically significant elevations of serum calcitonin, a marker of thyroid C-cell proliferation, were numerically more frequent in Adlyxine-treated patients.

No significantly increased incidence of adverse events related to acute renal failure was seen with Adlyxine use. Other GLP-1 receptor agonists have been associated with precipitation or exacerbation of renal failure, most often in the setting of drug-induced dehydration due to vomiting, diarrhea, and/or decreased oral intake.

In a randomized, double-blind, placebo-controlled clinical trial ELIXA, cardiovascular outcomes were evaluated during treatment with Adlyxine in patients with type 2 diabetes mellitus after a recent acute coronary syndrome event. The primary composite efficacy endpoint was the time to the first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. The trial was designed as a non-inferiority study with a prespecified risk margin of 1.3 for the hazard ratio comparing Adlyxine to placebo. The hazard ratio for Adlyxine versus placebo was 1.017, with a two-sided 95% CI of 0.886 to 1.168. The upper boundary of the CI excluded a risk margin larger than 1.3, thus demonstrating non-inferiority to placebo. A thorough electrocardiogram (ECG) QT study was also conducted, which demonstrated increases in heart rate and PR interval, as observed for other GLP-1 receptor agonists.

The identified safety concerns and uncertainties associated with Adlyxine, including anaphylaxis and serious hypersensitivity reactions, pancreatitis, gastrointestinal adverse reactions, hypoglycemia when used concomitantly with sulfonylurea or basal insulin, renal failure, immunogenicity, heart rate increase, PR interval prolongation, and risk of thyroid C-cell tumours have been appropriately addressed in the Adlyxine Product Monograph.

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