Phase III trial met primary endpoint, significantly reducing blood sugar (HbA1c) versus placebo
The first trial to assess a once weekly glucagon-like peptide-1 receptor agonist in adolescents aged 10–17 with type 2 diabetes
WILMINGTON, Del., June 25, 2021 – Positive results from the Phase III pivotal trial (NCT01554618) showed AstraZeneca’s exenatide extended-release 2mg once weekly significantly reduced blood sugar—as measured by HbA1c—versus placebo in adolescents aged 10–17 with type 2 diabetes (T2D).
This Phase III trial is the first and only completed trial of a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) in adolescents aged 10–17 with T2D. The results were presented today at the 2021 American Diabetes Association (ADA) Virtual 81st Scientific Sessions.
The trial met its primary endpoint, demonstrating that exenatide once weekly significantly reduced HbA1c from baseline compared with placebo at 24 weeks, with least squares (LS) mean changes of −0.36% and +0.49%, respectively and a between-group LS mean difference of −0.85% (P=0.012).
Data at week 24 also showed that exenatide once weekly was generally well tolerated and consistent with the existing safety profile in adults. The most common adverse events were upper respiratory tract infections (10% in the exenatide group) and abdominal pain (13% in the placebo group). Gastrointestinal disorders were reported less frequently in the exenatide once weekly group than in the placebo group (22% vs. 26%).
James Ruggles, BYDUREON Medical Lead, said: “We’re greatly encouraged by these results in adolescents with type 2 diabetes. We hope that, once approved, exenatide once weekly will serve as a much needed convenient treatment option for adolescent patients.”
The International Coordinating Investigator of the trial, William Tamborlane, MD, Department of Pediatrics, Yale School of Medicine, said: “T2D is a chronic disease that can lead to serious long-term issues if not adequately treated in children. The rise in frequency of this disorder in pediatric patients corresponds to the international epidemic of childhood obesity, resulting in increased insulin resistance and beta cell disfunction in adolescents. It is particularly noteworthy that no once weekly injection of a GLP-1 receptor agonist has been approved for older children or adolescents with T2D by the US Food and Drug Administration. Consequently, once weekly injections of exenatide could fill that gap in treatment options for T2D patients in this age group.”
Secondary endpoints for the trial included proportion of participants with HbA1c < 7.0% at week 24, change in fasting glucose, and change in body weight. A significantly higher proportion of patients receiving exenatide once weekly met the <7% HbA1c glycemic target versus placebo (31% vs. 8.3%; P=0.02). Nonsignificant between-group LS mean differences from baseline to 24 weeks favoring exenatide once weekly versus placebo were observed for fasting glucose (-21.6 mg/dL; P=0.119) and body weight (-1.22 kg; P=0.307). Overall, the adverse events in this adolescent population were consistent with those observed in the adult population.
Exenatide extended release was first approved in the US as a once-weekly treatment for T2D in adults in January 2012, with the latest formulation BYDUREON BCise approved in October 2017. Additionally, the FDA granted AstraZeneca a priority review for its supplemental new drug application for the use of exenatide in adolescents 10–17 years old.
In the US, exenatide is currently indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D.
INDICATION AND LIMITATIONS OF USE
BYDUREON BCise is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- Not recommended as first-line therapy for patients inadequately controlled on diet and exercise
- Should not be used to treat type 1 diabetes
- Do not coadminister with other exenatide-containing products
- Not studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF THYROID C-CELL TUMORS
- Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON BCise causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined
- BYDUREON BCise is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of BYDUREON BCise and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for detection of MTC in patients treated with BYDUREON BCise
- Personal or family history of MTC, patients with MEN 2
- Prior serious hypersensitivity reactions to exenatide or product components
- History of drug-induced, immune-mediated thrombocytopenia from exenatide products
WARNINGS AND PRECAUTIONS
- Acute Pancreatitis including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been reported. After initiation, observe patients carefully for symptoms of pancreatitis. If suspected, discontinue promptly and do not restart if confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis
- Hypoglycemia Risk of hypoglycemia, including severe hypoglycemia, is increased when exenatide is coadministered with insulin or insulin secretagogues. Consider lowering the dose of these agents when coadministered with BYDUREON BCise
- Acute Kidney Injury May induce nausea and vomiting with transient hypovolemia and may worsen renal function. Increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation have been reported. Not recommended in patients with eGFR <45 mL/min/1.73 m2
- Gastrointestinal Disease Because exenatide is commonly associated with gastrointestinal adverse reactions, not recommended in patients with severe gastrointestinal disease (eg, gastroparesis)
- Immunogenicity Patients may develop antibodies to exenatide. Patients with higher titer antibodies may have an attenuated HbA1c response. In clinical trials, attenuated glycemic response was associated with BYDUREON BCise-treated patients. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy
- Hypersensitivity Reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYDUREON BCise and promptly seek medical advice
- Drug-induced, immune-mediated thrombocytopenia and associated bleeding has been reported with exenatide. Serious bleeding, which may be fatal, has been reported. Discontinue promptly if suspected and avoid re-exposure to exenatide
- Injection-Site Reactions Serious reactions (eg, abscess, cellulitis, and necrosis), with or without subcutaneous nodules, have been reported
- Acute Gallbladder Disease has been reported in GLP-1 receptor agonist trials, including exenatide. If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated
Most common (≥5%) in clinical trials: injection-site nodule (10.5%), nausea (8.2%).
- Oral Medications BYDUREON BCise slows gastric emptying and may reduce the rate of absorption of orally administered drugs
- Warfarin Increased international normalized ratio (INR) sometimes associated with bleeding has been reported with concomitant use of exenatide with warfarin. Monitor INR frequently until stable upon initiation of BYDUREON BCise
Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Type 2 Diabetes
T2D is a chronic disease characterized by pathophysiologic defects leading to elevated glucose levels, or hyperglycemia. Over time, this sustained hyperglycemia contributes to further progression of the disease. The prevalence of diabetes is projected to reach 578 million people worldwide by 2030 and 700 million by 2045. T2D accounts for approximately 90%–95% of all cases of diagnosed diabetes.
The incidence of T2D in children and adolescents is increasing worldwide, possibly due to the obesity epidemic.
Phase III trial (NCT01554618)
This is a Phase III, double-blind, placebo-controlled, randomized, multi-center, parallel trial assessing the safety and efficacy of exenatide compared to placebo in adolescents (between the ages of 10 and <18 years) with T2D. It is the first completed trial of a once-weekly GLP-1 RA in adolescents aged 10–17 with T2D. The trial included 83 adolescents aged 10–17 treated with diet and exercise alone or in combination with an oral antidiabetic agent (metformin and/or sulfonylurea [SU]) and/or insulin. As clinical studies have demonstrated that once-weekly exenatide improved glycemic control in adults with T2D, the Phase III trial was designed to evaluate the effects of exenatide on glycemic control in adolescents aged 10–17 with T2D.
AstraZeneca in CV, Renal & Metabolism
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