Regulatory Decision Summary for BYDUREON

Information from the ongoing EXSCEL cardiovascular outcomes trial was reviewed and considered to address the concerns raised in the NOD.

Including all controlled and uncontrolled clinical studies and study extensions, 1,748 patients with T2DM of varying severity and treatment backgrounds were exposed to Bydureon for at least 26 weeks, 974 for at least 52 weeks and 699 for at least 104 weeks.

The efficacy evaluation was based primarily on the reduction in HbA1c from baseline in four phase III clinical trials. Study GWCH was a 26-week trial that compared Bydureon to the active comparators sitagliptin, metformin and pioglitazone, in patients on a background of diet and exercise only. Study BCB108, a 24-week trial and 2993LAR-105, a 30-week trial, compared Bydureon to Byetta, a twice daily formulation of exenatide, in patients on a background of diet and exercise alone or in combination with up to two oral antidiabetic agents, including metformin and/or a sulfonylurea. Study GWBR provided supportive evidence for the durability of efficacy relative to insulin glargine for up to 48 weeks in patients on a background of metformin with or without a sulfonylurea.

Data from these clinical studies showed that Bydureon resulted in a marked mean HbA1c reduction from baseline, statistically significant HbA1c decreases from baseline relative to sitagliptin, was non-inferior to metformin, and statistically significantly greater than Byetta.

The secondary efficacy endpoints were supportive of the primary endpoint, with a high proportion of patients achieving the therapeutic target of HbA1c <7.0% and reductions in fasting plasma glucose levels. In addition, Bydureon produced a sustained reduction in body weight, which is of clinical importance in this patient population.

Despite having comparable efficacy with that of metformin, Bydureon was not considered appropriate for first line use, as metformin has a long-history of use, robust efficacy, a well-known safety profile and ease of use. The monotherapy indication was amended to apply only to patients for whom metformin was inappropriate due to intolerance or contraindication.

While the clinical program did include patients on a background of pioglitazone, the evidence was not considered sufficient to warrant the proposed add-on indication with pioglitazone or add-on to pioglitazone and metformin.

Safety was based on the individual pivotal studies and on data pooled from the comprehensive clinical program.

More common adverse drug reactions included gastrointestinal and injection site reactions, which were generally mild to moderate in severity and self-limiting. Rare cases of serious local reactions, including necrosis and cellulitis, were reported. Patients who developed anti-exenatide antibodies were more likely to experience skin reactions than antibody negative or Byetta-treated patients.

No clear signal emerged for any serious adverse event, although uncertainties and concerns exist based on nonclinical data for medullary thyroid carcinoma, and a possible risk of pancreatitis, renal impairment and hypersensitivity based on post-market reports with exenatide.

Nonclinical data from a rat carcinogenicity study produced a statistically significant dose-dependent increase in thyroid C-cell tumours at clinically relevant doses, an effect seen with other drugs in the class of glucagon-like protein-1 receptor agonists and for which human relevance has not been determined.

Other potential safety concerns include an increased in heart rate, and a modest PR interval prolongation in the thorough QT study. The clinical significance of these findings is uncertain.

The clinical benefit and harm of Bydureon in patients with moderate renal impairment, women of childbearing potential, pregnant or nursing women, pediatrics and geriatrics have not been sufficiently studied.

Risk mitigation includes a risk management plan reviewed by the Marketed Health Products Directorate (MHPD) and labeling which adequately reflects the safety, efficacy and quality assessments, with added contraindications, serious warnings, and advice against use in poorly studied populations.

Long-term cardiovascular safety, electrocardiogram monitoring, the risk of pancreatic cancer and thyroid neoplasms will also be assessed in the ongoing long-term cardiovascular outcomes trial EXSCEL. The risk of medullary thyroid cancer will also be assessed in a registry of at least 15 years duration.

The overall benefit-harm-uncertainty profile of Bydureon is positive, including the added convenience of requiring only weekly injections.