BRENZAVVY Cardiovascular Safety Profile
Meta-Analysis Design
In 2008, FDA published a Guidance for Industry that required sponsors to comply with standards to ensure the cardiovascular safety of products designed to treat diabetes. The Agency established two criteria: a pre-market threshold and a post-approval threshold. To satisfy the first criterion, the upper bound of the 95% confidence interval for the hazard ratio for major adverse cardiovascular events (MACE) caused by the product had to be less than 1.8. For the second criterion, the sponsor had to demonstrate that the upper bound was less than 1.3. The endpoint for the pre-approval standard could include more events than the endpoint for the post-approval standard.
The pre-specified analysis included all BRENZAVVY double-blind, controlled, phase 2 and phase 3 studies. The largest number of events were provided by phase 3 study THR-1442-C-476, which evaluated the safety and efficacy of BRENZAVVY in a population at increased risk for major adverse cardiovascular events. TheracosBio planned THR-1442-C-476 to meet the 1.8 criterion and intended to follow up with a second study if necessary. As a result, THR-1442-C-476 was relatively small, with 1699 evaluated subjects, compared to other SGLT2 inhibitor programs, which had up to 17160 participants. The trial was event-driven and planned to be continued until at least 134 events were recorded.
The primary objective of the meta-analysis was to demonstrate the upper limit of the two-sided 95% confidence interval of the hazard ratio of BRENZAVVY to placebo was below 1.8, for a composite endpoint consisting of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction and hospitalization for unstable angina (MACE+). The first key secondary objective was to demonstrate that the upper limit of the two-sided 95% confidence interval of the hazard ratio of BRENZAVVY to placebo was below 1.3 for a composite endpoint consisting of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction (MACE).
Study Population
The average age of patients included in the meta-analysis at baseline was 61.7 years with 41.3% of patients ≥ 65 years and 9.0% of patients ≥75 years. Patients had an average duration of diabetes of approximately 11.6 years, a mean baseline HbA1c level of 8.13%, and most patients (82.8%) had eGFR at baseline ≥ 60 mL min-1 per 1.73 m2 . Some patients reported a cardiovascular disease history including myocardial infarction (22.7%), arterial revascularization (22.8%), congestive heart failure (12.4%), and/or stroke (5.4%). Patients resided in North America (50.1%), Europe (33.3%), Asia (15.1%), and South America (1.5%).
Time to First Adjudicated MACE (3-event composite endpoint)
The hazard ratio for MACE for patients in the BRENZAVVY arm was 0.815 (95% CI 0.590, 1.125; p-value for noninferiority at 1.3 of 0.0023). Since the upper limit of the two-sided 95% confidence interval of the hazard ratio of BRENZAVVY to placebo was below 1.3, the hypothesis that BRENZAVVY would increase the risk of MACE by a factor of 1.3 or more was rejected.
BTime to First Adjudicated MACE+ (4-event composite endpoint)
The hazard ratio for MACE+ for patients in the BRENZAVVY arm compared to patients in the placebo arm was 0.795 (95% CI 0.578, 1.094; p-value for noninferiority at 1.8 < 0.0001). Since the upper limit of the two-sided 95% confidence interval was below 1.8, the noninferiority of BRENZAVVY to placebo for the pre-approval criterion was demonstrated.
Conclusions of the Meta-Analysis
A meta-analysis of major adverse cardiovascular events in the pre-approval program showed that both the pre-approval and post-approval requirements were met for BRENZAVVY. This was possible because the point estimates were substantially less than the value of 1.0 chosen for study planning purposes.
REFERENCES: 1. McMurray JJV, Solomon SD, Lock JP, et al. Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin. Diabetes Obes Metab. 2024;26(3):971-979.