Lilly's tirzepatide aces 5th phase 3, teeing up approval filings

Eli Lilly has completed a fifth global registration study of tirzepatide, teeing it up to seek approval of the dual GIP/GLP-1 agonist by the end of the year. All three doses of tirzepatide bettered the blood glucose reduction and weight loss seen in the insulin glargine arm of the latest phase 3 trial.

Lilly has guided tirzepatide through a series of late-phase tests in recent months, chalking up wins over drugs including insulin glargine — the active ingredient in products including Sanofi’s Lantus — and Novo Nordisk’s semaglutide along the way. The last of the five registration studies, SURPASS-4, delivered data from Type 2 diabetics with increased cardiovascular risk on Thursday that confirmed the efficacy seen in the earlier trials.

SURPASS-4 provided further evidence of the dose-dependent effects of tirzepatide on blood sugar and body weight. After 52 weeks, the proportion of patients across the three tirzepatide arms with A1C of 5.7% or less, the threshold for normal blood sugar, ranged from 23% to 43%, compared to 3% in the insulin glargine cohort. Weight reduction from baseline in the tirzepatide cohorts spanned 8% to 13%, while the insulin glargine group gained 2% over the course of the study.

Lilly used 52-week data in its analyses but kept dosing and tracking patients after that point to gather information about the cardiovascular safety of tirzepatide. As the completion of the study was based on the accrual of major adverse cardiovascular events, Lilly has up to two years of data on some of the 2,000 subjects, making SURPASS-4 the longest and largest of the registrational clinical trials. 

The cardiovascular events seen in SURPASS-4 formed the bulk of the 116 cases Lilly reviewed in a meta-analysis focused on death from cardiovascular or undetermined causes, myocardial infarction, stroke and hospitalization for unstable angina. 

Comparing tirzepatide to a pooled analysis of controls used across the studies, Lilly generated a hazard ratio of 0.81. The hazard ratio for SURPASS-4 was 0.74. Both hazard ratios have confidence intervals that are above 1 at the upper end, but favor tirzepatide. Lilly didn’t answer a question on its results conference call last month about whether it could still file if tirzepatide trended worse than the control, stating only that it is “very confident in its [cardiovascular] profile.”

Lilly illustrated its confidence last year by initiating a 12,500-subject cardiovascular outcome study. The study, which is set to run until 2024, will show how tirzepatide holds up against Trulicity in terms of major cardiovascular events. Compared to placebo, Trulicity had a hazard ratio of 0.88 in a large cardiovascular outcome trial Lilly ran from 2011 to 2018.