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LATITUDE–TIMI 60: Losmapimod does not reduce CV events in patients with acute MI
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CHICAGO — Patients with acute MI did not benefit from losmapimod, a p38 mitogen-activated protein kinase inhibitor, according to results from the first part of the LATITUDE–TIMI 60 study.
In a phase 2 study, losmapimod (GlaxoSmithKline) improved inflammation, but that did not translate into improved CV outcomes for patients with acute MI in the first part of the phase 3 LATITUDE–TIMI 60 trial, which was presented at the American College of Cardiology Scientific Session and published in JAMA.
Michelle L. O’Donoghue, MD, MPH, cardiologist and investigator with the TIMI Study Group, cardiovascular division, Brigham and Women’s Hospital, and colleagues conducted a randomized, placebo-controlled, double blind, parallel-group trial that was scheduled to have two stages.
Michelle L. O’Donoghue
In the first phase, presented at ACC 2016, 3,503 patients (median age, 66 years; 30% women; 25% with STEMI) with acute MI and at least one other CV risk factor were randomly assigned losmapimod 7.5 mg twice daily or placebo in addition to guideline-recommended therapy. The second phase was to have randomized up to 22,000 patients, but GlaxoSmithKline announced in October 2015 that this phase will not go forward as planned.
The primary endpoint was a composite of CV death, MI or severe recurrent ischemia requiring revascularization at 12 weeks. The investigators followed the patients for an additional 12 weeks.
During a press conference, O’Donoghue said 7% of those assigned placebo and 8.1% of those assigned losmapimod experienced the primary endpoint at 12 weeks (HR = 1.16; 95% CI, 0.97-1.24).
There was no difference between the groups in the key secondary endpoint of CV death or MI at 12 weeks (HR = 1.13; 95% CI, 0.88-1.47). No other secondary endpoints showed any benefit associated with losmapimod, according to the researchers, who noted that the 24-week results were similar to the 12-week results.
At 24 weeks, the rate of on-treatment serious adverse events was 16% in the losmapimod group and 14.2% in the placebo group.
O’Donoghue said there there could be consideration to further investigate losmapimod in patients with STEMI, since they appeared to have some suggestion of benefit compared with those with non-STEMI (primary endpoint for STEMI: HR = 0.84; 95% CI, 0.51-1.4; primary endpoint for non-STEMI: HR = 1.27; 95% CI, 0.96-1.68). However, she noted, that would require a new trial.
“Losmapimod did have a significant effect on biomarkers of inflammation, as demonstrated by the reduction in C-reactive protein, both during the acute phase of early hospitalization and also sustained during treatment,” she said at the press conference. “This did not translate into a reduction in CV events.” – by Erik Swain
Reference s :
O’Donoghue ML, et al. Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
O’Donoghue ML, et al. JAMA. 2016;doi:10.1001/jama.2016.3609.
Disclosure: The study was funded by GlaxoSmithKline. O’Donoghue reports receiving grants from AstraZeneca, Eisai and Merck. Please see the full study for a list of the other researchers’ relevant financial disclosures.
Perspective
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Athena Poppas, MD, FACC
These findings were surprising because there were promising pre-trial data and some signals in other areas. This study tells us that some soft endpoints such as biomarkers are a good way to screen drugs, but the hard endpoints are where the proof has to be. There were some compelling findings in patients with STEMI, so that might be a good place to focus future efforts.
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