Losmapimod failed to beat placebo in acute MI trial

Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.

Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.

“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.

Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.

Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).

The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”

Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.

GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.

Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.

Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.

“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.

Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.

Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).

The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”

Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.

GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.

Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.

Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.

“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.

Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.

Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).

The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”

Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.

GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.