Darapladib flunks another phase III trial

A drug designed to stabilize atherosclerotic plaques failed to reduce the risk of major coronary events when given to patients hospitalized with an acute coronary syndrome.

After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, myocardial infarction, or urgent coronary revascularization (16.3% vs. 15.6%). Nor did the drug confer any significant benefit when each of these outcomes was separately examined, Dr. Michelle L. O’Donoghue and her colleagues reported at the annual congress of the European Society of Cardiology. The study was simultaneously published online in the Journal of the American Medical Association (JAMA 2014 [doi:10.1001/jama.2014.11061]).

Subgroup analyses of the SOLID-TIMI 52 study also failed to identify any patient group that experienced any significant benefit in the composite or individual endpoints, reported Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, and her coauthors.

Darapladib is an investigational selective inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂); it has been shown to prevent the expansion of necrotic cores in atherosclerotic plaques.

The study randomized 13,026 patients to either darapladib 160 mg/day or placebo. They were a median of 64 years old; 75% were male. The initial acute coronary events were ST-elevation myocardial infarction (45%), non-ST-elevation MI (43%), and unstable angina (12%). Cardiac catheterization was common (86%), as was percutaneous coronary intervention (77%)

Nearly all patients were taking statins at baseline (95%). More than 85% were also taking other recommended therapies, including aspirin, beta-blockers, and antiplatelet agents.

By the end of the follow-up period, the primary combined endpoint had occurred in 903 patients in the active group and 910 in the placebo group (HR 1.00). The secondary endpoint (cardiovascular death, MI, or stroke) occurred in 824 taking darapladib and 838 taking placebo (15% each; HR 0.99).

Death occurred in 7% of each group (HR 0.94).

The authors conducted several subgroup analyses and failed to find a significant benefit regardless of age, geographical region, renal dysfunction or any other baseline comorbidities. Baseline low-density lipoprotein cholesterol had no interaction with outcomes.

Darapladib was considered safe; the incidence of any serious adverse events was similar to placebo (45% vs. 46%). Alamine aminotransferase elevations occurred in less than 1% of each group.

Adverse events leading to discontinuation occurred in 17% of the active group and 12% of the placebo group. This significant difference was mostly driven by body odor events in the darapladib group.

"Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group," at 11% vs. 2%, the authors noted.

These included skin odors (4% vs. 0.4%), urine odors (5% vs. 1%), and feces odors (8% vs. 1%). Diarrhea was also significantly more common among those taking the study drug (11% vs. 6%).

SOLID-TIMI 52 is the drug’s second failed phase III trial. The STABILITY study, which followed almost 16,000 patients for more than 3 years, also found that darapladib conferred no significant benefit in major cardiovascular outcomes.

These findings, combined with the current study, suggest that Lp-PLA₂ may not be a good therapeutic target for a population already sufficiently treated with plaque-stabilizing statins, Dr. O’Donoghue and her coauthors said. "In addition, although unlikely, the possibility that Lp-PLA remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study."

The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.

[email protected]

A drug designed to stabilize atherosclerotic plaques failed to reduce the risk of major coronary events when given to patients hospitalized with an acute coronary syndrome.

After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, myocardial infarction, or urgent coronary revascularization (16.3% vs. 15.6%). Nor did the drug confer any significant benefit when each of these outcomes was separately examined, Dr. Michelle L. O’Donoghue and her colleagues reported at the annual congress of the European Society of Cardiology. The study was simultaneously published online in the Journal of the American Medical Association (JAMA 2014 [doi:10.1001/jama.2014.11061]).

Subgroup analyses of the SOLID-TIMI 52 study also failed to identify any patient group that experienced any significant benefit in the composite or individual endpoints, reported Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, and her coauthors.

Darapladib is an investigational selective inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂); it has been shown to prevent the expansion of necrotic cores in atherosclerotic plaques.

The study randomized 13,026 patients to either darapladib 160 mg/day or placebo. They were a median of 64 years old; 75% were male. The initial acute coronary events were ST-elevation myocardial infarction (45%), non-ST-elevation MI (43%), and unstable angina (12%). Cardiac catheterization was common (86%), as was percutaneous coronary intervention (77%)

Nearly all patients were taking statins at baseline (95%). More than 85% were also taking other recommended therapies, including aspirin, beta-blockers, and antiplatelet agents.

By the end of the follow-up period, the primary combined endpoint had occurred in 903 patients in the active group and 910 in the placebo group (HR 1.00). The secondary endpoint (cardiovascular death, MI, or stroke) occurred in 824 taking darapladib and 838 taking placebo (15% each; HR 0.99).

Death occurred in 7% of each group (HR 0.94).

The authors conducted several subgroup analyses and failed to find a significant benefit regardless of age, geographical region, renal dysfunction or any other baseline comorbidities. Baseline low-density lipoprotein cholesterol had no interaction with outcomes.

Darapladib was considered safe; the incidence of any serious adverse events was similar to placebo (45% vs. 46%). Alamine aminotransferase elevations occurred in less than 1% of each group.

Adverse events leading to discontinuation occurred in 17% of the active group and 12% of the placebo group. This significant difference was mostly driven by body odor events in the darapladib group.

"Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group," at 11% vs. 2%, the authors noted.

These included skin odors (4% vs. 0.4%), urine odors (5% vs. 1%), and feces odors (8% vs. 1%). Diarrhea was also significantly more common among those taking the study drug (11% vs. 6%).

SOLID-TIMI 52 is the drug’s second failed phase III trial. The STABILITY study, which followed almost 16,000 patients for more than 3 years, also found that darapladib conferred no significant benefit in major cardiovascular outcomes.

These findings, combined with the current study, suggest that Lp-PLA₂ may not be a good therapeutic target for a population already sufficiently treated with plaque-stabilizing statins, Dr. O’Donoghue and her coauthors said. "In addition, although unlikely, the possibility that Lp-PLA remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study."

The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.

[email protected]

A drug designed to stabilize atherosclerotic plaques failed to reduce the risk of major coronary events when given to patients hospitalized with an acute coronary syndrome.

After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, myocardial infarction, or urgent coronary revascularization (16.3% vs. 15.6%). Nor did the drug confer any significant benefit when each of these outcomes was separately examined, Dr. Michelle L. O’Donoghue and her colleagues reported at the annual congress of the European Society of Cardiology. The study was simultaneously published online in the Journal of the American Medical Association (JAMA 2014 [doi:10.1001/jama.2014.11061]).

Subgroup analyses of the SOLID-TIMI 52 study also failed to identify any patient group that experienced any significant benefit in the composite or individual endpoints, reported Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, and her coauthors.

Darapladib is an investigational selective inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂); it has been shown to prevent the expansion of necrotic cores in atherosclerotic plaques.

The study randomized 13,026 patients to either darapladib 160 mg/day or placebo. They were a median of 64 years old; 75% were male. The initial acute coronary events were ST-elevation myocardial infarction (45%), non-ST-elevation MI (43%), and unstable angina (12%). Cardiac catheterization was common (86%), as was percutaneous coronary intervention (77%)

Nearly all patients were taking statins at baseline (95%). More than 85% were also taking other recommended therapies, including aspirin, beta-blockers, and antiplatelet agents.

By the end of the follow-up period, the primary combined endpoint had occurred in 903 patients in the active group and 910 in the placebo group (HR 1.00). The secondary endpoint (cardiovascular death, MI, or stroke) occurred in 824 taking darapladib and 838 taking placebo (15% each; HR 0.99).

Death occurred in 7% of each group (HR 0.94).

The authors conducted several subgroup analyses and failed to find a significant benefit regardless of age, geographical region, renal dysfunction or any other baseline comorbidities. Baseline low-density lipoprotein cholesterol had no interaction with outcomes.

Darapladib was considered safe; the incidence of any serious adverse events was similar to placebo (45% vs. 46%). Alamine aminotransferase elevations occurred in less than 1% of each group.

Adverse events leading to discontinuation occurred in 17% of the active group and 12% of the placebo group. This significant difference was mostly driven by body odor events in the darapladib group.

"Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group," at 11% vs. 2%, the authors noted.

These included skin odors (4% vs. 0.4%), urine odors (5% vs. 1%), and feces odors (8% vs. 1%). Diarrhea was also significantly more common among those taking the study drug (11% vs. 6%).

SOLID-TIMI 52 is the drug’s second failed phase III trial. The STABILITY study, which followed almost 16,000 patients for more than 3 years, also found that darapladib conferred no significant benefit in major cardiovascular outcomes.

These findings, combined with the current study, suggest that Lp-PLA₂ may not be a good therapeutic target for a population already sufficiently treated with plaque-stabilizing statins, Dr. O’Donoghue and her coauthors said. "In addition, although unlikely, the possibility that Lp-PLA remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study."

The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.

[email protected]