Purified Fish Oil Formulation Cuts Triglycerides

ORLANDO – A 12-week treatment regimen with a purified formulation of fish oil led to a greater-than-20% reduction of elevated triglyceride levels, as well as other favorable lipid changes, in a phase III, randomized, placebo-controlled trial in about 700 patients.

"AMR101, pure eicosapentaenoic acid, at both 4 g/day and 2 g/day significantly reduced triglyceride levels in statin-treated patients with optimized low-density lipoprotein cholesterol levels and persistently elevated triglyceride levels," Dr. Christie M. Ballantyne said at the annual scientific sessions of the American Heart Association. The results he reported from the ANCHOR trial came from a group of 702 patients who had high cardiovascular disease risk and were on "optimized" statin therapy, with an LDL cholesterol level of 100 mg/dL or less, but with a triglyceride level of 200-500 mg/dL.

Although the highest dosage of AMR101 tested (4 g/day) produced an average 22% reduction in triglyceride level beyond the placebo effect after 12 weeks of treatment, the clinical benefit from this triglyceride reduction remains uncertain until results accrue from a longer-term study that has clinical end points but is only now starting, he added.

"The key issue is, What does this mean for outcomes?" said Dr. Ballantyne, professor of medicine and pediatrics and chief of the section of atherosclerosis and vascular medicine at Baylor College of Medicine in Houston. "Omega-3 fatty acids have proven safety, but the question is, What will be the event reduction? There was prior evidence for efficacy in ... JELIS [Japan EPA Lipid Intervention Study]. I think the odds are higher for this working than for many other treatments," he said in an interview. But, he acknowledged, "no one has ever done a trial on patients with elevated triglycerides."

JELIS enrolled more than 18,000 men and postmenopausal women, both with and without documented coronary artery disease, who had a total cholesterol level of at least 6.5 mmol/L (251 mg/dL), and an LDL cholesterol level of at least 4.4 mmol/L (171 mg/dL). JELIS randomized patients to treatment with either a statin alone or a statin plus 1.8 g/day eicosapentaenoic acid (EPA), purified from omega-3 fatty acids in fish oil. After an average follow-up of 4.6 years, people in the combined statin-plus-EPA group had a 2.8% incidence of a major coronary event, compared with a 3.5% rate in those who were treated with a statin only, a 19% relative risk reduction that was statistically significant (Lancet 2007;369:1090-8). According to Dr. Ballantyne and others, the JELIS result remains the only evidence documenting that treatment with EPA can reduce the incidence of coronary events, although JELIS did not specifically enroll patients with elevated triglyceride levels at baseline.

"There is no evidence" that lowering triglycerides cuts coronary events, agreed Dr. Eliot A. Brinton, director of atherometabolic research at the Utah Foundation for Biomedical Research in Salt Lake City. "Results from five fibrate treatment trials were all suggestive that lowering triglycerides led to reduced events. And the JELIS results showed clinical benefit with fish oil and greater benefit in people who entered with high triglycerides and low levels of HDL cholesterol. The EPA [that was] used in JELIS was essentially the same drug as AMR101," a highly purified form of EPA, Dr. Brinton said in an interview. "But we won’t know what AMR101 will do for events until we do a study," added Dr. Brinton, who is on the steering committee for the AMR101 clinical trial scheduled to soon begin.

"I think we have a very good chance of showing benefit. It’s very exciting. If any drug can show a statistically significant benefit on top of a statin, it will be a huge step forward," Dr. Brinton commented.

In September, Amarin, the company developing AMR101, announced that it had filed a New Drug Application with the Food and Drug Administration seeking marketing approval for AMR101 for treating elevated triglyceride levels, based on both the ANCHOR results and the results of a similarly designed study, the MARINE (Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With an Open-Label Extension) trial, which randomized 229 patients with fasting triglyceride levels of at least 500 mg/dL (average baseline level, about 680 mg/dL) to treatment with either the 4-g/day or 2-g/day dosages of AMR101 or placebo. Results from the MARINE study, published in September, showed that after 12 weeks the 4-g/day dosage of AMR101 led to an average 45% placebo-corrected cut in triglycerides (Am. J. Cardiol. 2011;108:682-90).

The clinical end point trial – REDUCE-IT (Reduction of Cardiovascular Events With EPA–Intervention Trial) – that Amarin plans for AMR101 will enroll about 8,000 patients with elevated triglycerides and will last for 6 years. However, Amarin announced last August that it arranged a Special Protocol Assessment with the FDA that may allow the FDA to approve AMR101 for treating the mixed dyslipidemia patients who are enrolled in ANCHOR before the REDUCE-IT trial is completed.

The ANCHOR trial ran at 97 U.S. sites, and enrolled patients who were, on average, 61 years old, 61% of whom were men. Their average body mass index was 33 kg/m² and 73% had diabetes. Some 63% were on a "medium" efficacy statin regimen, 30% were on a "high" efficacy regimen, and 7% were on a "low" efficacy statin regimen. The study’s primary end point was the change in triglyceride level, compared with placebo treatment, and the secondary end points included the change in LDL cholesterol, compared with placebo.

The 4-g/day dosage produced an average placebo-corrected 21.5% reduction in triglyceride level, an average 6.2% cut in LDL cholesterol, an average 13.6% decrease in non-HDL cholesterol, and an average 4.9% reduction in HDL cholesterol, all statistically significant changes. The 2-g/day dosage produced smaller placebo-corrected reductions, including a 10.1% cut in triglycerides that was statistically significant, and a nonsignificant 3.6% decrease in LDL cholesterol. The results also showed that triglyceride reductions were larger in patients who started with higher triglyceride levels at baseline, and in patients on higher-efficacy statin regimens, Dr. Ballantyne reported.

Both EPA dosages tested were well tolerated, with adverse effects that were mild to moderate and most appearing to be unrelated to the study medication. "In general, omega-3 fatty acids have been very well tolerated and very safe in numerous studies over many years," Dr. Ballantyne said. "GI tolerability was quite good, but the taste issue remains," he said.

Dr. Ballantyne said that he currently prescribes EPA to some of his patients. He prefers to prescribe Lovaza (a brand-name, prescription-only formulation of omega-3 fatty acid ethyl esters that contains both EPA and docosahexaenoic acid) because it is a "high quality agent," he said in an interview. "If a patient cannot afford that, we give them tips on how to purchase high-quality supplement" formulations of omega-3 fatty acids, he added.

ANCHOR was sponsored by Amarin, the company developing AMR101. Dr. Ballantyne said that he has been a consultant for Amarin and has consulted for, received honoraria from, and/or been a speaker for numerous other pharmaceutical companies. Dr. Brinton said that he has been a consultant to Amarin and has also consulted for and/or been a speaker for several other firms.

ORLANDO – A 12-week treatment regimen with a purified formulation of fish oil led to a greater-than-20% reduction of elevated triglyceride levels, as well as other favorable lipid changes, in a phase III, randomized, placebo-controlled trial in about 700 patients.

"AMR101, pure eicosapentaenoic acid, at both 4 g/day and 2 g/day significantly reduced triglyceride levels in statin-treated patients with optimized low-density lipoprotein cholesterol levels and persistently elevated triglyceride levels," Dr. Christie M. Ballantyne said at the annual scientific sessions of the American Heart Association. The results he reported from the ANCHOR trial came from a group of 702 patients who had high cardiovascular disease risk and were on "optimized" statin therapy, with an LDL cholesterol level of 100 mg/dL or less, but with a triglyceride level of 200-500 mg/dL.

Although the highest dosage of AMR101 tested (4 g/day) produced an average 22% reduction in triglyceride level beyond the placebo effect after 12 weeks of treatment, the clinical benefit from this triglyceride reduction remains uncertain until results accrue from a longer-term study that has clinical end points but is only now starting, he added.

"The key issue is, What does this mean for outcomes?" said Dr. Ballantyne, professor of medicine and pediatrics and chief of the section of atherosclerosis and vascular medicine at Baylor College of Medicine in Houston. "Omega-3 fatty acids have proven safety, but the question is, What will be the event reduction? There was prior evidence for efficacy in ... JELIS [Japan EPA Lipid Intervention Study]. I think the odds are higher for this working than for many other treatments," he said in an interview. But, he acknowledged, "no one has ever done a trial on patients with elevated triglycerides."

JELIS enrolled more than 18,000 men and postmenopausal women, both with and without documented coronary artery disease, who had a total cholesterol level of at least 6.5 mmol/L (251 mg/dL), and an LDL cholesterol level of at least 4.4 mmol/L (171 mg/dL). JELIS randomized patients to treatment with either a statin alone or a statin plus 1.8 g/day eicosapentaenoic acid (EPA), purified from omega-3 fatty acids in fish oil. After an average follow-up of 4.6 years, people in the combined statin-plus-EPA group had a 2.8% incidence of a major coronary event, compared with a 3.5% rate in those who were treated with a statin only, a 19% relative risk reduction that was statistically significant (Lancet 2007;369:1090-8). According to Dr. Ballantyne and others, the JELIS result remains the only evidence documenting that treatment with EPA can reduce the incidence of coronary events, although JELIS did not specifically enroll patients with elevated triglyceride levels at baseline.

"There is no evidence" that lowering triglycerides cuts coronary events, agreed Dr. Eliot A. Brinton, director of atherometabolic research at the Utah Foundation for Biomedical Research in Salt Lake City. "Results from five fibrate treatment trials were all suggestive that lowering triglycerides led to reduced events. And the JELIS results showed clinical benefit with fish oil and greater benefit in people who entered with high triglycerides and low levels of HDL cholesterol. The EPA [that was] used in JELIS was essentially the same drug as AMR101," a highly purified form of EPA, Dr. Brinton said in an interview. "But we won’t know what AMR101 will do for events until we do a study," added Dr. Brinton, who is on the steering committee for the AMR101 clinical trial scheduled to soon begin.

"I think we have a very good chance of showing benefit. It’s very exciting. If any drug can show a statistically significant benefit on top of a statin, it will be a huge step forward," Dr. Brinton commented.

In September, Amarin, the company developing AMR101, announced that it had filed a New Drug Application with the Food and Drug Administration seeking marketing approval for AMR101 for treating elevated triglyceride levels, based on both the ANCHOR results and the results of a similarly designed study, the MARINE (Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With an Open-Label Extension) trial, which randomized 229 patients with fasting triglyceride levels of at least 500 mg/dL (average baseline level, about 680 mg/dL) to treatment with either the 4-g/day or 2-g/day dosages of AMR101 or placebo. Results from the MARINE study, published in September, showed that after 12 weeks the 4-g/day dosage of AMR101 led to an average 45% placebo-corrected cut in triglycerides (Am. J. Cardiol. 2011;108:682-90).

The clinical end point trial – REDUCE-IT (Reduction of Cardiovascular Events With EPA–Intervention Trial) – that Amarin plans for AMR101 will enroll about 8,000 patients with elevated triglycerides and will last for 6 years. However, Amarin announced last August that it arranged a Special Protocol Assessment with the FDA that may allow the FDA to approve AMR101 for treating the mixed dyslipidemia patients who are enrolled in ANCHOR before the REDUCE-IT trial is completed.

The ANCHOR trial ran at 97 U.S. sites, and enrolled patients who were, on average, 61 years old, 61% of whom were men. Their average body mass index was 33 kg/m² and 73% had diabetes. Some 63% were on a "medium" efficacy statin regimen, 30% were on a "high" efficacy regimen, and 7% were on a "low" efficacy statin regimen. The study’s primary end point was the change in triglyceride level, compared with placebo treatment, and the secondary end points included the change in LDL cholesterol, compared with placebo.

The 4-g/day dosage produced an average placebo-corrected 21.5% reduction in triglyceride level, an average 6.2% cut in LDL cholesterol, an average 13.6% decrease in non-HDL cholesterol, and an average 4.9% reduction in HDL cholesterol, all statistically significant changes. The 2-g/day dosage produced smaller placebo-corrected reductions, including a 10.1% cut in triglycerides that was statistically significant, and a nonsignificant 3.6% decrease in LDL cholesterol. The results also showed that triglyceride reductions were larger in patients who started with higher triglyceride levels at baseline, and in patients on higher-efficacy statin regimens, Dr. Ballantyne reported.

Both EPA dosages tested were well tolerated, with adverse effects that were mild to moderate and most appearing to be unrelated to the study medication. "In general, omega-3 fatty acids have been very well tolerated and very safe in numerous studies over many years," Dr. Ballantyne said. "GI tolerability was quite good, but the taste issue remains," he said.

Dr. Ballantyne said that he currently prescribes EPA to some of his patients. He prefers to prescribe Lovaza (a brand-name, prescription-only formulation of omega-3 fatty acid ethyl esters that contains both EPA and docosahexaenoic acid) because it is a "high quality agent," he said in an interview. "If a patient cannot afford that, we give them tips on how to purchase high-quality supplement" formulations of omega-3 fatty acids, he added.

ANCHOR was sponsored by Amarin, the company developing AMR101. Dr. Ballantyne said that he has been a consultant for Amarin and has consulted for, received honoraria from, and/or been a speaker for numerous other pharmaceutical companies. Dr. Brinton said that he has been a consultant to Amarin and has also consulted for and/or been a speaker for several other firms.

ORLANDO – A 12-week treatment regimen with a purified formulation of fish oil led to a greater-than-20% reduction of elevated triglyceride levels, as well as other favorable lipid changes, in a phase III, randomized, placebo-controlled trial in about 700 patients.

"AMR101, pure eicosapentaenoic acid, at both 4 g/day and 2 g/day significantly reduced triglyceride levels in statin-treated patients with optimized low-density lipoprotein cholesterol levels and persistently elevated triglyceride levels," Dr. Christie M. Ballantyne said at the annual scientific sessions of the American Heart Association. The results he reported from the ANCHOR trial came from a group of 702 patients who had high cardiovascular disease risk and were on "optimized" statin therapy, with an LDL cholesterol level of 100 mg/dL or less, but with a triglyceride level of 200-500 mg/dL.

Although the highest dosage of AMR101 tested (4 g/day) produced an average 22% reduction in triglyceride level beyond the placebo effect after 12 weeks of treatment, the clinical benefit from this triglyceride reduction remains uncertain until results accrue from a longer-term study that has clinical end points but is only now starting, he added.

"The key issue is, What does this mean for outcomes?" said Dr. Ballantyne, professor of medicine and pediatrics and chief of the section of atherosclerosis and vascular medicine at Baylor College of Medicine in Houston. "Omega-3 fatty acids have proven safety, but the question is, What will be the event reduction? There was prior evidence for efficacy in ... JELIS [Japan EPA Lipid Intervention Study]. I think the odds are higher for this working than for many other treatments," he said in an interview. But, he acknowledged, "no one has ever done a trial on patients with elevated triglycerides."

JELIS enrolled more than 18,000 men and postmenopausal women, both with and without documented coronary artery disease, who had a total cholesterol level of at least 6.5 mmol/L (251 mg/dL), and an LDL cholesterol level of at least 4.4 mmol/L (171 mg/dL). JELIS randomized patients to treatment with either a statin alone or a statin plus 1.8 g/day eicosapentaenoic acid (EPA), purified from omega-3 fatty acids in fish oil. After an average follow-up of 4.6 years, people in the combined statin-plus-EPA group had a 2.8% incidence of a major coronary event, compared with a 3.5% rate in those who were treated with a statin only, a 19% relative risk reduction that was statistically significant (Lancet 2007;369:1090-8). According to Dr. Ballantyne and others, the JELIS result remains the only evidence documenting that treatment with EPA can reduce the incidence of coronary events, although JELIS did not specifically enroll patients with elevated triglyceride levels at baseline.

"There is no evidence" that lowering triglycerides cuts coronary events, agreed Dr. Eliot A. Brinton, director of atherometabolic research at the Utah Foundation for Biomedical Research in Salt Lake City. "Results from five fibrate treatment trials were all suggestive that lowering triglycerides led to reduced events. And the JELIS results showed clinical benefit with fish oil and greater benefit in people who entered with high triglycerides and low levels of HDL cholesterol. The EPA [that was] used in JELIS was essentially the same drug as AMR101," a highly purified form of EPA, Dr. Brinton said in an interview. "But we won’t know what AMR101 will do for events until we do a study," added Dr. Brinton, who is on the steering committee for the AMR101 clinical trial scheduled to soon begin.

"I think we have a very good chance of showing benefit. It’s very exciting. If any drug can show a statistically significant benefit on top of a statin, it will be a huge step forward," Dr. Brinton commented.

In September, Amarin, the company developing AMR101, announced that it had filed a New Drug Application with the Food and Drug Administration seeking marketing approval for AMR101 for treating elevated triglyceride levels, based on both the ANCHOR results and the results of a similarly designed study, the MARINE (Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With an Open-Label Extension) trial, which randomized 229 patients with fasting triglyceride levels of at least 500 mg/dL (average baseline level, about 680 mg/dL) to treatment with either the 4-g/day or 2-g/day dosages of AMR101 or placebo. Results from the MARINE study, published in September, showed that after 12 weeks the 4-g/day dosage of AMR101 led to an average 45% placebo-corrected cut in triglycerides (Am. J. Cardiol. 2011;108:682-90).

The clinical end point trial – REDUCE-IT (Reduction of Cardiovascular Events With EPA–Intervention Trial) – that Amarin plans for AMR101 will enroll about 8,000 patients with elevated triglycerides and will last for 6 years. However, Amarin announced last August that it arranged a Special Protocol Assessment with the FDA that may allow the FDA to approve AMR101 for treating the mixed dyslipidemia patients who are enrolled in ANCHOR before the REDUCE-IT trial is completed.

The ANCHOR trial ran at 97 U.S. sites, and enrolled patients who were, on average, 61 years old, 61% of whom were men. Their average body mass index was 33 kg/m² and 73% had diabetes. Some 63% were on a "medium" efficacy statin regimen, 30% were on a "high" efficacy regimen, and 7% were on a "low" efficacy statin regimen. The study’s primary end point was the change in triglyceride level, compared with placebo treatment, and the secondary end points included the change in LDL cholesterol, compared with placebo.

The 4-g/day dosage produced an average placebo-corrected 21.5% reduction in triglyceride level, an average 6.2% cut in LDL cholesterol, an average 13.6% decrease in non-HDL cholesterol, and an average 4.9% reduction in HDL cholesterol, all statistically significant changes. The 2-g/day dosage produced smaller placebo-corrected reductions, including a 10.1% cut in triglycerides that was statistically significant, and a nonsignificant 3.6% decrease in LDL cholesterol. The results also showed that triglyceride reductions were larger in patients who started with higher triglyceride levels at baseline, and in patients on higher-efficacy statin regimens, Dr. Ballantyne reported.

Both EPA dosages tested were well tolerated, with adverse effects that were mild to moderate and most appearing to be unrelated to the study medication. "In general, omega-3 fatty acids have been very well tolerated and very safe in numerous studies over many years," Dr. Ballantyne said. "GI tolerability was quite good, but the taste issue remains," he said.

Dr. Ballantyne said that he currently prescribes EPA to some of his patients. He prefers to prescribe Lovaza (a brand-name, prescription-only formulation of omega-3 fatty acid ethyl esters that contains both EPA and docosahexaenoic acid) because it is a "high quality agent," he said in an interview. "If a patient cannot afford that, we give them tips on how to purchase high-quality supplement" formulations of omega-3 fatty acids, he added.

ANCHOR was sponsored by Amarin, the company developing AMR101. Dr. Ballantyne said that he has been a consultant for Amarin and has consulted for, received honoraria from, and/or been a speaker for numerous other pharmaceutical companies. Dr. Brinton said that he has been a consultant to Amarin and has also consulted for and/or been a speaker for several other firms.