'Revolutionary' LDL lowering shown in evolocumab phase III trials

WASHINGTON – The novel low-density lipoprotein cholesterol–lowering agent evolocumab took day 1 of the annual meeting of the American College of Cardiology by storm on the strength of three resoundingly positive phase III clinical trials.

"These three studies presented today I think are nothing short of revolutionary," session cochair Dr. Gregory S. Thomas said in an interview after the presentations.

"To be able to uniformly achieve a 50%-60% further reduction in LDL in patients already on diet, on statins, and often on ezetimibe, and to bring almost all the patients down to LDL levels that most clinicians would be satisfied with is just remarkable," observed Dr. Thomas, medical director of the MemorialCare Heart & Vascular Institute at Long Beach (Calif.) Memorial.

Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays a major role in regulating LDL cholesterol levels. In earlier phase II studies it showed impressive efficacy in LDL lowering. As a result, the eagerly anticipated phase III trials drew throngs. Even before the new-research session got underway, fire marshals stood in the doorways and turned away large numbers of disappointed meeting attendees.

The showstopper was DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study), to date by far the longest randomized, double-blind, placebo-controlled clinical trial of any PCSK9 inhibitor. The 52-week study randomized 901 participants 2:1 to evolocumab by subcutaneous injection at 420 mg every 4 weeks or placebo on top of background lipid-lowering therapy optimized in an effort to reach National Cholesterol Education Campaign ATP III LDL goals. The background therapy options ranged from diet alone, to diet plus atorvastatin at either 10 or 80 mg/day, to high-dose atorvastatin plus ezetimibe at 10 mg/day. DESCARTES participants had to have an LDL cholesterol level of 75 mg/dL or more after up to 16 weeks of the run-in background therapy. At randomization, their mean LDL cholesterol level was 104 mg/dL.

The mean placebo-adjusted reduction in LDL cholesterol from baseline to week 52 – the primary study endpoint – was 57% in the evolocumab group. Moreover, 82% of patients in the evolocumab group achieved an LDL below 70 mg/dL, compared with just 6.4% of the control group, reported Dr. Dirk J. Blom of the University of Cape Town, South Africa.

The LDL cholesterol lowering was accompanied by a placebo-adjusted 42% reduction in apolipoprotein B, a 28% drop in lipoprotein(a), a 9% decrease in triglycerides, a 6% boost in HDL cholesterol, and a modest but statistically significant 2% rise in apolipoprotein A1, he added.

There was no diminution in evolocumab’s LDL cholesterol–lowering effect over the duration of the study. It was the same at week 52 as at week 12. The evolocumab group showed no significant changes over time in fasting blood glucose or glycosylated hemoglobin. Rates and types of all adverse events, including injection site reactions, abnormal liver function tests, and elevations in creatine kinase, were essentially the same in the evolocumab and control groups. One patient developed transient anti-evolocumab–binding antibodies during treatment with the PCSK9 inhibitor; however, no one developed anti-evolocumab–neutralizing antibodies.

The same themes of massive reductions in LDL cholesterol along with a side effect profile mirroring placebo emerged from the other two phase III trials, RUTHERFORD-2 and MENDEL-2.

RUTHERFORD-2 (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder) was a 12-week, double-blind, placebo-controlled trial in 329 patients with heterozygous familial hypercholesterolemia. Their mean baseline LDL cholesterol was 154 mg/dL, even though all were on statin therapy and about 60% were also on ezetimibe. They were randomized 2:1 to evolocumab or placebo on top of their background lipid-lowering regimen. The evolocumab group was randomized to monthly injections at 420 mg, as in DESCARTES, or to home biweekly injections at 140 mg delivered by prefilled autoinjector using a 27-gauge needle. The two dosing regimens proved clinically equivalent in efficacy and lack of side effects. At 12 weeks, 68% of patients on biweekly evolocumab and 63% on monthly therapy had an LDL cholesterol level below 70 mg/dL, compared with 2% on placebo, according to Dr. Frederick J. Raal of the University of the Witwatersrand in Johannesburg, South Africa.

A new and effective treatment option for patients with heterozygous familial hypercholesterolemia would be most welcome, he noted. This is the most common of all autosomal dominant inherited disorders, with an estimated prevalence of 1 in roughly 300, meaning more than 1 million people are affected in the United States alone. The disorder is characterized by markedly elevated LDL levels that often can’t be brought down to target despite maximal current therapies. Untreated men with heterozygous familial hypercholesterolemia typically have their first coronary event in their 40s, women a decade later.

Dr. Michael J. Koren presented the findings of MENDEL-2. This 12-week, double-blind, placebo- and ezetimibe-controlled, multicenter, phase-III study included 614 patients with a baseline LDL cholesterol level of 100-190 mg/dL. None were permitted to be on a statin. Statins are known to upregulate PCSK9 production, so it was important to find out whether evolocumab performs differently depending upon whether patients are on that workhorse therapy. As in RUTHERFORD-2, the evolocumab group was randomized to 140 mg biweekly by autoinjector or to monthly treatment at 420 mg. Over the course of 12 weeks, LDL dropped by 57% with biweekly evolocumab and 56% with monthly injections.

"Though we anticipate that evolocumab will find use primarily as a treatment for high-risk patients in conjunction with statins, MENDEL-2 has demonstrated that evolocumab produces large LDL-lowering effects as monotherapy," said Dr. Koren of the Jacksonville (Fla.) Center for Clinical Research.

Dr. Thomas, the session cochair, said it will be interesting to see how the Food and Drug Administration responds to the new phase III data. Large studies with cardiovascular event endpoints are ongoing. The FDA may want to wait for evidence from those studies showing that large-magnitude LDL cholesterol lowering reduces events, or the agency might be inclined to approve PCSK9 inhibitor therapy for selected high-risk populations.

"I think the RUTHERFORD-2 trial in heterozygous familial hypercholesterolemia patients was particularly interesting. Perhaps the new agents could first be approved for use in that population, because those patients clearly have a very high rate of premature coronary disease," the cardiologist said.

As for safety, Dr. Thomas said "We’ve continued to look for problems with these agents, but so far, we can’t find any off-target effects. Results 2-3 years out in ongoing open-label studies will be very important."

Dr. Blom, Dr. Raal, and Dr. Koren reported receiving research grants and consultant’s fees from Amgen, which sponsored the evolocumab phase III trials. Dr. Thomas reported receiving research grants and consultant’s fees from Sanofi, which is developing another PCSK9 inhibitor.

Simultaneous with Dr. Blom’s presentation, the DESCARTES results were published online (N. Engl. J. Med. 2014 March 29 [doi:10.1056/NEJMoa1316222]). The MENDEL-2 study was also simultaneously published (J. Am. Coll. Cardiol. 2014 March 29 [doi:10.1016/j.jacc.2014.03.018]).

[email protected]

WASHINGTON – The novel low-density lipoprotein cholesterol–lowering agent evolocumab took day 1 of the annual meeting of the American College of Cardiology by storm on the strength of three resoundingly positive phase III clinical trials.

"These three studies presented today I think are nothing short of revolutionary," session cochair Dr. Gregory S. Thomas said in an interview after the presentations.

"To be able to uniformly achieve a 50%-60% further reduction in LDL in patients already on diet, on statins, and often on ezetimibe, and to bring almost all the patients down to LDL levels that most clinicians would be satisfied with is just remarkable," observed Dr. Thomas, medical director of the MemorialCare Heart & Vascular Institute at Long Beach (Calif.) Memorial.

Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays a major role in regulating LDL cholesterol levels. In earlier phase II studies it showed impressive efficacy in LDL lowering. As a result, the eagerly anticipated phase III trials drew throngs. Even before the new-research session got underway, fire marshals stood in the doorways and turned away large numbers of disappointed meeting attendees.

The showstopper was DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study), to date by far the longest randomized, double-blind, placebo-controlled clinical trial of any PCSK9 inhibitor. The 52-week study randomized 901 participants 2:1 to evolocumab by subcutaneous injection at 420 mg every 4 weeks or placebo on top of background lipid-lowering therapy optimized in an effort to reach National Cholesterol Education Campaign ATP III LDL goals. The background therapy options ranged from diet alone, to diet plus atorvastatin at either 10 or 80 mg/day, to high-dose atorvastatin plus ezetimibe at 10 mg/day. DESCARTES participants had to have an LDL cholesterol level of 75 mg/dL or more after up to 16 weeks of the run-in background therapy. At randomization, their mean LDL cholesterol level was 104 mg/dL.

The mean placebo-adjusted reduction in LDL cholesterol from baseline to week 52 – the primary study endpoint – was 57% in the evolocumab group. Moreover, 82% of patients in the evolocumab group achieved an LDL below 70 mg/dL, compared with just 6.4% of the control group, reported Dr. Dirk J. Blom of the University of Cape Town, South Africa.

The LDL cholesterol lowering was accompanied by a placebo-adjusted 42% reduction in apolipoprotein B, a 28% drop in lipoprotein(a), a 9% decrease in triglycerides, a 6% boost in HDL cholesterol, and a modest but statistically significant 2% rise in apolipoprotein A1, he added.

There was no diminution in evolocumab’s LDL cholesterol–lowering effect over the duration of the study. It was the same at week 52 as at week 12. The evolocumab group showed no significant changes over time in fasting blood glucose or glycosylated hemoglobin. Rates and types of all adverse events, including injection site reactions, abnormal liver function tests, and elevations in creatine kinase, were essentially the same in the evolocumab and control groups. One patient developed transient anti-evolocumab–binding antibodies during treatment with the PCSK9 inhibitor; however, no one developed anti-evolocumab–neutralizing antibodies.

The same themes of massive reductions in LDL cholesterol along with a side effect profile mirroring placebo emerged from the other two phase III trials, RUTHERFORD-2 and MENDEL-2.

RUTHERFORD-2 (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder) was a 12-week, double-blind, placebo-controlled trial in 329 patients with heterozygous familial hypercholesterolemia. Their mean baseline LDL cholesterol was 154 mg/dL, even though all were on statin therapy and about 60% were also on ezetimibe. They were randomized 2:1 to evolocumab or placebo on top of their background lipid-lowering regimen. The evolocumab group was randomized to monthly injections at 420 mg, as in DESCARTES, or to home biweekly injections at 140 mg delivered by prefilled autoinjector using a 27-gauge needle. The two dosing regimens proved clinically equivalent in efficacy and lack of side effects. At 12 weeks, 68% of patients on biweekly evolocumab and 63% on monthly therapy had an LDL cholesterol level below 70 mg/dL, compared with 2% on placebo, according to Dr. Frederick J. Raal of the University of the Witwatersrand in Johannesburg, South Africa.

A new and effective treatment option for patients with heterozygous familial hypercholesterolemia would be most welcome, he noted. This is the most common of all autosomal dominant inherited disorders, with an estimated prevalence of 1 in roughly 300, meaning more than 1 million people are affected in the United States alone. The disorder is characterized by markedly elevated LDL levels that often can’t be brought down to target despite maximal current therapies. Untreated men with heterozygous familial hypercholesterolemia typically have their first coronary event in their 40s, women a decade later.

Dr. Michael J. Koren presented the findings of MENDEL-2. This 12-week, double-blind, placebo- and ezetimibe-controlled, multicenter, phase-III study included 614 patients with a baseline LDL cholesterol level of 100-190 mg/dL. None were permitted to be on a statin. Statins are known to upregulate PCSK9 production, so it was important to find out whether evolocumab performs differently depending upon whether patients are on that workhorse therapy. As in RUTHERFORD-2, the evolocumab group was randomized to 140 mg biweekly by autoinjector or to monthly treatment at 420 mg. Over the course of 12 weeks, LDL dropped by 57% with biweekly evolocumab and 56% with monthly injections.

"Though we anticipate that evolocumab will find use primarily as a treatment for high-risk patients in conjunction with statins, MENDEL-2 has demonstrated that evolocumab produces large LDL-lowering effects as monotherapy," said Dr. Koren of the Jacksonville (Fla.) Center for Clinical Research.

Dr. Thomas, the session cochair, said it will be interesting to see how the Food and Drug Administration responds to the new phase III data. Large studies with cardiovascular event endpoints are ongoing. The FDA may want to wait for evidence from those studies showing that large-magnitude LDL cholesterol lowering reduces events, or the agency might be inclined to approve PCSK9 inhibitor therapy for selected high-risk populations.

"I think the RUTHERFORD-2 trial in heterozygous familial hypercholesterolemia patients was particularly interesting. Perhaps the new agents could first be approved for use in that population, because those patients clearly have a very high rate of premature coronary disease," the cardiologist said.

As for safety, Dr. Thomas said "We’ve continued to look for problems with these agents, but so far, we can’t find any off-target effects. Results 2-3 years out in ongoing open-label studies will be very important."

Dr. Blom, Dr. Raal, and Dr. Koren reported receiving research grants and consultant’s fees from Amgen, which sponsored the evolocumab phase III trials. Dr. Thomas reported receiving research grants and consultant’s fees from Sanofi, which is developing another PCSK9 inhibitor.

Simultaneous with Dr. Blom’s presentation, the DESCARTES results were published online (N. Engl. J. Med. 2014 March 29 [doi:10.1056/NEJMoa1316222]). The MENDEL-2 study was also simultaneously published (J. Am. Coll. Cardiol. 2014 March 29 [doi:10.1016/j.jacc.2014.03.018]).

[email protected]

WASHINGTON – The novel low-density lipoprotein cholesterol–lowering agent evolocumab took day 1 of the annual meeting of the American College of Cardiology by storm on the strength of three resoundingly positive phase III clinical trials.

"These three studies presented today I think are nothing short of revolutionary," session cochair Dr. Gregory S. Thomas said in an interview after the presentations.

"To be able to uniformly achieve a 50%-60% further reduction in LDL in patients already on diet, on statins, and often on ezetimibe, and to bring almost all the patients down to LDL levels that most clinicians would be satisfied with is just remarkable," observed Dr. Thomas, medical director of the MemorialCare Heart & Vascular Institute at Long Beach (Calif.) Memorial.

Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays a major role in regulating LDL cholesterol levels. In earlier phase II studies it showed impressive efficacy in LDL lowering. As a result, the eagerly anticipated phase III trials drew throngs. Even before the new-research session got underway, fire marshals stood in the doorways and turned away large numbers of disappointed meeting attendees.

The showstopper was DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study), to date by far the longest randomized, double-blind, placebo-controlled clinical trial of any PCSK9 inhibitor. The 52-week study randomized 901 participants 2:1 to evolocumab by subcutaneous injection at 420 mg every 4 weeks or placebo on top of background lipid-lowering therapy optimized in an effort to reach National Cholesterol Education Campaign ATP III LDL goals. The background therapy options ranged from diet alone, to diet plus atorvastatin at either 10 or 80 mg/day, to high-dose atorvastatin plus ezetimibe at 10 mg/day. DESCARTES participants had to have an LDL cholesterol level of 75 mg/dL or more after up to 16 weeks of the run-in background therapy. At randomization, their mean LDL cholesterol level was 104 mg/dL.

The mean placebo-adjusted reduction in LDL cholesterol from baseline to week 52 – the primary study endpoint – was 57% in the evolocumab group. Moreover, 82% of patients in the evolocumab group achieved an LDL below 70 mg/dL, compared with just 6.4% of the control group, reported Dr. Dirk J. Blom of the University of Cape Town, South Africa.

The LDL cholesterol lowering was accompanied by a placebo-adjusted 42% reduction in apolipoprotein B, a 28% drop in lipoprotein(a), a 9% decrease in triglycerides, a 6% boost in HDL cholesterol, and a modest but statistically significant 2% rise in apolipoprotein A1, he added.

There was no diminution in evolocumab’s LDL cholesterol–lowering effect over the duration of the study. It was the same at week 52 as at week 12. The evolocumab group showed no significant changes over time in fasting blood glucose or glycosylated hemoglobin. Rates and types of all adverse events, including injection site reactions, abnormal liver function tests, and elevations in creatine kinase, were essentially the same in the evolocumab and control groups. One patient developed transient anti-evolocumab–binding antibodies during treatment with the PCSK9 inhibitor; however, no one developed anti-evolocumab–neutralizing antibodies.

The same themes of massive reductions in LDL cholesterol along with a side effect profile mirroring placebo emerged from the other two phase III trials, RUTHERFORD-2 and MENDEL-2.

RUTHERFORD-2 (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder) was a 12-week, double-blind, placebo-controlled trial in 329 patients with heterozygous familial hypercholesterolemia. Their mean baseline LDL cholesterol was 154 mg/dL, even though all were on statin therapy and about 60% were also on ezetimibe. They were randomized 2:1 to evolocumab or placebo on top of their background lipid-lowering regimen. The evolocumab group was randomized to monthly injections at 420 mg, as in DESCARTES, or to home biweekly injections at 140 mg delivered by prefilled autoinjector using a 27-gauge needle. The two dosing regimens proved clinically equivalent in efficacy and lack of side effects. At 12 weeks, 68% of patients on biweekly evolocumab and 63% on monthly therapy had an LDL cholesterol level below 70 mg/dL, compared with 2% on placebo, according to Dr. Frederick J. Raal of the University of the Witwatersrand in Johannesburg, South Africa.

A new and effective treatment option for patients with heterozygous familial hypercholesterolemia would be most welcome, he noted. This is the most common of all autosomal dominant inherited disorders, with an estimated prevalence of 1 in roughly 300, meaning more than 1 million people are affected in the United States alone. The disorder is characterized by markedly elevated LDL levels that often can’t be brought down to target despite maximal current therapies. Untreated men with heterozygous familial hypercholesterolemia typically have their first coronary event in their 40s, women a decade later.

Dr. Michael J. Koren presented the findings of MENDEL-2. This 12-week, double-blind, placebo- and ezetimibe-controlled, multicenter, phase-III study included 614 patients with a baseline LDL cholesterol level of 100-190 mg/dL. None were permitted to be on a statin. Statins are known to upregulate PCSK9 production, so it was important to find out whether evolocumab performs differently depending upon whether patients are on that workhorse therapy. As in RUTHERFORD-2, the evolocumab group was randomized to 140 mg biweekly by autoinjector or to monthly treatment at 420 mg. Over the course of 12 weeks, LDL dropped by 57% with biweekly evolocumab and 56% with monthly injections.

"Though we anticipate that evolocumab will find use primarily as a treatment for high-risk patients in conjunction with statins, MENDEL-2 has demonstrated that evolocumab produces large LDL-lowering effects as monotherapy," said Dr. Koren of the Jacksonville (Fla.) Center for Clinical Research.

Dr. Thomas, the session cochair, said it will be interesting to see how the Food and Drug Administration responds to the new phase III data. Large studies with cardiovascular event endpoints are ongoing. The FDA may want to wait for evidence from those studies showing that large-magnitude LDL cholesterol lowering reduces events, or the agency might be inclined to approve PCSK9 inhibitor therapy for selected high-risk populations.

"I think the RUTHERFORD-2 trial in heterozygous familial hypercholesterolemia patients was particularly interesting. Perhaps the new agents could first be approved for use in that population, because those patients clearly have a very high rate of premature coronary disease," the cardiologist said.

As for safety, Dr. Thomas said "We’ve continued to look for problems with these agents, but so far, we can’t find any off-target effects. Results 2-3 years out in ongoing open-label studies will be very important."

Dr. Blom, Dr. Raal, and Dr. Koren reported receiving research grants and consultant’s fees from Amgen, which sponsored the evolocumab phase III trials. Dr. Thomas reported receiving research grants and consultant’s fees from Sanofi, which is developing another PCSK9 inhibitor.

Simultaneous with Dr. Blom’s presentation, the DESCARTES results were published online (N. Engl. J. Med. 2014 March 29 [doi:10.1056/NEJMoa1316222]). The MENDEL-2 study was also simultaneously published (J. Am. Coll. Cardiol. 2014 March 29 [doi:10.1016/j.jacc.2014.03.018]).

[email protected]