FDA Advisory Committee Meeting

This week, an expert panel convened by the Food and Drug Administration will vote on whether two biologic lipid-lowering treatments, administered subcutaneously every 2 weeks, should be approved for lowering low-density lipoprotein cholesterol (LDL-C) in different groups of patients.

Alirocumab and evolocumab are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels. If approved, they will be the first PCSK9 inhibitors, a new class of lipid-lowering agents, to be approved in the United States.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review alirocumab, developed by Sanofi and Regeneron, on June 9, and will review evolocumab, developed by Amgen, on June 10.

The votes on whether the data on the drugs support approval will be based on whether the LDL-C–lowering benefits of the drugs exceed their risks, since lipid-lowering drugs are currently approved using the LDL-C endpoint as a surrogate for cardiovascular benefit, “provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit,” according to the FDA draft questions.

For each drug separately, however, the FDA also is asking the panel to discuss whether their LDL-C–lowering effects are “sufficient to substitute for demonstrating its effect on clinical outcomes,” such as a evidence from a cardiovascular outcome trial.

Promising CV outcomes data are available for both drugs, but CV outcomes trials have not been completed and those data are not addressed in the questions.

 Alirocumab

The Sanofi/Regeneron briefing document proposes that alirocumab be approved before the results of the ongoing 18,000-patient CV outcomes study – the ODYSSEY Outcomes trial – are available, and that approval “at this time is based on the unmet needs of patients for additional LDL-C lowering, the demonstration of substantial LDL-C lowering by alirocumab, and an acceptable safety profile.” Patients enrolled in the ODYSSEY Outcomes study have recent acute coronary syndrome, are on high intensity statin treatment, and are randomized to alirocumab or placebo.

Two different dose regimens of alirocumab have been studied in 10 multicenter phase III studies – the ODYSSEY program – which include five 12- to 18-month placebo-controlled studies in about 3,500 patients and five 6- to 24-month studies comparing alirocumab with ezetimibe in about 1,800 patients, which evaluated the percent change in LDL-C at 24 months as the primary endpoint.

The FDA’s briefing document posted before the meeting states that, in studies, alirocumab “demonstrated early and sustained LDL-C lowering from baseline across patient populations, regardless of background lipid-modifying therapies, and is generally well-tolerated.” Treatment was associated with reductions of LDL-C ranging from 36% to 61% from baseline, and differences of 39%-62%, compared with placebo – which were statistically significant – and differences of 24%-36%, compared with ezetimibe. Differences over ezetimibe were statistically significant in all but one of the five studies using ezetimibe as the comparator.

The rate of serious adverse events among those who received alirocumab in placebo-controlled studies were similar to placebo (about 14%) but were slightly higher, compared with ezetimibe (13.1% vs. 11.2%). Rash and pruritus were the most common adverse events associated with alirocumab.

Compared with fewer than 1% of those on controls, about 20% of those treated with alirocumab had at least one LDL-C value that dropped below 15 mg/dL and about 40% had one value that dropped below 25 mg/dL. So far, a review of adverse events “divided by levels of LDL-C achieved did not demonstrate a safety signal,” but patients have not been treated long enough to determine what “if any, adverse effects of prolonged exposure to very low levels of LDL-C will be,” according to the FDA briefing document.

The proposed indication for alirocumab is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non–high-density lipoprotein C, apolipoprotein B, triglycerides, and lipoprotein (a) [Lp(a)], and to increase HDL cholesterol and apolipoprotein A-1(Apo A-1). It is proposed for use in combination with a statin, with or without another lipid-modifying therapy, and as monotherapy, or as add-on to other nonstatin lipid-modifying therapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C).

 Evolocumab

This month, Amgen expects to complete enrollment of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a CV outcomes study of about 27,500 patients, which started in 2013 and should end by 2017. This also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL, according to Amgen’s briefing documents posted on the FDA website before the meeting.

The Amgen data include four 12-week double-blind randomized studies comparing evolocumab to placebo or ezetimibe in about 3,100 patients. Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe.

In studies of over 6,000 patients with primary hyperlipidemia or mixed dyslipidemia, evolocumab resulted in LDL-C reductions of 55%-75% compared with placebo, and 35%-45% compared with ezetimibe, according to Amgen. In studies of patients with homozygous familial hypercholesterolemia (HoFH), treatment was associated with LDL-C reductions of about 30%, compared with placebo. To date, no safety risk has been identified with low LDL-C levels in patients with levels that dropped below 25 mg/dL or 40 mg/dL, compared with levels of 40 mg/dL or greater, according to the company.

The proposed indication for evolocumab includes treatment of adults with hyperlipidemia or mixed dyslipidemia. Treatment would be in combination with a statin or a statin with other lipid-lowering therapies, or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate. It also is being reviewed for treatment of patients with HoFH who are aged 12 years and older in combination with other lipid-lowering therapies. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.

If approved, Sanofi and Regeneron plan to market alirocumab as Praluent and Amgen plans to market evolocumab as Repatha.

[email protected]

This week, an expert panel convened by the Food and Drug Administration will vote on whether two biologic lipid-lowering treatments, administered subcutaneously every 2 weeks, should be approved for lowering low-density lipoprotein cholesterol (LDL-C) in different groups of patients.

Alirocumab and evolocumab are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels. If approved, they will be the first PCSK9 inhibitors, a new class of lipid-lowering agents, to be approved in the United States.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review alirocumab, developed by Sanofi and Regeneron, on June 9, and will review evolocumab, developed by Amgen, on June 10.

The votes on whether the data on the drugs support approval will be based on whether the LDL-C–lowering benefits of the drugs exceed their risks, since lipid-lowering drugs are currently approved using the LDL-C endpoint as a surrogate for cardiovascular benefit, “provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit,” according to the FDA draft questions.

For each drug separately, however, the FDA also is asking the panel to discuss whether their LDL-C–lowering effects are “sufficient to substitute for demonstrating its effect on clinical outcomes,” such as a evidence from a cardiovascular outcome trial.

Promising CV outcomes data are available for both drugs, but CV outcomes trials have not been completed and those data are not addressed in the questions.

 Alirocumab

The Sanofi/Regeneron briefing document proposes that alirocumab be approved before the results of the ongoing 18,000-patient CV outcomes study – the ODYSSEY Outcomes trial – are available, and that approval “at this time is based on the unmet needs of patients for additional LDL-C lowering, the demonstration of substantial LDL-C lowering by alirocumab, and an acceptable safety profile.” Patients enrolled in the ODYSSEY Outcomes study have recent acute coronary syndrome, are on high intensity statin treatment, and are randomized to alirocumab or placebo.

Two different dose regimens of alirocumab have been studied in 10 multicenter phase III studies – the ODYSSEY program – which include five 12- to 18-month placebo-controlled studies in about 3,500 patients and five 6- to 24-month studies comparing alirocumab with ezetimibe in about 1,800 patients, which evaluated the percent change in LDL-C at 24 months as the primary endpoint.

The FDA’s briefing document posted before the meeting states that, in studies, alirocumab “demonstrated early and sustained LDL-C lowering from baseline across patient populations, regardless of background lipid-modifying therapies, and is generally well-tolerated.” Treatment was associated with reductions of LDL-C ranging from 36% to 61% from baseline, and differences of 39%-62%, compared with placebo – which were statistically significant – and differences of 24%-36%, compared with ezetimibe. Differences over ezetimibe were statistically significant in all but one of the five studies using ezetimibe as the comparator.

The rate of serious adverse events among those who received alirocumab in placebo-controlled studies were similar to placebo (about 14%) but were slightly higher, compared with ezetimibe (13.1% vs. 11.2%). Rash and pruritus were the most common adverse events associated with alirocumab.

Compared with fewer than 1% of those on controls, about 20% of those treated with alirocumab had at least one LDL-C value that dropped below 15 mg/dL and about 40% had one value that dropped below 25 mg/dL. So far, a review of adverse events “divided by levels of LDL-C achieved did not demonstrate a safety signal,” but patients have not been treated long enough to determine what “if any, adverse effects of prolonged exposure to very low levels of LDL-C will be,” according to the FDA briefing document.

The proposed indication for alirocumab is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non–high-density lipoprotein C, apolipoprotein B, triglycerides, and lipoprotein (a) [Lp(a)], and to increase HDL cholesterol and apolipoprotein A-1(Apo A-1). It is proposed for use in combination with a statin, with or without another lipid-modifying therapy, and as monotherapy, or as add-on to other nonstatin lipid-modifying therapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C).

 Evolocumab

This month, Amgen expects to complete enrollment of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a CV outcomes study of about 27,500 patients, which started in 2013 and should end by 2017. This also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL, according to Amgen’s briefing documents posted on the FDA website before the meeting.

The Amgen data include four 12-week double-blind randomized studies comparing evolocumab to placebo or ezetimibe in about 3,100 patients. Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe.

In studies of over 6,000 patients with primary hyperlipidemia or mixed dyslipidemia, evolocumab resulted in LDL-C reductions of 55%-75% compared with placebo, and 35%-45% compared with ezetimibe, according to Amgen. In studies of patients with homozygous familial hypercholesterolemia (HoFH), treatment was associated with LDL-C reductions of about 30%, compared with placebo. To date, no safety risk has been identified with low LDL-C levels in patients with levels that dropped below 25 mg/dL or 40 mg/dL, compared with levels of 40 mg/dL or greater, according to the company.

The proposed indication for evolocumab includes treatment of adults with hyperlipidemia or mixed dyslipidemia. Treatment would be in combination with a statin or a statin with other lipid-lowering therapies, or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate. It also is being reviewed for treatment of patients with HoFH who are aged 12 years and older in combination with other lipid-lowering therapies. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.

If approved, Sanofi and Regeneron plan to market alirocumab as Praluent and Amgen plans to market evolocumab as Repatha.

[email protected]

This week, an expert panel convened by the Food and Drug Administration will vote on whether two biologic lipid-lowering treatments, administered subcutaneously every 2 weeks, should be approved for lowering low-density lipoprotein cholesterol (LDL-C) in different groups of patients.

Alirocumab and evolocumab are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels. If approved, they will be the first PCSK9 inhibitors, a new class of lipid-lowering agents, to be approved in the United States.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review alirocumab, developed by Sanofi and Regeneron, on June 9, and will review evolocumab, developed by Amgen, on June 10.

The votes on whether the data on the drugs support approval will be based on whether the LDL-C–lowering benefits of the drugs exceed their risks, since lipid-lowering drugs are currently approved using the LDL-C endpoint as a surrogate for cardiovascular benefit, “provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit,” according to the FDA draft questions.

For each drug separately, however, the FDA also is asking the panel to discuss whether their LDL-C–lowering effects are “sufficient to substitute for demonstrating its effect on clinical outcomes,” such as a evidence from a cardiovascular outcome trial.

Promising CV outcomes data are available for both drugs, but CV outcomes trials have not been completed and those data are not addressed in the questions.

 Alirocumab

The Sanofi/Regeneron briefing document proposes that alirocumab be approved before the results of the ongoing 18,000-patient CV outcomes study – the ODYSSEY Outcomes trial – are available, and that approval “at this time is based on the unmet needs of patients for additional LDL-C lowering, the demonstration of substantial LDL-C lowering by alirocumab, and an acceptable safety profile.” Patients enrolled in the ODYSSEY Outcomes study have recent acute coronary syndrome, are on high intensity statin treatment, and are randomized to alirocumab or placebo.

Two different dose regimens of alirocumab have been studied in 10 multicenter phase III studies – the ODYSSEY program – which include five 12- to 18-month placebo-controlled studies in about 3,500 patients and five 6- to 24-month studies comparing alirocumab with ezetimibe in about 1,800 patients, which evaluated the percent change in LDL-C at 24 months as the primary endpoint.

The FDA’s briefing document posted before the meeting states that, in studies, alirocumab “demonstrated early and sustained LDL-C lowering from baseline across patient populations, regardless of background lipid-modifying therapies, and is generally well-tolerated.” Treatment was associated with reductions of LDL-C ranging from 36% to 61% from baseline, and differences of 39%-62%, compared with placebo – which were statistically significant – and differences of 24%-36%, compared with ezetimibe. Differences over ezetimibe were statistically significant in all but one of the five studies using ezetimibe as the comparator.

The rate of serious adverse events among those who received alirocumab in placebo-controlled studies were similar to placebo (about 14%) but were slightly higher, compared with ezetimibe (13.1% vs. 11.2%). Rash and pruritus were the most common adverse events associated with alirocumab.

Compared with fewer than 1% of those on controls, about 20% of those treated with alirocumab had at least one LDL-C value that dropped below 15 mg/dL and about 40% had one value that dropped below 25 mg/dL. So far, a review of adverse events “divided by levels of LDL-C achieved did not demonstrate a safety signal,” but patients have not been treated long enough to determine what “if any, adverse effects of prolonged exposure to very low levels of LDL-C will be,” according to the FDA briefing document.

The proposed indication for alirocumab is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non–high-density lipoprotein C, apolipoprotein B, triglycerides, and lipoprotein (a) [Lp(a)], and to increase HDL cholesterol and apolipoprotein A-1(Apo A-1). It is proposed for use in combination with a statin, with or without another lipid-modifying therapy, and as monotherapy, or as add-on to other nonstatin lipid-modifying therapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C).

 Evolocumab

This month, Amgen expects to complete enrollment of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a CV outcomes study of about 27,500 patients, which started in 2013 and should end by 2017. This also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL, according to Amgen’s briefing documents posted on the FDA website before the meeting.

The Amgen data include four 12-week double-blind randomized studies comparing evolocumab to placebo or ezetimibe in about 3,100 patients. Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe.

In studies of over 6,000 patients with primary hyperlipidemia or mixed dyslipidemia, evolocumab resulted in LDL-C reductions of 55%-75% compared with placebo, and 35%-45% compared with ezetimibe, according to Amgen. In studies of patients with homozygous familial hypercholesterolemia (HoFH), treatment was associated with LDL-C reductions of about 30%, compared with placebo. To date, no safety risk has been identified with low LDL-C levels in patients with levels that dropped below 25 mg/dL or 40 mg/dL, compared with levels of 40 mg/dL or greater, according to the company.

The proposed indication for evolocumab includes treatment of adults with hyperlipidemia or mixed dyslipidemia. Treatment would be in combination with a statin or a statin with other lipid-lowering therapies, or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate. It also is being reviewed for treatment of patients with HoFH who are aged 12 years and older in combination with other lipid-lowering therapies. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.

If approved, Sanofi and Regeneron plan to market alirocumab as Praluent and Amgen plans to market evolocumab as Repatha.

[email protected]