Panel Supports Approval of Cholesterol Drug for Rare Disorder

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13:2 that lomitapide, a first-in-class cholesterol-lowering drug, should be approved for adults with homozygous familial hypercholesterolemia, but cautioned against its use beyond this small group of patients, at a meeting on Oct. 17.

The panelists agreed that treatment with lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, was highly effective in reducing LDL cholesterol after 26 weeks, in the pivotal study of 29 adults with homozygous familial hypercholesterolemia (HoFH), acknowledging the reduction in LDL cholesterol is a surrogate end point for a reduction in cardiovascular morbidity and mortality. But the panel was concerned about the potential risk of hepatotoxicity with long-term treatment, and about off-label use in children and adolescents with HoFH, patients with heterozygous FH, as well as patients with difficult-to-treat hypercholesterolemia.

Like other panelists, Dr. William Hiatt, professor of medicine in the division of cardiology at the University of Colorado, Aurora, said that despite a clear signal for hepatic risk and an undefined absolute risk of hepatotoxicity, he voted in favor of approval because the benefits outweigh the risks for patients with this rare condition. Although there were individual variations in responses, the 50% reduction in LDL cholesterol (the highest response achieved in the pivotal trial), "if sustained, is a pretty impressive benefit and one that is probably worth the risk of liver toxicity," he said.

Panelist Dr. Caleb Alexander of Johns Hopkins Bloomberg School of Public Health, Baltimore, who supported approval, said that said despite plans to discourage off-label use, substantial use of the drug in patients who do not have HoFH was highly likely, which changes the risk-benefit balance. "For someone who has a high likelihood of having a coronary bypass by their 20th birthday, I could certainly see a very favorable risk-benefit profile," but that profile would be different "for someone who simply has recalcitrant hyperlipidemia and an LDL of 380 whose primary care physician is comfortable using this therapy," he said. "The elephant in the room is how this will be used in the real world," he added.

The two pediatric gastroenterologists on the panel voted against approval, because the question posed by the FDA did not specify the adult population.

Lomitapide, administered once a day at doses up to 60 mg, inhibits MTP, which is required for the secretion of very low-density lipoprotein, reducing the production of VLDL, the precursor to LDL, according to the manufacturer, Aegerion Pharmaceuticals. If approved, it would be the first MTP inhibitor to become available in the United States. The proposed indication for approval is as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis, to reduce LDL cholesterol, total cholesterol (TC), apolipoprotein B (apoB), and triglycerides (TG) in patients with HoFH.

In the phase III international study of 29 patients with HoFH (most were white, 55% were male, and mean age was aged 31 years), whose mean LDL level was 336 mg/dL, despite intensive lipid-lowering treatment (including apheresis in 62%), were treated with lomitapide at a starting dose of 5 mg/day titrated to 60 mg/day, as tolerated. At 26 weeks, the mean LDL level had dropped to 190 mg/dL, a 40% drop from baseline that was highly significant. The reductions from baseline LDL-C level ranged from 28% to 52%. LDL-C reductions were maintained through the 56-week extension study.

Of the 23 patients who completed the treatment period, 8 (35%) had LDL-C levels below 100 mg/dL at week 26, including 1 patient whose LDL level had dropped below 70 mg/dL. There were also significant reductions in total cholesterol, apoB, non-HDL cholesterol, triglycerides, and VLDL cholesterol from baseline; HDL and apoA1 levels dropped from baseline to the 26th week of treatment, but in the extension study, increased to baseline by the 56th week of treatment. Six patients discontinued treatment for reasons that included gastrointestinal symptoms.

The main safety concern was the potential for hepatotoxicity with treatment. In the study, four patients developed elevated transaminase levels, which responded to dose reductions or interruption in treatment, and were reversible, according to the company. Patients also had modest increases in hepatic fat while the dose was increased, which then stabilized. No malignancies have been reported in patients treated with lomitapide; however, mice developed hepatocellular adenomas and carcinomas at two to nine times the human doses.

Aegerion has proposed a risk evaluation and management plan (REMS), which would require prescribers to enroll in the program and confirm that they have been trained with the educational materials, and that they understand the indication and associated risks and the need to monitor hepatic transaminases. Under the REMS, distribution of the drug would be available only through a specialty pharmacy. The company also proposed a registry study that would follow long-term safety of the drug including serious hepatic effects, malignancies, cardiac events, and pregnancy outcomes – as well as long-term effectiveness in at least 300 patients on lomitapide for 5 years.

Because it is intended to treat a disease that affects fewer than 200,000 people in the United States at any one time, lomitapide was designated an orphan drug for the treatment of HoFH, and in June 2011, the FDA agreed that the data from the pivotal study would be adequate to support the submission of the approval application. Dr. James Smith, a medical officer in the FDA’s division of metabolism and endocrinology products, pointed out that lomitapide is one of the first lipid-lowering drugs that is being considered for approval for an orphan disease, "without the benefit of having a large phase III safety database derived from a broader population."

If approved, Aegerion plans to study the drug in a pediatric population. The company has submitted an application for approval of lomitapide for the adult indication in the European Union.

The FDA is expected to make a decision on approval by Dec. 29, according to the company. The agency usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential financial conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13:2 that lomitapide, a first-in-class cholesterol-lowering drug, should be approved for adults with homozygous familial hypercholesterolemia, but cautioned against its use beyond this small group of patients, at a meeting on Oct. 17.

The panelists agreed that treatment with lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, was highly effective in reducing LDL cholesterol after 26 weeks, in the pivotal study of 29 adults with homozygous familial hypercholesterolemia (HoFH), acknowledging the reduction in LDL cholesterol is a surrogate end point for a reduction in cardiovascular morbidity and mortality. But the panel was concerned about the potential risk of hepatotoxicity with long-term treatment, and about off-label use in children and adolescents with HoFH, patients with heterozygous FH, as well as patients with difficult-to-treat hypercholesterolemia.

Like other panelists, Dr. William Hiatt, professor of medicine in the division of cardiology at the University of Colorado, Aurora, said that despite a clear signal for hepatic risk and an undefined absolute risk of hepatotoxicity, he voted in favor of approval because the benefits outweigh the risks for patients with this rare condition. Although there were individual variations in responses, the 50% reduction in LDL cholesterol (the highest response achieved in the pivotal trial), "if sustained, is a pretty impressive benefit and one that is probably worth the risk of liver toxicity," he said.

Panelist Dr. Caleb Alexander of Johns Hopkins Bloomberg School of Public Health, Baltimore, who supported approval, said that said despite plans to discourage off-label use, substantial use of the drug in patients who do not have HoFH was highly likely, which changes the risk-benefit balance. "For someone who has a high likelihood of having a coronary bypass by their 20th birthday, I could certainly see a very favorable risk-benefit profile," but that profile would be different "for someone who simply has recalcitrant hyperlipidemia and an LDL of 380 whose primary care physician is comfortable using this therapy," he said. "The elephant in the room is how this will be used in the real world," he added.

The two pediatric gastroenterologists on the panel voted against approval, because the question posed by the FDA did not specify the adult population.

Lomitapide, administered once a day at doses up to 60 mg, inhibits MTP, which is required for the secretion of very low-density lipoprotein, reducing the production of VLDL, the precursor to LDL, according to the manufacturer, Aegerion Pharmaceuticals. If approved, it would be the first MTP inhibitor to become available in the United States. The proposed indication for approval is as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis, to reduce LDL cholesterol, total cholesterol (TC), apolipoprotein B (apoB), and triglycerides (TG) in patients with HoFH.

In the phase III international study of 29 patients with HoFH (most were white, 55% were male, and mean age was aged 31 years), whose mean LDL level was 336 mg/dL, despite intensive lipid-lowering treatment (including apheresis in 62%), were treated with lomitapide at a starting dose of 5 mg/day titrated to 60 mg/day, as tolerated. At 26 weeks, the mean LDL level had dropped to 190 mg/dL, a 40% drop from baseline that was highly significant. The reductions from baseline LDL-C level ranged from 28% to 52%. LDL-C reductions were maintained through the 56-week extension study.

Of the 23 patients who completed the treatment period, 8 (35%) had LDL-C levels below 100 mg/dL at week 26, including 1 patient whose LDL level had dropped below 70 mg/dL. There were also significant reductions in total cholesterol, apoB, non-HDL cholesterol, triglycerides, and VLDL cholesterol from baseline; HDL and apoA1 levels dropped from baseline to the 26th week of treatment, but in the extension study, increased to baseline by the 56th week of treatment. Six patients discontinued treatment for reasons that included gastrointestinal symptoms.

The main safety concern was the potential for hepatotoxicity with treatment. In the study, four patients developed elevated transaminase levels, which responded to dose reductions or interruption in treatment, and were reversible, according to the company. Patients also had modest increases in hepatic fat while the dose was increased, which then stabilized. No malignancies have been reported in patients treated with lomitapide; however, mice developed hepatocellular adenomas and carcinomas at two to nine times the human doses.

Aegerion has proposed a risk evaluation and management plan (REMS), which would require prescribers to enroll in the program and confirm that they have been trained with the educational materials, and that they understand the indication and associated risks and the need to monitor hepatic transaminases. Under the REMS, distribution of the drug would be available only through a specialty pharmacy. The company also proposed a registry study that would follow long-term safety of the drug including serious hepatic effects, malignancies, cardiac events, and pregnancy outcomes – as well as long-term effectiveness in at least 300 patients on lomitapide for 5 years.

Because it is intended to treat a disease that affects fewer than 200,000 people in the United States at any one time, lomitapide was designated an orphan drug for the treatment of HoFH, and in June 2011, the FDA agreed that the data from the pivotal study would be adequate to support the submission of the approval application. Dr. James Smith, a medical officer in the FDA’s division of metabolism and endocrinology products, pointed out that lomitapide is one of the first lipid-lowering drugs that is being considered for approval for an orphan disease, "without the benefit of having a large phase III safety database derived from a broader population."

If approved, Aegerion plans to study the drug in a pediatric population. The company has submitted an application for approval of lomitapide for the adult indication in the European Union.

The FDA is expected to make a decision on approval by Dec. 29, according to the company. The agency usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential financial conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13:2 that lomitapide, a first-in-class cholesterol-lowering drug, should be approved for adults with homozygous familial hypercholesterolemia, but cautioned against its use beyond this small group of patients, at a meeting on Oct. 17.

The panelists agreed that treatment with lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, was highly effective in reducing LDL cholesterol after 26 weeks, in the pivotal study of 29 adults with homozygous familial hypercholesterolemia (HoFH), acknowledging the reduction in LDL cholesterol is a surrogate end point for a reduction in cardiovascular morbidity and mortality. But the panel was concerned about the potential risk of hepatotoxicity with long-term treatment, and about off-label use in children and adolescents with HoFH, patients with heterozygous FH, as well as patients with difficult-to-treat hypercholesterolemia.

Like other panelists, Dr. William Hiatt, professor of medicine in the division of cardiology at the University of Colorado, Aurora, said that despite a clear signal for hepatic risk and an undefined absolute risk of hepatotoxicity, he voted in favor of approval because the benefits outweigh the risks for patients with this rare condition. Although there were individual variations in responses, the 50% reduction in LDL cholesterol (the highest response achieved in the pivotal trial), "if sustained, is a pretty impressive benefit and one that is probably worth the risk of liver toxicity," he said.

Panelist Dr. Caleb Alexander of Johns Hopkins Bloomberg School of Public Health, Baltimore, who supported approval, said that said despite plans to discourage off-label use, substantial use of the drug in patients who do not have HoFH was highly likely, which changes the risk-benefit balance. "For someone who has a high likelihood of having a coronary bypass by their 20th birthday, I could certainly see a very favorable risk-benefit profile," but that profile would be different "for someone who simply has recalcitrant hyperlipidemia and an LDL of 380 whose primary care physician is comfortable using this therapy," he said. "The elephant in the room is how this will be used in the real world," he added.

The two pediatric gastroenterologists on the panel voted against approval, because the question posed by the FDA did not specify the adult population.

Lomitapide, administered once a day at doses up to 60 mg, inhibits MTP, which is required for the secretion of very low-density lipoprotein, reducing the production of VLDL, the precursor to LDL, according to the manufacturer, Aegerion Pharmaceuticals. If approved, it would be the first MTP inhibitor to become available in the United States. The proposed indication for approval is as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis, to reduce LDL cholesterol, total cholesterol (TC), apolipoprotein B (apoB), and triglycerides (TG) in patients with HoFH.

In the phase III international study of 29 patients with HoFH (most were white, 55% were male, and mean age was aged 31 years), whose mean LDL level was 336 mg/dL, despite intensive lipid-lowering treatment (including apheresis in 62%), were treated with lomitapide at a starting dose of 5 mg/day titrated to 60 mg/day, as tolerated. At 26 weeks, the mean LDL level had dropped to 190 mg/dL, a 40% drop from baseline that was highly significant. The reductions from baseline LDL-C level ranged from 28% to 52%. LDL-C reductions were maintained through the 56-week extension study.

Of the 23 patients who completed the treatment period, 8 (35%) had LDL-C levels below 100 mg/dL at week 26, including 1 patient whose LDL level had dropped below 70 mg/dL. There were also significant reductions in total cholesterol, apoB, non-HDL cholesterol, triglycerides, and VLDL cholesterol from baseline; HDL and apoA1 levels dropped from baseline to the 26th week of treatment, but in the extension study, increased to baseline by the 56th week of treatment. Six patients discontinued treatment for reasons that included gastrointestinal symptoms.

The main safety concern was the potential for hepatotoxicity with treatment. In the study, four patients developed elevated transaminase levels, which responded to dose reductions or interruption in treatment, and were reversible, according to the company. Patients also had modest increases in hepatic fat while the dose was increased, which then stabilized. No malignancies have been reported in patients treated with lomitapide; however, mice developed hepatocellular adenomas and carcinomas at two to nine times the human doses.

Aegerion has proposed a risk evaluation and management plan (REMS), which would require prescribers to enroll in the program and confirm that they have been trained with the educational materials, and that they understand the indication and associated risks and the need to monitor hepatic transaminases. Under the REMS, distribution of the drug would be available only through a specialty pharmacy. The company also proposed a registry study that would follow long-term safety of the drug including serious hepatic effects, malignancies, cardiac events, and pregnancy outcomes – as well as long-term effectiveness in at least 300 patients on lomitapide for 5 years.

Because it is intended to treat a disease that affects fewer than 200,000 people in the United States at any one time, lomitapide was designated an orphan drug for the treatment of HoFH, and in June 2011, the FDA agreed that the data from the pivotal study would be adequate to support the submission of the approval application. Dr. James Smith, a medical officer in the FDA’s division of metabolism and endocrinology products, pointed out that lomitapide is one of the first lipid-lowering drugs that is being considered for approval for an orphan disease, "without the benefit of having a large phase III safety database derived from a broader population."

If approved, Aegerion plans to study the drug in a pediatric population. The company has submitted an application for approval of lomitapide for the adult indication in the European Union.

The FDA is expected to make a decision on approval by Dec. 29, according to the company. The agency usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential financial conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.