Hepatic Concerns Influence Panel's Vote on ApoB Inhibitor

SILVER SPRING, MD. – In as many days, two potential treatments for a rare lipid disorder have gained the support of a Food and Drug Administration advisory panel.

At a meeting on Oct. 18, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9:6 to support approval of mipomersen as a treatment for homozygous familial hypercholesterolemia (HoFH), but panelists voting on both sides expressed concerns about the drug’s safety profile and its modest, variable effects on lowering low density lipoprotein cholesterol.

One day earlier, the panel voted 13:2 that lomitapide, a microsomal triglyceride transfer protein inhibitor, should be approved for the same condition.

During the Oct. 18 meeting, the panel reviewed the safety and efficacy data on mipomersen, an apolipoprotein B synthesis inhibitorthat reduces the production of apolipoprotein B (ApoB). The proposed indication for mipomersen is as an adjunctive treatment to maximally tolerated lipid-lowering medications and diet to reduceLDL cholesterol, ApoB, total cholesterol (TC), and non-HDL cholesterol at a dose of 200 mg administered in a subcutaneous injection once a week. Genzyme Corp. is partnering with Isis Pharmaceuticals to develop the drug.

The main safety concern was the potential for drug-induced liver injury because of increased transaminase levels associated with treatment, and the potential for steatohepatitis with chronic use because of cases of hepatic steatosis associated with treatment. Panelists also raised issues about other safety issues, including the development of anti-mipomersen antibodies in a significant portion of treated patients, and the high dropout rate (55%) in the open-label extension study of 141 patients. Most of the patients who discontinued due to adverse effects did so because of injection site reactions and flu-like symptoms associated with treatment.

Mipomersen was studied in a pivotal phase III study and three supportive phase III studies of almost 400 patients with HoFH; all were randomized, double-blind studies comparing the once weekly dose of mipomersen to placebo added to the maximally tolerated lipid-lowering treatments for 26 weeks. Almost all patients were on a statin; none was being treated with lipid apheresis.

The pivotal study enrolled 51 patients, aged 12-53 years (mean age was 31). At week 28, 2 weeks after the last dose, the mean LDL level was reduced by a mean of 113 mg/dL (from a baseline of 439 mg/dL) in those on mipomersen, compared with a mean reduction of 12 mg/dL (from 400 mg/dL at baseline) in those on placebo, a significant difference. The mean percent change at 28 weeks in LDL cholesterol from baseline, the primary end point, was almost 25% among those on mipomerson, compared with 3.3% lower in those on placebo, a 21.4% absolute difference. Statistically significant reductions were also seen in ApoB, TC, and non-HDL cholesterol levels, and "nominally significant" reductions were seen in lipoprotein A, triglycerides, and the LDL/HDL ratio.

Panelists agreed that the studies showed that mipomersen was effective in lowering LDL cholesterol, but they described the reductions as relatively modest and variable, noting that few patients achieved an LDL level below 100 mg/dL. And while they agreed that reduction of LDL cholesterol is an appropriate surrogate for reduced cardiovascular morbidity and mortality, several panelists said that it was not clear whether the reductions in LDL of the magnitude seen in this study would have meaningful beneficial effects.

Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes certification of prescribers and pharmacies, who can only dispense the drug if the prescriber is certified and attests that the treatment is medically appropriate and that the patient will be monitored for hepatoxicity.

If approved, the drug will be marketed as Kynamro, according to Genzyme. The company is planning a trial where mipomersen is combined with apheresis in patients with HoFH, and has started to enrolled patients with heterozygous FH in another study of mipomersen.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential 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. – In as many days, two potential treatments for a rare lipid disorder have gained the support of a Food and Drug Administration advisory panel.

At a meeting on Oct. 18, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9:6 to support approval of mipomersen as a treatment for homozygous familial hypercholesterolemia (HoFH), but panelists voting on both sides expressed concerns about the drug’s safety profile and its modest, variable effects on lowering low density lipoprotein cholesterol.

One day earlier, the panel voted 13:2 that lomitapide, a microsomal triglyceride transfer protein inhibitor, should be approved for the same condition.

During the Oct. 18 meeting, the panel reviewed the safety and efficacy data on mipomersen, an apolipoprotein B synthesis inhibitorthat reduces the production of apolipoprotein B (ApoB). The proposed indication for mipomersen is as an adjunctive treatment to maximally tolerated lipid-lowering medications and diet to reduceLDL cholesterol, ApoB, total cholesterol (TC), and non-HDL cholesterol at a dose of 200 mg administered in a subcutaneous injection once a week. Genzyme Corp. is partnering with Isis Pharmaceuticals to develop the drug.

The main safety concern was the potential for drug-induced liver injury because of increased transaminase levels associated with treatment, and the potential for steatohepatitis with chronic use because of cases of hepatic steatosis associated with treatment. Panelists also raised issues about other safety issues, including the development of anti-mipomersen antibodies in a significant portion of treated patients, and the high dropout rate (55%) in the open-label extension study of 141 patients. Most of the patients who discontinued due to adverse effects did so because of injection site reactions and flu-like symptoms associated with treatment.

Mipomersen was studied in a pivotal phase III study and three supportive phase III studies of almost 400 patients with HoFH; all were randomized, double-blind studies comparing the once weekly dose of mipomersen to placebo added to the maximally tolerated lipid-lowering treatments for 26 weeks. Almost all patients were on a statin; none was being treated with lipid apheresis.

The pivotal study enrolled 51 patients, aged 12-53 years (mean age was 31). At week 28, 2 weeks after the last dose, the mean LDL level was reduced by a mean of 113 mg/dL (from a baseline of 439 mg/dL) in those on mipomersen, compared with a mean reduction of 12 mg/dL (from 400 mg/dL at baseline) in those on placebo, a significant difference. The mean percent change at 28 weeks in LDL cholesterol from baseline, the primary end point, was almost 25% among those on mipomerson, compared with 3.3% lower in those on placebo, a 21.4% absolute difference. Statistically significant reductions were also seen in ApoB, TC, and non-HDL cholesterol levels, and "nominally significant" reductions were seen in lipoprotein A, triglycerides, and the LDL/HDL ratio.

Panelists agreed that the studies showed that mipomersen was effective in lowering LDL cholesterol, but they described the reductions as relatively modest and variable, noting that few patients achieved an LDL level below 100 mg/dL. And while they agreed that reduction of LDL cholesterol is an appropriate surrogate for reduced cardiovascular morbidity and mortality, several panelists said that it was not clear whether the reductions in LDL of the magnitude seen in this study would have meaningful beneficial effects.

Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes certification of prescribers and pharmacies, who can only dispense the drug if the prescriber is certified and attests that the treatment is medically appropriate and that the patient will be monitored for hepatoxicity.

If approved, the drug will be marketed as Kynamro, according to Genzyme. The company is planning a trial where mipomersen is combined with apheresis in patients with HoFH, and has started to enrolled patients with heterozygous FH in another study of mipomersen.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential 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. – In as many days, two potential treatments for a rare lipid disorder have gained the support of a Food and Drug Administration advisory panel.

At a meeting on Oct. 18, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9:6 to support approval of mipomersen as a treatment for homozygous familial hypercholesterolemia (HoFH), but panelists voting on both sides expressed concerns about the drug’s safety profile and its modest, variable effects on lowering low density lipoprotein cholesterol.

One day earlier, the panel voted 13:2 that lomitapide, a microsomal triglyceride transfer protein inhibitor, should be approved for the same condition.

During the Oct. 18 meeting, the panel reviewed the safety and efficacy data on mipomersen, an apolipoprotein B synthesis inhibitorthat reduces the production of apolipoprotein B (ApoB). The proposed indication for mipomersen is as an adjunctive treatment to maximally tolerated lipid-lowering medications and diet to reduceLDL cholesterol, ApoB, total cholesterol (TC), and non-HDL cholesterol at a dose of 200 mg administered in a subcutaneous injection once a week. Genzyme Corp. is partnering with Isis Pharmaceuticals to develop the drug.

The main safety concern was the potential for drug-induced liver injury because of increased transaminase levels associated with treatment, and the potential for steatohepatitis with chronic use because of cases of hepatic steatosis associated with treatment. Panelists also raised issues about other safety issues, including the development of anti-mipomersen antibodies in a significant portion of treated patients, and the high dropout rate (55%) in the open-label extension study of 141 patients. Most of the patients who discontinued due to adverse effects did so because of injection site reactions and flu-like symptoms associated with treatment.

Mipomersen was studied in a pivotal phase III study and three supportive phase III studies of almost 400 patients with HoFH; all were randomized, double-blind studies comparing the once weekly dose of mipomersen to placebo added to the maximally tolerated lipid-lowering treatments for 26 weeks. Almost all patients were on a statin; none was being treated with lipid apheresis.

The pivotal study enrolled 51 patients, aged 12-53 years (mean age was 31). At week 28, 2 weeks after the last dose, the mean LDL level was reduced by a mean of 113 mg/dL (from a baseline of 439 mg/dL) in those on mipomersen, compared with a mean reduction of 12 mg/dL (from 400 mg/dL at baseline) in those on placebo, a significant difference. The mean percent change at 28 weeks in LDL cholesterol from baseline, the primary end point, was almost 25% among those on mipomerson, compared with 3.3% lower in those on placebo, a 21.4% absolute difference. Statistically significant reductions were also seen in ApoB, TC, and non-HDL cholesterol levels, and "nominally significant" reductions were seen in lipoprotein A, triglycerides, and the LDL/HDL ratio.

Panelists agreed that the studies showed that mipomersen was effective in lowering LDL cholesterol, but they described the reductions as relatively modest and variable, noting that few patients achieved an LDL level below 100 mg/dL. And while they agreed that reduction of LDL cholesterol is an appropriate surrogate for reduced cardiovascular morbidity and mortality, several panelists said that it was not clear whether the reductions in LDL of the magnitude seen in this study would have meaningful beneficial effects.

Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes certification of prescribers and pharmacies, who can only dispense the drug if the prescriber is certified and attests that the treatment is medically appropriate and that the patient will be monitored for hepatoxicity.

If approved, the drug will be marketed as Kynamro, according to Genzyme. The company is planning a trial where mipomersen is combined with apheresis in patients with HoFH, and has started to enrolled patients with heterozygous FH in another study of mipomersen.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.