Merck’s Combination Of Ezetimibe And Atorvastatin Back On NDA Path 1

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A combination tablet containing the cholesterol-lowering drugs ezetimibe and atorvastatin is back on the path to possible FDA approval, according to Merck, which already markets Zetia (ezetimibe) and Vytorin, the combination of ezetimibe and simvastatin. Merck has repeatedly stumbled in its efforts to gain FDA approval of the proposed new drug, which has been dubbed “Son of Vytorin.” The new drug application (NDA) submission was first rejected by the FDA in 2009 and, again, last year.

Merck said yesterday that the FDA had accepted Merck’s resubmission of its NDA, which included additional data provided by Merck in response to the FDA’s rejection of the application last year. Merck said it also planned to pursue approval of the drug in other countries.

Despite its potent cholesterol-lowering effects, the clinical benefits of ezetimibe have never been demonstrated, prompting furious debates about the proper role of surrogate endpoints. Last year the FDA rejected a new indication for Vytorin and  Zetia (ezetimibe alone) in chronic kidney disease patients, as the independent effect of ezetimibe had not been assessed in SHARP, the pivotal study for the indication. Results of the IMPROVE-IT trial, expected this year, may finally resolve the question of whether ezetimibe is beneficial.
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PCSK9 Inhibitor Enhances Cholesterol-Lowering Effect Of Atorvastatin Reply

When added to low-dose atorvastatin a much-discussed new monoclonal antibody to PCSK9 significantly lowers cholesterol more effectively than atorvastatin alone, according to a phase 2 study published in the New England Journal of Medicine. Earlier this year, in March, the findings of three phase 1 trials demonstrating the cholesterol-lowering effects of the drug in healthy volunteers and in people with familial or nonfamilial hypercholesterolemia were also published in NEJM.

In the new trial, Eli Roth and colleagues studied 92 patients with LDL levels over 100 mg/dl despite taking atorvastatin 10 mg. Patients were then randomized to 8 weeks of treatment with 80 mg atorvastatin plus the PCSK9 inhibitor SAR236553, 10 mg atorvastatin plus SAR236553, or 80 mg atorvastatin alone. SAR236553 was administered as an injection once every 2 weeks. PCSK9 inhibition significantly improved LDL reduction:

Reduction in LDL cholesterol from baseline:

  • SAR236553 + atorvastatin 80 mg: 73.2% + 3.5
  • SAR236553 + atorvastatin 10 mg: 66.2% + 3.5
  • atorvastatin 80 mg: 17.3% + 3.5

The investigators reported that 100% of patients in the two groups that received SAR236553 achieved target LDL levels of less than 100 mg/dl, compared with only 52% who received atorvastatin 80 mg only.

The results, write the authors, suggest that SAR236553 “may benefit patients in whom LDL cholesterol has not been reduced to recommended levels, either because of an inadequate lipid-lowering response with high-dose statins alone or because of unacceptable side effects with high-dose statins.”

James Stein told CardioBrief:

“These results are very promising.    What we need now are larger studies of SAR236553 with a longer duration, to determine its safety and tolerability.  If it is safe and effectively lowers total and LDL cholesterol over long periods of time, it would be expected to reduce cardiovascular dissease risk, but of course outcomes studies eventually will be needed to prove that.”

In July the companies developing SAR236553, Sanofi and Regeneron, announced a large phase 3 program for the drug, including an 18,000-patient outcomes trial. Next Monday, at the American Heart Association scientific sessions, the results of two more phase 2 studies of SAR236553 will be presented, as well as a study with another PCSK9 monoclonal antibody from Pfizer, RN316 (PF-04950615).

FDA Panel Recommends Approval Of Mipomersen For Familial Hypercholesterolemia 1

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, an antisense oligonucleotide inhibitor manufactured by Genzyme, for use in homozygous familial hypercholesterolemia (FH). With its relatively close 9-6 vote, and with its comments, the committee expressed concerns about both the efficacy and safety of the drug, but ultimately the severity of homozygous FH led the panel to recommend approval.

“We need a toolkit, we need as many options as possible for these patients,” said one panel member.

On Wednesday the same committee voted 13-2 in favor of  a similar indication for lomitapide capsules, manufactured by Aegerion. On both days, panel members strongly urged the FDA to restrict use of lomitapide and mipomersen to patients with homozygous FH and “avoid the slippery slope” of using the drugs in heterozygous FH or in patients with resistant hypercholesterolemia.

Some panel members voiced concern that the clinical trials with mipomersen excluded patients with apheresis. During the section for public comments Sidney Wolfe said that the trials were unethical for this reason, since apheresis represents the gold standard of treatment for these patients. One panelist responded that though it was an unfortunate exclusion it was not unethical. A Genzyme spokesperson reported that a trial is now underway looking at mipomersen on top of apheresis.

The panel agreed that mipomersen was effective in lowering cholesterol but felt the reduction was “modest” and that most patients would not reach LDL levels under 100. As with lopitamide, trials were not powered for clinical endpoints. Panelists wondered about the clinical effect of lowering LDL cholesterol from 400 to 300.

The committee did not appear to be greatly concerned about the possibility of a cancer signal brought up in the FDA review. Several panelists thought that the cancer signal may have reflected an ascertainment bias, and, further, that a young homozygous FH population would be less susceptible to an elevated cancer risk. Most of the cancers observed in the clinical trials occurred in elderly patients who did not have homozygous FH.

The biggest obstacle to mipomersen was the question over liver safety. Committee members wrestled with the issue without reaching a consensus, perhaps reflecting their faith (or hope) that the FDA’s proposed Risk Evaluation and Mitigation Strategies (REMS) will work as intended. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

 

 

FDA Reviewers Recommend Approval For Lomitapide For Homozygous Familial Hypercholesterolemia 2

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 13-2 to recommend approval of Aegerion Pharmaceuticals’ cholesterol-lowering drug lomitapide for use in patients with homozygous familial hypercholesterolemia (FH).

The lopsided vote does not completely reflect the views of many of the panel members, who expressed considerable concern  that the drug might be used in lower risk populations, in particular, patients with heterozygous FH. The committee also expressed concern about the use of lomitapide in children with homozygous FH, since they were not included in clinical trials, but might be considered candidates for therapy in clinical practice.

Panel members appeared to largely agree with one panel member, who explained that his yes vote was “specific for this condition” (homozygous FH) only. He said he could accept the “trade-off between a near-certain early demise versus the possibility of liver disease.”

Aegerion estimates that there are about 6,000 homozygous FH patients in the US and Europe.

The committee expressed support for the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would  require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

On Thursday the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Following the release of a highly critical FDA review, many observers believe the mipomersen panel will be much more contentious.

FDA Review Raises Safety Concerns About Mipomersen 1

An FDA review raises a number of potentially significant safety concerns about the cholesterol-lowering drug mipomersen. The review appears ahead of a Thursday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to evaluate Genzyme’s new drug application (NDA) for use of the drug as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce LDL, apolipoprotein B, total cholesterol, non-high density lipoprotein-cholesterol and lipoprotein (a) in patients with homozygous familial hypercholesterolemia (FH). Mipomersen is an antisense oligonucleotide inhibitor which targets apoB-100. (On Wednesday the same committee will meet to discuss a similar indication for lomitapide capsules, manufactured by Aegerion.)

FDA reviewers said that mipomersen was generally effective in lowering LDL cholesterol. More than half of patients in clinical trials had more than a 20% decrease in LDL levels. In the pivotal trial with homozygous FH patients mipomersen reduced LDL by 24.7%. As expected, mipomersen also resulted in significant reductions in app B, total cholesterol, and non-HDL cholesterol.

Because of their small size the mipomersen trials were not powered to assess cardiovascular outcomes, though cardiovascular benefit is of course the ultimate intended effect of the drug. However, the numbers in the phase 3 studies ran in the wrong direction. Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen  group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”

More troubling is the FDA safety review, mostly centering on liver-related problems. Mipomersen was associated with increases in serum transaminases and hepatic fat. In phase 3 trials, hepatic steatosis occurred in 7.3% (19/261) of mipomersen-treated patients compared with 1.6% (2/129)of  placebo-treated patients. ALT increased in 9.6% of mipomersen treated patients compared with 0.8% of placebo-treated patients. In a long-term extension trial one-quarter of mipomersen-treated patients had an average liver fat fraction greater than 20%. The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.

Other safety issues in the trials included injection site reactions and flu-like symptoms. The committee will also likely spend time discussing the cancer findings. According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that “there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”

The FDA will also ask the panel to evaluate a proposed Risk Evaluation and Mitigation Strategies (REMS) if the drug gains approval. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

Given the severity and rarity of homozygous FH it is difficult to predict how the committee will vote, but the safety concerns raised by the FDA make it extremely unlikely the drug could receive an expanded indication for heterozygous FH anytime in the near future.

FDA Reviewers Raise No New Red Flags Over Lomitapide 1

FDA reviewers have raised no new concerns about lomitapide ahead of a Wednesday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.  The FDA today released briefing documents that evaluate the new drug application (NDA) for lomitapide capsules, the microsomal triglyceride transfer protein (MTP) inhibitor from  Aegerion Pharmaceuticals for use as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and triglycerides in patients with homozygous familial hypercholesterolemia. (On Thursday the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Briefing documents for that meeting will be released on Tuesday.)

The reviewers concluded that lomitapide was effective in lowering LDL cholesterol by about 40%. The drug also effectively reduced total cholesterol, apoB, triglyceride, non-HDL, VLDL, and Lp(a) levels. Lomitapide also lowered potentially beneficial HDL and Apo A1 levels. The reviewers said that “the clinical consequences, if any, of these changes are unknown.”

The committee will likely focus on side effects and safety issues related to lomitapide. Gastrointestinal side effects are common with the drug. More troubling are concerns about possible liver damage associated with the drug. In the pivotal trial 38% of the patients had ALT elevations greater than three times the upper limit of normal, and 24% had elevations five times the ULN. Most patients in the trials also had significant elevations in hepatic fat. The reviewers also noted that lomitapide might induce deficiencies in fat-soluble nutrients.

To address the safety issues related to lomitapide the FDA will ask the committee to evaluate a Risk Evaluation and Mitigation Strategies (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would  require special certification for health care professionals and pharmacies that prescribe and dispense the drug.