IMPROVE-IT Trial Scheduled For Presentation In November Reply

Results of the eagerly-awaited and highly controversial IMPROVE-IT trial are finally going to be revealed. The American Heart Association has announced that the  trial will be presented by Chris Cannon on November 17 at 11:51 AM (central time) in Chicago at the group’s annual scientific sessions . IMPROVE-IT compared the effect on cardiovascular outcomes of the statin simvastatin with Vytorin (the combination of simvastatin and ezetimibe, manufactured by Merck) in more than 18,000 patients with acute coronary syndromes.

Both Vytorin and IMPROVE-IT have been the subject of considerable controversy.

Click here to read the full post on Forbes.

 

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12.8 Million More Adults Now Eligible For Statin Therapy Reply

Millions more people are now eligible for statin therapy under the new cholesterol guideline, according to a new estimate published in the New England Journal of Medicine.

There have been many attempts to quantify just how many more people are now eligible for statin therapy under the new guideline. Now in the new paper in NEJM, Michael Pencina and colleagues estimate that the new guideline results in a net increase of 12.8 million people who are now eligible for statins.

Click here to read the full post on Forbes.

 

FDA Sprinkles Some Rain On the PCSK9 Inhibitor Parade Reply

In the last few years the PCSK9 inhibitors have been one of the few bright lights in an otherwise dismal field of new cardiovascular drugs. Now the FDA is raising questions that could dramatically slow down the progress of these new cholesterol-lowering drugs.

Last month Regeneron disclosed that it had been “advised by the FDA that it has become aware of neurocognitive adverse events in the PCSK9 inhibitor class.”

Click here to read the full post on Forbes.

 

Aegerion Warns About Negative Impact Of DOJ Investigation Reply

Earlier this week in its annual report Aegerion Pharmaceuticals provided an update on its ongoing problems with the FDA and the Department of Justice. As previously reported here and on The Street and on CNBC, the company landed in hot water with the FDA last year after its CEO made a series of off-label statements on the CNBC Fast Money show. (The company’s only product, Juxtapid (lomitapide) is a cholesterol-lowering drug indicated for the rare condition of homozygous familial hypercholesterolemia. It sells for $250,000 a year.) Now the company reports that by running “a corrective advertisement on CNBC” and by reviewing additional promotional material  it believes it will be able to resolve its problems with the FDA.

But the DOJ investigation may prove to be a bigger and more serious problem….

Click here to read the full post on Forbes.

 

Pfizer Starts Testing For Over-The-Counter Lipitor Reply

Looking backward to improve its future, Pfizer will once again try to gain FDA approval to market its blockbuster drug, atorvastatin (Lipitor), over-the-counter (OTC). Peter Loftus reports in the Wall Street Journal that the company has started a clinical study to support the application for low-dose atorvastatin (10 mg).

Click here to read the full post on Forbes.

 

Dispatch From The Wild Frontier Of The Statin Wars Reply

The long simmering controversy over the relative benefits and harms of statins has heated to a high boil with the release of the new AHA/ACC US guidelines. But nowhere is the battle more intense right now than in Australia where, according to the National Heart Foundation, a TV show may be the cause of 2,000 heart attacks and strokes over the next five years.

The show was a 2-part documentary  (click here for part 1 and part 2) broadcast in October on the Australian ABC network about dietary fat and cholesterol.

The program, wrote Amy Corderoy, the health editor of the Sydney Morning Herald, “claimed the causal link between saturated fat, cholesterol and heart disease was ‘the biggest myth in medical history’… [and described statins] as toxic and potentially deadly.”

Catalyst delved into a raging debate: has dietary guidance telling us to avoid fats pushed us towards more harmful sugar and carbohydrates instead?

But the program also went a step further, arguing cholesterol was just an innocent bystander in the body’s attempts to deal with the sugar-damage. It was not a big leap to claim statins were dangerous, and the research supporting them fraudulent.

Click here to read the full post on Forbes.

 

Heart of the Matter screen shot

 

 

Slouching Toward Phase 3: Progress Report On New Cholesterol Drugs At The AHA Reply

The American Heart Association meeting in Dallas this year brought new phase 2 data about several promising new cholesterol drugs. But before jumping on any bandwagons it would be good to remember that even for the drugs most far along in development we still haven’t seen any phase 3 data. In addition, it bears repeating that the FDA may well be raising the entry bar for new cholesterol medications. As I wrote not too long ago, there is a good chance that the FDA will require completed outcomes studies for new cholesterol drugs. There’s good reason to be interested in these drugs but any predictions at this point would be hopelessly speculative.

One Year Results For Amgen’s PCSK-9 Inhibitor 

HDL Drug From CSL Limited

Esperion’s Novel Agent

Click here to read the full story on Forbes.

The Fate Of New Cholesterol Drugs Depends On IMPROVE-IT Reply

Prospects for the highly anticipated new class of cholesterol-lowering drugs, the PCSK9 inhibitors, took a wild roller coaster ride this week. The publication of new lipid guidelines by the American Heart Association and the American College of Cardiology led many observers to think that the promising new drugs under development by Regeneron (in partnership with Sanofi), Amgen, and Pfizer might suffer significant delays.

The guidelines delivered a strong statement questioning the increasingly controversial theory that LDL lowering by itself is beneficial. “We found that non-statin therapies really didn’t provide an acceptable risk reduction benefit compared to their potential for adverse effects in the routine prevention of heart attack and stroke,” said the co-chair of the guideline. This led many observers to think that the FDA would likely require the developers of PCSK9 inhibitors to complete cardiovascular outcome trials before getting US approval. This decision would delay approval for several years.

Then, on Thursday, the companies developing PCSK9 inhibitors received some apparent good news. Bloomberg News reported that an FDA official said that the drugs “will only have to meet the U.S. Food and Drug Administration’s existing standards for clearance, including whether they cut cholesterol and reduce blood pressure or inflammation.”

But then the FDA added one other very important caveat. Here’s how they phrased it to me:

Click here to read the full post on Forbes.

 

After Long Wait, Updated US Cardiovascular Guidelines Now Emphasize Risk Instead Of Targets 1

Updated cardiovascular health guidelines were released today by  the American Heart Association (AHA) and the American College of Cardiology (ACC). The guidelines are designed to provide primary care physicians with evidence-based expert guidance on cholesterol, obesity, risk assessment, and healthy lifestyle.

The new guidelines reinforce many of the same messages from previous guidelines, but also represent a sharp change in philosophy. That change is most evident in the new lipid guidelines, in which the focus has shifted away from setting numerical targets for cholesterol levels in favor of treatment decisions based on individual risk status.

“This guideline represents a departure from previous guidelines because it doesn’t focus on specific target levels of low-density lipoprotein cholesterol, commonly known as LDL, or ‘bad cholesterol,’ although the definition of optimal LDL cholesterol has not changed,” said Neil J. Stone, chair of the lipid expert panel that wrote the new guideline. “Instead, it focuses on defining groups for whom LDL lowering is proven to be most beneficial.”

The long-awaited and often controversial guidelines are the successors to the extremely influential NHLBI guidelines, including the Adult Treatment Panel (ATP) series of guidelines that brought cholesterol to the consciousness of millions of people. Earlier this year the NHLBI announced that it would no longer issue guidelines but would, instead, provide support for guidelines produced by other organizations. Following the NHLBI announcement, the AHA and the ACC said that they would take over publication of the guidelines.

Statins Indicated for Four Broad Groups

Click here to read the full post on Forbes.

Guideline Maze

Original illustration by Max Husten

 

Prevalence Of Cardiovascular Disease Likely To Increase Despite Gains In Treatment Reply

It is the best of times and the worst of times in the battle against cardiovascular disease. On the one hand, mortality rates from cardiovascular disease in the US have dropped by more than half in the last 30 years, likely due in large part to improvements in treatment for elevated blood pressure and cholesterol levels and big declines in smoking. On the other hand, it is uncertain whether these gains will continue, and many experts think that cardiovascular disease may well be on the rise once again, largely due to the aging of the population and to increases in obesity and diabetes.

In an article in Health Affairs, Ankur Pandya and colleagues (including cardiologist Thomas Gaziano of the Brigham and Women’s Hospital) forecast cardiovascular disease trends through the year 2030 using data from the National Health and Nutrition Examination Survey. They project that although the age-adjusted risk for cardiovascular disease is likely to continue to decline through 2030, because of an aging population and the increase in obesity the overall incidence of cardiovascular disease will increase.

Click here to read the full story on Forbes.

 

 

 

The Guidelines Are Dead. Long Live The Guidelines. Reply

Following last month’s surprising announcement that the National Heart, Lung, and Blood Institute would no longer issue guidelines, leaders of the American Heart Association and the American College of Cardiology have now announced that are “officially assuming the joint governance, management and public distribution” of the enormously influential cardiovascular prevention guidelines, including the much-delayed and much-anticipated hypertension and cholesterol guidelines (formerly known as JNC 8 and ATP IV). The ACC and AHA will also assume responsibility for guidelines on cardiovascular risk assessment, cardiovascular lifestyle interventions and obesity.

In an editorial published in Circulation and the Journal of the American College of Cardiology, leaders of the NHLBI, AHA, and ACC provide a little more information on how the new model will work. One important announcement, that “all chairs and members of the current writing panels have been invited to continue to work together with the ACC and AHA to finalize the guidelines,” might indicate that the hypertension and cholesterol guidelines could see the light of day in the not-too-far-distant future. In June the NHLBI’s Michael Lauer expressed confidence that these guidelines would appear in less than a year, but the AHA said that no timeline had yet been established.

Click here to read the full story on Forbes.

English: sm team guidelines logo

Hypertension And Cholesterol Guidelines Delayed Again As NHLBI Gets Out Of The Guidelines Business Reply

The National Heart, Lung, and Blood Institute (NHLBI) will no longer issue guidelines, including the much-delayed and much-anticipated hypertension (JNC 8) and cholesterol (ATP IV) guidelines. Instead, the NHLBI will perform systematic evidence reviews that other organizations, including the American Heart Association and the American College of Cardiology, will use as a resource for their own guidelines.

The exact fate and form of the delayed hypertension and cholesterol guidelines has not yet been decided, though the NHLBI’s Michael Lauer said he was confident that these guidelines would appear in less than a year. But a lot of work remains before the documents can be published. ACC President John Harold said that  “the ACC has not formally agreed to or begun the process of updating” the NHLBI documents, “but we are open to this role and look forward to working out details with NHLBI and the American Heart Association.”

Click here to read the full story on Forbes.

 

NHLBI Director Dr. Gary Gibbons

NHLBI Director Dr. Gary Gibbons

Unconventional Analysis Finds Threshold For LDL Reduction With Statins Reply

Using an unconventional mathematical approach, a group of Japanese researchers say there may be no good reason to reduce LDL cholesterol more than 40 mg/dl. Their research letter has been published online in JAMA Internal Medicine.

According to the authors, members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group, most meta-analyses use linear models that assume “a constantly increasing or decreasing risk as the exposure increases or decreases.” Linear models, however, can be “misleading,” they write, because they assume a specific dose-response relationship. By contrast, their new analysis utilizes “flexible” models that can more readily uncover “threshold effects.”

Click here to read the full post on Forbes.

 

Lifelong Statin Sentence Now Includes Furloughs 1

Although the benefits of statins are among the best documented in all of medicine, continuous lifelong statin therapy is not always easy to achieve in clinical practice. Now a new retrospective study suggests that although clinical events causing temporary cessation of statin therapy occur often, most of these patients are later able to resume statin therapy.

In a paper published in Annals of Internal Medicine, researchers analyzed data from 107,835 patients with a statin prescription treated by physicians associated with Massachusetts General Hospital and Brigham and Women’s Hospital. 18,778 of these patients had documented events that were statin related, resulting in 11,124 patients who stopped taking statins. Within a year more than half of these (6,579) were rechallenged with a statin, and most of these (92.2%) were taking a statin a year after the initial statin-related event.

Click here to read the full story on Forbes.

 

 

Large Meta-Analysis Finds No Harm Associated With Eggs 2

No food has had more ups and downs over the last century or so than the common egg. Following a long period in which eggs were ubiquitous and highly regarded, eggs fell from favor with the rise of concerns over cholesterol. Currently the American Heart Association recommends that people restrict dietary cholesterol to 300 mg per day, which effectively limits people to 1 egg per day at most. However, the relationship of dietary cholesterol and serum cholesterol  is, at best, tenuous, and a significant number of experts now believe that egg consumption poses no risk to cardiovascular health.

In a new paper published in BMJ, a group of researchers from China and Boston performed a meta-analysis of 8 studies that included 263 938 participants for coronary heart disease (CHD) and 210 404 participants for stroke and followed them for 8 to 22 years. The authors found no evidence for an association between egg consumption and either coronary heart disease or stroke…

Click here to read the full story on Forbes.

Should Niacin Still Be Prescribed? William Boden Versus Harlan Krumholz 1

In the wake of HPS2-THRIVE many have argued that there is no longer any reason to prescribe niacin. William Boden, the lead investigator of AIM-HIGH and COURAGE, thinks there were enough flaws in the design of the niacin trials to justify the cautious use of niacin in certain circumstances. Says Boden:

“There is evidence of clinical outcome improvement (i.e., CHD death/MI reduction) from VA-HIT for gemfibrozil; there is similar clinical outcome improvement for niacin from the Coronary Drug Project. Numerous studies show niacin’s benefit on surrogate outcome measures (i.e., quantitative coronary angiography, IVUS, cIMT, etc.). What more evidence do you need?”

” I have not given up on niacin.”

Harlan Krumholz  disagrees:

“We have to face the facts about the trials. They have failed to be supportive, and despite concerns about their flaws, they were developed by some of the best minds in our profession (including yours) and had millions of dollars devoted to them. I just feel that we cannot justify millions of people being prescribed a drug that has failed in two recent, large, prominent trials, which actually had signals of harm…”

Read the entire fascinating discussion over on CardioExchange.

Boden

William Boden

Harlan Krumholz

Harlan Krumholz

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

English: Logo of the .

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.
Click here to read the Merck press release…

Following Earlier Recall, Ranbaxy Halts Manufacturing Atorvastatin Reply

Ranbaxy, the often-troubled manufacturer of generic drugs, will temporarily stop manufacturing generic atorvastatin. On November 9, 2012 the company announced a voluntary recall of some lots of atorvastatin because of possible contamination with glass particles. An FDA statement today said that Ranbaxy will discontinue making the drug “until it has thoroughly investigated the cause of the glass particulates and remedied the problem.”

To date, no reports of harm from the contamination have been received by the FDA. Both FDA and Ranbaxy believe there is only a low likelihood that there will be adverse events related to the problem.

The FDA said it does not anticipate a shortage of atorvastatin because of the recall, but that it “is working with other manufacturers of atorvastatin to ensure adequate market supply.”
Click to read the FDA statement…

Early Look: New Methods To Enhance Cholesterol Efflux Reply

Although clinical trials of HDL-boosting CETP inhibitors have so far failed to produce positive results, many other avenues of HDL-related research remain active.  A glimpse at the very early phases of two intriguing lines of research in this area was offered on Monday at the AHA.

Apo A-1 is thought to be the key HDL component that removes cholesterol from cells. Almost a decade ago a study demonstrating regression of atherosclerosis with apo A-1 Milano caused tremendous excitement, but the recombinant product has not yet undergone further research or commercial development. A somewhat similar approach is now being developed by by CSL Limited with a novel formulation of human apo A-1, known as CSL112. At the AHA, Andreas Gille and colleagues reported giving CSL112 to healthy volunteers and observing dramatic increases in the ability of the HDL in their blood plasma to remove cholesterol from cells.

Gille reported that the increase in cholesterol efflux capacity was higher and occurred faster than any previous therapy, more than doubling within two hours, as opposed to a 2.9% increase after 4 weeks with niacin or 6.8% after 24 months with dalcetrapib. “CSL112 may offer a novel means to rapidly remove cholesterol from plaque following a heart attack,” said Gille. To date two phase 1 studies have demonstrated a favorable safety profile, he reported. A phase 2 study of CSL112 in patients with an acute coronary syndrome is planned.

An even more unusual approach is being explored by Alan Fogelman and his team, who have genetically engineered a tomato to produce a small peptide, 6F, that mimics the action of apo A-1. They then fed the tomatoes to mice with high LDL levels. After consuming the tomatoes along with a high-fat and high-calorie diet, there were a number of signs suggesting a beneficial effect, including significantly lower levels of inflammation, higher levels of the antioxidant paraoxonase, higher HDL levels, and less atherosclerotic plaque.

“To our knowledge this is the first example of a drug with these properties that has been produced in an edible plant and is biologically active when fed without any isolation or purification of the drug,” Fogelman said in an AHA press release.
Click here to read the press releases from the AHA…

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.

News Briefs: Cholesterol Trends, AHA Late-Breakers, FDA Updates On Rivaroxaban And Heartware HVAD Reply

Cholesterol Trends

The Centers for Disease Control issued a new report with the latest details about the prevalence of cholesterol screening and high blood cholesterol in US adults. Here is their summary of the key findings:

…cholesterol screening increased from 72.7% in 2005 to 76.0% in 2009, whereas the percentage of those screened who reported being told they had high cholesterol increased from 33.2% to 35.0%. Previously identified demographic disparities persist.

AHA Previews LBCTs

The American Heart Association has published a preview of the late-breaking clinical trials scheduled for presentation in November at the scientific sessions in Los Angeles. 28 LBCTs have been selected, including the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial and the controversial Trial to Assess Chelation Therapy (TACT).

J&J Provides More Information To FDA About Rivaroxaban

Johnson & Johnson said today that it had fully responded to the FDA’s request for more information about the use of rivaroxaban (Xarelto) in patients with acute coronary syndromes. The company also said it had resubmitted its supplemental New Drug Application (sNDA) for the drug to reduce the risk of stent thrombosis in ACS patients.

Heartware HVAD Close To FDA Approval

The Heartware HVAD ventricular assist system may be approved soon by the FDA, according to Wells Fargo analyst Larry Biegelsen. Robert Kormos, a cardiothoracic surgeon at the University of Pittsburgh, who also consults for Heartware,  said during a session at a Society of Thoracic Surgeons symposium that the device would be approved in the next few weeks.

Republished with permission from CardioExchange, a NEJM group publication.