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.

About these ads

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

 

Why The FDA Probably Won’t Approve An Expanded Indication For Amarin’s Vascepa Reply

On Wednesday an FDA advisory  panel will consider an expanded indication for Amarin Pharmaceuticals’ Vascepa, an EPA fish oil product currently indicated only for people with severe hypertriglyceridemia (>500 mg/dl). The new indication would greatly expand the patient population eligible to receive Vascepa, from the relatively few people with severe hypertriglyceridemia to the many millions with elevated triglycerides (>200 mg/dl) and existing CV disease or at high risk for CV disease. The NDA for this indication is based on the ANCHOR trial, which showed that Vascepa lowered triglycerides in the target patient population.

The FDA review (available here) raises 2 troubling issues. The first is fairly simple and relates to the performance of the placebo in ANCHOR.  In its briefing documents the FDA raises the disturbing and unusual possibility that the mineral oil placebo used in the trial may not have been biologically inert. LDL levels in the placebo group went up 9% in the placebo group and this will make it difficult to assess the true effect of Vascepa. It’s unlikely that this issue by itself will entirely derail the NDA, but it may well serve to undermine confidence in the trial and put the panel in a critical frame of mind.

More significant, to my mind, is the lack of any evidence for any important improvement in clinical outcomes that can be tied to Vascepa….

Click here to read the full post on Forbes.

News From Our ‘Statin Civilization’: High-Dose Statins Found To Reduce Gum Disease Inflammation Reply

In addition to their well-known benefits in heart disease, high-dose statins appear to reduce gum inflammation caused by periodontal disease, a new report published in the Journal of the American College of Cardiology shows. The findings offer more evidence that heart disease and gum disease may be linked, and also help support the view that statins achieve at least some of their effect not through their cholesterol-lowering effect but through separate inflammation-fighting mechanisms.

Researchers reported findings from 59 patients with cardiovascular disease or at high risk for cardiovascular disease who had evidence  of arterial inflammation on a  PET scan. The patients were randomized to a low (10 mg per day) or high (80 mg per day) dose of atorvastatin. After 12 weeks there was a significant reduction in periodontal inflammation as measured by PET in patients taking high dose atorvastatin. The effect was greatest in those patients who had active periodontal disease. There was evidence of a significant effect as early as 4 weeks. Furthermore, there was a strong correlation between reductions in periodontal inflammation and atherosclerosis, though the authors acknowledged that the precise nature of the association remains undefined.

Click here to read the full story on Forbes.

English: Periodontal bone loss shown in X-Ray ...

Periodontal bone loss shown in X-Ray image. (Photo credit: Wikipedia)

Small Study Suggests Statins May Blunt Benefits Of Exercise 1

A small study is raising big questions about whether statins may blunt the beneficial effects of exercise. The study has been published online in the Journal of the American College of Cardiology and was the subject of a New York Times blog today.

The authors concluded: “Given the strong independent cardio-protective effects of increasing cardiorespiratory fitness or lowering LDL, the benefits and risks of each should be carefully considered when choosing treatment modalities.”

Click here to read the full story on Forbes.

 

John Thyfault

 

FDA Approves Combination Of Ezetimibe And Atorvastatin Reply

The FDA has approved a new combination drug from Merck for lowering cholesterol. The drug, which will carry the brand name of Liptruzet, is a combination of two previously approved cholesterol-lowering drugs, ezetimibe and atorvastatin.

Merck said the new drug (pronounced “LIP-true-zett”) would be commercially available starting next week. Liptruzet will be available as a once-daily tablet combining 10 mg of ezetimibe with either 10, 20, 40, or 80 mg of atorvastatin. In clinical trials Liptruzet lowered LDL cholesterol from 53% to 61%, depending on dosage.

Click here to read the full post on Forbes.

 

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.

 

HPS2-THRIVE: A ‘Disappointing But Clear’ Result Reply

The results of HPS2-THRIVE were “disappointing but clear,”  said Jane Armitage, who presented the results this morning at the ACC in San Francisco.

HPS2-THRIVE randomized 25,673 high-risk patients who could tolerate niacin to either placebo or extended-release niacin plus laropiprant (Tredaptive, Merck), an anti-flushing agent, in addition to background therapy. The primary endpoint was the time to first major vascular event, defined as the composite of non-fatal MI or coronary death, any stroke or any arterial revascularization.

Major vascular events occurred in 13.2% of the niacin arm and 13.7% of the placebo arm (p=0.29), despite causing average reductions in LDL of 10 mg.dL and triglycerides of 33 mg/dL, in addition to a 6 mg/dL increase in HDL. Armitrage reported that based on data from previous trials and observational studies, “it was anticipated such lipid differences might translate into a 10-15% reduction in vascular events.”

HPS2-THRIVE study chairman, Rory Collins, responded to a question in the press conference: “To the question is niacin dead? Well, it’s not healthy!”

Click here to read the full story on Forbes.

 

Study Casts Doubt On Value Of Genetic Testing For Familial Hypercholesterolemia Reply

new study published online in the Lancet suggests that one of the main screening plans that relies on genetic tests will fail to identify a substantial portion of people with familial hypercholesterolemia.

Investigators from the UK and Belgium analyzed DNA from several cohorts of FH and non-FH patients. Their chief finding was that a large percentage of FH patients did not have one of the single genetic mutations known to cause FH. Instead, these patients, termed “polygenic,” were found to have variants in multiple genes, each of which had a small LDL-raising effect, but when combined resulted in LDL levels similar to those in people with known FH mutations.

According to one cholesterol expert: 

The take home is that genetic screening is not a panacea and that screening based on fasting ipids makes most sense. Indeed, I never understood genetic screening for this disease anyway, since the phenotype (hypercholesterolemia) is what kills people, not the genotype, the phenotype is readily available with a blood test, the disease is not immediately fatal (It takes years to develop), and treatment is based on the numbers. It is like asking for a gene test fro sickle cell anemia. You can look at blood and make the diagnosis.

Click here to read the complete story on Forbes.