Tuesday, March 5, 2013

Vascepa the latest option for lowering elevated triglycerides

  I think that you can tell from my previous post that I have had a long term interest and use of fish oil ( omega 3 fatty acids) for my patients with diabetes and elevated triglycerides. The development of highly purified forms of omega 3 fatty acids has been a major step forward in providing safe effective medications for all of us.
Vascepa just approved by the FDA in Janurary 2013 is a highly purified form of EPA.  My interest in Vascepa peaked after reading Jelis Study last year.

 Jelis Study (Japan EPA Lipid intervention Study) reported in Lancet 2007;369: 1090-8

 This study was included 18,000 patients with and without heart disease with total cholesterol of 251 mg/dl (6.5 mmol/L ) and LDL of 171 ( 4.4 mmol/L ) and randomized to a low dose statin alone or a statin plus 1.8 grams of EPA purified from omega - 3- fatty acids in fish oil and followed for an average of 4.6 years.
 Results ;
       Statin only group  --- ------------     3.5%  had a major coronary event
       Statin  plus 1.8 grams of EPA --   2.8%  had a major coronary event

A 19% relative risk reduction in the group receiving 1.8 gms of EPA

 There was a followup analysis of this study reported in Artherosclerosis 2009 may:204(1):233.
 This analysis looked at people in the Jelis study with elevated Triglycerides > 150 mg/dl and
  HDL < 40 mg/dl. In this higher risk group, EPA treatment resulted in a 53% relative risk reduction.


 Two other studies , Marine Trial and Anchor Trial , 
demonstrated Vascepa's effectiveness in lowering triglycerides and inflammatory risk markers such as hsCRP  levels. 

   The Marine trial was done in patients with triglyceride levels 500 mg/dl or higher
   The Anchor trial was done in patients with triglycerides between 200 and 500 mg/dl



These studies pointed out one interesting difference between Vascepa and Lovaza ( highly purified EPA and DHA ) is, Vascepa lowers LDL cholesterol ( the bad cholesterol) while Lovza slightly increases LDL cholesterol.I have not seen an analysis of this difference but it could be as simple as LDL particle size. Lowering triglycerides has been shown to increase LDL size which is a good thing . Small dense LDL particles increase the risk of heart disease.

Question- Can you name one test available in your doctors office that may help understand LDL particle size ?

A third trial is in progress , Reduce It ,
designed to evaluate the effectiveness of Vascepa in reducing cardiovascular risk.


Have fun , Be Smart and think about the fish oil your taking
David Calder,MD

ps. What about the Orgin study fish oil fans ? more tomorrow.
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I have attached information from the Amarin web site because they did a good job outlining the existing  studies mentioned above.
The efficacy and safety of Vascepa were studied in two Phase 3 clinical trials, the MARINE trial and the ANCHOR trial. Both studies were conducted under Special Protocol Assessment (SPA) agreements with the U.S. Food and Drug Administration (FDA). Amarin is also enrolling patients in a cardiovascular outcomes study designed to evaluate the efficacy of Vascepa in reducing major cardiovascular events in a high-risk patient population on statin therapy called REDUCE-IT. REDUCE-IT is also being conducted under a Special Protocol Assessment, or SPA, with FDA.
The MARINE study: A Phase 3, multi-center, placebo-controlled, randomized, double-blind, 12-week study that treated patients with severe (≥500 mg/dL) hypertriglyceridemia (very high triglycerides) with 229 patients enrolled. The primary endpoint in the trial was the percentage change in triglyceride level from baseline compared to placebo after 12 weeks of treatment. In November, 2010, Amarin reported top-line data for the MARINE trial which met its primary endpoints.
The MARINE trial demonstrated that Vascepa significantly lowered triglyercides without increasing LDL-C (non-significant decrease of -2%). In addition, MARINE demonstrated a statistically significant decrease in multiple other important lipid biomarkers including non-HDL-C, apolipoprotein B (apo B), lipoprotein-phospholipase A2 (Lp-PLA2), very low-density lipoprotein cholesterol (VLDL-C), Total Cholesterol (TC) and high-sensitivity C-reactive protein (hsCRP).
Vascepa® (icosapent ethyl) capsules, a therapy approved by the U.S. Food and Drug Administration (FDA) as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia (patient population studied in the MARINE trial), more commonly known as very high triglycerides, or VHTG, is now available by prescription.
In the MARINE study, the only reported adverse reaction with an incidence >2% and greater than placebo in Vascepa treated patients was arthralgia (2.3% for Vascepa vs. 1.0% for placebo).*

*based on pooled data across two clinical studies (MARINE and ANCHOR) that included patients with triglycerides values of 200 to 2000 mg/dL

For more information see www.vascepa.com.
The ANCHOR trial: A multi-center, placebo-controlled, randomized, double-blind, 12-week pivotal Phase 3 study in patients with high triglycerides (≥200 mg/dL and <500 mg/dL) who were also on statin therapy. 702 patients were enrolled in this trial. The primary endpoint in the trial was the percentage change in triglyceride level from baseline of Vascepa-treated subjects compared to placebo after 12 weeks of treatment. In April 2011, Amarin reported top-line results from the ANCHOR trial. The ANCHOR trial met its primary and secondary endpoints.
One of the ANCHOR trial's key secondary endpoints was to demonstrate a lack of elevation in LDL-C in order to avoid offset to the target of cholesterol lowering therapy. The trial's non-inferiority criterion for LDL-C was met at both Vascepa doses. For the 4 grams per day Vascepa group, LDL-C decreased significantly (-6.2%, P=0.0067) from baseline versus placebo, demonstrating superiority over placebo.
Other secondary efficacy endpoints included the median placebo-adjusted percent change in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), and lipoprotein-associated phospholipase A2 (Lp-PLA2) and very-low-density lipoprotein cholesterol (VLDL-C).
In this trial, the safety profile of Vascepa was comparable to placebo and there were no treatment-related serious adverse events.
The FDA has not completed its review of the ANCHOR trial. Vascepa is not approved for use in this patient population.
The REDUCE-IT (Reduction of Cardiovascular Events Outcomes trial): A multi-center, prospective, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the effectiveness of Vascepa as an add-on to statin therapy, in reducing the first major cardiovascular event in an high-risk patient population compared to statin therapy alone. Patients enrolled in the study have elevated triglyceride levels (>150 mg/dL) and at least one other defined cardiovascular risk factor. The control arm of the study is comprised of patients on optimized statin therapy. The active arm of the study is comprised of patients on optimized statin therapy plus Vascepa. Entry requirements for participants in this study include elevated triglyceride levels and either coronary heart disease or risk factors for coronary heart disease. This study is being conducted internationally and Amarin anticipates utilizing more than 300 clinical sites in connection with the trial, the largest number of which will be in the United States. In December 2011, Amarin announced that the first patient was dosed in the REDUCE-IT study. The study is scheduled to be completed in approximately six years and is anticipated to include approximately 8,000 patients.
This page was last updated on January 25, 2013.

 

3 ANCHOR Study Results Presented at American Heart Association's Scientific Sessions 2011

BEDMINSTER, N.J., and DUBLIN, IrelandNov. 16, 2011 (GLOBE NEWSWIRE) -- Amarin Corporation plc (Nasdaq:AMRN), a late-stage biopharmaceutical company with a focus on cardiovascular disease, announced today the first presentation in a scientific session of data from Amarin's Phase 3 clinical trial, the ANCHOR study, in which patients with high triglycerides who were also on statin therapy experienced a significant reduction in triglyceride levels and other lipid parameters, as well as important inflammatory biomarkers. The data, from Amarin's ANCHOR Phase 3 pivotal trial, were presented by Christie M. Ballantyne, M.D., at the American Heart Association's Scientific Sessions 2011.
As reported in April 2011, the ANCHOR trial met its primary endpoint, which was defined as themedian placebo-adjusted percentage change in triglyceride levels from baseline after 12 weeks of treatment. This endpoint was achieved at doses of 4 grams and 2 grams per day with median placebo-adjusted reductions in triglyceride levels of 21.5% (P<0.0001 value) for 4 grams and 10.1% (P=0.0005) for 2 grams. The median baseline triglyceride levels were 259 mg/dL, 265 mg/dL and 254 mg/dL for the patient groups treated with placebo, 4 grams and 2 grams of AMR101 per day, respectively. The analysis of subgroups by baseline triglyceride tertiles showed that higher baseline triglycerides resulted in greater triglyceride reductions.
Secondary efficacy endpoints included the median placebo-adjusted percent change in non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and lipoprotein-associated phospholipase A2 (Lp-PLA2). The 4 gram dose was associated with statistically significant reductions in non-HDL-C (13.6%), LDL-C (6.2%), apo B (9.3%), Lp-PLA2 (19%) and high-sensitivity C-reactive protein (hsCRP )(22%) at week 12 compared to placebo. The 2 gram dose was associated with statistically significant reductions in non-HDL-C (5.5%), apo B (3.8%), Lp-PLA2 (8.0%) and a non-statistically significant reduction in LDL-C (3.6%) and high-sensitivity C-reactive protein (hsCRP) (6.8%) at week 12 compared to placebo. 
Importantly, neither the 2 gram or 4 gram dose showed any significant increase in LDL-C compared to placebo; this was a pre-specified endpoint in this study using a non-inferiority test and, at the 4 gram dose, demonstrated not only non-inferiority but a statistically significant 6.2% reduction for patients who were optimally treated with atorvastatin, simvastatin, or rosuvastatin.
In the trial, AMR101 appeared to be safe and well tolerated, with incidence of treatment-emergent adverse events similar to placebo. No significant changes in fasting blood glucose, hemoglobin A1C, vital signs, electrocardiograms, or liver or kidney function with either AMR101 dose.
"The positive data from the ANCHOR study show that AMR101 may be an important therapeutic option for mixed dyslipidemia patients with persistent high triglyceride levels on statin-therapy," said Dr. Ballantyne. "One of the potential explanations for the continued elevation of cardiovascular risk in patients with persistent high triglyceride elevations despite statin therapy may be due to increased inflammation. Patients in the ANCHOR study who received AMR101 at 4 grams/day experienced a significant reduction in median placebo-adjusted inflammation biomarkers, specifically hsCRP and Lp-PLA2. The REDUCE-IT cardiovascular outcomes study will investigate the extent to which lipid and other biomarker changes observed by AMR101 will translate into a reduction in cardiovascular events."
The ANCHOR trial was a Phase 3, multi-center, placebo-controlled, randomized, double-blind, 12-week pivotal study. The ANCHOR trial investigated AMR101 as a treatment for high triglycerides (≥200 and <500mg/dL) in 702 patients with mixed dyslipidemia (two or more lipid disorders) on background statin therapy at LDL-C (low-density lipoprotein cholesterol) goal who were at high risk of cardiovascular disease. The majority of these patients were diabetic (73%). This is the largest trial with omega-3 therapy conducted in this important patient population. All patients were on background statin therapy with simvastatin, atorvastatin or rosuvastatin. Despite the benefits of statin therapy, patients in this population have significant residual risk for cardiovascular events. The trial was conducted under a Special Protocol Assessment (SPA) agreement with the FDA.
About AMR101
AMR101 is a prescription-grade omega-3 fatty acid, comprising not less than 96% ultra pure EPA (icosapent ethyl), that Amarin is developing for the treatment of patients with very high triglyceride levels (≥500 mg/dL) and as a potentially first-in-class therapy for patients with high triglyceride levels (≥200 and <500mg/dL) who are also on statin therapy for elevated LDL-cholesterol levels (which we refer to as mixed dyslipidemia). Triglycerides are fats in the blood. Significant scientific and clinical evidence support the efficacy and safety of ethyl-EPA in reducing triglyceride levels and other important lipid and inflammation biomarkers, including Apo-B, non-HDL-C, Total-Cholesterol, VLDL-C, Lp-PLA2, and hs-CRP. AMR101 demonstrated a safety profile comparable to placebo in two completed Phase 3 clinical trials.
About Amarin
Amarin Corporation plc is a late-stage biopharmaceutical company with expertise in lipid science focused on the treatment of cardiovascular disease. The Company's lead product candidate is AMR101 (icosapent ethyl). Amarin reported positive, statistically significant top-line results for both of its two pivotal Phase 3 clinical trials, the MARINE trial (investigation of AMR101 as a treatment for patients with very high triglycerides [≥500 mg/dL]), as reported in November 2010, and the ANCHOR trial (investigation of AMR101 for the treatment of patients on statin therapy with high triglycerides [≥200 and <500mg/dL] with mixed dyslipidemia), as reported in April 2011. Both the MARINE and ANCHOR trials were conducted under Special Protocol Assessment (SPA) agreements with the U.S. Food and Drug Administration (FDA). Amarin also has next-generation lipid candidates under evaluation for preclinical development. In September 2011Amarin submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for the marketing and sale of AMR101 for treatment of the patient population studied in the MARINE trial. Amarin plans to separately seek approval for the population studied in the ANCHOR trial after its REDUCE-IT cardiovascular outcomes trial is substantially underway. In August 2011, an SPA agreement with the FDAwas reached for the REDUCE-IT cardiovascular outcomes study. The Company seeks to have this study substantially underway before the end of 2012. 

         Sen

6 comments:

  1. Thank you for recognizing Vascepa...I am also an MD with a special interest in chronic inflammation..(not and employee or representative of AMRN).

    You may not be aware that EPA plays a crucial role as a moderator of inflammation..acting at the cellular level..it slows down the conversion of Omega6 Linoleic Acid derived DGLA into Arachidonic Acid (AA).AA is known to be the principal pro inflammatory signalling molecule in the inflammatory cascade...

    Diabetes, like other "degenerative diseases is an inflammatory disease..Insulin is known to activate the conversion of DGLA into AA thus increasing inflammation...EPA (and glucagon) are known to suppress the reaction..The most important benefit of EPA in diabetics, may be the anti inflammatory (diet controlled) action of EPA in combination with insulin control, rather than viewing it as simply a Trig reducing drug...Check out this reference...

    AMW

    http://www.drsears.com/portals/6/documents/inflammation%20medical%20brochure.pdf

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Your comments and questions are appreciated. David Calder,MD