MyFatDog        

August 2009

Wow, it's been a while!  We tried an experiment to see what would happen if we only reported what we considered (as opposed to company hype)  to be relevant news items. The news was a little slower than we expected... no news were hoping for ... but, alas, we have some news!  Kowa Pharmaceuticals announced that they received FDA approval on a "new" statin (pitavastatin) with the trade name call "Livalo".   In actuality this is a drug that has been approved for use outside the US for many years and was written off for use in the US by it's maker, Novartis.  The drug has since been licensed by Kowa and just obtained approval for use in the US.  Why would you  want to use Livalo?  Maybe if you don't tolerate other statins on the market, maybe because of the cost (remains to be seen).   Pitavastatin was just reported to reduce atherosclerotic plaque volume, similar to artorvastatin, so it sems to be effective for that in addition to it's cholesterol-lowerinfg properties.  For whatever reason, we are happy to report the approval in the US of a new cholesterol-lowering drug!

May 2009

Anthera  announced intial results from the FRANCIS (Fewer Recurrent Acute coronary events with Near-term Cardiovascular Inflammation Suppression) trial with varespladib.  The company announced that varespladib, a  secretory phospholipase A2 inhibitor, met its primary goal of reducing LDL in patients with acute coronary syndrome (ACS) when given in combination with atorvastatin.   The company also reported that a greater proportion of patients treated with varespladib in combination with atorvastatin reached and maintained a LDL cholesterol level of less than 70 mg/dl.  More detailed results are expected to be reported at scientific meetings. 

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BioInvent announced that BI-204, a drug designed specifically to lower levels of oxidized LDL, successfully completed phase I studies in safety and tolerability.  This study was conducted in 80 subjects with elevated LDL cholesterol.  No information on effectiveness was reported.  The drug will now likely advance to phase II.  BI-204 is being co-developed with Genentech.

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Results were reported for a study that compared the effect of consuming a diet rich in fructose or glucose on the development of obesity and pre-diabetes.  Consistent with previous studies in animals, the results showed that both diets promoted weight gain.  However, the fructose diet promoted an increase in abdominal fat which is associated with pre-diabetes, while the glucose diet did not.  Not surprisingly the group receiving the fructose diet did develop pre-diabetes while those consuming the glucose diet didn’t.  The group consuming the fructose diet also had an increase in LDL and other atherogenic lipoproteins while the glucose group didn’t.  The take-home message would be not to consume foods rich in fructose, especially if you are obese or otherwise predisposed to having pre-diabetes or diabetes.

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April 2009

In their quarterly update, Roche announced that development of their lead CETP inhibitor dalcetrapib (R1658, or RO4607381 or JTT-705), which is currently in phase III trials, is proceeding according to plan.  Phase III studies with dalcetrapib are scheduled for completion in early 2012.  Due to the progress of this compound they have made the decision to discontinue their backup CETP inhibitor, R7232, which was in phase I development.  CETP inhibitors are designed to raise HDL (good) cholesterol levels. 

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A paper was recently published in The Cochrane Library, a publication by a group that is supposed to give opinions on medical treatments based on unbiased reviews of the medical literature, concluded that treatment with statin drugs later in life no not prevent Alzheimer's Disease or dementia (mental deterioration).  This conclusion is based on data from two large studies that included patients over the age of 70 that were treated with either statins or placebo (sugar pill).  Despite significant lowering of plasma cholesterol, there was no evidence of improved cognitive function (memory, speed of thinking, logic and reasoning, etc.) between patients who were treated with statin or placebo after 3.2 to 5 years after treatment.  The paper concludes that statins cannot be recommended for treatment of Alzheimer's Disease or dementia.

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Tekmira announced that they have submitted an Investigational New Drug application for their lead drug candidate apoB SNALP.  SNALP is an acronym for Stable Nucleic Acid-Lipid Particles.  This technology has enabled delivery of RNA interference drugs which disrupt the RNA templates that are used to make proteins, in this case apoB which is needed to make VLDL and LDL.  Delivery of RNA interference drugs to cells has been problematic and it has been shown that by surrounding the active part of the drug with lipid increases the delivery of the drug to cells.  Here's a link to a schematic that shows this.  This drug, if approved, would compete with ISIS/Genzyme's mipomersen which also disrupts apoB synthesis.

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Pfizer updated their pipeline (pipeline pdf document) and, as we expected, they discontinued their two CETP inhibitors (CP-800569 and PF-3185043) that were in phase I of development.  Pfizer announced a strategic decision several months ago to discontinue development of cardiovascular drugs.  Instead it appears that this was simply limited to antidyslipidemics since they are still  developing cardiovascular drugs but appear to be focusing more on acute coronary syndrome (i.e. sudden heart attacks), atrial fibrillation (heart rhythm disorders) and thrombosis (thick blood that results in clotting) as well as certain metabolic diseases.

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The Wall Street Journal had a story of twins with a rare disease called Nieman Pick type C disease.  This is a disease where a protein (not surprisingly called Niemann-Pick C or NP-C) is missing or doesn't work properly.  The protein functions to move cholesterol and other lipids between different parts of cells.  If you're missing the protein the cells accumulate cholesterol and lipids in all the wrong spots and the cells either don't function normally or may die.  Some individuals with this disease die during childhood while others survive into adulthood.  Cyclodextrin is a molecule that allows cholesterol (and possibly other lipids) to move freely around the different parts of the cell.  It's often used in research studies and has recently been identified as a potential therapeutic agent since it seems to correct the cholesterol defect in mice missing the one version of the NP-C protein.  The article in the Wall Street Journal describes the story of a mother with twins who have this disease and her quest to get compassionate use approval from the FDA to use cyclodextrin to treat her children.  If this experimental treatment is successful it would pave the way for use of cyclodextrin as an orphan drug for treating similar rare disorders. You can read more about these children here.

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March 2009

The results of a study testing a new "Polypill" developed by Cadila Pharmaceuticals were announced at the American College of cardiology Meeting in Orlando, Fl and simultaneously published in the Lancet.  The study measured a number of outcomes in patients treated with the polypill, which contains three blood pressure medications, simvastatin, aspirin, and folic acid.  These outcomes were compared to those for patients treated with either individual components or various combinations of different components of the pill - sounds complicated?  That's because it is.  The actual study design is described here.  Patients in each group were treated for three months.  While not surprising that the pill reduced LDL cholesterol (because it contains simvastatin) it actually was less effective in LDL lowering than the same dose of simvastatin alone (not in a polypill).  There were also benefits in reducing blood pressure, heart rate and antiplatelet effects in patients treated with the polypill.  The safety profile was similar to that for patients in the other groups.  The long-term benefit of the Polypill will need to be addressed in a larger outcome study.

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The results of a clinical trial in which subjects were treated with an extract from the seed of the African mango, Irvingia gabonensis were reported eariler this month.  The results of the trial showed that 10 weeks of treatment with this extract reduced LDL cholesterol levels by 27% and also reduced body weight over that period by about 12%, falling from approximately 212 lbs to 187 lbs.  They also report that plasma glucose levels were signficantly reduced.  According to the article there were no signfiicant differences in the reported side effects between the group receiving the seed extract and those receiving placebo (sugar pill).  The most frequent side effects were headache, sleep difficulty and flatulence.  One potential downside that was not mentioned in the article is that there was a likely reduction in HDL (good) cholesterol levels that appears to be fairly large.

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Chuck wanted to know about a new dietary supplement called Resvida.  Unfortunately his email bounced back so we couldn't respond directly but we'll answer you here.  Resvida is the brand name for a dietary supplement called resveratrol that is marketed by DSM Nutritional products. Resveratrol is a compound that is present in red wine that has been associated with anti-aging and antidiabetic effects in animals. It has also been reported to have antioxidant properties and has been shown to reduce LDL oxidation.  Most studies testing resveratrol in animals have produced beneficial effects but a few studies have reported toxic effects.

Very little has been published about the effects of resveratrol in humans. There is currently a study ongoing that is testing Resvida to see if it has anti-aging and antidiabetic effects and to demonstrate that it is safe to use in humans. The resultsfor that study should be reported in 2010.

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We recently started working on a LDL goal calculator.  It calculates what the LDL goal should be based on the ATP 3 Cholesterol Guidelines.  It still needs some work but is ready for testing.  Here's the link to the beta version of the LDL Goal Calculator.

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The American College of Cardiology meeting is being held in Orlando at the end of this month.  Some presentations of interest include the following:

1) A study showing that among patients hospitalized for sepsis (blood infection), those taking statins at the time of hospitalization were less likely to die than those not taking statins.

2) Red yeast rice has been shown to have a component similar to the active ingredient in statin drugs.  A study to be presented a the meeting  compares two different formulations of red yeast rice and shows a difference in their effectiveness.  One lowered LDL cholesterol by 27% while the other lowered LDL by 42%.

3) A study showing that the secretory phospholipase A2 inhibitor varespladib lowers LDL cholesterol by 15% in patients with both normal blood sugar and those with diabetes.

4) A study showing that a short-chain polysaccharide, HEP-40, lowered LDL cholesterol by about an additional 15% when given to patients currently taking stains.

5)  A study showing that RVX-208 significantly increased the major protein on HDL, apoA-I, but not HDL cholesterol in subjects treated for 7 days.

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We're entering a busy part of the year for drug updates.  Dara Biosciences just announced approval of their Investigational New Drug application for their PPAR delta/gamma activator DB959.  This drug has been shown to improve insulin sentivity in diabetic animal models in preclinical studies as well as increasing HDL.  In our view this drug faces an uphill battle since the vast majority of dual PPAR activators to date have had undesirable safety profiles.

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   In lighter news, we're almost a year old and someone got creative with the My Fat Dog mascot, Roscoe, and dressed him up for St. Patrick's day.  We like it so we're leaving it up for a few days.  We hope you like it too. 

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An abstract entitled "Statins reduce orgasm: results from the UCSD statin study" was presented at the American Psychosomatic Society Annual Meeting in Chicago.  According to an article in USA Today, the abstract reported on results of the UCSD Statin Study which was originally conducted between 2000 and 2004.  The study compared the effect of simvastatin (Zocor), pravastatin (Pravastatin), or placebo (sugar pill)  treatment for 6 months on sexual pleasure.  Study subjects were men and women over 20 years of age with LDL cholesterol levels between 115-190 mg/dl who had no evidence of heart disease.   The study found that subjects treated with simvastatin had a reduction in sexual pleasure over the course of the 6 month treatment period.  There was no effect of pravastatin treatment on sexual pleasure.  It's unknow what effect atorvastatin (Lipitor) has on sexual pleasure since it wasn't tested in this study.    The study seems to be a tertiary analysis, meaning that it wasn't part of the original study design, so the results may be subject to some unknown bias or may be due to statistical chance and should be interpreted with caution.  The lead investigator of this study also heads a group is that is actively studying statin side effects. This same group has also reported that simvastatin, but not pravastatin, also reduces sleep quality.

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Metabasis announced that preclinical findings about its lead antidyslipidemic compound MB07811 were published in 4 separate articles.  MB07811 is a thyroid receptor beta activator that lowers LDL, triglycerides and Lp(a).  Two articles describe the how the drug is synthesized and metabolized.  The other two describe the additive effect that the drug has on lowering LDL in different animal models as well as its effect of reducing liver fat in rodents.   In June 2008 the company reported results from a phase I study in which LDL, triglycerides and Lp(a) were reduced in humans.  In that study there were "mild" increases in liver enzymes at the higher doses which could indicate some liver damage.  They are planning to begin a phase II trial in subjects with high LDL cholesterol levels in the first half of 2009.

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February 2009

A "Medical News" story appeared in the Journal of the American Medical Association (JAMA) describing the FDA's stance on the use of ezetimibe/simvastatin (Vytorin) in the treatment of increased LDL cholesterol levels (listed under January 2009, below).  The story described the controversy surrounding the use of this combination resulting a delayed clincal trial that was found to be negative.  The delay in the release of negative findings led to accusations that the the company that sponsored the trial may have tried to influence the reported outcome.  The story also mentions comments from scientists who criticise the FDA's decision to approve the use of the ezetimibe/simvastatin combaintion based strictly on cholesterol lowering rather than the results of a large clinical outcome study.  Finally the story ends with more controversey regarding the association with cancer that was seen in one trial in patients treated with the combination drug.  Susbequent studies have indicated that this was a fluke and that there is no increased risk of cancer. The FDA is currently investigating this and will report an opinion in the Spring of 2009.

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The company MDRNA reported that their proprietary UsiRNA constructs have been used to reduce expression of two genes related to increased LDL cholesterol levels in mice.  The genes whose expression was reduced are apolipoprotein B and PCSK9.  These new constructs may be replacing the apoB siRNA MDR-04227 that was reported as being a pipeline candidate in August 2008 but appears to have been discontinued.

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An article was published in the British Medical Journal that examined the effect of raising HDL (good) cholesterol levels on the risk of cardiovascular disease.  The analysis was conducted on data pooled from 108 published studies that involved 299,310 people.  The study found that in a simple analysis, raising HDL cholesterol was associated with a reduction in the risk of cardiovascular disease.  However, since LDL (bad) cholesterol levels  often decrease in studies where HDL cholesterol levels increase, the authors did a more sophistocated analysis to account for the change in LDL cholesterol levels.  When they did this they found that raising HDL cholesterol levels had no effect on the risk of cardiovascular disease.  Instead, they found that all the benefit of treatments that raise HDL cholesterol levels comes from their effect of reducing LDL cholesterol.   They also found that there was no direct benefit to lowering plasma triglyceride levels.  Instead, the benfit associated with the triglyceride-lowering effect of different drugs could also be accounted for by the effects of these drugs on reducing LDL cholesterol levels.  The good news is that most treatments designed to lower triglyceride or raise HDL levels also reduce LDL cholesterol levels.  If this study is confirmed then it may signal the start of a shift towards monitoring the effect of all lipid-altering drugs on their LDL lowering effcts rather than their effects on triglyceride or HDL levels.

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An article was published in the Lancet that tested the effect of the secretory phospholipase A2 (sPLA2) inhibitor varespladib (also known as A-002; Anthera Pharmaceuticals) on a number of biomarkers in patients with coronary heart disease.  The drug produced a dose-dependent reduction in plasma levels of sPLA2 and had a modest effect of reducing LDL cholesterol levels by 8%.  There were 36 dropouts in the A-002 treated group vs. 9 in the placebo group.  The major side effects were headache, nausea and diarrhea.  The study concludes that the drug may show promise as an anti-atherosclerotic agent.  There is a trial underway, the FRANCIS trial, that is designed to test whether or not A-002 has any benefit on reducing recurring cardiac events when given in combination with high dose atorvastatin in patients who have recently had a coronary event such as a heart attack.

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Cerenis Therapeutics announced that they are licensing an HDL technology developed at the Montreal Heart Institute for the treatment of narrowing of a major blood vessel in the heart.  While the technology is described as being an apoA-I mimetic peptide, it is actually a reconstituted HDL made of a mixture of phospholipids that contains an apoA-I mimetic peptide.  This is very similar to ET-216, a reconstituted HDL containing apoA-I(Milano),  that was developed by Esperion and later purchased by Pfizer.  ET-216 was covered by a previously issued US patent "Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias" that included adminstering phospholipid liposomes that contain apoA-I or synthetic fragments of apoA-I as a means of enhancing reverse cholesterol transport.

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January 2009

There was interesting paper published in the journal Endocrinology this week that showed that the side effects of the CETP inhibitor torcetrapib were likely due to effects of that specific the drug itself on blood pressure and adrenal hormones rather than due to the inhibition of CETP.  They shosed that these side effects could be replicated using compounds that were similar in chemical structure to torcetrapib but did not inhibit CETP.  They also showed that these side effects were not seen using at least one CETP inhibitor that is currently in clinical trials, that being anacetrapib (MK-859) .  This study provides additional support for the idea that raising HDL (good) cholesterol levels using CETP inhibitors will reduce the risk of cardiovascular disease.

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A paper was published this week in the Journal of the American Chemical Society that describes a method to make synthetic HDL.   The method creates an HDL particle that contains gold, lipid and protein.  While there has been a lot of attention paid to this paper this week which was cited by several news organizations, the method is not that different in concept to the drug that was discontinued by Pfizer earlier this year. That drug, ET-216, (originally developed by Esperion) was a complex of phospholipid and apolipoprotein A-I that also created a synthetic HDL.   While the technology held promise since it could reverse heart disease, it was apparently plagued by apoA-I production problems.  CSL Limited also developed and tested a similar drug, CSL111, that  had somewhat disappointing results when tested.

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The US FDA released guidance on the use of Vytorin (ezetimibe/simvastatin combination) to lower LDL levels to reduce risk of cardiovascular disease.    After further review of available data, the FDA continues to believe that the use of Vytorin to lower LDL cholesterol levels is of benefit.  They recommend that, based on currently availabe information, patients should not stop taking Vytorin and should consult with their doctor if they have questions about Vytorin.  They point out that a large 18,000 patient outcome trial, the IMPROVE-IT trial, that is scheduled to be completed in 2012 will provide definitive information regarding the additional clinical benefit of adding ezetimibe to simvastatin treatment.

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Trilipix, a new fenofibrate formulation co-developed by Solvay Pharmaceuticals and Abbott, was approved by the US FDA.  The drug is approved to lower plasma triglyceride levels and increase HDL levels.  The drug also lowers LDL levels in most patients except those with high plasma triglyceride levels.

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