MyFatDog        

April 2008

The Eurpoean Atherosclerosis Society Meeting was held in Turkey this week.  Two presentations included updates of two drugs under development.  The first was  a presentation about the CETP inhibitor RO460738 (JTT-705) currently being developed by Roche.  The study compared the effect of RO-460738 and torcetrapib on blood pressure in rats.  Torcetrapib was the CETP inhibitor from Pfizer that was discontinued due to off-target effects that included adverse effects on blood pressure. The study found that the off-target effects on blood pressure seen with torcetrapib were not seen with RO-460738.

A second presentation at the Eurpoean Atherosclerosis Society Meeting was about RVX-208, a drug being developed by Resverlogix to increase HDL levels.  The study looked at the mechanis of how RVX-208 increases HDL and the effects on reverse cholesterol transport.  These studies were done in cells from mice and humans as well as in monkeys.  The study showed that RVX-208 increased HDL in monkeys by up to 63%.  The drug also increased apoA-I expression in human cells and was associated with increased effects on on reverse cholesterol transport in a cell culture assay.  The study concluded that RVX-208 increases HDL by increasing HDL production and that this is associated with improved HDL function.

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Merck announced that they received a non-approvable letter from the FDA for Cordaptive, their combination drug for raising HDL.  Cordaptive is a combination of extended-release niacin and laropiprant, a prostaglandin D2 receptor antagonist.  The combination drug is designed to increase HDL and reduce triglyceride levels (from niacin) while minimizing the subcutaneous flushing and itching (laropiprant) that is frequently associated with niacin.  There was no reason announced regarding this decision.  Merck said that they will provide the FDA with additional information to allow the FDA to further evaluate the risks and benefits of the combination drug.  The FDA also said that the trade name for the combination drug, "Cordaptive", was unacceptable.  Merck announced that they will pursue the name "Tredaptive" as an alternative trade name.

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Isis and Genzyme announced that they received guidance from the FDA regarding their orphan drug application for use of the the apoB antisense compound, mipomersen (formerly ISIS 301012) in homozygous familial hypercholesterolemia (FH).  The FDA has indicated that carcinogenicity studies, currently being conducted in mice and rats, must be complete before the application will be considered.  This pushes back the possibility of approval from 2009 to 2010.  The companies originally thought that they could get approval before the second study was complete.  The companies also indicated that they will speed up plans for an outcome study that will test the effect of the drug on cardiac events and deaths in a population of patients that have high cholesterol but are resistant to currently available treatments.  This is being done for an application for use of mipomersen in less severe forms of high-cholesterol.  They expect that they will be able to conduct such an outcome study with a relatively small number of patients and with a short timescale (18-24 months was mentioned) since they anticipate that mipomersen can effectively lower cholesterol levels to 70 mg/dl or lower in 50% of patients that are to be enrolled.  They appear to be basing this on results from the ASTEROID trial, which showed regression of atherosclerosis in respose to aggressive LDL lowering with rosuvastatin (Crestor), and the JUPITER trial which was stopped  early when it was shown that rosuvastatin (Crestor) unequivically reduced cardiovascular morbidity and mortality.

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Lipid Sciences announced their presenation about their apoA-I mimetic peptide, LSP-518P, at the American Heart Association Meeting in Atlanta.  They released a copy of the poster presentation on their website.  Some of the data in the presentaition regarding the ability of LSP-518P to promote cholesterol efflux and reduce atehrosclerosis, appear to have been released previously.  New data show that the drug is able to lower the inflamatory marker CD11b as well as the adhesion molecule VCAM-1, but not ICAM-1 in cultured cells.  In an unrelated report scientists from the Montreal Heart Institute Research Center published results from a study designed to look at the effect of an apoA-I mimetic peptied on aortic valve stenosis (narrowing).  They showed that treatment of animals with an apoA-I mimetic peptide could significantly improve atortic valve stenosis.

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A second announcement from ISIS Pharmaceuticals this month.  ISIS provided an update regarding their lead antidyslipidemic compound, mipopersen.  Mipomersen in an antisense oligonucleotide that targets apolipoprotein B resulting in reduced VLDL, LDL and Lp(a) levels in plasma. The company announced that patients treated with mipomersen in an open label extension study tolerated the drug well and said that there was no evidence of toxicity or serious adverse events.  There were a small number of patients (3 homozygous FH and 17 heterozygous FH patients) selected from a larger pool that had participated in phase I studies.  All patients in the study self-administered the drug, which is given by injection, at some point during the study.  Analysts on the conference call asked questions regarding changes in ALT levels (a marker of liver toxicity), injection site reactions (a known side effect of this drug), patient selection for this study and effects on HDL cholesterol.   The company responded that there was no evidence of worsening ALT levels or injection site reactions, that there was no bias in patient selection for the study, and that there was no effect of the drug on HDL levels.

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ISIS Pharmaceuticals announced that they received a $2 million milestone payment from Bristol-Myers Squibb (BMS).   The payment resulted from selection of one of ISIS' antisense oligonucleotide compounds that targets proprotein convertase subtilisin kexin 9 (PCSK9).  This drug works by reducing PCSK9 levels in plasma.  PCSK9 has been shown to reduce LDL clearance from plasma so reducing this protein should result in reduced levels of LDL.

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In light of the unexpected results of the ENHANCE trial which showed no difference in the thickening of the vascular wall when comparing Vytorin (simvastatin + ezetimibe) to treatment with simvastatin alone  Merck announced that they were placing enrollment for the ACHIEVE study on hold.  The ACHIEVE study is testing the effect of their new drug, Cordaptive (extended release niacin and the anti-flushing drug laropiprant) since they suspect flaws in the study design (i.e.  treatment of the target population with statins for a long time prior to entering the trial may reduce chnaces of seeing any effect of the drug).

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Takeda announced that they were discontinuing development of their squalene synthase inhibitor TAK-475 (lapaquistat).  This drug made news in October 2007 when the US FDA recommended that the use of higher doses in clinical trials be suspended due to elevations in liver enzymes.  The  company said that their decision to discontinue TAK-475 was based on the judgement that the drug was not better than existing drugs to lower LDL in terms of effectiveness or safety. 

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The American Heart Association Arteriosclerosis, Thrombosis, and Vascular Biology Annual Conference is going to be held from April 16-18.  Some upcoming presentations include:

* A presentation about PCSK9 inhibitors by scientists from GlaxoSmithKline.

* A presentation about the effect of locked nucleic acid antisense oligonucleotide against PCKS9 on LDL receptor levels in a live animal (Santaris Pharma).

* A study examining the effect of a sPLA2 inhibitor (? varespladib) on LDL levels in patients with coronary heart disease and diabetes (Anthera Pharmaceuticals).

*  A study that looks at the effect of the apoA-I mimetic peptide LSI-518P on inflammation and cholesterol movement out of cells (Lipid Sciences).

* A study looking at the effect of LCAT activators on HDL levels of rodents (Amgen).

* A study examining the effect of an oral apoE mimetic peptide on atherosclerosis in mice.

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Results from the Results from the STRADIVARIUS trial were reported at the ACC meeting. This study examined the effect of the weight loss drug rimonabant on the pregression of atherosclerosis.  Activation of the CB1 receptor in the brain causes enhanced food craving and a feeling of euphria.  Rimonabant works by blocking the CB1 receptor.   Though not technically a lipid-altering drug, there was a significant 20% reduction in triglycerides and a significant increase in HDL of 22% in those that were treated with the drug.  These changes in plasma lipids were presumably in response to reduced food intake.  This was accomanied by an average change in body weight from 228 pounds to about 219 pounds over 1.5 years of treatment.  There was no change in the primary endpoint, the total amount of atheosclerotic plaque in the coronary arteries.  There was also a significantly higher incidence of psychiatric side effects following rimonabant treatment.

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Results from the PLASMA trial were reported at the ACC meeting.  The trial is designed to determine the effect of varespladib, a sPLA2 inhibitor, on LDL, oxidized LDL, and CRP levels.  Treatment with varespladib resulted in decreases in LDL, oxidized LDL and CRP levels.  These changes were observed in patients treated with statins.

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Results were presented at the ACC meeting for the ASTEROID trial.  This study examined the effect of high-dose (40 mg) Crestor (rosuvastatin) treatment for 24 months on the progression of atherosclerosis.  The study found that treatment with high-dose rosuvastatin sigificantly reduced LDL levels and increased HDL levels.  More importantly, there was significant regression or stablilazation of plaque progression in a large number of study subjects.

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March 2008

Alnylam presented data at the Keystone Symposium.  They presented data showing that targeting PCSK9 in rodents using RNAi sigificantly reduced LDL and apoB levels.  This effect was rapid and lasted up to 3 weeks following a single injection.  There was no effect of the PCSK9 RNAi on liver triglyceride or apoB levels.  They also reported improvements in RNAi delivery using new formulations developed by Tekmira as well as delivery of cholesterol-conjugated RNAi constructs using intralipid, a commercially-available lipid emulsion.

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The results of the ENHANCE study were presented at the ACC meeting on Sunday the 30th.  The results were simultaneously published in the New England Journal of Medicine.  The results, which showed no additional benefit of adding ezetimibe to existing simvastatin treatment, had been announced in January 2008.  While the results presented at the ACC meeting were not new there was a panel discussion about the results of the trial.  The panel recomended that doctors should treat patients with statins rather than Vytorin, the combination of simvastatin and ezetimibe.   They cited the use of hormone replacement as a treatment that lowered LDL but was not associated with better clinical outcomes.  Merck issued a response to the study indicating that the lack of an beneficial effect in adding ezetimibe to existing treatment may be due to the fact that these patients had been treated with statins for a long time prior to entering the trial.  They suspect that these patients had relatively low measures of atherosclerosis due to their previous treatment and may not have been able to have any further improvement in atherosclerosis.

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Genfit announced that their pan PPAR alpha/gamma/delta agonist was effective in reducing plasma triglyceride levels and in increasing apoA-I and apoA-II levels in a phase II study.  The goal of treatment with this compound is to reduce plasma triglyceride and LDL levels while increasing HDL levels.  The company has now decided to pursue development of this compound over their first compound GFT14 , a PPAR alpha agonist.

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Karo Bio announced that they have initiated a second dose-ranging study with their thyroid receptor agonist, eprotirome.  The study will examine the effect of eprotirome in combination with the cholesterol absorption inhibitor ezetimibe.  The company also currently has studies in which eprotirome is being give in combination with the statins simvastatin or atorvastatin.  The results of these studies are anticipated to be ready towards the end of 2008.

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A study in the journal Nature reports on a new approach to RNA interference (RNAi) using microRNAs.  The study targeted a microRNA in liver that regulates cholesterol and fat metabolism (miR-122).  The results showed that this approach was successful in lowering cholesterol levels in the blood of monkeys.  The company that the developed the micro RNA, Santaris, plans to being phase I studies in humans in the first half of 2008.

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The American College of Cardiology (ACC) Meeting in Chicago starts this weekend.  Some of the presentations include:

* Data from the ILLUSTRATE study that patients treated with a CETP inhibitor (torcetrapib) that have regression of atherosclerosis have a similar level HDL increase as patients with a progression of atherosclerosis.  The major difference is that patients with regression had lower total cholesterol, LDL, and apoB levels when compared to patients with progression of atherosclerosis.

* Studies involving Roche's CETP inhibitor R1658 (JTT-705) that show that there is no change in blood pressure or adverse events in reponse to treatment with the drug.

* Treatment of transgenic mice with the ISIS/Genzyme compound mipomersen (ISIS 301012) reduced Lp(a) levels and oxidized phospholipids.

* A long-awaited presentation about the Enhance trial (Merck/Schering Plough) which was originally reported to have no additional benefit of Vytorin (simvastatin+ezetimibe) on the change in atherosclerosis as comapred to simvastatin alone.

* Some studies showing that treatment with Abbott's new fibrate ABT-335 in combination with statins has the additional benefit of reducing triglyceride and increasing HDL as compared to statin alone with no change in the safety profile.

* Treatment of patients with coronary heart disease with GlaxoSmithKline's new Lp-PLA2 inhibitor, darapladib, reduced Lp-PLA2 activity in plasma.  Darapladib treatment at the highest dose was associated with reduced levels of the inflammatory markers IL-6 and hsCRP in plasma suggesting an effect of the drug on reducing inflammation.

* A reduced flushing response to Merck's new niacin formulation Cordaptive (extended release niacin/larapiprant), as compared to Niaspan.  The results suggest that patients treated with Cordaptive can quickly tolerate the recommended 2 gram dose of niacin.

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A busy month for Lipid Sciences.   They also announced that their phase I trial with their plasma delipidation procedure, PDS-2, was successful.  They announced a "strong trend of effectiveness" in regards to reducing atheroma volume.   In contrast, the company noted that the statin drugs reduce clinical events by reducing the progression of atherosclerosis. It's worth noting that the trial that demonstrated the efficacy of the recombinant HDL with apoA-I (Milano) (ETC-216) had about 34 patients in the treatment group so its not surprising that there wasn't a statistically significant reduction in this phase I trial involving only 14 patients in the treatment group. 

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Lipid Sciences reported that their apoA-I mimetic peptide, LSI-518P, significantly reduced atherosclerosis in a mouse model of atherosclerosis.  The company announced they are now moving towards conducting toxicology studies to support an Invetigational New Drug (IND) application with FDA so they can begin phase I studies in humans.

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ISIS reported that, in collaboration with ther partner, BristolMyersSquibb, they expect to select a developmet candidate for their antisense oliglonuclotide against PCSK9 in the near future.

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Abbott received a $100 million payment from Solvay following FDA approval of Simcor, the combination sivastatin & Niaspan (extended release niacin).

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Pfizer announced an update of their pipeline.  Somewhat surprisingly they have discontinued two drugs that they acquired with their purchase of Esperion for $1.3 billion in 2004.  These drugs were ET-642, a synthetic HDL that contains an apoA-I mimetic peptide, and ET-216, a synthetic HDL that containined recombinant apoA-I(Milano).   ET-216 made headlines in 2004 after it was shown to regress atherosclerotic plaque in a small study.  The drug was subsequently dubbed "artery Drano" by the press.  The reason for the discontinuation wasn't immediately known but it appears that the company is narrowing its focus on drugs that it considers to be the most strategic and viable candidates. 

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February 2008. 

Abbott received FDA approval to market Simcor in the US.  Simcor is a combination pill that combines Abbott's Niaspan, an extended release form of niacin, with the generic drug simvastatin (marketed by Merck as Zocor).  The drug is effective in lowering triglyceride and LDL levels and raising HDL levels.  Annual sales are expected to reach about $500 million.

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