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Alnylam Pharmaceuticals, Inc. Message Board

  • thirdmeinvestor thirdmeinvestor Jul 23, 2006 12:26 PM Flag

    PCSK9 revisited

    The Science article I posted the link to a few days ago was not available free online. So I condensed the article by selecting relevant paragraphs for us. The facts are NOT altered, but I tried to emphasize the importance of PCSK9 targeting rather than the importance of life-long use of statin drugs, which the title of the article appears to imply without a concrete proof.

    It is known that treatment with cholesterol-lowering statins for 5 years reduces the incidence of heart attacks by 40% at best (even when LDL cholesterol (LDLC) concentration is reduced by 80 mg/dl). A likely explanation is provided by Cohen, Hobbs, and their colleagues in the March issue of the New England Journal of Medicine.

    Cohen et al. studied middle-aged Americans with lifelong low LDL levels, owing to loss-of-function mutations in the gene encoding PCSK9, a secreted enzyme of the serine protease family. In a small number of subjects with severe nonsense mutations, the concentration of LDLC was reduced by 38 mg/dl, and the prevalence of coronary heart disease declined by a remarkable 88%. In a larger number of subjects with a less severe missense mutation, LDL-C concentration was reduced by only 21 mg/dl, yet coronary heart disease incidence declined by 47%. Hence, Cohen et al. has demonstrated the cardio-protective effect of the LDL-lowering mutations in PCSK9. They analyzed data from a prospective study of 15,792 Caucasians and African-Americans from four U.S. communities that was initiated in 1987.
    Elimination of the PCSK9 gene in mice through gene-knockout technology increased the number of LDL receptors in liver and enhanced the clearance of LDL from the plasma (work of UT Southwestern Medical). This striking finding indicates that PCSK9 functions tonically in mice to keep LDL receptor number lower and plasma LDL concentration higher than they would be otherwise.
    PCSK9 appears to have the same effect on LDL in humans. A role for PCSK9 was first recognized in families with hypercholesterolemia, owing to amino acid substitutions in PCSK9 that are postulated to increase its function. As expected, affected individuals suffered from premature heart attacks. Cohen et al. have now demonstrated the opposite effect--namely, that loss-of-function mutations in PCSK9 lower LDL levels and reduce the incidence of heart attacks.


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    • ALNY initiated the PCSK9 program against hypercholesterolemia. There is no comparison for the robustness of siRNA technology. ALNY technology induces minimal immune response if at all. Cell targeting for PCSK9 is not a problem because: (1) ALNY already has the technologies to target liver cells(liposomal), (2) siRNA against PCSK9 does not have to be targeted because people who congenitally lack or have dysfunctional PCSK9 gene thrive and have far less heart attacks (see above earlier posts).

      • 1 Reply to thirdmeinvestor
      • If what you say is TRUE, "There is no comparison for the robustness of siRNA technology.", then why did Bristol-Myer-Squibb select ISIS (Antisense) for the $200 million PCSK9 deal, rather than ALNY?

        I think you, as an investor, should be asking the ALNY management some serious QUESTIONS? Is ALNY's DELIVERY sound? What HAPPENS to efficacy with that delivery mode? What are the COST comparisons with Antisense? Does ALNY have a competitive advantage here? Why did ALNY lose out to ISIS? Is ALNY really, "Not Ready for Prime Time!"??

        If you cannot answer those questions to some degree, and be satisfied, then perhaps you should be investing elsewhere. This is NOT investment advice - - just my honest opinion.

        Go to the Head-of-the-Class with ISIS!

    • From

      07:31 ALNY Alnylam Pharmaceuticals and ISIS working together to consolidate intellectual property in miRNA field - Rodman & Renshaw (18.01 )

      Rodman & Renshaw notes that ALNY and ISIS are working together to consolidate the intellectual property in the miRNA field. Firm syas the cos announced today that the United States Patent and Trademark Office has allowed claims in a patent application that covers microRNAs and therapeutic molecules that target these miRNAs. The U.S.P.T.O. issued a Notice of Allowance for patent application 10/490,955, which is derived from the Tuschl III patent series licensed co-exclusively to Alnylam and Isis for miRNA therapeutics on a world-wide basis. The Tuschl III patent series pertains to the discovery of over 120 novel mammalian miRNAs. The co expect final issuance of the patent within six months. Firm says ALNY expects to file two additional INDs from its development pipeline in 2007 (pandemic influenza and PCSK9 for hypercholesterolemia) and also intends to advance two or more new development programs.

    • Review the posts. siRNA against this molecule plus a statin drug could solve cholesterol problem.

    • The lesson of PCSK9 is clear. If we are to attain an 88% reduction in the incidence of coronary heart disease, we must lower LDL levels well before atherosclerosis has become advanced. If we start early enough, it may be sufficient to lower LDL-C concentration only to 100 mg/dl, a goal that should be attainable for most people. These individuals must be prepared for lifetime treatment. Early intervention is designed to prevent a heart attack that might not occur for many years.
      Statin drugs (and possibly apoB targeting RNA drugs) lower LDL, but they also increase the level of PCSK9 in liver cells.
      Admittedly, our knowledge of the pathogenesis of atherosclerosis is incomplete, and more research is needed. We do not know precisely how LDL particles cause the inflammatory and proliferative lesions of the atherosclerotic plaque. Although we measure LDL by its cholesterol content, the most toxic component may be its fatty acids or phospholipids. Also, we cannot be certain that the atherogenic effect of PCSK9 is due solely to its LDL-elevating action. It is possible that PCSK9 also exerts a direct toxic effect on the arterial wall and that loss-of-function mutations reduce atheroscle-rosis by avoiding this toxicity as well as by lowering LDL levels. Despite these unanswered questions, the data on PCSK9 are consistent with the extensive genetic, epidemiologic, experimental, and therapeutic data that justify an aggressive public health program aimed at lowering LDL levels before the atherosclerotic process has become advanced. Early intervention may well put an end to the epidemic of coronary heart disease that ravaged Western populations in the 20th century.

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