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Alnylam Pharmaceuticals, Inc. Message Board

thirdmeinvestor 13 posts  |  Last Activity: Feb 16, 2015 10:38 PM Member since: Feb 25, 2004
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  • thirdmeinvestor by thirdmeinvestor Feb 16, 2015 10:38 PM Flag

    Gene editing using CRISPR technology in higher animals and plants is very new, and potentially allows fixing genetic problems at the very root. Today people are talking about an exact CRISPR procedure to repair the sickle cell anemia gene. It can delete sections of the genome with precision. And a gene engineering could refill the void with normal codes in the future.
    It is amusing to think about CRISPR/Cas9 techniques as new technology because bacteria have been using the method for a billion years to fight off bacteriophage infection. About ten years ago, researchers found that the bacteria carried CRISPR [Clustered Regularly Interspaced Short Palindromic Repeats] sequence in their DNA body. It took a few more years to figure out the reason. It turned out that the repeated genetic codes contained the code of phage which had attacked the bacteria before, and when attacked again by the same phage, the code sequence would be transcribed into RNA, then chopped into small pieces, each containing phage gene codes. Then Cas9 nuclease goes into action by cleaving the bonds holding the phage DNA double strands where the chopped RNA recognizes as the phage gene. Next Cas9 shreds the phage DNA and kills the phage. So, CRISPR/Cas9 is an immune system for the bacteria.
    Only less than two years ago, a few groups reported that they can cut to produce a DNA double-strand break in human or mouse embryonic cells, and some reported that they repaired the cut with another gene segment to produce a new organism. They say that the technique is simple, fast, and reliable that any graduate student in biology can master it to apply to different model systems. If so, could this system be used to treat genetic abnormalities in human? Some challenges are still remaining, but those too may be overcome in future.

  • thirdmeinvestor thirdmeinvestor Jan 31, 2015 7:42 PM Flag

    Glad, the full trial results are apparently not known to the sponsor of the trial. They may know the number of dropout rate for example. Should they disclose such events without knowing the full circumstances? They have to have a consistent picture of the results before reporting them. The most important fact reported for us is that the FDA approved the huge (1120 people altogether) Phase 3 trial for the 661 combo. If there were a possibility of serious safety issues, the FDA would not have allowed the trial. The efficacy is concerned, it should be better than that of 809 combo.

    Glad, I am certain that the share price will reach 200 in two years. The market is mad right now. Most Wall Street analyst assume that the 809 drug combo will cost 150K per year per person. What Karnauskas found out by talking to the management is that 150K is too low a value. She told this in CNBC several weeks ago.

    Good luck to you.

  • thirdmeinvestor thirdmeinvestor Jan 30, 2015 7:17 PM Flag

    Robyn Karnauskas at Deutsche Bank has been bullish with the Vertex CF program. She or other members of the bank raised the target price to 155 after the Q4 earnings report because they don't see much risk for this year's clinical trial or regulatory approval.

    However, I think that the interim VX-661 Ph 2b trial reading was inconsistent with previous results. This was a tiny trial with only 20 people receiving the drug combo. It should not weigh on the share price one way or another.

    I am optimistic on the future of Vertex because the new CSO, Dr. Altshuler is not only a first rate scholar, but also came from the Broad Institute. Remember CRISPR/Cas9 ? A company called EDITAS is dedicated to clinical applications of this revolutionary technology. Founders of EDITAS did their work at the Broad Inst.. I guess that the name came from gene EDITing with RNASE. In vitro, they can edit DNA codes by replacing mutated sequences with normal ones. Some says that gene editing using a CRISPR technology can enter clinic in a few years. That may be too optimistic. I would be surprised if one of very first attack is not CF. Vertex pulled off a coup in being able to recruit Altshuler. I promise to post more about the gene therapy applied to CF.

  • Robin is the smartest of all analysts.

  • thirdmeinvestor thirdmeinvestor Jan 24, 2015 8:24 PM Flag

    The only serious side effect coming from CD19-targeting CARs has to do with CRS (= cytokine release syndrome). But even this, it was found that an anti-interleukin-6 receptor antibody, with or without a steroid, has effectively and quickly reverse CRS, and has become a critical part of the CRS management. You can find this and other facts from a Journal of Clinical Oncology article called [Are all chimeric antigen receptors created equal?] written by JH Park and RJ Brentjens.

    Sentiment: Strong Buy

  • Reply to


    by sluggobear Jan 8, 2015 5:21 PM
    thirdmeinvestor thirdmeinvestor Jan 9, 2015 10:06 PM Flag

    I want to add to the excellent and conservative reply by Applejungle. For the next several years Vertex will not see any competition in treating underlying cause of CF unlike other biotech companies. Vertex CEO does not advertise drugs in preclinical development. Gilead's Harvoni sales will decrease by 60% or more when Regulus' RG-101 is launched in a few years. Celgene will face serious competition from several immunoncology drugs which are already marketed. For all drugs Isis develops against liver based proteins Alnylam can create far better ones...more effective and safer.

  • thirdmeinvestor thirdmeinvestor Jan 1, 2015 5:30 PM Flag

    Specifically, Altshuler and his colleagues have shown that certain mutations in the SLC30A8 gene protects the carriers from contracting type 2 diabetes. This means that deletion of this gene would help people with T2D!!! However, other groups have shown that T2D is caused by mutation in the same gene in mice. This inconsistency can be resolved in favor of Altshuler if Vertex found an inhibitor to “loss of function” zinc transporter ZnT8 (encoded by SLC30A8) mutations. It is possible that Vertex has already found several compounds which exactly treat animal model T2D. This is a good reason for Altshuler to join the Vertex research group.

    In real life, a mutation that abolishes the function of a protein useful in normal people, can reduce the risk of human disease in others. Examples include knockdown of antithrombin to treat hemophilia, or inhibition of PCSK9 function to treat hypercholesterolemia to potentially reduce heart attacks. But no target have yet been exhibited for type 2 diabetes (T2D) until this year. Would Vertex have potential drug candidates?

  • Dr. David Altshuler had been the second man in command at the prestigious Broad Institute in Cambridge, MA. Dr. Altshuler was also an associate professor of Genetics and Medicine at Harvard Medical School. His scientific research has focused on the discovery of causal connections between genetic mutation and health/disease. His most recent work involves genetic basis for the risk of developing type 2 diabetes (=T2D). Hence, he is an academic physician who is devoted for patient care. He is only 49 years young and a former classmate at Harvard Med tells me that he has a dynamic and friendly personality as well. He could have taken a position in any research or educational institution. Vertex is dedicated to bringing revolutionary medicine to the world, but it is not a pure research institution. I could not help but ask; what is he looking for at Vertex and what does Vertex expect to achieve by appointing an academic physician to occupy the position of CSO? As a geneticist Dr. Altshuler would be most gratified by finding out the genetic cause for a particular disease. Vertex as a biotech is interested in what molecule can cure the disease. Could these two separate goals converge?

    Those two distinct goals can converge if medicine can be found based on genetic codes. What better way is there that can prove genetic basis of disease than inventing a molecule or a molecular process that can precisely repair the mutation? Altshuler’s hypothesis that certain genetic makeup is protected from T2D. This hypothesis is shown by genetic analysis of 150,000 human data, but other groups have shown earlier that the opposite is true. [read on]

  • Reply to

    What to expect in January-February time frame

    by thirdmeinvestor Dec 27, 2014 10:12 PM
    thirdmeinvestor thirdmeinvestor Dec 27, 2014 10:14 PM Flag

    [cont' from above]

    A single subcutaneous dose of this anti-miR followed by a few weeks of any oral DAA will be good enough. And this will be preferred if the price for cure is lower. Furthermore, the best trial results for Genotype 3 with oral DAA combination is 90% or lower after 24 wks of dosing. Sovaldi + Riba combination cures only 65% of Genotype 3 patients. RG-101 can treat Genotype 3 patients as well as Genotype 1 or 2 because it knocks down the host molecule miR-122 which protects all Genotypes equally. There are a large number of Genotype 3 patients in EU and US. 20 - 50% of all HCV patients are infected with Genotype 3.

  • Direct-acting-antiviral (DAA) combos are remarkably effective in treating HCV patients. However, the dynamics of the marketing war among makers of DAAs will change in the future. Gilead, AbbVie, Merck, or J&J cannot ignore the potential of antimir-122 because a single dose of RG-101 at the lowest dose 2mg/kg can reduce the viral load by 4.1 log. This means that a single injection of 2mg/kg RG-101 destroys 99.99% of the viral genome present in patient blood 4 weeks later. Regulus is to report the clinical data for the single 4 mg/kg dosing in a month or so. The viral load reduction will be greater than 4 log at this dose. Regulus is also testing a single 8 mg/kg dosing.

    Regulus also reported that at the 2mg/kg dose, 6 out of 14 patients had HCV RNA levels below the limit of quantification at day 29 and the 3 patients from this group who have reached day 57 still have HCV RNA levels below the limit of quantification. It is possible that some patients can achieve the SVR without any DAA, but when DAA combos are combined with RG-101, the remaining 0.01% of virus can be eliminate with a 99% SVR efficiency in a short duration of dosing.

    All is possible because HCV RNA genome has an Achilles’ heel. DAAs don’t take advantage of this weakness of the virus. Sarnow, the godfather of miR-122 and HCV link, and colleagues published their latest results last August and found that miR-122, liver-specific miRNA, protects HCV from degradation by human RNAse called XRN2. When miR-122 is absent or reduced, XRN2 simply degrades the viral RNA. As far as I know, DAAs do not mess with miR-122. On the other hand, antimir-122 such as RG-101 can knockout miR-122 enough to cause XRN2 to destroy HCV genome profoundly without regard to the genotypes.

    The treatment duration is important for compliance and cure. The shortest combo dosing for treatment available now is 8 weeks. [to continue]

  • Reply to

    Diabetes and gene base therapies

    by rojospan Dec 18, 2014 9:16 AM
    thirdmeinvestor thirdmeinvestor Dec 22, 2014 8:22 PM Flag

    Rojo, I learned after seeing your post that David Altshuler is a leader author of the 150 K man gene scanning NATURE GENETICS paper which identified the function of SCL30A8 and its relevance to type II diabetes. The strength of Vertex lies in finding structure-based inhibitors, or finding by screening a large number of small molecule inhibitors to a protein. Vertex could buy a CRISPR/Cas9 technology company to edit genes of SCL30A8 to disable its zinc transport function. Tell us more about your thinking.

  • Reply to


    by gladpick Dec 22, 2014 9:42 AM
    thirdmeinvestor thirdmeinvestor Dec 22, 2014 3:42 PM Flag

    Greed by the management of Gilead and high price of Sovaldi caused collapse for Gilead's stock price this morning. Fear mongers took advantage of that.

  • Reply to

    Bought it at $121,

    by w_rookwood Dec 22, 2014 11:12 AM
    thirdmeinvestor thirdmeinvestor Dec 22, 2014 3:31 PM Flag

    Buy more around 116, and sell at 170 in the coming summer.

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