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Vical Incorporated Message Board

  • genetherapy genetherapy Feb 10, 2013 4:16 AM Flag

    A Therory

    The event rate while once being relatively robust, has clearly slowed as evidenced by the continual re-estimates of when the target event rate should be met. It might be assumed that this is due to one of the arms (DTIC) behaving according to historical norms while the treatment arm outperforms. As fewer and fewer DTIC subjects still remain alive, they become a smaller and smaller factor in the equation. IMO this could perfectly explain why the event rate has dramatically decreased ie. most of the control arm are no longer breathing.

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    • This thread from early February begins with genetherapy's simple, straightforward logic which I liked then and like now. I'm wondering what's going on quietly behind the scenes within the Company in anticipation of a positive Allovectin outcome?! We know they are making preparations for filing with the FDA and are hiring key positions needed to scale up production of Allovectin, per Vical postings on the web site. We know they just added a powerful new Board member with extensive big biopharma experience from Amgen. And we know the CFO got a nice package including a month of transitional support back to Vical since she left on April 1st. A perfect storm could be brewing here with share price having moved up nicely so far this year. Question: Will the next 2 million share trading day go upward or drop? IMO upward to a new 52 week high.

      Sentiment: Hold

      • 1 Reply to gofordna
      • As always Gofor your right. The stars are aligned. As I told Shorty at 2.75 and again at 3.20 His strategy is Pathetic. Holding down a stock that wants to trade higher. Pure Desperation. The icing on the Cake here is his last hire. Viclo (fabless. In our house he's known as 50 wt sandpaper(the most abrasive) ), probably a referral from Lacy.I tried to help shorty out I even gave him a good short. NFLX . I'm short at 194. 10% higher than a double top(177). Thats how its done shorty. You are terrible..Double top on VICL would break 5.25.plus 52c(10%). I'll try and help you one last time. Let VICL run to 5.77. Then if you think A-7 will fail, lay it out. Thats where we're going soon. Enjoy the Margin calls.. Hate to say this 50wt but the 200$ a month wires may stop soon.May have to get a real job.

    • Supporting theory:
      Treatment arm getting Allovectin will clear "the bar" for the durable response primary end point by a wide margin. Median survival for the DTIC subjects will be a bit better than historical norms due to FDA approved inclusion criteria with chemo naive, healthier people than aggregate historical DTIC studies. Median survival cannot be determined this year for treatment arm patients (a good thing) because Allovectin's superior durable response helps thwart metasticized cancer through systemic response beyond the injected tumors (similar to the Merial Oncept canine drug). Mean or Mode survival measures can be factored for the Allovectin arm upon data lock, enough for proceeding with FDA fast tracking as a very promising secondary end point. Vical's Naked DNA cancer franchise will live up to its "paradigm shifting" claims.

      • 1 Reply to gofordna
      • Gofordna,

        Your post is the most plausible explanation for the success of A-7 in the current phase III trial IMO also.

        I wonder if you are an Oncologist. You are extremely articulate and concise in the SPA trial design. Your conclusion for the primary and secondary endpoint data release is also my expectation.

        I have been holding VICL stock for two years now and believe your theory will be correct.

        Sentiment: Strong Buy

    • There are a few possibilities. A very good possibility is the selection criteria as being a major factor.
      The entire set may be acting the same no matter what drug they are taking. This of course would mean a marginal difference between the two drugs or arms. Hope i am wrong, but this is what i think has happened.

    • At this point in time, I would expect that 23% of the control patients are still alive and 35% of the Allovectin patients are still alive and we are at a point in the KM curve where approximately one patient in each arm is dying per month.

    • Your theory makes sense and is consistent with what we've heard from VICL over time relating to this and past trials. For those concerned that Yervoy is somehow affecting the results, your theory could actually support A-7 patients benefitting more from Yervoy than chemo patients since Yervoy was recently approved, presumably with proportionately more A-7 patients alive to benefit from it.

    • Look at any KM curve, there is a rapid decline in the population over the first 6 months and then the curve levels out and some of the subjects remain alive for years on a plateau. Since you are actually talking about a change in rates this is the same thing, just that the people in the control arm no longer contributing to the decline are not all dead. It is the same thing, except that it all depends on how many patients make up this part of the population as a percentage of the 1/3rd control arm input and how many in this plateau are from the 2/3rds treatment arm. At this point it can be up to ~10-20% for the control arm, the assumption was clearly 20% predicted for this arm when the trial was supposed to stop back in 2011, based on DTIC KM curves available in the literature We only know that the statisticians figured that at the Sept 2011 date the behavior of the control population should yield an expected result, ~20% survival for the control arm. For the trial to be continued solely due to the 1/3rd control arm outliving historically based expectations at this point and assuming that A7 is a bust, then you would have to state what the marginal increase above the expected 20% survival in the control arm you would need for the control arm to be holding things up, and this persisting for more than 18 months. I don't think it can be lower than an additional 50% survival in this arm to balance out the loss in a failed A7 arm, not knowing anything about actual numbers, i.e. the control arm is at such a mathematical disadvantage and it would still have to be significantly above the level of survival expectation originally set for Sept 2011. A failure of A7 makes this difference from expectation ever greater.

      What would be tragic is if A7 worked, but as a monotherapy functioned at only the level of DTIC. The FDA will likely kill the application and force a trial as a combined therapy that no one may be willing to fund at that point, maybe BMY. Immune therapies will likely only find their maximal efficacy in combination with other immune modulators and inducers of immunogenic cell death. Unfortunately, these panels are filled with medical oncologist, tied to a dogma that says you treat cancer by directly killing cancer cells, which works on blood cancers, but not solid tumors. Success in leukemia cemented a false paradigm, but it is a shiny object they can't get their eyes off of. They want to be Rambo, and kill them all, cancer is not a disease of mutation. It is a disease of immune manipulation and subversion by the mutated cells. Every mole on your body is a tumor, and they have activating V600E mutations in BRAF (the target of Zelboraf) at similar proportions as you find in actual melanomas in the cancer patient population, they are not cancer, similarly, GWAS sequencing of benign tumors from crash victims have shown the presence of mutations which according to dogma should denote full blown cancer, but these tumors will actuarially never present as disease. Current ontological models are flawed. This is a disease of the stroma, not the cancer cell, which acts to convert the stroma into a pathological neo-tissue. You can kill the cells here and there with systemic poisons or radiation, but as long as there are a quorum left that have the skill set of manipulating their fellow travelers, you will fail. I believe that A7 functions at several levels. The stimulation of an adaptive response is only a part of it, I don't know how much it is, but the fact that you are injecting a PAMP into the tumor (CpG island containing bacterial DNA) and a reported immune adjuvant (Vaxfectin) in addition to driving the expression of beta microglobin and a foreign protein (HLA-B7) suggests to me a greater chance of altering the immune suppression exerted by the tumor to reverse immunoediting. What is needed is to add in an immune stimulator (Yervoy-like antibodies works in animals) and an inducer of immunogenic cell death, such as radiation or an anthrocylin to stimulate a stronger immune response against the cancer cells in order to enhance tumor associated antigen sampling. Maybe Gencitabine and/or low dose cyclophosphamide to alter suppressor populations of immune cells. I don't know if A7 will work or not, but it is such a different animal compared with all the targeted therapies and new delivery systems for the primitive mallets of and crude hammers of drugs like alkyalating agents or the strange idea of pumping in recombinant cytokines to the entire system that are the basis of other approaches. It is also more efficient than DNDN et al approaches, which is basically operating on a similar principle (allowing for in immune response outside of the immunosuppressive grip of the tumor). Based on this, I don't think a historical comparison with other biotechs and their success or failure makes sense. I could be wrong, some or most of my thinking might be flawed with regard to translation to business success, but at least this is a much more clever approach, even though it seems like the company backed into part of what makes this interesting to me and like I said, application of A7 in combination with other agents will be key to its broader clinical success because of the nature of the disease. Trials are set up as initial experiments, the fact that the approach has to stand on its own is unfortunate, but I don't see a way around it.

 
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