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Exelixis, Inc. Message Board

  • wilderguide wilderguide Dec 15, 2012 1:26 PM Flag

    Regarding an OS Signal


    The following excerpt is from a BusinessWire article dated 2/24/12, and addresses the preclinical work conducted by Dr Donald McDonald of UCSF on combined MET & VEGF therapy. Though I realize this is a preclinical work-up, I wanted to revisit these statements as they are the closest we have to date wrt a positive overall survival signal.

    "In the research described in Cancer Discovery, tumor-bearing mice were treated with an anti-VEGF antibody or with sunitinib, which inhibits multiple tyrosine kinases including VEGF receptors. These treatments were tested alone or in combination with an inhibitor of MET. Separate groups of animals were treated with cabozantinib. Key findings include:

    – Cabozantinib reduced tumor invasiveness compared with VEGF inhibition alone, through a mechanism consistent with MET inhibition.

    – Liver metastases were completely absent in animals treated with cabozantinib.

    – Overall survival was longest in cabozantinib-treated animals. All animals treated with cabozantinib survived until the end of the study, whereas most or all animals in all other treatment groups did not survive until the end of the study."

    I think it's important to remember that Cabo - unlike many experimental compounds that make the transition from laboratory to clinic - has successfully carried it's many physiologic effects in that important transition from animal to human models.

    If the history of Cometriq's effective transition from lab to clinic is any useful guide, I'm convinced that the data upon which Dr Schwab has placed her recent bet is good news for all of us.

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    • Nice find Wilder, this more evidence in favor of Cabo, albeit heavily qualified. The FDA is a very utilitarian organisation and will want evidence of survival for a broad cross section of human patients with diverse profiles and very differently behaving tumors than the (presumably) controlled selection of cells with which the genetically similar mice have been afflicted.

      Still, the OS signal from earlier soft tissue P2 trials and the consensus that skeletal events are the main cause of morbidity make me pretty hopeful that Cabo will read out well in COMET-1. The trials are also being done at the manageable 60mg dose and the FDA has made it clear that the toxicities associated with 140 mgs of Cabo are tolerable for the therapeutic effects that it produces (albeit w/ an SPA for PFS) so I don't think that should be an issue in the COMET trials.

      Sentiment: Buy

    • Of course it is good. Target $12 on buyout first quarter 2013. You heard it here first.

      Sentiment: Strong Buy

    • $$$$

      Sorry to be so slow...Yahoo is beginning to give me fits...

      The latest Celetia Higano Cabo trial - an intended exploration of the bone tumor micro-environment would seem to be one of the more important of the recent additions - at least wrt further understanding of Cabo's bone effect.

      "Official Title: A Pilot Study of the Effects of Cabozantinib (XL184) on Bone Turnover and the Microenvironment in Men With Non-Metastatic and Metastatic Castration-Resistant Prostate Cancer
      Primary Outcome Measures:
      •Change in urinary N-telopeptide (uNTX) [ Time Frame: Baseline and 6 weeks ] [ Designated as safety issue: No ]
      Will be analyzed after log-transformation."

      It appears data for primary endpoint should be gathered 6 weeks following final patient recruitment and analyzed after log-transformation. What's that mean?
      Thanks for all your great replies, Ernie!


    • "I wanted to revisit these statements as they are the closest we have to date wrt a positive overall survival signal." Here is my perspective on mouse results. Judah Folkman was the discoverer of the angiogenesis phenomenon associated with carcinogenesis. He helped found Entremed as a commercial enterprise to exploit his discovery. Entremed eventually held a press conference to announce their startling preclinical results, in a mouse model one of their most promising antiangiogenesis drug had completely cleared implanted tumor tissue. It made headlines and many speculated that a possible cure was at hand. The stock of Entremed ran to $100+ in 2000. Unfortunately, the startling rodent results did not translate into the clinic and none of Entremed's drugs ever made it out of clinical development. Adjusting for reverse splits the pps is now 1 cent. That is one example of many rodent studies that led nowhere and I chased a few of those myself.

      Don't get me wrong, I think Comet is the real deal. I just have learned not to put much weight on mouse results. The mouse model is great for weeding out drugs that are ineffective or overly toxic, but efficacy signals in the mouse model do not always translate well, in fact they frequently do not. The Folkman story has a happy ending, Even though Entremed was not able to exploit his discovery, other companies have, and in fact, Comet as a VEGF inhibitor owes its existance to Dr. Folkman's work.

      • 1 Reply to erniewerner
      • $$$$

        "The mouse model is great for weeding out drugs that are ineffective or overly toxic, but efficacy signals in the mouse model do not always translate well, in fact they frequently do not."

        Interesting that so many of Cabo's valuable pharmacokinetic attributes have crossed the barrier from lab to clinic...or am I missing something? The UCSF newsletter that covered this study's publication was the same in which Dr McDonald (wrt Cabo's apparent synergy when comparing MET/VEGF combinations) was quoted as saying "With cabozantinib, 2 + 2 = 10"...which might even be said to have proven somewhat predictive of the low-dose efficacy we have since witnessed.
        Thanks for the history lesson, Ernie.

    • Very good.

      Transition from paradigms.
      Pharmacology and toxicology
      CFR 312.23 (A) (8)
      All biomarkers were shown predictive.
      CFR 312.23 (A) (11) pre evaluation.
      It's documented that the team was ready for questions and give more data than just abbreviated to the FDA on animal data than just providing probable bio markers.

    • $$$$

      " - Liver metastases were completely absent in animals treated with cabozantinib."

      This statement is particularly compelling, as Dr McDonald's preclinical work had been conducted in mouse models affected by pancreatic neuroendocrine tumors, which maintain a historic precedence of metastasis to the liver. This would seem to potentially bode well for the PanC Cabo trials already in progress.

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