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Exelixis, Inc. Message Board

  • icprecipice icprecipice Feb 8, 2011 11:26 AM Flag

    XL184: Could its activity be revealing something much more profound?

    At the risk of flying off into wildly speculative discussion, I would be interested in hearing from some of the science and medical professionals that frequent this board. As I understand, after taking XL184, the bone scans of prostate cancer patients have revealed a fairly rapid and unmistakeable amelioration of tumor formation in the bones of these patients. It strikes me that in order to have a rapid response to a therapeutic agent, the impact would almost certainly be occuring in the soft tissue - or bone marrow - of these patients. Given that production of blood cells occurs within the marrow and understanding that XL184 is demonstrating activity, which is heretofore unprecedented, is it not reasonable to speculate that there is something much more significant here than the development of a potential second line therapy for prostate cancer?

    It is my understanding that XL-184 was formulated as a therapy to interrupt the process of angiogenesis. It seems to me that the activity occurring within the bones offers up a biochemical response, which is unrelated to the intended target. Indeed, quite apart from impacting the formation of blood vessels around tumors, XL-184 appears to be active in the area where blood cell production begins. The notion that medical science now has a tool which is effective in such a progenitive environment would seem to carry with it the potential for therapies far beyond prostate and uterine cancer. Indeed, once researchers are able to understand the mechanisms by which this activity is occurring, is it unreasonable to suggest that XL-184 could provide a platform therapy in the treatment of cancer?

    All this speculation comes from a middle-aged man leaning on what he learned back in high school science classes. I am eager to hear what some of the real scientists and medical professionals have to say. Care to comment?

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    • Neers87,

      It appears that Bi-213 has a very short half-life approx. 45 minutes. With that in mind, having your own generator on hand would simplify expiration issues. Back in the day before unit doses became popular here in the U.S. we milked the Mo-99 generator every day for 99mTc daily needs. The prep on different radiopharmaceuticals is pretty easy. For example- eluting 99mTc a daughter product of Mo-99 from generator. (just stick an empty vial into these prongs that extract 99mTc that decayed from Mo-99) Than you have so much activity in that vial to prepare cold kits for daily needs.(vials of different radiopharmaceuticals depending on what exam your doing)


      So I'm guessing they are just eluding daughter product Bi-213 from Actinium-225, and basically just mixing into cold kit vial. There is probably some minor QA issues to test, but basically not that bad of a process.

      Mostly just think sites would prefer on site generator for logistical reasons due to short half-life.

    • HBomb, This is the reference to administration. Again I would point out that this process may be unique to their application rather than to all alpha emitters.

      http://www.actiniumpharmaceuticals.com/assembly.htm

      Assembly of Bi-213 based Alpha Particle Immunotherapies
      The antibody/chelator complex ensures consistent stability and quality. Shortly before clinical use, a precisely prepared single patient dose of antibody/ chelator complex will be mixed with freshly prepared Bismuth-213 isotope. The Bismuth-213 is easily and rapidly eluted from Actinium-225. In the hospital laboratory, the Actinium-225 is received as a generator and "milked" to obtain the Bismuth-213. The procedure has been developed and is currently being used in the first clinical trial against Acute Myeloid Leukemia at Memorial Sloan Kettering Cancer Center.

    • http://www.iptonline.com/articles/public/page363738loresnonprint.pdf

      This is the one article I could find discussing outpatient application of alpha emitters, however, when I was reviewing another small company, (other than Algera) that was working on an alpha emitter, I had looked up their clinical trials and reviewed their website, that site included a description of the application.

      I will have to get back to you if I can relocate that information. And it may not apply to all alpha emitters, however they were required to chleate the AE at the time of administration. That company was not listed on any exchanges I did not retain the info. Somewhat satisfied, I moved on. I'll see what I can drum up over the weekend.

    • "Very specific and much more challenging than oral administration. Essentially conjugating just prior to administration."

      Out of curiousity specific to which radiopharmaceutical?

      I ask, because it is my belief that these would be unit doses from radiopharmacy. All current monoclonal radiopharmaceuticals are already conjugated before they arrive at the clinic setting.(I don't think Alpharadin has an MAB association) From my past experience, you basically had to make sure blood counts were within range before dosing with Metastron, or Quadramet.(I believe Alpharadin didn't affect cell blood counts, but would have to check again) Starting an IV then slowly pushing over a few minutes or so.

    • <<Ok, but to run 5 - 10 trials at once will require them to dilute the shares down to 0.00001 to pay for them.>>

      There are 3 viable choices. You do a secondary, you partner or you sell the company or some combination thereof.

      <<Probably better for us if they run only one or two trials at first, before adding another 5+.>>

      There is another VEGF/MET inhibitor out there plus other MET inhibitors that can be paired with VEGF inhibitors. They have a lead right now, but it is a perishable commodity that will evaporate if they don't use it.

      <<It would also give them more negotiating leverage - big pharma companies will be competing for partnerships rather than lowballing.>>

      Next week they will release data on 100 CRPC patients---50 with bone mets. That's a large enough sample size for even the most skeptical to draw conclusions. We may also hear about Ovarian results from a large sampling. That's all the leverage they need. I don't even see the advantage of waiting for MTC topline results. It's a tiny indication.

    • HBomb,

      Thanks for the summary. I did a little more research, looks like they are truly in the early stages of development, the Alpha emitters potency is impressive, but in one instance I saw the process of administration, (should have copied it for this response) Very specific and much more challenging than oral administration. Essentially conjugating just prior to administration.

      I did not see specifics relative to Alpharadin, However your inclusion of the connection with Dr Sartor for both XL-184 and Alpharadin was beneficial insight.

      Regards,

    • neers87,

      Alpharadin is the next generation radipharmaceutical after Sr-89 metastron, and Sm 153 quadramet. Quadramet, and metastron are beta emitters that have a longer radiation particle wavelength, but less potent than alpha emitters. Alpharadin is the most advanced alpha emitter today. The difference between Alpharadin, and Thorium-227 is that Thorium is attached to a monoclonal antibody for a more specific targeting killing power to cancer cells. In essence next generation after Alpharadin. Both Alpharadin, and Thorium-227 are alpha emitters. Though I don't know the exact specs on wavelength, potency etc. You can find those pretty easy with a google search. The main point is targeted therapies are moving beyond beta radiation, and getting into more targeted approach with monoclonal antibodies, and alpha radiation with Thorium-227.

      There is a laundry list of alpha emitters reaching the clinic, so don't be surprised if your research shows many different targeted radioactive elements, and combinations.

      The earlier generation beta emitters don't show any survival benefit, but this alpharadin appears to according to phase 2 data. I don't believe alpharadin has shown any resolutions of bone lesions on bone scans other than flare effects. I am only speculating as Dr. Sartor is involved in trials seen here http://www.news-medical.net/news/20091118/Phase-III-randomized-clinical-trial-for-Alpharadin-to-be-commenced.aspx Remember Dr Sartor was on record stating he had not seen resolutions on bone scans like xl184 before, so I would imagine there was none. I would be shocked if bone scans were not done to determine this.

      I am a little surprised Bayer put some money into this after Zevalin commercial disappointment in NHL.

    • <<Any thoughts???>>

      Sorry, but I don't know anything about it.

    • emiewemer,

      I have followed this thread for a bit of an education on the topics, looked up the Alpharadin product. Oddly enough the Algeta company has another interesting compound in the thorium-227 alpha particle emitter. (conjugated antibody candidate) Looks to be in the very early stages. Any thoughts???

      Thanks to both yourself and and the other posters for insightful thread.

      Cheers E

    • <<You may want to also include Alpharadin which currently in a global phase III clinical trial for bone metastases.>>

      Good point.

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