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Keryx Biopharmaceuticals Inc. Message Board

zing21042 51 posts  |  Last Activity: Feb 25, 2015 11:02 AM Member since: Dec 28, 2000
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  • Reply to

    price target

    by swiz39 Feb 25, 2015 9:45 AM
    zing21042 zing21042 Feb 25, 2015 11:02 AM Flag

    swiz,

    Don't get rapped up into price targets. They are pretty much meaningless whether one is looking at a company that does not yet have a product or revenues (NWBO) or a company that has been around since the founding of the stock market (GE). They are all guesses...nothing more...nothing less. You would be better off placing your faith in the local weatherman's predictions than in stock price prognostications. For some reason, investors believe that automatically, if an analyst comes out tomorrow and raises the estimate to $50...this actually means that the company will soon be selling at $50. If tomorrow, phenomenal data comes out of the trials..it won't really matter if the prediction is $5 or $7 or $10. In like manner, if the current trials show absolutely no difference in life expectancy for DCVax and/or DCDirect patients....just how much weight will you want to place on a $5 or $7 or $10 price prediction? In the end, longs will only believe in the high numbers i.e. "why is price target staying at $5.00", and if you are short you will ignore the high numbers and only look to those predicting Armageddon. Ignore them all...keep your hair in and dark just a bit longer.

    Zing

  • zing21042 zing21042 Feb 20, 2015 8:36 AM Flag

    Ab!

    No offense, but lets put things into perspective a bit. Dendritic cells were first discovered in 1973 by Steinman and Cohn...that was 42 years ago. Do you think that the hundreds of millions if not billions of dollars spent on research, the 100's of thousands of research hours on DCs, T-cells, macrophages etc., all the failed trials that went before us, and the participation of those on other trials had anything at all to do with putative successes we maybe observing today? Really.....nine people? Do you also believe that Al Gore invented the internet?

    Sorry, I don't mean to be coming down on you so hard. I understand what you are saying, but you must understand that research on DCVax did not begin with NWBO; it was not initiated by 9 people. Most of the researchers who now work on DCVax were either in grade school when research on DCs was first begun or were not even born yet. It has just taken this long to (hopefully) reap the benefits of countless dollars and countless hours of research, and move bench top science into the mainstream of clinical relevancy as it relates to treating certain forms of cancer. You are seeing first hand why those of us in science really do believe in the meaning posed by Isaac Newton's statement in 1676, "If I have seen further it is by standing on the shoulders of giants."

    So, if you could see your way clear to add 10-20,000+ more names to that list of nine, I think you will have a better feel for who saved Allan Butler's life.

    Just one mans opinion!!
    Zing

  • Reply to

    Triferic Efficacy

    by investorpa Feb 14, 2015 11:36 AM
    zing21042 zing21042 Feb 17, 2015 8:18 AM Flag

    SR,
    Be careful and do some research before you write. Auryxia is the only phosphate bonder wherein the iron (Fe3+) dissociates and either binds phosphate or increases iron stores via binding apotransferrin. To the best of my knowledge, Velphoro is the only other iron-based binder currently on the market; however, it is designed to bind phosphate strongly through the entire iron(III)-oxyhydroxide moiety forming an iron-phosphate complex that is not easily dissociated once formed. The small amount of iron that may/does dissociate from Velphoro is extremely low thereby minimizing any iron absorption and providing no measurable source of Fe3+. Velphoro is an iron/sucrose/starch complex.

    I have been saying all along that both these products i.e. Triferric and Auryxia will find a niche in the treatment of this population of patients. Triferric will be good for early phase patients, but by virtue of their own data will not replace the iron in those with heavy iron losses; alternative measures will be necessary. Aurexia will indeed have to compete in a crowded market and it is my opinion that patients will be moved to Auryxia once the disease progresses and physicians find they can help control excessive iron loss via pills. Does not mean this will supplant Triferric. Each patient and each doctor will now have a multitude of new ways to make life more livable for these patients. THAT is the bottom line. This is not a competition.

    JMHO
    Zing

  • zing21042 zing21042 Feb 5, 2015 8:19 PM Flag

    Mr

    Again I agree ...to an extent.

    You ask, "Do digestive acids change the chemistry?" Yes...it could depending on whether we are talking about a chemical in the stomach (acidic) or in the intestines (neutral to basic) where most absorption takes place. pH can change the chemistry as it relates to absorption characteristics.

    "Would it cross the intestinal membrane?" It really does not matter because as I noted elsewhere, it is believed that most iron that binds transferrin is derived from blood and not from the intestines.

    Nonetheless, the points you raise are important ones. Most importantly, this is a treatment for dialysis patients. For some reason, others believe that there is this vast, untapped market for other than patients on dialysis. Other than for maybe TPN, I just don't see it.

    Zing

  • zing21042 zing21042 Feb 5, 2015 8:09 PM Flag

    Agreed. But for some reason, others believe (or suggest) that there is more to it above and beyond anemia...I don't see it. You cut to the chase. That is all I was trying to say...with some background.

    Zing

  • zing21042 zing21042 Feb 5, 2015 5:03 PM Flag

    MR,

    Good points. By the way the conversation was going, I assumed the comment "method of delivery" implied that the chemistry can be applied to a wide variety of problems i.e. delivering drugs for Multiple sclerosis; delivering drugs that cure cancer; delivering drugs for back ache. The synthesis of compounds that enhance the solubility of target drugs has been ongoing ...let's say forever. Keryx did the same thing with their drug...different mechanism, different structure, different chemistry. That method of delivery would not work for Triferic nor visa versa. Specifically chelating citrate to Ferric pyrophosphate (Triferic) has not been tried before for solubilizing ferric pyrophosphate (the foundation for triferic); hence its protection by patents. Ya know, I could be wrong, though. I remember reading somewhere where including citrate in the synthesis of ferric pyrophosphate increased solubility; however, the synthesis was not well controlled as in the synthesis of triferic so it could not be used for medical purposes...a lot of unwanted by-products were in the final compound. Anyway, that does not mean that linking citrate to cancer drugs will automatically make them more soluble and as such, better target the cells/mechanism of interest....if it was only that easy, huh??

    "Microdialysis" has been used in association with intracranial administration of drugs. Though likely novel for kidney's, dialysis has a very limited scope as a technique for administering drugs because it has an absolute requirement for the individual to be on a dialysis machine. It is highly unlikely (though not impossible) that a person would be put on dialysis and who has normally functioning kidneys, just for the administration of a drug.

    So for me, neither the use of dialysis as a holistic method for drug administration, nor the uniqueness of the chemistry would qualify as "new methods of delivery"

    Zing

  • zing21042 zing21042 Feb 5, 2015 3:41 PM Flag

    SA,
    That is it in a nutshell. It maybe useable as an IV injectable for iron deficiency (to be determined); however, I noted elsewhere that apotransferrin (transferrin that has no iron bound to it) is unlikely to chelate Fe3+ in the intestines if Triferic is given orally, because it is believed that most cells in the body acquire iron from plasma transferrin (the target area for Triferic) not from the intestines. This is why Keryx's drug can be given in massive amounts (orally) and why it affects iron stores and transferrin saturation, but not anywhere near the level one might expect with the administration of such high amounts of the ferric citrate (gram quantities).

    So, regardless of what others may be saying on this board, the use of Triferic will be for iron deficiency only. Right now that is achieved only through dialysis with microgram quantities of reagent because of its high solubility at neutral pH. It may become an additive in TPN (Total Parenteral Nutrition) IV bags where it is used in place of other iron supplements in IV bags. Right now, most IV bags contain buffered electrolytes (potassium and sodium salts) and often some dextrose (sugar)...but that is about it. TPN involves IV bags with substantially greater numbers of nutrients, electrolytes, minerals, amino acids etc. for people who cannot otherwise ingest food. The bags themselves have wide application; however, the iron inside those bags has but one use, to maintain iron levels for normal body homeostasis.

    Everything else you maybe reading here about all these other uses (other than for iron deficiency) is a bunch of hogwash.

    Good luck
    Zing

  • zing21042 zing21042 Feb 5, 2015 12:19 PM Flag

    Not sure what you mean by "method of delivery"....by dialyzate??? Triferic is basically ferric pyrophosphate chelated to citrate to enhance solubility. Ferric pyrophosphate has been around for eons. By enhancing solubility, it permits more rapid binding directly to apoprotein (apotransferrin) in the blood rather than having first circulate through the liver etc.. Examining the chemistry indicates that a serum anion (usually carbonate) is necessary for the binding of Fe3+ to apotransferrin so it is likely (though I do not know for sure) that once the iron is bound to apotransferrin, citrate is displaced by carbonate which I believe has a higher binding affinity for the transferrin. It could also be that the citrate anion is exclusively for solubility and does not enter into binding apotransferrin. Others more knowledgeable on this mechanism might be able to chime in. Either way, I do not see this as a broadly applicable "method of delivery" that may have holistic application to other systems. This mechanism and the associated chemistry is quite specific to this compound.

    JMHO
    Zing

  • Reply to

    Potential markets

    by srok57 Feb 1, 2015 11:13 PM
    zing21042 zing21042 Feb 2, 2015 5:49 PM Flag

    Ferric pyrophosphate has been around a long time, But as originally synthesized, it was highly insoluble...akin to many Fe3+ compounds.The FDA select committee on GRAS substances reviewed this over 25 years ago. In triferic, the citrate that chelates the Fe3+ enhances solubility of the entire complex...but the Fe3+ remains the active moiety in the complex.

    Transferrin contains two sites for Fe3+ and binding requires an anion. In the body this is probably carbonate, but I suspect (but do not know) that by chelating the citrate to the ferric pyrophosphate it both enhances solubility and provides the anion needed for initial binding to transferrin (more precisely, apotransferrin). The citrate is likely displaced from the Fe3+ upon binding apotransferrin and is replaced by carbonate.

    Since it was first synthesized, others have attempted to enhance solubility by incorporating Ferric pyrophosphate into lipid layers and in micro-particles where Fe3+ pyrophosphate is mixed with emulsifiers to keep it in solution when administered as a liquid.

    So, in the bloodstream, i.e. more neutral pH, Fe3+ basically has one primary goal and that is to bind apoprotein (transferrin). So it is very unlikely that this will have "wide application" since the product's main function is to deliver soluble Fe3+ to apotransferrin.

    If swallowed (pill form) the acidity of the GI tract will likely enhance solubility of Fe3+ but absorption will generally occur in the more neutral to basic intestines. Also, the hypothesis that apotransferrin secreted by intestinal cells chelates intestinal iron and facilitates its absorption is unlikely to be true. It is now believed that most cells in the body acquire iron from plasma transferrin...the target area for Triferic.

    So in the end, this product will likely have one (important) application and that is iron homeostasis via parenteral administration...dialysis or TPN (total parenteral nutrition).

    JMHO
    Zing

  • Reply to

    history lesson

    by srok57 Jan 29, 2015 6:20 PM
    zing21042 zing21042 Jan 30, 2015 3:48 PM Flag

    Thanks for the response lee, but in your example, you are comparing apples and oranges. Examples such as those you provided are referencing drugs with general and wide reaching modes of action such as aspirin. As example, aspirin is a vasodilator. As a vasodilator, any illness requiring increased blood flow might benefit from such a drug...so applications can be wide reaching...I get that.

    Also, though the mechanisms of action are not yet known for Trofanil, they are believed to involve blocking uptake of norepinephrine at nerve endings. Norepinephrine is involved in numerous pathways in the body. It can function as a neurotransmitter, a hormone and who knows what else. That means by controlling these via Trofanil one may be able to control other illnesses unrelated to the drugs original design.

    However, once Triferic enters the blood stream it quickly dissociates into its salt counterparts i.e., Fe3+ and pyrophosphate (though citrate, and phosphate also make up the compound). The benefit of Triferic is that is has been made more soluble by the inclusion of a citrate anion. Be that as it may, chemical sources of Fe3+ are numerous both naturally and artificially. Further, ferric pyrophosphate has been around for eons, just not very soluble. So my question remains., what applications, or more specifically, what diseases can a more soluble source of Fe3+ address that are unrelated to anemia? I am not saying you are wrong, I am only asking that someone identify the application of Fe3+ to a meaningful population of patients unrelated to anemia.

    Zing

  • Reply to

    history lesson

    by srok57 Jan 29, 2015 6:20 PM
    zing21042 zing21042 Jan 30, 2015 12:09 PM Flag

    You might have to be more explicit when you suggest, "...Rockwell will sell exclusive rights to non esrd applications. They don't want to spend the money bringing other applications through the fda but plenty of others will. They will keep dialysis for themselves profiting from the technology others need. This new little drug is a huge breakthrough in iron therapy."

    Rockwell converted a highly insoluble product (ferric pyrophosphate) into a soluble product i.e. Triferic. By doing so, AND administering it via dialysis, they created a safe treatment that over a period of hours is slowly absorbed by the body. This controls Hgb and iron stores. We know that highly soluble iron salts tend to be toxic when given parenterally (IV). When given enterally in large dosages it is probably not much different than any of the other ferric-based iron supplements. So, Triferic works because it is used in dialysate. So could you elaborate as to what you mean by "non-ESRD application"? Because Triferic has been defined as a treatment to replenish iron loss from dialysis, I suspect it can be used for any (or nearly any) indication as long as the patient is undergoing kidney dialysis. Effectiveness and safety in kidney dialysis does not automatically equate to an effective and safe IV treatment.

    Zing

  • zing21042 zing21042 Jan 29, 2015 3:05 PM Flag

    No offense MR, but that has to be one of the most ridiculous statements I have ever heard from an investor. The whole purpose of being in the market it to make money...it is that simple and yet that complicated. If this stock drops to $4#$%$ will be for a very good reason, and it won't be a "fluctuation" or " oscillation" It will be because the beliefs in Triferic and this company never materialized to the bottom line.

    Having a strategy to manage your money and investments is most important, not defining oneself as long or short. If you had been crazy enough to ascribe to that thesis and invest in QUALCOMM back in 2000, you would still today be in the negative column 15 years later. Oh, but you would have one redeeming quality to be sure....you could claim you were a true long. How bout Sun Microsystems which peeked at $125/sh in the same time frame only to be sold for less than 10% that value 13 years later....oh but you are a true long. GE peaked at $57/sh...today you would be sitting at less than 1/2 that number. The list is long and strong.

    Nope, it's like Kenny Rogers sings, "...You got to know when to hold 'em and know when to fold' em"......that is the smart play and it will always be the smart play when investing hard earned dollars in the market and in any company.

    Zing

  • zing21042 zing21042 Jan 29, 2015 7:20 AM Flag

    Kruk,

    In such a situation, one cannot use anecdotal, ancillary information upon which to draw a scientific conclusion. One cannot use the pseudo-German approval to conclude the treatment works. The Hospital exemption is an admission by Germany (and others) that this patient population has little available to substantially prolong life beyond the norms of an untreated patient population. So Germany has agreed based upon scant PI/PII data to allow this treatment to take place. It is an admission of a no win scenario, not an admission of success nor an admission that the treatment works.

    Also, the German approval is conditional, time sensitive and one that must be reapplied for after 5 years. When have you ever seen an "approved" drug or treatment require submission for re-approval? Germany feels (and I concur) that within 5 years this matter should be rendered academic. Sufficient information should be amassed by that time to make a more educated decision. If the data support the current PI /PII findings, the treatment will get permanent approval. If the patients receiving DCVax show no better response than those not receiving DCVax, NWBO will not be granted an extension...it is that simple and that complicated.

    There are trials ongoing that are assessing multiple cancer types. Within those trials, there is insufficient participation in any one CA group to generate scientifically meaningful data...only enough information to provide NWBO the data upon which to build a larger trial. Hence "throwing shyt against the wall to see what sticks" is precisely what the trial is. If some cancer types respond better than other, those will get precedent for future validation. Those that fail will be culled from further studies. Call it as you wish, but little if any statistically meaningful data will come from such a trial except possibly for DCVax as a holistic treatment for CA.

    JMHO
    Zing

  • zing21042 zing21042 Jan 29, 2015 6:48 AM Flag

    Buzz, It makes sense. I commented on this but in a round about way. If the glioma is capable of modulating and down-regulating host immunity (specifically T cell responses) , it follows that controlling the growth and dissemination of the glioma (DCVax) and enhancing T helper cells will enhance the overall well-being of the immune system. I am not sure if there is a different mechanism that is also involved, but I would be interested in hearing about it.

    Zing

  • zing21042 zing21042 Jan 29, 2015 6:41 AM Flag

    Good points. You are right about the 55 patient arm. I believe as I noted below (somewhere), they are merely throwing shyt against the wall to see what sticks and will venture foreword on positive responses in any subgroup.

    Also, I do not know why some continue to suggest that data is being concealed. As you noted, a blind trial is just that... blind (unknown) to all interested parties. If not, the trial becomes invalid.

    I get it! Not sure why others continue to refute it.

    Zing

  • zing21042 zing21042 Jan 28, 2015 10:42 AM Flag

    The concept is not difficult to understand ..the concept is morally, ethically and scientifically wrong. It is called "fudging the data".

    The FDA does not generate data. They evaluate the data presented to them.

    Finally, to be included in the trial, radiation therapy had to have been completed no less than two weeks prior to the first immunization and more importantly, lymphocyte levels which have been implicated in immunosuppressive effects, have to be no less than the lower end of the normal range. So you still have presented no evidence of your claim that these patients are "immune impaired" only as a result of radiation or chemotherapeutic treatments and not the result of the immunosuppressive effects of the cancer. I am sure there are data available that argue both sides of the fence, but to blindly assume that radiation is the only contributing factor is not well supported.

    So your thesis to "ignore the "IMMUNE IMPARED" is simply wrong.

    Zing

  • zing21042 zing21042 Jan 28, 2015 8:44 AM Flag

    Happy, my recommendation is to focus on the now. The only trials of importance are those on GBM. The others are all "throwing shyt against the wall to see what sticks". It may turn out in the future that DCVax becomes a panacea for solid tumors. That would be great; however, at present there is not yet enough data to support its effectiveness in GBM patients. So don't look too far down the road until we get through this intersection.

    Zing

  • zing21042 zing21042 Jan 28, 2015 8:37 AM Flag

    My apologies, if you do not understand, just say so.

    Specifically, you wrote,
    "These patients (2) should not be used in the calculation of any numbers. They (there) should be a reduction to the N count."

    I responded,
    "When data does not fit the hypothesis....delete it until the hypothesis is supported. Now there is a great thesis upon which to build a trial."..."This is not like buying a dozen apples where you handpick the good and leave the bad." My comments are right on topic. You seem to think that one can simply cull data to obtain predefined results. You cannot.

    The rest of your comments relate to " immunosupression" imposed by drug treatment. Your comments imply that the immune system is so completely decimated by drug treatment that it basically does not function. This is incorrect. Key immune-related blood cell parameters are all to be within or just slightly out of normal ranges for patient enrollment in the trial which means the patients are tolerating concomitant drug treatment. If not, these patients would be dying of unrelated illnesses i.e. infections, long before they succumbed to cancer.

    That is not to say the immune system is not taxed. However, at present they are unable to quantify the effects of drug treatment on the immune system of glioma patients. Reason being, it has been published that gliomas inhibit T-cell proliferation and activation, induce regulatory T cells, and cause T-cell apoptosis by one or more mechanisms. So the cancer is doing a fine job of inhibiting the immune system all by itself. Indeed, the drug may actually be enhancing the immune response by depressing the tumor, albeit minimally.

    One key purpose for DCVax therapy is to help the body circumvent the immunosuppression imposed by the glioma by priming the DC cells in vitro rather than depending on in vivo activation where the iimmunosupression activities of the glioma may take precedent.

    All is not as obvious as it seems.

    JMHO
    Zing

  • zing21042 zing21042 Jan 27, 2015 2:55 PM Flag

    I see,
    When data does not fit the hypothesis....delete it until the hypothesis is supported. Now there is a great thesis upon which to build a trial. The whole point of large trial sizes is that aberrant data should become less of a factor in establishing the norm and the effectiveness of treatment. It is the same reason why smaller PII trial sizes often result in failures when drugs (treatments) are subjected to larger PIII trials. In smaller trials, anomalies can happen that generate both pseudo-negative as well as pseudo-positive results. This is not like buying a dozen apples where you handpick the good and leave the bad. If a treatment is good, it all comes out in the wash. Quite frankly, you should prefer it this way because the results becomes more difficult to refute when under review i.e......" see, even when we include these outliers, we still show the positive effectiveness of treatment..."

    Think about it!!!
    JMHO
    Zing

  • Reply to

    Interim Analysis - DCVax-L

    by anotherday1225 Jan 22, 2015 1:16 PM
    zing21042 zing21042 Jan 23, 2015 7:50 AM Flag

    Great post, Buzz. At last a voice of reason.

    I remember back on the Keryx board when the cancer drug perifosine was being "modeled" during its PIII trial, by a number of pretty sharp posters. When the "modeled" trigger date came and went by at least a month or two (well beyond norms from other trials), I introduced similar cautions regarding comparators to placebo groups from unrelated trials. Of course that immediately labeled me a short .....until the data came out. Lo and behold, the placebo group in that particular trial unexpectedly lived much longer than the norms and the trial was to say the least, a bust.

    The greater the number of prior data points, the easier it becomes to model; however, the smaller the current trial size, the higher the probability that the norms may not be acquired during that trial. GBM is one of those whose mean patient life-span is well established but whose range in patient life-expectancy is all over the place. Also, since the FDA approved temozolomide for the treating newly diagnosed glioblastoma in 2005, the 2-year survival rate of glioblastoma patients has doubled, from 12% to about 25%. These and many other similar factors become difficult to account for when modeling.

    Nice post!!
    Zing

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