This is just my second post on this board , but have been lurking here for over 3 years. While we wait for the final results i am nervous but at the same time very confident. I would like your thoughts on this particular point. In one of your last posts you said that you we're a little concerned ( maybe concerned is a strong word) about having too much iron absorbed in the patients system. Correct me if i am wrong. Also , and this the reason for my post, we already know that Zerenex works as confirmed by the 2 phaseIII studies conducted by Keryx and it's japanese partner. But the main reason why i strongly believe in a positive outcome is specific to the compassionate/ extension of their phase III,and here is why.The way i see it ,even if Keryx or the patients would have wanted to start this extension study,i think the most important factor that made this extension possible was just the opinions of the doctors who have been following their patients all this time. What i mean is that the doctors must have at regular intervals ( every month or so, or sooner ) the results of their patients blood tests and so they can clearly see for example if the phosphorous is at a acceptable level or if they absorb too much iron in their system or any other potentially dangerous side effect. i do not think any doctor in his right mind would volontarily accept to participate in a extension study with a experimental drug that would put any of his patients at risk. Also he could probably be sued for negligence. I would think his patients safety is his top priority. Worse case he would have probably switched back his patients on another phosphate binder as there are already 3 others already approved to threat this disease. Also,even if the FDA did not request this extension study, i would think that they could have stopped it from even starting if they had even the slightest worry that it could be dangerous. And finally i do not think that Keryx would have started this study without a strong backing from the doctors opinions. For me this is the best indication of a positive outcome and, it's like Ron was screaming to us without talking that , hey boys , we have something that is working,and it is working great. I hope i am not wrong, for me, and all the longs who have patiently suffered trough the perifosine nightmare. Good luck to all.
I agree. The compassionate use extension is huge. I was not saying that i was concerned about too much iron absorption. I own a ton of shares. If I was concerned i would be at least partially hedged, which I am not. I was only saying that iron can be a tricky thing -- too little is a problem and so is too much. I think that liver toxicity and other negative iron side effects are a big part of what the DSMB was monitoring when it examined interim safety results something like five or six different times during the course of this trial. I think the fact that they allowed the trial to continue without modification and the fact as you pointed out that the FDA authorized (and even requested) a compassionate use extension all but eliminates the risk of a safety issue in my view. And I feel positive about the phosphate control, the lower pill burden and the more favorable side effect profile. The only open issue in my mind is the strength of results in the secondary endpoint. Fingers crossed. We should hear something from Japan or the company or both very soon. We are down to days and not weeks. GLTA
For the techies here: Personally, I’m not so concerned about the practical results of the clinical study as I am of the theoretical issue of the iron absorption with respect to the field of pharmacogenomics. This is, that while the iron absorption may be acceptable in the majority of people, there is the potential for a considerable diversity in the chemistries and metabolism involved. And, it’s the unpredictability of this diversity and potential for an individual chemistry to support or induce a toxic uptake of iron that could cause the reviewers to deny the application. On the other side, there are similar concerns for most any drug. It's just that there is sooo much iron, that if an individual has some added capability to take it up, well....
I do not think that genetic heterogeneity will come into play in this circumstance though no drug works 100% of the time on 100% of patients. Reason I say this is that we are talking more about a chemical reaction (or should I say chemical interaction) between Fe III and transferrin and ferritin proteins. If people produce these proteins in forms that are unable to bind iron, they have a bigger problem.
I have mentioned before that my concern regarding iron benefits is more related to supply and demand and whether or not ferritin binding and TSAT levels can be considered good markers for adequate iron stores in ESRD patients. Given that most of the iron will chelate with the phosphate, and given iron depletion in these patients, will the high demand for iron by the body be met by what can be supplied by the stores? Under the best case scenario right now, all Keryx will be able to claim (if that) will be exactly what was measured; namly that Z increases iron stores; they will not be able to claim that Z can supplant supplementary iron treatment unless this is specifically evaluated in a new set of trials. Where genetic variability might come to play is in normal levels of transferrins and ferritins produced by any individual. I suspect that these might vary somewhat. In normal circumstancs it is probably not a problem; however, when the body is perturbed as badly as those with ESRD, these seemingly inconsequential variations can become big issues.