First, if someone has other information and thoughts, I would appreciate them chiming in on this thread and my logic. After looking over the CKD trial design, I have given it some thought and the information below is the only conclusion I can arrive at.
According to the trial, Keryx listed TSAT, Ferritin AND phosphate levels as primary endpoints, not just TSAT and Ferritin. Initially, it was not clear to me the strange inclusion criteria. Namely, to be included on the trial, the pretrial levels of Ferritin and TSAT were to be 300 ng/mL or less, and 30% or less, respectively, and serum phosphorus levels of 4.0-6.0 mg/dL. So, the levels for TSAT,Ferritin and hemoglobin for that matter, all had to already be within normal ranges whereas the phosphorus levels of all patients were to be a bit above the norm. While these levels maybe OK for Stage 3 patients, by the time they hit Stage 5, problems with iron stores can start to surface; however, by definition these patients could not be included in the trial i.e. the iron stores of all patients are to be "normal".
Also, the trial is to consist of 150 patients randomized 1:1, placebo:treatment group. If we assume strictly for the sake of argument that the treatment group will contain 33% in each of the 3 stages of disease i.e. 33% Stage 3, 33% Stage 4, and 33% Stage 5 (which I think is unlikely), we are only looking at 25 patients per "stage-related" treatment group. As such, a small deviation from this proportion in either or both the placebo and treatment groups can dramatically sway the trial results....positively or negatively. In a trail design, this would make little sense except for the fact that two consistent parameters link all patients; normal iron/hemoglobin levels and elevated phosphorous levels.
I think we can all agree that controlling phosphate levels is one key measurement. However, measurements of TSAT and ferritin are included as primary endpoints to be sure that Z does not upset the pie cart and cause iron overload. We already know that iron from Z will be absorbed, and we also know that the iron stores of these patients are already within normal ranges. So iron overload is a distinct possibility in CKD patients treated with Z. Clearly this will depend on the pill burdon, "...The number of placebo pills will depend on the patient's serum phosphorus results at each treatment visit..." My point, however, is that there is not necessarily the direct link between the success of Z in ESRD where nearly all patients are iron deficient, and its success in CKD where iron levels are normal. If Z successfully controls the phosphate (which we all expect it to do) but causes iron stores to increase to unsafe levels (none of us knows what those predefined levels are right now), the trial will not be viewed as a success.
Intelligent thoughts/comments are welcome.
I don't know about iron but we are overloading this thread, yahoo is cutting out my posts...
ok, here it is again...
for patients on dialysis or CKD-stage-5 the guidelines for the serum phosphorus range is 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L)..so, Zerenex meets the requirement for dialysis patients as results of PIII show serum phosphorus level in 4.9 to 5.3 range during 56weeks trial...and this is by the way is the same range that is achieved by Renvela... however, the guidelines for the serum phosphorus for patients with CKD at stage 3 and 4 is different, it's in the 2.7 mg/dL (0.87 mmol/L) to 4.6 mg/dL (1.49 mmol/L), the upper limit on the required range is lower, I don't think Renvela was able to push phosphorus level down below 4.6, or at least I didn't find yet evidence of that.. I also doubt that Zerenex can push phosphorus level below 5mg/dL, thus taking pts with phosphorus levels between 4 to 6 makes sense, to me big question is can Zerenex show that phosphorus levels can be reduced to 4.6mg/dL (from let's say 5mg/dL) in order to be effective for CKD-3&4 pts?...or just maintaining iron level in CKD-3&4 is sufficient for FDA approval?
I know we can get CKD-5 pts, that's not an issue in my mind
You are right. Thread is gettig pretty thick. I read your last one but it had no response block. Glad you repeated here.
Anyway, you have an interesting point. I think that in a round about way you mentioned this in an earlier thread. Maybe the whole point was to see if Z could simply maintain phosphate levels. It could be difficult indeed to get levels to within the range acceptable for "normal" individuals. As you indicated, normal individuals have much lower levels of phosphate; however, higher levels are tolerable up to 4-5 mg/dL probably without drug intervention and simply using diet/protein control. So in the end, binders are probably only used in those CKD patients (predominantly S4 and certainly in S5) where phospate levels have become unmanagable by other means. Your point is interesting because it is hard to guess what the investment world is looking for. Will they be expecting to see phosphate levels more in line with normal individuals i.e. 2.7 mg/dL, or will they be willing to accept "maintaining the status quo".....very interesting point. Would be nice to start a new thread asking that question.
This may have been asked and answered, The board is so overloaded that it is hard to follow. But the point that I think bears repeating is that the iron overload issue is the most surprising aspect of the second Phase III trial. That is, the patients plateaued at a homeostatic level determined by the individual's body. This is far preferable to IV iron and the major reason that there is likely to be a benefit for CKD patients sufficient to merit a label.
One question that I have is whether there could be a stand-alone indication for iron-deficient induced anemia.
I would also add that a constant level of iron absorption is far preferable than the spikes that accompany IV iron injection. That is over and above the administrative costs and risks associated with IV iron. Lastly, I would point out that the hemoglobin figures that Ron mentioned yesterday are actually more positive than they may appear at first glance. That is, if one assumes treating to an equivalent hemoglobin level, the ESA benefit would likely be even greater. (Personally, if I were a patient, I would prefer a higher hemoglobin level but the dialysis centers have a different set of priorities, I imagine.)
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I do believe that there could potentially be an indication for stand alone iron deficiency anemia but the major stumbling block would be that, if hyperphosphatemia were not also present, hypophosphatemia would likely be a frequent complication. The fact is that this product shows much better iron absorptioin than any oral iron that I am aware of, but the iron that is not absorbed binds phosphorus and the end product is excreted in the feces. This is good for people with high phos but not so for people with normal or low levels. Taking the ferric citrate on an empty stomach may be a way arround this but I am not sure how the drug would perform under these conditions.
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Hello Mud...good to hear from you. All good points as usual. Ivan had raised similar arguments.
I began this thread to try and generate discussion around the logic for picking patients whose iron levels were coonsidered normal by all current standards...normal to the point that if they did not meet these levels they were excluded from the study. That logic/reasoning escapes me other than to determine if patients with normal levels of iron respond the same with respect to absorption as those whose iron levels are out of whack. Also, it is very possible (though not guaranteed) that this may in all probablility exclude most of those who are Stage 5 and many who are Stage 4 from participating in the trial. I have been looking for other input but have not necessarily gotten much on that specific point; however, it was nice that so many chimed in with opinions and good comments. It has been a while since we had a good discussion going. For just this reason I have not been posting much.
nearly all CKD and ESRD pts have low iron issues and iron overload would be exceedingly rare, especially in an oral iron formula. However, we watch for hypercalcemia with phoslo and tums for phosphate bindeing. Iron level are measured quartery or more in ESRD pts by protocol so I doubt this would be much of an issue as if it arose we could hold or back off the Zenerex.
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That makes perfect sense. But coming back to my original question, the trial required that all patients had TSAT levels greater than 30% and Ferritin levels greater than 300. By most standards (and I understand there are extenuating circumstances), this would classify an individual as not anemic. The requirements for hemoglobin were arguably borderline, but if the stores were sufficiently high this reduces the concern over hemoglobin. Anemia in CKD has classically been defined as TSAT
Good questions Zing, but why aren't you asking them on some nephrology board such as the one found on the USMLE website? Don't you think your chances of finding the answers are much better over there?
As a layman, it seems to me that the rationale of these endpoints is to maintain iron levels while controlling phoshpates, and prevent patients from becoming increasingly anemic over time. Iron overload is a concern, but this is a P2 trial after all.
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While this is entirely possible, inasmuch as they already have (relatively) normal iron levels, and because Stage 3-5 do not generally have requirements for iron, I do not think these endpoints relate to anemia...especially in light of the fact they are primary endpoints. If such was the case, why were these same enpoints not considered primary enpoints in ESRD? Also, I do not think that P2 vs P3 affects the decision making process as it relates to trial design and patient care/patient health. Neither can be compromised in any trial.
But your point is well taken. A different board would probably garner a different perspective.
IF this drugs give a little increase in Fe in the system is better, most renal disease have low in Fe.The symptom of low Fe is a big factor in a human body.Your body absorbs too much ca is bad for your hearts,or too much Fe or low in Fe. but the key is ... this drugs provide balances in the system as a treatment with no side eff..
Hemoglobin is between 9.5 and 11.5. That clearly is not normal but indicates an anemic state. In this context ferritin and TSAT are also not normal. You cannot look at these blood chemistry measures individually and draw conclusions. Always look at the context.
Wrt iron overload eg indicated by ferritin 1000 ng/dl it will be extremely unlikely not to say impossible. You can infer this from the ESRD study. TSAT leveled off after 12 weeks and ferritin did after 24 weeks. Listen to the cc again when Dr Lewis explained how smart the body is compared to pouring iron in by iv.
Hope that helps to ease your concerns.
Thanks. As for hemoglobin, I agree that biochemical parameters would indicate that the person is anemic; however, most individuals would see no adverse physiological affects in this range. The ferritin and TSAT levels I was referring to were not those achieved by treatment with Z, but those acieved from what I assume were alternative iron supplements.
thanks for a thoughtful post, I didn't know those inclusion criteria you posted..so, now I am confused..if FDA says that controlling phosphorus level in CKD patients is not the main objective and is not enough to get approval for CKD market (Ron yesterday reiterated the same point) then why would KERX select patients for the trial with normal iron levels and only elevated serum phosphorus?...how they will show iron advantage of Zerenex if iron level is already normal?...
This is my question exactly. Those in this study are generally considered to have normal iron levels. Granted these are ranges, but nonetheless, the numbers defined by the trial are within those normal ranges. As I mentioned above the hemoglobin maybe a bit low, but most would not feel the affects at these levels. I did not mean to imply that phosphate was not "A" main objective i.e. primary endpoint, but it is only 1 of 3 primary endpoints; the other two are TSAT and Ferritin levels. You must now switch your thought process from Z increasing iron levels (ESRD) to Z not have adverse effects on patients with otherwise normal iron levels (CKD). So my reasoning for, "...why KERXwould select patients for the trial with normal iron levels and only elevated serum phosphorus..." is to validate no adverse effects on patients that do not require iron.
I dion't know all the facts but I believe that there are no products that are FDA approved for phos binding in pre dialysis pts because the problem of hyperphosphatemia is not severe enough in this population to adequately #$%$ risk/benefit. The approach of keryx is likely that you can show a risk/benefit profile that is favorable by treating the 2 conditions of elevated phos and iron deficiency anemia together. In practice, many nephrologists do use phoslo, renagel and fosrenol in pts with ckd with high levels in an off label manner.
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I think you're right that it can't do everything. I look at it this way, if it does raise iron levels, well that's good for those iron deficient. If it raises them a lot, well then yes, it may be too much for those with "normal" levels.
So, you must admit, then, if it dosent raise levels much, it's then great for those with normal levels.