Aggression is met with aggression, "Stop thanking him kole/a_gas/zing. Pat yourself on the back why don't ya?"
Another insignificant and uneducated post from Stockathlete.
Please stop dribbling...you are messing up your keyboard....it comes out in your incoherent posts. At least I do not keep giving a "thumbs up" to my own posts (via an alias poster).
Currently I have Kole on ignore for several reasons; 1) he never has anything of significance to say (much like you) and 2) because as much and many times as people like you comment on his posts, he never responds. Did you ever notice that? He never, ever responds and yet you continue to egg him on. He is like a virus on your computer...only there to aggravate you. And people like you bite everytime. He must love reading the responses to his posts knowing he has got you right where he wants you. I in turn (unlike Kole) try and respond to all comments on my posts and with something other than the dribble you constantly post. So unless you have something of intelligence to add which is doubtful, put me on ignore, stick your head in the sand and be on your way. Invest your time responding to an idiot and one who will never respond to you (now there is a positive use of your time) rather than reading and understanding (if you are able) the posts the many on this board who are trying to put it all together.....
That is a tuff question that in my opinion has no easy answer. First, most iron supplements consist of Fe2+ not Fe3+ so the ferrous salts go directly to targeting functional i.e. hemoglobin binding, iron levels in the body. Fe3+ targets the iron stores and allows the body to call upon them when iron (Fe2+) is needed. As such, I believe there are fewer side effects from Fe3+ salts than Fe2+ salts. That being said, the Fe3+ targets hemoglobin as a secondary response or indirectly rather than as a primary target. Patients with kidney disorders need as many pieces of ammunition as possible to deal with the plethora of complications that arise from not having functional kidneys. So it is my opinion that no one treatment will supplant another. With that in mind, the comment by mgm then comes into play wherein the easiest and least aggressive approach will be taken initially. If it is decided that Zerenex is the baseline than the doctors will start here. If added help is needed in some patients they may start to supplement Zerenex with oral iron, followed by IV iron and ESA....I really think that your question attempts to identify a standard of care that in the end will be dictated by the condition of the patient. If I was a physician, I would certainly start with the least aggressive approach which would be Zerenex given that phosphate binding is a must, and then monitor the situation and move forward from there.
One caveat is Velphoro. If I understand correctly, it has a much lower pill burden than other phosphate binders. Further a big obstacle to patient care is getting the patient to ingest the large numbers of pills each day. If this is correct, some doctors may opt for fewer pills i.e. Velphoro supplemented with oral iron rather than many pills i.e.. Zerenex and less iron. As much as we all see Zerenex as a panacea to anemia and hyperphosphatemia, the patient and market will make the final call.
To nephrologycat: I do not dispute the points you raise. The issue at hand is not data on dual activity but what was in the NDE and if sufficient research and trial information is available to make the iron claim on the label (in the eyes of the FDA). It is a much different claim to indicate that Zerenex increases Ferritin levels, TSAT levels and hemoglobin than to indicate it is a drug for anemia. The two are not necessarily synonymous (Doctors may view it that way but the review panel will look at it differently). So the issue remains before us. I noted that I also am unaware of such a product, but what you and I know will have no affect on what the FDA approves.
I thought you would figure it out....!!!! It would be great if coffee could solve all my problems that easily!!
If I understand correctly, we must consider that the data IMUC based their PI trials against were historical norms rather than a placebo. This is the same mistake those on the Keryx board made when trying to glean information from the Peri trial. All statistics and projections were predicated upon controls from historical norms. One cannot simply predict variation in placebos. It makes sense, but it is not scientifically sound. The PII trial for IMUC is one of many examples of inconsistencies in taking this approach. Granted, these inconsistencies get normalized in PII and PIII trials when they are conducted with more scientific integrity, but it can be misleading and demonstrates the potential lack of congruence among controlled vs non-controlled studies.
I do agree with you about the anemia/phosphate marketing; however, what you and I agree upon may not be what the FDA sees and approves. That is why I qualified my statement above by saying, "one simply cannot predict how the FDA will collectively assess these data during the review process."
I only assumed that Keryx would seek approval for that purpose (iron), otherwise, why would they have examined those endpoints in their studies....for off label use only? That make little sense to me. It's their ace in the hole. Unfortunately, all this is speculation on my part because we simply do not know what Keryx included in their NDA for Z. So, if phosphate binding is the only game in town, as you state, this need has been met by the industry. A single pill to kill two birds...this has not been met.
Another question is what happens if the iron component is submitted and not approved? Then Z becomes just another in the pack of phosphate binders to compete with Renvela (and now Velphoro).
Lots of unanswered question before us.
Gassy, it sort of depends on the labeling that Z gets. If the labeling is limited to phosphate binding than I agree there are other drugs that serve this population of patients. We can question benefits and efficacy, but as a phosphate binder only, Z is not an "unmet medical need". But I hope you will agree that the whoopla over Z is more related to the iron stores and anemia as a secondary benefit. In this regard, I am unaware of any other drug that simultaneously addresses both the anemia and the hyperphosphatemia associated with ESRD patients without causing iron toxicity. So if labeling is extended to include anemia in one form or another, I do believe that Z can be regarded as a drug that addresses an "unmet medical need". As I have been saying all along, however, one simply cannot predict how the FDA will collectively assess these data during the review process.
This part of the CEOs comment gets to the heart of the question. Will the FDA view Zerenex in its entirety (ferric citrate) or will they view only the active moiety i.e. Fe3+. If they view the entire molecule, or if the Fe3+ somehow remains attached to the citrate anion during binding to ferritin or phosphate, then Zerenex has as good a chance as any to get NCE designation. However, (according to FDAs definition of an NCE) if the FDA only views the presentation of a solubilized Fe3+ molecule which is the only 'functional' portion of Zerenex i.e. citrate does not bind to ferritin and citrate does not bind phosphate, then NCE designation will come under significant scrutiny. Indeed, Zerenex is a salt of a heavy metal ion which means that when the Fe3+ binds to the phosphate or ferritin, it is completely dissociated from the citrate anion...it is a free circulating iron molecule. There in lies the million dollar question and how the committee will interpret the submission is anyone's guess including mine. But I submit based upon all my concerns that NCE is not the slam dunk that many believe it to be. This concern seems to be mirrored in your posted CEO comments.
By the way...I am not a basher, I am not short, I am long 3K sh. My comments above were made without blinders as are all my comments and opinions.
Part 2 NCE:
With respect to the NCE, the CEO seems to use an argument against Velphoro, but does not apply that same argument to Zerenex. As example, he says "...has been approved numerous times in the modern era as IV iron formulations..." Fe3+ has also be approved in numerous formulations for human use (note: purity should not matter for an NCE but does matter for a patent). Also, the CEO mentions, "...Ferrlecit, another ferric oxy-hydroxide based IV iron formulation actually received NCE for its ferric oxy-hydroxide formulation with a gluconate coating." Of this I was unaware. However, I assume that Velphoro was denied NCE because Ferrlecit had already been approved. Like Velphoro, both involve ferric oxy-hydroxide linked to a carrier (carbohydrate/sugar). Even though the carrier is different, the active moiety i.e.ferric oxy-hydroxide, had previously received NCE designation so subsequent requests (Velphoro) were denied. So how is the Fe3+ in Zerenex different from the Fe3+ in other approved versions of Fe3+ salts? I agree that Zerenex is indeed different and more pure, but the NCE specifically references "the active moiety" not the entire molecule (case in point Velphoro and Ferrlecit). If the modifications to Zerenex involved modifications to the Fe3+ cation, than NCE designation may ensue. If however, modifications were made to the citrate complex to enhance solubility, in the end this was done just to make the Fe3+ (previously approved) more available to the patient. I assume (but do not know) that modifications were made to the entire ferric citrate complex inasmuch as direct modifications to the iron may have interfered with its ability to bind ferritin. Again, I simply do not know.
Anyway, that is my take. Not saying I am right, just expressing my concerns over NCE approval. But I also agree with the CEO who stated above, "...we have always maintained that NCE designation is a nice to have, not a need to have, for Zerenex..."
There appear to be two general issues in the comment 1) patent protection and 2) NCE approval.
With respect to patent protection, there has been a lot of controversy over the product patents but less controversy over the manufacturing patents. The CEO seems to address this issue in his comment, "Moreover, the bioequivalence path for any generic will be extremely lengthy, costly, and difficult." This relates more to manufacturing than product patents. Even if the PTE and product patent is challenged and unfortunately not approved, the manufacturing patents can still offer protection because if generic Zerenex is manufactured in a manner different than that in the patent, those making the changes will have to demonstrate bioequivalency. Generics would NOT have to demonstrate bioequivalency if the same exact manufacturing protocol is followed. A few years ago the Obama administration made these changes in order to get generics to the market quicker. The CEO comments that, "several sophisticated healthcare funds that have done significant due diligence on our patents." This is quite reassuring, but in the end, it will be the patent attorneys and a jury that will decide the validity of any patents. You can just look to the tech industry to see that key issued patents are sometimes challenged and lost in a court of law. In the end, I have less concern over patent protection than I do over the impending NCE.
See second post on NCE
Sure...if you water it regularly and fertilize it 4 times a year
To Cutugno: That maybe your bottom line...it is not mine. But time will only tell. There is no real way to know how the referees/reviewers will evaluate a drug for NCE.
Your right. It made/makes little sense that it would not be approved because it was covalently linked to the sugar/carbohydrate complex....but you never know how the FDA views these things. On this we can agree 100%.
Again, as I read what you posted above, the answer is 'yes', the chemical moiety in Zerenex COULD be granted an NCE... if it had not already been approved for use. Fe3+ in many salt forms is an FDA approved substance for human consumption...it is a food additive I believe. I think (but do not know) that NCE weighs structure and prior approval over application. Application is left to the US Patent Office (in addition to structure).
This is probably the basis upon which the PA-21 NCE was rejected. Even though it was linked to a sugar/carbohydrate complex, the Fe3+ was nonetheless the operative "moiety" and for this, the NCE was rejected (I admit there are a few assumptions on my part here).
This is what will guide the review process in determining the NCE status for Zerenex and what the referees will grapple with. That being said, I have been wrong before and I have always been told never to go to trial because you can never predict how a group of people (jury) will view the data in front of them. So in contrast to those who reviewed the PA21 application, those reviewing the Zerenex application may look at it differently and more favorably. Flip a coin!!!
In the long run, if the manufacturing patents hold, it may not matter much.
Nope. Fe3+ is not converted to Fe2+ upon binding ferritin. If I implied that I apologize. It happens in conjuncton with its release from ferritin. In the absence of reducing agents, the iron (Fe3+) bound to ferritin is quite stable, it does not exchange among molecules but can undergo slow release by other competing chelators of Fe3+. Surprisingly, not much is known about the physiological mechanisms causing the release of iron from ferritin. It is believed that conversion of Fe3+ to Fe2+ results from exposure of the ferritin to physiologically-occurring reducing agents like flavins and thiols among others. Not sure. Upon reduction, however, the Fe3+ is released as Fe2+.
Agreed, the salt is indeed critical to making the Fe3+ available; however this seems not to be a consideration for an NCE. Reiterating portions of the initial post from mgm, 'New chemical entity means a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the act' (of note, both Fe3+ and citrate have been previously approved for use in humans).
Further from that post, '...the definition of active moiety is "the molecule or ion [in this case Fe3+], excluding those appended portions of the molecule that cause the drug to be an ester, salt [in this case citrate] (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance."
So, while you are correct and I agree that modifications to the entire salt make Zerenex more soluble and increase bioavailability, the fact is that in the end, Fe3+ is the bioactive moiety and not the citrate. In contrast to your example, if one made the exact same salt but randomly replaced the Fe3+ with another heavy metal cation, you would probably find that it does not bind phosphate or binds it very poorly even in the presence of the citrate complex and increased bioavailability. So the 'active moiety' is not the citrate but the Fe3+. The FDA defines the 'active moiety' as that part which is 'responsible for the physiological or pharmacological action of the drug substance.
In the end, it is hard to know how the FDA will view the submission and I could be way off base. But based upon the definitions before me, that is how I interpret the guidelines.
I am aware that Fe3+ does not bind hemoglobin. Even though the PA21 involves complexed Fe3, studies had to be undertaken to investigate the uptake of iron after oral administration of PA21 in order to assess the risk of iron overload. This would have involved looking at indicators of both Fe3+ and Fe2+. I assume that the iron attached to the sugar, binds phosphate and the entire polynuclear iron(III)-oxyhydroxide /phosphate complex is eliminated from the body. However, prior to approval, they had to show that the complexed iron did not somehow get released (chemically or biochemically) from PA21 and become available to the patient. This in turn would have resulted in increases in iron stores and hemoglobin levels (reduction of Fe3+ in ferritin to Fe2+ when needed). One cannot easily separate the two when it comes to drug treatment...it is not black and white.