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Post by silentbob on Aug 16, 2016 11:34:03 GMT -5
Some have argued that 'fast' acting insulin analogs like lispro (humalog) and aspart (novolog) and glulisine (apidra) are delivered in monomers so Afrezza can not make the claim to be unique in this respect. This is not the complete truth: 1) Afrezza is true regular human insulin (RHI). It is identical to the insulin native to the human body. All the analogs have changes in their amino acid sequence (let's call them mutations) in order to give them a better time-action profile. Because of the mutations, they are not called 'insulin', but rather 'insulin analogs'. In other words, while there might be 'monomeric insulin analogs', Afrezza is the only 'monomeric insulin'. 2) Lispro and Aspart might not self-assembly into hexamers, but the producers still add zinc and excipients that ENCOURAGE formation of hexamers, to improve stability and prevent fibrillization. So delivery is still in large part hexameric which is reversed upon injection as the excipients diffuse and hexamers disassociate faster then injected RHI. In other words, monomers are only a small part of lispro and aspart upon injection. 3) Apidra is indeed an hexamer-free (and zinc free) analog that has only monomers and dimers. The mutations seem more significant to me. While apidra still self-assembles into dimers (helping stability in absense of hexamers), it seems there is still a large amount of the mutated insulin in monomeric form. This would explain why it is somewhat faster then lispro & aspart. This is a very unpopular analog, but that might be because it is marketed by Sanofi - we do have some anecdotal evidence after all. The only real downside as compared to lispro & aspart that I've found is that it degenerates faster then the others (esp when not kept very cold). Note that the main reason for hexamers is stability of the solution (and prevention of fibril formation). In Afrezza this problem is solved by suspending monomers in technosphere (fdkp) particles. As to what is more important: being monomeric or being inhaled; look no further then this comparison of Exubera vs analogs vs RHI: www.ncbi.nlm.nih.gov/pubmed/15855570In this study it was shown that (hexameric) Exubera was in the blood for longer then Lispro, even though its time-to-action was faster. This was due entirely to its hexameric state. So if this delay is due to hexamers, but a (partially?) monomeric injected analog (Apidra) is also in the blood for very long, is it the injection or the hexamers that make other insulins linger? Both. If there are either hexamers or the insulin or analog is injected, it will add hours to the time-action profile. These times are mostly overlapping, which explains why a monomeric injected insulin is not twice as fast as a hexameric injected insulin, and why hexameric inhaled is similar to monomeric injected.
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Post by derek2 on Aug 16, 2016 12:38:48 GMT -5
Hi silentbob Being one of the some that say RAAs are mostly monomeric, I'll start off by saying that I hold you in the highest of esteem - when you talk (type) folks should listen. Probably more than when I type. You have added some great nuance to the hexamer / monomer, insulin / analog discussion. Personally, I think the classification of analogs as "not insulin" is parsing the language a bit too much. If you only allow recombinant human insulin (which is not made by humans) as the only insulin, then of course Afrezza is the only monomeric insulin. However, I think it's great that you didn't stop there and explained further, including source material as support. Your final paragraph has me intrigued - I like the idea of there being multiple factors involved. Thanks, even if it contradicts some of what I've written. More rationally grounded information is better.
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ron
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Post by ron on Aug 16, 2016 13:07:35 GMT -5
Ultimately, all that matters is what endos think matters.
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Post by agedhippie on Aug 16, 2016 13:15:23 GMT -5
This [Apidra] is a very unpopular analog, but that might be because it is marketed by Sanofi - we do have some anecdotal evidence after all. The only real downside as compared to lispro & aspart that I've found is that it degenerates faster then the others (esp when not kept very cold). It's not that Apidra is unpopular but rather that so few insurers cover it. I would swap to it in a heartbeat but I have yet to have an insurer who covers it.
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Post by mnholdem on Aug 16, 2016 13:26:30 GMT -5
One significant point that may be overlooked in this post by silentbob is that marketing an insulin based on speed alone simply may not be enough in this crowded market. If it were, then (Sanofi marketing ineptitude notwithstanding) the RAA insulin Apidra should be in front or at least competitive in the marketplace. The speed of RAA insulin compared to regular human insulin is what made them into blockbusters, and yet Aprida finds itself at a distant 3rd place within the prandial space behind the slower RAA's Novolog and Humalog, even though it has empirical proof of being the fastest RAA insulin of the three.
My point is that MannKind may have recognized that it may be wiser to market Afrezza in a different way. Mike Castagna put out the teaser about "OUTsulin" indicating that the marketing plan is to show some of the the benefits of Afrezza quickly exiting the blood stream, namely:
• LESS hypoglycemic episodes; • LESS hospital visits; • LESS worry about going to sleep at night.
In regards to being a monomer insulin, I have read a number of journals that indicate (and this is still a debatable phenomena) the ultra-fast Afrezza inhaled insulin imitates a healthy pancreas 1st Phase insulin response, which is presented in the post mnkd.proboards.com/thread/3407/blood-sugar-101-tell-diabetes?page=1&scrollTo=36728, and which results in signaling the liver to produce
which, in turn, means
I find the entire subject of how the human pancreas and insulin works and interacts with the body - especially the electrochemical signaling that occurs for glocuse to be taken into muscles - to be a fascinating subject. That said, the reading I have done on this subject suggests that academics are a long way from fully understanding how it all works.
To me, this simply means that, in light of the real world results being achieved, there may be much more to Afrezza than medical science understands or can explain. I think that as time progresses (investors loathe that word "time") more academic studies will flesh out quite a number of reasons why Afrezza works so remarkably well.
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Post by centralcoastinvestor on Aug 16, 2016 14:08:03 GMT -5
The other interesting thing that has been observed by early adopters is the extreme storage stability of Afrezza. Some of the early adopters have either intentionally or unintentionally left Afrezza in hot conditions for weeks and sometimes months. They have found no adverse degradation of the Afrezza and that it works just as well as new Afrezza packages. Amazing. And yet, all of these awesome findings cannot be claimed unless the FDA says so.
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Post by silentbob on Aug 16, 2016 15:19:47 GMT -5
Hi silentbob Being one of the some that say RAAs are mostly monomeric, I'll start off by saying that I hold you in the highest of esteem - when you talk (type) folks should listen. Probably more than when I type. You have added some great nuance to the hexamer / monomer, insulin / analog discussion. Personally, I think the classification of analogs as "not insulin" is parsing the language a bit too much. If you only allow recombinant human insulin (which is not made by humans) as the only insulin, then of course Afrezza is the only monomeric insulin. However, I think it's great that you didn't stop there and explained further, including source material as support. Your final paragraph has me intrigued - I like the idea of there being multiple factors involved. Thanks, even if it contradicts some of what I've written. More rationally grounded information is better. Hi Derek, Thanks for your praise but I don't deserve it; all I do is google now and then. If you are 'Dereklinders' from the yahoo days I hold you in high regard as well. The reason why I feel the analog differentiation is important is that in humans a single amino acid change at any point can mean a massive difference. Yes the RAA may hit the insulin receptors, but that does not make them equal. They are different molecules. Some argue that there are unknowns dangers with Afrezza. I argue there are both serious known and unknown dangers with RAA. I can look for sources on the RAA mono/dime/hexameric solutions if you want... BTW, recombinant refers to the production method - both that of RHI and RAA. It was a good differentiator back in the days of pig insulin, but now insulin and analogs are both produced this way and so it no longer confers information. For that reason I feel it is a poor name for RHI, and I think this is also why the term 'regular' seems to be used more often these days.
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Post by silentbob on Aug 16, 2016 15:21:41 GMT -5
Ultimately, all that matters is what endos think matters. All that matters is giving diabetics back their health and their life. But yes we need endo's to cooperate.
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Post by silentbob on Aug 16, 2016 15:23:30 GMT -5
This [Apidra] is a very unpopular analog, but that might be because it is marketed by Sanofi It's not that Apidra is unpopular but rather that so few insurers cover it. Excactly. Poor coverage seems to be a Sanofi specialty. Let's hope MNKD does a better job without them.
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Post by silentbob on Aug 16, 2016 15:30:10 GMT -5
One significant point that may be overlooked in this post by silentbob is that marketing an insulin based on speed alone simply may not be enough in this crowded market. If it were, then (Sanofi marketing ineptitude notwithstanding) the RAA insulin Apidra should be in front or at least competitive in the marketplace. The speed of RAA insulin compared to regular human insulin is what made them into blockbusters, and yet Aprida finds itself at a distant 3rd place within the prandial space behind the slower RAA's Novolog and Humalog, even though it has empirical proof of being the fastest RAA insulin of the three.
My point is that MannKind may have recognized that it may be wiser to market Afrezza in a different way. Mike Castagna put out the teaser about "OUTsulin" indicating that the marketing plan is to show some of the the benefits of Afrezza quickly exiting the blood stream, namely:
• LESS hypoglycemic episodes; • LESS hospital visits; • LESS worry about going to sleep at night.
In regards to being a monomer insulin, I have read a number of journals that indicate (and this is still a debatable phenomena) the ultra-fast Afrezza inhaled insulin imitates a healthy pancreas 1st Phase insulin response, which is presented in the post mnkd.proboards.com/thread/3407/blood-sugar-101-tell-diabetes?page=1&scrollTo=36728, and which results in signaling the liver to produce
which, in turn, means
I find the entire subject of how the human pancreas and insulin works and interacts with the body - especially the electrochemical signaling that occurs for glocuse to be taken into muscles - to be a fascinating subject. That said, the reading I have done on this subject suggests that academics are a long way from fully understanding how it all works.
To me, this simply means that, in light of the real world results being achieved, there may be much more to Afrezza than medical science understands or can explain. I think that as time progresses (investors loathe that word "time") more academic studies will flesh out quite a number of reasons why Afrezza works so remarkably well.
The post was not about marketing, but your point is well taken. Don't forget though that we have plenty of evidence for significantly reduced hypos and superior action profile. The only problem is that the FDA doesn't allow it on the label because of their limited scientific understanding and because they handicapped the newest studies by forcing MNKD to do a rigid dose-to-dose study instead of allowing patients to freely determine their dosages and corrections like they would in the real world. Why Afrezza works so well has been well understood for many years. But not by the FDA. And my best guess is that 'outsulin' is MNKD's way to get around the incompetence of the FDA and still get the message out.
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Post by silentbob on Aug 16, 2016 15:35:50 GMT -5
The other interesting thing that has been observed by early adopters is the extreme storage stability of Afrezza. Some of the early adopters have either intentionally or unintentionally left Afrezza in hot conditions for weeks and sometimes months. They have found no adverse degradation of the Afrezza and that it works just as well as new Afrezza packages. Amazing. And yet, all of these awesome findings cannot be claimed unless the FDA says so. Yes, no moisture means no motility or biologic activity. Physical seperation also means it is impossible for fibrils to form. Perfectly logical from a scientific point of view. The FDA however does not care about science, only about massive and expensive studies so I have no doubt they have made it prohibitively expensive for MNKD to prove that Afrezza is safe outside of the fridge (at least for a few weeks - maybe months).
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Post by derek2 on Aug 16, 2016 16:02:50 GMT -5
Hi silentbob Being one of the some that say RAAs are mostly monomeric, I'll start off by saying that I hold you in the highest of esteem - when you talk (type) folks should listen. Probably more than when I type. You have added some great nuance to the hexamer / monomer, insulin / analog discussion. Personally, I think the classification of analogs as "not insulin" is parsing the language a bit too much. If you only allow recombinant human insulin (which is not made by humans) as the only insulin, then of course Afrezza is the only monomeric insulin. However, I think it's great that you didn't stop there and explained further, including source material as support. Your final paragraph has me intrigued - I like the idea of there being multiple factors involved. Thanks, even if it contradicts some of what I've written. More rationally grounded information is better. Hi Derek, Thanks for your praise but I don't deserve it; all I do is google now and then. If you are 'Dereklinders' from the yahoo days I hold you in high regard as well. The reason why I feel the analog differentiation is important is that in humans a single amino acid change at any point can mean a massive difference. Yes the RAA may hit the insulin receptors, but that does not make them equal. They are different molecules. Some argue that there are unknowns dangers with Afrezza. I argue there are both serious known and unknown dangers with RAA. I can look for sources on the RAA mono/dime/hexameric solutions if you want... BTW, recombinant refers to the production method - both that of RHI and RAA. It was a good differentiator back in the days of pig insulin, but now insulin and analogs are both produced this way and so it no longer confers information. For that reason I feel it is a poor name for RHI, and I think this is also why the term 'regular' seems to be used more often these days. I am indeed the same Derek . I agree with you that recombinant human insulin is really human insulin, just not produced by a human. Probably safer as well, since it lacks other proteins / antigens / pathogens that you would get from extracting from humans (shudder) or from pigs.
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Post by matt on Aug 16, 2016 16:21:39 GMT -5
The FDA however does not care about science, only about massive and expensive studies so I have no doubt they have made it prohibitively expensive for MNKD to prove that Afrezza is safe outside of the fridge (at least for a few weeks - maybe months). That is an uncalled for slander against the reputation of a the world's best drug regulatory agency. To say that you cannot have a reasoned scientific discussion with the FDA is simply not true, and I have sat in the office of more stubborn and bone-headed regulators around the world than I would like to think about. FDA is the best of them all, bar none. The people that work there cannot be compared to the stereotypical bureaucrat at the DMV; these are people with advanced degrees (many of them multiple advanced degrees) and they have spouses, children, and extended families affected by disease just like everybody else. Most are extremely contentious. FDA approves what the sponsor submits, and that is a molecule in a particular form. If the sponsor can show that the molecule is unaffected by temperature, humidity or other factors then the storage conditions on the label reflect that. Stability testing is a standard requirement for all drugs, and the tests are not particularly expensive to perform. In most cases it consists of taking a samples of a drug and putting it on a shelf in controlled conditions and periodically testing one of the samples to show the drug has not changed. Physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form. In the case of Afrezza, that means that the drug is molecularly stable and atomizes as intended for delivery into the lung. It is not unreasonable to require a manufacturer to show that their drug works under various real world conditions. Why are there rules on stability testing? Because of the numerous examples of drugs that are ineffective for treating patients when the drug is unstable. FDA has a legal obligation to insure that all drugs sold in this country are both safe and effective, and it is Mannkind's responsibility to produce the data to show that Afrezza meets that standard. If Mannkind had good stability data at room temperature and uncontrolled humidity, they would be able to say so. Either they elected to take a short cut and didn't do the testing, or they did the testing and the results showed that Afrezza is not stable. Either way, it is up to Mannkind to address the issue.
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Post by brotherm1 on Aug 16, 2016 16:36:35 GMT -5
I'm not necessarily agreeing with the post you replied to; and whether or not the former chief of the FDA is guilty of conspiracy and racketeering remains to be seen, it is suffice to say that big money influences everything.
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Post by centralcoastinvestor on Aug 16, 2016 23:10:25 GMT -5
The FDA however does not care about science, only about massive and expensive studies so I have no doubt they have made it prohibitively expensive for MNKD to prove that Afrezza is safe outside of the fridge (at least for a few weeks - maybe months). That is an uncalled for slander against the reputation of a the world's best drug regulatory agency. To say that you cannot have a reasoned scientific discussion with the FDA is simply not true, and I have sat in the office of more stubborn and bone-headed regulators around the world than I would like to think about. FDA is the best of them all, bar none. The people that work there cannot be compared to the stereotypical bureaucrat at the DMV; these are people with advanced degrees (many of them multiple advanced degrees) and they have spouses, children, and extended families affected by disease just like everybody else. Most are extremely contentious. FDA approves what the sponsor submits, and that is a molecule in a particular form. If the sponsor can show that the molecule is unaffected by temperature, humidity or other factors then the storage conditions on the label reflect that. Stability testing is a standard requirement for all drugs, and the tests are not particularly expensive to perform. In most cases it consists of taking a samples of a drug and putting it on a shelf in controlled conditions and periodically testing one of the samples to show the drug has not changed. Physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form. In the case of Afrezza, that means that the drug is molecularly stable and atomizes as intended for delivery into the lung. It is not unreasonable to require a manufacturer to show that their drug works under various real world conditions. Why are there rules on stability testing? Because of the numerous examples of drugs that are ineffective for treating patients when the drug is unstable. FDA has a legal obligation to insure that all drugs sold in this country are both safe and effective, and it is Mannkind's responsibility to produce the data to show that Afrezza meets that standard. If Mannkind had good stability data at room temperature and uncontrolled humidity, they would be able to say so. Either they elected to take a short cut and didn't do the testing, or they did the testing and the results showed that Afrezza is not stable. Either way, it is up to Mannkind to address the issue. I appreciate what you are saying about quality people working for the FDA and that they are the best in the world at what they do. However, I don't know if you are familiar with the shady circumstance surrounding the first attempt by MannKind to gain approval for Afrezza from the FDA. Please read : www.gurufocus.com/news/159641/mannkinds-afrezza-was-to-be-approved-what-happened-next-Something was really wrong with the way MannKind was treated by the FDA in the approval process. So unfortunately, I have some distrust of the FDA because of this. Also, I followed the advisory committee meeting just prior to approval of Afrezza. The FDA staff that presented the "facts" about Afrezza did not appear to even understand the drug they were presenting. At one point, one of the panel members chastised one of the FDA officials for recommending a course of treatment that would kill a patient. Having followed MannKind since 2007, I must say at times it appeared that the FDA just didn't want Afrezza approved. If not for the overwhelming support of the Adcom members, I don't think Afrezza would have been approved.
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