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Post by cm5 on Jun 5, 2016 21:26:14 GMT -5
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Post by capnbob on Jun 5, 2016 21:49:49 GMT -5
"I disagree with your interpretation that it was a failure." But it was a failure in the sense that their model -- whatever it was -- failed to predict what afrezza would do. Granted, that is not a failure of afrezza itself. However, this is a meeting and docs are moving past rapidly. They see "Within-Subject Variability of Insulin Exposure and Metabolic Activity following Replicate Doses of Technosphere® Insulin Inhalation Powder (TI) in Patients with T1DM" and they glance down and see that there was more variability than was expected per the model. They don't stop and ask whether the model was correct or not. They walk away with the impression that afrezza was more variable than expected. I didn't mean to imply they should have "pulled" the abstracts. Five of them I just didn't think should have been submitted -- I mentioned those above. Their data wasn't that impressive -- to me at least -- and they dilute the effect of whatever favorable impression might be gained from the one that said something suggestive of signifcance. As far as the "posters" go, I, for one, looked at past afrezza presentations at the ADA and could find nothing but the abstracts. Has Mannkind ever published the posters anywhere. Regargless, if a statistical analysis was done, then the abstract should include at least a statement to that effect and whether the results were significant or not. Again, this is a meeting with tons of data being thrown at viewers, the big stuff like statistical significance needs to stand out and really be pushed in their faces. As regards "use the word "onset," I interpret that to mean "onset" of the glucose lowering effect. And yes, the first number is to 50%-GIRmax and the second number is time to 100%-GIRmax. The problem is that lispro does not reach its GIRmax until 90-120 minutes AFTER afrezza: You can see that going from onset at "0" to 50% of afrezza's peak is about 30 minutes while its peak is 55 minutes. For lispro, it doesn't hit the 50% point until around 60 minutes while it's peak is around 90-120. You can't say afrezza's onset is faster simply because time expended from onset to 50% or 100% is less than lispro's beeause, obviously, afrezza's number necessarily must be less since it peaks sooner. Consequently, you can't conclude anything about actual time of onset from that data alone. The above graph suggests time of onset of effect was near identical. What is really needed is a graph of the abstract data to clarify the "25-35" minute earlier onset claim. That is more or less the "crux" of the matter. so can you break down it down for us please in short concise form? of all the pros and cons or a better to way put it so the docs get it...for good or bad Can you be more specific about what you want broken down? If you're referring to the abstract that had the most potential, the very first problem is the title: "Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset and Shorter Duration than Insulin Lispro (Lispro)" Again, remember we're taslking about people moving by, glancing at titles and results, looking for things pertinent to their own interests. So say someone sees that title and thinks it is interesting. The first thing looked for is a graph -- the simplest, most rapid way to convey information.There isn't any. Lacking that a search commences for statistics to see if the difference is significant. No statistics. Someone else said these would be in the poster but I've looked at past MNKD abstracts and have been unable to find corresponding posters to confirm that. Nevertheless, if the abstract is all that is presented, then two golden opportunities to make an impression have been lost. The next point is that the abstract seems to imply that the "onset" to 50% of peak effect to 100% peak effect somehow justifies their claim of more rapid onset. As I point out above and as can be seen by looking at the graph, afrezza's times must be shorter by virtue of it having a peak 60-90 minutes before lispro. All I see that they have basically confirmed what is already known and displayed on that graph above. The most difficult point is their claim that afrezza's onset of effect was "25-35 minutes" ahead of lispro. As pointed out earlier lispro typically is reported to take effect within 10-20 minutes. Even if afrezza's effect were instantaneous, how could it possibly be 25-35 minutes before lispro? Hopefully, they will produce a graph somewhere that clarifies the abstract.
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Post by capnbob on Jun 5, 2016 22:01:01 GMT -5
Lispro is an hexamer--Successful Drug Discovery, Volume 1 edited by Janos Fischer, David P. Rotella p.47, Figure 3.7 ISBN: 978-3-527-33685-2 256 pages May 2015 If you look at your reference on page 47 of the 2015 edition, you'll see that it explains how the "breakdown" upon injection is so rapid that lispro is effectively a monomer. Indeed, the rate limiting step is not forming the monomer but diffusion into the capillary bed. Ultimately, however, from a label changing perpsective, what really only matters is the PD graph. The current one -- which I reproduced elsewhere -- shows afrezza and lispro have about the same time of onset of effect as well as nearly the same effect for the first 50-60 minutes. To claim "ultra rapid," an abstract or trial needs to show a significant difference in those aspects.
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Post by cathode on Jun 5, 2016 22:31:29 GMT -5
capnbob , you are fabricating things, ignoring others' statements, providing misdirection, and doing all the classic moves of FUDsters and bashers. A simple investigation reveals you are almost certainly fragslap on YMB. A known basher and anti-mnkd zealot. I suggest that anyone serious here should ignore capnbob. I won't be responding to any more of his posts. To everyone else: statistical measures are given in the tables, don't think they aren't. As is standard procedure they are given in parentheses after the mean. Onset of activity is clearly defined in the abstract text. These abstracts are positive, as CEO Pfeffer has stated. Disregard the noise and FUD.
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Post by brotherm1 on Jun 5, 2016 22:44:03 GMT -5
Agree. Thank you Cathode!
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Post by avichen on Jun 6, 2016 10:58:33 GMT -5
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Post by capnbob on Jun 6, 2016 11:11:03 GMT -5
capnbob , you are fabricating things, ignoring others' statements, providing misdirection, and doing all the classic moves of FUDsters and bashers. A simple investigation reveals you are almost certainly fragslap on YMB. A known basher and anti-mnkd zealot. I suggest that anyone serious here should ignore capnbob. I won't be responding to any more of his posts. To everyone else: statistical measures are given in the tables, don't think they aren't. As is standard procedure they are given in parentheses after the mean. Onset of activity is clearly defined in the abstract text. These abstracts are positive, as CEO Pfeffer has stated. Disregard the noise and FUD. "...statistical measures are given in the tables..." Means and standard deviations do not convey information about the significance of differences. Unless you carry along your own statistics calculator or have a remarkable talent for mental arithmetic, you're simply faced with a bowl of numbers. As I said before, this is a meeting, not a journal. People are going by and looking for things relevant to their interests. As I recall, there are two to three thousand abstracts and posters, not to mention lectures and presentations. Put yourself in their place. Would you stand there and try to decipher and analyze all that data when so much other stuff is going on? All the important data should be presented graphically and should include measures of significance. If they have something dramatic, it should presented as such and rammed into the conciousness of the viewer. I just don't believe this conclusion will do that: "Cmax and AUC were dose proportional for TI but slightly sublinear for Lispro; saturable GIRmax was obtained over the dose range for both insulins. Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro. TI duration of action is about 2 hours shorter than an equivalent dose of Lispro. Dose-response was almost linear up to 48U TI and 30 U Lispro."
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Deleted
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Post by Deleted on Jun 6, 2016 11:13:56 GMT -5
capnbob , you are fabricating things, ignoring others' statements, providing misdirection, and doing all the classic moves of FUDsters and bashers. A simple investigation reveals you are almost certainly fragslap on YMB. A known basher and anti-mnkd zealot. I suggest that anyone serious here should ignore capnbob. I won't be responding to any more of his posts. To everyone else: statistical measures are given in the tables, don't think they aren't. As is standard procedure they are given in parentheses after the mean. Onset of activity is clearly defined in the abstract text. These abstracts are positive, as CEO Pfeffer has stated. Disregard the noise and FUD. "...statistical measures are given in the tables..." Means and standard deviations do not convey information about the significance of differences. Unless you carry along your own statistics calculator or have a remarkable talent for mental arithmetic, you're simply faced with a bowl of numbers. As I said before, this is a meeting, not a journal. People are going by and looking for things relevant to their interests. As I recall, there are two to three thousand abstracts and posters, not to mention lectures and presentations. Put yourself in their place. Would you stand there and try to decipher and analyze all that data when so much other stuff is going on? All the important data should be presented graphically and should include measures of significance. If they have something dramatic, it should presented as such and rammed into the conciousness of the viewer. I just don't believe this conclusion will do that: "Cmax and AUC were dose proportional for TI but slightly sublinear for Lispro; saturable GIRmax was obtained over the dose range for both insulins. Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro. TI duration of action is about 2 hours shorter than an equivalent dose of Lispro. Dose-response was almost linear up to 48U TI and 30 U Lispro." you sure hope mannkind will print a poster size of the scree capture posted here and nothing else?
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Post by Deleted on Jun 6, 2016 12:01:52 GMT -5
capnbob , you are fabricating things, ignoring others' statements, providing misdirection, and doing all the classic moves of FUDsters and bashers. A simple investigation reveals you are almost certainly fragslap on YMB. A known basher and anti-mnkd zealot. I suggest that anyone serious here should ignore capnbob. I won't be responding to any more of his posts. To everyone else: statistical measures are given in the tables, don't think they aren't. As is standard procedure they are given in parentheses after the mean. Onset of activity is clearly defined in the abstract text. These abstracts are positive, as CEO Pfeffer has stated. Disregard the noise and FUD. I dont want to toot my own horn but I have been pretty good at spotting him. He is getting better at hiding as of late. Anway, I have a question where does your experience come from to understand these abstracts? I dont mean this as a slight either. You are one of the only responses about the abstracts that are well thought out but I have no clue on how to read this stuff. Did you have experience in the medical field?
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Post by mnholdem on Jun 6, 2016 12:07:49 GMT -5
What makes this discussion frustrating is that there are so many different definitions of the term "onset of action" that, depending on the definition of the person posting, EVERYONE could, by their own definitions, be correct.
Here are only a few of the definitions published by prominent medical resources:
Onset of Action
- "The time required after administration of a drug for a response to be observed." - Mosby's Medical Dictionary, 9th edition. © 2009, Elsevier.
- "Pharmacology: The length of time needed for a medicine to become effective." - McGraw-Hill Concise Dictionary of Modern Medicine. © 2002 by The McGraw-Hill Companies, Inc.
- "The time from drug administration until the drug exerts an observable specific effect or response." - Medical Dictionary for the Health Professions and Nursing © Farlex 2012
- "The time between the administration of a medication or other form of treatment and the first evidence of its effect." - Medical Dictionary, © 2009 Farlex and Partners
- "The time it takes a drug to reach the minimum effective concentration after a drug is administered." - Key Terms - Pharmacology: A Nursing Process Approach (6th ed)
- "Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration." - Wikipedia
Naturally, a debater making an argument will choose the definition that best suits his/her argument.
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Not to put words in anyone's mouth, but capnbob appears to be using a definition that describes "Onset of Action" as the of time it takes from when the insulin is administered to when it enters the bloodstream...similar to the definition used within the Humalog website.
However, for the sake of discussion, that is not the definition defined by the authors. Regarding the abstracts under discussion, the authors published a specific definition of the term "onset of action" that is used in the study and presented in the abstract/publication.
Therefore, if you, capnbob , or anybody else wishes to unilaterally alter the authors' definition of "Onset of Action" to your own definition, you can basically say anything you want and it's supported by your specific definition(s).
Unfortunately (or fortunately, depending how you look at it) you are no longer validly arguing the merits of the authors' presentations.
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Post by peppy on Jun 6, 2016 12:37:42 GMT -5
What makes this discussion frustrating is that there are so many different definitions of the term "onset of action" that, depending on the definition of the person posting, EVERYONE could, by their own definitions, be correct.
Here are only a few of the definitions published by prominent medical resources:
Onset of Action
- "The time required after administration of a drug for a response to be observed." - Mosby's Medical Dictionary, 9th edition. © 2009, Elsevier.
- "Pharmacology: The length of time needed for a medicine to become effective." - McGraw-Hill Concise Dictionary of Modern Medicine. © 2002 by The McGraw-Hill Companies, Inc.
- "The time from drug administration until the drug exerts an observable specific effect or response." - Medical Dictionary for the Health Professions and Nursing © Farlex 2012
- "The time between the administration of a medication or other form of treatment and the first evidence of its effect." - Medical Dictionary, © 2009 Farlex and Partners
- "The time it takes a drug to reach the minimum effective concentration after a drug is administered." - Key Terms - Pharmacology: A Nursing Process Approach (6th ed)
- "Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration." - Wikipedia
Naturally, a debater making an argument will choose the definition that best suits his/her argument.
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Not to put words in anyone's mouth, but capnbob appears to be using a definition that describes "Onset of Action" as the of time it takes from when the insulin is administered to when it enters the bloodstream...similar to the definition used within the Humalog website.
However, for the sake of discussion, that is not the definition defined by the authors. Regarding the abstracts under discussion, the authors published a specific definition of the term "onset of action" that is used in the study and presented in the abstract/publication.
Therefore, if you, capnbob , or anybody else wishes to unilaterally alter the authors' definition of "Onset of Action" to your own definition, you can basically say anything you want and it's supported by your specific definition(s).
Unfortunately (or fortunately, depending how you look at it) you are no longer validly arguing the merits of the authors' presentations.
To continue on the discussion of onset of action. From Cathode. Regarding the Lispro-Afrezza speed comparison -- You use the word "effect" exclusively in your analysis. That word is not found in the "Earlier Onset and Shorter Duration" abstract. Rather, they use the word "onset", which they are defining as the time to 50% of the maximum glucose infusion rate (GIR). I don't know whether the phrase "onset of activity" is legally defined by the FDA, but the 50% metric certainly demonstrates that Afrezza has a faster time of onset in that regard. This 50% metric seems to be used by Novo as well, from this press release/ article on "faster aspart". The current FDA label has this important caveat: "Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro." The clamp study seems to be able to directly address that statement and provide a more favorable view of Afrezza. Read more: mnkd.proboards.com/thread/5598/ada-2016-afrezza-abstracts#ixzz4Ap1HhdPg
screencast.com/t/3nhCLlkW
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Post by tchalaa on Jun 6, 2016 12:52:16 GMT -5
capnbob like it or not Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset and Shorter Duration than Insulin Lispro (Lispro). The dose-response curve of TI (4, 12, and 48 U doses) was compared to that of Lispro (8, 30, and 90 U doses) in a cross-over hyperinsulinemic, euglycemic clamp with 30 T1DM patients. Key parameters: PD - onset, time to 50% max GIR (T50%-GIRmax), max effect (GIRmax), duration (T100% of GIR-AUC0-end), total effect (GIR-AUC0-end). PK - max insulin conc (INS-Cmax), time of max conc (Tmax) and exposure (INS-AUClast). Cmax and AUC were dose proportional for TI but slightly sublinear for Lispro; saturable GIRmax was obtained over the dose range for both insulins. Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro. TI duration of action is about 2 hours shorter than an equivalent dose of Lispro. Dose-response was almost linear up to 48U TI and 30 U Lispro. Source: www.abstractsonline.com/pp8/#!/4008/presentation/44503 This means Afrezza is faster and better than Lispro (Humalog)
Each insulin has its own unique therapeutic effect. The onset of action of a particular insulin is how long it takes the hormone to start working at lowering blood glucose levels. The insulin peak is the point at which the dose is at the height of its therapeutic effectiveness, and the duration is how long the blood glucose lowering effect of a given insulin lasts from injection to end. Following is a list of insulin types available in the United States, along with their onset, peak, and duration. Talk to your healthcare provider about your insulin regimen. Insulin preparation Onset of action Peak Duration of action Lispro (Humalog) <15 minutes 1-2 hours 3-6 hours Aspart (Novolog) <15 minutes 1-2 hours 3-6 hours Glulisine (Apidra) <15 minutes 1-2 hours 3-6 hours Afrezza <15 minutes Approx. 50 minutes 2-3 hours Source: www.dlife.com/diabetes/insulin/about_insulin/insulin-chart
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Post by peppy on Jun 6, 2016 13:05:55 GMT -5
capnbob like it or not Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset and Shorter Duration than Insulin Lispro (Lispro). The dose-response curve of TI (4, 12, and 48 U doses) was compared to that of Lispro (8, 30, and 90 U doses) in a cross-over hyperinsulinemic, euglycemic clamp with 30 T1DM patients. Key parameters: PD - onset, time to 50% max GIR (T50%-GIRmax), max effect (GIRmax), duration (T100% of GIR-AUC0-end), total effect (GIR-AUC0-end). PK - max insulin conc (INS-Cmax), time of max conc (Tmax) and exposure (INS-AUClast). Cmax and AUC were dose proportional for TI but slightly sublinear for Lispro; saturable GIRmax was obtained over the dose range for both insulins. Onset of activity for TI occurred ca. 25-35 minutes earlier than for Lispro. TI duration of action is about 2 hours shorter than an equivalent dose of Lispro. Dose-response was almost linear up to 48U TI and 30 U Lispro. Source: www.abstractsonline.com/pp8/#!/4008/presentation/44503 This means Afrezza is faster and better than Lispro (Humalog)
Each insulin has its own unique therapeutic effect. The onset of action of a particular insulin is how long it takes the hormone to start working at lowering blood glucose levels. The insulin peak is the point at which the dose is at the height of its therapeutic effectiveness, and the duration is how long the blood glucose lowering effect of a given insulin lasts from injection to end. Following is a list of insulin types available in the United States, along with their onset, peak, and duration. Talk to your healthcare provider about your insulin regimen. Insulin preparation Onset of action Peak Duration of action Lispro (Humalog) <15 minutes 1-2 hours 3-6 hours Aspart (Novolog) <15 minutes 1-2 hours 3-6 hours Glulisine (Apidra) <15 minutes 1-2 hours 3-6 hours Afrezza <15 minutes Approx. 50 minutes 2-3 hours Source: www.dlife.com/diabetes/insulin/about_insulin/insulin-chart Look at how those numbers being worked. Onset SC 13 to 35 mins. onset lispro in the above definition is at 20% GIR, just squeezed into the 15 min time frame.
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Post by tchalaa on Jun 6, 2016 13:07:21 GMT -5
Lispro is an hexamer--Successful Drug Discovery, Volume 1 edited by Janos Fischer, David P. Rotella p.47, Figure 3.7 ISBN: 978-3-527-33685-2 256 pages May 2015 If you look at your reference on page 47 of the 2015 edition, you'll see that it explains how the "breakdown" upon injection is so rapid that lispro is effectively a monomer. Indeed, the rate limiting step is not forming the monomer but diffusion into the capillary bed. Ultimately, however, from a label changing perpsective, what really only matters is the PD graph. The current one -- which I reproduced elsewhere -- shows afrezza and lispro have about the same time of onset of effect as well as nearly the same effect for the first 50-60 minutes. To claim "ultra rapid," an abstract or trial needs to show a significant difference in those aspects. Please here we discuss about fact, because so is science, i'm very sorry to call you out here, HEXAMER will NEVER be MONOMER and like in a 100 meter race today you can not say the second was almost the first noway, Usain himself will go crazy. I SAY NO (sorry to be loud but science is precise, i can not just allow such falsely declaration). Some reminder from the abstract TI- 4 U ->onset=10.2; Lispro - 8 U ->onset=16.6 :: It is pretty clear 10.2<16.6 the difference is significant 60%
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Post by comnkd on Jun 6, 2016 14:18:11 GMT -5
Pardon for going OT. Cathode - Thanks for calling he/she out.
capnbob also likely known as poster: oscar lonzo moneyunderthemattress (I believe this was the poster who challenged Matt Bendall's coke challenge results and Matt responded with the extreme glucose challenge) *Bill Vestor - a quick look up of comments on Matt's Coke challenge posted to YouTube - moneyunderthemattress changed YouTube profile name to Bill Vestor? fragslap
At the very least they are all trolls and bashers.
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