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Post by peppy on Jun 3, 2016 21:36:40 GMT -5
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Post by edvarney on Jun 4, 2016 10:27:12 GMT -5
Not a scientist here,but, what I see and understand from this table comparing Afrezza with Lispro makes it very clear how much more rapid TI is in and out of the body..
Sanofi had to bury Afrezza!!!! They understood the ramifications for their own product developments and most likely wouldnt give Al Mann the necessary money to outright purchase it from MNKD.
These studies certainly confirm what the early user base for Afrezza have been claiming over past year!!!
Properly marketed now with this knowledge to back it up; The Endos that have stood back this whole time will come forward and admit their skepticism was wrong all along...
Good luck to Mike C and his team at Phoenix next week... should be fun..
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Post by ilovekauai on Jun 4, 2016 11:07:08 GMT -5
Wow!! Bring it! We got this. As long as the cash burn can last until the sales force can make a difference in the field, we are good to go!! This is most excellent news. I love it and adding more on Monday. (again). There, have I said enough? Aloha!
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Post by kc on Jun 4, 2016 16:26:55 GMT -5
Not a scientist here,but, what I see and understand from this table comparing Afrezza with Lispro makes it very clear how much more rapid TI is in and out of the body.. Sanofi had to bury Afrezza!!!! They understood the ramifications for their own product developments and most likely wouldnt give Al Mann the necessary money to outright purchase it from MNKD. These studies certainly confirm what the early user base for Afrezza have been claiming over past year!!! Properly marketed now with this knowledge to back it up; The Endos that have stood back this whole time will come forward and admit their skepticism was wrong all along... Good luck to Mike C and his team at Phoenix next week... should be fun.. Ed, well stated glad to have you onboard
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Post by dg1111 on Jun 4, 2016 19:21:20 GMT -5
Two questions for the board:
1. With respect to changing the label, it has been inferred that the label can be changed based on these studies. Does anybody know the timing for that or what other approvals would be needed first? I'm really asking if it's possible that during the 3rd quarter launch, the label reflects the results included in these studies.
2. Is there anything in these studies that would allow stating that there are reduced hypos? I can't see that spelled out, but it is possible that it is implied in the faster acting.
Thank you.
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Post by capnbob on Jun 4, 2016 21:10:10 GMT -5
I don't quite understand why MNKD chose to present these abstracts as they did. Three of them are done as meta-analyis on pooled data from other studies. These are not good studies to present at a meeting. They have a reputation for being little more than attempts to salvage something from past failures. Consequently, endos, insurers, and the FDA have practically no respect for them.
One of the studies is on healthy subjects and compares afrezza to regular insulin. What purpose did that serve? I'm pretty sure that everyone accepts that afrezza acts faster than regular insulin. Moreover, doing any study at this point in healthy individuals doesn't seem like a worthwhile investment.
The "Within-Subject Variability of Insulin Exposure" -- as I interpreted it -- was basically a failure. It showed within subject variability was, in fact, greater than what their model predicted. How is that supposed to help?
Finally, the one that had some potential -- "Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset" -- is poorly presented. They should have had graphs. Docs at meetings are flooded with information. The most effective presentation is visual, dramatic, and to the point. Second, they present no statistical analysis. By the same token, docs don't feel like wading through mounds of data; they usually try to go for the "meat" of the question -- was there a statistically significant effect. Third, with reference to a primary point -- speed of onset -- I don't see any data detailing exactly when each drug started to take effect. Another problem in this respect is their claim that afrezza started 25-35 minutes before lispro. Well, that contradicts pactically all other research that shows that lispro's effect starts within 10-20 minutes. That would mean that afrezza's effect actually started 20-30 minutes before the patient even inhaled it! The authors attempt no explanation of the remarkable difference that they measured. Fourth, they appear to try and imply that afrezza acts faster by comparing time from onst to 50% of peak and to peak activity to lispro. The problem there is that lispro peaks 90-120 minutes while afrezza peaks at around 60 minutes, so obviously afrezza reaches its peak faster and basically confirms what is already known. Finally, there is their conclusion:
"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."
That seems to me to be pretty weak. All of it is essentially already known except for the "25-35 minutes earlier" which, as I pointed out, is bound to be viewed as questionable by meeting attendees.
MNKD should have forgotten all except the last one. For it, they should have collected as much data as possible to confirm the "25-35 minutes," done a statistical analysis to demonstrate a significant difference from lispro, and then provided a single large, dramatically colored graph to force the point home. That might at least given them some ammunition to claim "ultrafast acting." As it stands, I don't seen anything to be gained from these abstracts.
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Post by mnholdem on Jun 4, 2016 21:53:46 GMT -5
Humalog's label doesn't give the precise minutes claimed by capnbob . Instead, this is what you'll find on the label (footnote numbers omitted for ease of reading): The earlier onset of activity of Humalog is directly related to its more rapid rate of absorption. The time course of action of insulin and insulin analogs such as Humalog may vary considerably in different individuals or within the same individual. The parameters of Humalog activity (time of onset, peak time, and duration) as designated in Figure 3 should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables (see PRECAUTIONS, General).The "variables" mentioned that affect the onset of activity are not an issue with Afrezza. Because it's pulmonary delivery, Afrezza goes directly into the blood stream with significantly greater predictability than lispro and other fast-acting insulin analogs. So capnbob's claims of lispro onset of activity are unsupported by the Humalog label and thus cannot be used in marketing a comparison between lispro and Afrezza. You will also find that that Humalog (lispro) label, including the graphs, only compare Humalog to regular insulin, so why would that be an issue with Afrezza? It sounds like capnbob has a dual set of standards at work within in his arguments. For example, the Humalog label also presents some data based on trials with "normal volunteers" in addition to data from trials with T1 and T2 volunteers, so why attack Afrezza data from trials that also used normal (healthy) volunteers? I think capnbob's statement that endos will not find these abstracts to be credible is a stretch and that his arguments suggest that he is hoping that will be the case, for whatever reasons...
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Post by tayl5 on Jun 4, 2016 22:32:47 GMT -5
It's also important to recognize that these are just the abstracts, not the full presentations. The poster presentations will have some supporting data and analysis but they are themselves summaries of studies that may eventually be published in the scientific literature.
From a marketing standpoint, it's best to make the material presented in the poster easily understood by a general audience, with a message that pops right out. That's balanced by the need to have data, analysis and substance that will impress and convince the specialist scientists and endos who take their continuing education seriously. That can make the content less accessible for the casual reader.
No doubt MannKind would like to have more extensive data on all of these topics, but given the limitations created by our financial and partnership issues, I'm delighted we have what we have. Hopefully MannKind will make the poster files available as soon as possible after the meeting.
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Post by mnkdfann on Jun 5, 2016 0:03:11 GMT -5
Humalog's label doesn't give the precise minutes claimed by capnbob . Instead, this is what you'll find on the label (footnote numbers omitted for ease of reading): The earlier onset of activity of Humalog is directly related to its more rapid rate of absorption. The time course of action of insulin and insulin analogs such as Humalog may vary considerably in different individuals or within the same individual. The parameters of Humalog activity (time of onset, peak time, and duration) as designated in Figure 3 should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables (see PRECAUTIONS, General).The "variables" mentioned that affect the onset of activity are not an issue with Afrezza. Because it's pulmonary delivery, Afrezza goes directly into the blood stream with significantly greater predictability than lispro and other fast-acting insulin analogs. So capnbob's claims of lispro onset of activity are unsupported by the Humalog label and thus cannot be used in marketing a comparison between lispro and Afrezza. You will also find that that Humalog (lispro) label, including the graphs, only compare Humalog to regular insulin, so why would that be an issue with Afrezza? It sounds like capnbob has a dual set of standards at work within in his arguments. For example, the Humalog label also presents some data based on trials with "normal volunteers" in addition to data from trials with T1 and T2 volunteers, so why attack Afrezza data from trials that also used normal (healthy) volunteers? I think capnbob's statement that endos will not find these abstracts to be credible is a stretch and that his arguments suggest that he is hoping that will be the case, for whatever reasons... About time to onset of activity, I think capnbob merely stated what the literature showed. A quick google search I ran seemed to support what he said. I don't know what the Humalog lispro label says (I don't have one handy) but Humalog certainly does advertise that lispro is fast acting and starts within 15 minutes. As on the website below: www.humalog.com/about-mealtime-insulin.aspxI'm not a medical doctor, so I am probably missing something. At first glance, though, the abstract claiming Afrezza acts 25-35 minutes faster than lispro does seem curious.
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Post by mnholdem on Jun 5, 2016 8:31:59 GMT -5
I suggest that when you are visiting the Humalog website that you click the link to Full Prescibing Information where you will get the details of what I posted in section 12 Clinical Pharmacology. Also note the graph comparing Humalog to Humalin (Eli-Lilly's Regular Insulin) and, while you will notice that Humalog begins lowering blood glucose at about the 50 minute mark and regular insulin Humalin takes even longer, Afrezza begins significantly lowering blood glucose levels approximately 30 minutes quicker. I suspect the graphs missing from the various Technosphere insulin abstracts will become available in the full publications when they are released.
One of the latest Afrezza abstracts also confirms what you will discover is already stated in the Full Prescribing Information for Humalog:
Distribution — When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of HUMALOG appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively).
Afrezza data shows it proved to be dose proportionate, which is especially critical to those T2 diabetics who must administer significantly higher doses of insulin.
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Post by peppy on Jun 5, 2016 9:29:47 GMT -5
I don't quite understand why MNKD chose to present these abstracts as they did. Three of them are done as meta-analyis on pooled data from other studies. These are not good studies to present at a meeting. They have a reputation for being little more than attempts to salvage something from past failures. Consequently, endos, insurers, and the FDA have practically no respect for them. One of the studies is on healthy subjects and compares afrezza to regular insulin. What purpose did that serve? I'm pretty sure that everyone accepts that afrezza acts faster than regular insulin. Moreover, doing any study at this point in healthy individuals doesn't seem like a worthwhile investment. The "Within-Subject Variability of Insulin Exposure" -- as I interpreted it -- was basically a failure. It showed within subject variability was, in fact, greater than what their model predicted. How is that supposed to help? Finally, the one that had some potential -- "Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset" -- is poorly presented. They should have had graphs. Docs at meetings are flooded with information. The most effective presentation is visual, dramatic, and to the point. Second, they present no statistical analysis. By the same token, docs don't feel like wading through mounds of data; they usually try to go for the "meat" of the question -- was there a statistically significant effect. Third, with reference to a primary point -- speed of onset -- I don't see any data detailing exactly when each drug started to take effect. Another problem in this respect is their claim that afrezza started 25-35 minutes before lispro. Well, that contradicts pactically all other research that shows that lispro's effect starts within 10-20 minutes. That would mean that afrezza's effect actually started 20-30 minutes before the patient even inhaled it! The authors attempt no explanation of the remarkable difference that they measured. Fourth, they appear to try and imply that afrezza acts faster by comparing time from onst to 50% of peak and to peak activity to lispro. The problem there is that lispro peaks 90-120 minutes while afrezza peaks at around 60 minutes, so obviously afrezza reaches its peak faster and basically confirms what is already known. Finally, there is their conclusion: "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." That seems to me to be pretty weak. All of it is essentially already known except for the "25-35 minutes earlier" which, as I pointed out, is bound to be viewed as questionable by meeting attendees. MNKD should have forgotten all except the last one. For it, they should have collected as much data as possible to confirm the "25-35 minutes," done a statistical analysis to demonstrate a significant difference from lispro, and then provided a single large, dramatically colored graph to force the point home. That might at least given them some ammunition to claim "ultrafast acting." As it stands, I don't seen anything to be gained from these abstracts. These studies were mandated by the FDA to be done, upon Afrezza FDA approval. Sanofi was the sponsor. The results just released, were held by Sanofi. Not sure that answers the question. We on this board have been over the differences in action of technosphere insulin vs the subq analogues. The big hit of insulin monomers delivered by afrezza to the liver signals the liver to stop neoglucogenesis. PHASE 1 is not seen with subq insulin. We need that difference to show up. Then phase 2 the insulin dimers formed preform the phase two. Still faster action and break down of the molecule. screencast.com/t/AhnFhHunq The differences between the mechanism of action showing up. Let's all act shocked. Consider your words, Quote, "Another problem in this respect is their claim that afrezza started 25-35 minutes before lispro. Well, that contradicts pactically all other research that shows that lispro's effect starts within 10-20 minutes." Inappropriate reply: We do know all the European car makers had the vehicles computers change the emission information when tested. Subq lispro 10 to 20 minutes, my assets. Pep
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Post by kc on Jun 5, 2016 9:35:14 GMT -5
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Post by Deleted on Jun 5, 2016 9:40:11 GMT -5
Is Toujeo better or worse than. Based on what this person surmise on YouTube this may be in issue that severalln pharmas bring up against sanofi in the future. Based on this if true Sanofi will rue the day Brandicourt Terminated the partnership. Payers will eventually realize this issue too. People may Somebody posted this link to a guy on YouTube who did a expose (his own) on toujeo If this is factually true this is not a good situation long-term for Sanofi. "Toujeo...A Better Basal Insulin...Seriously?"l m.youtube.com/watch?v=5to6u28pmcM Read more: mnkd.prboards.com/thread/5672/toujeo-trhow is toujeo related to this thread? and you already cross posted this.. smh
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Post by cathode on Jun 5, 2016 9:56:05 GMT -5
I don't quite understand why MNKD chose to present these abstracts as they did. Three of them are done as meta-analyis on pooled data from other studies. These are not good studies to present at a meeting. They have a reputation for being little more than attempts to salvage something from past failures. Consequently, endos, insurers, and the FDA have practically no respect for them. One of the studies is on healthy subjects and compares afrezza to regular insulin. What purpose did that serve? I'm pretty sure that everyone accepts that afrezza acts faster than regular insulin. Moreover, doing any study at this point in healthy individuals doesn't seem like a worthwhile investment. The "Within-Subject Variability of Insulin Exposure" -- as I interpreted it -- was basically a failure. It showed within subject variability was, in fact, greater than what their model predicted. How is that supposed to help?Finally, the one that had some potential -- "Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset" -- is poorly presented. They should have had graphs. Docs at meetings are flooded with information. The most effective presentation is visual, dramatic, and to the point. Second, they present no statistical analysis. By the same token, docs don't feel like wading through mounds of data; they usually try to go for the "meat" of the question -- was there a statistically significant effect. Third, with reference to a primary point -- speed of onset -- I don't see any data detailing exactly when each drug started to take effect. Another problem in this respect is their claim that afrezza started 25-35 minutes before lispro. Well, that contradicts pactically all other research that shows that lispro's effect starts within 10-20 minutes. That would mean that afrezza's effect actually started 20-30 minutes before the patient even inhaled it! The authors attempt no explanation of the remarkable difference that they measured. Fourth, they appear to try and imply that afrezza acts faster by comparing time from onst to 50% of peak and to peak activity to lispro. The problem there is that lispro peaks 90-120 minutes while afrezza peaks at around 60 minutes, so obviously afrezza reaches its peak faster and basically confirms what is already known. Finally, there is their conclusion: "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." That seems to me to be pretty weak. All of it is essentially already known except for the "25-35 minutes earlier" which, as I pointed out, is bound to be viewed as questionable by meeting attendees. MNKD should have forgotten all except the last one. For it, they should have collected as much data as possible to confirm the "25-35 minutes," done a statistical analysis to demonstrate a significant difference from lispro, and then provided a single large, dramatically colored graph to force the point home. That might at least given them some ammunition to claim "ultrafast acting." As it stands, I don't seen anything to be gained from these abstracts. I want to make a few responses to the points raised here. First, this is a scientific session. The ethics of science require that there are no "good" or "bad" outcomes in terms of expectations. Rather, the results are used to either support, reject, or a make no impact on a hypothesis. With regard to the "Within-subject variability" abstract, I disagree with your interpretation that it was a failure. Rather, it seems that the linear mixing model they used does not accurately capture the variability. This is only a failure for the model. Is this finding inherently "bad"? No, it is informative. How does it help? It allows them to iterate on the results and find a model that better fits the experimental data. On why "MNKD chose to present these abstracts as they did", look at the fact that MNKD employees are the first author on zero of the regular session abstracts. The abstracts were likely written by Sanofi employees or contractors. MNKD pulling abstracts would not be good publicity and downright stupid if the findings were positive, as they are. In addition, other posters above have stated that these are not the actual presentations. These are abstracts. The full set of statistical methods shouldn't be expected to be given in the abstract. Graphs will likely be shown on the posters. 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.
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Post by ilovekauai on Jun 5, 2016 10:24:14 GMT -5
Excellent points Catode, and I suspect that once we get past these abstracts next weekend at the ADA, it's only a matter of time before some articles come out in scientific journals, (can we say NEJM anyone?), heralding Afrezza as the fastest acting insulin on the market, (with no lows!), for diabetics. I've been waiting ever since last summer for this to happen and hope the time draws nigh. We need this IMO, for a label change, so our sales force can use that important info as a marketing tool when in the field to offer more success in their efforts. Aloha.
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