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Post by dreamboatcruise on Dec 10, 2015 18:00:03 GMT -5
No, the FDA does not allow that. It is not like a supplement where you can show one person that has lost 100 lbs with small type at the bottom of the screen saying "results may vary". This would circumvent the entire FDA process... and it is bad science. You can't pick a group of users because they have been proactive in promoting benefits of Afrezza (i.e. in scientific experiment terms... self selection) and present that as expected results for a wider population. That said, I think in doctor to doctor education meetings they might be able to use observational anecdotes as long as it is clearly presented as anecdotal (perhaps some of our docs would know the constraints in that case). Also, I really do not think a study to show superiority would need to be huge, long and expensive. SNY simply needs to do that. That will be what allows a better label and better marketing material and adverts for consumers. The results of the early adopters are real and I certainly think they are more indicative of the potential of Afrezza than were the FDA clinical trials with their very suboptimal protocols. I thought there was a recent court ruling that said a pharma company can make product performance claims if they believed them to be true or had some type of supporting documentation beyond trials. I know this would be a can of worms, sorry I do not have the link for it. When you say superiority you mean lower A1c, less volatility in day to day blood glucose readings, weight loss or some or all of these combined with xx% reduction in basal dosage? I don't believe representing anecdotal self selected patients in advertising would be allowed. The court case may have loosened what data can be used... i.e. a trial not necessarily vetted by FDA, but it doesn't turn anecdotal data into what drug manufacturers can use for advertising. I personally think it would be a bad development for healthcare if SNY could take results from a handful of users like Sam and Eric and turn that into a commercial. I think Afrezza is an amazing product and can win in the market using sound science, and not needing marketing techniques of supplements. A trial has to be conducted where you select the patients first and then report on all the results, not selecting the patients because of their results. |
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Post by charleyd on Dec 10, 2015 19:46:41 GMT -5
Great info, thanks for sharing. For any of you who know and understand the regulatory process, will any of the studies that Sanofi has just completed allow the label to be changed to say "Ultra Rapid Acting" and / or "Reduces incidences of hypoglycemia" and / or "Reduces A1c"? If none of the current studies (assuming the data supports the claim) will allow for these label changes, what kind of studies would allow for this and how long would they take to complete? Ultra Rapid Acting and Reduced Hypoglycemia on the label and we are off the to races. Even if the Spirometery requirement and Prior Authorization issues stayed around. Ditto on that tweet... indeed, very encouraging. Put a smile on my face even with the share price where it is. I'm no expert on regulatory filings (though I guess I've learned a lot more about them than I ever would have thought because of MNKD), but the clamp studies are way to short to effect A1c and by there very nature wouldn't have any incidence of hypoglycemia (unless they are being done by a dangerously incompetent clinician). So those two metrics have nothing to do with these clamp studies. As for "ultra", these studies are basically more exhaustive versions of clamp studies already done. We already had data clearly showing quicker clearance from the system, and that didn't warrant "ultra" in FDA's eyes... though the graph is clearly in the material supplied to physicians and patients. If these new clamp studies clear up the issue of faster onset, would the FDA then allow "ultra" in the description... maybe? I wouldn't count on it though. They may well want to have a trial showing that there is some clinical benefit to the time profile in order to give a designation setting Afrezza apart from other insulins. If the FDA does grant "ultra" simply from clamp studies, I think we'd clearly have SNY to thank, because MNKD has not been treated kindly by the FDA in the past and "ultra" at this point is going to require a friendly hearing at the FDA, not a hostile one... because "ultra" would be a judgement call not one where there is any agreed on end point in the studies as to what would qualify as "ultra". Anyone besides me notice that the PK & PD graphs presented on Dr. Edelman's Slides (Middle Slide on page 15: tcoyd.org/PDF/2015-postp-sandiego-slides.pdf) are considerably different from those listed in the Afrezza insert (Page 15: Afrezza Insert), which are footnoted with the following: "Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro." Dr. Edelman's PD graph does appear to show much faster action than what is shown on the graph in the insert, which in my opinion would help justify an "ultra-rapid" acting label. Wondering if Dr. Edelman's data is from the recently completed clamp studies.... If anyone is clever enough to be able to post the images side-by-side, that would be most helpful to the discussion. |
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Post by compound26 on Dec 10, 2015 20:03:16 GMT -5
Ditto on that tweet... indeed, very encouraging. Put a smile on my face even with the share price where it is. I'm no expert on regulatory filings (though I guess I've learned a lot more about them than I ever would have thought because of MNKD), but the clamp studies are way to short to effect A1c and by there very nature wouldn't have any incidence of hypoglycemia (unless they are being done by a dangerously incompetent clinician). So those two metrics have nothing to do with these clamp studies. As for "ultra", these studies are basically more exhaustive versions of clamp studies already done. We already had data clearly showing quicker clearance from the system, and that didn't warrant "ultra" in FDA's eyes... though the graph is clearly in the material supplied to physicians and patients. If these new clamp studies clear up the issue of faster onset, would the FDA then allow "ultra" in the description... maybe? I wouldn't count on it though. They may well want to have a trial showing that there is some clinical benefit to the time profile in order to give a designation setting Afrezza apart from other insulins. If the FDA does grant "ultra" simply from clamp studies, I think we'd clearly have SNY to thank, because MNKD has not been treated kindly by the FDA in the past and "ultra" at this point is going to require a friendly hearing at the FDA, not a hostile one... because "ultra" would be a judgement call not one where there is any agreed on end point in the studies as to what would qualify as "ultra". Anyone besides me notice that the PK & PD graphs presented on Dr. Edelman's Slides (Middle Slide on page 15: tcoyd.org/PDF/2015-postp-sandiego-slides.pdf) are considerably different from those listed in the Afrezza insert (Page 15: Afrezza Insert), which are footnoted with the following: "Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro." Dr. Edelman's PD graph does appear to show much faster action than what is shown on the graph in the insert, which in my opinion would help justify an "ultra-rapid" acting label. Wondering if Dr. Edelman's data is from the recently completed clamp studies.... If anyone is clever enough to be able to post the images side-by-side, that would be most helpful to the discussion. I think this is another case that the FDA is sandbagging Mannkind and Afrezza. My understanding is that the onset of activity does not mean much in this case. Sure, both Afrezza and Humalog probably started to have some initial effects after say 15 minutes after inhalation/injection, but what if Afrezza gets the job done in 30 minutes while Humalog gets job done in 90 minutes? |
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Post by mnkdfann on Dec 10, 2015 20:04:45 GMT -5
Charleyd, those slides of Edelman's on page 15 are sourced from data in a 2014 paper he cites, so I do not think they contain anything new.
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Post by peppy on Dec 10, 2015 20:33:27 GMT -5
Ditto on that tweet... indeed, very encouraging. Put a smile on my face even with the share price where it is. I'm no expert on regulatory filings (though I guess I've learned a lot more about them than I ever would have thought because of MNKD), but the clamp studies are way to short to effect A1c and by there very nature wouldn't have any incidence of hypoglycemia (unless they are being done by a dangerously incompetent clinician). So those two metrics have nothing to do with these clamp studies. As for "ultra", these studies are basically more exhaustive versions of clamp studies already done. We already had data clearly showing quicker clearance from the system, and that didn't warrant "ultra" in FDA's eyes... though the graph is clearly in the material supplied to physicians and patients. If these new clamp studies clear up the issue of faster onset, would the FDA then allow "ultra" in the description... maybe? I wouldn't count on it though. They may well want to have a trial showing that there is some clinical benefit to the time profile in order to give a designation setting Afrezza apart from other insulins. If the FDA does grant "ultra" simply from clamp studies, I think we'd clearly have SNY to thank, because MNKD has not been treated kindly by the FDA in the past and "ultra" at this point is going to require a friendly hearing at the FDA, not a hostile one... because "ultra" would be a judgement call not one where there is any agreed on end point in the studies as to what would qualify as "ultra". Anyone besides me notice that the PK & PD graphs presented on Dr. Edelman's Slides (Middle Slide on page 15: tcoyd.org/PDF/2015-postp-sandiego-slides.pdf) are considerably different from those listed in the Afrezza insert (Page 15: Afrezza Insert), which are footnoted with the following: "Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro." Dr. Edelman's PD graph does appear to show much faster action than what is shown on the graph in the insert, which in my opinion would help justify an "ultra-rapid" acting label. Wondering if Dr. Edelman's data is from the recently completed clamp studies.... If anyone is clever enough to be able to post the images side-by-side, that would be most helpful to the discussion. screencast.com/t/SuJ6Ev50
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Post by charleyd on Dec 10, 2015 20:42:33 GMT -5
Charleyd, those slides of Edelman's on page 15 are sourced from data in a 2014 paper he cites, so I do not think they contain anything new. Hey mnkdfann, Thanks. I see that now. Nevertheless, there is still a significant difference in the graphs. I cannot help but think that if Dr. Edelman's graph was considered by the FDA, that they would not come to the conclusion that the onset of activity between the two is comparable. |
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Post by charleyd on Dec 10, 2015 20:44:48 GMT -5
Anyone besides me notice that the PK & PD graphs presented on Dr. Edelman's Slides (Middle Slide on page 15: tcoyd.org/PDF/2015-postp-sandiego-slides.pdf) are considerably different from those listed in the Afrezza insert (Page 15: Afrezza Insert), which are footnoted with the following: "Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro." Dr. Edelman's PD graph does appear to show much faster action than what is shown on the graph in the insert, which in my opinion would help justify an "ultra-rapid" acting label. Wondering if Dr. Edelman's data is from the recently completed clamp studies.... If anyone is clever enough to be able to post the images side-by-side, that would be most helpful to the discussion. screencast.com/t/SuJ6Ev50
Thanks Peppy. This is very helpful in illustrating my point. |
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Post by hankscorpio7 on Dec 10, 2015 21:21:42 GMT -5
Thanks Peppy. This is very helpful in illustrating my point. They are basically same graphs, charted differently. Time more compact with Edelmans. I also need help understanding how label is the way it is with these kind of graphs. Never mind SEC, should sue FDA. |
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Post by charleyd on Dec 10, 2015 23:08:17 GMT -5
Thanks Peppy. This is very helpful in illustrating my point. They are basically same graphs, charted differently. Time more compact with Edelmans. I also need help understanding how label is the way it is with these kind of graphs. Never mind SEC, should sue FDA. I agree that the PK graphs are basically the same, but still do not see it for the PD graphs. For the PD insert graph, which is what the FDA is going by, Afrezza and injected insulin mimic each other for the first hour, whereas in Edelman's graph, Afrezza's peak infusion rate is reached in about 30 minutes, whereas the injected insulin is barely off the ground. This is really a striking difference. I guess I am still missing something. |
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Post by rrtzmd on Dec 10, 2015 23:09:11 GMT -5
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Post by mnkdfann on Dec 10, 2015 23:15:01 GMT -5
And apparently the 2012 paper obtained the graphs from a 2009 ADA presentation. I think we can safely conclude that there is nothing new to got excited over here. |
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Post by charleyd on Dec 11, 2015 0:31:03 GMT -5
And apparently the 2012 paper obtained the graphs from a 2009 ADA presentation. I think we can safely conclude that there is nothing new to got excited over here. Agreed. Thanks for digging. I am now focused on why the difference between what the FDA considers to be the correct PD plot (Afrezza insert), vs. what Edelman presents. They are significantly different, and it could mean the difference between being considered "ultrafast" or not. Probably a non-value added discussion, but the discrepancy is bugging me. It also makes me wonder more what the PD plot from the new clamp study will look like. |
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Post by peppy on Dec 11, 2015 8:01:34 GMT -5
And apparently the 2012 paper obtained the graphs from a 2009 ADA presentation. I think we can safely conclude that there is nothing new to got excited over here. Agreed. Thanks for digging. I am now focused on why the difference between what the FDA considers to be the correct PD plot (Afrezza insert), vs. what Edelman presents. They are significantly different, and it could mean the difference between being considered "ultrafast" or not. Probably a non-value added discussion, but the discrepancy is bugging me. It also makes me wonder more what the PD plot from the new clamp study will look like. A better look at the charts side by side. screencast.com/t/FiCnyq01eg
more charts: screencast.com/t/VQJhkSyQrr the said duration of afrezza classified as fast acting, has always bothered me.
On a side note, Matt, said, he thinks part of the affectiveness of afrezza is; Afrezza signals the first phase insulin response: which signals the liver to stop putting glucose into the blood. I kept a chart of normal first phase insulin response. screencast.com/t/ssSzINDM his point, subq fast acting insulin does not mimic that first phase insulin response. It seems to me that information could be significant (to studies and labeling.)
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Post by barnstormer on Dec 11, 2015 10:13:17 GMT -5
Just so you know there were only 3 drugs that were discussed in any detail at the La Jolla meeting. Lantus, Toujeo and Afrezza so I think it is safe to assume who was buying dinner.
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Post by rrtzmd on Dec 11, 2015 13:14:57 GMT -5
Agreed. Thanks for digging. I am now focused on why the difference between what the FDA considers to be the correct PD plot (Afrezza insert), vs. what Edelman presents. They are significantly different, and it could mean the difference between being considered "ultrafast" or not. Probably a non-value added discussion, but the discrepancy is bugging me. It also makes me wonder more what the PD plot from the new clamp study will look like. A better look at the charts side by side. screencast.com/t/FiCnyq01eg
more charts: screencast.com/t/VQJhkSyQrr the said duration of afrezza classified as fast acting, has always bothered me.
On a side note, Matt, said, he thinks part of the affectiveness of afrezza is; Afrezza signals the first phase insulin response: which signals the liver to stop putting glucose into the blood. I kept a chart of normal first phase insulin response. screencast.com/t/ssSzINDM his point, subq fast acting insulin does not mimic that first phase insulin response. It seems to me that information could be significant (to studies and labeling.)
You should note in your last "screencast" that they are administering an IV bolus of 20 grams of glucose. That's a lot -- about a tenth of a cup. And, being pure glucose, it has no metabolic conversion barriers that need to be overcome. Consequently, the "first phase" you see is simply the beta cells dumping their stored insulin in response to this massive slug of glucose. The "second phase" represents the beta cells recovering and synthesizing more insulin which takes longer and produces no spike. Type 2s have a "blunted" response simply because they aren't able to store any insulin. Their insulin factory can't keep up with demand as it is and, consequently, they can't store any for glucose "emergencies." Restoring the "first phase" in a type 2 doesn't matter per se. First, in real life it doesn't exist. Food is digested gradually and most sugars require one or more metabolic steps before becoming glucose. This means that invariably the rise in glucose after a meal is relatively slow. In a type 2, it really doesn't matter anyway. They are already hyperinsulinemic -- their liver is continuously bombarded with signals "to stop putting glucose into the blood." The problem is that the insulin no longer has any significant effect on liver glucose production. Indeed, scientists are working on drugs that directly affect the liver's production of glucose: Targeting glucose production in liver may lead to new diabetes therapiesNote that the article mentions one of the effects of metformin is to disrupt liver glucose production. In any case, adding more insulin won't help shut down liver glucose production. With an RAA or long acting insulin, all you're really doing is jacking up already high insulin levels and trying to overwhelm all available insulin receptors. If you're really, really interested in the subject, this is a thorough recent review on the topic: Pathogenesis of Type 2 Diabetes Mellitus |
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