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Post by symbil on Dec 14, 2015 12:56:16 GMT -5
jpg He is not a Dr. He is a short. Google his name and add a HAW to the search. I have posted it a few times but my posts keep getting deleted by someone. Which ever mod keeps deleting my posts message me I will point out the similarities in posts and how I figured it out. There is no point in replying to him because he will keep trying to spin it. yep, i get mine deleted to. I guess informing the people on here what/who they are dealing with is looked at negatively. Ashame too, because hes claimed to be an expert in everything from pain management, to crohns to napster. And hes been banned from a bunch of forums for it. |
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Post by liane on Dec 14, 2015 13:03:27 GMT -5
We frown on making accusations or labeling people in the open forum. If you have a concern about another member, just let us know privately. Thanks!
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Post by Deleted on Dec 14, 2015 13:08:38 GMT -5
jpg He is not a Dr. He is a short. Google his name and add a HAW to the search. I have posted it a few times but my posts keep getting deleted by someone. Which ever mod keeps deleting my posts message me I will point out the similarities in posts and how I figured it out. There is no point in replying to him because he will keep trying to spin it. yep, i get mine deleted to. I guess informing the people on here what/who they are dealing with is looked at negatively. Ashame too, because hes claimed to be an expert in everything from pain management, to crohns to napster. And hes been banned from a bunch of forums for it. I think they try and give everyone the freedom to discuss. We dont have much street cred on this board so I can understand why it was deleted. The guy is fascinating to me. The effort he puts in is incredible. He has to be a paid shill. Theres no way anyone would put this much effort into their short position. |
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Post by Deleted on Dec 14, 2015 13:10:35 GMT -5
We frown on making accusations or labeling people in the open forum. If you have a concern about another member, just let us know privately. Thanks! Understood. I wanted him to know I figured it out. You cant hide from the word HAW. Every MNKD investor knows that word. |
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Post by tommix321 on Dec 14, 2015 14:44:17 GMT -5
It could be because the graph used by Dr. Edelman is comparing afrezza to lispro in normal subjects while the graph in the insert used type 1 diabetics. Look at this powerpoint presentation: Afrezza Approved by the FDASlide 55 compares the results of trial 176 using normal subjects and trial 177 using type 1 diabetics. The graph from trial 176 looks like the one used by Edelman. The one from 177 looks like the one in the insert. tommix321, looks like you found it. Thanks, and excellent sleuthing, as I had spent a fair amount of time trying to understand this. Not that this is what I was hoping, but Dr. Edelman appears to be somewhat misrepresenting Afrezza's performance (since it is meant to be used on diabetics instead of normal subjects), and he must be aware of the later data from the 177 study. Still does not make complete sense to me that Afrezza can enter the blood stream faster as a monomer, compared to Lispro which is slower and must be broken down to monomeric form, and yet they both have a similar onset of action and effect on glucose (for the first hour). But the data is the data. "Lispro which is slower and must be broken down to monomeric form..." This seems to be a common misconception. Genetically modified monomeric insulin development was reported as far back as 1988: Monomeric insulins obtained by protein engineering and their medical implications.Lispro was subsequently developed: [Lys(B28), Pro(B29)]-Human Insulin: A Rapidly Absorbed Analogue of Human InsulinIt was approved in 1996. In the bloodstream, insulin exists in a state of equilibrium: monomer <=> dimer <=> multimer <=> hexamer Indeed, beta cells store insulin as the hexamer, and they release it into the blood as the hexamer which then dissociates according to that equation. The monomer is the only active form, however. Lispro is modified by substituting some amino acids to produce a monomer that resists combining to form dimers, etc. The equilibrium equation helps explain a number of things. When afrezza is inhaled, the monomer is quickly absorbed. In the circulation -- since it is just regular unmodified insulin -- it immediately enters the equilibrium reaction producing inactive dimers, multimers, and hexamers. Insulin degrading enzyme(IDE) is responsible for clearing insulin that is not used. It degrades all four polymers of insulin and immediately begins degrading all four kinds in the bloodstream. So three quarters of the inhaled insulin is basically unused and removed. This why you have the 4U afrezza cartridge as equivalent to 1U of lispro -- 3 of the afrezza insulin are simply metabolized away. This is also why you have such rapid elimination of afrezza insulin from the system. Two processes are at work simultaneously. As the monomer is being used, the equation is constantly re-equilibrating, pulling monomeric insulin to the inactive forms. All the while, IDE is doing its thing on all four to remove the them. This also helps explain a phenomenon that afrezza users have reported and which was observed during the trials as well: afrezza appears to require increasing doses over time to maintain adequate glucose control. Enzymes such as IDE are susceptible to induction. If an enzyme is used frequently -- as would be the case with IDE with the very high concentrations of insulin achieved after dosing afrezza -- a cell is sometimes induced to make more of the enzyme -- the cell adapts by tuning its internal factory to increase output of the enzyme to meet its perceived need. Of course, the more IDE available, the more rapidly insulin is degraded. This is likely what is happening in patients who exhibit a need for increased afrezza dosing. The graph on the insert makes more sense than the one Dr. Edelman uses. The reason for the dramatic spike in the afrezza concentration in the PK graph is because a relatively large dose is being administered and because it is being administered to a site -- the lung -- where the drug moves almost immediately into the bloodstream. However, as I pointed out, that insulin immediately begins to enter the equilibrium reaction above. That high concentration also means the insulin is more exposed to IDE and, consequently, more rapidly disposed of. Like I said, only about one quarter of the inhaled remains as active monomer, but all four forms are degraded. As the insulin concentration decreases, there is less exposure and afrezza eventually produces its own "tail." Lispro, on the other hand, is injected into the subcutaneous tissue. It resists aggregation into dimers, etc, so that equation is not pulling monomers over into inactive forms. There is no IDE subcutaneously and hence the insulin won't be exposed to enzyme degradation until it reaches the bloodstream. Its monomers have to diffuse down a concentration gradient through connective tissue. When the concentration is high -- such as immediately after injection -- the diffusion is rapid, hence the time of onset is basically the same as for afrezza. That is also why the graphs are very similar for the first 60 minutes -- once in the blood, one unit of lispro monomers perform just like afrezza monomers and are degraded in a similar fashion. As the concentration of lispro decreases, the lispro diffusion slows down and produces the tail. At the lower concentrations, less of the insulin is exposed to IDE and removal of the insulin is gradual. No doubt more than you probably wanted to know. |
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Post by charleyd on Dec 14, 2015 16:12:31 GMT -5
tommix123, thanks for the detailed explanation, which is actually not more than I wanted to know. I am familiar with Le Chatelier's principle, so your description of the equilibrium between the various insulin polymers, and the rapid addition of the Afrezza monomer affecting that equilibrium makes sense to me. Your comments on the role of IDE in explaining the observed need for increasing Afrezza dosages over time (at least in some instances) are also illuminating, although this effect cannot be considered to be a positive characteristic.
As you point out, the short tail that Afrezza exhibits is also at least partially an artifact of this IDE action. Do you think this short tail allows Afrezza to better match the instantaneous demand for insulin that occurs during digestion, than Lispro or other alternatives, thus producing a differentiated therapeutic benefit? Otherwise, it appears that anecdotally, Afrezza is lowering the HbA1c values for some early adopters. Do you believe this is a systemic benefit of Afrezza, and if so what is the mechanism for this?
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Post by tommix321 on Dec 15, 2015 0:04:01 GMT -5
tommix123, thanks for the detailed explanation, which is actually not more than I wanted to know. I am familiar with Le Chatelier's principle, so your description of the equilibrium between the various insulin polymers, and the rapid addition of the Afrezza monomer affecting that equilibrium makes sense to me. Your comments on the role of IDE in explaining the observed need for increasing Afrezza dosages over time (at least in some instances) are also illuminating, although this effect cannot be considered to be a positive characteristic. As you point out, the short tail that Afrezza exhibits is also at least partially an artifact of this IDE action. Do you think this short tail allows Afrezza to better match the instantaneous demand for insulin that occurs during digestion, than Lispro or other alternatives, thus producing a differentiated therapeutic benefit? Otherwise, it appears that anecdotally, Afrezza is lowering the HbA1c values for some early adopters. Do you believe this is a systemic benefit of Afrezza, and if so what is the mechanism for this? First, allow me to correct my one sentence: "As the monomer is being used, the equation is constantly re-equilibrating, pulling monomeric insulin to the inactive forms." That should read: "As the polymers are degraded, the equation is constantly re-equilibrating, pulling monomeric insulin to the inactive forms." Now, as far as "Do you think this short tail allows Afrezza to better match the instantaneous demand for insulin that occurs during digestion, than Lispro or other alternatives, thus producing a differentiated therapeutic benefit?" Neither RAA nor afrezza can match the instantaneous demand for insulin as glucose fluctuates during digestion. Only the beta cells can do that, although if an artificial pancreas is ever developed, it might come close. I hope Sanofi publishes the results of the "Single Dose Clamp Study to Evaluate Concentration-time Profile and Metabolic Activity of 3 Dose Levels of Afrezza and 3 Dose Levels of Insulin Lispro in Patients With Type 1 Diabetes Mellitus." That should provide considerable more information. As it stands now, given the information provided by the PD graph in the insert, the only benefit from afrezza that I can see, aside from avoiding needles, is that the short tail provides less exposure to hypoglycemia. This benefit is offset, however, by exposure to late hyperglycemia due to slow digesting carbs. And, "Do you believe this is a systemic benefit of Afrezza, and if so what is the mechanism for this?" I doubt afrezza in itself contributes much to lowering A1C. I think the "mechanism" for what develops is simply that the users are more highly motivated to succeed and end up doing a better job of attending to their illness -- checking their glucose regularly and more frequently, better attention to dosing time and frequency, more attention to proper diet, augmenting effects through exercise, etc. The extent to which afrezza's ease of use augments attending to those details would arguably be a benefit. On the other hand, I suspect the same could be accomplished even with old fashioned humulin 70/30 if the motivation was there. |
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Post by mbracket1234 on Dec 15, 2015 1:45:30 GMT -5
motivation (i.e. lack of) = non-compliance.
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Post by figglebird on Dec 15, 2015 6:46:50 GMT -5
Thank you for that - science aside you just PINPOINTED why Afrezza will succeed - Prick or breathe?
Adherence.
If 30pct of the diabetic population opts to feel like crap rather than prick themselves with a needle... you do the math.
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Post by ezrasfund on Dec 15, 2015 9:06:44 GMT -5
And, "Do you believe this is a systemic benefit of Afrezza, and if so what is the mechanism for this?" I doubt afrezza in itself contributes much to lowering A1C. I think the "mechanism" for what develops is simply that the users are more highly motivated to succeed and end up doing a better job of attending to their illness -- checking their glucose regularly and more frequently, better attention to dosing time and frequency, more attention to proper diet, augmenting effects through exercise, etc. The extent to which afrezza's ease of use augments attending to those details would arguably be a benefit. On the other hand, I suspect the same could be accomplished even with old fashioned humulin 70/30 if the motivation was there. I am not sure that this is correct. Users report being able to eat more spontaneously and also to eat more foods like pizza or ice cream and still manage blood glucose successfully. Here is a recent Twitter comment as one example of many. Gustavo Basualdo @guasaman 8h8 hours ago Being able to go hard in the pool, and then eat all the recovery carbs I need with no crazy planning/bolus/counting is sooo awesome #afrezza |
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Post by tommix321 on Dec 15, 2015 10:47:44 GMT -5
And, "Do you believe this is a systemic benefit of Afrezza, and if so what is the mechanism for this?" I doubt afrezza in itself contributes much to lowering A1C. I think the "mechanism" for what develops is simply that the users are more highly motivated to succeed and end up doing a better job of attending to their illness -- checking their glucose regularly and more frequently, better attention to dosing time and frequency, more attention to proper diet, augmenting effects through exercise, etc. The extent to which afrezza's ease of use augments attending to those details would arguably be a benefit. On the other hand, I suspect the same could be accomplished even with old fashioned humulin 70/30 if the motivation was there. I am not sure that this is correct. Users report being able to eat more spontaneously and also to eat more foods like pizza or ice cream and still manage blood glucose successfully. Here is a recent Twitter comment as one example of many. Gustavo Basualdo @guasaman 8h8 hours ago Being able to go hard in the pool, and then eat all the recovery carbs I need with no crazy planning/bolus/counting is sooo awesome #afrezza "Users report...." Therein lies a problem. To really compare, you need some sort of well documented lifestyle/therapy history before and after starting afrezza. More importantly for afrezza, there needs to be solid clinical documentation to show insurance companies that patients in general are getting consistent improved results and that those results are in some fashion due to afrezza. This sort of documentation invariably requires a large and prolonged trial. I can't find anywhere that Sanofi has indicated whether they plan on any other trials other than those mandated by the FDA. |
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Post by Deleted on Dec 15, 2015 11:29:50 GMT -5
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Post by mssciguy on Dec 15, 2015 11:31:48 GMT -5
A Guest Post on Afrezza by Jeremy Pettus I wanteJeremy Pettusd to write today about Afrezza. My tune on this med has changed slightly after Dr. Steve Edelman and I put on a very interesting focus group on a during the first weekend of December to discuss the medication. The purpose of the group was to learn how successful Afrezza users use Afrezza successfully (say that 10 times fast!) with the intent of designing a clinical trial around this info. Some of the comments we heard during the focus group: “Efficient – Administration using the Afrezza inhaler rather than injections provides an efficient method for using insulin and transporting supplies.” “Modern – It’s the beginning of a new age for administering insulin.” “Having control..... with the Afrezza-CGM combo I can literally keep my BG from ever rising above 150, even after big meals, and I never crash.” "Easy (to use), I can use Afrezza almost anytime anywhere." “Afrezza is in and out of your system quickly and effectively and helps steady my blood glucose levels. The improvements to my overall health have been amazing. Proof is in the pudding over sustained reasonable A1C results.” “Revolutionary! I have never had such success with insulin in my life. Being on Afrezza means I do not have to count carbs. Not only is it inhalable, it works better, faster and more effectively than any injectable I have ever used.” "I can do all the things anybody else can do.” “Mealtime is like tying a weight around your ankle for 4-5 hours. Afrezza is more forgiving.” “I finally have the freedom to eat the food I want like other people.” "There is a lot less fear about hypos when using Afrezza, which greatly improves quality of life for many patients. There is better prediction of glucose values with Afrezza, which helps with planning activities." A big takeaway from this focus group meeting: There are people out there using this medication very well to achieve crazy-low A1Cs, like in the 5s, along with low rates of hypoglycemia. I mean these people got pissed when their BG was above 130! So how are they doing it? |
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Post by dreamboatcruise on Dec 15, 2015 11:48:58 GMT -5
I loved reading the comment that one purpose was designing a clinical trial... exactly what I expected.
Did not at all like reading "So if you haven’t tried it, or the doctors haven't offered or discussed it with patients, time might be running out!" coming from someone that attended the SNY meeting. How could the meeting both be known to be about an upcoming clinical trial, and yet leave one of its medical professional attendees unclear whether Afrezza will continue to be on the market? Hopefully that comment is merely to spur more doctors and patients to give Afrezza a try... though I'm not sure I see the logic in it, as people may also rightly question whether it worth the effort (often onerous effort) to give it a try if Afrezza may go the way of Exubera.
Great quotes from the participants. Why would SNY pull a drug with that sort of feedback? Why might time be running out?
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Post by Deleted on Dec 15, 2015 11:54:53 GMT -5
Great article once the portion of Jeremy starts. This author annoys me. He is such a hypocrite. The lung issues are a concern? Homeboy you eat like shit and drink a lot for a diabetic. Was this about a new treatment for diabetics or SNY dropping MNKD. Also great to hear he writes for a diabetes page but couldn't figure out how to use Afrezza correctly. I guess he could of asked Amy but then again she didnt know how to use either.... |
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