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Post by peppy on Jun 17, 2015 14:23:59 GMT -5
Some of this information has gotten my attention. you wrote: I didn't say that. I said that type 1s are much more sensitive to insulin. Typical type 1s take 20-40U a day, divided about 2/3 slow, 1/3 fast. There have already been reports of type 1s requesting a 2U dose because the 4U was simply too much. You also have to consider that a 4U dose actually contains 10U of insulin. It's labelled as 4U because -- on average -- only 40% actually reaches the lungs, but since it is only an average, one can assume there is variability around that average.. Then from the lungs there is further variability of absorption as demonstrated on the PK graph in the insert. Note that the rapid peak in serum insulin concentration from afrezza has very high variability when compared to lispro. Also, many people have reported assorted difficulties inhaling afrezza -- inhalation interrupted by coughing, powder still in the inhaler, powder in the back of their throat, etc -- which also contributes to variability of dosing. Type 1s are increasingly reporting difficulties with achieving proper dosing, most often problems with hyperglycemia 1-2 hours post mealtime use requiring yet further afrezza dosing. In other words, afrezza may not be suitable for most type 1s.
Quote: I said that type 1s are much more sensitive to insulin. Typical type 1s take 20-40U a day Reply: I buy that Quote: There have already been reports of type 1s requesting a 2U dose because the 4U was simply too much. You also have to consider that a 4U dose actually contains 10U of insulin. Reply: ok quote: It's labelled as 4U because -- on average -- only 40% actually reaches the lungs, but since it is only an average, one can assume there is variability around that average.. Then from the lungs there is further variability of absorption as demonstrated on the PK graph in the insert. ****Note that the rapid peak in serum insulin concentration from afrezza has very high variability when compared to lispro Reply:**** I would expect that. Two different forms of delivery with two different peak times. Also variable the food. other possible varibles effecting rapid peak serum concentration, perhaps the shape of the liver, the heart, the circulatory system. Just talking, I will continue. Consider requiring further afrezza dosing because they ate a piece of cake. It this a controlled human study? An animal study? Just asking. To me there would be variability for multiple reasons under human beings trying to live there lives conditions. Just asking.
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Post by gomnkd on Jun 17, 2015 16:03:33 GMT -5
I hesitated to comment on Oscar's posts. But thought I'll give my 2 cents.
I don't know if he is doing it on purpose or just being naive/clueless about how markets/drugs work.
Issue 1: He posts links from 5 different click/bait articles that criticize MNKD and then states that MNKD should issue a PR for the trial. My response: Many articles are critical for various reasons. These are just opinions from random folks and issuing a PR doesn't solve any problems. SNY controls trials & marketing. SNY initiates 100's of trials a year and they don't issue PR for everything. Afrezza is owned by the partnership and MNKD is a minority partner.
Issue 2: "Type 1s are increasingly reporting difficulties with achieving proper dosing, most often problems with hyperglycemia 1-2 hours post mealtime use requiring yet further afrezza dosing. In other words, Afrezza may not be suitable for most type 1s."
My response: Sweeping generalizations. He quotes 1-2 users who have had issues due to unique circumstances. PatOppa due to asthma and others due to not taking another dose 1-2 hours after a meal. He uses this to make sweeping generalizations about usefulness of the drug for entire Type 1 or 2. This reflects lack of intelligence or just a poor attempt to create FUD.
Issue 3: His comment: Why? Shouldn't that already have been done like years ago? Although I notice a lot of people are reporting the need to use considerably more afrezza insulin than lispro insulin, maybe trying to figure that out.
and
I still the think the problem is the increasing reports of diabetics needing to take substantially larger doses of afrezza to match their old lispro dose effect. SNY knows that insurance companies won't pay for 2 or more doses of afrezza when one of lispro will work just as well. Reimbursement is essential to afrezza success -- especially tier 2 status. I think SNY wants to know what kind of dosing issues it's facing.
My response: Total conjecture. He hasn't done a survey of all pt's. He reads one or two posts and makes assumptions. There are several reasons as to why Pt's are needing more doses. They could be eating more, some like Mallomars and Afrezza could give them the freedom to eat more. Another reason could be that some pt's are learning not to inhale hard. They may be losing some due to cough. Once they start on Afrezza, some report reduction in insulin resistance. Some use less basal and use more bolus insulin. There are just so many variables and each experience is unique.
No amount of new trials and data are going to change the way Finta and Spiro use Afrezza. Afrezza is a tool with its unique profile. The way it will work on a pt and the way it alters patients behavior and response are unique. It is like a kid riding a bicycle and learning to balance.
Fact is, Afrezza is not suitable for everyone. It has dosage limitations, exclusion etc. To compound this issue, endos/pcp's have preconceived notions about efficacy, usefulness etc. Old trials reflect the fact that around 10% or more quit taking Afrezza.
Bottom line is, if Afrezza works well 20%+ of diabetics then it is a success.
At a glance his posts look legit. Once you dig deeper, you'll realize that reading those will lower your IQ.
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Post by james on Jun 17, 2015 16:12:37 GMT -5
One of the more interesting things I have picked up in the past few months was regarding the mechanisms behind insulin dose and glucose absorption. There is a frequently mistaken assumption that the body utilizes insulin to burn glucose and therefore the amount of insulin provided needs to be factored in relation to the amount of glucose present. In reality, insulin is a hormone that binds to cellular receptors and provides a signal to cells to uptake glucose (glucose then being stored for later use which is a process that does not require insulin - I think). This action of uptake is essentially an on/off switch. The rate of glucose uptake is determined by the quantity of receptors stimulated and the voracity of individual cells. The reason why dosing does not provide a linear response in glucose reduction is due to saturation of insulin receptors, essentially marking a threshold above which additional insulin provides very little affect. Insulin persists in the body with a half life of about 6 minutes as it is broken down by insulinase excreted from the liver, so the time of action for an individual insulin molecule is quite short. Therefore, perhaps the greatest factors in determining quantity of glucose removed is the speed at which full dosing is achieved and the length of time insulin continues to be absorbed into the body. While there will be some variability in absorption rate for Afrezza, this necessarily will be much lower than for injected insulin as site selection and proximity to blood supply provides substantial variability for injectables. I don't fully understand why insulin sensitivity varies though my working hypothesis is that the receptors become blocked in some why which requires a higher concentration of insulin to give an equal change that the receptor is stimulated.
So, this question of safety in regards to hypoglycemia for T1 use and varying sensitivities is a critical point as there will be little difference in safety once saturation has been achieved. Though there is certainly a difference, a 4U or 8U dose will generally be only somewhat riskier than a 2U dose for an insulin sensitive patient because the time of action will be similar for each dosing. With injectibles, the action is so much different because reaching saturation would be exceedingly dangerous and rarely experienced. Since the action persists for an extended period, the difference between 2U and 4U in an injectible could be highly significant in terms of risk.
In light of the above, I would suggest that this "hyperglycemia" issue should be characterized differently. Hyperglycemia might more likely arise due to variability in the basal insulin than an issue with prandial. The extended time action for prandials can have a masking affect on insufficient basal usage or non-linearity in action thereof as some patients have come to find out. For foods (or patients) that digest more slowly than ideal for the rapid curve of Afrezza action, a follow up dose might certainly be desired. I would suggest that while there is definitely an inconvenience to this, it pales by comparison to the guesswork that seems so prevalent in everyday dosing issues with subcutaneous prandial. A great quote I came across on this was along the lines of: "the need for precise dosing in subcutaneous insulin is not a feature to be desired". What is truly inconvenient is the need for exogenous insulin in the first place. The fact that in some circumstances, an additional dose of Afrezza is indicated in no way means that it is not suitable for the situation. This is something that I imagine patients, physicians, and insurers will eventually be faced with accepting. It may also be something that Sanofi should consider as they review pricing policies. I am a bit dismayed as I read of patients running out early due to the natural response of taking additional doses. Insulin is not a product that should be packaged, priced, or reimbursed in a way that requires rationing; of course, I don't know how to fix that.
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Post by peppy on Jun 17, 2015 16:39:16 GMT -5
Oscar I did read over the study presentation on the package insert. medlibrary.org/lib/rx/meds/afrezza-1/Non inferiority. The glucose lowering effect of AFREZZA may be decreased when co-administered with atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required when AFREZZA is co-administered with these drugs. The glucose lowering effect of AFREZZA may be increased or decreased when co-administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when AFREZZA is co-administered with these drugs. Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro. In a study of 32 healthy subjects, the pharmacodynamic effect of AFREZZA, measured as area under the glucose infusion rate — time curve (AUC-GIR) from an euglycemic clamp, increased in a less than dose-proportional manner. This effect has been observed for subcutaneously administered insulins, but it is unknown if the diminishing pharmacodynamic benefit at higher dosage of AFREZZA parallels that which is seen with subcutaneously administered insulin. screencast.com/t/iyiu4cYFI9mKI read the FDA link. I am trying to understand your point regarding variability (human insulin has the empirical formula C257 H383 N65 O77 S6)
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Post by mannmade on Jun 17, 2015 17:18:55 GMT -5
Issue 3: His comment: Why? Shouldn't that already have been done like years ago? Although I notice a lot of people are reporting the need to use considerably more afrezza insulin than lispro insulin, maybe trying to figure that out.
and
I still the think the problem is the increasing reports of diabetics needing to take substantially larger doses of afrezza to match their old lispro dose effect. SNY knows that insurance companies won't pay for 2 or more doses of afrezza when one of lispro will work just as well. Reimbursement is essential to afrezza success -- especially tier 2 status. I think SNY wants to know what kind of dosing issues it's facing.
The other point I might make about his comment above is that Afrezza has been shown to reduce insulin resistance and that along with ability to lower a1c's to non-diabetic numbers will create long term health cost savings that will dwarf the cost of the drug once the insurance companies put 2 & 2 together...
Lastly I expect the price to come down a bit as someone on this board previously pointed out that likely done on purpose so that as they negoiate for Tier 2 status and Tier 3 with no preconditions they have some room on the price to give up in the negoiations with insurance companies.
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Post by gomnkd on Jun 17, 2015 18:35:23 GMT -5
Here Dr. Lonzo goes medieval with his insightful comments www.healthline.com/diabetesmine/amazing-afrezza-non-invasive-insulin-works#5-------------------------------------------------------- one more www.healthline.com/diabetesmine/how-afrezza-changing-life-type-1-diabetic-pilot#6If only he read his tweets before casting aspersions on Brian (see ) Oscar Lonzo
Readers may also wish to check out Brian's posts on the "diabetesdaily" blog. On 2/12 he picks up his first doses of afrezza. On 2/13, he opens a twitter account and begins a near continuous stream of positive comments about afrezza.
Over on the "diabetesdaily" blog he tells everyone:
"I can tell you that Exubera was a game changer in the control of my diabetes. It was super convenient and easy to use. Fast acting and was not embarrassing."
Google a photo of an exubera dispenser and judge for yourself how "super convenient," "easy to use," and "not embarrassing" it was. Only two DAYS after "bsharp6669" started posting there, someone named "Karena"remarked:
"I am glad it is working for you bsharp6669 and your enthusiasm is almost legend already. BUT, it does seem as if you are here to promote a product that has yet to be proven to many of us who have no trouble with the current product and delivery systems, enjoy excellent management, control, and are not looking to increase the mess of crap we must carry and certainly not the cost."
I think "Karena" is quite perceptive. ---------------------------------------------------------------------------
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Post by james on Jun 17, 2015 18:48:37 GMT -5
Well shut my mouth if this is the same guy.
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Post by jpg on Jun 17, 2015 20:25:42 GMT -5
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Post by savzak on Jun 17, 2015 20:50:52 GMT -5
Fugacity has asked him about his position. I don't think he's responded but I may have just missed it.
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Post by mnholdem on Jun 17, 2015 21:30:52 GMT -5
You guys allowed oscarlonzo's post-by-post blitz distract you in the first thread I posted (I was on a business trip and by the time I read his questions and your responses, the thread had been locked). He seems pretty knowledgeable about the trial data, so his questions did seem disingenuous.
I think we've answered his questions to the best of our ability and now that we've bantered his motives around a bit, I think I'd like to get back to the endpoints Sanofi filed and try to determine the label ramifications, besides the one mentioned by the FDA.
clinicaltrials.gov/ct2/show/NCT02470637
Further study details as provided by Sanofi:
Primary Outcome Measures: •Assessment of PD parameter: Area under the glucose infusion rate curve within 24 hours after administration of the investigational medicinal product or until administration of rescue insulin (GIR-AUC0-end) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
Secondary Outcome Measures: •Assessment of PD parameters: Maximum smoothed glucose infusion rate (GIRmax) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Assessment of PD parameters: Time to GIRmax (GIR-Tmax) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Duration of blood glucose control (time to elevation of smoothed blood glucose profile above different prespecified clamp levels) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Assessment of PK parameters: Area under the baseline-corrected serum insulin concentration-time curve over 24 hours or until administration of rescue insulin (INS-AUClast) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Assessment of PK parameters: Baseline-corrected maximum serum concentration (INS-Cmax) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Assessment of PK parameters: Time to INS-Cmax (INS-Tmax) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Assessment of PK parameters: Area under the concentration-time curve (INS-AUClast) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Number of patients with adverse events [ Time Frame: Up to 2 days ] [ Designated as safety issue: Yes ]
----
What I am most interested in gathering your opinions about is whether this trial can possibly lead to a claim of superiority or First-in-Class. I don't mind admitting that the science at this level, well, it's a little over my head.
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Post by Deleted on Jun 17, 2015 21:34:42 GMT -5
I know who he is. And I know he won't answer the question. People have engaged him with facts and he's only cherry picked comments in order to support his agenda.
He's multiple people in multiple media (here, Twitter, ST, SA, etc)
its funny watching who defends him, too.
I'm quite sure the admins can do an IP check, as when I've run websites before it was quite easy. and I'm also quite sure if they could, the results would be astounding.
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Post by mnholdem on Jun 17, 2015 21:46:50 GMT -5
I don't think he's crossed that particular line yet, IMHO. I'm quite satisfied with knowing that he must face a crowd here on this forum that is tougher to fool than the other board he may troll.
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Post by oscarlonzo on Jun 17, 2015 22:39:03 GMT -5
"...simply not aware of the mostly very positive reviews out there." What I'm aware of is that overall endos apparently show little enthusiasm for the drug. Just a few quotes from a Washington Post article recently released: "Only a few Washington-area endocrinologists have completed the process of meeting with drug reps to determine if they will offer the new product, training their staff on its use and identifying patients they believe are candidates.... Janicic-Kahric is not sure she will offer it to Type 1 patients, uncertain it can provide the precise glucose control they require, since it comes in prepackaged doses. With injections, patients can vary the amount of insulin they receive by tiny amounts...“The inhaled option is convenient,” she said. "But I would prefer to wait a little longer to conclude whether it is effective.” Farhad Zangeneh, an endocrinologist in Sterling, Va., began his first patient on Afrezza in March. The patient had long-standing, poorly controlled Type 2 diabetes, despite a daily long-acting injection, multiple pills, a good diet and exercise. Even that one shot was hard, as he deeply feared needles. Zangeneh said he, too, would rarely prescribe Afrezza for Type 1 diabetics. If they are averse to shots, he prefers that they use a pump, which delivers insulin through a catheter placed under the skin." Curiously, Dr. Zangeneh was also quoted a month ago here: not for type 1s
"Dr. Farhad Zangeneh, a endocrinologist who practices in Sterling, Va., recently switched one patient with a fear of needles to Afrezza. He says every practice has one or two patients with similar fears. 'Would I call this Lorenzo's oil? No,' he said. 'But it does have an application.'" So in that one month between those articles, not only has he not changed his mind about afrezza's usefulness, he's more specifically stated he will rarely use it in type 1s, and even in type 2s, he suggests that he'll only use it in the worse patients who "deeply" fear needles. Now, maybe he's ignorant and/'or stupid and needs to "read up on insulin," but he is the guy you're supposed to be selling the drug to, and right now he clearly isn't buying what you're selling. He represents a relatively small proportion of the insulin market -- type 1s. How much time and energy do you invest in trying to "turn" him, so to speak?
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Post by MnkdMainer (MM) on Jun 17, 2015 23:12:03 GMT -5
"So in that one month between those articles, not only has he not changed his mind about afrezza's usefulness, he's more specifically stated he will rarely use it in type 1s, and even in type 2s, he suggests that he'll only use it in the worse patients who "deeply" fear needles."
Oscar, are you assuming that the information reported as coming from the doctor came from him at two different times a month apart based upon the date of each article?
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Post by oscarlonzo on Jun 17, 2015 23:44:15 GMT -5
"He quotes 1-2 users who have had issues due to unique circumstances." First, I suggest just a general review of the "tudiabetes" board to note how often afrezza crops up in the posts overall: hard to find afrezza Consequently, given the apparently limited number of subjects available, one might be able to argue that even "1-2" might be significant. Nevertheless, reviewing just the two largest threads: www.tudiabetes.org/forum/t/taking-the-plunge-with-afrezza/23384www.tudiabetes.org/forum/t/i-started-on-afrezza-last-night/23316I found these comments: "green_pear" "I use about double the afrezza than I do regular insulin." and in a more recent post: "However, I have learned that Afrezza is such a different drug that you can't equate 8U of Afrezza with 8U of other insulins. I would say I need at least twice the amount of it than I do Apidra." "V11" " How often to you need follow-up dose? I have try to understand how to use Afrezza but so far, I haven't had good results. I often have to use a correction with Humalog and end up taken so much Humalog that it covers almost my entire meal even if I waited 30 min after the first bite." "tonilynn20" "I just started with Afrezza and I am noticing the same thing. I'm needing to use a lot of it to get coverage. I'm wondering if it's worth it but will stick with it for a bit. My numbers have been ok and I really like my pump break. I can see that I will need a larger prescription though if I want to stick with Afrezza." "gabarito" "I was also bummed as further testing was revealing that I would need 3 instances of inhaling afrezza to get really smooth flat coverage." "sam19" "Seeing more and more of the 3rd hour increases that others have noted.... This wouldn't be a terribly big deal but if I'm going to have to often wrestle down 3rd hour spikes I'm going to need my quantity adjusted to have a whole lot more 4u cartridges per month.... It's also frustrating to me because as I've said my entire goal is to simplify this entire situation to the point I can almost forget about it." Also I found on twitter: "laureen" "I find about a 1 to 3 ratio of humalog to afrezza, different medicine" "IG:TheCorinneMarie" "W/ Humalog I was 20-30 units per day. Afrezza I'm at 40U+ & still have highs. Frustrating." Now, considering that overall, I've found probably less than 20-25 people on the entire internet posting about allegedly taking afrezza themselves, seven of them reporting dosing issues seems relatively significant. As an addendum, I would note that "mikep," who started the second thread, had to give up afrezza because of a cough: "...a couple weeks back I developed a pretty bad cough. It wasn't just a small dry cough, it was a significant constricting like cough. My wife on numerous occasions commented that she thought it was from the Afrezza. At first, I thought it was from allergies, but I decided to take a couple days off using Afrezza exclusively for all of my meal and correction boluses and my cough disappeared. Just to be sure, I went back to using Afrezza as I was using before and the cough came back again. So long story short, I've cut back my Afrezza usage significantly and only use for those high carby meals and for significant corrections. Also - just to confirm, I did have a Spirometry test before starting the Afrezza and all was good with that test."
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