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Post by sophie on May 11, 2017 11:39:36 GMT -5
Peppy beat me to the link. What's an RRA? Quote: What's an RRA? reply: good question. I do not know why subq rapid acting are called RRA. Anyone know what the acronym means? Aged?
my guess "_____ rapid acting" is it recombinant?
acronyms.thefreedictionary.com/RRA
peppy I was having my fun with @kastanes for always playing science lecturer. RRAs don't exist, at least for our discussion. RAAs do. Kasty, by your analogue is an analogue logic, how come Lantus, tresiba, toujeo, etc aren't considered rapid-acting? Because being an analogue has nothing to do with speed. Insulin analogue simply means it binds to the insulin receptor. So your argument doesn't work for keeping Fiasp as an RAA. We'll just have to wait and see what the FDA decides.
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Post by akemp3000 on May 11, 2017 11:41:37 GMT -5
I find the term "partnering" to be interesting and indicative that companies other than MannKind will be handling distribution of Afrezza in these countries. Good catch!! The word partnering would not have been used unless it's on the front burner and in play.
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Post by sophie on May 11, 2017 11:56:27 GMT -5
The reason afrezza was not given the ultra label is the 171 and 175 studies had nothing to do with speed of action. They were about A1c which is like comparing "miles per gallon" to how fast a car can go. They are very much different. If afrezza gets ultra first - Fiasp will have to show non-inferiority. I suspect BP's plan was by now MNKD would be bankrupt. Still mostly agreeing with you. Just saying- what happens if FDA finds Fiasp superior to RAAs, but inferior to Afrezza? They'd have to create 2 new classes for only 2 drugs. I don't see them wanting to do that. We'll probably find out if I'm wrong by year end.
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Post by Deleted on May 11, 2017 12:03:55 GMT -5
@reverselo you obviously did not paying attention to Castagna's discussion regarding scripts and cartridges. I recommend you listen again to the call to get your facts straight. Kastanes you could tell me the sky is blue and I wouldn't listen to a word you say. That's how little I value your interpretation to anything related to MNKD. I listened to the call and have drawn my own conclusions. I stated earlier in the thread that I thought the call was not as bad as investors are claiming.
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Post by sophie on May 11, 2017 17:23:45 GMT -5
I find the term "partnering" to be interesting and indicative that companies other than MannKind will be handling distribution of Afrezza in these countries. Would you expect MNKD to get sale of insulin plus royalty?
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Post by sayhey24 on May 11, 2017 18:01:36 GMT -5
The reason afrezza was not given the ultra label is the 171 and 175 studies had nothing to do with speed of action. They were about A1c which is like comparing "miles per gallon" to how fast a car can go. They are very much different. If afrezza gets ultra first - Fiasp will have to show non-inferiority. I suspect BP's plan was by now MNKD would be bankrupt. Still mostly agreeing with you. Just saying- what happens if FDA finds Fiasp superior to RAAs, but inferior to Afrezza? They'd have to create 2 new classes for only 2 drugs. I don't see them wanting to do that. We'll probably find out if I'm wrong by year end. All RAAs prior to afrezza were compared to R human insulin just for A1c. afrezza was already human insulin in monomer form. The question in front of the original FDA review team was do we even need to test afrezza since human insulin is already approved. Then it got really really political. What was suppose to be tested was the inhaler. The entire 171/175 fiasco was a big mess and very poorly designed. Al just needed the inhaler approved and all he wanted was initial approval so he could do all the tests to show speed and time in range. When we are talking "ultra" we are no longer talking A1c which think of as average "Miles per Gallon" with a car. What we want is a race car not a Honda Civic and not a Yugo. If afrezza gets this label it will be because of the clamp studies, i.e. how fast it responded to keep time in range. Fiasp will have to do the exact same clamp studies and be as good as afrezza but the science already tells us it can't be. When people talk A1c any insulin given the equivalent amount over time will produce about the same A1c, give or take. They will all have about the same average "Miles per Gallon", for example 20 to 22 MPG. However they do not all have the same Zero to 60 "punch". At best Fiasp is a Honda Accord. If you look at its profile it is almost the exact same as Novolog shifted left on the time line 15 minutes. Fiasp will never provide the same phase one release afrezza does. It just does not have the initial "punch" the liver needs to stop glucose production. And, it will still hang around a long time as the tail profiles just like Novalog. Also, it is an analog which we already know reacts different in different people and also raises the cancer concerns they are now seeing with the analogs. We know AspB10 did not turn out well and the studies from Europe may be starting to answer the growing rate of cancer in analog users. What we do know is diabetics have a higher cancer rate but the cause has been a mystery.
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Post by sayhey24 on May 11, 2017 18:24:44 GMT -5
The reason afrezza was not given the ultra label is the 171 and 175 studies had nothing to do with speed of action. They were about A1c which is like comparing "miles per gallon" to how fast a car can go. They are very much different. If afrezza gets ultra first - Fiasp will have to show non-inferiority. I suspect BP's plan was by now MNKD would be bankrupt. The problem is that the inferiority measure is against HbA1c and Fiasp has trial data supporting superiority over analogs whereas Afrezza doesn't. Shifting to time in range helps but that requires educating the market which takes time. A better and quicker line is probably quality of life since that is an understood metric. I can see the argument that gets used already and it will be that Afrezza requires follow up doses to be effective whereas Fiasp doesn't which will give better long term results. The trouble is that their characteristics make each good at particular roles; Fiasp for meal time, Afrezza for corrections. Read my prior post - when it comes to the "ultra" label afrezza will only get this based on the clamp studies. Fiasp will need to do the exact same studies and be "as good". Based on the science that will not be possible. We are talking speed of action to maintain time in range. Now think about your comment - their characteristics make each good at particular roles; Fiasp for meal time, Afrezza for corrections. The human body evolved over a long time, maybe millions of years, who knows. It is a finely tuned machine and what it uses best at meal time is a molecule which is C257H383N65O77S6 and a molecular weight of 5808 aka human insulin. Fiasp is C256H381N65079S6 and 5825.8 g/mole. Now at best Fiasp is a little faster than Novolag but almost profiles exactly the same. At worst it is a Frankenstein GMO with totally unknown long term safety issues. What we do know is it will never profile like the pancreas and afrezza do so it will not provide the needed phase one release. So NO, Fiasp is not a better meal time insulin. And, I would take any comers on a bet that properly dosed on the initial dose and then providing any 90 minute follow-up dose afrezza will provide better time in range, hands down.
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Post by peppy on May 11, 2017 18:45:00 GMT -5
The problem is that the inferiority measure is against HbA1c and Fiasp has trial data supporting superiority over analogs whereas Afrezza doesn't. Shifting to time in range helps but that requires educating the market which takes time. A better and quicker line is probably quality of life since that is an understood metric. I can see the argument that gets used already and it will be that Afrezza requires follow up doses to be effective whereas Fiasp doesn't which will give better long term results. The trouble is that their characteristics make each good at particular roles; Fiasp for meal time, Afrezza for corrections. Read my prior post - when it comes to the "ultra" label afrezza will only get this based on the clamp studies. Fiasp will need to do the exact same studies and be "as good". Based on the science that will not be possible. We are talking speed of action to maintain time in range. Now think about your comment - their characteristics make each good at particular roles; Fiasp for meal time, Afrezza for corrections. The human body evolved over a long time, maybe millions of years, who knows. It is a finely tuned machine and what it uses best at meal time is a molecule which is C257H383N65O77S6 and a molecular weight of 5808 aka human insulin. Fiasp is C256H381N65079S6 and 5825.8 g/mole. Now at best Fiasp is a little faster than Novolag but almost profiles exactly the same. At worst it is a Frankenstein GMO with totally unknown long term safety issues. What we do know is it will never profile like the pancreas and afrezza do so it will not provide the needed phase one release. So NO, Fiasp is not a better meal time insulin. And, I would take any comers on a bet that properly dosed on the initial dose and then providing any 90 minute follow-up dose afrezza will provide better time in range, hands down. Just because this has become a conversation: About the product Fiasp is insulin aspart in a new formulation. Insulin aspart, with the global trade name NovoRapid, has been on the market worldwide for more than a decade for the treatment of diabetes mellitus. Compared to NovoRapid, Fiasp contains two additional excipients: nicotinamide (also known as niacinamide or vitamin B3) and L-arginine hydrochloride (an amino acid). The addition of nicotinamide is intended to result in a faster initial absorption of insulin aspart following subcutaneous (s.c.) injection. The addition of L-arginine hydrochloride should support stabilisation of the Fiasp formulation. The insulin aspart molecule in Fiasp and NovoRapid is identical and therefore, once systemically absorbed, it has the same biological action at the insulin receptor as that of NovoRapid. Fiasp is intended to be used for the treatment of patients with diabetes mellitus (T1DM and T2DM) both for basal-bolus therapy in combination with intermediate- or long-acting basal insulin (± oral antidiabetic drugs; OADs), and for CSII by external pump, where both basal and bolus requirements can be covered by Fiasp. Fiasp can be injected at the start of a meal or postmeal (within 20 minutes after starting a meal). Moreover, Fiasp can also be delivered intravenously by health care professionals when the clinical situation requires this route of administration. The indication sought is: “Treatment of diabetes mellitus in adults”. Here is the time of action comparison www.screencast.com/t/I07xbIQCT6TV
"They are playing with us."
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Post by agedhippie on May 11, 2017 18:46:54 GMT -5
What we do know is it will never profile like the pancreas and afrezza do so it will not provide the needed phase one release. So NO, Fiasp is not a better meal time insulin. And, I would take any comers on a bet that properly dosed on the initial dose and then providing any 90 minute follow-up dose afrezza will provide better time in range, hands down. The problem is the need to test for follow on dosing after meals with Afrezza. The danger is that when this hits the wider community that testing is going to be skipped as it is today with RAA. Consequently you are not going to see the A1c reductions expected. A longer tail lets diabetics ignore the need for a second test even if they shouldn't (I put my hand up, and I don't know anyone who does it either but there must be some).
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Post by peppy on May 11, 2017 18:53:49 GMT -5
What we do know is it will never profile like the pancreas and afrezza do so it will not provide the needed phase one release. So NO, Fiasp is not a better meal time insulin. And, I would take any comers on a bet that properly dosed on the initial dose and then providing any 90 minute follow-up dose afrezza will provide better time in range, hands down. The problem is the need to test for follow on dosing after meals with Afrezza. The danger is that when this hits the wider community that testing is going to be skipped as it is today with RAA. Consequently you are not going to see the A1c reductions expected. A longer tail lets diabetics ignore the need for a second test even if they shouldn't (I put my hand up, and I don't know anyone who does it either but there must be some). I can see why. (Or why bother) I am going to guess this individual gives themselves insulin after eating, like you do.
www.slideshare.net/StephenPonder/sugar-surfing-with-a-cgm-copyright-tlc-advanced-diabetes-retreat-april-26-2014
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Post by agedhippie on May 11, 2017 18:58:39 GMT -5
Just because this has become a conversation: About the product Fiasp is insulin aspart in a new formulation. Insulin aspart, with the global trade name NovoRapid, has been on the market worldwide for more than a decade for the treatment of diabetes mellitus. Compared to NovoRapid, Fiasp contains two additional excipients: nicotinamide (also known as niacinamide or vitamin B3) and L-arginine hydrochloride (an amino acid). The addition of nicotinamide is intended to result in a faster initial absorption of insulin aspart following subcutaneous (s.c.) injection. The addition of L-arginine hydrochloride should support stabilisation of the Fiasp formulation. The insulin aspart molecule in Fiasp and NovoRapid is identical and therefore, once systemically absorbed, it has the same biological action at the insulin receptor as that of NovoRapid. Fiasp is intended to be used for the treatment of patients with diabetes mellitus (T1DM and T2DM) both for basal-bolus therapy in combination with intermediate- or long-acting basal insulin (± oral antidiabetic drugs; OADs), and for CSII by external pump, where both basal and bolus requirements can be covered by Fiasp. Fiasp can be injected at the start of a meal or postmeal (within 20 minutes after starting a meal). Moreover, Fiasp can also be delivered intravenously by health care professionals when the clinical situation requires this route of administration. The indication sought is: “Treatment of diabetes mellitus in adults”. Here is the time of action comparison www.screencast.com/t/I07xbIQCT6TV
"They are playing with us."
I have said a few times that I don't like the look of Fiasp because I am not sure of the effect of the additions. It will be interesting to see how the insurers take to it. Arguably there is not a huge gain over existing RAA so they may well be slow. Fiasp is launched in Canada, and should be launched this quarter in Europe so this is where we see if doctors view it as the next step in RAA, or just another insulin.
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Post by peppy on May 11, 2017 19:08:53 GMT -5
Just because this has become a conversation: About the product Fiasp is insulin aspart in a new formulation. Insulin aspart, with the global trade name NovoRapid, has been on the market worldwide for more than a decade for the treatment of diabetes mellitus. Compared to NovoRapid, Fiasp contains two additional excipients: nicotinamide (also known as niacinamide or vitamin B3) and L-arginine hydrochloride (an amino acid). The addition of nicotinamide is intended to result in a faster initial absorption of insulin aspart following subcutaneous (s.c.) injection. The addition of L-arginine hydrochloride should support stabilisation of the Fiasp formulation. The insulin aspart molecule in Fiasp and NovoRapid is identical and therefore, once systemically absorbed, it has the same biological action at the insulin receptor as that of NovoRapid. Fiasp is intended to be used for the treatment of patients with diabetes mellitus (T1DM and T2DM) both for basal-bolus therapy in combination with intermediate- or long-acting basal insulin (± oral antidiabetic drugs; OADs), and for CSII by external pump, where both basal and bolus requirements can be covered by Fiasp. Fiasp can be injected at the start of a meal or postmeal (within 20 minutes after starting a meal). Moreover, Fiasp can also be delivered intravenously by health care professionals when the clinical situation requires this route of administration. The indication sought is: “Treatment of diabetes mellitus in adults”. Here is the time of action comparison www.screencast.com/t/I07xbIQCT6TV
"They are playing with us."
I have said a few times that I don't like the look of Fiasp because I am not sure of the effect of the additions. It will be interesting to see how the insurers take to it. Arguably there is not a huge gain over existing RAA so they may well be slow. Fiasp is launched in Canada, and should be launched this quarter in Europe so this is where we see if doctors view it as the next step in RAA, or just another insulin. Novo Nordisk A/S will have to negotiate the price in Canada and Europe. It is difficult to see an advantage. I suppose if the cost is the same, they will not care. I think it is non inferior.
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Post by sayhey24 on May 11, 2017 19:11:33 GMT -5
What we do know is it will never profile like the pancreas and afrezza do so it will not provide the needed phase one release. So NO, Fiasp is not a better meal time insulin. And, I would take any comers on a bet that properly dosed on the initial dose and then providing any 90 minute follow-up dose afrezza will provide better time in range, hands down. The problem is the need to test for follow on dosing after meals with Afrezza. The danger is that when this hits the wider community that testing is going to be skipped as it is today with RAA. Consequently you are not going to see the A1c reductions expected. A longer tail lets diabetics ignore the need for a second test even if they shouldn't (I put my hand up, and I don't know anyone who does it either but there must be some). The follow-up dosing is really not the problem. The follow-up dosing is the advantage. I would not recommend stacking your Fiasp. What the problem is, is the users are only getting about 30% of the insulin out of the cartridge so the 4u which has 10u of insulin is acting more like 3u. The problem is the initial dose needs to be larger than most are taking. I suspect they are all take the small - 4u when they should be doing atleast the medium or the large. Interesting is One Drop wants to use the Bluehale to automatically feed into their software how much insulin the user took. A nice chrome Bluehale would be a nice addition to their leather pouch.
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Post by agedhippie on May 11, 2017 19:13:44 GMT -5
The problem is the need to test for follow on dosing after meals with Afrezza. The danger is that when this hits the wider community that testing is going to be skipped as it is today with RAA. Consequently you are not going to see the A1c reductions expected. A longer tail lets diabetics ignore the need for a second test even if they shouldn't (I put my hand up, and I don't know anyone who does it either but there must be some). I can see why. (Or why bother) I am going to guess this individual gives themselves insulin after eating, like you do.
www.slideshare.net/StephenPonder/sugar-surfing-with-a-cgm-copyright-tlc-advanced-diabetes-retreat-april-26-2014
It's an idealized graph (numbers are rather suspect) but the effect is showing is real - you continue to rise while the insulin kicks in. It's one reason they give IV insulin in hospitals because of the speed of onset. That's why I think Afrezza makes a good insulin for corrections because it blunts the rise faster. By the way that sort of spike can just happen randomly, it doesn't require food!
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Post by sophie on May 11, 2017 19:24:57 GMT -5
I understand everything you're saying. For some reason I'm having trouble getting you to understand what I'm saying. I understand that Afrezza is non-inferior due to A1c results. I'm not talking about A1c, I'm talking about speed, just like you. Fiasp has been genetically engineered to get absorbed more quickly through subcutaneous tissue, thus decreasing the time to become bioavailable in the blood. It is faster than current RAAs at doing this, which is why it works more quickly. Afrezza becomes bioavailable in the blood essentially within seconds, whereas Fiasp takes several minutes to cross through sub q tissue to reach a therapeutic level. I'm not arguing that point. I'm not arguing that Fiasp should be in the same class as Afrezza. More or less, I'm saying Fiasp won't get labeled as an RAA, which would leave it with only one option (ultra rapid) because I also don't think the FDA will create a class just for Afrezza, since that's essentially what they'd be doing if they deny Fiasp ultra rapid status. I would argue (as you are) that Fiasp is more similar to RAA than it is to Afrezza. However, I think it is different enough from RAA's that it should not be labeled with the RAAs. As I've been saying since my initial post, it matters what metric they use to determine speed. Does area under the curve matter (Afrezza's first phase vs Fiasp's vs RAAs)? Does onset of action matter? Does time to peak concentration matter? What metric are they going to use to determine "ultra rapid?" On top of that, what time frame will they allow for ultra rapid? If you look at the TABLE, you'll see that several onset of actions as well as time to peak concentrations exist within the same class. There is a spectrum. How will the FDA handle that? Where is their cutoff for ultra rapid vs rapid acting? Europe has already decided that it met their cutoff for ultra rapid, which is the basis for why I believe the FDA will as well. The FDA has a mind of its own and doesn't have to follow anyone else, but you also have to consider that with the political power a company like NOVO has, they're not going to invest the money it takes to create a drug just to have it placed into the same class as the one it's replacing, especially if they already got recognized as being different by another large regulatory body. NOVO is going to flex all their muscles to ensure Fiasp becomes Ultra rapid. It all depends on the parameters the FDA decides to use to structure the ultra-rapid class. We'll probably get our answer by the end of the year.
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