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Post by agedhippie on Jun 15, 2023 19:37:21 GMT -5
There is no way anyone in the medical is going to take a TIR for only part of the day seriously. This is the trap people fall into, Afrezza regulates my levels wonderfully, but if my levels are out of range at night that's 33% of the day so TIR has a hard cap at 67% assuming the daytime numbers are perfect (which they never are). Now if I am averaging 75% TIR with an AID pump which is the better option? ... Now I'm feeling guilty. So here is how you fix the problem; do basal testing to make sure people have their basal properly set. If you are consistently going high at night then your basal needs adjusting. RAA has a longer tail so these errors are not as visible and you get pulled back into range, Afrezza has cleared so there is nothing to help. Fix that and you can get beyond the hard cap of 67%, don't fix it and you will stay capped.
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Post by agedhippie on Jun 15, 2023 19:28:19 GMT -5
True, we wanted TIR. What we didn’t count on was it being set appropriate for old less effective therapies. We should have seen that coming. Fighting it would have been futile of course. But, what we can do now is kick it’s ass, and your example of a way to do that is valid. Do you suppose the upcoming(?) pump switch trial might have improved TIR as a goal? There is no way anyone in the medical is going to take a TIR for only part of the day seriously. This is the trap people fall into, Afrezza regulates my levels wonderfully, but if my levels are out of range at night that's 33% of the day so TIR has a hard cap at 67% assuming the daytime numbers are perfect (which they never are). Now if I am averaging 75% TIR with an AID pump which is the better option? That is the problem, nights matter. If you can't get past 67% that's nearly an extra two hours I am going to be out of range. Now I think you can do better than that but it will require changes to get there and exactly what those would be I don't know - higher doses would be a guess? The pump switch trial has TIR as a secondary goal (actually in a lot of different flavors!) Details here: clinicaltrials.gov/ct2/show/NCT05243628
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Post by agedhippie on Jun 15, 2023 17:43:30 GMT -5
... I have a real problem with the way TIR is being evolved and is being used. The 70-180 24hr TIR which is becoming the "norm" is not giving us a true picture at addressing the hard problem. The hard problem is when people eat their blood sugar goes crazy. IMO, at a minimum TIR needs broken into two separate TIRs; awake; and sleeping. For the T2 do we really care about when they are sleeping? I would say for the most part no. If when they go to bed they are at 95 mg/dl their pancreas should carry them through the night with no issues. The key is post prandial control and returning the T2 to a non-diabetic range under 140 asap. For the T1 its a different story as their basal needs to carry them through the night and requires adjustment. For Aged's AID pump - it does a super job when the T1 is sleeping but can not match up to afrezza for post prandial control. However, when you mush the two TIR periods together and you provide the 180 upper limit, it tells a different story but its the story the AID pump vendors want to tell. Time in Range is defined as time between 70-180 over 24hr. You can argue that's not fair, but that's the agreed measure. The idea that T2 diabetics don't care about high levels when they are asleep is simply wrong. That's a third of the day with elevated levels which is not a good idea. They still have insulin resistance, they are still not producing enough insulin, their body is still churning out glucose. This approach will not even get to the starting gate. People here wanted TIR as the measure and now you have it. The catch is that diabetes treatment comprises both basal and prandial with TIR being the value for that entire treatment. Just prove that Afrezza plus basal gives better TIR than an AID pump and you are in business. If it looks like MNKD are making excuses it just destroys credibility with the endos.
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Post by agedhippie on Jun 15, 2023 17:06:53 GMT -5
Michael Castagna agrees with everyone here that a big partner is needed. He's mentioned this several times in the past. For whatever reason, possibly the Sanofi debacle, a good partnership has never been reached. I like to imagine that a BP deal could be progressing behind the scenes and is only pending pediatric approval. That could be the ideal time for a serious BP to step in. The problem is simply that BP no longer believes in inhaled insulin. They have seen two of their own fail (Pfizer and Sanofi), and eight years after launch Afrezza sales are a rounding error in the market. It's hard to emphasis how negligible the Afrezza market share. Take just Humalog (ignore Novolog and all the newer insulins) who had TRx 726.4k in May, Afrezza TRx was 3.8k. Afrezza undersold even Humulin R which nobody should be using at this point by 8:1. I think pediatrics has the potential to double Afrezza sales, but not much beyond that because endos are pushing AID pumps. That's my opinion, but it based on talking to several endos in the big NYC teaching hospitals (donate to hospital groups; (a) it helps the diabetes centers which are never profit generating, (b) it gets you access to people) I think it's likely correct. Mannkind owns Afrezza whether they want to or not so it's high time they did something about improving sales and that means large trials to get the data proving superior outcomes in various scenarios. Then you may see a partner emerge, but maybe you wouldn't want one at that point...
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Post by agedhippie on Jun 14, 2023 22:44:41 GMT -5
Aged what would you like to see statistically right across the board for Afrezza to be commercially effective The way you see it must be done .. to make Afrezza a success ! It's a good question and obviously this is just my opinion. I reckon a TIR of an absolute minimum of 70%, ideally about 75%, over a three month period. Minimal second doses 4 or 5 doses a day is viable, 7 doses isn't, basically not twice every meal. An A1c on the lower side RAA, it doesn't need to be superior just better. The lower hypos is good. Sort out the RAA to Afrezza unit mapping - the double it and round down looks good. They are going to need a higher capacity cartridge because the 12u is not big enough, you need a single hit rather then two or three cartridges for a dose. You need solid trial data to support the claims which means properly sized arms of around 100 people each for a minimum of three months. The data is critical because that drives papers in Diabetes Care which is the chief source of information for endos, probably Lancet or NEJM for the general medical population. Those papers change minds.
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Post by agedhippie on Jun 14, 2023 17:13:34 GMT -5
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Post by agedhippie on Jun 14, 2023 17:09:07 GMT -5
It's peanuts in the grand scheme of things, but I guess it's a start if they are serious and will go after larger entities... I am pretty certain that Sabby were a big MNKD shareholder at one point.
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Post by agedhippie on Jun 14, 2023 17:06:59 GMT -5
In my opinion? You are changing the delivery paradigm, the behavior of the treatment, and the dosing all in one go. That's a huge ask for a life supporting drug without a ton of compelling data and papers. I feel that Al Mann, being at heart an engineer rather than an endo, underestimated that. With Tyvaso DPI you are going from an inhaled (nebulized) to an inhaled (DPI) drug and that is a far more comfortable change. I think choosing insulin was a bridge to far (to echo an earlier poster), but if you could prove TS with insulin by getting a big win then you would have a queue at the door. Thank you agedhippie. Can you elaborate the phrase in bold please? (Not stting a trap, but didn't understand.) Fundamentally it's echoing what was said earlier by others. This is my supposition based on why I would have taken this decision; various pharmas were developing inhaled insulins and letting them drive the changes needed made sense (never be the one to educate the market), coupled with insulin being a critical drug (the patient dies if it doesn't work) made this a high profile choice. If Technosphere could deliver this the expectation is that it could deliver any small molecule. So what went wrong. In a word, Exubera. Commercially it was an utter failure because there was no compelling case. Non-diabetics fixate on needles and build a whole mythology around injecting, this is at complete odds with reality - largely Tupe 1s don't care, it doesn't hurt, and we use insulin when we want and if someone objects that's their problem. (This is my experience with other Type 1s.) The selling point of inhaled insulin, no needles, is fundamentally flawed and we need to move beyond that to outcomes. What is the problem now? The market place has completely changed from when Afrezza was launched. The competition in the Type 1 world is no longer MDI and the occasional CGM (I used to pay for my own they were so hard to get on insurance), it's AID pumps that watch your levels and autocorrect every 5 minutes giving TIR in the mid 70 and upwards range with minimal work. In the Type 2 world the problem is GLP-1, has become GLP-1/GIP combinations, and will probably evolve to GLP-1/GIP/Glucagon combinations. In other words insulin is no longer an automatic next step with these drugs addressing more than just glucose levels, but also lipid and cardiac issues as well (weight loss is not great with the doses diabetics use). Well that's bleak. So I think Afrezza should be abandoned? No. People like VDEX have proven it can work if used correctly, Dr Edelman and Dr Hirsch have shown how it can be used as a supplement to AID pumps, and the absorption is still not to be underestimated. There is a definite market for Afrezza and I would be loathed to see it scrapped (contrary to what people think) as I think it has roles, but it's never going to replace RAA because the drugs and technology of today have moved on from where they were fifteen years ago. There you go, a far longer answer than I intended so congratulations if you made it to the end
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Post by agedhippie on Jun 14, 2023 14:23:24 GMT -5
Just curious, why would diabetes be the "highest mountain"? - - due to BP cartel organized opposition? Otherwise, based on need and market size, it seems Al was right on target. Thoughts please (happy face). In my opinion? You are changing the delivery paradigm, the behavior of the treatment, and the dosing all in one go. That's a huge ask for a life supporting drug without a ton of compelling data and papers. I feel that Al Mann, being at heart an engineer rather than an endo, underestimated that. With Tyvaso DPI you are going from an inhaled (nebulized) to an inhaled (DPI) drug and that is a far more comfortable change. I think choosing insulin was a bridge to far (to echo an earlier poster), but if you could prove TS with insulin by getting a big win then you would have a queue at the door.
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Post by agedhippie on Jun 14, 2023 10:58:48 GMT -5
That's my sense too. I've assumed the reason for a general lack of interest was not because of a lack of willingness to consider it as much as being "complicated". Bridge too far as it were. VDEX is a great arm's length partner and I hope Bill is richly rewarded for putting his money where his mouth is. That's the proof of conviction and I respect it. ^This. It's a problem with any jump in treatment/technology/change - you have to educate the market and that is a heavy lift because you are changing perceptions. Bill saw the potential, set up VDEX, and was prepared to devise a protocol that didn't strictly tie to the label. The problem is that the rest don't move as fast. My old endo prescribed metformin off-label for Type 1 patients for years despite the FDA and ADA being fairly solidly against that idea - now it's mainstream. Educating the market in this case is about trial data. Papers are written about the results and gradually the idea becomes talked about and after a couple of years the SoC starts to change.
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Post by agedhippie on Jun 13, 2023 22:48:27 GMT -5
Mango - did you have chance to read through the paper I provided the link for earlier? www.ncbi.nlm.nih.gov/pmc/articles/PMC5602594/There is a line in the paper which says - "The secretion of GLP-1 in the ileum is induced after meals. β cells contain the most GLP-1 receptors; however, adipose cells and cells in the central nervous system (CNS) also express GLP-1 receptors. In the brain, GLP-1 decreases appetite and increases satiety, resulting in lower water and food intake." Above - Lenny states from the point Aged has been making - "Native GLP-1 has a very short half-life (about 2 minutes) because of rapid degradation by the endogenous enzymes dipeptidyl-peptidase-IV (DPP-4)67) and neutral endopeptidase (NEP)68)" The question is, once the native glp-1 hits the brain how long does the satiety last? Is it dose dependent? Does it have to hang around like the analogs do for the brain to think you are full and don't need to eat? If we give 100 pmol/L of native glp-1 will the brain think the body is full for 5 minutes, 5 hours, or something else? ... The brain will think it is full for about 3 minutes and then the GLP-1 is gone, the receptor is clear, and the brain is looking around for a snack. The way the body handles this is by producing waves of GLP-1 which keep the receptors occupied as long as the digestion triggers are being hit. That's why, as the paper explains, you need these analogs (the paper is actually a discussion about the methods for constructing analogs).
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Post by agedhippie on Jun 12, 2023 22:52:39 GMT -5
Has anyone ever tried to do GLP-1 analog intravenously? That's the comparison that will be helpful. How much GLP-1 analog does it take to be effective? If it's 1/100th the amount needed for subcutaneous or 1/10,000th of what would be needed for an oral med, maybe it's worth looking at. Is this likely, or not?
Could more frequent small doses of non-analog be a better choice?
"Once daily DoNoVomit works better then other semiglutides..." yada yada
I don't know of anyone who has tried IV delivered analogs. It would sort of defeat the purpose of the analog which is to slow down delivery. The quantity to achieve a certain serum level is not really important as these drugs are essentially free once you have covered the capital overhead (and discovery). My guess is that frequent small doses of the non-analog would be the best job. By frequent I mean every three minutes or so. If you are going to do that though you would use a pump because that's the sort of task a pump is perfect for, it's how they simulate basal insulin today.
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Post by agedhippie on Jun 12, 2023 15:00:42 GMT -5
Analogs work by not going away and leaving you not feeling hungry as a result. If you let the analog wear off you will feel hungry, if you let the TS GLP-1 clear you will feel hungry. Your body is naturally using GLP-1 and when they clear you feel hungry. This is not difficult. If the idea is that after taking GLP-1 (not an analog) via TS will somehow be the once case that is different then, yes, I am going to want to see evidence especially since the only trial to date did not look at that.
Ok so lets load a GLP-1 analog onto TS because we need that persistence (definitely doable IMHO) and now we are back at the old problem - GLP-1 analog being present longer than it should be. Cue nausea and vomiting. This looks pretty clear which is why you are not going to get anyone to come up with the cash for this until MNKD produces hard evidence because the science suggests it will not work.
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Post by agedhippie on Jun 12, 2023 8:46:03 GMT -5
...
This trial is of marginal use since it uses GLP-1 and not a GLP-1 analog. The half life of GLP-1 is about 1.5 minutes whereas Ozempic or Mounjaro is a week so the window to get nausea with GLP-1 itself is minimal. I thought you were going away for a year? Something is buggy you about the potential of putting some form of a glp-1 on TS. What is it? ... That's wishful thinking. We will see in a year if anyone wanted to pick this up - my bet would be no. What's bugging me? The idea that a TS GLP-1 analog will prevent nausea despite there being no evidence to support the claim. That is why nobody will bite on the idea. GLP-1 is not the same as a GLP-1 analog any more than Afrezza or human insulin are the same as RAA.
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Post by agedhippie on Jun 11, 2023 8:55:34 GMT -5
I suppose we should check: What is the purpose of a Phase 1 trial in the FDA process? What were the primary and secondary measures for the MKC253 trial? I shouldn't be idle and expect others to do my work Phase 1: Researchers test an experimental drug or treatment in a small group of people for the first time. The researchers evaluate the treatment’s safety, determine a safe dosage range, and identify side effects. So will it kill you if you take a dose, not what does it do and will it work (that's phase 2 - T he experimental drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.) Trial record: NCT00475371Description: This Phase 1a , single-dose trial incorporates an open-label, ascending dose strategy to determine the safety & tolerability of MKC253 (GLP1/Technosphere®)Inhalation Powder.
The trial consists of a screening, dosing and a follow-up visit. Single dose administration of MKC253 occurs at the dosing visit. Five doses are being assessed: 0.05, 0.45, 0.75, 1.05 & 1.5 mg GLP-1. Dosing of each ascending cohort will occur after the Principal Investigator has reviewed all safety/tolerability data
Primary Outcome Measures : Determine the safety and tolerability of ascending doses of MKC253 Inhalation Powder [ Time Frame: 2 weeks ]
Secondary Outcome Measures : Incidence of pulmonary and other AEs [ Time Frame: 2 weeks ]Pharmacokinetic (PK) parameters of plasma GLP-1 [ Time Frame: 2 weeks ]
This trial is of marginal use since it uses GLP-1 and not a GLP-1 analog. The half life of GLP-1 is about 1.5 minutes whereas Ozempic or Mounjaro is a week so the window to get nausea with GLP-1 itself is minimal.
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