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Post by sayhey24 on Oct 21, 2022 12:27:53 GMT -5
In many industries, facts learned in the lab take about five more years to reached a point where those facts are integrated into codes, legislation, etc. Then it takes another five years for the information in the codes, legislation, etc. to become commonly known by officials, inspectors and the mainstream. The only means to expedite this process requires money or policy which have always been giant road blocks for Mannkind. I remain hopeful a financially strong and reputable partner will step in once Afrezza is approved for pediatrics and doctors will learn what they were all taught in school about insulin being the last resort because of the potential of hypos and death is now outdated with TS. Lets remember why Sanofi signed the deal with MNKD, their focus was the T2 market. Of course with Brandicourt showing up nothing happened. Thats the $40B opportunity. The kids trial will be great for the kids and great for afrezza but it is not addressing the T2 market. It will also not bring much awareness to the GPs who are prescribing metformin, the GLP1s, etc. For the endos today and the T1 market insulin is not a last resort. It is what all T1s get day one. For the T2s its a last resort. Remember, after diet pre-1960, insulin was the go to med for T2 diabetics. Then BP started seeing a huge $$$ opportunity to sell non-insulin into this market and now we have the ADA's "Treat to Fail" standard of care with insulin as the last step. That T2 SoC is what the GPs are being taught in school. Remember what Aged and Stevil keep saying - T2 is not an insulin problem. T2s are releasing insulin - insulin is not the issue - which is the marketing line BP is selling and they have GPs believing. My hope is Mike figures out what his plan is going to be to address the $40B opportunity. The kids study and the pump study are good but will have limited impact with T2s and GPs. |
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Post by prcgorman2 on Oct 21, 2022 17:11:09 GMT -5
My impression is T1s are looked at like SMEs when it comes to using insulin, so I would argue they are influential and will help, but I understand your laser focus on the T2 market and agree that has to be the end goal that no MNKD investor should forget.
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Post by agedhippie on Oct 21, 2022 19:49:55 GMT -5
Lets remember why Sanofi signed the deal with MNKD, their focus was the T2 market. Of course with Brandicourt showing up nothing happened. Thats the $40B opportunity. ...Remember, after diet pre-1960, insulin was the go to med for T2 diabetics. Then BP started seeing a huge $$$ opportunity to sell non-insulin into this market and now we have the ADA's "Treat to Fail" standard of care with insulin as the last step. That T2 SoC is what the GPs are being taught in school. Remember what Aged and Stevil keep saying - T2 is not an insulin problem. T2s are releasing insulin - insulin is not the issue - which is the marketing line BP is selling and they have GPs believing. Pre-1960 there were no option other than insulin (French lilac aside!) so it's not surprising it was used for T2. Look back further, pre-1920 the treatment for Type 1 was diet and that didn't go so well either. Thankfully new drugs keep appearing and provide options. There is nothing wrong with the "treat to fail" method, medically it is pretty much universal. If I have a cut, I want an antiseptic not an amputation, if that doesn't work lets try a mild antibiotic and so on. Type 2 in it's end state absolutely is an insulin problem, but even then not insulin alone. Type 2 diabetics, for the most part, still make insulin and this is why getting a pump as a Type 2 is hard because your c-peptide (insulin production) will be in the normal range which disqualifies you. The problem is that you cannot effectively use that insulin. At that point your options are either trying to reduce the impact, or simply keep adding more and more insulin. At the start of this thread Stevil explained why excessive amounts of serum insulin is a bad idea. I can see Afrezza having an impact in the Type 1 market (obviously my interest) over the long term because insulin is not optional. I cannot see any change to insulin in the Type 2 SoC though. There simply isn't the data to show that people will get better outcomes than the newer options. Data is how sulfonylureas got largely replaced, they were out-performed by later drugs. GLP-1 got established by producing long term outcomes data. Outcomes matter, features don't. |
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Post by letitride on Oct 22, 2022 4:24:00 GMT -5
There is everything wrong with the treat to fail method. Why treat at all? The problem is proving afrezza is safe for type2 without severe hypo. Can a non diabetic inhale 4 units of afrezza safely during a meal without a hypo?
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Post by akemp3000 on Oct 22, 2022 5:30:38 GMT -5
In many industries, facts learned in the lab take about five more years to reached a point where those facts are integrated into codes, legislation, etc. Then it takes another five years for the information in the codes, legislation, etc. to become commonly known by officials, inspectors and the mainstream. The only means to expedite this process requires money or policy which have always been giant road blocks for Mannkind. I remain hopeful a financially strong and reputable partner will step in once Afrezza is approved for pediatrics and doctors will learn what they were all taught in school about insulin being the last resort because of the potential of hypos and death is now outdated with TS. Lets remember why Sanofi signed the deal with MNKD, their focus was the T2 market. Of course with Brandicourt showing up nothing happened. Thats the $40B opportunity. The kids trial will be great for the kids and great for afrezza but it is not addressing the T2 market. It will also not bring much awareness to the GPs who are prescribing metformin, the GLP1s, etc. For the endos today and the T1 market insulin is not a last resort. It is what all T1s get day one. For the T2s its a last resort. Remember, after diet pre-1960, insulin was the go to med for T2 diabetics. Then BP started seeing a huge $$$ opportunity to sell non-insulin into this market and now we have the ADA's "Treat to Fail" standard of care with insulin as the last step. That T2 SoC is what the GPs are being taught in school. Remember what Aged and Stevil keep saying - T2 is not an insulin problem. T2s are releasing insulin - insulin is not the issue - which is the marketing line BP is selling and they have GPs believing. My hope is Mike figures out what his plan is going to be to address the $40B opportunity. The kids study and the pump study are good but will have limited impact with T2s and GPs. IMO, pediatric acceptance, even if only for T1, is the stepping stone path to acceptance for the T2 market. Afrezza is not yet mainstream today because all doctors are wrongly taught prescribing insulin must be the last resort that can lead to hypos and death. Removing the safety concern by doctors is key. Pediatric approval should inspire a BP giant to step in and realize now's the time to go after both markets. On another topic, If the options are pumps, shots or inhalation, Afrezza inhalation will be preferred by an overwhelming majority...again IMHO. |
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Post by sportsrancho on Oct 22, 2022 11:33:01 GMT -5
There is everything wrong with the treat to fail method. Why treat at all? The problem is proving afrezza is safe for type2 without severe hypo. Can a non diabetic inhale 4 units of afrezza safely during a meal without a hypo? “A nondiabetic can inhale 4 units WITHOUT EVEN EATING and not have a problem. I know. I’ve done it many times.” ~Bill McCullough CEO/VDex Diabetes |
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Post by letitride on Oct 22, 2022 13:52:27 GMT -5
Can a non diabetic take 4 units of a sub cutaneous insulin without a hypo?
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Post by sayhey24 on Oct 23, 2022 8:22:30 GMT -5
Lets remember why Sanofi signed the deal with MNKD, their focus was the T2 market. Of course with Brandicourt showing up nothing happened. Thats the $40B opportunity. ...Remember, after diet pre-1960, insulin was the go to med for T2 diabetics. Then BP started seeing a huge $$$ opportunity to sell non-insulin into this market and now we have the ADA's "Treat to Fail" standard of care with insulin as the last step. That T2 SoC is what the GPs are being taught in school. Remember what Aged and Stevil keep saying - T2 is not an insulin problem. T2s are releasing insulin - insulin is not the issue - which is the marketing line BP is selling and they have GPs believing. Pre-1960 there were no option other than insulin (French lilac aside!) so it's not surprising it was used for T2. Look back further, pre-1920 the treatment for Type 1 was diet and that didn't go so well either. Thankfully new drugs keep appearing and provide options. There is nothing wrong with the "treat to fail" method, medically it is pretty much universal. If I have a cut, I want an antiseptic not an amputation, if that doesn't work lets try a mild antibiotic and so on. Type 2 in it's end state absolutely is an insulin problem, but even then not insulin alone. Type 2 diabetics, for the most part, still make insulin and this is why getting a pump as a Type 2 is hard because your c-peptide (insulin production) will be in the normal range which disqualifies you. The problem is that you cannot effectively use that insulin. At that point your options are either trying to reduce the impact, or simply keep adding more and more insulin. At the start of this thread Stevil explained why excessive amounts of serum insulin is a bad idea. I can see Afrezza having an impact in the Type 1 market (obviously my interest) over the long term because insulin is not optional. I cannot see any change to insulin in the Type 2 SoC though. There simply isn't the data to show that people will get better outcomes than the newer options. Data is how sulfonylureas got largely replaced, they were out-performed by later drugs. GLP-1 got established by producing long term outcomes data. Outcomes matter, features don't. Aged - its not that as you say "The problem is that you cannot effectively use that insulin". The problem is there is not enough "good insulin" being produced and when the pancreas starts releasing its "stuff" it seems to block the receptors. If we give the afrezza before the pancreas starts releasing its "stuff" as the blood glucose level rises the body seems to use the afrezza insulin much better. Why is that? Maybe there is something in the c-peptide? Something is not right with what the pancreas is releasing. If you wait until until 2nd phase release you need 2x, 3x the afrezza. Why is that? I don't know whats blocking the receptors but I sure know if you take the afrezza before the pancreas releases its "stuff" the body is using the afrezza much better. You would think if the pancreas has already released its insulin you would have more insulin on board and need less afrezza. I am just saying whatever the pancreas is releasing is not working right and its making a mess. IMO we really want the pancreas releasing as little of its "stuff" as possible. I do agree with you I don't see any changes to the "treat to fail" standard but not because insulin does not have better outcomes. Aren't there a ton of studies showing better outcomes with early insulin intervention? Its not going to change because neither the ADA nor BP want to disrupt the $40B industry. Does anyone think orinase or diabenese were a good thing. They were the miracle drugs of the 60s. They started this huge $$$ BP market. Does anyone think metformin does anything useful? Defronzo no longer does but some how he started getting big GLP1 contracts. |
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Post by agedhippie on Oct 23, 2022 9:44:20 GMT -5
Aged - its not that as you say "The problem is that you cannot effectively use that insulin". The problem is there is not enough "good insulin" being produced and when the pancreas starts releasing its "stuff" it seems to block the receptors. If we give the afrezza before the pancreas starts releasing its "stuff" as the blood glucose level rises the body seems to use the afrezza insulin much better. Why is that? Maybe there is something in the c-peptide? Something is not right with what the pancreas is releasing. ]If you wait until until 2nd phase release you need 2x, 3x the afrezza. Why is that? I don't know whats blocking the receptors but I sure know if you take the afrezza before the pancreas releases its "stuff" the body is using the afrezza much better. You would think if the pancreas has already released its insulin you would have more insulin on board and need less afrezza. I am just saying whatever the pancreas is releasing is not working right and its making a mess. IMO we really want the pancreas releasing as little of its "stuff" as possible. I do agree with you I don't see any changes to the "treat to fail" standard but not because insulin does not have better outcomes. Aren't there a ton of studies showing better outcomes with early insulin intervention? Its not going to change because neither the ADA nor BP want to disrupt the $40B industry. Does anyone think orinase or diabenese were a good thing. They were the miracle drugs of the 60s. They started this huge $$$ BP market. Does anyone think metformin does anything useful? Defronzo no longer does but some how he started getting big GLP1 contracts. Taking these in order; There is no difference between the insulin released by your pancreas and the insulin provided by Afrezza, they are literally identical. The receptors are down regulated by the volume of insulin, it's like wearing ear defenders against loud noise - it protects against the noise, but now it takes more volume for you to hear things. Afrezza, and RAA, work in that case by simply providing extra insulin (volume) to overcome the down regulation. This is where metformin and some of the other drugs work, they partially fix the down regulation which increases the insulin sensitivity. I cannot remember the exact mechanics as to why it happens, but if your levels are elevated it reduces your insulin sensitivity and hence takes more insulin to reduce back to normal. Thinking about it this *may* be why Afrezza is so effective and why pre-bolusing RAA works - it stops that rise early which results in better insulin sensitivity. To be clear - that's a guess  Drugs come and go. Drugs that were once the gold standard get surpassed by newer better drugs and sulfonylureas have definitely been surpassed! Remember, metformin only became available in the US in 1995 (20 years after it became the frontline in the rest of the world - thank you the FDA). There are some studies on early use of insulin (which I am strongly in favor of BTW), but they are almost exclusively focused on either basal insulin, or short term intensive treatment. It's not a heavily researched area because of patient resistance to insulin (a treatment is no use if nobody takes it, and Type 2 compliance is notoriously poor). A lot of medicine seems to be the art of the possible rather than the ideal in that respect. As to DeFronzo; I see no evidence that he is not genuine. My view is that his research led him to his current position, that's the nature of academia - your research leads you down rabbit holes and your positions change. |
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Post by sayhey24 on Oct 24, 2022 10:43:05 GMT -5
Aged - I hear what you are saying but what we see is different in clinical results. For some reason what is being released by the pancreas is not working properly with the T2s. I will agree the c peptide levels seem normal but most of the insulin is not working. There is something wrong with it. In fact, the less we have the pancreas release whatever it is releasing the better. When we off load the pancreas with afrezza we can stop the spike and the progression can be stopped and maybe reversed. If you give the afrezza early the body properly uses it. We can demonstrate this over and over. If you give it after the pancreas releases its "stuff" the "insulin sensitivity" is significantly less. It can take 2x, 3x more afrezza. I am a simple guy. It sure seems to me something is wrong with the insulin or whatever is being released by the pancreas. We also know the mass of the pancreas is less and in a non-diabetic they would have grown significant mass if they needed more insulin. Something has destroyed the beta cells. Here is a study which is focused on the beta cells. It demonstrates beta cell destruction by SARS2. However, what I am proposing goes beyond this and just beta cell destruction. My theory is this same virus gets released when the pancreas releases its "stuff" for phase 1/2. I am not aware of any study results to back this up but my theory is this virus is damaging the receptors or blocking the receptors causing the decreased "insulin sensitivity". What I can tell you is the theory of the receptors being down regulated by the volume of insulin does not hold up as they work just fine if you get them the afrezza before they get the pancreatic insulin or what am calling the "stuff". What else my theory supports is Bill's tag line from VDex "afrezza first, afrezza always". It seems the more we can reduce whatever is being released by the pancreas the better. By giving them the afrezza first the pancreas needs to release less of whatever it is releasing since we can stop the spike and get the BG back to baseline and the pancreas goes back into a fasting phase. I can tell you GLP1s seem to be masking the underlying issue so I just am not buying what DeFronzo has been pitching. www.ncbi.nlm.nih.gov/pmc/articles/PMC8312902/ |
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Post by agedhippie on Oct 24, 2022 18:38:24 GMT -5
Aged - I hear what you are saying but what we see is different in clinical results. For some reason what is being released by the pancreas is not working properly with the T2s. I will agree the c peptide levels seem normal but most of the insulin is not working. There is something wrong with it. In fact, the less we have the pancreas release whatever it is releasing the better. When we off load the pancreas with afrezza we can stop the spike and the progression can be stopped and maybe reversed. If you give the afrezza early the body properly uses it. We can demonstrate this over and over. If you give it after the pancreas releases its "stuff" the "insulin sensitivity" is significantly less. It can take 2x, 3x more afrezza. I am a simple guy. It sure seems to me something is wrong with the insulin or whatever is being released by the pancreas. We also know the mass of the pancreas is less and in a non-diabetic they would have grown significant mass if they needed more insulin. Something has destroyed the beta cells ... You are making a common mistake - there are lots of different Type 2 variants with lots of different pathologies. Giving people insulin will always work because it is topping up a deficiency. That fixes the problem by masking the symptom in the same way that topping up the air in a tire with a slow puncture works - it's a viable solution provided you don't mind the regular top-ups but it's not fixing the problem. The problem with Type 2 is that it is defined by what it isn't. Anything with auto-immune cell destruction is Type 1 or 1.5 (LADA), everything else is Type 2 (well, excluding MODY). There are a *lot* of variants and their causes vary wily. There is Flatbush Syndrome that will suddenly stun all your beta cells every few years, "thin" diabetics who are normal weight and insulin sensitivity (or not), the stereotype overweight insulin resistant diabetic, Asian pattern diabetes that is liver focused, the Pima Indians, lots of different kinds and causes. Some lucky individuals even manage double diabetes - Type 1 and Type 2! The upshot is that there isn't a single cause of Type 2, last I saw they reckoned there were about 120 genes involved and nobody had more than 20% of them. For this reason you are not going to get an endo to accept that Afrezza is a magic bullet without a lot of evidence. Since those endos write the SoC, and Type 2 is principally treated by PCPs who will follow that SoC you can see the problem... There is nothing wrong with a Type 2's insulin, it's unchanged. The problem is at the uptake end. Maybe look at Actos, it's what they used to give thin T2s before GLP-1 and acts on the muscles and liver to improve their sensitivity to insulin. |
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Post by akemp3000 on Oct 25, 2022 5:49:50 GMT -5
The perspective that it's a mistake to believe Afrezza will help or fix the problem implies that something else exists that will. What would that be? Or is it the belief that all options are treat-to-failure? Just wondering.
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Post by prcgorman2 on Oct 25, 2022 7:30:51 GMT -5
I am eager to see agedhippie’s perspective, but the thread I’ve seen is, essentially, “There is no magic. Invest in at-scale studies proving SAFETY and superiority. Afterwards, assume there will be more success in lobbying for a change in the SoC.”
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Post by agedhippie on Oct 25, 2022 8:28:04 GMT -5
The perspective that it's a mistake to believe Afrezza will help or fix the problem implies that something else exists that will. What would that be? Or is it the belief that all options are treat-to-failure? Just wondering. To be clear here; the problem that is being fixed is Type 2 diabetes. Will Afrezza help? Absolutely - it's a fast insulin with rapid clearance and reliable absorption. Will it fix Type 2? Depends what fix means - taken to be fix systemic insulin resistance, there is no evidence to support this and it seems unlikely to me since the problem is on the utilization rather than availability side. All options except insulin are treat to fail. Insulin isn't TTF because you can always add more insulin so it cannot fail. However,, historically you will need to progressively increase your insulin dosage as diabetes progresses, and you get the issues Stevil talked about from excessive insulin. If it is claimed there is no long term progression with Afrezza then that needs to be evidenced with trials (treat to target) and not just claimed. |
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Post by sayhey24 on Oct 27, 2022 15:20:18 GMT -5
The perspective that it's a mistake to believe Afrezza will help or fix the problem implies that something else exists that will. What would that be? Or is it the belief that all options are treat-to-failure? Just wondering. I think we have to ask the question "what is the root cause" so we know what we are trying to fix. One of the good things coming out of this covid mess is a refocusing on T2 root cause since so many people became T2s after covid. Blaming it on weight and that causing insulin resistance became a really hard argument. It became even harder when the tech diet companies started hooking all their clients up to CGMs and saw that the weight gain was coming after they lost post prandial control. Here is some info from a German study about Covid and a 28% increase in T2s diabetologia-journal.org/2022/03/17/new-study-finds-higher-rates-of-newly-diagnosed-type-2-diabetes-after-infection-with-mild-covid-19/The below paper summarizes some of the viruses which seem to be involved in T2 including SARS-2, Influenza A, cytomegalovirus and herpes simplex. Its also getting harder to argue the root cause for T2 is not viral based now that we can see the virus in the beta cells. The thing is it seems to be more than one virus which would make sense as there is a wide range of T2s. You ask is there a fix - the answer seems to be maybe. The immune system can or at least contain its damage. A big factor is how much damage has been done to the beta cells. While insulin can't kill the virus it will offload the load on the pancreas and provide the immune system a fighting chance. Depending on the damage the beta cells may have they may be so damaged that the body will always need exogenous insulin which today is nearly always. Figure 2 in the paper is pretty simple but its rather interesting. It outlines what they believe is the feedback loop causing insulin resistance -IR. If they are correct based on this feedback loop the T2 is in a "recursive plunge" and is basically doomed. Now that we know the virus is in the beta cells it would then seem reasonable that the pancreas is shedding the virus at higher rates during phase 1/2 release. What we can demonstrate today is by providing the afrezza at meal time we can reduce the IR. Al Mann was seeing afrezza stopping the progression and in some cases reversing it. This would seem to make sense if by reducing phase 1/2 release by taking the afrezza, the shedding is reduced and the immune system can contain the virus in the beta cells and there are less cytokines which this paper outlines as the cause of IR. What we know is only insulin is going to reduce glucose levels and we also know the pancreas is going to keep trying to release insulin until we get the BG down. We also know we can get the BG down really fast with afrezza. So the fix is off loading phase 1/2 from the pancreas until the immune system can contain the virus and the beta cells can regenerate. The thing is only afrezza is fast enough to replicate phase 1/2 so the pancreas does not need to stay in phase 1/2. Nothing else can provide the immune system a fighting chance. The thing is afrezza needs to be taken as soon as post prandial control is being lost which means everyone needs to be walking around with a CGM to provide the best chance of the immune system limiting the damage. Maybe one day Apple will release their non-invasive CGM watch. In the mean time we need more and more research on the viral link to T2 and we need research demonstrating Al Mann's observations on afrezza stopping progression. We also need a plan from Mike on how afrezza is going to crack into the T2 market which IMO is some type of partnership with Mounjaro. ncbi.nlm.nih.gov/pmc/articles/PMC8050380/ |
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