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Post by sayhey24 on May 25, 2023 14:01:18 GMT -5
Mike has mentioned that we will be starting the investigative afrezza/GLP-1 study. IMO, that was very exciting news. If afrezza can further reduce A1c another 0.5 - 1% that would be a huge finding and would justify a large scale trial so we have the proper data to take to the ADA for SoC T2 changes. Mike has not mentioned anything about TS GLP-1. I was hoping by now he would have. I know a year ago Mike did not seem to know about the work Peter Richardson had done but Mango posted the patent submission back in December so it seems Mike must have found it. Here is a summary of the Phase 1 which Richardson did. IMO the most important line which needs immediate attention is "MKC253 inhalation releases endogenous insulin and reduces plasma glucose in fasting, healthy subjects without nausea and vomiting." It does not say it also reduces the diarrhea but it would be nice to find out. Back in the day they were not looking at GLP1s for the diet market. professional.diabetes.org/abstract/pulmonary-administration-glp-1-technosphere%C2%AE-powder-elicits-dose-dependent-insulin-responseThere is a Reddit group with more than 30,000 members where users share their most embarrassing GLP-1 stories. The below link points to an article discussing some of the issues these folks are seeing. One thing we do know is the diet market for GLP1s is huge and growing. From the article "In 2022, more than five million prescriptions for Ozempic, Mounjaro, Rybelsus (for another Novo drug that uses semaglutide), or Wegovy were written for weight management. This is compared with just over 230,000 in 2019 — an increase of more than 2,000 percent over three years." What if TS GLP1 could reduce nausea and vomiting and did not require a shot? I think TS GLP-1 could take significant market share and has blockbuster potential. www.dailymail.co.uk/health/article-12119851/People-Ozempic-say-theyre-defecating-bed-symptom-affects-30-takers.html |
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Post by prcgorman2 on May 30, 2023 8:49:58 GMT -5
Had a conversation over dinner over the weekend where GLP1 (Ozempic) came up. The horror stories sounded crazy. I assumed they must be fabrications because they sounded so outlandish. The shots, nausea, but worst of all (I thought) was the weight loss was concentrated in muscle mass, not fat cells with the result being that a larger percentage of body mass is fat then before taking the drug. No idea if that's true, but if so, that ought to be very concerning.
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Post by agedhippie on May 30, 2023 9:22:28 GMT -5
Had a conversation over dinner over the weekend where GLP1 (Ozempic) came up. The horror stories sounded crazy. I assumed they must be fabrications because they sounded so outlandish. The shots, nausea, but worst of all (I thought) was the weight loss was concentrated in muscle mass, not fat cells with the result being that a larger percentage of body mass is fat then before taking the drug. No idea if that's true, but if so, that ought to be very concerning. Sports will correct me if I am wrong here because I may well be as I am not sure where I got this idea from... If you try and lose weight by diet alone (which Ozempic effectively is) your body will destroy the material that takes the least energy to replace which is muscle. You need to exercise as well in which case your body sees you are using the muscle and instead breaks down fat since muscle would need to be immediately replaced wasting energy. With Ozempic you will lose fat, but you are also going to lose muscle unless you exercise - effectively "skinny fat". The symptoms usually subside after the first month. Stevil talked about this in an earlier post about what he sees in his patients. |
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Post by sayhey24 on May 30, 2023 11:54:44 GMT -5
I thought what Stevil said was I was exaggerating things and his patients really did not see these symptoms. Maybe I don't remember correctly.
Aged - how should I take your comment as a good thing or bad - the symptoms usually subside after the first month". My god, who wants to be that sick for a month especially if Peter Richardson was correct and TS GLP1 solves that issue.
It would also be interesting to see if with TS if they can better control the dosage so the weight loss is not as severe so they lose less muscle mass. Richardson had no focus on weight loss when they ran the phase 1.
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Post by agedhippie on May 30, 2023 17:00:47 GMT -5
I thought what Stevil said was I was exaggerating things and his patients really did not see these symptoms. Maybe I don't remember correctly. Aged - how should I take your comment as a good thing or bad - the symptoms usually subside after the first month". My god, who wants to be that sick for a month especially if Peter Richardson was correct and TS GLP1 solves that issue. It would also be interesting to see if with TS if they can better control the dosage so the weight loss is not as severe so they lose less muscle mass. Richardson had no focus on weight loss when they ran the phase 1. What Stevil actually said - Mostly, if you start at the correct dose and titrate slowly, most patients tolerate it without much issue. Maybe the first day they’ll be uncomfortable, but not really enough of a reason to stop treatment. Notice the word "mostly"? His other point - if it was that ghastly why is it easily in the top 10 drugs every week? The short answer is because for most people it's not a problem. The problem with inhaled GLP-1 is that nobody know how it will behave beyond that a single dose will not kill a healthy person. It's several years out even assuming it works and they can solve the delayed action which, I suspect, is why there hasn't been much done on it. The muscle loss would be the same since that's down to the inherent calorie restriction. |
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Post by sayhey24 on Jun 1, 2023 5:53:54 GMT -5
I thought what Stevil said was I was exaggerating things and his patients really did not see these symptoms. Maybe I don't remember correctly. Aged - how should I take your comment as a good thing or bad - the symptoms usually subside after the first month". My god, who wants to be that sick for a month especially if Peter Richardson was correct and TS GLP1 solves that issue. It would also be interesting to see if with TS if they can better control the dosage so the weight loss is not as severe so they lose less muscle mass. Richardson had no focus on weight loss when they ran the phase 1. What Stevil actually said - Mostly, if you start at the correct dose and titrate slowly, most patients tolerate it without much issue. Maybe the first day they’ll be uncomfortable, but not really enough of a reason to stop treatment. Notice the word "mostly"? His other point - if it was that ghastly why is it easily in the top 10 drugs every week? The short answer is because for most people it's not a problem. The problem with inhaled GLP-1 is that nobody know how it will behave beyond that a single dose will not kill a healthy person. It's several years out even assuming it works and they can solve the delayed action which, I suspect, is why there hasn't been much done on it. The muscle loss would be the same since that's down to the inherent calorie restriction. Aged- I think from the Phase 1 trial we know more than a single dose will not kill a healthy person - "The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events. Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose" We also know that they did not get the typical vomiting - "GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation. Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." I find it mind boggling. We have had a potential blockbuster drug sitting in the freezer for 15 years. Its not clear Mike even knew about it until I asked him about it last year. Maybe he did but it didn't seem so. Mango then points out in December that MNKD filed a patent for it. If Peter Richardson was correct and I remember him being very excited about this at the time, this would make Tyvaso DPI sales look like peanuts. "The pulsatile administration of MKC253 achieved with our proprietary Technosphere delivery technology appears to avoid the dose-limiting vomiting characteristically associated with GLP-1 and replaces a physiological response lost in patients with diabetes that cannot be replicated by other forms of GLP-1," said Dr. Peter Richardson, Corporate Vice President and Chief Scientific Officer. "As well, with pulsatile delivery, we may potentially avoid unusual adverse effects such as the acute pancreatitis that has been described with presently marketed GLP analogues." www.diabetesincontrol.com/positive-results-for-inhaled-glp-1-cpd/ |
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limo
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Post by limo on Jun 1, 2023 6:44:12 GMT -5
What Stevil actually said - Mostly, if you start at the correct dose and titrate slowly, most patients tolerate it without much issue. Maybe the first day they’ll be uncomfortable, but not really enough of a reason to stop treatment. Notice the word "mostly"? His other point - if it was that ghastly why is it easily in the top 10 drugs every week? The short answer is because for most people it's not a problem. The problem with inhaled GLP-1 is that nobody know how it will behave beyond that a single dose will not kill a healthy person. It's several years out even assuming it works and they can solve the delayed action which, I suspect, is why there hasn't been much done on it. The muscle loss would be the same since that's down to the inherent calorie restriction. Aged- I think from the Phase 1 trial we know more than a single dose will not kill a healthy person - "The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events. Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose" We also know that they did not get the typical vomiting - "GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation. Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." I find it mind boggling. We have had a potential blockbuster drug sitting in the freezer for 15 years. Its not clear Mike even knew about it until I asked him about it last year. Maybe he did but it didn't seem so. Mango then points out in December that MNKD filed a patent for it. If Peter Richardson was correct and I remember him being very excited about this at the time, this would make Tyvaso DPI sales look like peanuts. "The pulsatile administration of MKC253 achieved with our proprietary Technosphere delivery technology appears to avoid the dose-limiting vomiting characteristically associated with GLP-1 and replaces a physiological response lost in patients with diabetes that cannot be replicated by other forms of GLP-1," said Dr. Peter Richardson, Corporate Vice President and Chief Scientific Officer. "As well, with pulsatile delivery, we may potentially avoid unusual adverse effects such as the acute pancreatitis that has been described with presently marketed GLP analogues." www.diabetesincontrol.com/positive-results-for-inhaled-glp-1-cpd/What would be really interesting is if we knew how much API is needed. The biggest barrier for oral GLP-1 is the amount of the API required is huge! Not only do they struggle to produce the API in the quantities required its hard for them to get the pricing right too to make the economics work. Also of course more API means more side effects. |
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Post by agedhippie on Jun 1, 2023 7:47:33 GMT -5
Aged- I think from the Phase 1 trial we know more than a single dose will not kill a healthy person - "The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events. Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose" We also know that they did not get the typical vomiting - "GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation. Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." ... www.diabetesincontrol.com/positive-results-for-inhaled-glp-1-cpd/The nausea result is interesting but would need to be repeated on Type 2 diabetics who were not fasting over a period of time. The theory goes that the nausea and vomiting is caused by the slowing of the digestive process (you see the same effect with Symlin, and gastroparesis). The advice to avoid nausea is eat small meals, fasting fits that guide  The trial found that the GLP-1 cleared in about 20 minutes so the question would be if that is long enough to have a material effect on glucose levels which given the mechanisms GLP-1 uses may be difficult. The drug would need to be modified to avoid fast clearance which could take time, but once that is done it would definitely be worth a small study at least. A daily, or longer, dosing interval combined with no nausea would be huge (although I am skeptical about the lack of nausea in normal diet) |
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Post by sayhey24 on Jun 1, 2023 11:29:11 GMT -5
Aged- I think from the Phase 1 trial we know more than a single dose will not kill a healthy person - "The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events. Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose" We also know that they did not get the typical vomiting - "GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation. Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." I find it mind boggling. We have had a potential blockbuster drug sitting in the freezer for 15 years. Its not clear Mike even knew about it until I asked him about it last year. Maybe he did but it didn't seem so. Mango then points out in December that MNKD filed a patent for it. If Peter Richardson was correct and I remember him being very excited about this at the time, this would make Tyvaso DPI sales look like peanuts. "The pulsatile administration of MKC253 achieved with our proprietary Technosphere delivery technology appears to avoid the dose-limiting vomiting characteristically associated with GLP-1 and replaces a physiological response lost in patients with diabetes that cannot be replicated by other forms of GLP-1," said Dr. Peter Richardson, Corporate Vice President and Chief Scientific Officer. "As well, with pulsatile delivery, we may potentially avoid unusual adverse effects such as the acute pancreatitis that has been described with presently marketed GLP analogues." www.diabetesincontrol.com/positive-results-for-inhaled-glp-1-cpd/What would be really interesting is if we knew how much API is needed. The biggest barrier for oral GLP-1 is the amount of the API required is huge! Not only do they struggle to produce the API in the quantities required its hard for them to get the pricing right too to make the economics work. Also of course more API means more side effects. The article say "Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." It would seem 100 pmol/L was the upper end. How much does it cost to produce 100 pmol/L? |
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Post by sayhey24 on Jun 1, 2023 14:57:13 GMT -5
Aged- I think from the Phase 1 trial we know more than a single dose will not kill a healthy person - "The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events. Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose" We also know that they did not get the typical vomiting - "GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation. Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." ... www.diabetesincontrol.com/positive-results-for-inhaled-glp-1-cpd/The nausea result is interesting but would need to be repeated on Type 2 diabetics who were not fasting over a period of time. The theory goes that the nausea and vomiting is caused by the slowing of the digestive process (you see the same effect with Symlin, and gastroparesis). The advice to avoid nausea is eat small meals, fasting fits that guide The trial found that the GLP-1 cleared in about 20 minutes so the question would be if that is long enough to have a material effect on glucose levels which given the mechanisms GLP-1 uses may be difficult. The drug would need to be modified to avoid fast clearance which could take time, but once that is done it would definitely be worth a small study at least. A daily, or longer, dosing interval combined with no nausea would be huge (although I am skeptical about the lack of nausea in normal diet) Aged - I don't care about glucose levels with TS GLP1. I see this targeting the diet market. For glucose control nothing is better than afrezza. Hopefully Mike will soon start the afrezza/GLP1 investigative study I have been asking him for for the T2s. We should see afrezza as an add on to GLP1s bring about a 1% further decline in A1c. What I don't know is how many GLP1 users the India trial has. I really don't see any downsides to running a Phase 2/3 TS GLP1 trial except cost. But then again not running it is probably a much bigger opportunity lost cost. GLP1s are already approved and Technosphere is already approved. If TS GLP1 is half as good as what Peter thought this could be a really HUGE opportunity in the diet space. Peter mentioned in the past about seeing similar appetite loss to subq GLP1. This IMO can make MNKD the $100+ stock. |
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Post by agedhippie on Jun 1, 2023 17:36:59 GMT -5
...What I don't know is how many GLP1 users the India trial has. ... Per protocol; none as it's an exclusion criteria ("Use of glucagon-like peptide 1 receptor agonists, thiazolidinediones, or weight loss drugs in the past 3 months.") CIPLA is not trying to prove superiority. They are there to get sign-off and be able to sell Afrezza as that's all they need. |
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limo
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Post by limo on Jun 2, 2023 3:20:26 GMT -5
What Stevil actually said - Mostly, if you start at the correct dose and titrate slowly, most patients tolerate it without much issue. Maybe the first day they’ll be uncomfortable, but not really enough of a reason to stop treatment. Notice the word "mostly"? His other point - if it was that ghastly why is it easily in the top 10 drugs every week? The short answer is because for most people it's not a problem. The problem with inhaled GLP-1 is that nobody know how it will behave beyond that a single dose will not kill a healthy person. It's several years out even assuming it works and they can solve the delayed action which, I suspect, is why there hasn't been much done on it. The muscle loss would be the same since that's down to the inherent calorie restriction. Aged- I think from the Phase 1 trial we know more than a single dose will not kill a healthy person - "The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events. Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose" We also know that they did not get the typical vomiting - "GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation. Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed." I find it mind boggling. We have had a potential blockbuster drug sitting in the freezer for 15 years. Its not clear Mike even knew about it until I asked him about it last year. Maybe he did but it didn't seem so. Mango then points out in December that MNKD filed a patent for it. If Peter Richardson was correct and I remember him being very excited about this at the time, this would make Tyvaso DPI sales look like peanuts. "The pulsatile administration of MKC253 achieved with our proprietary Technosphere delivery technology appears to avoid the dose-limiting vomiting characteristically associated with GLP-1 and replaces a physiological response lost in patients with diabetes that cannot be replicated by other forms of GLP-1," said Dr. Peter Richardson, Corporate Vice President and Chief Scientific Officer. "As well, with pulsatile delivery, we may potentially avoid unusual adverse effects such as the acute pancreatitis that has been described with presently marketed GLP analogues." www.diabetesincontrol.com/positive-results-for-inhaled-glp-1-cpd/The molecular weight of semaglutide, a medication used to treat type 2 diabetes, is approximately 4113.64 grams per mole (g/mol). To convert 100 picomoles per liter (pmol/L) of semaglutide to milligrams (mg), you can use the following conversion: 1 pmol/L = (molecular weight of semaglutide in grams/mole) * 10^-9 mg/pmol Substituting the values: 100 pmol/L = (4113.64 g/mol) * 10^-9 mg/pmol * 100 pmol/L Performing the calculation: 100 pmol/L = 0.411364 mg/L Therefore, 100 pmol/L of semaglutide is approximately equal to 0.411364 mg/L. |
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limo
Researcher
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Post by limo on Jun 2, 2023 3:38:02 GMT -5
so for context on dosing and API the starter dose for WEgovy is 0.25mg, the oral form which recently showed up to 15% weight loss is a massive 50mg!! the mg tested by mannkind back in 2007 was 0.5mg!
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Post by figglebird on Jun 2, 2023 5:59:26 GMT -5
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Post by lennymnkd on Jun 2, 2023 7:31:47 GMT -5
Pfizer would be an interesting candidate for some sort of partnership,
They seem quite interested in this space . Would that be to good to be true 🤔
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