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Post by uvula on Jun 10, 2023 18:58:30 GMT -5
I think I found Aged Hippie's car. (Yes, I know this is off topic.)  |
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Post by agedhippie on Jun 10, 2023 19:55:53 GMT -5
I do have a quote from Peter somewhere about this but in the link provided and you posted above Pete mentioned about weight loss and the possibility of this being a weight loss drug. Why would he even bring that up when it was not what the phase 1 was about??? 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? |
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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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Post by lennymnkd on Jun 11, 2023 9:00:00 GMT -5
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).
I got it !
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Post by sayhey24 on Jun 12, 2023 7:18:03 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. 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? Thanks for listing out the goal of the Phase1a. Great news, we did not kill anyone. I don't see appetite suppression in the outcome list. What the heck was that guy Peter doing mentioning satiety effects as a possibility? No wonder he got fired. This guy wanted to do follow-on studies and thought he had a potential for an obesity drug. Everyone knew glp-1s back in 2007 were for T2 diabetes. And to think he had Al Mann excited too. How crazy was Al? Who knows maybe someone is half as crazy as Al and wants to load some Victoza on TS or a glp-1r. Of course for MNKD we should just keep loading V-Gos in the sales reps bags and should not even consider TS and glp-1s. How big is the V-Go market - $10M versus $90B for "oral" glp-1 diet market? The great news for MNKD is Mike is focused on the V-Go so you may not need to worry about MNKD having a blockbuster TS GLP1 drug. |
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Post by uvula on Jun 12, 2023 8:11:16 GMT -5
This thread is becoming unpleasant to read.
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Post by lennymnkd on Jun 12, 2023 8:21:23 GMT -5
This thread is becoming unpleasant to read. Maybe so ..but it’s a important thread |
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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 sayhey24 on Jun 12, 2023 13:53:03 GMT -5
Aged - you always want more evidence. "That is why nobody will bite on the idea" seem like strong words when Peter said "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"
With TS, Peter was not looking at an analog. With afrezza we don't need the analog to try and breakdown the hexamer faster. Maybe with TS GLP1 if its taken daily no analog is needed. Pfizer is looking at a twice daily pill. Maybe fast in and fast out just won't work with the glp-1. Then again maybe it will. I really don't know.
Here is what Peter said "Moreover, 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". I am assuming the other forms are analogs. Maybe you take a puff when you wake in the morning and you have no appetite all day with no nausea. If so, no analog is needed and TS GLP1 seems like it could capture some of the "oral" market. Maybe it would be a good fit for Weight Watchers.
Peter also said "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."
The question for the diet market is can Peter's non-analog "demonstrate the same weight reduction or satiety effects seen with long-acting analogues"? IDK, it seems to me we need some further testing to get a better understanding of what Peter was thinking. But, what you are telling me is "nobody will bite on the idea" because we need more evidence". I am not sure how we get more evidence without some further testing.
What I do know is Albert Bourla thinks this is a $90B market. If MNKD could get just 1% of that, its a lot more than they will ever get from V-Go or the other things Mike currently has in his pipeline except afrezza.
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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 prcgorman2 on Jun 12, 2023 15:46:03 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
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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 mango on Jun 13, 2023 11:24:36 GMT -5
Ozempic side effects could lead to hospitalization — and doctors warn that long-term impacts remain unknown Dr. Meera Shah, an endocrinologist at the Mayo Clinic, said that by far the most common side effect she sees in patients is nausea, followed by abdominal pain, constipation and diarrhea. These side effects can sometimes get better over time but, Shah said, at least 10% of patients who start these drugs have to be taken off of them because the side effects do not improve.
Constant nausea and abdominal pain is an unpleasant reality. The stomach and brain are so connected that intestinal issues can lead to stress, anxiety and depression — it's what's known as the "gut-brain connection." Other serious side effects of Ozempic include thyroid tumors, pancreatitis, changes in vision, hypoglycemia, gallbladder issues, kidney failure and cancer.
The most severe complications Shah sees in her patients are pancreatitis and gallbladder issues — either can lead to hospitalization. Though it is not mentioned on Ozempic's website, doctors have reported some patients, their appetites so suppressed, experience malnutrition. Shah said she commonly has to advise patients to take multivitamins or protein supplements in addition to the medication because they aren't getting the nutrients they need from food.
Model and TikTok star Remi Bader said on the "Not Skinny But Not Fat" podcast earlier this year that a doctor prescribed her Ozempic after she was found to be pre-diabetic and insulin resistant. Weight loss was also a goal. But after going off the medication, Bader gained back the weight she lost while on Ozempic, which subsequently intensified her binge eating disorder.
Eating disorder experts have stressed that hunger suppressants of any kind can lead to or worsen eating disorders. Eating disorders are not cured by weight loss or weight gain. It's unclear how these drugs, when prescribed for weight loss, affect the body after years of use.www.cbsnews.com/news/ozempic-side-effects-weight-loss-drugs-wegovy-mounjaro-doctors-warn/
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Post by sayhey24 on Jun 13, 2023 18:20:15 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? I think this is what Peter was seeing but we don't know. I have reached out to the expert on this to see if I can an answer. I have not heard back but I will keep trying. If the brain thinks 10 hours with 100pmol/L maybe all the issues which you listed above with the analogs can be avoided as we would have native GLP-1 in and out of the system just like the body would do. I think it would be pretty crazy that human insulin on technosphere solves the prandial glucose control issue and "maybe" native glp-1 on technosphere could solve the diet problem. |
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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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