Sanofi milestone payments

[dreamboatcruise]

Dec 14, 2015 9:30:41 GMT -5 kdaddyfresh2000 said:

Dec 11, 2015 21:09:33 GMT -5 suebeeee1 said:

Sue
What about the argument that we aren't seeing new users on Twitter etc bc the endos are improperly instructing the new patients on use, leading to deficient results and thus low retention? This seems to be happening and is very frustrating. Aside from the fact that endos are locked in the past.

Maybe I'm just showing my age... but I wouldn't expect huge numbers of people to rush to tweet about #afrezza.  Sam obviously had an interest in promoting Afrezza having been in the trial and developed a passion to seeing it get approved.  The Afrezza tweets seem to break down to a few passionate users and a few passionate shareholders... arguing with a few MNKD bashers.  I don't think tweeting about a new drug one takes is a normal thing for people.  Likewise I really doubt a lot of diabetics would be following #afrezza on twitter.

User of Afrezza may make reference to it on social media, such as facebook, targeted at their friends/family that we'd never know about.  That is different than trying to market something or spread ideas such as using brand hashtags on twitter.

[stevil]

Finally got some time in the late hours to check out your study. I couldn't find any information that I would deem "new". I posted earlier in this thread that beta cell deterioration would stop and that insulin therapy for type 2's could potentially lead to what would appear to be "remission", while the individual would still have decreased beta function, and thus, be at a higher risk later on of acquiring diabetes if they return to their old habits of diet/exercise, or their beta function decreases even after their habit change.

I'll be honest, it's late, and I didn't scour every word. But I felt like I skimmed the gist of it with the attached quote:


There is general agreement that mitigating the long-term glycaemic exposure in type 2 diabetes would be achieved by selecting a treatment that can preserve beta-cell function [17-19]. This is critical because progressive deterioration in beta-cell function is the pathophysiological process underlying the natural history of type 2 diabetes [20, 21]. Consequently, as the UKPDS and A Diabetes Outcome Progression Trial (ADOPT) trials demonstrated, therapies that are based on stimulating endogenous secretion of insulin [e.g. sulfonylureas] are bound to fail when physiologically stressed beta-cells reach the limit of their ability to respond [22, 23]. As the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial demonstrated, basal insulin used in the setting of dysglycaemia reduced progression to diabetes [24].

Unlike therapies such as sulfonylureas, which stimulate endogenous insulin secretion and therefore require progressively greater beta-cell response at the very time that their ability to respond is levelling off or decreasing, insulin therapy can theoretically provide some beta-cell rest. The potential beta-cell sparing action of exogenous insulin represents an opportunity to slow and maybe reverse beta-cell deterioration, with potential impact on the natural history of type 2 diabetes.

The closest they got was "maybe reverse beta-cell deterioration". This study was published in Sept of this year, but none of this appears to be new information from what I was taught. They even dismissed the tests that showed beta cell mass regeneration from GLP-1's. 

They later qualified the study with:


It should be noted however that, in this trial, the goal was to assess the beta-cell sparing effect of early insulin treatment and so the investigators did not attempt to pursue a period of drug-free remission.


I appreciate you doing your homework, mnholdem. But this study does not claim (unless I missed that part... possible because I stopped reading after the intro) that insulin can regenerate beta cells. 

Merry Christmas and happy New year to all!

[mnholdem]

Various types of evidence supporting the use of STII therapy in patients with newly diagnosed type 2 diabetes are available. Anecdotally, our own clinical experience with patients and their families has repeatedly shown that following STII therapy, some patients are able to sustain prolonged remissions [periods of euglycaemia] despite having discontinued drug therapy. There are also numerous formal clinical studies demonstrating that STII therapy can normalize glycaemic control, improve beta-cell function, and/or restore first-phase insulin secretion and decrease insulin resistance in newly diagnosed type 2 diabetes [29-49]. STII therapy has also been favourably assessed in a recent meta-analysis [50] as well as in review articles, where it has been either the focus of the review (e.g. [51, 52]) or discussed along with other treatment options as a new therapeutic approach [6, 18, 53].

Footnotes will lead you to other research which make or support claim of restoration of pancreas beta-cell function. One of the reasons that I posted the link (earlier in this thread) to this study was because the team provided many references to similar studies whose results indicate Al Mann's remarks that early intensive insulin treatment can result in "prolonged remissions", "restore first-phase insulin secretion and decrease insulin resistance in newly diagnosed type 2 treatment."

Remarks made at several MannKind Corporation investor/earnings conferences indicate that early type 2 diabetes is the primary target for Afrezza. Progress will be understandably slow until Afrezza, itself, is used in a short-term intensive insulin (STII) therapy study. This monomeric insulin is perfect for this early type 2 therapy because of it's remarkable speed. More importantly, if empirical evidence proves that Mann's assessment was correct all along, STII should become the standard first-line treatment of Type 2 diabetes mellitus. Hands down. 

Understandably, you have scant time to further research this because of your own studies. The studies are out there, some of it is decades old. No insulin was fast enough for effective STII until now. Afrezza is a game changer. Whether Sanofi sees this is unknown at this time. Former CEO Veihbacher indicated that Sanofi is very much aware, when he talked about "the lost decade" of early diabetes treatment and how Afrezza could be the answer. Do new CEO Brandicourt and the new head of Sanofi's GBU for diabetes Pascale Witz feel the same way?

[stevil]

I think it's important for people to know what they're investing in... So for those who think I'm here to soft bash- I'm not... But it's important to get facts straight. 

sciencelife.uchospitals.edu/2014/10/13/for-patients-with-type-2-diabetes-remission-is-rare-but-not-impossible/

if you read here, you'll see that diet/exercise has been deemed the best treatment for type 2 diabetes. Diet/exercise has also shown to cause remission. Bariatric surgery has actually been called a cure by some because it reduces the amount of insulin needed to keep glucose levels at appropriate levels. But even that should not be considered a cure as it does nothing for the pancreas other than relieving the amount of work needed to keep glucose low. 

Im not saying that early insulin therapy isnt beneficial. For many people, lifestyle changes may not be realistic. It may even prove to be better for all to relieve beta exhaustion. But remission and cure are not the same. 

Ill explain the difference. 

Type 2 is largely genetic. Let's say the average person is born with 100 beta cells (for simplicity). A type 2 is born with 75 beta cells. 50 beta cells are needed to show disease. Over time, they lose the function of some of their beta cells. Let's say they have 65 left that are trying to do the job of 100. They get overworked. In essence, they get inflamed. So even though some beta cells are lost, there are still enough to function properly, but even the ones that are left are overworked so they aren't working efficiently. So those 65 act like 50 because they get tired. So if you start insulin, you allow those cells to relax and get back up to 100% of 65 but they don't gain back the 10 they've lost over the years. Thats what the remission is. Remission is when a disease is still present but isn't actively presenting. So type 2s still have the disease but they're healthy enough to not have symptoms. Again, this is not a cure. It's just beta relaxation, which is what the study was talking about. 

As far as I know, only peptides have shown beta cell mass increases. 

Afrezza is an amazing drug, but it won't cure diabetes. It is, however, the best drug we currently have for diabetes. 

[mnholdem]

While others may have, I have steadfastly refused to use the word "cure". The word I use (& Al Mann uses) is "remission". I, too, think that Afrezza is not a cure and that it may well be the best treatment available whether by itself or in combination. Happy Holidays.

[liane]

"Controlled" would be the proper terminology.

[grandpoobah]

Dec 27, 2015 18:39:31 GMT -5 stevil said:

I think it's important for people to know what they're investing in... So for those who think I'm here to soft bash- I'm not... But it's important to get facts straight. 

sciencelife.uchospitals.edu/2014/10/13/for-patients-with-type-2-diabetes-remission-is-rare-but-not-impossible/

if you read here, you'll see that diet/exercise has been deemed the best treatment for type 2 diabetes. Diet/exercise has also shown to cause remission. Bariatric surgery has actually been called a cure by some because it reduces the amount of insulin needed to keep glucose levels at appropriate levels. But even that should not be considered a cure as it does nothing for the pancreas other than relieving the amount of work needed to keep glucose low. 

Im not saying that early insulin therapy isnt beneficial. For many people, lifestyle changes may not be realistic. It may even prove to be better for all to relieve beta exhaustion. But remission and cure are not the same. 

Ill explain the difference. 

Type 2 is largely genetic. Let's say the average person is born with 100 beta cells (for simplicity). A type 2 is born with 75 beta cells. 50 beta cells are needed to show disease. Over time, they lose the function of some of their beta cells. Let's say they have 65 left that are trying to do the job of 100. They get overworked. In essence, they get inflamed. So even though some beta cells are lost, there are still enough to function properly, but even the ones that are left are overworked so they aren't working efficiently. So those 65 act like 50 because they get tired. So if you start insulin, you allow those cells to relax and get back up to 100% of 65 but they don't gain back the 10 they've lost over the years. Thats what the remission is. Remission is when a disease is still present but isn't actively presenting. So type 2s still have the disease but they're healthy enough to not have symptoms. Again, this is not a cure. It's just beta relaxation, which is what the study was talking about. 

As far as I know, only peptides have shown beta cell mass increases. 

Afrezza is an amazing drug, but it won't cure diabetes. It is, however, the best drug we currently have for diabetes. 

I can't quite agree altogether with your analysis. First, just to perhaps help clarify your point about the difference between remission and cure. Officially, remission is "abatement of the signs and symptoms of a disease." Practically, however, it simply means the condition has "improved" so that a patient may require lower doses of previous medications and/or may no longer even need meds. As Dr. Huang said in the article you provided:

“The rates of remission appear very low in this study, but I suspect part of it may be because doctors in real clinical practice may keep people on medications because they don’t believe remission is possible..."

Cure, of course, indicates that the original pathology has been completely resolved.

For the vast majority of type 2 diabetics, remission is extremely simple. Since obesity is the primary cause of type 2 DM in over 80-90 plus percent of the cases, remission is simply a matter of weight loss. Technically, you can't assess a "cure" in a diabetic unless you know the exact etiology of the DM. If the etiology is, in fact, simple insulin resistance due to obesity, then one could argue that someone who achieves and maintains a normal BMI is "cured."

While type 2 DM does have a genetic component, it is the interaction of that component with other conditions -- especially obesity -- that predisposes to DM:

Type-2 diabetes: a cocktail of genetic discovery

"It is believed that polygenic T2DM results from inheritance of a set of susceptibility genes and that each exerts only a partial effect contributing to the development of the disease in full. Only when the effect of these genes is added together in particular combinations and in the presence of certain risk factors, such as obesity, will we see disease."

The recurring and overriding theme in type 2 DM is obesity. Even the World Health Organization acknowledges that:

Genetics and Diabetes

"Unlike T1D, T2D can generally be prevented by maintaining an age-appropriate body weight and engaging in physical activity."

That is the reason that the first strategy in any type 2 DM management flowchart always focuses on increasing physical activity and on losing weight. It's also the reason insurance companies are willing to reimburse bariatric surgery to treat type 2s. In the long run, the surgery, even though very expensive, will cost the insurance company less.

[suebeeee1]

As one who is married to one of those Type 2s without an obesity problem, I hate that all of the research and literature focuses on this population. With so great a number of overweight people in the world, why is it that the vast majority of those who are rotund are NOT diabetic? It would seem, to a great extend, that genetics either predisposes you to diabetese or it doesn't. Would be nice to be able to replicate a gene therapy which would eradicate the predisposition within those who are predisposed, however, that isn't coming soon.

For now Afrezza is as good as it gets. A1c that is near or at normal level without hypoglycemia or risk thereof. Theoretically, it should be possible to reduce bg to the point where it never leaves "normal" level. When we get some experience, perhaps we will put more time and effort into experimentation. Up till then, we consider it "control", damn good control!

[nadathing]

I've always wondered that as well. I was diagnosed 12 years ago and was about 20 pounds overweight. There is no history of diabetes in my family. I lost the weight and have better control of my diabetes, but the fact remains I still have diabetes. I know people who are morbidly obese and have normal glucose readings. Guess it is just the luck of the draw for many.

[grandpoobah]

Dec 28, 2015 12:43:48 GMT -5 suebeeee1 said:

As one who is married to one of those Type 2s without an obesity problem, I hate that all of the research and literature focuses on this population. With so great a number of overweight people in the world, why is it that the vast majority of those who are rotund are NOT diabetic? It would seem, to a great extend, that genetics either predisposes you to diabetese or it doesn't. Would be nice to be able to replicate a gene therapy which would eradicate the predisposition within those who are predisposed, however, that isn't coming soon.

For now Afrezza is as good as it gets. A1c that is near or at normal level without hypoglycemia or risk thereof. Theoretically, it should be possible to reduce bg to the point where it never leaves "normal" level. When we get some experience, perhaps we will put more time and effort into experimentation. Up till then, we consider it "control", damn good control!

"...vast majority of those who are rotund are NOT diabetic..." The answer was in a quote I provided:

"It is believed that polygenic T2DM results from inheritance of a set of susceptibility genes and that each exerts only a partial effect contributing to the development of the disease in full. Only when the effect of these genes is added together in particular combinations and in the presence of certain risk factors, such as obesity, will we see disease."

In other words, obesity by itself does not necessarily lead to type 2 DM. Multiple other factors interact to predispose to development of the disease. By the same token, obesity is not always present in type 2s. Lack of obesity, however, suggests a search for alternate explanations of the cause -- e.g. autoimmunity, exposure to toxic chemicals, etc.  Regardless, for the vast majority of type 2s, obesity is the primary factor which, when eliminated, effectively cures the disease.

[suebeeee1]

grandpoobah said: "By the same token, obesity is not always present in type 2s. Lack of obesity, however, suggests a search for alternate explanations of the cause -- e.g. autoimmunity, exposure to toxic chemicals, etc."

This is exactly what I am referring to: there is no real research into the reasons for diabetes in those that are not overweight. It is here that researcher might be able to identify either the genetic code or other predispositions for the disease. It would be like stripping off the main cause and then dealing with the rest. Perhaps treatments tailor-made to the individual will be the answer, but it would seem that some one should be asking the questions.

Instead, pharmaceuticals are happy to just treat the disease. There is no real money in a cure.

[stevil]

Your confusion lies in your understanding of remission. Remission is the alleviation of symptoms while still being susceptible to the disease. I've tried to simplify the science the best I can. I don't have all the answers, but I have to trust that my education is correct. I have been taught both by peer reviewed journals and PhD professors who have done extensive research in their field. 

You, or anyone else, may disagree with the current literature and accepted scientific fact- Lord knows scientists have been wrong before. But I feel like I have a very good grasp of what I've been taught and "cure" should not be used. 

If you've known anyone who has been diagnosed with cancer, remission should be an easy concept to understand. The cancer is considered to be in remission for 5 years after no detectable cells are found in the blood. But they don't use cure until those 5 years because the individual is at a higher risk of getting cancer because only one cancer cell needs to survive to manifest the disease again.  It sometimes takes years for pathologies to present- as they need time to grow and multiply.

that might be a poor example because it's not the same kind of idea with diabetes. Cancer is the lack of harmful cells while diabetes is the lack of beta cells. And unlike cancer cells, beta cells do not replenish themselves. That is why it's considered remission. It appears to be a cure because the symptoms alleviate, but the individual is still susceptible to getting the disease because their body isn't properly healthy. In other words, if they were to keep the same diet/exercise that lead to the disease, they likely would be insulin dependent the rest of their lives in short order, whereas a healthy person could continue to eat what they want without manifesting the disease. 

Im sorry if this still doesn't make sense. If it doesn't, I'd encourage you to keep studying and find someone who can explain it in a way that will make sense to you. But I feel I have a very strong grasp of the latest information and there is a very broad distinction between cure and remission/treatment and thus should not be used when describing Afrezza or any other insulin product. 

Ill answer any direct questions that I haven't already addressed if I can help clear anything up, but I hope you'll forgive me for bowing out from future discussion on this matter. 

[suebeeee1]

Dec 28, 2015 12:53:54 GMT -5 nadathing said:

I've always wondered that as well. I was diagnosed 12 years ago and was about 20 pounds overweight. There is no history of diabetes in my family. I lost the weight and have better control of my diabetes, but the fact remains I still have diabetes. I know people who are morbidly obese and have normal glucose readings. Guess it is just the luck of the draw for many.

...or genetics.  I was involved in the "Twins Seperated a Birth" studies nearly 20 years ago.  After compiling data and realizing there was even a preponderance of evidence for correlating percentages in mono-zygote twins in a category as subjective as "religiousity" as compared to non-identical twins also seperated at birth, one realizes how pre-programmed we really are.  

You and my husband are two in this study that I would propose.  Unfortunately, I don't see anyone doing research into Type 2 diabetics that don't fit the medical model of obesity in adulthood.
 

[agedhippie]

Dec 28, 2015 13:12:10 GMT -5 grandpoobah said:

Regardless, for the vast majority of type 2s, obesity is the primary factor which, when eliminated, effectively cures the disease.

It defers rather than cures the disease. I am a thin Type 2 so the debate about how I ended up with diabetes is of obvious interest to me. There is a process where the body kills aging cells and replaces them with new cells. The current leading theory is that there are genetics in Type 2 that prevent a complete replacement, the body under-produces replacement beta cells. Humans become diabetic when they have lost around 40% of their beta cells (rats can lose 60%) so there is quite a safety margin.

At last count there are over 80 genes associated with Type 2 diabetes. The combination of genes and the particular genes involved decide the size of the error and hence how aggressive the decline will be. This is also where obesity comes in since as you gain weight you become more insulin resistant. Your body deals with this by building more beta cells and in the vast majority of people that is fine. In diabetics however the genetic error means less beta cells are built than required which exacerbates the condition. Losing weight may pull you down below the magic 60% mark so you are again living within your insulin production, but it does not address the underlying issue of a declining beta cell count.

In mine and most thin Type 2 diabetics the genetics are aggressive. We don't need the additional insulin resistance from obesity as our cell replacement is sufficiently badly mismatched as to achieve this regardless. And as for the idea that obesity as the cause in itself remember that 88% of obese people will never develop diabetes (numbers from the CDC) and if obesity was the cause those numbers would be far higher.

At this point I expect half the audience to be asleep from boredom. That explains why Afrezza is a treatment and not a cure, it treats the symptoms and not the cause. If you think it's a cure or even remission just try and eat a stack of pancakes with syrup and a large OJ and see what happens. Afrezza gives control and that is enough.

[spiro]

Spiro has stopped trying to figure out what's going on with his Afrezza use. All he knows is that Afrezza works great and it works real fast. Just yesterday, Spiro went out to eat at his favorite Barbecue restaurant and had a corn on the cob dripping in butter and onion rings for appetizers, followed by a beef brisket sandwich on Texas toast with French Fries. Spiro then reached into his pocket and discovered that he had left his trusted Afrezza at home. Not smart on Spiro's part, but these things happen with Spiro. One hour later Spiro finally got home and immediately checked his BG. As expected it was 162 and most likely climbing. That was one of Spiro's highest readings since starting Afrezza. Spiro then immediately inhaled a 4 unit dose of Afrezza. Thirty two minutes later, Spiro's BG was down to 120.

Spiro here