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Post by mnholdem on Jun 16, 2015 14:44:00 GMT -5
Although the thread I started about Sanofi's upcoming euglycemic glucose-clamp study has been locked, the question as to why the trial is being conducted seems to be simple. I think the study appears to be one of the four post-market trials mandated by the FDA. If you go to the link (below) you need to click the Search button to get to the list of post-market trials the FDA is requiring to be conducted with Afrezza:
www.accessdata.fda.gov/scripts/cder/pmc/index.cfm
#2 Required Under: FDAAA Section 505(o)(3)
Original Projected Completion Date: 03/31/2017
Description: Conduct a dose-ranging PK-PD euglycemic glucose-clamp trial to characterize the dose-response of Afrezza relative to subcutaneous insulin in patients with type 1 diabetes. Select at least three to four doses for each route of insulin administration to ensure both the linear and curvilinear portions of the dose-response curves are adequately captured and characterized. Compare the dose-response curves for Afrezza and subcutaneous insulin noting the dose at which the response becomes curvilinear for each. These data may impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis, which has been observed with Afrezza.
Current Status: Pending
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Although the recent filing by Sanofi may be worded differently, I believe that the wording in their recent filing of the upcoming trial captures the FDA requirements and adds a few more endpoints. Please note that the Sanofi filing is a 7-month (maximum) trial, while the FDA has a projected completion date that is a year longer. Perhaps that's what the FDA thought originally and Sanofi has negotiated a shorter timeline. 
All the other points made by board members, such as EMA requirements, may also have been engineered into the trials by Sanofi. They certain know what all needs to be done and will likely try to accomplish as much as possible with these trials.
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Post by jpg on Jun 16, 2015 19:37:07 GMT -5
#2 Required Under: FDAAA Section 505(o)(3)
Original Projected Completion Date: 03/31/2017
Description: Conduct a dose-ranging PK-PD euglycemic glucose-clamp trial to characterize the dose-response of Afrezza relative to subcutaneous insulin in patients with type 1 diabetes. Select at least three to four doses for each route of insulin administration to ensure both the linear and curvilinear portions of the dose-response curves are adequately captured and characterized. Compare the dose-response curves for Afrezza and subcutaneous insulin noting the dose at which the response becomes curvilinear for each. These data may impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis, which has been observed with Afrezza.
Current Status: Pending
These data may impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis, which has been observed with Afrezza.
Back to the concept of label modification and with the guidance and help of the FDA... Thank you for this simple but important 'connecting the dots'. And yes it makes sense that this study will serve more than one purpose. |
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Post by oscarlonzo on Jun 17, 2015 0:22:43 GMT -5
Why wasn't all that done years ago? It seems very odd to wait until after approval to do a phase one study to determine PK/PD at various doses. When will they do one for type 2s? The FDA report indicated that there was a lack of proportionality in dosing -- that as the dose increased, the effect produced decreased. Since type 2s require considerably higher doses of insulin, it seems that a corresponding study should be done. And if they're going to do type 1s, why not go ahead and do type 2s as well. We're talking only an additional 30 patients and a clamp study is relatively inexpensive.
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Post by babaoriley on Jun 17, 2015 2:09:36 GMT -5
Why wasn't all that done years ago? It seems very odd to wait until after approval to do a phase one study to determine PK/PD at various doses. When will they do one for type 2s? The FDA report indicated that there was a lack of proportionality in dosing -- that as the dose increased, the effect produced decreased. Since type 2s require considerably higher doses of insulin, it seems that a corresponding study should be done. And if they're going to do type 1s, why not go ahead and do type 2s as well. We're talking only an additional 30 patients and a clamp study is relatively inexpensive. Simple answer: neither the people at MNKD, nor those at SNY are nearly as smart as you are, oscar. I'm sure most everyone on this board wishes you were working full time, around the clock, for either Mannkind or Sanofi or both. |
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Post by gomnkd on Jun 17, 2015 6:49:43 GMT -5
Why wasn't all that done years ago? It seems very odd to wait until after approval to do a phase one study to determine PK/PD at various doses. When will they do one for type 2s? The FDA report indicated that there was a lack of proportionality in dosing -- that as the dose increased, the effect produced decreased. Since type 2s require considerably higher doses of insulin, it seems that a corresponding study should be done. And if they're going to do type 1s, why not go ahead and do type 2s as well. We're talking only an additional 30 patients and a clamp study is relatively inexpensive. Simple answer: neither the people at MNKD, nor those at SNY are nearly as smart as you are, oscar. I'm sure most everyone on this board wishes you were working full time, around the clock, for either Mannkind or Sanofi or both. It is even better if Oscar can work for FDA. That would save more lives. #LonzoForFDA |
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Post by Deleted on Jun 17, 2015 6:57:34 GMT -5
Oscar, disclose your position.
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Post by mnholdem on Jun 17, 2015 7:14:02 GMT -5
Why wasn't all that done years ago? It seems very odd to wait until after approval to do a phase one study to determine PK/PD at various doses. When will they do one for type 2s? The FDA report indicated that there was a lack of proportionality in dosing -- that as the dose increased, the effect produced decreased. Since type 2s require considerably higher doses of insulin, it seems that a corresponding study should be done. And if they're going to do type 1s, why not go ahead and do type 2s as well. We're talking only an additional 30 patients and a clamp study is relatively inexpensive. All very good questions, oscarlonzo. Assuming yours are not rhetorical questions, I'm not certain anyone here (or at any board) can know all the answers. Regarding what was or wasn't done years ago, please note that Hakan Edstrom has been very good about responding to my questions for nearly a year now. I suggest that you email him at hedstrom@mannkindcorp.com and then come back here to post his reply. I'd think we would all be interested in knowing why certain things were done the way they were.
It does seem odd to wait until after approval and I'm wondering if the reasoning is two-fold. First, according to trial documents, MannKind used different dosages, and the original Medtone inhaler used vials rather than cartridges. You have a good memory regarding the increase dose vs effect. I believe one of the ADCOM physicians also asked some questions regarding that. Those questions may be, in part, why FDA wants further studies conducted, because of the different dosages that were used in the trials compared to the 4-, 8- and 12-unit cartridges available to diabetics today (the 12-unit is coming soon). Secondly, I believe, is that this trial may be the result of an earlier disagreement between MannKind scientists and the FDA regarding the timing of patients administering Afrezza. Al Mann has been somewhat vocal in his belief that the FDA protocols resulted in Afrezza being inhaled too early with the trial patients. Some argue that MannKind management was incompetent while others argue that the FDA was belligerent and insisted on Afrezza being inhaled 15-30 minutes before trial patients took their meals in order to provide a "better" evaluation of Afrezza against the comparator SC insulin, which must also be administered well in advance of a meal. I am not a physician, but I feel that this particular protocol resulted in Afrezza peaking too soon after the meal because of its ultra-rapid action. This skewed the trial results to show more hypos than would have been the case if Afrezza had been administered properly to peak at, rather than before, the glucose spike that occurs after meals. Sanofi had yet to have been named as a partner at the time, so it's difficult to know if they were involved, but this #2 Post-Market study was likely the result of label negotiation that typically occurs between FDA and the company after its drug has been approved.
We may never know what really happened behind the scenes. Again, I urge you to call/email Hakan with your question.
Regarding your 2nd question, the data that is collected in this trial compares the dose-response curves for Afrezza and subcutaneous insulin, noting the dose at which the response becomes curvilinear for each. The final assessment of various endpoints in this trial will certainly be applicable to the treatment of Type 2 diabetics. However, since Sanofi now has responsibility for Afrezza development, your question would be better sent to them rather than MannKind.
While many who participate in this forum may be qualified to answer your questions in a technical sense, why not go to the source and ask them? Again, I'm certain that everybody here would appreciate you taking the time and making the effort to discuss this with Sanofi and then returning here to post Sanofi's response. I don't have an email address off the top of my head, but you should have little problem locating the appropriate person to contact.
Excellent questions...for which Sanofi should be able to provide you with meaningful answers, rather than the guesswork you'd get on this or any discussion board.
Good fortune.
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Post by jpg on Jun 17, 2015 8:34:17 GMT -5
One thing to keep in mind is that dosing increased it is physiologically normal for measured glycemic uptake effect to decrease. This does not mean larger doses work less than sc prandial insulin. It just means higher doses work more like the pancreas and that, as hard as it is for patients (and sadly many endos), prandial pk/pd is substandard and only the best that was available before Afrezza. The dosing with the new inhaler and more doses make this type of study meaningful.
By extrapolation and by the logic of some 'usual suspects' the 'worst' non linear performer would be the pancreas itself if measured against sc insulins... This also partially explains why doing these studies in patients with active insulin production (type 2's) would be much less informative for what they want to demonstrate. I would guess normal or high c peptide levels would be an exclusion criteria.
Basically Sanofi and Mannkind seem to know what they are doing and this study will probably have multiple uses.
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Post by rak5555 on Jun 17, 2015 8:53:51 GMT -5
Thanks JPG (and Oscar) for working this issue to a constructive conclusion. I may be in the minority, but I appreciate having an adversarial perspective on this board. It keeps us on our toes. Until the scripts close that 8 week gap Hakan mentioned, I suggest we consider all possible outcomes and the clues that may provide advanced warning.
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Post by mnholdem on Jun 17, 2015 10:00:39 GMT -5
One thing to keep in mind is that dosing increased it is physiologically normal for measured glycemic uptake effect to decrease. This does not mean larger doses work less than sc prandial insulin. It just means higher doses work more like the pancreas and that, as hard as it is for patients (and sadly many endos), prandial pk/pd is substandard and only the best that was available before Afrezza. The dosing with the new inhaler and more doses make this type of study meaningful. By extrapolation and by the logic of some 'usual suspects' the 'worst' non linear performer would be the pancreas itself if measured against sc insulins... This also partially explains why doing these studies in patients with active insulin production (type 2's) would be much less informative for what they want to demonstrate. I would guess normal or high c peptide levels would be an exclusion criteria.Basically Sanofi and Mannkind seem to know what they are doing and this study will probably have multiple uses. Good call.
Inclusion criteria :
- Male or female patients, between 18 and 65 years of age, inclusive, with diabetes mellitus type 1 for more than one year, as defined by the American Diabetes Association.
- Total insulin dose of <1.0 U/kg/day.
- Body weight between 50.0 and 95 kg, inclusive, body mass index between 18.5 and 29 kg/m², inclusive.
- Fasting serum C-peptide <0.3 nmol/L. [emphasis added]
- Glycohemoglobin (HbA1c) ≤75 mmol/mol (≤9%).
- Stable insulin regimen for at least 2 months prior to study (with respect to safety of the patient and scientific integrity of the study).
- Certified as otherwise healthy for type 1 diabetes mellitus patient by assessment of medical history and physical examination (cardiovascular system, chest and lungs, thyroid, abdomen, nervous system, skin and mucosae, and musculoskeletal system), unless the Investigator considers any abnormality to be clinically irrelevant and not interfering with the conduct of the study (with respect to safety of the subject and scientific integrity of the study).
- Having given written informed consent prior to undertaking any study-related procedure.
- Non-smoking at least for the last 6 months before screening (to be confirmed by urine cotinine <500 µg/L).
- Pulmonary function test at screening: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) >70% of the individual prediction according to the equation of the Third National Health and Nutrition Examination Survey (NHANES III).
clinicaltrials.gov/ct2/show/NCT02470637
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From Diabetes Health, Interpreting Your C-peptide Values by Thomas Connors:
Normal C-peptide levels for a fasting test are generally considered to be anything between 0.5 nanograms (ng) per millileter (ml) and 3 ng/ml, although people who do not have diabetes may occasionally stray out of this range. The following is a range of C-peptide values in people without diabetes, as compiled by Endocrine Sciences, Inc., a California-based laboratory that conducts the test. It should be noted that, in some cases, subjects fell below the normal range of C-peptide values, but were still not found to have diabetes. The range of values may also vary according to what lab your health care practitioner uses.
Children (< 15 years old) 8:00 a.m. fasting: 0.4 to 2.2 ng/ml
Adults 8:00 a.m. fasting: 0.4 to 2.1 ng/ml
Two hours postprandial (after a meal): 1.2 to 3.4 ng/ml
Two hours post glucose load: 2.0 to 4.5 ng/ml
Although anything less than these numbers is generally an indicator of type 1 diabetes, values within the normal range can mean different things.
“Type 2s with insulin resistance could actually be making more insulin than a non-diabetic slim person,” says Richard Bernstein, MD, FACE, FACN, CWS, of the Diabetes Center in Mamaroneck, New York. Values on the lower end may also indicate a honeymoon phase of type 1, when insulin production is slowing down but has not yet ground to a halt.
Bernstein also points out that even in type 1s, a positive C-peptide test should be a source of optimism.
“Of all my patients, I only have two who don’t make any C-peptide, and I’m one of them,” Bernstein says. He says this proves that most type 1s still produce at least some insulin and raises the possibility that therapies like beta-cell regeneration may eventually restore normal BG levels.
www.diabeteshealth.com/blog/interpreting-your-c-peptide-values/
I don't know about you, but I find that last quote to be quite remarkable.
I recall Al Mann saying in an interview that early intensive insulin therapy studies have demonstrated beta-cell regeneration does, in fact, occur. At least one study that I perused last year stated that hexameric insulins don't lend themselves for effective intensive insulin therapy, but that a monomeric human insulin like Afrezza would work perfectly. I believe Al actually used the word "remission" in his interview.
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Post by oscarlonzo on Jun 17, 2015 11:28:21 GMT -5
"The final assessment of various endpoints in this trial will certainly be applicable to the treatment of Type 2 diabetics.
"
Not necessarily. Type 2s usually require considerably higher doses -- 40U and up is not unusual because they are usually very insulin resistant. And the FDA document noted that as dosages increased, the effect was not proportional -- e.g. 12U afrezza wouldn't translate into three times the effect of 4U. s I understood it, originally afrezza was in fact aimed at treating the larger type 2 market. The type 1 market necessarily requires very specific dosages because they are usually so insulin sensitive and have to work within a narrow margin of safety. Endos, who usually manage type 1s, have already shown resistance to afrezza at least partly because of the difficulty in "focusing" the dose to the need. Type 1s themselves are reporting difficulty establishing correct doses and requiring higher doses of afrezza than lispro. Also, since type 1's market is small relative to type 2's, it seems like it might be more reasonable to put more effort into developing the latter.
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Post by jpg on Jun 17, 2015 12:27:09 GMT -5
Oscar, Did you understand my explanation as to the normal and physiological non linearity of insulin dosing? From your last statement I would venture to say no you did not understand my explanation? It was very brief but this is well documented and I strongly encourage you to read up on normal pancreatic insulin PK/PD and then use that info to compare to basal and prandial sc insulin than to Afrezza. You will then start to understand the basics of how insulin works and why your requests of doing these studies in type 2 patients misses the mark and is almost futile. Happily these studies are proof that our scientists at Mannkind and Sanofi are knowledgeable and using resources wisely. Just to be clear: doing these studies (as you suggest) on type 2s to 'develop' that part of the market would be less useful then some other types of studies that can (and will) be done in type 2 patients on Arezza. On a somewhat unrelated topic (which you somehow mixed into your last post) you wrongly insinuate that type 1s have a narrower margin of safety with Afrezza than with traditional prandial sc insulins. I will again refer you to the basic concepts insulin PK/PD to demystify that as repeating the same thing over and over does not seem to be productive. Sadly , and as you point out, many endos are not yet versed in the complexities of normal pancreatic insulin pk/pd and how Afrezza mimics this so closely as to make traditional sc prandial's pk/pd clunky and the old way of understanding things. I would speculate that a time goes by the uniformed will slowly start to understand all these basic concepts or simply look clueless. As a side note a MB is not the best place to acquire the very basic understanding of how insulin works.  |
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Post by oscarlonzo on Jun 17, 2015 13:38:30 GMT -5
"...you wrongly insinuate that type 1s have a narrower margin of safety with Afrezza than with traditional prandial sc insulins." I didn't say that. I said that type 1s are much more sensitive to insulin. Typical type 1s take 20-40U a day, divided about 2/3 slow, 1/3 fast. There have already been reports of type 1s requesting a 2U dose because the 4U was simply too much. You also have to consider that a 4U dose actually contains 10U of insulin. It's labelled as 4U because -- on average -- only 40% actually reaches the lungs, but since it is only an average, one can assume there is variability around that average.. Then from the lungs there is further variability of absorption as demonstrated on the PK graph in the insert. Note that the rapid peak in serum insulin concentration from afrezza has very high variability when compared to lispro. Also, many people have reported assorted difficulties inhaling afrezza -- inhalation interrupted by coughing, powder still in the inhaler, powder in the back of their throat, etc -- which also contributes to variability of dosing. Type 1s are increasingly reporting difficulties with achieving proper dosing, most often problems with hyperglycemia 1-2 hours post mealtime use requiring yet further afrezza dosing. In other words, afrezza may not be suitable for most type 1s. Hence my argument to concentrate on type 2s. Interestingly, SNY gave a presentation last November: SNY presentationSNY devoted only 8 slides to afrezza (versus 30 for toujeo) but everything Purcell said was referenced towards type 2 DM. I didn't see a single reference to type 1 in those slides. If that reflects SNY's intentions, then it seems like they should focus more on accurate dosing for type 2s. I already pointed out the FDA says that the dosing is not linear -- 8U does not produce the double the effect of 4U -- and the problem gets worse with higher doses. I mentioned elsewhere one type 2 trying afrezza: trying afrezza...but found that he required extraordinary amounts of afrezza: couldn't handle itGiven that endos have already shown resistance to using it, and given that SNY seemed more interested in type 2 than type 1, and given that the type 1 market is relatively small anyway, might it not be reasonable to focus instead on finding correct dosing for the bigger type 2 market. By the way, for those interested, the FDA document referred to in the original post can be found more directly here: FDA requirements |
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Post by Deleted on Jun 17, 2015 13:56:08 GMT -5
Pat had asthma issues..why dont you point out Spiro and Howard who are type 2's? |
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Post by jpg on Jun 17, 2015 14:04:52 GMT -5
Oscar you state:
I already pointed out the FDA says that the dosing is not linear -- 8U does not produce the double the effect of 4U -- and the problem gets worse with higher doses.
As I have tried to point out in various ways this 'non linear thing 's not a problem but how the normal pancreas works when secreting insulin. Afrezza is the only insulin that can mimic this pk/pd profile. As peak doses get bigger you have different (better and more desirable) phase 1 effect than 'slow in and slow out' sc prandial insulin. With your logic the normal pancreas and Afrezza are both inferior to traditional prandial sc insulin because they both don't have the linear relationship you seem to think better? Does that make a lot of sense?
You spin an advantage of Afrezza into a disadvantage. You are doing this either out of lack of understanding of how insulin works (and answering my posts without having taken the time to learn how normal insulin works) or ignoring the facts about insulin physiology that don't suit your preconceived notions. I've seen students with these learning blockages. They usually do poorly on tests...
As for type 1s not suited for Afrezza: compared to what? Traditional prandial insulins? If measured against traditional prandials (by pump or by individual injections) I would say you are being disingenuous or simply not aware of the mostly very positive reviews out there.
You should go and read up on insulin and on top of that hang out in social media and see the vastly positive opinions of type 1 users of Afrezza. Saying that type 1s aren't happy or satisfied with Afrezza is not factual or representative of reality. Is Afrezza perfect? No. Will it be for everyone? No. But is there a huge type 1 and type 2 patient pool that will love Afrezza and do very well on it? Absolutely yes.
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