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Post by compound26 on Jun 18, 2015 0:04:18 GMT -5
Oscar, just curious, are you long or short on MNKD? If you do not mind, could you disclose that?
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Post by oscarlonzo on Jun 18, 2015 0:23:50 GMT -5
"I am trying to understand your point regarding variability." First, bear in mind the underlying main point that type 1s are, in general, highly sensitive to insulin dosage. Once the type 1 figures the carb and related content of a given meal, they need to calculate quite specifically the amount of fast acting insulin required, and they especially need to know that the dose they administer will match what they calculate. Now, obviously, unlike a pen, there is no way to "dial" in any dose other than a multiple of 4U with afrezza. So right off, the diabetic who might need only 1U of lispro has to question whether he wants to risk the consequences of taking 4U of afrezza. But also important is that the diabetic doesn't even know that he is in fact getting 4U. There is actually 10U in each 4U dose. The 4u is based upon the average amount observed being delivered to the lungs. We're not given the standard deviation, so we really don't know the probability of whether a patient is actually getting only 2U or maybe 6U or maybe even more. Once it is in the lungs, there will be variability of absorption. Type 1 diabetics experience a generalized deterioration of their microvasculature and this includes alveolar microangiopathy which, in long term type 1 can be significant. As I type I can't recall the exact numbers, but type 1s lose something like 1-3% of their lung capacity per year for every year they've had diabetes. It's reasonable to assume this would affect afrezza absorption. How does all this impact the type 1 response to afrezza? If you look at the insert: insertObserve figure 3B and you will see a graph of "Baseline-Corrected Serum Insulin Concentrations (B) after Administration of AFREZZA or Subcutaneous Insulin Lispro in Type 1 Diabetes Patients." Pick a data point during the spike of afrezza and note the bars extending above and below the dot. I believe that represents the standard deviation -- I can't be 100% sure since they chose not to label it but it makes the most sense. In any case, if you look at, say, the 30 minute data, you see it corresponds to an average of 50 microunits. The bars above and below indicate that 95% of the time you can expect serum insulin to be between 35 and 65. Now that represents substantial variability in serum levels. Compare that with one of the lispro points where you see, say at 30 minutes again, the average is about 24 with 95% expectation of falling between 22 and 26. Now it is possible that the variability is insignificant in terms of final effect and/or risk. Regardless, it is definitely not a desirable trait for any insulin directed at type 1 treatment. For type 2s, on the other hand, it doesn't matter so much since most of them are insulin resistant, which dampens the effect of any significant swings in insulin levels. I hope that makes things somewhat clearer.
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Post by oscarlonzo on Jun 18, 2015 0:28:05 GMT -5
"Oscar, just curious, are you long or short on MNKD? If you do not mind, could you disclose that? "
I have zero financial interest in MNKD stock or in any derivative thereof.
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Post by oscarlonzo on Jun 18, 2015 0:29:15 GMT -5
"...are you assuming that the information reported as coming from the doctor came from him at two different times a month apart based upon the date of each article?"
Yes.
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Post by oscarlonzo on Jun 18, 2015 0:36:40 GMT -5
"SNY initiates 100's of trials a year and they don't issue PR for everything. Afrezza is owned by the partnership and MNKD is a minority partner. "
Does being a "minority partner" restrict them from issuing a PR noting that SNY had started a trial to meet FDA requirements. Like I said, after a string of negative headlines, it wouldn't seem to be asking much or require a great deal of exertion to issue a PR that might assuage shareholder concerns just a little, would it?
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Post by compound26 on Jun 18, 2015 0:38:55 GMT -5
"Oscar, just curious, are you long or short on MNKD? If you do not mind, could you disclose that?"
I have zero financial interest in MNKD stock or in any derivative thereof.
Thanks, Oscar.
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Post by oscarlonzo on Jun 18, 2015 1:04:43 GMT -5
"What I am most interested in gathering your opinions about is whether this trial can possibly lead to a claim of superiority or First-in-Class. "
I would doubt it. Given the results already obtained from the 8U PK/PD, I don't see any reason why a significant difference might be noted with 4U or 12U. At best, it might clear up some of the dosing issues that I mentioned above.
What I don't understand is this:
"We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess known serious risks of diabetic ketoacidosis, hypoglycemia, or decline in pulmonary function, to assess a signal of a serious risk of pulmonary malignancy, and to identify an unexpected serious risk of cardiovascular events."
So now the FDA is actually saying that even though "adverse event" reporting is not enough to assess all these "serious risks," that they were willing to go ahead and approve it and then try to prove it's really safe after it's been used by who knows how many diabetes? That hardly seems like it will make a good selling point. Who wants to volunteer to be a guinea pig for the FDA?
Moreover, how exactly does a PK/PD study comparing afrezza to lispro contribute to achieving that goal? It says:
"These data may impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis, which has been observed with Afrezza."
"These data may impact labeling recommendations for glucose monitoring and thereby mitigate the risk of hypoglycemia, which has been observed with Afrezza."
Well, DKA almost invariably results from patients skipping their insulin doses and/or infections. I really don't see what information this PK/PD study would offer in that respect.
For hypoglycemia, afrezza is already superior for mild hypoglycemia, and equivalent for "serious" hypoglycemia. What from a PK/PD comparison would alter those results?
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Post by kimi on Jun 18, 2015 3:48:58 GMT -5
The fda is not the issue - Europe and a better label (may be ultra rapid - or superior to Humalog) is the target of this trial.
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Post by cretin11 on Jun 18, 2015 6:05:45 GMT -5
"Oscar, just curious, are you long or short on MNKD? If you do not mind, could you disclose that? " I have zero financial interest in MNKD stock or in any derivative thereof. Thanks Oscar for that answer and for all your contributions to the message board. Follow up questions: how many hours do you spend on average per day posting about Afrezza? (Including your posts on SA as "Bear Crusher" and other boards, article comments, etc.) Since you have zero financial interest in MNKD stock, would you please share with us your motivation for making all your lengthy and detailed posts?
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Post by beardawg on Jun 18, 2015 6:29:51 GMT -5
Will there be interim results posted, even though the trial ends pretty quickly (Jan 2016)? Have they done that in the past or just waited for final results on such a short trial? Just wondering how soon we could expect to see any results.
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Post by jpg on Jun 18, 2015 6:55:01 GMT -5
Will there be interim results posted, even though the trial ends pretty quickly (Jan 2016)? Have they done that in the past or just waited for final results on such a short trial? Just wondering how soon we could expect to see any results. It would seem unlikely to me that they would post interim results.
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Post by peppy on Jun 18, 2015 7:02:35 GMT -5
Oscar, I read your reply regarding variability. I got the jest of what you are looking at in the chart. Have you considered the effect of variability from the long tail. As far as I can tell most Type one experience a lot of variability in their blood glucose levels. Type 1 diabetics I have known adjust what they do and make their own decisions. Talk about variability. One of the type ones I knew well injected insulin subq. for 32 years. Before pumps. Died of a heart attack at 44. I know another type one on a pump. This person swings wildly. The GCOM pictures posted, people are showing us their glucose levels are swinging in a better range and staying there. That is another definition of variability. I'll stop. Dosages are adjusted. That is part of medicine. There is a lot of variability to the following statement. "Here is my kit in case I go low and do not wake up in the morning." Attachment Deleted
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Post by MnkdMainer (MM) on Jun 18, 2015 8:11:51 GMT -5
"...are you assuming that the information reported as coming from the doctor came from him at two different times a month apart based upon the date of each article?" Yes. Really? I thought you were more critical than that. How many more of your comments are based on assumptions which may prove to be inaccurate?
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Post by mnholdem on Jun 18, 2015 8:21:45 GMT -5
"What I am most interested in gathering your opinions about is whether this trial can possibly lead to a claim of superiority or First-in-Class. " I would doubt it. Given the results already obtained from the 8U PK/PD, I don't see any reason why a significant difference might be noted with 4U or 12U. At best, it might clear up some of the dosing issues that I mentioned above. What I don't understand is this: "We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess known serious risks of diabetic ketoacidosis, hypoglycemia, or decline in pulmonary function, to assess a signal of a serious risk of pulmonary malignancy, and to identify an unexpected serious risk of cardiovascular events." So now the FDA is actually saying that even though "adverse event" reporting is not enough to assess all these "serious risks," that they were willing to go ahead and approve it and then try to prove it's really safe after it's been used by who knows how many diabetes? That hardly seems like it will make a good selling point. Who wants to volunteer to be a guinea pig for the FDA? Moreover, how exactly does a PK/PD study comparing afrezza to lispro contribute to achieving that goal? It says: "These data may impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis, which has been observed with Afrezza." "These data may impact labeling recommendations for glucose monitoring and thereby mitigate the risk of hypoglycemia, which has been observed with Afrezza." Well, DKA almost invariably results from patients skipping their insulin doses and/or infections. I really don't see what information this PK/PD study would offer in that respect. For hypoglycemia, afrezza is already superior for mild hypoglycemia, and equivalent for "serious" hypoglycemia. What from a PK/PD comparison would alter those results?
In the 12.2 Pharmacodynamics section of the link you provided, the paragraph below the graphs states, "In a study of 32 healthy subjects, the pharmacodynamic effect of AFREZZA, measured as area under the glucose infusion rate -time curve (AUC-GIR) from an euglycemic clamp, increased in a less than dose-proportional manner. This effect has been observed for subcutaneously administered insulins, but it is unknown if the diminishing pharmacodynamic benefit at higher dosage of AFREZZA parallels that which is seen with subcutaneously administered insulin." [emphasis added]
I find it interesting that you brought up the issue of Afrezza's diminishing effect at higher dosage, but failed to mention that this diminishing effect is a characteristic "which is seen with subcutaneously administered insulin." I believe that your omission was intentional in an attempt to portray Afrezza in a bad light. No matter. The FDA states that it is UNKNOWN whether Afrezza parallels the SC insulin, which seems to be one of the reasons for this post-market test.
Secondly, the fact that Afrezza as been judged, as you put it, to be "equivalent for 'serious' hypoglycemia" is EXACTLY my point. Had Afrezza been administered at the proper time, 15-30 minutes later than was mandated in the FDA trials, then Afrezza IMO may very well have provided the empirical evidence to have demonstrated that it is superior to the comparator RAA for serious hypoglyclemia, which is EXACTLY what Sanofi and MannKind want on the label.
With such a crowded market, physicians pay attention to the word "superior" when it comes to prescribing all drugs. "Superior" also allows us, as one poster recently worded it, to "get a seat at the table" with insurance companies reviewing drug reimbursement ratings. "Superior" virtually guarantees Preferred or Tier 2 status and can sometimes even justify charging a premium.
The FDA, as you quoted, has determined that this post-marketing test may:
- "impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis". You appear to challenge the credibility of the FDA when you reply, "I really don't see what information this PK/PD study would offer in that respect."
- "impact labeling recommendations for glucose monitoring and thereby mitigate the risk of hypoglycemia, which has been observed with Afrezza."
By questioning the logic of the FDA for mandating this test for these two label impacts, you judge the credibility of the FDA to be lacking. While I may agree with anybody questioning the FDA's credibility in fairly assessing Afrezza, I wholeheartedly disagree with your propensity to "pick and choose" some data to the exclusion of others. This indicates that you are biased. If you challenge the credibility of the FDA, then you must do so in every area which you argue, not selectively throw out or ignore, as you did with the diminishing pharmacodynamic benefit of increased dosages of subcutaneously administered insulins, such as Humalog and Novolog, the datum or assessments which derail your thesis.
The bottom line for me is that many qualified individuals, including several physicians who participate on this forum, would argue the opposite of what you are posting here related to this post-marketing trial. Since you choose NOT to reveal your credentials, I give your statements less credibility. No offense.
This is an important discussion because that word "SUPERIOR", if included in Afrezza's labeling, could be worth $billions.
Good fortune all.
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Post by LongMNKD on Jun 18, 2015 9:02:07 GMT -5
I don't reply much... just read. But I can't help but notice how Oscar has succeeded in making all replies in this thread about Oscar lol. I think we all know his position has to be Short, as he has the constant negativity only a short basher would have.
Back to the topic: I think these tests by Sanofi are Great news! The outcomes will only positively effect the PPS IMO and is the first step in further validating Afrezza as the superior drug it is.
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