You Know, The Whole MannKind Situation Could Turn On A Dime

[derek2]

Actually, I'm mostly in agreement with what you have written. I also think that Al was speaking about severe hypo and simply mis-spoke. And then Matt failed to correct him. And then it spawned this whole "no hypo" misunderstanding - that's what I was speaking to.

The reality, as you lay out quite nicely, is more down to earth.

I buy into the view that in the trials the participants were exposed to less insulin when using Afrezza due to the dosing rules, leading to: 1. Slightly lower efficacy (barely proved non-inferiority (but yes did prove it) and surprised management, who had been expectiung approximately twice the effect on HbA1c) 2. Lower side effect (weight gain, hypo). There's nothing magical about Afrezza. It's insulin. Take a bigger dose, get a bigger primary effect and side effect. Take a smaller dose (as many have argued the trial design forced participants into) get a smaller primary effect and fewer side effects.

[Deleted]

Oct 25, 2016 12:24:05 GMT -5 derek2 said:

Actually, I'm mostly in agreement with what you have written. I also think that Al was speaking about severe hypo and simply mis-spoke. And then Matt failed to correct him. And then it spawned this whole "no hypo" misunderstanding - that's what I was speaking to.

The reality, as you lay out quite nicely, is more down to earth.

I buy into the view that in the trials the participants were exposed to less insulin when using Afrezza due to the dosing rules, leading to: 1. Slightly lower efficacy (barely proved non-inferiority (but yes did prove it) and surprised management, who had been expectiung approximately twice the effect on HbA1c) 2. Lower side effect (weight gain, hypo). There's nothing magical about Afrezza. It's insulin. Take a bigger dose, get a bigger primary effect and side effect. Take a smaller dose (as many have argued the trial design forced participants into) get a smaller primary effect and fewer side effects.

Trial protocols required patients to dose Afrezza 15 minutes prior to the beginning of each meal.  Had the trial required dosing at the time the meal began or five minutes into the meal, results would have been dramatically different.  A1c improvement would have been off the chart, data published and NRx today north of 10,000 / week.  But it wasn't and we are where we are.  

Some have said Afrezza does not lower blood glucose levels but simply stops it from rising.  1st phase or glycogenesis thing perhaps?  

If you go to Afrezzauser.com you can see where Sam(T1 & trail participant) doses Afrezza in the morning on an empty stomach and does fingerstick / capillary blood glucose testing every two minutes and shows these results in conjunction with his Dexcom continuous monitor.  While one person does not a clinical trial make his demonstration shows, at least for him, that a hypo with Afrezza would be highly unlikely.  Sam commented on the dosing protocols for the trial and indicated dosing at the time the meal began would have produced far better results.  

[compound26]

Oct 25, 2016 12:24:05 GMT -5 derek2 said:

Actually, I'm mostly in agreement with what you have written. I also think that Al was speaking about severe hypo and simply mis-spoke. And then Matt failed to correct him. And then it spawned this whole "no hypo" misunderstanding - that's what I was speaking to.

The reality, as you lay out quite nicely, is more down to earth.

I buy into the view that in the trials the participants were exposed to less insulin when using Afrezza due to the dosing rules, leading to: 1. Slightly lower efficacy (barely proved non-inferiority (but yes did prove it) and surprised management, who had been expectiung approximately twice the effect on HbA1c) 2. Lower side effect (weight gain, hypo). There's nothing magical about Afrezza. It's insulin. Take a bigger dose, get a bigger primary effect and side effect. Take a smaller dose (as many have argued the trial design forced participants into) get a smaller primary effect and fewer side effects.

derek2 , I generally agree with you are saying. However, IMHO, Afrezza significant reduces the risk of hypo events mainly because its unique PK/PD profile, not because of whether ones used less insulin or arrived at a slightly higher A1C.  Yes, Afrezza is insulin, however, because of its unique PK/PD profile, it is entirely a difference class of insulin, in many respects very different from RAAs.

According to this study of Yale University (www.medpagetoday.com/Endocrinology/Diabetes/40764), compared to a baseline HbA1c of 7% to 7.9%, no level of HbA1c -- ranging from less than 6% to 9% or higher -- had a significantly different relative risk of hypoglycemia in a model fully adjusted for age, diabetes duration, and category of diabetes medication, they wrote online in Diabetes Care.

So based on the above article, significant difference in A1C actually does not automatically lead to significant difference in hypo events.  

Given the marginal difference between Afrezza and RAAs in A1C results, the significant difference in hypo rate between the two arms can not be explained by the slightly higher A1Cs of the Afrezza arm (as the FDA reviewer obviously has concluded, without any study supporting his/her conclusion).  The FDA reviewer obviously did not think through this issue or did much research on this issue. Most likely, he/she just does not want to find out the real explanation why Afrezza causes less hypos.

[derek2]

Oct 25, 2016 12:48:14 GMT -5 compound26 said:

Oct 25, 2016 12:24:05 GMT -5 derek2 said:

According to this study of Yale University, compared to a baseline HbA1c of 7% to 7.9%, no level of HbA1c -- ranging from less than 6% to 9% or higher -- had a significantly different relative risk of hypoglycemia in a model fully adjusted for age, diabetes duration, and category of diabetes medication, they wrote online in Diabetes Care.

Interesting - I'll check that out.

Thanks!

[radgray68]

"Trial protocols required patients to dose Afrezza 15 minutes prior to the beginning of each meal. Had the trial required dosing at the time the meal began or five minutes into the meal, results would have been dramatically different. A1c improvement would have been off the chart, data published and NRx today north of 10,000 / week. But it wasn't and we are where we are." Exactly what I meant.


All I was saying was that the trials were for the benefit of the FDA and NOT the drug. I would also not accept as final word, any hypos on patients with one or two other oral drugs as they are no longer valid in my mind. Those guys polluted the sample IMHO. I want Afrezza ONLY trials. Then, and only then, will we have proven the science effectively. That is when this thing "turns on a dime"

[compound26]

Oct 25, 2016 15:25:24 GMT -5 radgray68 said:

"Trial protocols required patients to dose Afrezza 15 minutes prior to the beginning of each meal. Had the trial required dosing at the time the meal began or five minutes into the meal, results would have been dramatically different. A1c improvement would have been off the chart, data published and NRx today north of 10,000 / week. But it wasn't and we are where we are." Exactly what I meant.


All I was saying was that the trials were for the benefit of the FDA and NOT the drug. I would also not accept as final word, any hypos on patients with one or two other oral drugs as they are no longer valid in my mind. Those guys polluted the sample IMHO. I want Afrezza ONLY trials. Then, and only then, will we have proven the science effectively. That is when this thing "turns on a dime"

radgray68  generally agree with what you stated. However, the "Trial protocols required patients to dose Afrezza 15 minutes prior to the beginning of each meal" part does not appear to be accurate. 

Below is what Al Mann stated in an interview.

www.diabetesincontrol.com/an-exclusive-interview-with-al-mann-founder-and-ceo-mannkind-corp/

SF: Was that when you changed to the new device?

AM: No, I think that a problem during the trials was that some patients took their dose of Afrezza even before starting to eat. The trial protocols called for Afrezza to be dosed “at the beginning of the meal,” but sometimes it was taken even before. We need to do additional trials to gain more experience with optimized dosing times. Actual ingestion of food in most meals in the United States except in restaurants takes only about 30 minutes, so I believe that the first Afrezza dose really ought to be taken ten or fifteen minutes after starting to eat. For a longer meal, which is not very common, a second dose might be taken fifty or sixty minutes after starting to eat. For a long feast that lasts for an hour and a half or more, I suggest a third dose be taken at maybe one and a half hours after start. Interestingly I believe the size of all those doses should probably be the same for most patients. Unfortunately the trial protocols called for dosing at the beginning of the meal so we will need to do more trials to be able to gain FDA label approval of optimized dosing.

[centralcoastinvestor]

This discussion on the trials has been very interesting to me.  The trial protocols were not set up to show off what Afrezza could really do.  I think we were damn lucky to have achieved the non inferior determination.  Just shows how effective Afrezza is.  Thanks everyone who has contributed to this so far.

[agedhippie]

Oct 25, 2016 15:32:59 GMT -5 compound26 said:

AM: No, I think that a problem during the trials was that some patients took their dose of Afrezza even before starting to eat. The trial protocols called for Afrezza to be dosed “at the beginning of the meal,” but sometimes it was taken even before. We need to do additional trials to gain more experience with optimized dosing times. Actual ingestion of food in most meals in the United States except in restaurants takes only about 30 minutes, so I believe that the first Afrezza dose really ought to be taken ten or fifteen minutes after starting to eat. For a longer meal, which is not very common, a second dose might be taken fifty or sixty minutes after starting to eat. For a long feast that lasts for an hour and a half or more, I suggest a third dose be taken at maybe one and a half hours after start. Interestingly I believe the size of all those doses should probably be the same for most patients. Unfortunately the trial protocols called for dosing at the beginning of the meal so we will need to do more trials to be able to gain FDA label approval of optimized dosing.

This is part of why you have large trials. You can tell people when to dose but they are not going to consistently obey the protocol. Part of what you are looking for is what happens when you apply the protocol to a large population - are they compliant, do the dose as directed, what is the impact of deviations, etc. All of these deviations have an impact, some good and some bad, but they represent the real world. This is also why the early adopters are useful for refining the protocol but not very useful for predicting the impact of the drug in the broader population.

[bwills]

Oct 25, 2016 11:21:30 GMT -5 compound26 said:

Oct 25, 2016 10:50:39 GMT -5 derek2 said:

"There was one patient that had almost half of the hypoglycemic incidents"


 

It is clearly established that Afrezza causes less hypos. That is discussed in detail in the FDA briefing document.

Afrezza has lower hypo events and incidences in every category as compared with RAAs. See pages 124-126 of the document (the version I looked has 248 pages as noted on the document itself). And when we are discussing hypo rate, we are mainly look at study 171 (the study for Type ones), i.e., a comparison with RAAs.  

www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM390864.pdf

As for what Al Mann was referring to, even though he did not specify, IMHO, he was referring to severe hypos events. For Afrezza (on Generation 2 device), there were only 65 severe hypo events (as compared to 7979 total hypo events). It is quite possible that one or two subjects accounted for a significant percentage of these severe hypo events.

And if one looks at the severe hype events, which I believe is the most important to the PWDs, Afrezza ((on Generation 2 device, i.e. dreamboat) beats RAAs hands down.  

Number of severe hypo events 65 vs 130 and event rate 8.05% vs 14.45%.  

Hypo events with Glucose <= 36 mg/dl  94 vs 230 and event rate 11.64% vs 25.57%.  

Too bad that FDA does not allow Mannkind to include less hypo in the label.

FDA reviewer had the following comment reagrding this. (Reviewer’s comment: For the T1DM trial, conclusions regarding hypoglycemia are confounded by the difference in efficacy observed between the two study arms and are entirely consistent with the fact that Afrezza was demonstrated to be less effective than comparator. For the T2DM trial, the result of greater hypoglycemia risk vs. placebo is expected.)  

If this is FDA's reason or excuse for not allowing Mannkind to include less hypo in the label, I personally found it to be less than persuasive.

This because the Afrezza trial was designed and approved by FDA to show non-inferior and the trial did show non-inferior.  I.e., FDA is acknowledging that Afrezza is non-inferior to RAAs in terms of reducing A1Cs. If so, how can FDA ignore the significant reduction in hypo events and incidence rates? Other than BP influence embedded in the FDA review process, I personally cannot find any other explanation.

IMHO, the choice of words there "entirely consistent" clearly reflects FDA reviewer's bias.  Afrezza is shown to be "non-interior" to RAAs (i.e., if less effectively, only marginally so, in terms of reducing A1Cs), why is this "entirely consistent" with Afrezza's significant reduction in hypo events and incidence rates (especially severe hypo events and incidence rates)?  

Did the FDA reviewer cite any study backing up his/her conclusion or showing how he/she arrives with such "entirely consistent" conclusion? At least I did not find any!

(There is no reason to look at the hypo rates for study 172, as study 172 is Afrezza vs placebo.  So that is insulin vs no-insulin.  Afrezza is expected to have higher hypo rates in study 172. If you add insulin to the system, you are increasing the possibility for hypo events. The FDA briefing document made that clear.)  Because of this, even though Al Mann did not specify, when he was speaking about Hypo events, IMHO, he must be referring to the 171 study, not the 172 study.

It's curious that the insert shows only the results for type 2 diabetics:

Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled
Study of Patients with Type 2 Diabetes

                                                 Placebo (N=176)     AFREZZA (N=177)
Severe Hypoglycemia                        1.7%                       5.1%
Non-Severe Hypoglycemia                 30%                        67%

[letitride]

How does a placebo produce severe hypoglycemia?
Placebo (N=176)     AFREZZA (N=177)
Severe Hypoglycemia                        1.7%                       5.1%
Non-Severe Hypoglycemia                 30%                        67%

[derek2]

Oct 26, 2016 1:24:19 GMT -5 letitride said:

How does a placebo produce severe hypoglycemia?
Placebo (N=176)     AFREZZA (N=177)
Severe Hypoglycemia                        1.7%                       5.1%
Non-Severe Hypoglycemia                 30%                        67%

Type 2s were on either (oral meds + Afrezza) or (Oral meds + placebo)

You're seeing the contribution of the oral meds to hypo risk

[letitride]

Thanks derek I was beginning to wonder if you could think your BG down

[peppy]

www.mannkindcorp.com/Collateral/Documents/English-US/12-2009_EASD_009_Poster_982.pdf

[nadathing]

Oct 26, 2016 6:03:52 GMT -5 letitride said:

Thanks derek I was beginning to wonder if you could think your BG down

Well... now that you mention it, stress can cause an increase in BG. Maybe some chanting might help. Just thought I'd throw that tidbit out.

I've experienced lows after exercising or doing nothing. Last night I got up at 1:00 AM feeling sweaty and shaky and was at 60. A few years ago I had 45 grams of carbs for breakfast and started to feel a low coming on an hour later while driving. Pulled over and found my BG at about 38. Pretty scary.

This is a crappy disease. No rhyme or reason for a lot of what occurs. My first doctor said we would try one drug and if that didn't work we'd add another. If those two didn't work we'd add a third. I spent years obsessing over trying to control my BG. I now use a GLP-1 (Trulicity) and metformin. I've got tight control, for the most part, so I don't obsess much anymore except for the pps of MNKD.

[alethea]

Oct 25, 2016 12:24:05 GMT -5 derek2 said:

Actually, I'm mostly in agreement with what you have written. I also think that Al was speaking about severe hypo and simply mis-spoke. And then Matt failed to correct him. And then it spawned this whole "no hypo" misunderstanding - that's what I was speaking to.

The reality, as you lay out quite nicely, is more down to earth.

I buy into the view that in the trials the participants were exposed to less insulin when using Afrezza due to the dosing rules, leading to: 1. Slightly lower efficacy (barely proved non-inferiority (but yes did prove it) and surprised management, who had been expectiung approximately twice the effect on HbA1c) 2. Lower side effect (weight gain, hypo). There's nothing magical about Afrezza. It's insulin. Take a bigger dose, get a bigger primary effect and side effect. Take a smaller dose (as many have argued the trial design forced participants into) get a smaller primary effect and fewer side effects.

You are wrong about the statement bolded above.  There absolutely IS something, if not magical then ALMOST magical about Afrezza.  It works very, very fast.  Much, MUCH faster than injectable insulin.  AND it is out of your system far, FAR faster than injectable insulin.

I KNOW, I USE it.  While I certainly have experienced numerous mild hypos, ones I can feel.... slightly light headed, confused, minor sweating, I have never been close to a severe hypo.  I'm Type 2.

It is simply the very best, fastest acting most effective mealtime insulin I have ever used.  I have used Humalog, Novalog and the cheap, old-fashoined insulins such as N and R.