Can A 2U Cartridge Be Added Without Further Study

[kball]

May 6, 2015 10:27:52 GMT -5 mnholdem said:

Maybe you'll get a smile back on your avatar (chuckle). It does look a little weird without the mouth.

Avatar without mouth was paying proper respect to Mannkind communication strategy

[jpg]

May 6, 2015 5:34:57 GMT -5 ezrasfund said:

I asked Matt about this. His e-mail response yesterday: "We are considering it. We really don't think it is needed for the type 2's we are servicing now, but the fanatical type 1's might use it to deal with snacks. It might also be needed for kids."

It's hard to write so few words and us them so badly.
I am relieved Sanofi is in charge. I'm rather certain they wouldn't call their patients fanatical and use the word service them.

Matt; type 1s are the gateway to wider acceptance of our product. Wanting an option to safely correct is a no brainer. You are competing with a pump. And no type 2s don't need 2 units but 12 and 20 but for now your customers are type 1s. Treat that group well and others will follow. This is rather simple marketing.

[seanismorris]

I don't have a problem with Matts statement calling it "fanatical".

When Afrezza is approved for the younger age groups the "2U" will be released. Just like at the initial launch 12U wasn't immediately necessary to have available. But, now that the number of patients taking Afrezza is increasing more people will benefit from having 12U so it's being released. It sounds like a natural progression (to me) and a wise use of resources to do what they are doing.

Matt's very aware of what Afrezza is and what the health risks are (minimal) so someone talking a 4U when 2U would work isn't that important. Now if someone wanted to 'micro manage' or be "fanatical" about trying to manage their diabetes. I.e. Taking the blood test every 15min. And trying to adjust the a1c using Afrezza they're ignoring the fact that changes in a1c are completely normal and safe (as long as they are kept in a certain range) and that's not Mannkinds problem.

I think people are overreacting to the use of the word "fanatical" because it's commonly used to describe religious 'nut jobs'.

Relax everyone, discussions like this is why Mannkind is afraid to say anything without their lawyers scrutinizing it first and that's not helpful for investors.

[compound26]

jpg and seanismorris, both of your arguments made sense to me. However, I do think Sanofi and Mannkind need to release the "2U" whenever they can do it to address the needs of the type 1s. I do not envision Afrezza to get approved by FDA for use by the youth in the near future as Sanofi and Mannkind will need to conduct new clinical studies to support an application like that. That will take years and may not be in their priority lists at all. I understand that, a lot of times, drug companies get into the youth markets just by off-label prescriptions. Especially if the size of the youth market is relatively small compared with the adult market.

[jpg]

I would point out that any manager that regularly uses that kind of language to describe it's biggest advocates should not be permitted to make any public statement. As a clinician I find the statement and attitude towards 2 unit dosing frighteningly uninformed and lacking in insight. This has nothing to do with lawyers. If I knew this was a widespread belief at Mannkind and Sanofi I would be very nervous.

I will also point out that people with CGM have frequent data points and that frequent corrections will probably improve positive and negative feedback loops in a good way.

What Matt is basically saying is that anyone with a CMG is fanatical because the second you have real time data you necessarily want therapeutic tools to deal with real time data. It rather simple. Afrezza is THE perfect insulin for this. That this is not obvious to management really worries me. No one will be a better salesforce than satisfied T1.

[james]

This is such an awesome opportunity. A real revolution in how insulin therapy is approached; less thought, more convenience, lower risk, superior control.... What's amazing is how quickly patients are realizing this and looking to put it into action. There's nothing fanatical about that, its simply taking a step towards something not been previously attainable but sorely needed.

My fear is that the current dosing guidelines have no provision for a 2U increment which will prevent this from being brought to market without study. It seems completely intuitive, so maybe there is no barrier other than demonstrating manufacturing capability and requesting a change in the label to add a 2U entry point. I should look myself, but does anyone know right off if lower dose / response rates were established in a previous trial? Does it remain linear below 4U? There is bound to be a threshold below which the characteristics of airflow start to impede intake.

[xoxoxoxo]

Maybe they just need to get a sharpie and write "2u" on cartridges currently marked as "4u"

If it's just psychological where the action ends up being nearly identical then you could just pull the wool over the eyes of the fanatical T1s who try to control things extremely tight.

A sharpie only costs like $1.99

[jpg]

May 6, 2015 19:55:45 GMT -5 xoxoxoxo said:

Maybe they just need to get a sharpie and write "2u" on cartridges currently marked as "4u"

If it's just psychological where the action ends up being nearly identical then you could just pull the wool over the eyes of the fanatical T1s who try to control things extremely tight.

A sharpie only costs like $1.99

Having a hypoglycemic seizure may seem nearly identical as not having a hypoglycemic seizure; but it's not. Dosage matters. They aren't 'fanatical'.

They have a life altering disease and use medication with a very narrow therapeutic window and as they gain better control of their disease they become more sensitive and need less (and react more).
Again calling our only customers names is not wise. Especially when they are more knowledgable and right...

[james]

May 6, 2015 15:18:15 GMT -5 james said:

My fear is that the current dosing guidelines have no provision for a 2U increment which will prevent this from being brought to market without study. It seems completely intuitive, so maybe there is no barrier other than demonstrating manufacturing capability and requesting a change in the label to add a 2U entry point. I should look myself, but does anyone know right off if lower dose / response rates were established in a previous trial? Does it remain linear below 4U? There is bound to be a threshold below which the characteristics of airflow start to impede intake.

A bit of (incomplete) research indicates that the phase I dose increments for Technosphere Insulin were selected with the idea of delivering insulin relative to body weight.  The initial stops being selected at 0.3, 0.6, 1.2, and 1.8 U/kg (not sure how - perhaps by some therapeutic norm).  With an ideal body weight at 100lbs (45.4kg for a female at 5' - Hamwi ideal) this works out to 13.6U, 27.2U, 54.5U, 81.7U.  Bioavailability was identified at 25.8% vs. subcutaneous insulin which sets the dose equivalency in the subsequent trials.

clinical.diabetesjournals.org/content/19/1/13.full

The phase II study 005 was run with TI dosages of 14, 28, 42, 56 (so the upper range was eliminated and a .9U/kg stop added) that yield dose equivalence to SC of 3.6, 7.3, 10.9, and 14.6U.

dst.sagepub.com/content/2/1/47.full.pdf+html

The Gen2 inhaler improved the bioavailability ratio to about 30% and the later studies alter the TI dose levels to 10, 20, 30, etc. from which the first equivelance rates were given as 3/6/9U and were later raised to be labeled as 4/8/12U.  (I think that's how it went...)  I don't know why the units were relabeled and this certainly also caused confusion for the FDA.

In any case, it doesn't appear that a study was ever performed that included dosing below a target of .3U/kg and a lower bound for effectiveness has not been established.  If there is good news here, it is that glucose reduction has consistently been shown as a linear relationship with Afrezza dosing (it falls off somewhat at higher dosages) and there is little reason to believe the curve should not extend downward.  See section 2.2 of the Clinical Pharmacology Summary in the FDA briefing documents:

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

Does that mean another study is necessary to approve a 2U cartridge for adults?  I have no idea...

[saxcmann]

I was told the 2U will come but wasn't near as important/needed as getting the 12U approved.

[ezrasfund]

I think your reaction to Matt was a bit harsh. This was just a quick e-mail response to an investor. We all know what happens when private e-mails are put under the microscope. I don't know why he wrote "servicing" rather than "serving" but it might be a terminology they use. As for the "fanatical" Type 1's, I do not think Matt is refering to people like Afrezzauser and other advocates. What he is talking about is diabetics who try to micro-manage their BG by taking a very small bolus (like 0.3 units) from pump or pen after a small snack or to lower their BG by a few points.

In fact one Twitter poster seems to have removed a tweet about this subject, probably because she got a mountain of negative feedback, most of it from those other fanatics, MNKD investors.

So while you guys are sandbagging Matt please remember not to pile on when reading posts from diabetics on social media.