Why Medtone A1c is Necessary for Proving BioEquivalence

[gallen]

The comment below was copied from the Yahoo MB. Can we begin some discussion on this topic? It's important and requires expertise I don't have on proving BioEquivalence. Does anyone believe that Mannkind in withholding data regarding Medtone A1c results that would damage the stock? 


Why Medtone A1c is Necessary for Proving BioEquivalence

"Al Mann Q3, 2009 Earnings Call: "All preliminary studies have confirmed that we have successfully improved the efficacy of the device by over 30 percent, delivering the same amount of insulin to patients using only two thirds of the powder and with a single inhalation and lower air flow than with the first generation Med-Tone device."

Did 171 prove this is well? It looks doubtful, but we won't know until Medtone A1c data is released.

You cannot bridge the safety of the devices without first analyzing the efficacy of the devices. The differences in the amount of powder vs insulin each device delivers into the body and absorbed by the body is what the FDA wants to find out. A 30 U dose of Afrezza in Medtone delivers how much insulin into the body vs a 20 U dose of Afrezza in Dreamboat? This is the main question. Importantly, we're not just asking how much overall powder is delivered via the inhaler. That is obvious. We're asking how much insulin from that overall powder is getting delivered, absorbed and utilized by the body. For example, how much insulin is used by the body with a 20 U dose from the Dreamboat inhaler vs. how much insulin is used by the body with a 20 U dose from the Medtone inhaler.

There is a big difference in the total U of dose and how much insulin is used via that dose. This is important when analyzing safety because if one inhaler is catching more of the insulin/powder into the lungs before being utilized by the body, then they are not bio =. Think of it in terms of how the change of inhaler size affects the change of the insulin particle size. Regardless, the only way to measure how much insulin is being caught in the lungs, is to measure the efficacy (i.e. A1c's) of both inhalers vs. the RAA arm.

This was the entire purpose of 171 and the main reason for the last 2 CRL's. MNKD has yet to prove this. If they don't prove it this time, the FDA may reject the drug and not waste its time with another CRL."

[StevieRay]

Here's an excerpt from the Q&A section of the 8/14 transcript:
"Operator Our next question come from Graig Suvannavejh from MLV & Company. Please go ahead

Graig Suvannavejh MLV & Company Good afternoon Thank you taking my questions and congratulations on the data. I just had a few questions if I could, my first if you could just confirm for us that the data that you did generate from these two trials you feel is completely adequate to address the complete response letters that were issued or the latest complete response letter that was issued by FDA specifically as it relates to anything related to the device.

Robert A. Baughman Vice President, Experimental Pharmacology Related to the device. Yes as you would imagine we've had a number of correspondents back and forth to the agency to ensure that we understood where they wanted information from the complete response letters. And we are comfortable that the information that we have generated over the on the device will satisfy the reviewing division."

The trial protocols were developed in collaboration with the FDA.

Also from the YMB PFG_01 wrote the following:


Why Medtone efficacy with Dreamboat is NOT required for FDA approval
.

- Per articles and presentations posted by those who currently do, or have in the past worked with the FDA, the only thing required for FDA approval is proven efficacy with currently "APPROVED" drugs, and equivalent safety records. So the first thing to note is the Medtone inhaler is NOT approved by the FDA, so efficacy between it and the Dreamboat inhaler do not need to be proved.

- Afrezza is the drug that provides the benefit, not the inhaler. While both inhalers may be used to deliver different quantities of Afrezza, Mannkind is only requesting approval for Afrezza delivered via the Dreamboat device. Therefore, efficacy only needs to be proved between the Dreamboat inhaler and a currently approved RAA being delivered by a current approved delivery device.

- Any difference in efficacy related to the size of the Afrezza dose, may be adjusted for by both inhalers, and therefore efficacy between the devices is irrelevant as it may be eliminated by simply adjusting dosage size.

- Safety relates to utilization of the drug, as well as the size of the dose, not the inhaler used. Therefore, since the same Afrezza formulation is used by both devices, one only needs to show in a clinical trial comparable safety data for equal or smaller doses, to bridge similar or related safety data from other trials.

- MNKD reported they communicated with the FDA numerous times to be sure the understood what was needed to address the issues raised in the last CRL. In addition the FDA reviewed both trials' protocols. If efficacy between the inhalers was required, this would of been identified by the FDA and it would of been made a primary end point in the Affinity 1 trial. However, this is not a primary end point. In fact it is not a secondary endpoint either.

- If efficacy needed to be proved between the two inhalers, then both efficacy and safety data would be bridged. Therefore, there would of been no need for the insulin aspart arm in the 171 trial.

[gallen]

Thanks! It appears black and white, so why the suspicion about the absence of comparative data between MT and DB? 

Do you follow the Yahoo board?

[gallen]

Aug 25, 2013 17:36:01 GMT -5 StevieRay said:

Here's an excerpt from the Q&A section of the 8/14 transcript:
"Operator Our next question come from Graig Suvannavejh from MLV & Company. Please go ahead

Graig Suvannavejh MLV & Company Good afternoon Thank you taking my questions and congratulations on the data. I just had a few questions if I could, my first if you could just confirm for us that the data that you did generate from these two trials you feel is completely adequate to address the complete response letters that were issued or the latest complete response letter that was issued by FDA specifically as it relates to anything related to the device.

Robert A. Baughman Vice President, Experimental Pharmacology Related to the device. Yes as you would imagine we've had a number of correspondents back and forth to the agency to ensure that we understood where they wanted information from the complete response letters. And we are comfortable that the information that we have generated over the on the device will satisfy the reviewing division."

The trial protocols were developed in collaboration with the FDA.

Also from the YMB PFG_01 wrote the following:


Why Medtone efficacy with Dreamboat is NOT required for FDA approval
.

- Per articles and presentations posted by those who currently do, or have in the past worked with the FDA, the only thing required for FDA approval is proven efficacy with currently "APPROVED" drugs, and equivalent safety records. So the first thing to note is the Medtone inhaler is NOT approved by the FDA, so efficacy between it and the Dreamboat inhaler do not need to be proved.

- Afrezza is the drug that provides the benefit, not the inhaler. While both inhalers may be used to deliver different quantities of Afrezza, Mannkind is only requesting approval for Afrezza delivered via the Dreamboat device. Therefore, efficacy only needs to be proved between the Dreamboat inhaler and a currently approved RAA being delivered by a current approved delivery device.

- Any difference in efficacy related to the size of the Afrezza dose, may be adjusted for by both inhalers, and therefore efficacy between the devices is irrelevant as it may be eliminated by simply adjusting dosage size.

- Safety relates to utilization of the drug, as well as the size of the dose, not the inhaler used. Therefore, since the same Afrezza formulation is used by both devices, one only needs to show in a clinical trial comparable safety data for equal or smaller doses, to bridge similar or related safety data from other trials.

- MNKD reported they communicated with the FDA numerous times to be sure the understood what was needed to address the issues raised in the last CRL. In addition the FDA reviewed both trials' protocols. If efficacy between the inhalers was required, this would of been identified by the FDA and it would of been made a primary end point in the Affinity 1 trial. However, this is not a primary end point. In fact it is not a secondary endpoint either.

- If efficacy needed to be proved between the two inhalers, then both efficacy and safety data would be bridged. Therefore, there would of been no need for the insulin aspart arm in the 171 trial.

[StevieRay]

Aug 25, 2013 18:45:55 GMT -5 gallen said:

Thanks! It appears black and white, so why the suspicion about the absence of comparative data between MT and DB? 

Do you follow the Yahoo board?

In my opinion, the motivation behind the suspicion is more important.  I assume they are just trying to raise doubt and create a sense of fear.
Take a look at the resource library. 
mnkd.proboards.com/board/8/mnkd-resource-center

I've posted 171 & 175 trial studies from the ClinicalTrials.gov website.   All primary end points have been met according the Mannkind.  PRs posted too.

These studies were developed in collaboration with the FDA so the fact that we have met all our Primary end points should satisfy the FDA for approval of Afrezza.  However, between now and FDA acceptance be prepared for a lot FUD.  Make your decisions based on FACTS from reliable sources.  And the YMB is not a reliable source.  You can take what the say and then go off and attempt to verify what was said is true or false.  But, to accept really any message board without verification is not very wise. 

I personally prefer this forum here because it is more tame.  The YMB is like the wild wild west and everyone carries a 6 shooter with a hairpin trigger finger!

[liane]

I personally prefer this forum here because it is more tame. The YMB is like the wild wild west and everyone carries a 6 shooter with a hairpin trigger finger!

So very true StevieRay. I read the YMB, but have no desire to jump into the fray. That "rapp" guy has been going non-stop for many days now. What you just posted now - the primary endpoints - is all we need to know. The FUDster's are working triple overtime, and it's best to just tune it out. How long they will continue to drive the share price down - I don't know. But you can bet there's a lot of accumulation going on here. Ask yourself - who's buying all these shares???

[swingtrader88]

Why Medtone A1c is Necessary for Proving BioEquivalence

"Al Mann Q3, 2009 Earnings Call: "All preliminary studies have confirmed that we have successfully improved the efficacy of the device by over 30 percent, delivering the same amount of insulin to patients using only two thirds of the powder and with a single inhalation and lower air flow than with the first generation Med-Tone device."

OPC taught me math a few months ago...But you have to assume Al is speaking factually....

If Dreamboat uses 66.7% of the powder for the same amount absorbed it means a 30U MedTone dose would need to equal a 21U Dreamboat dose. 30Ux 70% = 21U
As far as I know Afrezza using Dreamboat is planned to launch using 20U and 30U. A 30U Dreamboat dose would equate to roughly a 43U MedTone dose. 42.9Ux 70% = 30.01U

Much has been made about the Dreamboat being quite a bit more efficient than MedTone. If you run the numbers on how much Afrezza could be manufactured using both inhalers, a 30% greater efficiency with the Dreamboat has a huge impact on the COGS on the first $10B in sales. Especially when one considers how little MannKind paid for the raw insulin.

[mdcenter61]

Aug 25, 2013 19:18:14 GMT -5 liane said:

I personally prefer this forum here because it is more tame. The YMB is like the wild wild west and everyone carries a 6 shooter with a hairpin trigger finger!

So very true StevieRay. I read the YMB, but have no desire to jump into the fray. That "rapp" guy has been going non-stop for many days now. What you just posted now - the primary endpoints - is all we need to know. The FUDster's are working triple overtime, and it's best to just tune it out. How long they will continue to drive the share price down - I don't know. But you can bet there's a lot of accumulation going on here. Ask yourself - who's buying all these shares???

Amen, Liane.  Great volume today.  My hope is that true investors and funds are accumulating rather than weak handed traders.