AFREZZA Ad comm meeting April 1

The FDA's Endocrinologic and Metabolic Drugs Advisory Committee meets April 1 to discuss Mannkind's (MNKD) AFREZZA NDA.

The company originally submitted the New Drug Application for its ultra fast-acting inhalable insulin in March 2009. A couple of CRLs and clinical trials later, CEO Al Mann hopes this is the long-awaited breakthrough in light of his $1B+ investment to date.

Considering the inherent risk in a binary event such as an Ad comm vote, longs might want to hedge their positions.

Shares are up 12% premarket on heavy volume.

The firm's market cap is ~$2B.

Briefing docs.

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Comments (17)
  • WhitneyB
    , contributor
    Comments (903) | Send Message
    I don't have a lot of experience reading the briefing documents, but these seem to have a few potholes in them.
    28 Mar 2014, 09:26 AM Reply Like
  • CC1972
    , contributor
    Comments (91) | Send Message
    Like what? Seems there are a lot more positives that originally thought.
    28 Mar 2014, 09:35 AM Reply Like
  • WhitneyB
    , contributor
    Comments (903) | Send Message
    Failure to satisfy non-inferiority criterion, for one. See excerpts below in following comments.
    28 Mar 2014, 11:04 AM Reply Like
  • slowbullet
    , contributor
    Comments (8) | Send Message


    As good as it get a day later?


    Hats off to yesterday's writer. April fools day is near for the Motley ones. I'll be buying as always a little here and a little there. :)


    28 Mar 2014, 09:39 AM Reply Like
  • chicofromdeland
    , contributor
    Comments (17) | Send Message
    alfred mann is a proven winner,he believes.after meeting with the fda to see what evactly they were looking for,well,here goes the gutwrench phase.
    28 Mar 2014, 10:03 AM Reply Like
  • bernardc
    , contributor
    Comments (31) | Send Message
    From my very inexpert perspective I have to say the briefing docs conclusions are not very positive. But draw your own conclusions:
    The primary analysis from the T1DM trial (Study 171) met the criterion that TI (prandial insulin), delivered via a Gen2 inhaler, was non-inferior to insulin aspart in lowering HbA1c after 24 weeks of treatment in subjects whose disease were suboptimally controlled with their current basal insulin regimens (insulin glargine, insulin detemir, or NPH insulin). However, the comparative efficacy shown here was not compelling since the upper bound (0.37%) of the 95% CI of the treatment difference (TI-Gen2 minus insulin aspart) in change from baseline in HbA1c at Week 24 was almost right at the boundary of the pre-specified margin (0.4%), and the mean reduction in the TI-Gen2-treated patients was actually statistically significantly worse (by an estimate of 0.22%) when compared with that in the insulin aspart-treated patients. There were 25% and 11% dropouts in the TI-Gen2 and insulin aspart treatment arms which could have potentially impacted the primary non-inferiority analysis. Among the sensitivity analyses conducted by the sponsor, all showed similar findings to the primary analysis except for the multiple imputation under the non-inferiority null method where 0.4% was added to every discontinued patient in the TI-Gen2 group. That analysis showed a treatment difference of 0.3% (TI-Gen2 minus insulin aspart) with 95% CI = (0.15%, 0.48%), failing to satisfy the non-inferiority criterion. The 95% confidence intervals for the primary and sensitivity analyses were all above zero, demonstrating that TI-Gen2 was inferior to insulin aspart in the HbA1c change from baseline to Week 24. There were approximately 55% and 73% of the TI-Gen2 and insulin aspart treated patients, respectively, having an improved HbA1c level (i.e., change < 0) after 24 weeks of treatment. At Week 24, the TI-Gen2 treated patients had a mean decrease in body weight from baseline (-0.5 kg), while the insulin aspart treated patients showed a mean increase (+0.9 kg). For any definition of hypoglycemic episodes (e.g., severe, mild/moderate, and all), the proportion of patients experiencing at least 1 specific event was lower in the TI-Gen2 group than in the insulin aspart group. Both the mean daily prandial and basal insulin doses used in this T1DM open-label trial were consistently higher in the TI-Gen2 group than in the insulin aspart group.
    Data from the T2DM trial (Study 175) have demonstrated that TI, delivered via a Gen2 inhaler, was statistically superior to placebo in lowering HbA1c after 24 weeks of treatment in subjects whose disease were suboptimally controlled on optimal/maximally tolerated doses of metformin only or 2 or more OAD agents. However, the treatment difference (TI-Gen2 minus placebo) in change from baseline in HbA1c at Week 24 was modest (-0.4%). There were 21% and 30% dropouts in the TI-Gen2 and placebo treatment arms (15% and 21%, respectively, if rescued and completed patients were discounted) which could have potentially impacted the primary superiority analysis. However, among the sensitivity analyses conducted, all showed similar findings to the primary analysis. There were approximately 86% and 72% of the TI-Gen2 and placebo treated patients, respectively,
    28 Mar 2014, 10:54 AM Reply Like
  • 3D Investing
    , contributor
    Comments (1552) | Send Message


    You are misleading people. The point of study 171 is to show bioequivalence, non-inferiority to Medtone. It accomplished that. There was nothing on the CRL regarding anything else.


    Study 175 showed it is not a placebo effect.


    If all you can dig up from this ~200 page paper is 2 paragraphs to back up your claim that it's "not good" then you don't have much of a case.
    28 Mar 2014, 03:21 PM Reply Like
  • balert2
    , contributor
    Comments (183) | Send Message
    There is a fundamental problem in laypeople trying to make sense of this. They assume that a lower HgA1c is analogous to superiority. There are several studies that have demonstrated that HgA1c (which is used to demonstrate effectiveness) can not be used to demonstrate superiority but only non-inferiority. This is why: When a person eats his glucose spikes up and when he receives an insulin injection the spike disappears and because too much insulin may be present the glucose drops too low so the average of the two is lower and that is the HgA1c number. Because the HgA1c spike is the same with Alfreza but because Afrezza is the most rapid acting (lasts just 2 hours instead of 5 hours) the bottom is not as low and not as long the HgA1c (average) number is not as low. But the key to glycemic control is to have the narrowest curve. That is why HgA1c CAN not demonstrate superiority. The threshold for FDA drug approval is not: Is the drug safe and effective? The threshold is the drug safe enough and effective enough. Afrezza is non-inferior at every meaningful level so it is safe enough and effective enough. Afrezza actually gives superior glycemic control (narrower high and low) and that is the holy grail of insulin treatment. HgA1c is just the best method we have to measure glycemic control but it has a major limitation that can result in inaccurate comparisons. I hope that when Mannkind makes their oral presentation, they make this point apparent to the laypeople on the panel.
    28 Mar 2014, 12:56 PM Reply Like
  • 9767081
    , contributor
    Comments (12) | Send Message
    Why can't they put it in plain english? is it better... worse... will it be a breakthrough in managing diabetes...? No wonder no one in government can get anything done. Just english please.
    I don't think Mr. Mann is interested in creating/developing a drug/treatment that's going to hurt someone! I do own stock but i'm a small potato.
    28 Mar 2014, 01:17 PM Reply Like
  • balert2
    , contributor
    Comments (183) | Send Message
    Dear 9767081. When you simplify something into "plain English" it is not always 100% correct.
    28 Mar 2014, 01:33 PM Reply Like
  • ChrisWestLA
    , contributor
    Comments (44) | Send Message
    Do we have any "experts" who have seen hundreds of these briefs and can chime in whether this level of conclusion (citing goods and bads) results more often in denials, or is this just standard briefing language and that has no correlation to the ultimate opinion from the FDA committee?
    28 Mar 2014, 01:40 PM Reply Like
  • gdavidson99
    , contributor
    Comments (64) | Send Message
    I added to my position today @ $5.02. Now I'm on my way to church to light some candles. See ya'all there.
    28 Mar 2014, 02:05 PM Reply Like
  • balert2
    , contributor
    Comments (183) | Send Message
    Yes, the briefing document should have an "abstract" at the beginning but they are not written for the investors. This 248 page document is prepared with the intention to present the facts and the reader make their own conclusions.


    For instance page 9 says Afrezza has a lower bioavailability than subcutaneous injections. As a rule, injected drugs have a greater bioavailability than any other route so a 20-30% bioavailability would be in the desirable range. If it just said normal, it would be easy for the investor to understand but not actually correct.


    Next paragraph says the dose relationship is atypical. That sounds like "not normal." Fact is a typical glucose response to subcutaneous insulin injection is glucose first spikes up (hyperglycemia) and then spikes down (hypoglycemia) and then returns to normal. When Afrezza is used properly the glucose spikes up and then returns to slightly below normal and then quickly to normal without causing hypoglycemia. That would be atypical to subcutaneous injections but actually the most desirable and most similar to the bodies natural response to insulin made by a nondiabetic. Some patients using Afrezza did experience hypoglycemia because diabetics typically receive their injection about 30 minutes before they eat so some used Afrezza this way and the drug was already peaking before they started to eat. This could cause a short duration of hypoglycemia. Afrezza should be used about the time or even a few minutes after the patient starts to eat. Patients and health care professionals need to be educated properly.


    Briefing documents assumes the reader has a lot of scientific knowledge and able to reach their own conclusions.


    The cliff notes version is the briefing document said efficacy is fine/nonissue but the panel members need to evaluate safety and it poses the questions/issues that need to be considered before they vote (such as what I just pointed out). I did not find the issues to be significant hurdles. I found the briefing document to be a positive. Absolutely not even one surprise.
    28 Mar 2014, 02:58 PM Reply Like
  • johnchowmd
    , contributor
    Comments (1458) | Send Message
    Afrezza will be approved.
    30 Mar 2014, 02:33 AM Reply Like
  • CapitalGrowth
    , contributor
    Comments (24) | Send Message
    I'm neither a Pharmacologist nor a Toxicologist, so I need from help other readers who are perhaps more qualified to tell me if this excerpt of the FDA Briefing Doc's has an error.
    On page 15 of the document, you'll find the Conclusion paragraph for the Nonclinical Pharmacology/Toxicology Summary. Here's the section of this paragraph that I'm questioning:
    "The results of these studies have suggested some potential for pulmonary irritation with Afrezza at maximum clinical exposures (99 mg Afrezza=TI =88.6 mg Technosphere + 10.4 mg insulin). This is based on minimal to mild respiratory irritation observed in rats and dogs following chronic exposure to Technospheres by inhalation at ≤2-fold higher exposures in animals relative to therapeutic
    exposure at the maximum clinical dose (99 mg Afrezza). These findings in test species did not have any functional significance on respiratory function. The respiratory irritation appeared to recover with discontinuation of Technosphere inhalation in animals."
    It looks to me like the first sentence should say "respiratory irritation" rather than "pulmonary irritation" because the justification/explanation that follows is all referring to respiratory irritation.
    Can someone out there who understands this issue better than me please comment?...thank you.
    30 Mar 2014, 02:34 AM Reply Like
    , contributor
    Comments (193) | Send Message
    I will not lie, I am hoping for a good outcome, I am reading this as a Med Tech, not an FDA reviewer. The numbers of .33 .22 .21 inferior are clinically insignificant and can be attributed to many other factors that have little to do with performance of the Alfreeza. With that being said, if that is the statistical difference of HbA1C and I was a diabetic, I'd be throwing away the needle any buying Alfreeza.
    31 Mar 2014, 09:09 AM Reply Like
    , contributor
    Comments (193) | Send Message
    Pulmonary is analogous to Respiratory in that it is one part of it. In anycase, the read says it was seen in test species not human subjects, (rats and mice.) It also says it was only seen at the maximum dose and was minor in the species mentioned. What is absent from the stat is % of test species experience the irritation, and was it double blind study, with distilled water being used as an inhale on a control group of the species. Spraying distilled water in you nostrils on a daily basis, washes nasal bacteria down into your lungs and causes infection and irritation. Many caged animals get respiratory infections without inhalers as well (kennel cough). So the question is what was the control group?
    31 Mar 2014, 09:19 AM Reply Like
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