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Summary

  • The historical foundation of the Afrezza application is made up of multiple identified deficiencies.
  • Missing data is now a black box concern of the FDA as well.
  • The seal of MannKind's fate will be broken on Tuesday, April 1, 2014.

The market response to the release of briefing documents this past Friday appeared to be neutral, especially when taking into account the overall sector deterioration. Shares were down $0.37, or 7.2%, to a closing price of $4.83. However, a pre-release surge to $5.64 indicates that an intra-day sell-off of 14.3% took place. MannKind (NASDAQ:MNKD) shareholder fortunes on Monday will certainly be of interest to all.

I've already written extensively on what I believe adcom panels to be, and not to be. I do, however, want to elaborate on those thoughts heading into Tuesday's showdown.

I hope that I've convinced you by now not to see these assemblies as sterile, unbiased, fact-gathering missions, but rather as formal proceedings that, for the most part, express preconceived adjudications. I suppose that many of you don't need to be convinced of this, because I often hear people saying that they know what the outcome of an advisory committee meeting will be well before it's taken place. Unfortunately, however, in most adcoms of this magnitude, they've come to the wrong conclusion.

So, how can I come to the right conclusion?

You can't! All you can hope to do is raise the tip of your wet finger in the air to assess which way the wind is blowing.

If you accept my proposition that the majority of advisory committee meetings are enactments of preconceived outcomes, then briefing documents become critical to assessing the tack that points toward the intended destination.

The composition of an advisory committee is not one in which the petitioning party has any input. For this reason alone, they aren't juries, screened to achieve impartiality, weighing the issues surrounding a claim. Rather, each panel is charged to act on behalf of the agency. This roundtable will be chaired by Dr. Robert J. Smith, and is comprised of specialists in the field of endocrinology.

Please keep in mind that according to MannKind, these committee members will selflessly be voting against their own material interests on Tuesday afternoon. This because Afrezza's lesser risk of hypoglycemic events and weight-neutrality will keep patients in the care of general practitioners longer, without requiring them to switch over to the care of specialists, as they now tend to do.

In the focus of my jaded eyes, I now see flags of red.

The meaning of an expressed thought is less what is stated, than how it is stated. So, when I got to page 4, which addresses the Regulatory History of MannKind's Afrezza, I was interested in how that story was conveyed.

After the first paragraph, which is a statement of facts regarding the date and nature of the application, paragraph two allows us to see how the builder of the argument has structured the historical foundation upon which the frame will be built.

Afrezza has had a complex regulatory history including two previous cycles of review that resulted in issuance of Complete Response Letters on March 12, 2010 and January 18, 2012 due to multiple identified deficiencies in the application. The members of the committee should familiarize themselves with the regulatory history synopses provided in Section 1.2 of the clinical background document and Section II of the pulmonary consult review.

If reading that doesn't give ardent supporters some degree of pause, then I must commend them on the power of their denial. It seems to me that it would be enough to state that there were two response letters, but to add that there were "multiple deficiencies" without a counterbalance of some positive reference is telling. It's as if the fortune builder would have committee members ever-mindful of the fact that what's been built today rests on a previously flawed foundation.

On page 8, the FDA is looking for "advice" on the risk benefit of Afrezza.

Bullet point two addresses the lower bioavailability of Afrezza, compared to subcutaneous insulin.

The relative bioavailability of Afrezza is ~20-30% that of subcutaneous insulin. The applicant accounted for the lower bioavailability in pivotal trials using a dose conversion algorithm (i.e., 10 units of Afrezza for 4 units of subcutaneous insulin).

When it comes to any medicine we take into our bodies, less is best, isn't it? I recognize that the absorption is more rapid than subcutaneous insulin, but this larger amount is entering three times daily through the patient's lungs. And this isn't happening for a few weeks or months, but for years on end.

I've heard people repeatedly talk about other inhaled medicinal treatments as evidence that this method of therapeutic delivery is common enough so as to allay fears related to it. However, most of these products are either lung-specific treatments - asthma inhalers, for instance, or emergent use therapeutics.

Approving Afrezza, which might be inhaled three times daily over a lifetime, is substantially different, especially when you consider that the treatment population is often subject to cardiopulmonary symptomatology to begin with.

The Dream Boat inhaler might not be so dreamy, after all.

Bullet points three and four seem to be related to each other in that an atypical dose response relationship involving glucose lowering effects might be complicated by the fact that inhalation flow rates are dependent upon the breath-powered mechanism of action intrinsic to the inhaler.

After reading this, I couldn't help but wonder how this might be complicated by persons who are sick, especially those with respiratory illnesses. Even the common cold could prove to be a substantial hurdle in achieving balanced and consistent therapeutic results. For instance, is it possible that someone might believe that they haven't inhaled enough insulin, and reflexively attempt to add a second or third dose? We are talking about human beings here, not machines that follow label instructions in strict robotic measure.

Accounting for the flawed nature of human beings, who also happen to be Afrezza users, will have to factor into the approval equation.

Black-boxed data set redux?

While we all await Adam Feuerstein's impressions of the briefing documents, likely to be published on Monday, I couldn't help but be sure that one item caught his attention, perhaps more so than others.

Page 11 raises several notable concerns. Among these are dropout rates in the active arm and inadequate optimization of insulin therapies in the control arm. But what should truly be troubling to all MannKind supporters is the reference made to missing data and assumptions made in the handling of that data.

This, to me, is the biggest black box of them all. How can a study be validated if portions of the data set are missing, or unavailable? Apparently, MannKind offered some suggestion as to what the cause might be, but the agency characterized these as "assumptions", which indicates to me that they may not be in agreement with what the company is putting forward.

Even if the data are as good as some have suggested, the FDA clearly has its doubts.

Where efficacy is concerned, in type one patients, Afrezza provides statistically less HbA1c reduction than subcutaneous insulin. And in type two patients, it's better than placebo, but less effective than its short-acting subcutaneous comparator. Either of these issues alone would be disconcerting, but ultimately, approval is inextricably linked to the Gen2 device with only six months of safety data to support its use.

While there is much to be optimistic about, as the trials indeed met their end-points, there remains the brutal fact that these studies were conducted outside of Special Protocol Assessment agreements, and therefore, must meet the agency's standards of commercial viability and not those arbitrarily established by the company.

All in all, I found a dark tone cast in the briefing documents that surprised even me. I, therefore, continue to offer a cautionary perspective moving into the meeting ahead.

Alfred Mann is a great man!

That stated, whatever happens on April 1st will look nothing like the coronation of a king. No matter how revered Alfred Mann might be, Afrezza approval will not be based upon such reverence.

The panel is charged to act on the agency's objectives, whatever those might be. And after having read the tone of the briefing documents, I now believe, more than ever, that disappointment awaits MannKind and her shareholders come Tuesday evening.

Until then, always be well.

Source: MannKind's Latest Critic: The FDA Has Joined The Chorus Of Missing Data Concerns

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