The long-awaited approval of MannKind's (NASDAQ:MNKD) Afrezza is sparking a torrent of articles about the implications of the drug's FDA-mandated label. However, few of those writing these commentaries seem to understand the truly important issues this label raises.
A drug's FDA-mandated label, known officially as its "Prescribing Information," lays out what is known about what a drug dose, how it is metabolized by the body, how it should be taken, what its known side effects are, whether it causes cancer in animals, whether it is safe in pregnancy, lactation, and for use in the elderly, and whether it can be used in people with kidney or liver disease. The label also describes how the drug interacts with other commonly prescribed drugs.
If you want to read the drug's full label, you can download it by clicking on the "Download PDF" link in the "Prescribing Information" box on the Afrezza.com web site.
The Black Box Warning
Much has been made of the fact that Afrezza's label contains a black box warning. This is a warning that appears in a box at the top of the prescribing information. It warns of specific, potentially dangerous issues associated with the drug. If you believe the doom cacklers, the presence of this black box warning will doom Afrezza, and with it, MannKind's stock.
But such statements show little understanding of the history of quite a few very successful drugs. Metformin (brand name Glucophage), the drug that all endocrinology practice guidelines state should be the first drug prescribed to anyone with Type 2 diabetes, carried a black box warning for many years, warning that it could cause the fatal condition, lactic acidosis. The label was only removed years after the drug came on the market, when large epidemiological studies showed this concern to be unwarranted. Millions of people were prescribed metformin during the period when it carried this black box label.
Other much-prescribed drugs that contain black box warnings include beta blockers, thyroid medication, Warfarin, Cipro, Abilify, Seoquel, Zyprexa and over-the-counter Tylenol.
The black box warning for Afrezza prohibits it from prescribed to people with lung diseases, in particular chronic obstructive pulmonary disease and asthma. It also mandates that patients should be given a simple test of lung function before being prescribed the drug and periodically afterwards. This is completely reasonable, and since many PCPs will be able to administer these lung function tests in their offices and bill extra for them -- a desirable outcome for a PCP -- this does not seem likely to limit Afrezza's use.
Who is Excluded from Using Afrezza?
The label, as mentioned, excludes people with COPD, asthma, people who are smokers, and people who have recently quit smoking. In addition, though it doesn't flat out prohibit the use of Afrezza in pregnant women, it contains wording that would discourage most doctors from prescribing it, along with some rodent research that very vaguely hints that the carrier used to deliver the insulin may pose problems for the fetus.
This is actually the one issue on the label that should disappoint investors who are long on the drug, as women with gestational diabetes are the one group of people without Type 1 diabetes who are routinely prescribed fast-acting insulin. Not only that, but these pregnant women are usually put on regular human insulin, not the newer analog insulins like Novolog and Humalog. This is out of concern that these analog insulins, which are made of molecules that are not identical to the insulin produced by human pancreas, might affect the developing fetus.
Since Afrezza delivers regular human insulin, a molecule identical to that produced by the human pancreas, it would have been a plus if it could have been prescribed to pregnant women. For now, however, doctors are likely to err on the side of caution and not prescribe it.
Much has been made of the fact that the data published in the label suggests that Afrezza does not lower blood sugar as well as injected insulins. To those who understand what the activity curve graphs included in the label imply, it should be clear that MannKind's explanation given during the ADCOM for this lack of superior performance -- that Afrezza was not dosed optimally during these studies, due to physician caution -- is likely to be correct.
The activity curves published with the label make it clear that Afrezza starts working at the same time that injected insulin does, roughly 53 minutes after it is inhaled, but unlike the injected insulins, Afrezza exercises its strongest impact on blood sugars when it first becomes active, and then immediately starts fading out.
This is very different from how injected insulins work. The injected insulins start working at that same 53 minutes, but then continue to work even more strongly for the following hour or two. This means that injected insulin is often working long after the glucose from a meal has been disposed of. When that happens, people have nasty, dangerous hypos.
This is why when injecting fast-acting insulin, the dose must be low enough that the amount that becomes active at that 53-minute time period is lower than what is needed to completely dispose of all the glucose released by the meal in the first hour, during which most digestion takes place. With Afrezza, however, because it stops working so quickly and is out of the body so quickly, it should be safe to use a much larger dose, which would result in a much more normal blood sugar at 1 hour after eating -- the time when blood sugars are most likely to be dangerously high.
This difference in how the two insulins work make it impossible to use a straight one-to-one dose equivalence table when prescribing Afrezza, though the label provides such a table.
It also may be why the FDA is asking for a future dose equivalence study. My guess, based on looking at these curves, is that it is safe to use 1.5 times as much Afrezza as injected fast-acting insulin, possibly even more. If this is the case, and Afrezza is not dosed with one-to-one dose equivalents, it may be possible to get much, much better control of meal time blood sugars, which should show up, over time, as superior improvements in A1c. Savvy endocrinologists should understand this. But it will take a few years of having those savvy doctors and even more savvy patients tweak the doses before we understand how best to use Afrezza.
The Efficacy in People with Type 2 Diabetes
The data provided on the label makes it clear that people with Type 2 using both Afrezza and injected fast-acting insulin got mediocre results from their insulin use, and ended up with fasting blood sugars and A1cs that were still far too high if the goal is to prevent complications and heart disease. Patients need to understand that Afrezza will only go so far in helping them stay healthy. For a much better outcome, they will need to add a long-acting basal insulin like Lantus or Levemir, along with Afrezza. We should hope that the marketing of Afrezza does not overemphasize freedom from needles, because people with Type 2 diabetes will be needing needles for long-acting insulin for quite a long time to come, if they are to avoid the ravages caused by out-of-control blood sugars.
Afrezza's Safety Profile
Though, as discussed above, Afrezza is prohibited for use in people with lung disease, it is very important to note that the label does not describe any significant issues associated with its use in the elderly. The "elderly" generally means people over 65 years old, and as such, takes in a huge percentage of the population who have Type 2 diabetes severe enough to require the use of fast-acting insulin.
In addition, the label cites no problem specific to Afrezza when it is prescribed for people with kidney disease. Since most people with Type 2 severe enough to require insulin have developed some degree of kidney disease, this is a major piece of good news for the drug.
The Dose Equivalence Table
Rather surprisingly, though the company stated for years that the smallest Afrezza cartridge, the one containing 10 units of Afrezza, would be equivalent to injecting 3 units of fast-acting insulin -- an equivalence that appeared in the data submitted to the ADCOM -- the label now states that the smallest cartridge is equivalent to 4 units of injected insulin.
This may pose a serious problem in marketing Afrezza for use by people with Type 1 diabetes, as 4 units of fast-acting insulin is a very big dose for most people with Type 1, many of whom use doses of only 1.5 units or 2 units at a time. If a person with Type 2 who usually uses 2 units at a meal injects 4 units, they are almost certain to experience a nasty hypo. So most people with Type 1, on learning that 4 units is the lowest available dose, are going to conclude that Afrezza is not safe for them to use.
However, as explained above, it is possible that Afrezza's activity curve, which is so different from that of the injected insulins people with Type 1 are currently using, would make it possible for someone used to injecting 1.5 or 2 units to use the "4-unit dose equivalent" cartridge safely.
But a quick scan of the diabetes discussion forums on Friday night shows that the immediate reaction of people with Type 1 posting on online discussion boards, after hearing that Afrezza was released, was to ask how the dosing works. People with Type 1 are more interested in getting the dosing right than they are in avoiding needles (which rarely the big deal to people who use them as they are to people who don't.) Until it is clear that it is safe for people used to taking much smaller doses to use these 4-unit doses, many people with Type 1 diabetes and their doctors are likely to give Afrezza a pass.
Hopefully, further study will make it clearer exactly how to dose Afrezza safely and effectively in people with Type 1 diabetes. And beyond that, if Afrezza is going to be tested in children, MannKind will have to come up with cartridges that deliver much smaller doses, which may also be useful for the many adults with Type 1 who use small doses.
Some commenters have stressed that an advantage of Afrezza is that it does not require refrigeration. This would be wonderful if it were true, because injected insulin does need to be refrigerated, if it is to retain its potency. This makes it a challenge to supply insulin to people in the many third-world countries where refrigerators aren't in every home. Even in prosperous places like the U.S., it is very easy to ruin the contents of an insulin pen by carrying it in a pocket or purse on a very cold or very hot day, as liquid insulin loses its potency when exposed to heat or cold.
However, the prescribing information for Afrezza makes no such claim as to its not requiring refrigeration. In fact, it states that Afrezza should be refrigerated before use, and that once the packets containing the cartridges are opened, they can be left at "room temperature," but room temperature is defined on the label as "59 to 86" degrees. So much for taking your Afrezza to the August picnic. Though the good news is that if you do, the worst that can happen is that you lose the one or two cartridges you brought, not a whole pen's worth of insulin.
The label also states that once the foil package containing two strips of 15 cartridges is opened, all 30 of the cartridges on those strips must be used within ten days. Once the strip is opened, the cartridges must be used within three days.
This raises the question of how stable Afrezza would be in harsher conditions. Again, time, and the experience of real-world insulin users will give us our answer. But the label errs on the side of great caution.
It is, however, likely that Afrezza will be less prone to being damaged by vibration -- an issue some insulin users have encountered when storing insulin vials or pens in a compartment on their refrigerator door, or which can occur during shipment.
What Does This Mean For Sales?
Afrezza can be prescribed for people with both Type 1 and Type 2 diabetes, but given the current dose equivalence table that appears in the prescribing information, it is most likely to be prescribed to people with Type 2 who are in very poor control, but have avoided using insulin out of fear of needles. Those who smoke or have asthma will not be getting Afrezza. But there should be enough people in that population without lung disease or smoking habits to provide a very good starting population for Afrezza.
It's important to realize that FDA labels are not static. As more data comes in, the label will change. The studies that the FDA has asked for are more likely to widen the potential market for Afrezza than to limit it.
Disclosure: The author is long MNKD. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it (other than from Seeking Alpha). The author has no business relationship with any company whose stock is mentioned in this article.