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Image via MannKind Corp.

“Wait, you can inhale insulin? Isn’t that something you have to inject?”

Good question! And the answer is that until the early part of the 21st century, shots were the only way to administer insulin. But an inhalable version of this life-sustaining drug has been in the works for decades, and finally came to market successfully in 2015 — yet its fate still hangs in the air (pun!)

For those who haven’t been following these developments (or even many who have), DiabetesMine presents this overview of the inhalable insulin story to date even as it continues being written for our Diabetes Community.

For over 85 years after the 1921 discovery of lifesaving liquid insulin, scientists were struggling to find a viable way to get insulin into the bodies of people with diabetes without needles.

Naturally, the idea of an insulin inhaler, similar to an asthma inhaler, was an appealing prospect. But it wasn’t until new technologies appeared on the scene in the late 1990s that researchers could really begin to experiment with turning insulin into a concentrated powder with particles sized for inhalation into the lungs.

Exubera, developed by San Francisco-based Nektar Therapeutics, became the first inhaled insulin product to be marketed in 2006 by pharma giant Pfizer. It was a “mealtime” insulin, meaning it works quickly to bring down blood glucose levels after patients eat carbohydrates, and then is out of the system quickly.

This fast-acting profile is one of the big advantages of inhalable insulin, but naturally patients who need basal insulin (a constant level of background insulin), have to combine its use with a long-acting, injectable insulin like Lantus or Levemir.

For this reason, Exubera was mainly targeted at people with type 2 diabetes, although a number of type 1 diabetes patients, who tend to be early adopters of new treatments, certainly gave it a try.

Although you would expect unbridled enthusiasm for an inhalable form of insulin, (Pfizer certainly did), unfortunately, Exubera was a flop and pulled from market just a year after its introduction, in 2007.

In a way, Exubera lived up to its name; Pfizer was positively “exuberant” about the financial gains expected from this new no-needles method for delivering insulin. They were so sure it would be the next “blockbuster drug” that they plowed ahead, bringing the product to market in complete denial of indications that the inhaler may not appeal to patients.

In fact, we know from reporting in the Wall Street Journal that Pfizer sought basically zero input from patients on the design of the device, and the few doctors who expressed reservations about the difficulty of use were summarily ignored.

The problem was, the inhaler was large and clunky — a bit larger than a full-size flashlight — and it quite clearly resembled a marijuana bong, making it embarrassing to use in public, to say the least. Not to mention the inconvenience of carrying it around, especially for men who don’t typically carry purses. Also, the foil powder packets (measured in 3 or 9 milligrams) were easily mixed up and confusing to patients and doctors to equate to familiar dosing levels.

Exubera was also more expensive, costing patients about $5 a day, as opposed to $2 to $3 a day for injectable insulin.

In the end, Exubera was a $2.8 billion flop — one of the pharmaceutical industry’s costliest failures ever.

And it seems quite clear that the “unlivable” design of the inhaler was the core problem.

Lesson learned: Involve patients (the people who will have to live with the drug or device) from the very beginning of product conceptualization, and focus on their real-life concerns throughout.

The newest inhaled insulin, Afrezza, is quite another story.

It is made by California-based MannKind Corp., which was created by the late medical entrepreneur Alfred Mann — who many may remember as the pioneer behind the rechargeable pacemaker and artificial retina. He led a whole new approach to designing the insulin inhaler and dosing cartridges, a dream going back before his days of creating the insulin pump company Minimed that would later be acquired by Medtronic.

After several attempts to get this through the Food and Drug Administration (FDA), Afrezza finally came to market in early 2015. This followed years of soliciting patient input and whittling the device down to the size of a little whistle dubbed “Dreamboat.”

The insulin comes in tiny dosing cartridges, which are color-coded so that patients and doctors can easily recognize them:

  • 4-unit (blue)
  • 8-unit (green)
  • 12-unit (yellow)

The little inhaler is disposable and meant to be replaced every 2 weeks; extras come in the product packaging.

The formulation of the insulin is also different. While it’s also a fast-acting (mealtime) insulin in powder form, it has the advantage of being delivered in the arterial blood system instead of the capillary system.

As Al Mann himself explained: “We’re actually delivering insulin monomers (molecules). Nobody ever did that before. It behaves much like normal pancreatic insulin does. Normal people don’t get hypoglycemia, and people (with type 2 diabetes) taking Afrezza don’t either, even if they dose and don’t eat.”

Afrezza peaks within 12 to 15 minutes and is out of the system within an hour, compared to current fast-acting insulins that usually take at least 20 minutes to kick in, peak at 2 to 3 hours, and can stay in the system for as long as 5 hours.

In a way, you might say Afrezza is the best diabetes treatment that most people never heard of.

Why is that?

In the early days of Afrezza availability, patients who used it were quite enthusiastic. But, MannKind lost its marketing deal with pharma giant Sanofi in 2016 after initial sales failed to take off. And ever since then, MannKind has been struggling to help the drug gain market traction.

While there is strong scientific evidence that Afrezza works well, a few things have held it back from widespread adoption so far:

  • The FDA didn’t allow Afrezza’s product labeling to mention anything about decreasing the likelihood of hypoglycemia (low blood sugar); the only mention of hypoglycemia on the label is the standard warnings that taking too much insulin (of any kind) could be life threatening.
  • Sanofi held back on running consumer ad campaigns, most likely to give their newest long-acting injectable insulin Toujeo a jump-start in the market.
  • Upon its launch, physicians hadn’t heard about inhalable insulin for several years — and lingering memories of the Exubera fiasco didn’t help.
  • Before patients can be started on Afrezza, there’s a requirement that they take a pulmonary function test — and doctors have to figure out where to refer patients for this, or shell out roughly $600 to get their own spirometry machines.
  • Insurance reimbursement has been a struggle, as Medicare and the other insurers already included one or more preferred rapid-acting insulin products on their formularies, so Afrezza gets bumped to a lower tier (meaning not covered so much).

First off, be aware that inhalable insulin is not recommended for smokers or anyone who has existing lung issues.

The biggest concern of course for anyone using inhaled insulin is the unknown long-term effects on the lungs. A number of long-term studies have been conducted in rats and dogs, and now over time, increasingly with people — but none of those have lasted the decades it could take for long-term effects to show up.

The FDA advisory committee on Afrezza estimated that a randomized clinical trial to detect high risk of lung cancer would require more than 60,000 participants, followed for many years. So, it’s fair to say that we’re a long way from really knowing about the long-term cancer risk.

In clinical trials of Afrezza and several other inhaled insulins, a number of patients experienced a cough. While the cough is inconvenient, there is no evidence that it’s linked to health risks. There was also some evidence of a reduction in pulmonary function with inhaled insulin — but the reduction seemed to dissipate after 3 months of use.

Meanwhile, MannKind was clearly able to present enough safety data to reassure FDA that any more serious risks are statistically insignificant (a fancy term for exceedingly rare).

As inhalable insulin appears to work very effectively as short-acting (mealtime) therapy, the biggest barriers to adoption seem to be mostly political: the Big Pharma insulin makers maneuvering to keep their top spots on insurance formularies.

Aeramie device

We are rooting for MannKind’s Afrezza and eventually others that move into this inhaled insulin market. For example, a California-based company known as Aerami Therapeutics, (formerly Dance Biopharm), is developing a version of its own, dubbed “Afina” that is a soft mist rather than a white powder like Afrezza. This ultra-concentrated recombinant insulin requires only a few drops vaporized into mist form as you breathe it deep into the lungs through a small handheld device.

Note that inhalable insulin is also now being tested for use in Artificial Pancreas systems, as an additional component to keep blood glucose levels in check. Exciting stuff!

In short, the story of inhalable insulin is still being written — and we plan to keep reporting on it to keep you all informed as its future unfolds.

Users have been almost universally positive about the ease of use and effectiveness of Afrezza. Some of the most prominent reports on social media include:

Is the Inhaled Insulin Afrezza the Real Deal? – diaTribe

Afrezza – The Inhaled Insulin: What will NICE say? – Diabettech blog

An Open Thank-You Letter to MannKind and the People Behind Afrezza – DiaTriGuy

AfrezzaUser – blog by Sam Finta

Afrezza: Just Breathe – blog maintained by an attorney who states he is not affiliated with MannKind Corp.

Afrezza The Possibilities videos on YouTube – by Eric Fenar