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

Good question! And the answer is that until very recently, 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 has recently come to market — yet its fate still hangs in the air (pun!)

For those who haven’t been following these developments (or even many who have), we present this overview of the inhalable insulin story to date.

For over 85 years after the 1921 discovery of life-saving 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 1990’s 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 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 (see details below).

But in February of 2015, a new formulation inhaled insulin called Afrezza, from Valencia, CA-based MannKind Corp. hit the market. It is available today, although the company is currently floundering a bit after losing their marketing and distribution agreement with Big Pharma partner Sanofi.

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 St. Journal that Pfizer sought basically zero patient input 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 — about as big as 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 three or nine 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 drug 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 / 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. The company, MannKind Corp., created by medical entrepreneur Alfred Mann — the recently-deceased pioneer behind the rechargeable pacemaker and artificial retina — led a whole new approach to designing the insulin inhaler and dosing cartridges.

The tiny “Dreamboat” Afrezza inhaler that came to market in early 2015 was the result of years of soliciting patient input, and whittling the device down to the size of a little whistle. The dosing cartridges are color-coded so that patients and doctors can easily recognize 4-unit (blue), 8-unit (green), or 12-unit (yellow) doses. The inhaler is disposable and meant to be replaced every two 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 2-3 hours, and can stay in the system for as long as five hours.

So far, patients who have used Afrezza are quite enthusiastic. But as noted, MannKind lost its marketing deal with Sanofi recently after initial sales failed to take off.

Some might say that overly aggressive investors have “poisoned the well” for patients on this drug, which really does have the potential to help many people.

Al Mann, with his history of successful medical innovations, was incredibly good at whipping up investor enthusiasm for his newest ventures. The financial community had huge expectations for Afrezza, and there are bears and bulls (people betting for and against this drug) who have been very vocal on social media pushing their own agendas. This has made it very difficult for the patient community (ourselves included!) to share our honest experiences testing out the drug and weighing its pro’s and con’s — as the Internet trolls tend to attack anyone mentioning #Afrezza.

While there is strong evidence that the drug 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 new long-acting injectable insulin Toujeo a jump-start in the market
  • Meanwhile, 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 Payors already have one or more preferred rapid-acting insulin products on their formularies, so Afrezza gets bumped to a lower tier (meaning not covered so much)

As it stands (as of late May 2016), MannKind has regained marketing rights of Afrezza and has hired a new Chief Commercial Officer now working on a comprehensive strategy to get the drug more widely used and accepted.

While several other major pharmaceutical companies have scrapped their plans to develop their own inhalable insulins, a small San Francisco-based outfit called Dance Pharmaceuticals is quietly working on “reformatting the Exubera formulation.”

The company is actually founded by people who worked on the original Exubera team, and their new Adagio product is “a high-purity liquid formulation of recombinant human insulin” delivered in a small hand-held mini-nebulizer.

Company execs have told us they are essentially just removing some of the chemical additives in Exubera, and using a liquid pulmonary device instead of a dry powder pulmonary device — which is similar to aerosol technology but provides a “gentle mist” to inhale.

Interestingly, this formulation works slower than Afrezza, which Dance claims is an advantage because “it better matches what the body does physiologically, naturally.”

Initial investigative trials have shown positive data on safety and reliability of Adagio, and the company received a $9.5 million private investment in February 2015, topping their total funds raised at over $33 million.

Clearly there are some folks out there who believe this newest inhalable insulin product has great potential.

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 apparently 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 definitely experienced a cough. While the cough is inconvenient, there’s 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 three 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.

We are rooting for MannKind’s Afrezza and eventually Dance Pharmaceuticals’ Adagio to become widely available as effective tools for us people with diabetes — who come in a variety of shapes and sizes, and insulin needs.

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.

We at the ‘Mine have been covering inhalable insulin developments since at least 2007. Here’s a sampling of some of our top articles on the topic:

Exubera Goes Phhhttt… What Now? (October 2007)

The Truth About Afrezza Inhalable Insulin A Chat with Al Mann (November 2009)

Inhalable Insulin: A Must-Have or Overrated? (January 2011)

Inhaled Insulin Exubera is Being Remade (January 2011)

Afrezza Inhaled Insulin Hits The Market (February 2013)

Inhalable Insulin and Other News from EASD 2013 in Barcelona (October 2013)

Holding Our Breath for Afrezza Inhaled Insulin (April 2014)

Inhaled Insulin, Biosimilars Will Change the Landscape of Diabetes Care (September 2014)

Test Driving New Inhaled Insulin Afrezza (March 2015)

Amazing Afrezza – Non-Invasive Insulin That Works! (April 2015)

Inhalable Insulin Works Well for Diabetic Pilot (April 2015)

Afrezza Inhaled Insulin Works Well for Type 1 Diabetes (May 2015)

Two Users of Inhaled Insulin Afrezza Share Their Experiences (May 2015)

6 Things to Know Before Starting Afrezza (July 2015)

Afrezza: Focus Group Changes Dr’s Mind on Inhaled Insulin (December 2015)

Five Diabetes Updates from JP Morgan Healthcare 2016 (January 2016)

See also these selected resources on Afrezza from around the Diabetes Community:

Is the Inhaled Insulin Afrezza the Real Deal? – DiaTribe (May 2015)

Afrezza – The Inhaled Insulin: What will NICE say? – Diabetes and Tech, Plus (November 2015)

An Open Letter to MannKind and the People Behind Afrezza – DiaTryGuy (January 2016)

Afrezza Down Under – blog by Matt Bendall

Afrezza User – blog by Sam Finta

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

Afrezza videos on YouTube – by Eric Fenar