For those who inhale their insulin — or would like to — big news came recently with word that MannKind Corp’s Afrezza will get updated labeling that promises to make it easier for doctors to prescribe and for patients to understand dosing.

On Oct. 2, the California company that makes Afrezza announced it had received FDA clearance for a revised product label on the inhaled insulin that substantiates the insulin’s quick action, clarifies how to ramp up dosing, and better defines which patients can benefit from it.   

As a result of the FDA sign-off on revised labeling, the company’s stock skyrocketed to levels unseen since the product’s launch in early 2015, and it’s generating quite a bit of buzz among the Afrezza community.

Whether this actually turns out to be game-changing depends on whom you believe, as the company and Afrezza fans are hailing the move as a panacea, while some physicians already prescribing Afrezza wonder if it means much at all.

Faster Action, Learned Dosing

Since Afrezza hit the market two years ago, it’s been compared to insulin lispro (Humalog) when talking with doctors and on the research front. Now, MannKind says that’s no longer the case.

“This is really a confidence builder for the company,” MannKind CEO Michael Castagna told the ‘Mine. “We were always tiptoeing around the truth of this product, having to basically say ‘Afrezza gets in the body faster, but doesn’t work any faster.’ We kept trying to tell prescribers that it’s different, but couldn’t clearly tell them it was a starting dose and this was different from any other insulin out there. We can do that now, to help them understand how to have conversations with patients about using Afrezza, for the starting dose and then to adjust accordingly.”

The FDA based its decision on clinical trial results published earlier this year showing that dosing adjustments make Afrezza more effective, and MannKind is confident this will make it easier for docs to write prescriptions — ultimately boosting the number of people prescribed this ultra fast-acting inhaled insulin.

Here’s what the updated label includes, specifically:

  • Study data that describes the time-action profile by dosage strength, showing that Afrezza is in the blood within a minute and the first measurable effect hits in approximately 12 minutes; peak effects occur ~35 to 45 minutes after dosing, and a return to “baseline” levels comes at 1.5 to 3 hours for the largest and smallest cartridges.
  • Description of “Starting” and “Adjusting” mealtime doses — making it clear that patients should begin using Afrezza with a starting dose at mealtimes, and expect to make adjustments after a meal with follow-up dosing.
  • Use in Specific Populations: The Pregnancy and Lactation sections of the label have been updated to conform to the current FDA label guidance, giving healthcare providers clearer risk-benefit information for these populations.

“So if you normally took an 8-unit dose of Novolog, you would start with 8 units of Afrezza and then titrate upward, depending on results. If you ate a bagel and coffee, and saw that the 8 units wasn’t enough, you’d adjust with another 4-unit cartridge and make a note that next time you need 12 units of Afrezza to cover that,” Castagna explains. “Because there is now documented evidence that Afrezza is out of the system within 1.5 hours, if your BG is still going up after that, you know you need another dose.”

“It comes down to a fear of the unknown and understanding this is not a 1-to-1 unit conversion, but a different way of titrating insulin from injected or subcutaneous insulin,” Castagna adds. “Doctors have been able to push back (on the traditional mindset) but we haven’t been able to fully explain this until now.”

MannKind says it’s making sure sales reps have the revised info and updated marketing materials, to take that into clinics as the final months of the year roll on.

No Hypo or Ultra Labels

What the new labeling does NOT address is Afrezza’s reported advantage in reducing hypoglycemia, or the fact that it outperforms Novo’s newly approved Fiasp insulin in terms of rapid action. 

Despite having clinical data showing a reduction in hypos using Afrezza, MannKind did not even bother asking FDA if they could include that info in new labeling. Why?

“This label change was all about dosage and PK data (pharmacokinetic, i.e. curve of insulin action), not hypoglycemia, for one thing. And the FDA does not see safety data as a marketing point,” Castagna explains, adding that the regulatory agency no longer allows competitive data in labeling anyway, as they once did. 

Meanwhile, data also shows that the new competing subcutaneous insulin Fiasp begins its first action within 17-20 minutes, peaks at two hours, and remains in the system for five hours at least. By comparison, Afrezza shows first action at 3-7 minutes, peaks in 30-45 minutes, and is out of the system within 1.5 to 3 hours depending on the dose, Castagna says. But he says FDA only allowed the Afrezza label to note that first measurable effects begin at the 12-minute mark, because the clamps used to measure this in studies have difficulty with accuracy at lower intervals.

Still, given the super-rapid course of action, MannKind did ask FDA for permission to label Afrezza as “Ultra” fast-acting. But regulators declined that because they are not prepared to create a whole new product category at this time. “What qualifies as ‘ultra’? We’d need consensus on a definition. And what’s the purpose? We knew it was longshot, but we thought we’d try anyway. This will take some work with FDA and the industry at large if we want to pursue that designation,” Castagna says.

Prescription Woes for Afrezza

No one seems to disagree with a basic fact: Doctors are not widely prescribing Afrezza, and most people with diabetes (PWDs) haven’t even heard of it. And a good chunk of those who do know about this inhaled insulin have concerns about it.

To date, MannKind says it has roughly 15,000 prescribers across the U.S. and more than 10,000 people have tried Afrezza. But a majority have decided to not continue using it — something this starting and adjustment dosing mentality can help address. It’s expected to help patients experience better real-world effect on blood sugars, and thus quality of life and A1C.

Interestingly, this video points out why that may be the case; it makes the fascinating analogy that doctors attempting to teach Afrezza is like trying to teach patients how to ride a bike. Some PWDs may need training wheels and some may need escorting before they’re eventually ready to let go and ride the bike on their own.

In an investor call on Oct. 3, Castagna was quite excited about the new label change. He described it as a “pivotal moment” in the company’s history, and also noted that prescription totals leading up to that label change had just hit the highest number per week than ever before.

Note that the FDA kept the Afrezza label’s safety warning, advising that bronchospasms have been observed in certain patients who have asthma or chronic obstructive pulmonary disease, and they kept intact a requirement that patients get a spirometry lung test before they can start on the inhaled insulin. This has been a concern for some exploring Afrezza, and some doctors have indicated that worries about potential lung effects are behind their hesitancy prescribing the medication.

While that wasn’t a part of the FDA label change here, Castagna said on the investor call that MannKind would like to work with the regulatory agency in the future to possibly revise or optionally include that information. But that’s all TBD down the road.

Still, in just the first few days following the Afrezza label change announcement, calls inquiring about the product were supposedly higher than they had been. MannKind’s stock also shot up by 45% in those first days to levels it hasn’t seen before. Observers noted that this new stock energy, combined with the label change, could help the company turnaround.

Whether that will really materialize is anyone’s guess at this point.

Endos Say…

We reached out to several providers across the U.S. who have experience with Afrezza, either as prescribers or having used this inhaled insulin themselves. While some agree that the label changes will help them and patients, others wondered whether doctors will really start flocking to Afrezza just based on this relatively minor change.

A theme we heard across the board is that the revised labeling still doesn’t address their biggest issues with Afrezza: the ‘Ultra’ fast aspect that it starts working and is out of the system in unprecedented time, and the reduction in hypoglycemia risk.

Dr. George Grunberger of the Grunberger Diabetes Institute in Michigan: Noted that he likes the visual table to figure out the initial dosing, and that’s a positive he sees from the label revision. But he wasn’t 100% sure if it would help more doctors prescribe it.

“I saw this update, but am not sure how it would influence existing prescribers or recruiting new ones,” he said. “There is no specific guidance for dose titration, so I’m not sure how that would help the ‘amateur’ prescribers.”

Dr. Michael Bush, clinical chief for the endocrinology division at Cedars-Sinai Medical Center in LA: Hadn’t heard about the label change in the initial days it was announced – something that he believes speaks to the overall lack of awareness about Afrezza in both the patient and prescriber community. He has roughly 10 patients on Afrezza, including one T2 physician. But in talking with other physicians, he doesn’t believe many have even a handful of patients on the inhaled insulin. He also isn’t sure what this label change may mean in helping that problem.

“Maybe it’s painting a slightly different picture for Afrezza, but this is not a breakthrough in doing what’s needed for physician or patient awareness,” he said, noting that one of the most influential marketing tactics could be for MannKind to piggyback onto Novo Nordisk’s promotions for the now-approved Fiasp – as far as how the two compare on the fast-action front.

Dr. Steve Edelman at Veterans Affairs Medical Center in San Diego, CA: “In my experience going around the country talking to patients and providers… most HCPs do not know much about Afrezza. At our TCOYD conferences, most patients have not heard of it. I am now emailing a participant who really wants it, as he is a cop and really would appreciate the route of administration but also the rapid-off. The new label should help.”

Dr. Tricia Santos Cavaiola at University of California, San Diego Health: “I think the new label is great, but I’m not sure how much it will help. Part of the problem is that most still think of the main benefit as having less injections and miss the real benefit of rapid on/rapid off. The real issue is getting enough patients and providers excited or knowledgeable to go read the label in the first place… then everyone would see how great it is.”

Dr. Jeremy Pettus, also at University of California, San Diego: “In my opinion, the new dosing guidelines are a little better but still don’t address the major gaps in knowledge and won’t really help move the needle in terms of getting more providers to use it. Lots more to say, but that’s the bottom line! The dosing needs to be adjusted (with better unit-to-unit conversion), the timing needs to be clarified relative to a meal, and the need for several doses for most meals… That should all be a part of it.”

Gary Scheiner, a CDE in Pennsylvania who lives with T1D himself: “The new labeling will definitely help, particularly since the old label included ineffective methods for dosage titration and failed to key in fully on the single most beneficial element of the product: SPEED. The new labeling will certainly support improving postprandial glucose management, and it will allow MannKind to promote the product in better ways and shorten the learning curve for those who start on it.”

The Future for Afrezza (?)

With recent news of Novo’s Fiasp approval helping MannKind compare the fast action of both insulins, and with both Dexcom CGM and the newly-approved Abbott FreeStyle Libre allowing more real-time data comparison, Castagna sees this as an especially exciting time for this Afrezza label change to happen.

“It’s important for us,” he says. “While it may seem simple on the surface, I would highlight that just being able to understand what a 4-unit cartridge does… is key. It’s the first time a doctor will be able to really see and understand, and that’s really important when you think of your child or loved one going to bed, and not seeing nocturnal hypoglycemia or sugars running high. To be able to know your sugars will comfortably come down over a certain period of time is really important. We think that’s critical as we go forward.”

Aside from these label changes, MannKind says it also recently dosed its first pediatric patient in the clinical trials setting (in collaboration with JDRF), and is exploring a 2-unit cartridge as a possibility for kids down the road. The company also just filed for regulatory approval in Brazil, as the first international country to start selling this inhaled insulin globally.

Importantly, MannKind also said it’s continuing conversations with payers for increased access, and the company expects this label change to help motivate more payers to put Afrezza on the formulary for patients. Improved access will be a crucial step in all of this, Castagna says.

We’re happy to hear of this progress for MannKind, and hope for the best on everything related to Afrezza. This product works well for us (both ‘Mine editor AmyT and I myself use it), and we certainly continue keeping our fingers crossed that Afrezza becomes an option for anyone who wants it. Whether this label change is really the trigger remains to be seen.

The long inhale continues in the story of Afrezza, but things are looking positive at the moment.