From Nektar’s award-winning technology to its later commercial failure as Pfizer’s Exubera®. Followed by new hopes for Mannkind’s Afrezza® that suffered more commercial disappointment [1,2,3,4]. The life of pulmonary delivery of insulin (inhaled insulin) has been a thrilling rollercoaster ride. Experts have openly asked whether inhaled insulin has come to the end of its ride or whether there is still a place for inhaled insulin in the future . In this blog article on inhaled insulin, we’ll have a look at what the future may look like and discuss the latest advances with a novel inhaled insulin.
Inhaled insulin: an ideal mealtime insulin?
Inhaled insulin development was a hot topic at the beginning of this century and many (large) pharmaceutical companies were in the race to bring inhaled insulin to the market. After all, inhaled insulin promised to be the first needle-free administration of insulin with high hopes for patient acceptance, treatment compliance and commercial potential (an inhaled insulin product was believed ‘to sell itself’). Moreover, insulin absorption via the lungs could provide a physiological advantage over subcutaneous injections. The lungs provide a good platform for drug absorption with a large (50-140 m2), well-perfused absorptive area and thin (0,2 μm) lung-blood barrier, which facilitates rapid drug absorption. Using the automated euglycaemic glucose clamp method, Profil researchers investigated the time-action profiles of many of the inhaled insulin developments . Various inhaled insulins demonstrated rapid onset of action, comparable to that of insulin lispro, which at the time was the state-of-the art sc injected mealtime insulin.
The dramatic failure of Exubera® on the marketplace however made clear that despite positive patient-oriented evidence and positive efficacy evidence, an inhaled insulin is not an ideal mealtime insulin . Believers in inhaled insulin blamed the commercial failure on Pfizer’s lack of marketing (‘the drug did not sell itself’) and emphasised that with the right marketing strategy and a few product updates such as a smaller inhaler, inhaled insulin could have a bright future. Large insulin manufacturers like Eli Lilly and Novo Nordisk did however quickly give up on the commercialisation plans for their inhaled developments.
The only company that continued inhaled insulin development after the Exubera® fiasco was Mannkind. With Technosphere Insulin (brand name Afrezza®), their inhaled insulin offers a unique profile, faster- and much shorter-acting than any other inhaled or injectable insulin seen to date. Afrezza® has been available on the US market since 2014, but continuing low sales numbers have raised questions about its commercial viability .
Inhaled insulin 3.0
It is not too surprising that after two non-successful commercial launches, inhaled insulin development activities are now scarce. To our knowledge, the only product in clinical development is 501 insulin from Aerami Therapeutics (formerly Dance Biopharm), also referred to as a 3rd generation product or inhaled insulin 3.0 . 501 is a liquid formulation of human insulin and is applied via a small, smart inhalation device. Profil have conducted the clinical pharmacology program for 501 insulin and recently presented the final trial results at the 80th Scientific Sessions of the American Diabetes Association . The selection for presentation at this prestigious meeting demonstrates that there still is a major interest in inhaled insulin and needle-free insulin administration within the scientific and diabetes community.
From our hands-on experience, we observed the following clinical pharmacology characteristics for 501 insulin:
- Fast absorption and fast onset of action vs. sc insulin lispro injection
In both people with type 1 and type 2 diabetes, 501 insulin is absorbed fast and detectable in the circulation after approximately 15 minutes, usually a few minutes prior to onset of appearance of insulin lispro. In people with type 2 diabetes, 28 to 50 % more insulin is absorbed in the first hour after an inhalation compared to a lispro injection, also resulting in a 6.5 to 20 minutes faster onset of inhaled insulin action and a 45 to 107 % greater early glucose lowering effect .
- Duration of action similar to insulin lispro
Despite a greater early glucose lowering effect with 501 inhaled insulin, its total glucose lowering effect is comparable to that of sc insulin lispro. This is because its duration of action of approximately 8 to 10 hours is at least as long as that of insulin lispro.
- Linear dose response
The response to 3 different clinically relevant doses shows a dose-dependent increase in both total and maximum glucose lowering action. Similar dose-dependent increases are seen with insulin lispro, showing that 501 inhaled insulin titration can be performed without the need for dose conversion.
- Relative delivery efficiency of 13 %
A consistent finding in the trials: compared to the lispro injection, the 501 insulin dose needs to be 7-8 times higher to achieve the same total glucose lowering effect. This may seem like a lot more, but it is actually a good number for insulin inhalation and alternative route insulin administration in general. The design of the 501 inhaler plays a major role in producing high and reproducible delivery efficiency: its breath-actuated design ensures that only upon correct inhalation, the liquid insulin is transformed into a gentle mist for subsequent absorption via the lungs .
- Similar dosing variability as insulin lispro enabling individual dose titration 
The response to repeated dosing in the same subject is as reproducible for 501 inhaled insulin compared to lispro injection. For selected PK and PD parameters, the inhaled response may even be less variable. This is a clinically meaningful outcome and enables individual dose titration of 501 insulin in future treatment
- No cough upon inhalation
The overall clinical pharmacology data summarised above show robust and promising results for further development of 501 insulin. Its key differentiator however is its liquid formulation of human insulin, whereas most other inhaled insulins, including Afrezza®, are dry-powder products. The 501 liquid formulation is transformed into a gentle mist and is inhaled without any irritation to the airways. In 5 clinical trials with more than 300 inhalations combined, zero cases of cough were reported. This is an important tolerability result as cough was the outstanding adverse event in the Afrezza® clinical program. Roughly a quarter of all Afrezza® users experienced cough upon therapy initiation and a substantial number (3 %) stopped inhaled therapy after experiencing cough.
The future for Inhaled insulin
Although Afrezza® and 501 insulin have addressed some of the limitations of Exubera®, such as the size of the inhaler and the ease of administration, it is clear by now that inhaled insulin will not sell itself and more major hurdles need to be overcome to reach a larger patient group. For 501 insulin, Aerami Therapeutics is first looking for a partner to progress into phase 3 and apply for market approval. Should this inhaled insulin reach the market, it will however encounter similar obstacles as Exubera® and Afrezza®. Pricing and reimbursement will play a major role; safety requirements such as the need for pulmonary function tests and remaining uncertainties about the long-term safety of inhaled insulin are further obstacles that do not seem to pass quickly.
Parallel to inhaled insulin developments, recent advances to improve injection comfort and to increase the speed of subcutaneous insulin absorption were made [12,13]. Automated insulin delivery is progressing towards systems with less manual intervention and may seem an increasing attractive treatment option, especially for some people with type 1 diabetes . These advances have raised the bar for future mealtime insulin products, both injectable and non-injectable. From the rollercoaster ride inhaled insulin enjoyed so far, predicting its direction for the future is therefore not straightforward. The global insulin market is however large and there will be a growing demand for a simple, fast and pain-free solution. That is why inhaled insulin will probably ride on for a little longer.