Inhaled insulin 20+ years on – what have we learned?

What are the benefits of inhalable insulin?

Type 2 diabetes is treated by oral delivery or injection however, a significant proportion of people are averse to the use of needles, which leads to compliance issues. There is a particular concern that needle aversion might delay the start of therapy.

The use of an inhaler to administer at least part of the treatment (in the early 2000s) was considered more desirable, as it avoids the use of needles and is relatively easy to administer. Clinical trial data at the time also highlighted that insulin delivery to the lung can be extremely fast acting. A likely treatment scenario is that a patient will inject themselves at home with slow-acting insulin and then take fast-acting insulin from an inhaler before meals.

With so much potential, why did inhaled insulin fail to take off as the medical industry expected it to? To help understand this, it is worth exploring an early inhaled insulin combination product.

Technical due diligence of an inhaled insulin combination product – a case study

In the early 2000s, Team was commissioned by a pharmaceutical company to conduct a technical due diligence on an inhaled insulin combination product. The scope of the due diligence included both the device and drug.

The project team included electronics, mechanical engineering, quality and regulatory experts, as well as a seasoned drug developer with experience in the development and scale-up of respiratory drugs.

As part of this exercise, we focused on the key development areas for both the drug and device, including:

• Development status
• Clinical trial strategy
• Regulatory strategy
• Intellectual property
• Development plans
• Supply chain, key development and commercial partners
• Scale-up strategy.

During the project, we visited sites in the UK, US and Europe, in addition to site visits to the licensing partner. It is worth noting that our remit excluded a review of the business case.

The primary focus of any technical due diligence assignment is to confirm that the technology meets the licensing partner’s claims and that there are no ‘show-stoppers’ – issues which would prevent the client from pursuing the technology.

We explore whether the client understands what challenges remain, what the target company will be like to work with and additional concerns.

In this case, we set out on the due diligence approach aware of a key limitation for inhaled insulin – titration.

Insulin pens allow patients to titrate, by which they can measure and adjust the dose they need to deliver. When considering the new technology, it was clear that inhalable insulin would not be able to offer the same flexibility. This was important to discuss with the licensing partner and our client, to help outline potential device strategies to address this known limitation.

The due diligence process concluded that the combination product met the majority of the claims made by the licensing partner, though we did identify a number of both high and medium risks – areas that required further effort in the early stages of the proposed collaboration.

Our due diligence team felt that, with the appropriate oversight, the combination product would meet our client’s requirements in terms of development/unit cost and time to market.

Following the due diligence exercise, we were commissioned to provide ongoing oversight and technical support in the development of the medical product, as well as monitoring competitor products. Interestingly, this was halted only a few years later due to lower-than-expected sales for the predicate product.

What was the cause of this drop in market interest and how did it shape the future of inhaled insulin?

The challenges of inhaled insulin

Before commencing any due diligence exercise, it is important to conduct background research to make sure you understand the technology you are assessing, especially in the case of a novel technology like inhaled insulin.

At the time of the due diligence activity mentioned above, the lead inhalation product was Exubera, which became a focus of my background research. This helped to identify the following potential challenges with the inhaled insulin combination product:

• Pen injectors allow the user to titrate in increments of 1 IU, whereas inhalers are fixed-dose capsules.
• Exubera was recognized as a large device, but it was thought to be justified as patients would accept this due to the benefits of not injecting. The device that Team supported was significantly smaller and we believed that this would create a competitive advantage over Exubera.
• Existing players will improve their product to protect their market share.

What lessons does this offer for the industry?

It may appear strange to reflect on a drug product that did not meet market expectations 20+ years ago however, I suggest that the lessons learned are equally valuable today.

Numerous articles have been published regarding Exubera, identifying different reasons for why the product was not successful. The on-market inhaled insulin product, Afrezza, has demonstrated that there is a demand for inhaled insulin, but the market is not as big as was initially projected.

With this in mind, is there anything we can learn from this?

Clearly, the potential benefits of inhaled insulin do not outweigh the limitations of titration and larger device size, which could well be a perceived issue for a number of potential users. Conducting a user preference study, ideally with both general and needle-phobic users, would be useful to better understand why there appears to be a lack of widespread interest in the inhaled insulin route. Without this data, it is difficult to determine the real reason behind it.

As a medical device manufacturer, it is also important not to underestimate the existing, competing technologies on the market—competitors will likely resist and improve their offering.

Finally, there is a clear need to understand the regulatory pathway and closely engage with the regulatory authorities. Even after Exubera gained authorization from the FDA, certain patient groups were excluded and the FDA recommended that patients’ lung functions be tested at 6 and 12 months after starting treatment with inhaled insulin.

What can device manufacturers do to help develop a successful new technology?

The importance of the KISS design principle for new technology

An important acronym for any technology developer, but probably more important for new technologies, is KISS: “keep it simple stupid.” This is a common design principle which states that designs and systems should be kept as simple as possible.

In the due diligence activity mentioned above, the device part of the combination product included electronics. This provided a number of opportunities to include, at very low or no additional cost to the device, additional features that would enhance the user experience. Despite the potential benefits of these features, many were not core features for inhaled insulin and may have been better suited to a gen 2 device, once the gen 1 had built up some market demand.

One example was confirmation of drug delivery to the lung. The device provided feedback that it functioned correctly, and therefore it could be assumed that the patient received the dose – where else could the drug go? However, the technical team felt that providing additional feedback that the drug had exited the device would provide extra reassurance to the patient. To explore this, we undertook a design activity to develop a sensor in the device mouthpiece to confirm that the drug had exited the device. While this led to some interesting design solutions, the benefits to the user did not outweigh the development costs and technical risks.

Another example of potentially unnecessary features was device connectivity. It’s worth emphasizing that this was 2002, meaning a long discussion was needed about what data should be captured and what value this would bring, as well as what patients would expect. Ultimately, this connectivity was a distraction from the core device for inhaled insulin and could have been included in a 2nd generation device. Once again, we need to consider the KISS acronym.

The future of inhaled insulin

The relative lack of success in inhaled insulin over 20 years ago and continued small market size to date suggests there may not be the appetite the industry once hoped for. However, this does not mean that the delivery route does not have potential. For anyone looking to innovate in the inhalable insulin space, they would do well to learn from the lessons of the past and focus on building devices with a clear user need, that keep things simple in the first instance, and that can truly beat the competition.