If you have hung around in Diabetes circles on line for long enough, you will have heard about inhaled insulins. They have a speckled history and have failed to have a significant impact on the market. Up until Afrezza, the most recent market participant, Exubera, was withdrawn from the market by Pfizer due to a lack of acceptance amongst both patients and physicians. There’s a good paper, published in 2008 when the product was coming off the shelves, on what they did wrong here. Some of which is the concern over the impact on lung function of inhaling insulin when, let’s face it, subcutaneous insulin works and doesn’t have the risk associated with your lungs or stopping you breathing!
Step forward a number of years and MannKind released their product Afrezza, which had extensive trials, but required three attempts to get through the FDA.
Now there has been a very vocal minority jumping on many Diabetes forums and groups, talking about how great Afrezza is and how it has changed their life. There has been a lot of suspicion that these people are investors in Mannkind, and that this was a co-ordinated PR campaign to get Afrezza in to the public domain. I therefore realise that in talking about it here, I’m probably playing with fire.
One of the most interesting blogs on the internet regarding using Afrezza comes from Matt Bendall in Australia. He has self funded Afrezza and Tresiba and his Afrezza Down Under blog has shown some interesting aspects of the insulin and how it works in conjunction with Tresiba. His answer seems to be “Very Effectively”.
So the anecdotal evidence from people using Afrezza is very good but in small amounts. As a new form of Diabetes Tech, it’s also novel. But here in the UK, it has to get past the Guardians of the NHS Galaxy (sorry Marvel), NICE.
Phase III clinical trials were undertaken in the EU in 2015 and the preliminary results of these are available. In addition, Phase III trials were undertaken in other parts of the globe. There is therefore an evidence body, and the details that we have are below:
- Jul 15: Results of PIII trail (n=345), published in Diabetes Care, found that in patients with T1DM, HbA1c reduction with inhaled insulin (-0.21%) was noninferior to that of aspart (-0.4%), with less hypoglycaemia, less weight gain, but increased incidence of cough
- Aug 15: Results of PIII trial, published in Diabetes care, found that in patient with TIIDM and HbA1c levels over or equal to 7.5% but less than 10% despite metformin alone or two or more oral antidiabetics, add-on prandial Afrezza reduced HbA1c by -0.4% (95% CI -0.575 to -0.23%) compared to placebo (p<0.0001)
So the data that NICE is working from is critically, not overwhelmingly in favour of Afrezza when taken from broad trials. It shows some benefits, but at a significant cost, and for the NHS, that cost is likely to be prohibitive.
Afrezza costs $7.54 per day for a daily dose of 12u versus $3.14 per day for Apidra, which is one of the more expensive rapid acting insulins.
Given the issues with getting Tresiba on the NHS due to cost, even if NICE do agree that it should be available, it will have restricted availability.
What’s notable is that for those with poor Hba1C measures, Afrezza has provided a better result.
In August 2013, the following data was published:
Aug 13: Preliminary results from the PIII Study 175 reported. In the double-blind study, 353 patients with T2DM inadequately controlled on metformin with or without a 2nd or 3rd oral medicine were randomized to AFREZZA or Technosphere Inhalation Powder (placebo), both administered using the Gen2 inhaler. The treatment period consisted of 12 weeks of prandial insulin titration followed by 12 weeks of relatively stable dosing. The primary endpoint was mean change in A1c levels from baseline to week 24 between the two groups. Mean A1c levels decreased by 0.82% in the AFREZZA group vs a decrease of 0.42% in the placebo group (between-group difference p<0.0001). 37.7% vs 19% achieved A1c levels <7.0% (p=0.0005), and 15.9% vs 4.2% achieved A1c levels <6.5% (p=0.0021), respectively. Patients on AFREZZA gained an average of 0.49 kg vs an average loss of 1.13 kg in the placebo group (p<0.0001). The incidence of mild and moderate hypoglycemia was higher in the AFREZZA group (67.2% vs 30.1%); severe hypoglyacemia, which was reported in nine (5.1%) and three (1.7%) patients (p=0.0943), respectively
Now, even though there is plenty of trials data available, one must always consider who ran and paid for the trials and as a result, what the selection was on the people that participated.
Even with the data from the inadequately controlled group, the relative improvement was 0.4% in Hba1C level. This can be equated to an improvement of around 0.5mmol/l in average blood glucose levels. These are not the kinds of numbers that the NHS is going to look favourably on.
The UK prescribing outlook is currently described as “Uncertain” in the last NHS Prescribing Outlook document from September 2015.
If you have a read of all the stories that have been posted on the web, they are nearly all positive. The thing that is striking is that there are few negative or “meh” type posts. An example can be found here on Reddit and on healthline.. It does seem that the people who are using Afrezza couldn’t give two hoots about how they eat and what they eat and are not necessarily ideal role models.
Finally, the Lancet’s meta-analysis in September 2015 stated:
“Glycaemic efficacy of Technosphere inhaled insulin is lower than that of subcutaneous insulin, but inhaled insulin has a lower risk of severe hypoglycaemia and weight gain. Long-term outcomes and safety with Technosphere insulin should be further investigated. Until further data for safety become available, Technosphere inhaled insulin should be reserved for healthy adults with diabetes who do not have pulmonary disease and who would otherwise delay initiating or intensifying insulin therapy because they are unwilling or unable to use injectable insulin.”
So given all that is presented here, just how good is Afrezza and will it ever be available on the NHS?
From the data I’ve been able to find, the answer to the first question is that it’s adequate, and no more. It seems to work, but if you are well controlled, it seems that it might not make a huge difference. It’s certainly very convenient.
Will it ever be available on the NHS? Well that’s a much harder one to answer. Given everything I can find and the limited range of effective trials, I suspect that, even if signed off by NICE, it will all come down to CCG funding, and given the current climate, there will be very specific cases where funding will be given. And being a well controlled or moderately well controlled type 1 (Hba1C lower than 7.5%) will not be one of those cases.
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Hey Tim, your blog and posts on diabetes.co.uk are what led me to use the FreeStyle Libre and led to my experiments switching away from Lantus to Levemir and finally Tresiba!
Can we get in contact for a Skype? There's so much I'd like to talk about. DM Twitter @mattybendall
I am curious if you know anyone who is using the product. There is nothing in your article about quality of life for people that are using MNKD’s product. How can you evaluate this product without discussing the difference between injecting one’s skin, the resulting scar tissue that occurs, the timing difference between eating and injecting vs eating and inhaling insulin? I look forward to your reply.
Hi Mark, at the time this article was written, back in 2015, European access to Afrezza was pretty much non-existent. This remains the case now as no approval for it has ever been sought by Mannkind. At the time I wrote it, there were few studies about user satisfaction, just a few loud voices.
In the UK, the model for getting new treatments included in our service is that firstly they have to be approved by the regulatory bodies, and then there has to be appropriate data available in order to allow an opinion to be formed. Our review body works on a QALYS equation that looks at a cost benefit basis, and while quality of life is important, so is the overall cost of the treatment. In order to recommend it, a treatment has to show a clear improvement in measurable factors, and at the time of writing, the one factor that was measurable was Hba1C, on which it gave no clear advantage. If you are aware of any studies that demonstrate improvement in quality of life through the use of Afrezza, I would be interested in seeing them as they can be submitted to the approval body for evaluation.
As a follow up to this article, I was able to try Afrezza (I undertook some testing on donated product). I was very impressed with it, but at the sametime, I was also looking at pump solutions. I found the speed of action of the insulin to be amazing, and it worked well with higher carb foods. I didn’t have a chance to fully test it as I didn’t have enough to undertake a proper test.
Whilst the points you raise are good ones, they have to be taken into consideration with whether Afrezza helps manage things like Dawn Phenomenon and the variability of glucose levels in relation to exercise. As I’m sure you’re away, as a T1, you can’t use Afrezza alone as your only insulin, so we also have to consider pump therapy as probably the best way of matching background insulin requirements. It also reduces the number of injections and for many timing of bolusing versus standard injection therapy. As a result the cost/quality of life equation becomes very complicated in this context, as our model doesn’t allow for unlimited cost.
So while I agree that the points you raise are good ones, the fact that Afrezza doesn’t have European Marketing Approval kills the question off in the first place. When it does, then the UK needs to evaluate whether the points you make are critically important and Afrezza should be on the menu. As I mentioned in the article, due to cost, and other available therapies, I suspect it will be on a case by case basis at first.