Exubera (recombinant human insulin with particle diameters between 1 and 5 mm) was a massive technical achievement, involving the stabilization of the insulin molecule to make it bioavailable in the dry powder form. It was also a catastrophic commercial development, which was withdrawn within a year of launch, ostensibly because of poor sales - and these were indeed abysmal - but also perhaps because of a number of reports of lung cancer, possibly accelerated by exposure to insulin. Given that new inhaled insulins are now reaching the market, with Afrezza launched in the USA in February 2015 the story of Exubera may be of some interest.
The dream of insulin administration without injection has been with us since the 1920s, and many different routes and formulations have been explored since then. The lung has a huge absorptive surface - often compared to one half of a singles tennis court - but the problem has always been to achieve a particle size capable of penetrating to the alveoli. There is no question that this achievement by scientists working at Pfizer was a major technical achievement, but insulin administration was a somewhat lengthy procedure which required use of a cumbersome inhaler.
Market analysts grossly overestimated the sales potential of Exubera, which gained FDA approval in January 2006, probably because they failed to appreciate that few insulin users are seriously troubled by insulin injection, uncomfortable although this undoubtedly is. The speed and convenience of pen injection clearly outweighed the inconvenience of inhaled insulin for many users. In the event, and although sales of $1-4 billion were anticipated, the product grossed a mere $12 million in 2007 before it was withdrawn in October of that year .
Disappointing sales were blamed for the drug's removal from the market, but the company must also have been aware of reports of lung cancer, resulting in this FDA warning in 2008:
"In clinical trials of Exubera, there have been 6 newly diagnosed cases of primary lung malignancies among Exubera-treated patients, and 1 newly diagnosed case among comparator-treated patients. There has also been 1 postmarketing report of a primary lung malignancy in an Exubera-treated patient. In controlled clinical trials of Exubera, the incidence of new primary lung cancer per 100 patient-years of study drug exposure was 0.13 (5 cases over 3800 patient-years) for Exubera-treated patients and 0.03 (1 case over 3900 patient-years) for comparator-treated patients. There were too few cases to determine whether the emergence of these events is related to Exubera. All patients who were diagnosed with lung cancer had a prior history of cigarette smoking".
How Effective was Exubera?
The following appraisal is based upon a Health Technology Assessment (HTA) published in September 2007 and based upon a systematic literature review up until November 2005.
Seven of nine trials of inhaled insulin used Exubera. There were five trials in type 1 and two in type 2 diabetes. Inhaled insulin was clinically effective, and is as effective as short-acting soluble insulin in controlling blood glucose. None of the published trials compared it with short-acting analogues - a surprising omission - but inhaled insulin had a somewhat faster onset of action. It should be noted that injection of intermediate-acting or long-acting insulin was still required for overnight control of blood glucose, and only two trials used the same basal insulin in both arms, possibly confounding the comparison between inhaled and short-acting injected insulins.
Patient preference was the only significant difference between inhaled and soluble insulin in the trials. Most patients preferred inhaled to injected short-acting insulin, and this had some effect on quality of life measures. It should however be noted that the control group generally used syringes and needles, rather than pens. As pens are more convenient, their use (with quick acting analogues) might have narrowed the difference in patient satisfaction. Getting the right dose of inhaled insulin may also be more difficult.
A key factor was the cost of inhaled insulin. Much more insulin has to be given by inhaler than by injection, and so the cost of inhaled insulin is much higher than injected. The extra cost depends on dosage but ranged from around 1000-1500 US dollars per patient per year.
The undoubted advantage of inhaled insulin is the avoidance of day-time insulin injection, although basal insulin injection is still necessary. Other potential advantages (earlier onset of action, possibly less hypoglycaemia) are minor, and must be set against the much greater cost (and in the case of Exubera) greater inconvenience of oral administration. The possibility of lung cancer also requires further scrutiny.