New ways of insulin delivery.

When Exubera (EXU), the first inhaled insulin formulation to make it through the clinical development process, was introduced to the market some years ago it was hoped that this would be the first in a series of novel insulin formulations applied by this route. In addition, it was hoped that inhaled insulin would pave the way for other alternative routes of insulin administration (ARIA), i.e. oral insulin, nasal insulin or transdermal insulin to mention only some of the different attempts that have been studied in the last 90 years. The failure of EXU, i.e. its withdrawal from the market due to insufficient market success, was followed by the cessation of nearly all other attempts to develop inhaled insulin formulations. Currently there is only one company (MannKind) which moves sturdily ahead with their Technosphere insulin. This company has submitted an NDA for their product recently and hopes to bring it to the market by the end of 2010 or early 2011. Even if the product is able to pass the approval hurdles in the USA and Europe, this does not guarantee that it will become a market success. Many diabetologists were sceptical about the need/advantages of inhaled insulin/EXU from the start and the introduction of this product has raised even more scepticism. Reports about 'side effects' (development of lung cancer in patients treated with EXU) of inhaled insulin are also not helpful, even if the causality of the appearance of cancer with this type of insulin therapy is not proven. One of the very negative consequences of stopping EXU are the huge financial losses to Pfizer. The managers in charge in other pharmaceutical companies and also most venture capitalists are reluctant to invest in ARIA nowadays. This in turn means that many of the small companies that try to develop new forms of insulin administration have issues when they try to find a big brother and/or sufficient financial support. Clearly the economic crisis has further aggravated this issue. One can foresee that with most new ways of insulin delivery the bioavailability/biopotency will be lower than with subcutaneous (SC) insulin administration. This in turn requires that more insulin has to be applied to induce the same metabolic (blood glucose lowering) effect in patients with diabetes. If the costs of insulin are of relevance for the price (this clearly depends on the source of insulin the individual company has to use) the price of the product will be higher relative to standard SC insulin therapy. The question is, clearly, what are the advantages of the new product? In times when SC insulin administration was painful and cumbersome it was clear that the ease of swallowing an insulin tablet was a good argument for many patients. With the invention of thin insulin needles that make the SC injection practically pain free in most cases, this argument of being 'convenient' becomes of limited relevance. However, for many patients (especially the public) the avoidance of 'injection' is an argument. The question is, how much is the patient (society) willing to pay for such a psychological 'advantage'? Most probably additional clear-cut clinical advantages must be demonstrable to convince the payers to reimburse a new product, especially when the price is higher than that of SC insulin. If, for example, postprandial glycaemic excursions are considerably better controlled because the pharmacodynamic (PD) effects are better than with SC injection of rapid-acting insulin analogues (this might be possible with inhaled Technosphere insulin), this would be a clinically relevant argument. Without such advantages, new products will have no market success. Most probably it will not be until one of the various ARIA developments (e.g. nasal insulin) makes it into a financially attractive product (sufficient return on investment) that more money will flow again in this area of research. The search for relevant articles about new ways to deliver insulin did not reveal very many, especially on clinical studies. However, it is fascinating to see that the imagination about improvements in existing ways to deliver insulin (e.g. insulin pens) and also about novel ways to improve insulin absorption (e.g. local heating of the injection site) is still there. At the same time the above-mentioned considerations (coming more from the viewpoint of pharmaceutical companies and more market oriented) appear not to be the focus of many scientists in pharmacological research institutes. Otherwise it is difficult to understand why every year a number of new oral insulin formulations are published in pharmacological journals, reporting impressive data from animal studies (mainly performed on rats), but only a very limited number of these are transferred to the clinical development process. It is well known that most drugs fail during the clinical development process and the resources of pharmaceutical companies that are willing to invest in, for example, oral insulin are very limited. Small companies tend to make a lot of smoke out of a little fire to gain access to these resources. Unfortunately, the limited financial resources also hamper the design and performance of pre-clinical experiments and clinical studies. The consequence is that many of the study results presented are inconclusive (to phrase it carefully). One good study that proves that a given approach works - or shows convincingly that it does not work - would be much better than a number of small studies. Sometimes one has the impression that this is done on purpose to show some activity and keep the company alive. Without a more stringent approach there is a high risk that many of the current developments will never make it into an available clinical product. These comments are not intended to be destructive but to strengthen a thorough scientific approach and to induce a more realistic view of the prospects: most probably an oral insulin pill will not be on the market next year! Nevertheless, this is the route of insulin administration where I would put my money (if I had enough). Also in this area of research it is not easy to make statements about which approaches are valid and will make it to a product. The fact that some large pharmaceutical companies are active in this area indicates that they also believe that oral insulin is the hottest candidate of the next ARIA that will come to the market.