1. Introduction
Diabetes is a very expensive disease with many serious late complications and a steadily increasing incidence, affecting more than 400 million people worldwide (WHO Global Report on Diabetes 2016) [Citation1]. During the last decades a number of new classes of chemical compounds with anti-hyperglycemic potency have been developed. Not all representatives of these new classes of antidiabetic drugs survived on the market, mostly due to undesirable side effects and some also due to insufficient efficiency. Nevertheless, meanwhile representatives of at least half a dozen different groups of anti-hyperglycemic agents are firmly established in everyday anti-diabetic therapy.
For many decades traditionally hypoglycemic sulfonylurea drugs and metformin were the only realistic therapeutic options, representing the therapeutic principles of stimulators of insulin secretion and insulin sensitizers, respectively. This has changed and resulted in a shift from monotherapies to combination therapies for patients with type 2 diabetes [Citation1,Citation2].
In spite of this significant increase in the number of therapeutic compounds, treatment options available remain unsatisfactory. Metformin is still the drug of first choice, alone or in combination [Citation3–Citation5]. Therefore there is a need for further active research and development of new better treatment options.
2. The diabetes patent situation
Looking upon the patent situation, during the time period 2008–2016, patent applications have been submitted for several hundred compounds with the potential to act as antidiabetic drugs, interacting with a total of more than 50 different gene targets as analyzed in a recent publication [Citation6]. The search for new drug candidates is concentrated mostly in 15 internationally acting pharmaceutical companies [Citation6].
The great number of new patents for chemical compounds with antidiabetic potency [Citation6] can be interpreted on the one hand as an indication for a continuing need for compounds with new attractive mechanisms of action, on the other hand there is always a motivation of companies to develop new therapeutic compounds which can replace compounds that lose patent exclusivity.
This is a commercial justification for the development of new drugs by the large research-driven pharmaceutical companies in spite of the ever increasing costs. Ideally, however, this should also be a motivation for a company to bring new compounds on the market without delay, but also for the sake of the patients, particularly when these new compounds offer hope for a cure of the disease.
Interestingly, however, most of the patent activities during this 8-year period were focused on established gene targets [Citation6]. Four of the most prominent of the top gene targets were DPP4 (coding for an enzyme protein), SLCSA2 (coding for a transporter protein), GLP1R and INSR (coding for receptor proteins), all of which are already established drug targets in anti-diabetic therapy [Citation6]. There is a legitimation for the search of chemical modifications and of new compounds which target the proteins coded by these genes, when they show for example pharmacokinetic characteristics superior to the already existing compounds (i.e. shorter or longer durations of action in the case of the INSR and GLP1R agonists), or when they offer advantages over established compounds of the respective drug family (i.e. lesser undesirable effects or desirable positive side effect such as a cardioprotective effect). Such an added value must be documented convincingly since drug agencies demand this. If successful, such a new compound promises both major health gains for patients and significant financial profits for the company and the society as a whole. Otherwise, when therapeutic superiority over existing drugs cannot be documented, health insurances, and authorities will not provide an adequate refund of investment.
When looking upon patent applications for new targets in this 8-year period that are not yet established targets for drugs, the pharmaceutical industry has studied a variety of new targets. However, this bears a greater risk since it is very difficult to foresee, whether compounds of such new groups of chemicals may ever prove to be of greater efficiency and equipped with a more favorable therapeutic profile than established drug compounds before documentation in clinical studies. An example for this are compounds, which target biological structures responsible for a potentiation of glucose-induced insulin secretion. Compounds for which patents have been applied for are, among many others, ligands for fatty acid receptors (i.e. GPR119, FFAR1, and FFAR4).
3. Perspectives
Thus, there is still space for new therapeutic principles with real breakthrough potential. These are therapies with curative potential. The combination therapy of hepatitis C with NS5A replication complex inhibitors [Citation7] is such a recent example. New therapies with curative potential provide a great perspective for patients but also in terms of financial revenues for the pharmaceutical company. However, such therapies with curative potential are not yet foreseeable for patients with type 2 diabetes. For established antihyperglycemic drugs such as metformin, SGLT2 inhibitors, and GLP1 receptor antagonists with a capability for the reduction of the cardiovascular risk, a reversal of the diabetic metabolic state has been documented to a significant extent only, when combined with lifestyle changes such as healthy nutrition, weight loss, and an increased exercise level.
The premises for this to happen are more promising in the field of type 1 diabetes. Meanwhile there is a broad consensus in the scientific community that this will be achieved only with combination antibody therapies (for review see [Citation8]). The precondition for a successful implementation of a curative combination therapy in type 1 diabetes is, however, the availability of the required therapeutic antibodies. While this is the case for the antibodies, already established in the therapy of other autoimmune diseases, this is not yet the case for the anti-CD3 antibody which is specifically needed to reverse immune cell infiltration and abolish the release of beta cell toxic proinflammatory cytokines. Two such therapeutic anti-CD3 antibodies, otelixizumab, and teplizumab, have been evaluated in clinical trials [Citation8,Citation9]. Since antibody monotherapies have not shown sufficient antidiabetic effectiveness, the scientific and medical communities are awaiting their availability for clinical trials to document their efficiency when administered together with at least a second therapeutic antibody [Citation8].
In conclusion, it can be said that the future of therapies of type 1 and type 2 diabetes will be, like for many other diseases, combination therapies. The great challenge for the pharmaceutical companies will therefore be to provide new compounds with the capability to achieve a long-term reversal of the diabetic metabolic state through beta cell regeneration and reinforcement of their function. Once this is achieved, such new compounds with curative potential will easily outweigh the profit losses for the pharmaceutical companies through loss of patent exclusivity for presently marketed drugs during the coming years. This is the great perspective but also a major challenge in the future development of new diabetes therapies; however, at the same time also the path into a bright future for the pharmaceutical industry.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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References
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