The research and development of new drugs is a complex time-and cost-consuming process. Based on the enormous progress in understanding of the biochemical principles of many diseases today the mechanism-based approach dominates.

In a first step, molecular receptors (enzymes) are identified (target identification), which presumably play an essential role in the development of diseases. These hypothetical targets for potential drug interaction are verified in animal models (target validation). When it can be shown in animal models that the addressed receptors are disease-relevant chemical substances are synthesized that act on these enzymes. Promising substances are optimized in multistep iterative processes (drug discovery and screening, lead optimization). Optimized compounds are subjected to detailed toxicological and pharmacological tests in the laboratory and in animals (ADMET: absorption, distribution, metabolism, excretion, toxicology). Only substances with a favorable profile of action go into clinical development (development). This proceeds in three phases. In Phase I, the tolerability and safety in humans is tested. In Phase II first efficacy data and the optimal dosage of the drug are determined in diseased patients. In phase III, all efficacy and safety data required for approval are determined in large-scale clinical trials. Based on all collected data a comprehensive registration dossier is prepared, in which all data for pharmaceutical quality (production, testing, durability), preclinical testing and clinical trials of the three phases are documented, summarized and evaluated. This dossier is submitted to the regulatory authorities and serves as the basis for deciding whether the drug is approved (registration). The whole process extends over a period of more than 10 years, with the unpleasant consequence that less than 10 years on the market remain secured by patent exclusivity.

Only clinical trials show whether the selected targets are disease relevant and whether the safety data of the selected compounds found in animals also apply to humans. The success rates are frustratingly low. Less than 10 percent of drug candidates that go into the very expensive clinical development, will reach the market.

Due to the high failure rates, whose costs become part of the development cost of successful products, the costs necessary for a successful development already amount to several billion euros. Therefore all research-based pharmaceutical and biotechnology companies seek to specifically reduce the failure rate of their development products.

A strategy pursued by many companies is not to work on drugs for new receptors (targets) but instead to focus on the search for drugs for receptors whose disease relevance has been validated by registered products and thus in clinical practice. Work on new, unvalidated receptors is up to research institutions and venture capital funded start-ups. But here too, disillusionment is spreading about the lack of success with a high risk of total loss of investment. There are hardly any venture capital funds that still invest in start-ups with preclinical research programs.

An equally often practiced strategy of minimizing risk is the "drug repurposing / repositioning". For known compounds with known ADMET profile and proven safety in humans new applications (indications) are sought. The focus of these efforts are particular applications for rare diseases (orphan diseases).

Pseudo innovation rather than therapeutic progress?

Not only the cost of developing new drugs have risen steadily in recent years. Also, the quality of new drugs is increasingly questioned. A survey conducted on behalf of the Techniker Krankenkasse (a German health insurance company) [1] concludes that new drugs are often not associated with detectable therapeutic progress and therefore represent no real therapeutic innovations, but must be addressed, in many cases simply as "commercial innovation," their use increases the cost of therapy without offering a patient-relevant benefit. Other studies confirm this assessment.

A study published in Health Affairs points out that the effectiveness of new drugs compared to placebo has fallen sharply since the 1970s [2]. 315 clinical studies that have been published in four of the best medical journals (BMJ, Journal of the American Medical Association, Lancet and New England Journal of Medicine) from 1966 to 2010 were considered and where a drug was compared with a placebo. In the 1970s, new drugs were on average 4.5 times as effective as placebo. In the 1980s, new drugs were less than four times better, in the 1990s, only twice as good, and in the 2000s only 36 percent were better than a placebo. The Magazine Prescrire in 2011 rated only 17 of the 984 in the USA newly approved drugs since 2001 as "real progress" [3]. Nature Reviews Drug Discovery has released a survey of 184 medical specialists, according to which the physicians preferred to classify older drug as "transformative" as opposed to new ones [4]. Against this background it is not surprising that world-wide stricter approval criteria are discussed to ensure that instead of pseudo-innovations with only marginal benefits for the patient only real therapeutic innovations are approved with significantly better efficacy.

Receptor blockade or modulation of systems?

Living organisms regulate their existence through multidimensional, in many cases crosslinked regulatory systems, which are protected by multiple redundant backup and repair mechanisms against the failure of individual components. Complex signaling cascades that may include hundreds of enzyme systems are involved in the regulation of cells, of organs, in their interaction and in control of the entire organism. Disturbances in single enzyme systems contribute to the development of diseases but only in very exceptional cases they are the sole cause of a disease. The vast majority of diseases is based on multisystemic disorders. Nevertheless, today by the mechanism based research approach predominantly used in pharmaceutical research it is attempted to treat diseases causally by acting on isolated enzymes (receptors). The following diagrams illustrate this approach by the example of heart disease.

The phenomenon of "ischemic preconditioning" is among the current most intensively researched areas in cardiology [5,6]. The "ischemic preconditioning" is the body's own defense mechanisms to protect the heart against oxygen deficiency. This protection mechanism is triggered by temporary interruption of the blood supply to individual organs. Several enzymes (targets) have been identified that play a role herein.

For many of these enzymes classes of substances are known or under development with which the activity of single enzymes can be regulated.

Some of the compounds listed in this chart are approved drugs. But none has cardioprotective effects, as can be achieved with ischemic preconditioning. This example clarifies that you can not treat a disease causally by acting on single enzymes. This also applies to the standard therapy of heart failure with beta-blockers and ACE inhibitors. The realizable therapeutic success with these agents (risk reduction, absolute RR) is only a few percentage points better than with a placebo.

For commercial reasons emphasis on "relative risk reduction" (RRR) is chosen. This suggests success rates, which can not be confirmed with therapeutic success rates observed in medical practice. Even with guidelines compliant therapy the prognosis of heart failure is still very unfavorable. The mortality rate for heart failure is similar to that of cancer diseases. Overall, half of the patients die within 4 years.

Activation of endogenous protective mechanisms

The limitations of the mechanism-based research approach outlined above are well known [7]. Alternative concepts such as systems biology so far have not yielded viable alternative approaches. One possible approach is the still largely misunderstood concept of "hormesis", where the activation and modulation of endogenous protective mechanisms is involved. A similar approach is currently intensively studied in cancer research with the approach of immune stimulation.

Ouabains therapeutic effects have been demonstrated impressively in decades of clinical use. Ouabain modulates the autonomous nervous system. Vagomimetic and sympatholytic effects characterize its therapeutic effects. Ouabain inhibits not only the adrenergic overstimulation but also supplies the heart vagomimetically by pronounced insulin-like anabolic effects with life-saving energy. At therapeutic concentrations, it induces intracellular signaling cascades, which are responsible for the stimulation of myocardial metabolism. Ouabain just like the currently intensively researched phenomenon of ischemic preconditioning activates endogenous protective mechanisms (RISK signaling cascade) against insufficient oxygen supply to the heart muscle. With this unique profile of mechanism of action ouabain qualifies as tailor made drug for the treatment of heart failure.

Literature

[1] Roland Windt, Daniela Boeschen, Gerd Glaeske, Zentrum für Sozialpolitik – Universität Bremen, Innovationsreport 2013, Auswertungsergebnisse von Routinedaten der Techniker

Krankenkasse aus den Jahren 2010 und 2011

[2] Olfson M, Marcus S C, Decline In Placebo-Controlled Trial Results Suggests New Directions For Comparative Effectiveness Research, Health Aff, June 2013 32:1116-1125

[3] New drugs and indications in 2010: inadequate assessment; patients at risk, Rev Prescrire February 2011; 31 (328): 134-141

[4] Kesselheim AS, Avorn J, The most transformative drugs of the past 25 years: a survey of physicians, Nature Reviews Drug Discovery 12, 425–431 (2013) doi:10.1038/nrd3977

[5] Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009 Oct 31;374(9700):1557-1565.

[6] Lavi S, Lavi R. Int J Cardiol. 2011 Feb 3;146(3):311-318. Conditioning of the heart: from pharmacological interventions to local and remote protection: possible implications for clinical practice.

[7] Patel A C, Clinical Relevance of Target Identity and Biology: Implications for Drug Discovery and Development. J Biomol Screen. 2013 Dec;18(10):1164-1185.