Precision medicine: do not neglect the hurdles

Tremendous expectations have been connected with precision medicine in the past years. Be-side the advantages that this type of therapy offers we should be aware of its challenges too. In this issue we will highlight on specific challenges that the pharmacological industry is opposed with when de-veloping new targeted therapies. In addition, we will discuss issues with the reproducibility of published scientific data

Advances in precision medicine — time for a new journal

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Identifying the active pharmaceutical ingredient from a mixture of fumaric acid esters for the treatment of psoriasis: Hints from in vitro investigations

A mixture of fumaric acid esters (FAEs) is approved for the oral therapy of psoriasis. However, for a long time the active ingredient of this mixture was unknown. We reviewed the in vitro data available for the different FAEs present in the multi compound drug and elaborate how they may contribute to possible clinical effects. Although helpful overall, many in vitro data must be viewed critically because the concentrations used in the experiments exceed the plasma levels reached in patients. The data suggest that dimethylfumarate (DMF) is the most active compound, mediating the major therapeutic effect after metabolization into MMF via an according receptor expressed on target cells. Identifying the active pharmaceutical ingredient within a mixture of compounds helps to subsequently eliminate unnecessary, potentially harmful compounds. This provides a promising example for an alternative precision medicine approach in clinical practice

Immunomodulation by Interleukin-10 Therapy Decreases the Incidence of Relapse and Prolongs the Relapse-free Interval in Psoriasis

The ability of interleukin-10 therapy to reduce the severity of exacerbated psoriasis has been demonstrated recently. Considering the immunobiologic properties of this cytokine we investigated the effects of long-term interleukin-10 application on the immune system and duration of psoriasis remission. We performed a placebo-controlled, double-blind, phase II trial using interleukin-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either interleukin-10 (10 µg per kg body weight; n = 7) or placebo (n = 10) three times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only two of seven patients (28.6%) relapsed in the interleukin-10-treated group. Kaplan–Meier analysis revealed a significantly lower relapse incidence in the interleukin-10 than in the placebo group (p = 0.02). The mean relapse-free interval time was 101.6 ± 12.6 d in the interleukin-10 group in comparison with 66.4 ± 10.4 d in the placebo group. Immunologic activity of interleukin-10 application was indicated by an increase in soluble interleukin-2 receptor plasma levels and higher ex vivo interleukin-4 secretion capacities. Remarkably, a significant negative correlation was demonstrated between the interleukin-4 secretion capacity and Psoriasis Area and Severity Index score (r = -0.36, p < 0.01). Our data suggest that interleukin-10 therapy is immunologic effective, decreases the incidence of relapse and prolongs the disease-free interval in psoriasis. Its value should be further determined in larger trials and for the prevention of re-exacerbation of other inflammatory disorders with a similar immunologic profile

The role of open innovation in biomarker discovery

Precision medicine aims to treat diseases with special consideration for the individual biological variability. Novel biomarkers (BM) are needed to predict therapeutic responses and to allow for the selection of suitable patients for treatment with certain drugs. However, the identification and validation of appropriate BMs is challenging. Close col-laboration between different partners seems to be a key success factor. While the importance of partnerships and larger, well-established consortia in BM discovery such as the pharmaceutical industry and academic institutions is well un-derstood and has been investigated in the past, the use of open-innovation models, also known as ‘crowd sourcing for biomarkers’, is still in its infancy. Crowd sourcing comprises of a —usually via internet— request for problem solution to an open group of users in a kind of an ‘open call’. The community (crowd) is asked to provide solutions. Since the application of the crowd sourcing method offers the possibility to collect as many as possible novel ideas from a broad community with different expertise, this approach is particularly promising for BM development. In this article we de-scribe the first examples of open-innovation models, such as the ‘grants for targets’ (G4T) and biomarkers initiative ‘InnoCentive’ (innovation/incentive) platform. They may be a fruitful basis for collaborative BM development in the future

Collaboration for success: the value of strategic col-laborations for precision medicine and biomarker discovery

Precision medicine aims to provide the precise treatment for the patient with the right dose at the right point of time. Biomarkers (BM) are vital for the identification of patients who would benefit the most from individualized treatment. In addition, they help to enable the prediction of prognosis, the detection of early therapeutic and adverse effects, and may serve as surrogate endpoints in clinical trials. BM are becoming essential tools to increase productivity in drug discovery and impressively enhance the way medicine is practiced. However, the identification, sufficient validation and implementation of such BM are challenging. This process requires expertise from different areas and high resource investments. Collaborations of different partners may be helpful to overcome these challenges. In the past decade, collaborations between diagnostics and pharmaceutical companies as well as industrial–academic collaborations have been increasingly pursued. Moreover, public funding may offer support and open new opportunities to form such consortia. Herein we give an overview of the different types of collaborations, their opportunities and challenges, and describe experiences in forming strategic partnerships with other companies

The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in the p38/TNF-α Pathway of Systemic and Cutaneous Inflammation

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream molecule of p38, involved in the production of TNF-α, a key cytokine, and an established drug target for many inflammatory diseases. We investigated the role of MK2 in skin inflammation to determine its drug target potential. MK2 deficiency significantly decreased plasma TNF-α levels after systemic endotoxin application. Deficient mice showed decreased skin edema formation in chronic 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritative dermatitis and in subacute 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity. Surprisingly, MK2 deficiency did not inhibit edema formation in subacute 2,4-dinitrochlorobenzene (DNCB)-induced contact allergy and even increased TNF-α and IL-1β levels as well as granulocyte infiltration in diseased ears. Ear inflammation in this model, however, was inhibited by TNF-α neutralization as it was in the subacute DNFB model. MK2 deficiency also did not show anti-inflammatory effects in acute DNFB-induced contact hypersensitivity, whereas the p38 inhibitor, SB203580, ameliorated skin inflammation supporting a pathophysiological role of p38. When evaluating possible mechanisms, we found that TNF-α production in MK2-deficient spleen cells was strongly diminished after TLR stimulation but less affected after T-cell receptor stimulation. Our data suggest that MK2, in contrast to its downstream effector molecule, TNF-α, has a rather elusive role in T-cell-dependent cutaneous inflammation

A call for transparent reporting to optimize the predictive value of preclinical research

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress

Trends in translational medicine: the value of external innovation

Collaborations between academic institutions and the diagnostics/pharmaceutical industry are increasingly being initiated and executed. It's assumed that these relationships could help to improve research and development productivity in industry, as well as enable academic institutions to better exploit the translational potential of their research. Identification and validation of targets and biomarkers, key elements of successful drug discovery, are challenging. Unfortunately according published data are frequently irreproducible. Thus we must not rely on published data only. Extensive joined efforts of multiple partners seem crucial to foster progress. Different models are used and required for different stages of the drug discovery and development process as well as for different kinds of targets and biomarkers. There isn't a ?one size fits all? solution. For the initial exploration of a new biomarker candidate, a novel technology, or a new target a project within a strategic partnership or an open innovation approach may be most suitable. For the comprehensive clinical validation, however, larger consortia may be more appropriate, as this requires high resources and complementary skills. We expect the high number of academic-industrial collaborations will further increase, in part (but not only) due to the increasingly availability of public funding. Each category of collaboration has its own needs to be successful. However, there are some general elements too