WP 7 Predictors of response to new therapies

This area of work will be lead by Partner 2 (Leiden) with input from Partner 1 (KI), Partner 3 (Berlin-Charité), Partner 4 (Vienna), Partner 5 (Dublin), Partner 6 (Amsterdam), Partner 14 (Manchester), Partner 15 (Genmab), Partner 18 (Evry-Paris), Partner 23(Future Partner) and Partner 24 (Biovitrum).

This workpackage aims to combine the clinical, immunological and molecular evaluation of clinical trials of new targeted therapies in patients with recent-onset disease. A prerequisite for the evaluation of clinical trails in the different centers is the availability of "well-coordinated" patient groups, where evaluation is performed in identical ways in the different centres. It is anticipated that the first "early trials" on targeted therapies will be feasible within the first 18 months, as a considerable level of coordination already exist between the different partners (e.g. partners .2, 3, 4 already coordinate a clinical trial called "SAVE"), and several targeted therapies (including two from the partner Genmab) are in the pipeline.

More unique for the present consortium will be the possibility for biological/immunological and molecular evaluation of therapies. These evaluations will be built on pathogenetic studies described in WP 2 and 3 as well as biomarker studies described in WP 5. Using carefully selected patient groups (for example with certain prognostic criteria and/or serological parameters and/or genetic profiles and/or molecular patterns in synovial tissues in common) we will be able to perform limited clinical trials in the centres contributing to this WP, where immune-reactivity or molecular patterns in cells of peripheral blood as well as in the synovial tissue will be analysed before and after a given targeted therapy. Such analyses should help us both to understand the principle effects in vivo of a given new therapy, and to describe whether a certain drug and/or timing of drug delivery leads to the most optimal clinical effects and their relation to changes in biological or molecular patterns. This procedure would thus both help to expand our knowledge of which molecules are indeed of pathogenic importance and how a certain biological response mode and/or molecular pattern is affected by a given targeted therapy in a given context. We believe that this approach will be of utmost importance for evaluating the effects of a single therapy and even more for establishing a basis for combination therapies with several agents hitting different targets. This approach should also allow the development of personalised targeted therapies in the future.

In the first 18 months, we aim to establish the common protocols for exchange of (historic) materials and to initiate one common targeted therapy using well-defined clinical read-outs. This will be driven as a multicentre study between involved partners, and where results will be evaluated by immunological, molecular as well as clinical means. Final results from such an initial multicentre trial will probably not be available within 18 months, but standards should have been set for further trials to be initiated.

In addition to these in vivo studies, the project will also aim to expand the local initiatives with regard to plasma protein profiles, especially with regard to autoantibodies. These markers will be associated with clinical outcome. In the period 18-60 months we expect that the data on biological phenomena such as T-cell and B-cell responses can be correlated with clinical outcome. Moreover, we anticipate that we will be able to predict better than today the outcome of a given targeted therapy as a large effort will be devoted towards the elucidation - at the start of therapy - of biological response modes, respectively plasma protein profiles and/or genetic make-up in relation to clinical outcome.