Resistance

R2

Prediction of effectiveness and understanding of treatment failures in patients with rheumatoid arthritis treated with biotherapies

Coordinators: C. Miceli, B. Maillère
Starting date: January 2012

Biotherapies in autoimmune and inflammatory diseases
Rheumatoid arthritis (RA) is the most frequent systemic autoimmune disease, affecting 0.5% of the adult population, i.e. more than 200.000 people in France. It is a severe disease due to cartilage destruction leading to irreversible handicap and to decrease of survival rate of about 8 years comparing to general population. The first biotherapies for RA were introduced in the market in 1998 and 1999, with the first 2 TNFα antagonists, etanercept (the soluble p75 TNF receptor fused with the Fc part of an IgG1) and infliximab (a chimeric anti-TNFα monoclonal antibody, [mAb]). These new therapies lead to a dramatic improvement of symptoms in 2/3 of the patients refractory to methotrexate, the corner stone of the treatment of RA patients. Moreover these biotherapies can completely stop the progression of radiologic structural deterioration responsible for the handicap of these patients. Today, 9 biotherapies have been approved for the treatment of RA, which includes 5 different TNFα antagonists (1 soluble TNF receptor and 4 mAb-derived molecules), 1 anti-CD20 mAb, which targets B lymphocytes, 1 IL-1 antagonist (IL-1RA), 1 inhibitor of co-stimulation between antigen presenting cells and T cells, and 1 IL-6 antagonist (anti-IL-6R mAb). TNFα antagonists largely predominate for biotherapy of RA. These new treatments have transformed the prognosis and quality of life of patients with RA. However, they are also very expensive. The cost of one year of treatment per patient is in the range of 10,000 to 15,000 Euros. And obviously, they can induce side effects, especially an increased risk of serious infections. The beneficial effect of biotherapies extends beyond RA, as they proved to be efficient in a variety of autoimmune and inflammatory disorders. The total number of patients receiving biotherapies in France is estimated to be 70.000 in 2010, and the total cost of such treatments for the French society is in the range of 1 billion euros per year, one of the two highest costs for social insurances, with new anti-cancer agents (among which are several other biotherapies). In fact, this high cost is an important factor limiting to the most severe forms the use of biotherapies in patients with autoimmune and inflammatory disorders. Partner 4 is one of the international leaders in the field of biotherapies in rheumatoid arthritis and is the coordinator of several national registries assessing long term safety and efficacy of these new agents.

Resistance to biotherapies in autoimmune and inflammatory diseases
Despite their dramatic effect on inflammation in most patients, a significant number of patients fail to respond to treatment, either immediately or after a transient improvement of clinical symptoms. With respect to TNFα antagonists, approximately 30% of patients fail to respond, regardless of the underlying inflammatory disease and regardless of the antagonist used.
At least three mechanisms account for failures of treatments with TNFα antagonists:
1. There is a significant correlation between treatment failures and insufficient circulating concentration of the drug. In many instances, these insufficient concentrations are associated with an immunization against the drug, arguing for a shorter half-life of the drug in immunized patients. Partner 3 has developed expertise for assessing immunization against biologic drugs.
2. However, there are also patients with low drug concentrations but no detectable immunization. This suggests that, in parallel to immunization, other yet unidentified mechanisms contribute to the large inter-individual heterogeneity of drug concentrations. It cannot be excluded that patients with low concentrations of the drug but without detectable anti-drug antibodies actually produce such antibodies, which are either cleared with the drug in immune complexes or are not detected in assays because of interference with an excess of drug.
3. The third cause of failure appears to be insensitivity of the disease to TNFα neutralization. This appears to be the main cause of failure in ankylosing spondylitis, but approximately 30% of RA patients with no response show drug levels within the therapeutic range.

This project will involve three main partners (Partners 3, 4 & 11) towards 3 major objectives:

1. To build an "Identity Card" of patients with Rheumatoid arthritis by combining immunophenotyping data genetics and transcriptomics in order to better predict before treatment initiation what kind of biotherapy could be efficient and to better understand the mechanisms of treatment failure.
This will spare patients from unwary treatment, preventing their exposure to potential drug-related adverse events. Avoiding inefficient treatments will also have a strong impact on health costs, considering the high expenses of TNF antagonist treatments given in patients who will subsequently fail. This illegitimate cost should be in the range of 150 millions euros per year (equivalent to the annual cost of ~80 LABEX)
2. To determine in patients insensitive to TNFα neutralization the mechanisms of resistance by evaluating their ADA status, the drug concentration and the dependence to TNFα of the drug
3. To document the mechanisms of immunization against the TNFα antagonists by searching for early markers of immune response and by identifying in TNFα antagonists the immunogenic sequences (T cell epitopes)