Monitoring of the patients treated by Anti-TNFα : a step towards the personalized medicine.

Transcription

1 10 th World Congress on Inflammation Paris (France) Satellite Symposium June 27 th 2011 Monitoring of the patients treated by Anti-TNFα : a step towards the personalized medicine. 1

2 Introduction Pr. Xavier Mariette, Rheumatology Department, Le Kremlin Bicêtre, France Anti-TNFα are biotherapies more and more used by clinicians in the management of inflammatory diseases such as Crohn Disease (CD) or Ankylosing Spondylitis (AS). Nevertheless, although they represent a real therapeutic revolution for the patients benefiting from them, a significant percentage of those patients does not respond in a satisfactory way and will require an adjustment of the therapeutic strategy. Since the launch of the 1 st anti-tnfα (Infliximab) in 1999, the therapeutic arsenal at the disposal of specialists considerably grew richer because in my only field (rheumatoid arthritis), nine compounds are already available. Today, the real stake for the practitioner is to not only be able to choose the good treatment for the good patient in order to maximize the chances of response but also to adapt at best the therapeutic strategy in case of relapse. To cross successfully this stage towards a personalized medicine, it is thus necessary to be able to both monitor the concentration of the drug and its potential immunogenicity (capacity to produce neutralizing antibodies against the drug). If the monitoring of the patients treated with anti-tnfα is a priority at the European level as shows it the creation of the group Innovative Medical Initiatives (ABI risks), we have to keep in mind that the monitoring of those patients is a very important topic in everyday life. The presentations which follow illustrate perfectly this notion, by the prism of 3 concrete examples in which the diagnostic tools given by Biomedical Diagnostics (LISA-TRACKER kits) were very useful and are doubtless going to allow to optimize, in the coming years, the treatments with anti-tnfα mainly in rheumatology and in gastroenterology. 2

3 Dosage of ADAb in the management of the treatment of inflammatory rheumatisms We know from now on that 30 to 40 % of the patients affected by Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) and treated with anti-tnfα are relapsing and that half of these non responders are improved either after therapeutic intensification or after rotation (change of anti-tnfα). This weak therapeutic response is associated, at the same time, with a low blood concentration of the administered anti- TNFα and with the presence of antibodies directed against the drug (ADAb). Our initial hypothesis is based on the existence of 2 groups of non responders: the patients presenting a lack of efficiency of the anti-tnfα (too low dose or production of ADAb) who would be good candidates for a rotation, and those whose disease could be poorly mediated by TNα and who rather be eligible to other treatments than a rotation. The main purpose of this work is to determine if the patients responding to a rotation have a lower concentration of the initial anti-tnfα (ETN, ADA or IFX) and more widely, to estimate if there is a link between the concentration of the anti- TNFα and the response to a rotation. The 69 patients (40 RA and 29 AS) included in this prospective multicenter study performed between 2003 in 2010 in the french hospitals of Kremlin Bicêtre, St Antoine and Rouen, face either a primary therapeutic failure (lack of response to the initial treatment), or a secondary failure (decrease of the response despite a validated initial efficacy) or are refractory to treatments with anti-tnfα. All relapsing patients with a therapeutic strategy of intensification as well as those presenting time limits overtaking respectively 1 week for ETN, 2 weeks for ADA and 8 weeks for IFX, were excluded. After 3 months, the response rate is close to 65% for RA patients and 41% for AS patients, which is consistent with data of the literature for patients relapsing after the initial anti-tnfα treatment. Dosages were made by two different methods - LISA-TRACKER kits and homebrew kits - and the correlation of both data is excellent. The dosage of the drug, in case of a failure with the initial anti-tnfα, does not allow to plan the response to a new anti-tnf after a switch. However, non responders to the switch have a significant higher concentration of the anti-tnfα (2,83 vs 1,52 mcg/ml). Even if in the population of this study the variance is not statistically significant, it shows a strong trend (P=0,09) that good responders to a switch have a lower blood rate of the previous anti-tnfα than non responders. If this trend is confirmed by further studies, it would be necessary to consider the hypothesis of a failure of this molecular class. Those patients would thus be rather eligible in a change of molecular class rather than in a rotation. Among the patients whose concentration in anti-tnfα is low, many of them present ADAb too. And the opposite is also true: the patients whose concentration in anti- TNFα is normal did not develop ADAb. The difference is significant and we can assert that there is a link between the presence of ADAb and the low concentration in anti-tnfα. Recent data from the literature confirm our results and particularly the existing correlation between the absence of ADAb and the response to a switch. Pr Corinne MICELI, Rheumatology Department, Le Kremlin Bicêtre, France All these results suggest that the dosage of the anti-tnfα, as the titration of ADAb, are parameters which will help the clinicians in the optimization of the monitoring of chronic inflammatory rheumatisms. 3

4 Infliximab (Remicade ), anti-drug antibodies (ADAb) and TNFα serum concentrations in patients with ankylosing spondylitis treated with Remicade Pr Maxime BREBAN, Ambroise Paré Hospital, Boulogne (France) Ankylosing spondylitis (AS) is a chronic articular affection spread within the Caucasian population (prevalence: 0,3 %) which is characterized in particular by the high frequency of its systematic clinical symptoms (uveitis, psoriasis, IBD). The therapeutic options were limited until the introduction of anti-tnfα which now allow to significantly improve the treatment of this affection, but unfortunately not for all the patients. The 3 available anti-tnfα in this indication Infliximab (IFX), Etanercept (ETN) and Adalimumab (ADA) present relatively similar results with success rates around 50 %. Since the availability of LISA-TRACKER kits, we can finally obtain additional information to better understand what happens for each of our patients. Our randomized multicenter control study involved 32 centers in France between 2003 and The 247 included AS patients were treated with Remicade (IFX) according to different protocols and followed over 58 weeks. First of all, patients were randomized into 2 groups: the Q6 group which, after the period of induction (3 infusions at W4, W6 and W10), received an infusion of IFX every 6 weeks. the «on demand» group which, after the period of induction, received infusions according to needs. This group is subdivided into 2 (with and without MTX) to identify a potential impact of Methotrexate ( MTX). Our results are consistent with the data of the literature: the clinical response (ASAS20 criteria and partial remission) is significantly higher in patients from the Q6 group. the dosage of ADAb allows to distinguish 2 types of failure: primary (early production of anti-drug antibodies) and secondary (late production of ADAb with a level which remains high). all patients from Q6 group with ADAb concentrations > 200 ng/ml have a blood level of IFX < 0.1 mg/ml. 22% of non responders develop ADAb while it is only the case for 7 % of responders. non responders have more often a high blood level of TNFα (27 %) than responders (10 %). the addition of MTX does not significantly change the clinical response; MTX does not influence the pharmacokinetics of anti-tnfα. The monitoring of these parameters seems to be a precious help to make the difference between the patients in primary failure and those who are refractory to anti-tnf treatments. It allows to detect a possible phenomena of immunization, these patients being then good candidates for a switch. However, these dosages must always be correlated with clinical data. Further studies are requested to validate these trends in order to better estimate the predictive value of these parameters in the case of a primary failure or relapse. The concomitant triple dosage of TNFα / anti-tnfα / ADAb obtained with LISA-TRACKER kits will represent a valuable diagnostic tool to improve the management of patients treated with anti-tnfα. 4

5 Monitoring of IBD patients treated by anti-tnfα IBD (Inflammatory Bowel Diseases) include various entities where TNFα plays a key role, such as Crohn Disease (CD) and ulcerative colitis (UC). Two biologics (anti- TNFα) are marketed for the treatment of these affections (IFX and ADA) but still 30 to 40 % of IBD patients failed to those anti-tnfα. We need biomarkers to find answers to essential questions such as the optimal moment to stop the treatment, the existence of predictive factors of a failure or an intolerance to anti-tnfα or even the better way to identify candidates for an optimization and those for a rotation. Among the most recent studies, two of them bring to light the undeniable interest to measure at the same time the anti-tnfα (IFX) and the possible presence of antibodies anti-drug (ADAb). A high concentration in IFX associated with the absence of ADAb is in favor of a good clinical response. On the other hand the association of a low concentration in IFX (<0,5μg/ ml) and a high concentration in ADAb (> 10 UI / ml) is predictive of a relapse. The optimization (increase of the dose) is ineffective for patients with a high concentration of ADAb but could be a good therapeutic strategy for those with a low concentration in IFX and no ADAb. The objective of our study is to estimate the interest of a kit for the dosage of TNFα / IFX / ADAb in the monitoring of 41 IBD patients treated either with IFX or with ADA. Our results confirm the data of the literature in this domain: we did not observe any correlation between the concentration in TNFα and the clinical response. non responders seem to have a higher concentration of IFX and this trend is more pronounced for UC patients. if the concentration of IFX is low, the patients will be responders to an optimization of their treatment. patients with high levels of ADAb are mostly non responders. If the concentration is superior to the cut-off value, we can be certain that the patient will relapse. there is an inverse correlation between residual IFX and presence of ADAb. Even if further studies are needed, LISA- TRACKER kit is already an interesting diagnostic tool for optimizing the monitoring of IBD patients treated by biotherapy. The interpretation of these dosages should help to adjust the therapeutical strategy for each patient: patients with low IFX and without ADAb would benefit from a dose optimization. patients with low IFX but high level of ADAb would be good candidates for a rotation. patients with normal IFX and no ADAb could be refractory and it would be more relevant to try other treatments. patients with normal IFX but high level of ADAb could develop non neutralizing antibodies. Residual IFX and ADAb could be very helpful to decide to stop anti-tnfα treatment for patients that go well. Dr Stéphane Paul, L. Rinaldi et X. Roblin, Hôpital Nord, Saint Étienne Studies with other anti-tnfα are necessary to validate these trends to a wider scale. A study is currently in progress to provide a valuable LISA-TRACKER kit for the dosage of TNFα, Adalimumab (ADA) and ADAb for AS patients and preliminary results are very encouraging. 5

6 Discussion Pr. Mariette : Is there really a need of measuring each time the 3 parameters (TNFα, anti- TNFα and ADAb)? Would not the only dosage of the anti-tnfα be enough to conclude because of the strong existing correlation between its blood level and the clinical response? Pr Breban : residual IFX did not allow to distinguish responders and non responders for AS patients. The dosage of ADAb is also very important. Even if for a small number of patients thetnfα was not biologically active, its dosage was nevertheless useful because patients with a high TNFα were all non responders. Dr Paul : we have the same perception for IBD patients; the dosage of ADAb is a good indicator for deciding what is the best way to adapt the therapeutic strategy between optimization and rotation. That is why the combination of the dosage of the anti-tnfα and the potential ADAb appears to be the best toll as of today to optimize the management of these patients Pr Miceli : during our study, we did not notice any significative difference between responders and non responders regarding the level of TNFα. Pr Cholet-Martin (Bichat) : before concluding that the dosage of TNFα is useless, we should question the preservation of samples. Indeed, the majority of the studies regarding the followup of the patients under anti-tnfα are retrospective and thus based on the analysis of more or less recent blood samples. Because TNFα is rather unstable, it is certainly possible that it could be difficult to detect it, if it has not been preserved in optimal conditions (fast freezing). Prospective studies are needed with a special care of serum conservation in order to assay if the dosage of TNFα is relevant or not. Pr. Mariette : Could the association with immunomodulators modify the immunogenicity of the different anti-tnfα? - Dr Paul : as RA patients, IBD patients who get MTX in association with their anti-tnfα develop less ADAb, what supports the hypothesis that the anti-tnfα is less immunogenic when its administration is associated with an immunomodulator. Pr Breban : our results are not consistent with this finding for AS patients and that is not an isolated case. MTX does not influence either the residual IFX or the production of ADAb. We can formulate the hypothesis that the Ankylosing Spondylitis (AS) is an exception and that it is probably a pathology on which MTX is less effective, unlike the rheumatoid arthritis for example. The association of MTX would decrease the production of TNF and facilitate the action of the drug on RA patients. 6

7 Discussion Pr. Mariette : Regarding the immunization, is there any difference among biotherapies? In other words, are certain anti-tnfα more immunogenic than others? Results from studies including Etanercept (ETN) tend to demonstrate that ETN is not immunogenic because we did not identify anti-etn antibodies. On the other hand, the results seem to indicate that the immunization generated by Adalimumab (ADA) and Infliximab (IFX) are similar Dr Paul : ETN is not indicated for IBD that is why we cannot provide data for this anti-tnfα. Nevertheless, we did not observe any difference between ADA and IFX regarding immunization during our studies, which is consistent with the fact that they are equally immunogenic. Pr Breban : ETN results from a natural protein which circulates in the body. The absence of anti-etn antibodies could be explained by the fact that antibodies directed against biologics are mostly anti-idiotypics and that the ETN has no idiotype because it is a soluble receptor coupled with a Fc fragment. On the other hand, antigens such as ADA would be more immunogenic especially because they are not present in the body in the natural state. Pr. Mariette : Do you think that we could use the result of these dosages to decrease or even to stop the treatment for patients who are going well? Dr Paul : in our populations, the production of ADAb by the patients is very different according to the frequency of administration of the biotherapy. The level of ADAb seems sharply superior when the treatment is occasional, comparatively to the patients treated on a long term basi. Pr Breban : we have a part of the answer concerning the use of IFX on AS patients. Because of a disparity of supply in countries, some of them faced a long period without the possibility of prescribing IFX. In the countries which had this phase without available treatment, 50 % of the patients to whom we re-introduced the treatment did not respond to it. This was absolutely not the case in the countries where the medicine was able to be continuously administere. Pr Miceli : as we raised it earlier, ADAb appear mostly within the first 6 months of treatment, which is a period where clinicians space out only rarely the administrations of anti-tnfα. It would confirm the hypothesis according to which the spacing of the administrations would favor the production of anti-drug antibodies but only for one third of the patients. Pr. Mariette : To your opinion, is it possible to predict what will be the response to an anti-tnfα and if it will be immunogenic or not? In other words, are there biomarkers that could help us even before the beginning of the treatment? Pr Miceli : : as far as I know, such data are not available for the moment. Dr Paul : to my knowledge, there is only a single study on this topic in my field (IBD). It is about the polymorphism of the TNFα and its link with the resistance to the treatment for patients affected by Crohn Disease. 7

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