Periodic Reporting for period 5 - BIOCYCLE (BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn’s disease)
Reporting period: 2021-04-01 to 2022-12-31
Crohn’s disease (CD) is a chronic, immune-mediated, inflammatory disease affecting gastro-intestinal tract, arising predominantly from an interaction between genetic and environmental factors. CD is characterized by recurrent attacks alternating with remission periods. Flares and chronicity of CD have an impact on patient’s Quality of Life (QoL) (i.e. co-morbidities, linked to CD itself, adverse events due to treatments). In EU, 3M people are affected by IBD, with a worldwide increase of CD incidence.
Curative therapies do not exist yet. The gold standard is the combination of anti-TNF/antimetabolites (CT), improving patients’ symptoms and decreasing intestinal tissue damage. CT is thought best used at early-stage of CD without interruption and, if needed, with dose escalation. However, antimetabolites and anti-TNF are associated with life-threatening side-effects and biologic treatments represent up to 50% of Inflammatory Bowel Disease (IBD) medical costs. There is an unmet need to improve safety and costs while maintaining treatment efficacy. Despite this, treatment de-escalation to monotherapy (antimetabolite or anti-TNF) has received limited attention.
BIOCYCLE objective is to assess benefits/risks of an innovative regimen, introducing treatment cycles (after reaching deep and prolonged remission), which alternate periods with both drugs and periods where anti-TNF or antimetabolites are withdrawn, to improve safety and costs while maintaining same level of therapy efficacy.
Curative therapies do not exist yet. The gold standard is the combination of anti-TNF/antimetabolites (CT), improving patients’ symptoms and decreasing intestinal tissue damage. CT is thought best used at early-stage of CD without interruption and, if needed, with dose escalation. However, antimetabolites and anti-TNF are associated with life-threatening side-effects and biologic treatments represent up to 50% of Inflammatory Bowel Disease (IBD) medical costs. There is an unmet need to improve safety and costs while maintaining treatment efficacy. Despite this, treatment de-escalation to monotherapy (antimetabolite or anti-TNF) has received limited attention.
BIOCYCLE objective is to assess benefits/risks of an innovative regimen, introducing treatment cycles (after reaching deep and prolonged remission), which alternate periods with both drugs and periods where anti-TNF or antimetabolites are withdrawn, to improve safety and costs while maintaining same level of therapy efficacy.
We have completed surveys on caregiver’s, healthcare authorities’ and patients’ perceptions on Treatment Cycles concept. It highlighted some key points: (1) important variations exist across patients and practitioners emphasizing the necessity of a personalized approach (2) Although patients and doctors put the priority on the control of the disease and the absence of flare, because of a fear of side effects, a substantial part would accept a small risk of relapse and some time with active disease to de-escalate therapy.
We have completed the SPARE study, a 3 arms-controlled clinical trial comparing continuous Combo Therapy (CT) to anti-TNF or anti-metabolites withdrawal, in moderate-severe CD patients in sustained remission under CT. More than 70 sites have been initiated in 7 countries (FR, UK, BE, SW, AU, DE, NL), 252 patients have been screened and 211 randomized. The two co-primary end-points and major secondary endpoints have been analysed and published. Our results allowed to draw a series of major conclusions: 1) we confirmed the higher relapse rate in patients stopping their biologic treatment (infliximab), 2) there was no increase in relapse rate in patients stopping their anti-metabolite/immunosuppressant, 3) the treatment strategy failure rate was similar across the three groups, 4) the time spent in remission over two years was only marginally lower in patients stopping their biologic. Overall, these results highlight the fact that biologic treatment withdrawal after longstanding steroid-free remission in CD, should not be systematic, but that some patients may be candidates for such withdrawal. Very promising markers to help and better determine the subgroup of patients who would be best candidates for treatment withdrawal have been identified. In particular, the risk of short term relapse was associated with the persistence of and increased blood concentration of acute phase reactants and markers of ongoing inflammation, while the longer term relapse (beyond 6 months) was associated with a more heterogenous pattern, including increased or decreased concentration of proteins involved in immune regulation, and the intestinal barrier function.
We have developed a pharmacoeconomic simulation model mimicking SPARE study and assessing treatment cycles concept. This model was populated with existing literature data. Sensitivity analyses were performed allowing preliminary conclusions on this pharmacoeconomic aspect. This model has now also been fed with the SPARE data. The first analyses bring some nuances to the conclusions of the theoretical model and highlights the conditions in which treatment cycles may become the most cost-effective strategy.
We have collected and synthesized arguments to build a structured pathway of care and such a dedicated pathway of care for treatment de-escalation in CD has been developed, allowing patients, doctors, and healthcare systems to contribute to complex decision in CD management, like the one of treatment de-escalation.
Finally, we have organized a European consensus conference on the topic of treatment de-escalation in Crohn’s disease based on the methodology of the ECCO topical reviews. A full manuscript has been published, three dissemination meetings were organized across Europe and e-learning tools are available for the inflammatory bowel disease community on the ECCO website.
We have completed the SPARE study, a 3 arms-controlled clinical trial comparing continuous Combo Therapy (CT) to anti-TNF or anti-metabolites withdrawal, in moderate-severe CD patients in sustained remission under CT. More than 70 sites have been initiated in 7 countries (FR, UK, BE, SW, AU, DE, NL), 252 patients have been screened and 211 randomized. The two co-primary end-points and major secondary endpoints have been analysed and published. Our results allowed to draw a series of major conclusions: 1) we confirmed the higher relapse rate in patients stopping their biologic treatment (infliximab), 2) there was no increase in relapse rate in patients stopping their anti-metabolite/immunosuppressant, 3) the treatment strategy failure rate was similar across the three groups, 4) the time spent in remission over two years was only marginally lower in patients stopping their biologic. Overall, these results highlight the fact that biologic treatment withdrawal after longstanding steroid-free remission in CD, should not be systematic, but that some patients may be candidates for such withdrawal. Very promising markers to help and better determine the subgroup of patients who would be best candidates for treatment withdrawal have been identified. In particular, the risk of short term relapse was associated with the persistence of and increased blood concentration of acute phase reactants and markers of ongoing inflammation, while the longer term relapse (beyond 6 months) was associated with a more heterogenous pattern, including increased or decreased concentration of proteins involved in immune regulation, and the intestinal barrier function.
We have developed a pharmacoeconomic simulation model mimicking SPARE study and assessing treatment cycles concept. This model was populated with existing literature data. Sensitivity analyses were performed allowing preliminary conclusions on this pharmacoeconomic aspect. This model has now also been fed with the SPARE data. The first analyses bring some nuances to the conclusions of the theoretical model and highlights the conditions in which treatment cycles may become the most cost-effective strategy.
We have collected and synthesized arguments to build a structured pathway of care and such a dedicated pathway of care for treatment de-escalation in CD has been developed, allowing patients, doctors, and healthcare systems to contribute to complex decision in CD management, like the one of treatment de-escalation.
Finally, we have organized a European consensus conference on the topic of treatment de-escalation in Crohn’s disease based on the methodology of the ECCO topical reviews. A full manuscript has been published, three dissemination meetings were organized across Europe and e-learning tools are available for the inflammatory bowel disease community on the ECCO website.
Most of the work foreseen in the 9 work packages of the BIOCYCLE action have been completed and this has generated a substantial amount of new data allowing to better determine the appropriateness of the treatment cycles strategy in Crohn’s disease and to delineate the conditions in which this could be practiced. More specifically, BIOCYCLE has demonstrated the broad heterogeneity of the perception of patients and health care providers concerning treatment de-escalation, withdrawal and cycles. This heterogeneity implies that such decision should be taken through an informed discussion with the patients. BIOCYCLE has also showed that the cost-effectiveness of the treatment cycles strategy highly depends on the risk of relapse and can thus be optimized by a better selection of the candidates, and also on the cost of the biologic treatments which has significantly decreased with biosimilars but still varies much across European countries. These aspects highlight the societal and ethical aspects of the implementation of treatment cycles in Crohn’s disease. BIOCYCLE has also showed that a treatment de-escalation is feasible in a substantial number of patients, with a prolonged period without flares of the disease, but that it should not be proposed as a systematic strategy after sustained steroid-free remission, because it may be followed by a definitive loss of response to the previously effective biologic treatment and by the development of complications. Along this line, BIOCYCLE has allowed to identify a series of biologic markers helping to predict the risk of relapse better than currently used markers. Finally, BIOCYCLE has developed tools to help clinicians and multidisciplinary teams to select best candidates and best timing for treatment cycles in Crohn’s disease and to implement it in routine practice. These tools include European guidelines on the topic, published in open access in the Journal of Crohn’s and colitis, e-learning tools available on the website of the European Crohn’s and Colitis Organisation, and the description of a multidisciplinary pathway of care to implement the treatment cycles strategy. These should help the patients, the clinicians and other health care providers to implement the treatment cycles strategy in appropriate situations, improving the quality of life of the patients and decreasing the costs for the society.