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BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn’s disease

Periodic Reporting for period 3 - BIOCYCLE (BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn’s disease)

Reporting period: 2018-04-01 to 2019-09-30

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 impact on patient’s Quality of Life (QoL) (i.e. co-morbidities, linked to CD itself, adverse events due to treatments).
Curative therapies do not yet exist. Current best treatments are symptoms relieving therapies. The gold standard is the combination of anti-TNF/antimetabolites, representing a significant progress in CD treatment and having influenced clinical practice. This is Combo Therapy (CT), with a demonstrated efficacy in clinical trials. 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.
In EU, 3M people are affected by IBD, with a worldwide increase of CD incidence. CD can’t be cured and its chronicity affects patients on personal, family and socio-professional plans, with high impact as they are often diagnosed at a young age and ill health may be lifelong. QoL is also impacted: each year, 15-20% of CD patients are hospitalized, with 57-80% for surgical interventions. The economic burden is estimated to 16.7BN€/year in EU and 15.5BN$ in US. Optimal long-term (LT) treatment is to maximize disease control and QoL and to decrease direct/indirect costs. Beyond that, one can assume that information collected in CD could be extrapolated to other Immune Mediated Inflammatory diseases (IMIDs), involving same kind of drugs and treatment strategies.
BIOCYCLE objective is to assess benefits/risks of an innovative regimen, optimizing LT treatment compared to current gold standard (monotherapy). The new one consists in including 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.
To assess and validate the suitability and implementation of the Treatment Cycles concept, the Project targets specific objectives. We will generate and collect clinical and biomarkers data [SPARE study: 3 arms-controlled clinical trial with 210-220 CD patients in stable remission under CT to compare anti-TNF or antimetabolites withdrawal to CT maintenance]; cost-of-illness/cost-effectiveness and patients’, caregivers’ and healthcare systems’ perceptions on Treatment Cycles. A critical appraisal of the new regimen and its impact on CD management will be performed, leading to recommendations and decision-making tools to optimize the maintenance therapy in function of patients’ needs and characteristics.
We have completed surveys on caregiver’s, healthcare authorities’ and patients’ perceptions on Treatment Cycles concept. It involved 309 CD gastroenterologists and 410 patients in US and EU to know their favourite treatment option for LT maintenance of moderate-severe CD, highlighting some key points: (1) Despite financial and societal impacts, health authorities have little knowledge and low priority on these infrequent chronic diseases and will have to be sensitized by relevant data as those generated by the BIOCYCLE action (2) In general patients and doctors have similar perceptions and priorities about LT treatments and their potential interruption but important variations exist across patients and practitioners emphasizing the necessity of a personalized approach (3) Although patients and doctors put the priority on the control of the disease and the absence of flare (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 progressed in the SPARE study, a 3 arms-controlled clinical trial comparing continuous 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), 50 sites have been active (at least one patient recruited). By the beginning of 2019, the target of 211 randomized patients out of 252 screened patients was reached, allowing to close the inclusion and plan the end-of-study in March 2021. 1st data from the trial should be available in the second half of 2021.
We have continued the activity of the Central Biobank (CHU) with regular samples transfers from participating centres. Samples from 180 patients are already stored in this Biobank (16.596 cryotubes aliquots/2.041 collecting tubes). CHU has optimized and documented processes according to European laws and has satisfied to internal audits (October 2018; November 2019). Work on discovery proteomics research has started at CHU-ULiège. 2 material transfer agreements were set-up, allowing samples transfer between the 3 partners involved in the biomarkers action (CHU, SHEBA, OXFORD). Baseline samples for 180 patients have been transferred to OXFORD.
We have worked to build the database centralized at INSERM. The general BIOCYCLE dataset has been tested and continuously fed by SPARE data.
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 will later be fed by the SPARE data. They will then be included in our multidimensional integrative decision-making tool.
We have collected and synthesized arguments to develop a clinical decision support system allowing patients, doctors, and healthcare systems to contribute to complex decision in CD management, like the one of treatment de-escalation. We have developed a beta version and will now make this evolve with practitioners’ and patients’ inputs and artificial intelligence
Most of the progress achieved comes from caregivers’ and patients’ surveys, pharmacoeconomic model and extensive/multi-dimensional literature reviews. It allows to confirm the need for new original data in treatment de-escalation and treatment cycles in CD and more broadly in IMIDs. We have confirmed that (1) patients’ and doctors’ expectations include the possibility of transiently withdrawing treatment to optimize safety, (2) at classical prices of biologic therapies, continuous treatment was not cost-effective although the dramatic cost reduction linked to biosimilars use may change this, (3) the need to generate intelligent/multidimensional clinical decision support system for these treatment choices.
In the coming months, we should be able to confirm safety and efficacy of transient treatment withdrawal in CD, to clarify appropriated and cost-effective patients profiles (including biomarkers) for treatment cycles, and to deliver a fully operational clinical decision support system to help clinicians, patients and healthcare systems to optimize LT therapies in CD and with some specific adaptations, in other IMIDs.
Group picture at ECCO 2019 - General assembly meeting