Periodic Reporting for period 4 - BIOCYCLE (BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn’s disease)
Reporting period: 2019-10-01 to 2021-03-31
Crohn’s disease (CD) is a chronic, immune-mediated, inflammatory disease affecting gastro-intestinal tract, arising from an interaction between genetic & environmental factors. CD is characterized by recurrent attacks alternating with remission periods. Flares & chronicity have impact on patient’s Quality of Life (QoL) (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, a significant progress in CD treatment with an influence on 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 & if needed, with dose escalation. However, antimetabolites & anti-TNF are associated with life-threatening side-effects & biologic treatments represent up to 50% of Inflammatory Bowel Disease (IBD) medical costs. There is an unmet need to improve safety & costs while maintaining treatment efficacy. Despite this, treatment de-escalation to monotherapy has received limited attention. In EU, 3M people are affected by IBD, with a worldwide increase of CD incidence. CD can’t be cured, its chronicity affects patients on personal, family & socio-professional plans, with high impact as they are often diagnosed at a young age & 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 & 15.5BN$ in US. Optimal long-term (LT) treatment is to maximize disease control & QoL & to decrease direct/indirect costs. Beyond that, one can assume information collected in CD could be extrapolated to other Immune Mediated Inflammatory diseases (IMIDs), involving same kind of drugs & 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(after reaching deep & prolonged remission), which alternate periods with both drugs & periods where one of them is withdrawn, to improve safety & costs while maintaining same level of therapy efficacy. To assess & validate the suitability & implementation of this concept, the Project targets specific objectives. We will generate & collect clinical & 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 & patients’, caregivers’ & healthcare systems’ perceptions on Treatment Cycles. A critical appraisal of the new regimen & its impact on CD management will be performed, leading to recommendations & decision-making tools to optimize the maintenance therapy in function of patients’ needs & characteristics.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We have completed surveys on caregiver’s, healthcare authorities’ & patients’ perceptions on Treatment Cycles concept (309 CD gastroenterologists & 410 patients in US & EU) to know their favourite treatment option for LT maintenance of moderate-severe CD, highlighting some key points: (1) Despite financial/societal impacts, health authorities have little knowledge & low priority on these infrequent chronic diseases & will have to be sensitized by relevant data as those generated by BIOCYCLE (2) In general patients & doctors have similar perceptions & priorities about LT treatments & their potential interruption but important variations exist across patients & practitioners emphasizing the necessity of a personalized approach (3) Although patients & doctors put the priority on disease control & absence of flare, due to a fear of side effects, a substantial part would accept a small risk of relapse & some time with active disease to de-escalate therapy. We have progressed in SPARE, 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), 58 sites have been active (at least one patient recruited). By the beginning of 2019, the target of 211 patients out of 252 screened patients were randomized, allowing to close the inclusion. On March 26th 2021 the last patient was out of the trial. We are cleaning the database, the database lock is planned in September 2021. Meanwhile we will start the analysis of the primary endpoint of the trial (relapse rate & time spent in remission over 2 years). We have continued the activity of the Central Biobank (CHU) with regular samples transfers from participating centres. Samples from 201 patients are already stored (20.334 cryotubes aliquots/collecting tubes). CHU has optimized & documented processes according to European laws & has satisfied to internal audits (10-2018; 11-2019). Work on discovery proteomics research has started at CHU-ULiège. 694 samples were transferred to SHEBA, 962 sample were sent to UOXF. Planned works on biomarkers are well-advanced. Almost all baseline samples have already been assessed for the biomarkers planned. We have worked to build the database centralized at INSERM. The general BIOCYCLE dataset has been tested & is fed by SPARE clinical data & biomarkers data. We have developed a pharmacoeconomic simulation model mimicking SPARE study & assessing treatment cycles concept. It was populated with existing literature data. Sensitivity analyses were performed allowing preliminary conclusions on this pharmacoeconomic aspect. This model will be fed by the SPARE data. They will then be included in our multidimensional integrative decision-making tool. We have collected & synthesized arguments to develop a clinical decision support system allowing patients, doctors & healthcare systems to contribute to complex decision in CD management. We have developed a beta version & will make this evolve with practitioners' & patients' inputs & artificial intelligence. We have also prepared a broad real-like retrospective European study with URCARE, ECCO/IBDIM database to assess the practice & treatment cycles, looking at the proportion of patients benefiting from this strategy & their outcome.
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
Most of the progress achieved comes from caregivers’ & patients’ surveys, pharmacoeconomic model & extensive/multi-dimensional literature reviews. It allows to confirm the need for new original data in treatment de-escalation & treatment cycles in CD & more broadly in IMIDs. We have confirmed that (1) patients’ & 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. Shortly, we should be able to confirm safety & efficacy of transient treatment withdrawal, to clarify appropriated & cost-effective patients profiles (including biomarkers) for treatment cycles, & to deliver a fully operational clinical decision support system to help clinicians, patients & healthcare systems to optimize LT therapies in CD & with some specific adaptations, in other IMIDs.