SILENE SwItch to ravulizumab in kidney transplant recipients under long-term eculizumab prophylaxis.

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

Atypical hemolytic uremic syndrome (aHUS) has been associated with a high risk of recurrence after kidney transplantation, entailing a poor graft survival (1). The risk of aHUS recurrence was stratified into three categories (high-, moderate- and low-risk), based on complement investigations and prior aHUS recurrence (1).
High-risk recipients include patients with history of graft loss due to aHUS post-transplant recurrence, and/or harboring one or several pathogenic variant(s) / gene rearrangement(s) in CFH (including CFH/CFHR1 hydrid gene), CFB and C3 genes. Moderate-risk recipients encompass patients with pathogenic variant(s) in CFI, circulating anti-CFH antibodies above detection levels at the time of transplantation, and those with homozygous at-risk H3 haplotype (1). Low-risk patients are those who fulfilled the following criteria: lack of prior post-transplant aHUS recurrence AND either isolated genetic variation in Membrane Cofactor Protein (MCP) or Diacylglycerol Kinase Epsilon (DGKE) genes, OR negative genetic screening despite an extensive complement screening (including Next-Generation Sequencing (NGS) and Multiplex Ligation-dependent Probe Amplification (MLPA) analyses), OR negative testing for anti-CFH antibody, fell into the low-risk group.
In 2012, the French aHUS study group implemented a nationwide risk-stratification-based strategy, which was later adopted by the 2017 KDIGO recommendations, to prevent aHUS recurrence using C5 blockers (2). The implementation of eculizumab prophylaxis in high- and moderate-risk patients has revolutionized post-transplant outcomes, fully prevented aHUS recurrence and dramatically improved graft survival (2). Although eculizumab could be successfully and durably withdrawn in several moderate-risk patients, many kidney transplant recipients remain under long-term treatment, including most high-risk patients or any recipients who experienced post-transplant recurrence after eculizumab disruption (3). However, long-term therapy presents drawbacks, impacting patient lifestyle. These drawbacks include the need of biweekly visits to the daycare hospital, restricted ability to travel abroad for a period longer than 2 weeks, frequent intravenous puncture, which overall significantly impede the quality of life. In this context, the recent availability of ravulizumab, which half-life is 3 to 4-fold longer than that of eculizumab, offers the opportunity to extend the interval between intravenous infusions to every two months. Ravulizumab was derived from eculizumab with the change of 4 amino-acids, in order to decrease the affinity of the antibody binding domain for C5 and to increase the affinity of Fc domain for the neonatal Fc receptor (FcRn) at low pH. Together, these changes promote antibody recycling from the endosomal compartment.
Ravulizumab has demonstrated strong efficacy in controlling complement-related thrombotic microangiopathy (TMA), both in adults and children, whether following a switch from eculizumab or in patients naïve to C5 blockers.
However, there are no controlled studies comparing ravulizumab to eculizumab in aHUS. Consequently, the non-inferiority of ravulizumab to eculizumab in treating aHUS has not been conclusively demonstrated. Ravulizumab achieved non inferiority compared to eculizumab for all efficacy endpoints assessed in two head-to-head phase III trials adults with paroxysmal nocturnal hemoglobinuria (PNH): The 301 study, focusing on PNH naïve patients and The 302 study, focusing on PNH patient switching from eculizumab to ravulizumab.
Furthermore, in the adult study (3), the low TMA response rate reported by Rondeau et al, has muddled the conclusions about the equivalence between the two C5 blockers. This uncertainty has been further fueled by the discordance between C5 and CH50 assays in aHUS patients treated with ravulizumab (3). In addition, aHUS kidney transplant recipients were not included in the 311 study and therefore, no efficacy nor safety data of Ravulizumab have been reported in this subpopulation. Further, none of the clinical studies have investigated the switch from eculizumab to ravulizumab, regardless of the kidney transplant (KTx) status of the patients.
Therefore, a retrospective study will be conducted focusing on KTx patients under long-term C5 inhibitors post-transplant prophylaxis switching from eculizumab to ravulizumab. The aim of the study is to demonstrate the safety and efficacy of a switch to ravulizumab in kidney transplant recipients with aHUS

To evaluate the rate of (complement-related thrombotic microangiopathy) TMA after the switch from eculizumab to ravulizumab at 351 days +/- 30 days of the switch (Day 0).

1. To assess the safety of ravulizumab

2. To assess the tolerability of ravulizumab

3. To assess the impact of ravulizumab on the serum creatinine levels

4. To assess the impact of ravulizumab on the proteinuria levels

5. To assess the impact of ravulizumab in the occurrence of graft rejection

6. To assess the impact of switching from a biweekly (every 2 weeks) to a bimonthly (every 2 months) regimen on the quality of life of patients at day 351 versus quality of life before or at the switch

7. Analysis of complement biomarkers performed in routine including CH50, C3, sC5b9, serological markers of C3 and C5 convertases (C3a, Bb, C5a)

8. To describe the use of ravulizumab (dosage, adherence and discontinuation) and to evaluate changes in biological parameters related to thrombotic microangiopathy during follow‑up.