OBinutuzumab’ Efficacy in comparison to gLucocorticoids in de novo adult-onset minimal change NEPHROtic Syndrome – OBELIX-NEPHROSIS

1) Wider research context/theoretical framework
In minimal change disease (MCD), a relapsing-remitting glomerular disease with significant impact on health-related quality of life, glucocorticoids remain the cornerstone of initial treatment. The OBELIX-NEPHROSIS trial will test whether obinutuzumab, a humanized monoclonal antibody targeting CD20 cells, may be an option to replace glucocorticoids in adult-onset MCD.

2) Hypotheses/research questions/objectives
Obiutuzumab is safe to use and more effective than glucocorticoids to maintain remission throughout follow-up, plus, will not lead to a significant increase in the Glucocorticoid Toxicity Index. B cell depletion leads to more rapid reduction of anti-nephrin antibodies. In-depth phenotyping will not only provide insights into disease pathogenesis, but subsequent investigations will also allow relapse prediction by employing single-cell RNA sequencing, plasma proteome and FACS analysis, thereby characterizing the B and T cell compartment. Drug levels will be higher and the frequency of anti-drug antibodies is lower in comparison to historically managed rituximab patients.

3) Approach/methods
OBELIX-NEPHROSIS is a Phase IIa trial, randomly assigning 44 patients to either receive glucocorticoids (tapering according to the RIFIREINS trial, PI Vincent Audard) or 2 doses obinutuzumab with 1000 mg each, a fortnight apart (22 patients each). Six experienced centers in the management of MCD will recruit the total sample. A sample size of 20 patients per arm will confer a power of 95% in the number of relapse-free patients; a drop-out rate of 10% is expected. Samples to perform trial-related investigations will be collected at different key time points, in order to account for relevance (i.e. drug levels will be assessed only after administration of obinutuzumab). Anti-nephrin antibodies will be tested at each trial visit.

4) Level of originality/innovation
The potential of obinutuzumab to induce complete remission and subsequent sustained remission in adults with MCD has never been investigated. The results of OBELIX-NEPHROSIS will provide efficacy estimates which are to be used to design a subsequent Phase III trial. This trial is the first to test potential promising biomarkers predicting first line responsiveness and/or subsequent relapse after remission. In addition, extensive phenotyping of patients by the use of plasma proteome and single-cell RNA sequencing is novel in this population. Drug levels and anti-drug antibodies for obinutuzumab in this patient population have not been reported thus far. In conclusion, we believe that this trial with its experimental medicine characters offers a high level of originality and innovation.

5) Primary researchers involved
As part of the bi-national funding call, the primary researchers are based in France (Prof Vincent Audard) and Austria (Prof Andreas Kronbichler), both clinical triallists with vast experience using B cell depleting agents for several indications.