mor202 for refractory mn

Conditions: Membranous Nephropathy

Summary: membranous nephropathy (mn) - the leading cause of nephrotic syndrome (ns) in adults - is an immune-mediated disease that results from the deposition of immunoglobulins and complement components onto the sub-epithelial layer of the glomerular capillary wall. the availability for clinical use of rituximab, a monoclonal antibody against the b-cell surface antigen cd20, offered the opportunity to test the effects of specific cd20-targeted intervention aimed to prevent b-cell dependent mechanisms resulting in the production of nephritogenic autoantibodies. rituximab-induced b-cell depletion reduced proteinuria in eight patients with mn while avoiding the adverse effects of steroids and other immunosuppressants. subsequent studies confirmed that rituximab is remarkably safer than non-specific immunosuppressive agents, including cyclosporine, and achieves remission in approximately two-thirds of patients with mn-associated nephrotic syndrome. after rituximab-induced remission, however, ns may relapse in approximately one third of patients. thus, novel therapeutic options are needed for a substantial proportion of patients with mn who may fail rituximab therapy. conceivably, in patients with mn refractory to cd20-targeted therapy, the production of nephritogenic autoantibodies is sustained by mechanisms that do not depend on autoreactive cd20+ b cells. recently, it was shown that cd19-negative bone marrow plasma cells, which express cd38, are enriched in chronically inflamed tissue and secrete autoantibodies. treatment of patients with mn with cd38-targeting antibodies may represent a new therapeutic approach. mor202 is a fully human recombinant monoclonal antibody against cd38 that has demonstrated in-vitro and in-vivo efficacy in experimental models of multiple myeloma. antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis are the principal mechanisms of action for mor202-induced lysis of myeloma cells. the working hypothesis is that cd38-targeted therapy with mor202 may abrogate autoantibody-dependent mechanisms in patients with plasma-cell mediated forms of mn who failed previous treatment with rituximab and second-generation anti-cd20 monoclonal antibodies such as ofatumumab. with this background, mor202 therapy may have an indication for patients with mn and ns resistant to cd20 targeted therapy.


Eligibility criteria:
inclusion criteria: * age ≥18 years. * biopsy-proven membranous nephropathy with or without detectable circulating anti-pla2r or anti-thsd7a antibodies. * background treatment with ras blocking agents (ace inhibitor and/or arbs), at maximum tolerated doses and adequately controlled blood pressure (bp \<140/90 mmhg in at least three consecutive readings at screening). * one condition between: * anti-cd20 resistance: residual proteinuria ≥3.5 g/day (mean of three consecutive 24-hour urine collections), with less than 50% reduction compared to pre-treatment values at least 12 months after anti-cd20 antibody therapy. * anti-cd20 dependence: frequently relapsing ns (nephrotic-range proteinuria for \>50% of time in the last five years or since disease onset, whichever is shorter) despite repeated treatments with anti-cd20 antibodies. * estimated gfr \>30 ml/min/1.73m2 (ckd-epi equation) and less than 50% of sclerotic glomeruli in patients receiving renal biopsy. * a minimum 12-month wash-out from last anti-cd20 therapy with rituximab and/or other monoclonal antibodies. * no significant (i.e. more than 2 weeks) immunosuppressive therapy over the last 6 months. * written informed consent. exclusion criteria: * clinically relevant neutropenia (neutrophils \ 1.5 x uln, alkaline phosphatase \>3.0 x uln). * significant uncontrolled cardiovascular disease (including arterial or venous thrombotic or embolic events over the last three months) or cardiac insufficiency (new york heart association \[nyha\] class iv) as judged by the investigator. * clinically relevant findings on a 12-lead electrocardiogram (ecg) as determined by the investigator at screening. * history of significant cerebrovascular disease (stroke or transitory ischemic attack over the last three months) or sensory or motor neuropathy of toxicity ≥ grade 3. * any clinical condition that in the investigator judgment could affect the possibility to complete the study or could have a major confounding effect on study findings and data interpretation. * known intolerance to the study drug or its excipients * any viral, bacterial or fungal infection without complete symptoms resolution from at least two weeks. * serologic or virologic markers positive for hiv, hepatitis c (patients with positive antihepatitis c virus \[anti-hcv\] antibody but negative hcv rna polymerase chain reaction \[pcr\] can enroll) or active or latent hepatitis b (patients with positive hepatitis b surface antigen \[hbsag\] are excluded). patients with isolated positive hepatitis b core antibody \[anti-hbc\], hepatitis b virus (hbv) dna test by pcr must be non-detectable to enroll. * history of malignancy within the prior 5 years. * participation in other clinical trials within 4 weeks of signing the consent form. * expected need of anti sars cov 2 vaccination during the study period * pregnancy or breast-feeding. * childbearing potential in males and females non using an highly effective method of contraception according to 2020 ctfg recommendations related to contraception and pregnancy testing in clinical trials (https://www.hma.eu/fileadmin/dateien/human_medicines/01-about_hma/working_groups/ctfg/2020_09_hma_ctfg_contraception_guidance_version_1.1_updated.pdf). * legal incapacity or limited legal capacity.

Keywords: membranous nephropathy anti-cd38 mor 202