Overview

Rescue Therapy With the Human Anti-CD38 Antibody MOR202 (Felzartamab) in Patients With Membranous Nephropathy Who Failed Anti-CD20 Target Therapy

Status:
Not yet recruiting
Trial end date:
2024-10-01
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research
Collaborator:
MorphoSys AG
Treatments:
Felzartamab
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:

- Intolerance to rituximab without rescue therapy with other humanized anti-CD20
antibodies.

- Clinically relevant neutropenia (neutrophils < 1.5 x 109/L), anemia (Hb levels <9.0
g/dL), thrombocytopenia (platelet count < 150.000/mm3), hypogammaglobulinemia (serum
immunoglobulin ≤5.0 g/L), increased liver transaminase or bilirubin levels (total
bilirubin, aspartate aminotransferase or alanine aminotransferase >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.

- Any active viral, bacterial or fungal infection.

- 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). For 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.

- Pregnancy or breast-feeding.

- Childbearing potential in males and females non using an effective method of
contraception according to 2014 CTFG Recommendations related to contraception and
pregnancy testing in clinical trials
(accessedat:"https://www.hma.eu/fileadmin/dateien/Human_Medicines/01About_HMA/Working_
Groups/C FG/2014_09_HMA_CTFG_Contraception.pdf").

- Legal incapacity or limited legal capacity.