MOR202 for Refractory MN (MONET)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Membranous Nephropathy
• Intervention / Treatment: Drug: MOR202

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Giuseppe Remuzzi, MD; Phone Number: 03545351; Email: giuseppe.remuzzi@marionegri.it

Study Locations

• Italy
  • BG
    • Bergamo, BG, Italy, 24100
      • ASST HPG23 - Unità di Nefrologia
    • Ranica, BG, Italy, 24020
      • Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 109/L), anemia (Hb levels <9.0 g/dL), thrombocytopenia (platelet count < 150.000/mm3), 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.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MOR202 (felzartamab) infusion; Participants will receive active treatment for a total of nine doses during 24 weeks.	Drug: MOR202; Each patient will be treated for 24 weeks and received a total of 9 doses. During the first treatment cycle, MOR202 will be administered weekly. For the following 5 months, patients will receive one dose every 4 weeks.; Other Names: FELZARTAMAB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 24-hour urinary protein excretion		Changes from screening and baseline, 1, 5,6,9,12,18 and 24 months after the first MOR202 administration.
Complete remission or partial remission of nephrotic syndrome.	Complete remission is intended as : 24-hour urinary protein excretion <0.3 g or urinary protein to creatinine ratio < 300 mg/g, with serum albumin > 3.5 g/dL. Partial remission is intended as: 24-hour urinary protein excretion <3.5 g or urinary protein to creatinine ratio < 3500 mg/g, with at least 50% reduction compared to baseline.	Changes from screening and baseline, 1, 5,6,9,12,18 and 24 months after the first MOR202 administration.

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: MorphoSys AG
• Investigators: Study Director: Giuseppe Remuzzi, MD, Istituto di Ricerche Farmacologiche Mario Negri IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2021
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: May 11, 2021
• First Submitted That Met QC Criteria: May 18, 2021
• First Posted (Actual): May 19, 2021

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: membranous nephropathy; Anti-CD38; MOR 202
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Glomerulonephritis, Membranous; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Felzartamab
• Other Study ID Numbers: MONET; 2021-000835-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No