Rescue Therapy with the Human Anti-CD38 Antibody MOR202 (felzartamab) in Patients with Membranous Nephropathy who Failed Anti-CD20 Target Therapy (MONET study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Istituto Di Ricerche Farmacologiche Mario Negri

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

22 Oct 2021 → 21 Feb 2025

Decision date (initial)

2024-06-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Human Immunology Biosciences, Inc (HI-Bio)

External identifiers

EU CT number

2024-513744-28-00

EudraCT number

2021-000835-30

ClinicalTrials.gov

NCT04893096

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety

To evaluate the efficacy of MOR202 in reducing and/or abrogating urinary protein excretion in MN patients with nephrotic-range proteinuria who are resistant to or dependent from anti-CD20 antibodies.

Secondary objectives 8

1. To assess the clinical efficacy of MOR202 over the whole follow-up period
2. To assess the effect of MOR202 on anti-PLA2R and anti-THSD7A levels over time
3. To assess the incidence of immunological and clinical relapses after the MOR202- induced immunologic and/or clinical NS remission.
4. To assess the effects of MOR202 on renal function, glomerular permselectivity and metabolic parameters over time
5. To assess the consequences of MOR202 administration on circulating NK-, T- and B-cell subsets
6. To assess the effects of MOR202 on patient-perceived outcomes
7. To assess the immunogenicity and pharmacokinetic profile of MOR202
8. To evaluate the safety of MOR202 administration

Conditions and MedDRA coding

Membranous nephropathy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age ≥18 years
2. Biopsy-proven membranous nephropathy with or without detectable circulating anti-PLA2R or anti-THSD7A antibodies
3. 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).
4. 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.
5. Estimated GFR >30 ml/min/1.73m2 (CKD-EPI equation) and less than 50% of sclerotic glomeruli in patients receiving renal biopsy.
6. A minimum 12-month wash-out from last anti-CD20 therapy with rituximab and/or other monoclonal antibodies
7. No immunosuppressive therapy with steroid, cyclophosphamide, cyclosporine, mycophenolate mofetil or any other immunosuppressant over the last 6 months; in case of therapies administered for less than 2 weeks, no washout time will be required prior to inclusion.
8. Completed anti SARS Cov 2 Vaccination
9. Written informed consent

Exclusion criteria 14

1. 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).
2. 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.
3. Clinically relevant findings on a 12-lead electrocardiogram (ECG) as determined by the investigator at screening
4. History of significant cerebrovascular disease (stroke or transitory ischemic attack over the last three months) or sensory or motor neuropathy of toxicity ≥ grade 3.
5. 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
6. Known intolerance to the study drug or its excipients
7. Any viral, bacterial or fungal infection without complete symptoms resolution from at least two weeks
8. 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.
9. History of malignancy within the prior 5 years
10. Participation in other clinical trials within 4 weeks of signing the consent form
11. Expected need of anti SARS Cov 2 vaccination during the study period
12. Pregnancy or breast-feeding
13. 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
14. Legal incapacity or limited legal capacity

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Reduction in 24-hour urinary protein excretion at 12 months after the first MOR202 administration compared to baseline.
2. Composite endpoint of complete remission (24-hour urinary protein excretion <0.3 g or urinary protein to creatinine ratio < 300 mg/g, with serum albumin > 3.5 g/dL) or partial remission (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) of nephrotic syndrome at 12 months from the first infusion.

Secondary endpoints 14

1. Reduction in 24-hour urinary protein excretion at 6, 9, 12, 18 and 24 months
2. Composite endpoint of complete or partial remission at 6, 9, 12, 18 and 24 months.
3. Complete remission at 6, 9, 12, 18 and 24 months
4. Depletion of circulating anti-PLA2R (defined as titers < 2 RU/mL by commercially available kits) or anti-THSD7A (defined as negative IIF test) at 6, 9, 12, 18 and 24 months from treatment in patients with PLA2R-related or THSD7A-related MN.
5. Time to NS relapse (defined as 24-hour proteinuria increase to >3.5 g in subjects with previous complete or partial remission)
6. Time to re-emergence of anti-PLA2R or anti-THSD7A in patients with initial depletion
7. Changes at 6, 9, 12, 18 and 24 months compared to baseline values in: body weight, serum albumin, anti-PLA2R or anti-THSD7A antibody levels, triglycerides, cholesterol (total, LDL, HDL)
8. Changes at 6, 12, 18 and 24 months compared to baseline values in GFR, RPF, as well as albumin, IgG and sodium fractional clearance and calculated FF, RVR and glomerular resistances
9. Changes in the frequency of circulating T- and NK-cell subpopulations and in B-cell subsets including plasmablasts and plasma cells
10. Changes in quality of Life (QoL) assessed by the SF-36 questionnaire
11. PK profile of MOR202 determined by serum concentrations over time
12. MOR202 immunogenicity, i.e. frequency of anti-MOR202 antibodies (ADA) detection after therapy
13. Serious and non-serious adverse events
14. Frequency, incidence, seriousness, relatedness, and severity of treatment-emergent adverse events (TEAEs), including severe hypersensitivity reactions to MOR202 (acute grade III or IV adverse reactions requiring advanced care, or late reactions including delayed serum sickness syndrome) that, independent of response to treatment, may preclude further exposure to the drug.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Istituto Di Ricerche Farmacologiche Mario Negri

Sponsor organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Address

Via Mario Negri 2

City

Milan

Postcode

20156

Country

Italy

Scientific contact point

Organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Contact name

[email protected]

Public contact point

Organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Contact name

[email protected]

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications